1352: Race Norming

Adam Curry & John C. Dvorak

3h 2m
June 3rd, 2021
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Executive Producers: Sir Macanudo de La Paz, Charlie Henry, Ella Kopistecki, Sir Mark Duke of Japan, and all disputed islands in the Japan Sea, Baron Sir Christopher Kessler, Kandy Walker, Madison McClure, Adam Provencher

Associate Executive Producers: Dame Astrid Duchess of Japan and all the Disputed Islands in the Japan Sea, Brad Fischer, Casey Gray, Philip Lyon Smith, Scott Tillema, Sir Andrew Panebianco, Summer Scace, Colin Preston

Cover Artist: Tante Neel

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Fauci Emails
TL;DR: Fauci's Response to Physicist Who Warned China Was Covering Up COVID '' Summit News
Wed, 02 Jun 2021 23:05
A coalition of liberties rights groups has warned that people in the UK are being convicted of breaking coronavirus ''laws'' without being provided the means to plead innocent.
The London Independent reports that cases are being processed under a system known as the 'Single Justice Procedure' where one magistrate decides the outcome of a case based solely on evidence supplied by police.
This means that anyone accused of breaching lockdown restrictions could be found guilty and notified by letter without even getting a court hearing.
The watchdog groups have penned a letter to the justice secretary outlining how ''likely thousands'' of people have been subject to miscarriages of justice, and calling for the practice to stop.
The Single Justice Procedure means people are being convicted + fined under confusing Covid laws in secretive 'trials' without meaningful oversight or review.It is likely that hundreds of people have been wrongly convicted under this process.
READ'¬‡¸
https://t.co/qrf6gu8ghL
'-- Big Brother Watch (@BigBrotherWatch) June 1, 2021The letter states that ''Hundreds of people have been wrongly charged and prosecuted under the Health Protection Regulations and the Coronavirus Act 2020 and we are concerned that many more unlawful charges brought via the Single Justice Procedure remain unchallenged.''
It continues, ''These charges and prosecutions are being brought without sufficient oversight, without any meaningful review process, and are resulting in guilty pleas and convictions for offences people have not committed, in a process they may also not be aware of. The current situation is unjust and the current process is unfit for purpose.''
The Independent notes that so far a third of prosecutions in England and Wales under coronavirus laws have been proven to to be wrongful, according to a review that is still ongoing.
Ministry of Justice figures reveal that 4,400 defendants were prosecuted and 3,500 convicted under such laws in 2020 alone. It is thought that close to half of those cases fell under the Single Justice Procedure.
Most cases are believed to relate to fines that have been issued by police and not paid. However, there is currently no way of appealing the fines other than to not pay them.
Human rights lawyer Kirsty Brimelow QC told the newspaper that the ''opaque'' Single Justice Procedure has since its introduction in 2015 been ''not easily accessible to the public''.
''It is a failing of the justice system that this has been allowed to continue when the consistent misuse and misunderstanding of the Covid laws is well known,'' Brimelow urged, adding ''People likely are paying financial penalties that they cannot afford in order to avoid prosecution of offences which do not exist.''
The Ministry of Justice has claimed that the Single Justice Procedure is only used for ''low level, non-imprisonable crimes'' and that people are able to ''request an open hearing''.
As we previously highlighted, a plethora of accounts and videos have surfaced highlighting how police in the UK are enforcing lockdown rules in an increasingly draconian manner. In one incident, a man was interrogated and arrested for refusing to provide his name, while another was hauled away for giving soup to homeless people.
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fauciemail.com
fauciemail.com now points to noagendashow.net!
Sir CAH
Fauci BillG Email
Feel like this email leak seems suspiciously designed to humanize him. But I did find this one little excerpt from a Gaurdian article funny.
Among the most revealing emails are those from wealthy or influential correspondents. In one dated 3 April last year, Fauci refers to a conversation with the Microsoft founder, Bill Gates, about a “collaborative and hopefully synergistic approach to Covid-19” with Gates’s charitable foundation.
Gates’s foundation director, Emilio Emini, says he is “seriously worried” about the health of Fauci, then 79, given his busy schedule. Fauci thanks Emini for his concern and says: “I will try to engage as much as I can given my current circumstances.”
When the Bill Gates foundation is saying they are 'worried about your health' I take it very differently LOL sounds Epstein esque to me. Especially when you reply not by saying thanks but, by saying you'll try to do something seemingly unrelated to being healthy.
FOIA email Fauci about man made virus
Lab vs Bat
Investigate the origins of COVID-19 | Science
Wed, 02 Jun 2021 19:11
On 30 December 2019, the Program for Monitoring Emerging Diseases notified the world about a pneumonia of unknown cause in Wuhan, China (1). Since then, scientists have made remarkable progress in understanding the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its transmission, pathogenesis, and mitigation by vaccines, therapeutics, and non-pharmaceutical interventions. Yet more investigation is still needed to determine the origin of the pandemic. Theories of accidental release from a lab and zoonotic spillover both remain viable. Knowing how COVID-19 emerged is critical for informing global strategies to mitigate the risk of future outbreaks.
In May 2020, the World Health Assembly requested that the World Health Organization (WHO) director-general work closely with partners to determine the origins of SARS-CoV-2 (2). In November, the Terms of Reference for a China''WHO joint study were released (3). The information, data, and samples for the study's first phase were collected and summarized by the Chinese half of the team; the rest of the team built on this analysis. Although there were no findings in clear support of either a natural spillover or a lab accident, the team assessed a zoonotic spillover from an intermediate host as ''likely to very likely,'' and a laboratory incident as ''extremely unlikely'' [(4), p. 9]. Furthermore, the two theories were not given balanced consideration. Only 4 of the 313 pages of the report and its annexes addressed the possibility of a laboratory accident (4). Notably, WHO Director-General Tedros Ghebreyesus commented that the report's consideration of evidence supporting a laboratory accident was insufficient and offered to provide additional resources to fully evaluate the possibility (5).
As scientists with relevant expertise, we agree with the WHO director-general (5), the United States and 13 other countries (6), and the European Union (7) that greater clarity about the origins of this pandemic is necessary and feasible to achieve. We must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data. A proper investigation should be transparent, objective, data-driven, inclusive of broad expertise, subject to independent oversight, and responsibly managed to minimize the impact of conflicts of interest. Public health agencies and research laboratories alike need to open their records to the public. Investigators should document the veracity and provenance of data from which analyses are conducted and conclusions drawn, so that analyses are reproducible by independent experts.
Finally, in this time of unfortunate anti-Asian sentiment in some countries, we note that at the beginning of the pandemic, it was Chinese doctors, scientists, journalists, and citizens who shared with the world crucial information about the spread of the virus'--often at great personal cost (8, 9). We should show the same determination in promoting a dispassionate science-based discourse on this difficult but important issue.
Nicholas Wade - Wikipedia
Wed, 02 Jun 2021 19:14
This article is about the science journalist. For the psychologist and academic, see
Nicholas J. Wade.
Nicholas Wade (born 17 May 1942) is a British author and journalist.[1]
He is the author of numerous books, and has served as staff writer and editor for Nature, Science, and the science section of The New York Times.[2][3]
His 2014 book A Troublesome Inheritance: Genes, Race and Human History was widely denounced by the scientific community for misrepresenting research into human population genetics.[4][5][6]
Early life and education [ edit ] Wade was born in Aylesbury, England[1] and educated at Eton College.[7] He earned a Bachelor of Arts degree in Natural Sciences from King's College, Cambridge in 1964.[1]
Wade immigrated to the United States in 1970.[1]
Career [ edit ] Wade was a science writer and editor for the journals Nature, from 1967 to 1971, and Science, from 1972 to 1982.[8] He joined The New York Times in 1982 and retired in 2012,[1] but he freelances occasionally for his former employer.[9] At the Times he served as an editorial writer covering science, environment and defence, and then as an editor of the science section.
His 1980 book, The Nobel Duel: Two Scientists' Twenty-one Year Race to Win the World's Most Coveted Research Prize, described the competition between Andrew Schally and Roger Guillemin, whose discoveries regarding the peptide hormone led to them sharing the 1977 Nobel Prize in Physiology or Medicine. According to the Washington Post Book World, it "may be the most unflattering description of scientists ever written." Betrayers of the Truth: Fraud and Deceit in the Halls of Science (1982), co-authored with William J. Broad, discusses historical and contemporary examples of scientific fraud.
In the 2000s, Wade's books began to focus on human evolution. He released Before the Dawn: Recovering the Lost History of Our Ancestors in 2006, which is about what Wade referred to as "two vanished periods" in human development, and The Faith Instinct in 2009, about the evolution of religious behavior.[10][11]
In 2014, Wade released A Troublesome Inheritance: Genes, Race and Human History, in which he argued that human evolution has been "recent, copious, and regional" and that genes may have influenced a variety of behaviours that underpin differing forms of human society.[12] The book has been widely denounced by scientists, including many of those upon whose work the book was based.[13][4][5][6] On 8 August 2014, The New York Times Book Review published an open letter signed by 139 faculty members in population genetics and evolutionary biology.[4][5] After publication, the letter was signed by 4 more faculty members.[6] The letter read:[13]
Wade juxtaposes an incomplete and inaccurate account of our research on human genetic differences with speculation that recent natural selection has led to worldwide differences in I.Q. test results, political institutions and economic development. We reject Wade's implication that our findings substantiate his guesswork. They do not.
We are in full agreement that there is no support from the field of population genetics for Wade's conjectures.
Wade issued a statement in response, saying that these scientists had misunderstood his intent.[4][5]
The book was further criticized in a series of five reviews by Agust­n Fuentes, Jonathan M. Marks, Jennifer Raff, Charles C. Roseman and Laura R. Stein. which were published together in the scientific journal Human Biology.[14] Marks, for instance, described the book as "entirely derivative, an argument made from selective citations, misrepresentations, and speculative pseudoscience."[15] Other reviews were more moderate in their criticism, such as that of H. Allen Orr, who wrote in The New York Review of Books that "Wade's survey of human population genomics is lively and generally serviceable. It is not, however, without error. He exaggerates, for example, the percentage of the human genome that shows evidence of recent natural selection."[16]
In May of 2021, Wade published an article which advanced the claim that COVID-19 originated from a leak at the Wuhan Institute of Virology.[17][18] This claim is at odds with the current scientific consensus that the virus most likely has a zoonotic origin.[19][20][21][22]
References [ edit ] ^ a b c d e "Nicholas Wade." Contemporary Authors Online. Detroit: Gale, 2011. Biography in Context. Web. 8 July 2014. ^ Amos Esty (25 May 2006). "The Bookshelf talks with Nicholas Wade". American Scientist. Archived from the original on 25 October 2007. ^ Gitschier, Jane (2005). "Turning the Tables'--An Interview with Nicholas Wade". PLOS Genetics. 1 (3): e45. doi:10.1371/journal.pgen.0010045. ISSN 1553-7390. PMC 1239940 . PMID 16205791. ^ a b c d Balter, Michael, "Geneticists decry book on race and evolution", Science, 8 August 2014 ^ a b c d Callaway, Ewen (8 August 2013). "Geneticists say popular book misrepresents research on human evolution". Nature. ^ a b c Michael Hiltzik (12 August 2014). "Racism, the Misuse of Genetics and a Huge Scientific Protest". Los Angeles Times. ^ "Spirit level". The Economist. 17 December 2009 . Retrieved 14 February 2018 . ^ "Nicholas Wade: Journalist & Science Author, Speaker | PRH Speakers Bureau". www.prhspeakers.com . Retrieved 9 December 2017 . ^ "Nicholas Wade". The New York Times. ^ Salevouris, Michael J. (2015). The methods and skills of history : a practical guide. Conal Furay (4 ed.). Chichester, West Sussex, UK. p. 273. ISBN 978-1-118-74544-1. OCLC 885229353. ^ Shulevitz, Judith (24 December 2009). "The God Gene". The New York Times. ISSN 0362-4331 . Retrieved 15 May 2021 . ^ Wade, Nicholas (2014). A Troublesome Inheritance: Genes, Race and Human History. New York: Penguin Publishing Group. ISBN 0698163796. ^ a b Coop, Graham; Eisen, Michael; Nielsen, Rasmus; Przeworski, Molly; Rosenberg, Noah (8 August 2014). "Letter to the Editor of The New York Times Book Review (Letter from Population Geneticists)" . Retrieved 25 September 2014 . We are in full agreement that there is no support from the field of population genetics for Wade's conjectures. ^ Human Biology 2014; 86 (3). ^ Marks, Jonathan M. (1 July 2014). "Review of a Troublesome inheritance by Nicholas Wade". Human Biology . Retrieved 15 May 2021 . ^ Orr, H. Allen (5 June 2014). "Stretch Genes". New York Review of Books . Retrieved 17 May 2014 . ^ Wade, Nicolas (5 May 2021). "The origin of COVID: Did people or nature open Pandora's box at Wuhan?". Bulletin of the Atomic Scientists. ^ Mukunth, Vasudevan (12 May 2021). "In COVID Origins Storm, Fauci Denies US Funded Controversial Study in Wuhan". The Wire Science. ^ Beaumont, Peter (27 May 2021). "Did Covid come from a Wuhan lab? What we know so far". The Guardian. ^ Hakim, Mohamad S. (14 February 2021). "SARS-CoV-2, Covid-19, and the debunking of conspiracy theories". Reviews in Medical Virology: e2222. doi:10.1002/rmv.2222. ISSN 1099-1654. PMC 7995093 . PMID 33586302. ^ Frutos, Roger; Gavotte, Laurent; Devaux, Christian A. (18 March 2021). "Understanding the origin of COVID-19 requires to change the paradigm on zoonotic emergence from the spillover model to the viral circulation model". Infection, Genetics and Evolution. doi:10.1016/j.meegid.2021.104812. ISSN 1567-1348. PMC 7969828 . ^ "COVID-19 Virtual Press conference transcript - 9 February 2021". www.who.int . Retrieved 13 February 2021 .
Apollo Capital Leon Black NBA Gates
Apollo NBA Links
Josh Harris, billionaire governor of the Philadelphia 76ers, co-founded Apollo.
Tony Ressler, billionaire governor of the Atlanta Hawks, co-founded Apollo.
Tony Ressler’s sister, Debra, is married to Leon Black, Apollo’s founder, chairman, and—until recently—CEO.
NBA commissioner Adam Silver’s college roommate at Duke, Jim Zelter, is the co-president of Apollo.
Paul Allen - Blazers
Steve Balmer - Clippers
Apollo United Banana
It didn’t take long for Eli Black to become chairman, CEO, and president of the very same United Fruit that had worked hand-in-glove with intelligence agencies. (In Part 2, we dug into United Fruit’s decades of intelligence connections.) Much has been written about the ensuing years. It’s something of a business whodunnit. United Fruit was suspected of paying a bribe, in some reports—which seems like a misdemeanor compared to a lot of what United Fruit did in its earlier days. In another telling, United Fruit was simply short of cash, and bedeviled by storms in the Caribbean, and the cost of fuel to bring bananas to North America.
Whatever happened, it ended badly. Eli’s son, Leon Black, a student at Harvard Business School, visited home for a weekend in 1975. Peter T. Kilborn writes in The New York Times:
“On Saturday, I took him to get a haircut, and he took me to a store and bought me a sweater,” Leon said. “We all went out to dinner that night. Dad ate a big steak. Then we went to see the ‘Orient Express.’ On Sunday, I cooked him an omelet for breakfast.
On Monday, Eli Black tumbled from the 44th floor window of his office building.
The NBA's most important source of cash - TrueHoop
Wed, 02 Jun 2021 11:32
This kicks off an ongoing TrueHoop series on Apollo Global, the NBA, and Jeffrey Epstein.
PART 2 PART 3 PART 4 PART 5 PART 6
PART 7 PART 8 PART 9 PART 10 PART 11 PART 12
BY HENRY ABBOTTTo the top executives of the NBA, Apollo Global is arguably the most important source of money on planet Earth. The billionaires who run the 76ers and Hawks made fortunes at Apollo. Apollo was born out of Drexel Burnham Lambert, whose alumni are a who's who of the billionaire set. The banker who raised money for Tilman Fertitta to buy the Rockets worked with Apollo's founders at Drexel. Apollo is around the corner from league headquarters; NBA commissioner Adam Silver is still close to his college roommate from Duke, who is Apollo's co-president.
Anyone who cares about the ''behind the curtain'' NBA should care about Apollo's recent crisis: According to an outside investigation, Apollo's founder, longtime CEO, and chairman, Leon Black, paid Jeffrey Epstein $158 million. Black was possibly Epstein's main source of cash over the last decade.
There's a mountain of evidence that Epstein was not only a predator and a pedophile, but also a schemer of a more profound variety, who'--according to depositions'--trafficked underaged women to powerful men and bragged about the leverage that resulted. There were compromising photos, compromising anecdotes, reportedly hidden cameras staffed by men in a secret room, and a trove of photos and video that has yet to see the light of day.
Epstein could pull the levers of power like no one else. In the mid-2000s, when Palm Beach police identified dozens of women telling similar stories of abuse, Epstein seemed destined for a long prison sentence. But a legal team befitting a president'--Alan Dershowitz, Ken Starr, Roy Black, Gerald Lefcourt'--rushed to Epstein's aid and negotiated a sweetheart deal from the U.S. Attorney, who himself went on to be a U.S. cabinet secretary.
Imagine what a guy like Epstein, who'd had powerbrokers like Bill Clinton and Prince Andrew on his private jet, could do in return for $158 million.
Why did Leon Black pay Epstein so much? For what?
It's a giant and profound question in understanding how the world of NBA billionaires works.
Apollo's three-member conflicts committee commissioned an outside investigation that found Black paid all those millions for ''legitimate advice on trust and estate planning, tax issues, issues relating to artwork, Black's airplane, Black's yacht, and other similar matters.''
The New York Times talked to experts in tax and estate matters, one of whom said ''you could be the best lawyer in Manhattan working on the most complicated trusts and estates and it would never come anywhere close to that kind of money,'' he said. Others pointed out that for $158 million you could purchase an entire law firm.
Largely, though, the media seems to accept the report's conclusions'--The Times notes the report, from the law firm Dechert, ''cleared Mr. Black of any wrongdoing.'' Apollo's stock has bounced back nicely since. Black's Apollo co-founders, like 76ers governor Josh Harris'--have been largely insulated from the fallout.
But looking deeper, that report raises as many questions as it answers. At TrueHoop, we are dissatisfied:
The Dechert attorney who led the investigation has reportedly known Epstein since the 1980s.
The report makes conclusions based on evidence (interviews, documents, and Black's text messages) which is not included.
Leon Black was exonerated, as far as the report goes, but nevertheless stepped down as Apollo's CEO. Why?
Epstein, the report notes, was fixated on using Black to reach others at Apollo, including co-founders like Josh Harris. How far did that go?
And then there's the Hollywood-esque character of A.B. ''Buzzy'' Krongard. He's married to a former Apollo executive, sits on Apollo's three-person conflicts committee which commissioned the Dechert report, and is fascinating:
The 9/11 commission looked into unusual investments that may have profited from 9/11. No evidence of wrongdoing was found, but Krongard's name was in the middle of it all.
He's the investment banker who took Microsoft public (which made Bill Gates, Clippers billionaire Steve Ballmer, and deceased Blazers billionaire Paul Allen rich).
''He would subscribe to these magazines which basically sold armaments,'' a colleague told the Baltimore Sun. ''If you wanted to get a shoulder-fired ground-to-air missile, you could order them through these magazines.'' He trained with SWAT teams on the weekend, reportedly had ''dangerous fish'' in his basement, and a bucket of rice'--to jam his fingers into to make them tougher.
And here's where it gets very Hollywood: He's CIA. Or at least sometimes. Was he working with the Agency all through the decades when he was ostensibly a banker? Perhaps. His banking colleagues joke about it. In a move that reportedly pissed off the CIA, a banker named Edwin F. Hale Sr. said Buzzy recruited him to the CIA in 1992.
But Hale and Krongard are birds of a feather: A few years apart, both Hale and Krongard were caught trying to carry loaded guns onto planes at Baltimore Washington International Airport. Krongard's was a 9mm. Hale had a .38.
A.B. ''Buzzy'' Krongard is a master of secrecy. As executive director of the CIA after 9/11, he gave a 2001 presentation to investors, broadcast on C-SPAN about the war on terror. ''I believe it will be won,'' he explained, ''in large part by forces you will not see deploy, fighting engagements you will not witness, and things occurring which you do not want to know about.''At times, Krongard has had prominent CIA jobs, and he is amazing at tough-guy talk. After 9/11, he said things like:
''We at CIA have been restricted from talking to people in the world other than Mother Teresa.''
''Certainly the rules have changed and today there's only one rule, and that's: there are no rules.''
''How do we resolve the tension between between prevention and protection vs. traditional civil liberties? Will racial profiling be re-examined? Will a national identification system be implemented? Will wiretap and other fourth amendment rights be revisited?''
As executive director he reportedly helped set up ''black sites'' where terrorism suspects were taken.
And his work at the CIA includes a famously ''outrageous'' (in the words of an elected official) episode of conflicted interest.
Buzzy had been instrumental in setting up CIA work for the private military contractor Blackwater, and at one point served on a Blackwater advisory panel. Blackwater came to be embroiled in scandal, accused of everything from mass murder to arms smuggling. A State Department inspector general took up multiple investigations. But his subordinates grew frustrated that their boss, the inspector general, may have in fact been stymying their Blackwater research.
It turns out their supervisor, the inspector general, the man accused of going soft investigating Blackwater'--was Buzzy's brother, Howard ''Cookie'' Krongard. Cookie would ultimately resign. (Headline: ''The cookie crumbles.'')
It's a longer story we'll explore, but fast forward to 2021 and Buzzy, who's 84 now, owns a chunk of Apollo Global, where he is on the board. And as of 2016, Apollo owns Blackwater, which has been through several iterations and is now called Constellis.
The Apollo conflicts committee was charged with exploring the well-hidden secrets of the extremely wealthy and powerful, especially Leon Black and Jeffrey Epstein. Is a master of secrecy, a former CIA executive with evident active current conflicts (equity in Apollo, ties to Blackwater), and a history of ''outrageous'' apparent conflicted interest, the person you'd pick if you actually wanted to unearth and disseminate the truth?
Epstein's story is the most troubling. It raises every question, tweaks every fear. Why do so many characters in that story have ties to intelligence, which is supposed to be about keeping us safe? Why do so many characters in that story have ties to the NBA, which is supposed to be about basketball?
READ PART 2 NOW.
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Ex-Apollo CEO Leon Black raped and harassed Russian model, lawsuit alleges
Wed, 02 Jun 2021 05:19
Leon Black, the former chief executive of Apollo Global Management, has been hit with a lawsuit claiming that he raped and harassed a young Russian model before manipulating her with promises of money and sham job interviews at Goldman Sachs.
The claims, which come weeks after Black stepped down from Apollo following scrutiny of his ties to the late paedophile Jeffrey Epstein, contradict Black's account of what he has characterised as a ''consensual affair'' with a woman who he claims later extorted him.
Guzel Ganieva was in her early 20s when she says Black picked her out of a crowd at a New York event marking International Women's Day, and invited her to discuss her future over dinner at the upscale restaurant La Grenouille.
She alleges that soon after that 2008 encounter, the Apollo Global Management founder took her to a bare studio apartment where, on a mattress on the floor, he subjected her to ''forced sadistic sexual acts''.
Black ''derived pleasure from humiliating and debasing'' Ganieva and intentionally caused her physical pain, according to a civil complaint filed in New York state supreme court on Tuesday.
But when Ganieva indicated she was cutting off contact, she says Black turned conciliatory '-- offering to finance a movie that she could produce, and to use his contacts to facilitate an application at Harvard Business School.
''This frivolous lawsuit is riddled with lies, and is nothing more than a wholesale fiction,'' a spokesperson for Black said on Tuesday, adding that Ganieva ''had a wholly consensual relationship with [Black] for six years'' and that her allegations of ''harassment and other inappropriate behaviour'' were ''categorically untrue''.
Black resigned from Apollo in March, citing ''relentless public attention and media scrutiny'' of his professional ties to Epstein, to whom he paid $158m for tax advice and art transaction services. An investigation by Dechert, the international law firm, found no evidence that Black had done anything wrong.
Ganieva's lawsuit claims that Black harmed her reputation by making false and malicious statements in response to news reports detailing some of her allegations of sexual harassment.
''The truth is that I have been extorted by Ms Ganieva for many years,'' Black said in an April statement that Ganieva's lawyers say was ''false and defamatory''.
''I made substantial monetary payments to her, based on her threats to go public concerning our relationship, in an attempt to spare my family from public embarrassment,'' the statement added.
Ganieva's lawsuit offers a different version of events surrounding the money she received from Black, beginning with a $480,000 loan that she says he offered in June 2011 to help her resume her college studies.
A photograph of a one-page ''loan agreement'' attached to the lawsuit appears to bear Black's flowing signature alongside Ganieva's, and arranges for her to receive $60,000 every three months for the subsequent two years.
''The principal loan will be repaid in full on June 1 2016 and will carry a simple interest rate of 5 per cent per annum,'' the document states, without calculating the amount to be repaid. Ganieva says she signed another, nearly identical ''loan agreement'' in 2013.
With her mathematics degree finished, Ganieva began looking for work, and she says Black offered help, arranging for her to meet top executives at Goldman Sachs. Among them was Alison Mass, who now chairs the investment banking division.
A person familiar with the 2014 meetings said the bank had not interviewed Ganieva for any specific position, and that it was not uncommon to enter into open-ended conversations about potential job openings at the request of a client. Goldman declined to comment.
In the end, no job materialised. ''Given the macro environment, there are no open jobs at Goldman Sachs right now that work for/are a fit for you,'' a Goldman banker wrote to Ganieva in an email, adding that a colleague ''would keep his eyes open'' for job openings with clients in Moscow.
''In hindsight Ms Ganieva knows that none of these arranged interviews were meant to be legitimate,'' her lawyers wrote in a court filing.
A year after the meetings at Goldman Sachs, Ganieva says she asked Black ''to leave her and her child alone, for good''.
At a meeting at New York's Four Seasons hotel, she says Black agreed to forgive her loans, and ordered her to sign two documents without allowing her to keep a copy. She says she now understands that she signed a non-disclosure agreement.
Afterwards, Ganieva says she began receiving regular payments from Black, but that the money stopped arriving in April. Weeks earlier Ganieva posted on Twitter that Black was a ''predator'' who had ''sexually harassed and abused'' her for many years.
Through a spokesperson, Black has acknowledged making payments to Ganieva and said he had ''advised the criminal authorities'' of her activities.
In Tuesday's legal filing, Ganieva's lawyers contended that Black was making a ''pre-emptive claim of extortion'' to make it harder for her to pursue legal action.
They wrote: ''He said many times to her, 'If you do not take the money, I will put you in prison.'''
CopyrightThe Financial Times Limited . All rights reserved. Please don't copy articles from FT.com and redistribute by email or post to the web.
Apollo announces that cofounder Josh Harris is stepping down, 2 months after former CEO Leon Black quit - Business Insider India
Wed, 02 Jun 2021 05:21
Kate Duffy May 20, 2021, 19:32 IST
Business Insider Josh Harris of Apollo Global Management speaks at the 2019 Delivering Alpha conference hosted by CNBC Heidi Gutman/CNBC Josh Harris, one of the cofounders of Apollo Global Management, is stepping down, the firm said Thursday. Harris would remain on the board of directors and executive committee, Apollo said. Leon Block, the Apollo cofounder who was investigated for ties to Jeffrey Epstein, quit the firm in March.Investment firm Apollo Global Management on Thursday announced that cofounder Josh Harris would step down as managing director.
He would step down once Apollo merges with its insurance affiliate Athene, the company said in a statement. Apollo's acquisition of Athene, which is set to create a $29 billion conglomerate, is expected to complete in the first quarter of 2022.
Harris would remain on the Apollo board of directors and executive committee, the firm said.
Harris said in the statement: "After nearly 31 years at Apollo, it is time for me to start the next chapter of my career, where I will focus full-time on the platforms I've created outside of the firm as well as deepen my commitment to philanthropy and social impact."
Read more: We talked to billionaires, business titans and an NBA star about the Apollo cofounder who wants to buy the New York Mets. Here's how he can apply his private equity turnaround playbook to a team that haven't won a World Series since 1986.
Fellow cofounder Leon Black, former CEO and chairman of Apollo, quit the firm in March. Black's departure followed an independent investigation into his relationship with the convicted sex offender Jeffrey Epstein, which showed Black paid $158 million to the disgraced financier between 2012 to 2017.
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The investigation found that neither Black nor Apollo employees were involved in Epstein's criminal activities.
MoMA Braces For a Showdown Over Epstein Pal Leon Black
Wed, 02 Jun 2021 05:27
Pressure is building on private-equity billionaire Leon Black to resign as chairman of the Museum of Modern Art ahead of a crucial board meeting next week as his ties to deceased sex trafficker Jeffrey Epstein continue to haunt him.
Fevered discussion about Black's possible departure from MoMA comes a day after Black quit Apollo Global Management, the $455 billion firm he co-founded in 1990. An internal review revealed Black paid the sex offender more than $150 million from 2012 to 2017'--three times higher than what was initially reported. The report found no evidence that Black knew of or participated in Epstein's sexual abuse of girls and young women.
But that same review found that Black and Epstein were unusually close, bound by a series of personal and professional connections stretching back decades. Black loaned Epstein $30 million in early 2017, only $10 million of which was paid back. Black once flew on Epstein's private plane, the so-called ''Lolita Express,'' and visited Epstein's ranch in Stanley, New Mexico and his private Caribbean island, where Epstein's victims were trafficked and abused. He also spent time with Epstein in Florida and in France, and they socialized in New York, often over breakfast. Black funded Epstein's favorite researchers at MIT and Harvard, and gave $10 million to Epstein's secret charity. ''Black confided in Epstein on personal matters, and Black introduced Epstein to his family,'' the report found, adding: ''Black stated that he was repulsed by the details of Epstein's crimes that were published in late 2018...'' By then, those crimes were well and widely known. Epstein's pyramid abuse scheme had been the stuff of headlines since 2010. The legal battles between Epstein's associates, his victims, and Epstein himself had dragged on, in public view, for years.
Black denies any involvement in Epstein's trafficking ring. In October, he told shareholders on an earnings call that palling around with Epstein after his 2008 conviction for soliciting a minor in Florida was a ''terrible mistake.''
''Let me be clear,'' Black said. ''There has never been an allegation by anyone that I engaged in any wrongdoing, because I did not. And any suggestion of blackmail or any other connection to Epstein's reprehensible conduct is categorically untrue.''
Black previously announced he was stepping down as CEO of Apollo and said he'd hand the reins to co-founder Marc Rowan on or before July 31. But on Monday, Apollo said the 69-year-old Wall Street mogul and art collector quit earlier than scheduled and had also relinquished his role as chairman. In a statement, Black said he planned to spend more time with his family and focus on his health and other passions like art. ''And time is precious,'' Black said. ''My wife, Debra, lost a close family member to the pandemic and faces considerable health challenges. I intend to address my own health issues, and take some personal time to pursue my many interests away from Apollo'--including the arts, culture, medical research, and philanthropy.''
Now Black may also lose one of his high-profile positions in the art world: the MoMA chairmanship he's held since 2018. That year, Black donated $40 million to the museum and had two floors of its film center named after him and his wife.
A rep for Black declined to comment. MoMA did not respond to multiple requests for comment.
Still, the museum looks likely to address Black's future on the board at its next meeting scheduled for March 30.
None of MoMA's nearly 80 officers and trustees would speak about Black on the record, though several said they supported him and viewed his relationship to Epstein strictly as business: Black was among a litany of high-powered people to associate with Epstein. One member told The Daily Beast, ''It's obvious to me people used [Epstein], not the least of which as ways to meet other people. And people did do business with him, ergo Leon.''
Another trustee, however, told The Daily Beast that they were troubled by Black's decades-long friendship and ties with a sexual predator. ''There's people who feel strongly, but there has not been a forum for people to express their thoughts yet,'' the person said, referring to the museum's decision to twice postpone its board meeting since February. Asked if they were bothered by the chairman's association with Epstein, the trustee added, ''Of course it disturbs me. I have a conscience and I have children.''
Last week, the New York Post revealed ''a number of MoMA trustees'' had contacted Black about resigning once his term ends on July 1. The report indicated the billionaire could rescind the museum's access to his vast art holdings'--including Edvard Munch's The Scream'--should he leave the board altogether. ''Remember, if MoMA kicks out Black, they lose a chance at his personal art collection,'' one source told the Post.
The Blacks' collection, said to be valued at $1 billion, also includes Head of a Young Apostle, a chalk drawing by Raphael purchased for $48 million; the $106-million Picasso sculpture Bust of a Woman; and the $27-million Constantin BrncuÈi sculpture Bird in Space, which is on display at MoMA.
Calls for Black's ouster have included a petition signed by a phalanx of prominent artists including Nan Goldin and Xaviera Simmons, who demanded MoMA boot Black over his links to Epstein. ''We, as artists and art workers, support the removal of Leon Black from the board of MoMA for reasons that have already been stated by many others. However, this should be considered the bare minimum,'' the group said in a statement. One of the signatories, Guerrilla Girls, the anonymous feminist art collective, said it terminated its book contract with Phaidon Press in 2019 because it's owned by Black. They said MoMA should axe not only Black but fellow trustee Glenn Dubin, a billionaire whose family has longstanding ties to Epstein and whom Virginia Roberts Giuffre, a survivor of Epstein's sex ring, accused of abuse.
Giuffre says Epstein and his alleged accomplice Ghislaine Maxwell kept her as a ''sex slave'' and sent her to powerful men including Britain's Prince Andrew, Dubin, and former New Mexico Gov. Bill Richardson. (All three of the men have denied Giuffre's accusations.)
''We were outraged by Black's silence about his relationship to a known pedophile,'' Guerrilla Girls said in a prior statement. ''So we put up a message outside MoMA demanding the museum kick Black off its Board, along with Epstein pal Glenn Dubin, and tell the world why. It was the least MoMA could do for victims of sexual assault everywhere.''
The art group said: ''How could Black, a shrewd businessman and guy around town, not have known his money subsidized Epstein's elaborate lifestyle, enabling Epstein to continue abusing and trafficking underage girls right up to his suspicious death in 2019? Was Black complicit in Epstein's crimes?''
''Why does MoMA tolerate people like Black and Dubin on its Board?'' Guerrilla Girls added. ''If we're stuck with a system where our tax-exempt, educational institutions have to depend on money from the superrich, they should at least choose donors who make the world a better, not a worse place.''
Black has been under fire in the press for his ties to Epstein since July 2019, when Manhattan federal prosecutors charged the 66-year-old financier with exploiting girls as young as 14 from 2002 to 2005. And the media firestorm didn't fade after Epstein killed himself in jail one month later.
Their relationship is also being investigated by at least one government official: Denise N. George, the attorney general for the U.S. Virgin Islands, who subpoenaed Black as part of her civil racketeering lawsuit against Epstein's estate and companies. (George has also subpoenaed Dubin for all communications relating to Epstein and Dubin's three children, along with records relating to a Swedish girl who traveled with Epstein.)
Shortly after Epstein's New York indictment, Black sent an email to Apollo employees addressing concerns about his relationship with the money manager. ''I was completely unaware of, and am deeply troubled by, the conduct that is now the subject of the federal criminal charges brought against him,'' Black wrote.
''There's people who feel strongly, but there has not been a forum for people to express their thoughts yet.''
At the same time, reports surfaced that Black had donated $10 million to the financier's secret foundation, Gratitude America Ltd., in 2015 using a shell company called BV70 LLC. ''Black felt comfortable making this donation because he understood that Epstein was a strong proponent of scientific innovation,'' Apollo's internal review said. Black also used BV70 to make $30.5 million in loans to Epstein ''in connection with an art transaction involving'' the perverted hedge funder, who repaid only $10 million despite Black's demands for repayment throughout 2018.
Their friendship dissolved, the report says, in October 2018 because of a long-running dispute over Epstein's fees. About a month later, Epstein became a household name after the Miami Herald published a three-part expos(C) into his Palm Beach trafficking ring and the lenient 2008 plea deal he negotiated with Miami federal prosecutors.
Apollo's internal report said Black and Epstein met through an unnamed mutual friend in the mid-1990s and ''developed a personal relationship.''
''While Black and Epstein discussed estate planning, philanthropy, and related issues over the years, Black did not engage Epstein to provide him with any services until 2012,'' the report claims. ''Initially, Black viewed Epstein as someone who was very intelligent and knowledgeable regarding issues relating to estate planning and taxation. Black also was impressed by Epstein's connections to many prominent figures in business, politics, and science. Epstein spoke knowledgeably about scientific innovation and technology. He introduced Black to well-regarded researchers at Harvard University and the Massachusetts Institute of Technology and encouraged Black to donate to charitable causes that supported scientific development.''
Indeed, Black's name has surfaced in multiple reports on Epstein's companies and donations'--including internal reviews by Harvard University and the Massachusetts Institute of Technology, as well as Deutsche Bank.
An MIT report said Epstein claimed to have set up anonymous donations for the school's Media Lab from Black and Microsoft co-founder Bill Gates. ''Black has publicly acknowledged donating to charities 'affiliated' with Epstein, but has not specifically addressed whether he donated to MIT or whether Epstein asked him to donate to MIT,'' the document concluded. ''Notably, we did not find any evidence that the money donated by Gates or Black actually was Epstein's money'--that is, there is no evidence that Gates and Black acted to 'launder' Epstein's money.'' The backlash over Epstein's donations to the MIT Media Lab caused director Joi Ito to resign in 2019.
For its part, Harvard noted that Epstein helped two professors obtain millions in donations from Black: Martin Nowak, who helmed the university's Program in Evolutionary Dynamics, and Harvard Medical School geneticist George Church. ''Jeffrey Epstein introduced Mr. Black to the research that was being undertaken by Professors Church and Nowak,'' a representative for Black told Harvard counsel for the university's own report. ''Mr. Black met with Professors Nowak and Church to discuss their research in Cambridge, Massachusetts and, in the case of Professor Church, also at Mr. Black's New York office. The gifts made in support of Professor Church's and Professor Nowak's research were made by Mr. Black. None of the funds were provided by Mr. Epstein and no attempt was made to conceal the source of these gifts.''
''Black viewed Epstein as a friend worthy of his trust.''
The Apollo report further illustrated the social and financial ties that bound Epstein and Black. In 1997, Black named Epstein a director of his family foundation, whose only other officers were himself and spouse Debra. While Black claims Epstein left this position in mid-2007'--when the FBI was investigating him in Palm Beach for abusing minors'--the foundation's tax forms continued to list Epstein through 2012.
And Black continued to socialize with Epstein and pay him for estate and tax planning, among other services, even after his 2008 conviction in Florida.
''Following Epstein's prison sentence, Black believed that Epstein had served his time and that it would not be inappropriate to maintain a personal and professional relationship with Epstein,'' the report notes. At the time, Black thought Epstein's crimes were ''limited to a single instance of soliciting a 17 year old prostitute that Black believed Epstein had mistakenly understood was older.'' The report also says Black ''believes in rehabilitation, and in giving people second chances.''
According to the report, ''Black viewed Epstein as a friend worthy of his trust.'' The billionaire regularly visited Epstein in New York, including at events with other prominent guests, and ''confided in Epstein on personal matters.'' Black and his wife visited Epstein at his residences in France, Florida, the Caribbean, and New Mexico but never spent the night, the report claims. ''At Epstein's request, Black and his wife provided transportation from Santa Fe to California on Black's plane to two or more of Epstein's adult guests in Santa Fe,'' a footnote in the report states.
''Black viewed Epstein as a confirmed bachelor with eclectic tastes, who often employed attractive women,'' the review says. ''However, Black did not believe that any of the women in Epstein's employ were underage. Black has no recollection of ever seeing Epstein with an underage woman at any time.''
The internal report says that for years, Epstein managed Black's art collection and counseled him on forming a new art partnership and ''obtaining a potential advisory opinion from the New York State Department of Taxation and Finance regarding a contemplated transaction involving Black's art.'' Epstein was also ''fairly involved in assisting Black in connection with the sale of certain pieces of artwork'' and advised him on ''the contested ownership of a Picasso sculpture.''
In 2015, Black purchased Bust of a Woman from the artist's daughter, Maya Widmaier Picasso, for $106 million. The Qatari royal family and their agents, however, challenged the transaction; they said they'd already reached a deal with Widmaier Picasso to buy the sculpture for about $42 million two years before. Both sides reached a settlement in 2016, with Black the winner of the piece.
Around the same time, Black and Epstein's relationship started to unravel. Epstein began demanding tens of millions in fees for supposedly coming up with a tax-planning transaction that saved Black $600 million. He emailed Black throughout 2016 and 2017 to pressure him to pay more for the expertise. ''Epstein also would invoke his friendship with Black in those emails,'' the Apollo report states, ''including by referencing personal matters that Black had shared with Epstein in confidence, although there is no evidence that those matters had any relationship to any of Epstein's criminal activity or to any of Black's payments to Epstein.''
Black, per the report, ''was shocked'' when Epstein's sex crimes made news in late 2018. ''Some witnesses noted specifically that they did not believe Black would have allowed Epstein to be introduced to Black's wife and children if Black had had any suspicion that Epstein had done anything inappropriate or illegal with girls or young women,'' the review says.
But at least one guest who attended a swanky pool party at Black's Hamptons property in 2015 was surprised to see Epstein among the swimsuit-clad revelers.
''Leon had a personal relationship with Jeffrey, and I found it odd,'' one witness told the Post. ''Why was what Jeffrey did not that bad?''
Apollo announces that cofounder Josh Harris is stepping down, 2 months after former CEO Leon Black quit | Business Insider India
Wed, 02 Jun 2021 17:44
Josh Harris of Apollo Global Management speaks at the 2019 Delivering Alpha conference hosted by CNBC Heidi Gutman/CNBC
Josh Harris, one of the cofounders of Apollo Global Management, is stepping down, the firm said Thursday. Harris would remain on the board of directors and executive committee, Apollo said. Leon Block, the Apollo cofounder who was investigated for ties to Jeffrey Epstein, quit the firm in March.Investment firm Apollo Global Management on Thursday announced that cofounder Josh Harris would step down as managing director.
He would step down once Apollo merges with its insurance affiliate Athene, the company said in a statement. Apollo's acquisition of Athene, which is set to create a $29 billion conglomerate, is expected to complete in the first quarter of 2022.
Harris would remain on the Apollo board of directors and executive committee, the firm said.
Harris said in the statement: "After nearly 31 years at Apollo, it is time for me to start the next chapter of my career, where I will focus full-time on the platforms I've created outside of the firm as well as deepen my commitment to philanthropy and social impact."
Read more: We talked to billionaires, business titans and an NBA star about the Apollo cofounder who wants to buy the New York Mets. Here's how he can apply his private equity turnaround playbook to a team that haven't won a World Series since 1986.
Fellow cofounder
Leon Black, former CEO and chairman of Apollo,
quit the firm in March. Black's departure followed an independent investigation into his relationship with the convicted sex offender Jeffrey Epstein, which showed
Black paid $158 million to the disgraced financier between 2012 to 2017.
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The investigation found that neither Black nor Apollo employees were involved in Epstein's criminal activities.
{{}}
Bill Gates and Jeffrey Epstein - TrueHoop
Wed, 02 Jun 2021 11:30
BY HENRY ABBOTTBill Gates is in the news because earlier this week, after 27 years of marriage, his wife Melinda filed for divorce.
The news got all kinds of people talking about Bill Gates. To my surprise, his name has popped up again and again in TrueHoop's ongoing investigation of Epstein's ties to Apollo Global and the NBA. Rooted in Drexel Burnham Lambert, Apollo has become the NBA's most important source of cash.
Of particular interest: Epstein and Gates both have had ties to the current leaders of the United Arab Emirates and Saudi Arabia.
A timeline:
1986Microsoft's IPO made Bill Gates one of the richest Americans. One of the main banks with which he did this is Alex. Brown, whose then head was A.B. ''Buzzy'' Krongard. Buzzy later became an executive at the CIA, and is now on the board of Apollo Global, "which is undergoing profound change following the revelation of its founder's relationship with sex trafficker Jeffrey Epstein."
1993A Seattle Times story describes the convicted felon, Robert Evans, who, at the time, invested much of Bill Gates' portfolio. It's a story of leverage: Evans reportedly got to decide which large bank handled Gates' routine sales'--reportedly about a million shares per quarter'--of Microsoft stock. In exchange, he expected to get in on the hottest initial public offerings the banks have to offer. ''Buzzy'' Krongard's Alex. Brown was one of Evans' most frequent partners.
1994A New Yorker profile of Gates includes a quote from an unnamed competitor: ''I think the guy is truly dangerous. Bill is the most surprisingly conscience-free individual I've ever met, and that amount of power in the hands of a guy without a conscience is dangerous.''
Bill and Melinda Gates were married in Hawaii.
2000Melanie Walker reportedly met Jeffrey Epstein in the early 1990s, when he offered to get her a Victoria's Secret audition. Later she became a neuroscientist and a scientific advisor to first Epstein and later the Bill and Melinda Gates Foundation. In 2000, Walker reportedly attended Prince Andrew's 40th birthday party, thrown by the Queen at Windsor Castle, with Jeffrey Epstein and Ghislaine Maxwell.
Later, London tabloids fixated on relations between Andrew and a young neuroscientist, who evidently spent a few days together at Epstein's New Mexico property. The Daily Beast's Tom Sykes:
Deidre Stratton worked at Epstein's notorious Zorro Ranch, and she told a podcast, Epstein: Devil in the Darkness, that Andrew was ''kept company'' by the woman for three days when he stayed at the ranch on his own. '... Epstein was not there, but he arranged for Andrew to be accompanied by the young medic, according to the former housekeeper. Stratton said: ''At the time, Jeffrey had this, she supposedly was a neurosurgeon, quite young, beautiful, young and brilliant, and she stayed in the home with him... At one point we had all these different teas and you could pick the teas that you wanted and she asked me to find one that would make Andrew more horny.''
2001Nigel Rosser of the Evening Standard wrote about Prince Andrew's fascination with Ghislaine Maxwell, and Maxwell's unusual partnership with Jeffrey Epstein. Rosser reported that Epstein ''has made many millions out of his business links with the likes of Bill Gates'':
Epstein was a guest at the Queen's birthday party at Windsor and travelled with Ghislaine to Andrew's country weekend at Sandringham before Christmas. He has made many millions out of his business links with the likes of Bill Gates, Donald Trump and Ohio billionaire Leslie Wexner, whose trust he runs.
Prince Andrew's friends can only speculate what Epstein gains from his association with British royals but clearly it can do no harm to his business reputation in New York.
(This report has evidently gone missing from the Evening Standard's website.)
2006In 2006 Melanie Walker joined the faculty of the University of Washington. As of May, 2021, she is reportedly married to one of Bill Gates' longtime, most trusted Microsoft colleagues, Steven Sinofsky. It's unclear when the wedding was, but some reports attach her moving to Seattle to her relationship with Sinofsky.
2008Bill Gates founded a ''mysterious'' new entity which at one point was called BCG3, and later Gates Ventures.
In June, Epstein began to serve about a year in prison after a plea agreement stemming from an investigation based on the testimony of many underaged girls in Florida.
2009 and 2010Gates was photographed at Edge Foundation events (''the billionaires dinner''). Epstein was the foundation's biggest backer, and he attended many years, including 2009 and 2010.
2011As reported in The New York Times, Gates visited Epstein's residence in New York City on January 31. ''His lifestyle is very different,'' Gates writes of Epstein in an email to colleagues, ''and kind of intriguing although it would not work for me.'' Later a Gates spokesperson claims Gates was referring to the house's decor. Dr. Eva Andersson-Dubin and her 15-year-old daughter were at dinner. ''A very attractive Swedish woman and her daughter dropped by and I ended up staying there quite late,'' added Gates.
Shortly thereafter, Epstein and Gates were reportedly deep in conversation at TED Long Beach.
On May 3, Gates was photographed at Epstein's mansion with JP Morgan executive James E. Staley, former Treasury Secretary Lawrence Summers, Jeffrey Epstein, and Boris Nikolic. Nikolic, at the time, was a science advisor to the Bill and Melinda Gates foundation who had reportedly become friends with Epstein after being introduced by Walker.
Following that, Gates Foundation teams reportedly visited Epstein's mansion twice more, to discuss a potential Global Health Investment Fund.
2012''Microsoft staff stunned'' that Steven Sinofsky, expected to be Microsoft's next CEO, stepped down.
2013Gates flew from Teterboro to Palm Beach on Jeffrey Epstein's plane in March.
In September, Gates and Nikolic were in New York to visit a medical company Gates had invested in. Gates and Epstein reportedly had dinner.
Mohammed bin Salman'--then a local official'--has his MiSK Foundation launch the Tweeps Forum, an annual networking event that includes Ivanka Trump, top officials from the United Arab Emirates, and Twitter executives.
2014BCG3 donated $2 million to the MIT Media Lab. The New Yorker's Ronan Farrow reports:
Epstein appeared to serve as an intermediary between the lab and other wealthy donors, soliciting millions of dollars in donations from individuals and organizations, including the technologist and philanthropist Bill Gates and the investor Leon Black. According to the records obtained by The New Yorker and accounts from current and former faculty and staff of the media lab, Epstein was credited with securing at least $7.5 million in donations for the lab, including two million dollars from Gates and $5.5 million from Black, gifts the e-mails describe as ''directed'' by Epstein or made at his behest. '...
In October, 2014, the Media Lab received a two-million-dollar donation from Bill Gates; Ito wrote in an internal e-mail, ''This is a $2M gift from Bill Gates directed by Jeffrey Epstein.'' Cohen replied, ''For gift recording purposes, we will not be mentioning Jeffrey's name as the impetus for this gift.''
Bill Gates reportedly rented the super yacht ''Serene,'' off the coast of Sardinia, for $5 million a week.
2015Saudi Prince Mohammed bin Salman purchased Serene.
U.S. investigators notify Twitter that some of its employees have been cultivated as agents of the Saudi government, for instance supplying personal information of Saudi dissidents. As Twitter investigates, one of the employees moves to Saudi Arabia and begins work at the MiSK Foundation. The New York Times:
According to court documents, the Saudi official who developed the Twitter employees was the ''secretary general'' of a charitable organization owned by a member of Saudi Arabia's royal family. That description pointed to the MiSK Foundation, a technology-focused nonprofit founded by Prince Mohammed.
2016Donald Trump was elected. His first visit would be to Saudi Arabia, where he touted enormous defense contracts with the kingdom.
2017Bill Gates visited Prince Mohammed bin Salman in Saudi Arabia, and gave a speech that said: ''I'm excited about this initiative because I love challenging young people to solve very tough problems, and pursue their dreams. I know that's an aspiration I share with the Crown Prince.''
Mohammed bin Salman's foundation becomes a member of the MIT Media Lab consortium'--which will soon undergo changes because of Epstein ties. In a press release MiSK says ''By becoming a MIT Media Lab member, the MiSK Foundation joins a network of over 80 member companies and organizations '... these include MiSK's partners such as Bill & Melinda Gates Foundation'...''
2018Mohammed bin Salman visited Gates' home in Washington. In the book MBS, by Ben Hubbard, MBS is quoted saying he wants to be a disruptive leader like Steve Jobs, Mark Zuckerberg, or Bill Gates.
Also that year, journalist James B. Stewart visited Jeffrey Epstein at his house in Manhattan, and wrote:
Before we left the room [Epstein] took me to a wall covered with framed photographs. He pointed to a full-length shot of a man in traditional Arab dress. ''That's MBS,'' he said, referring to Mohammed bin Salman, the crown prince of Saudi Arabia. The crown prince had visited him many times, and they spoke often, Epstein said.
In November, journalist Jamal Khashoggi was captured, assassinated, and carved to pieces in Istanbul. In November the CIA would report that MBS had ordered the assassination, a conclusion that was affirmed by a four-page report released by the Director of National Intelligence in 2021. Two of those reportedly responsible for the murder were among MBS's personal security detail.
Later, Donald Trump reportedly bragged that MBS was going to get in trouble for the episode but Trump ''saved his ass.''
U.S. Senator Tim Kaine suggested the killers may have been trained by a U.S. private military contractor called Tier One, whose main investor is Trump intelligence appointee and donor Stephen Feinberg. Feinberg worked at Drexel Burnham Lambert with the founders of Apollo Global.
The Bill and Melinda Gates Foundation reveals that it has suspended future work with the MiSK Foundation because of the killing of Jamal Khashoggi.
2019Jeffrey Epstein was arrested.
Joi Ito, head of the MIT Media Lab, resigned from MIT and a number of other boards and positions over his ties to Epstein.
Kobe Bryant, the NBA, and Madison Square Garden reportedly met with sports officials from Saudi Arabia. The Guardian's Karim Zidan:
More recently, Saudi Arabia's sports-centric lobbying offensive has been the result of an urgent need for the kingdom to rebrand itself following the murder of Jamal Khashoggi, a US-based Washington Post columnist and Saudi dissident who was last seen entering the Saudi consulate in Istanbul, where he was reportedly killed and dismembered with a bone-saw. Saudi's attorney general later stated that the murder was premeditated, and the CIA concluded that Prince Mohammed bin Salman ordered Khashoggi's murder.In light of Saudi's recent diplomatic controversy, the kingdom has doubled down on its lobbying strategy, which, according to recently released documents, included meetings and business calls with all the leading commissioners and sports bodies in the United States.
Town & Country magazine's Ben Widdicombe explored the role of Ghislaine Maxwell, and Gates' Microsoft co-founder'--and then Trail Blazers owner'--Paul Allen came up.
''She was a big part of the jet-set,'' said one person who has known her for 15 years. "I would see her in St. Barth's, on Paul Allen's yacht"'--the Octopus, an infamous 414-foot floating pleasure palace then owned by the late Microsoft co-founder'--''and at Heidi Klum's Halloween party in New York.'' '... Much like Epstein, her social circle also encompassed Britain's Prince Andrew; a Palm Beach set which included Donald Trump; and the Clinton family'--she even attended Chelsea Clinton's 2010 wedding. ''But the thing is, to hang around those billionaire guys, you either have to be sleeping with them or you're finding them girls. There is no in-between when you're in that crowd,'' said the friend, referring not to Ghislaine individually but the dark habits and rituals common at the highest echelons of power.
Jeffrey Epstein died in custody, days after reportedly changing his will and naming Boris Nikolic'--a longtime Gates confidante'--as his backup executor. Nikolic, who shared a private JP Morgan banker with Epstein and had other business ties, reportedly rejected the assignment.
2020Gates left the Microsoft board.
2021Melinda Gates filed for divorce, saying her marriage is ''irretrievably broken.'' The New York Times reports:
The couple deployed their connections last year in response to the pandemic, calling leaders like Chancellor Angela Merkel of Germany and Crown Prince Mohammed bin Zayed of Abu Dhabi to drum up support for their plans. The foundation has committed $1.75 billion so far to its Covid-19 response, and played a key role in shaping the global deal to bring vaccines to poor countries.
That prominence has also brought a fair share of scrutiny, throwing a spotlight on Mr. Gates's robust defense of intellectual property rights '-- in this case, specific to vaccine patents '-- even in a time of extreme crisis, as well as the larger question of how unelected wealthy individuals can play such an outsize part on the global stage.
Thank you for reading TrueHoop!
Jeffrey Epstein net worth: Did he try to marry Glenn Dubin's daughter? '' Film Daily
Wed, 02 Jun 2021 11:18
The case against Jeffrey Epstein is still afoot and new documents reveal U.S. Virgin Islands prosecutors are now exploring Epstein's ties with billionaire Glenn Dubin & his family. While the Dubins claim they are ''outraged'' by the allegations against them, the Dubins history with Epstein has made many suspicious of the Dubins' activities with the registered sex offender.
Epstein died shortly after his arrest, but prosecutors are continuing their investigations. Epstein's alleged madam Ghislaine Maxwell was also arrested for enticement & sex trafficking minors in July 2020. Depositions revealed the Dubins may have more to do with Epstein's alleged sex ring than they claim, but Epstein's relationship with their daughter, Celina, has also faced scrutiny, especially after the recent subpoena.
The Virgin Islands prosecutors have been investigating Epstein's alleged sex trafficking ring & alleged racketeering. Epstein owned a private island in the Virgin Islands where he allegedly groomed, sexually abused, & sex trafficked young women & girls. Here's why Epstein could have been interested in Glenn Dubin's daughter and what this latest subpoena has to do with the investigation.
Newest subpoena According to the Washington Examiner , U.S. Virgin Islands prosecutors issued a subpoena in September requesting Dubin to turn over any & all communications, including documents & messages, related to his three children & Epstein. Dubin & his wife, Dr. Eva Andersson, have three children together: two daughters, Maye & Celina, and one son, Jordan.
The Washington Examiner reported Epstein wanted to marry Celina. Epstein met Celina when she was twelve years old and the two had ''an especially close relationship'', according to the Washington Examiner , though there is no evidence of a romantic relationship. The paper stated Epstein possibly wanted to marry Celina only for ''financial incentives'' due to her inheritance, which could boost his net worth.
The subpoena also requested financial records between Dubin & Epstein and communication between Epstein and ''a Swedish female'' he traveled with & his former butler Rinaldo Rizzo, according to the Washington Examiner . The girl in question, who was fifteen at the time, was allegedly held against her will at Epstein's island, according to testimony by Rizzo, according to the Daily Mail .
Epstein & Dubin Even before Epstein met Glenn Dubin, Epstein dated Dubin's wife, Eva Andersson-Dubin, for eleven years, according to the Washington Examiner . Dubin has been personally connected to Epstein since July 2019, when it was revealed Epstein invested millions in Dubin's hedge fund & helped negotiate the acquisition of Dubin's firm with JPMorgan, according to Vanity Fair .
Even more, unsealed documents revealed Virginia Roberts Giuffre, one of the most significant Epstein survivors, accused Epstein & associate Ghislaine Maxwell of pressuring her to have sex with Dubin. Dubin is one of many Giuffre has alleged of being sex trafficked to. Giuffre has also alleged Maxwell of grooming her for Epstein. Maxwell is now facing sex trafficking charges and is awaiting her trial after pleading not guilty.
In addition, Dubin's aforementioned former butler Rinaldo Rizzo said in his deposition how he found a saw a Swedish girl who looked like the girls he had seen on Epstein's island. The girl was hired as a nanny Dubin & Eva Andersson-Dubin. Rizzo had asked the girl about her association with Epstein when the girl revealed how she was forced to have sex, according to The Daily Beast . The Dubins have maintained their innocence.
The Dubins' billionaire lifestyle Glenn Dubin grew his net worth by being a hedge fund manager & the co-founder of Highbridge Capital Management; however, he announced his retirement earlier this year, saying he would focus on his private investments, according to Reuters . He's amassed a net worth of $2 billion.
Glenn Dubin & Eva Andersson-Dubin have been married since 1994. They've been involved with philanthropy over the years, though they've faced plenty of controversies since their connection with Epstein was revealed. Even after Epstein was deemed a sex offender, Andersson-Dubin wrote a letter to Epstein's probation officer she was ''100% comfortable'' with Epstein around her children.
While the Dubins' have dialed back their association with Epstein, he was nevertheless a seemingly large part of their lives. According to the Daily Mail , Dubin told his friends in 2014 he would likely marry Celina. She was nineteen years old at the time. According to the tabloid, Epstein allegedly wanted to give Celina some of his net worth and named Celina as the beneficiary of a $50 million trust. She was subsequently removed in 2015.
Apollo Global Management - Wikipedia
Wed, 02 Jun 2021 05:23
Apollo Global Management, Inc., is a global alternative investment manager firm. It was founded in 1990 by Leon Black, Josh Harris,[4] and Marc Rowan.[5] Apollo is headquartered in New York City, with offices across North America, Europe and Asia.[6] The company's stock is publicly traded on the NYSE under the symbol 'APO'.
Apollo Global Management, Inc.TypePublicNYSE: APOISIN US0376123065 IndustryAsset managementFounded1990 ; 31 years ago ( 1990 ) FoundersLeon Black, John Hannan, Josh Harris, Marc Rowan, Craig Cogut, Arthur Bilger, Antony ResslerHeadquartersSolow Building,New York City
,U.S.
Key people
ProductsPrivate equity funds, credit funds, real estate funds, alternative investment, leveraged buyouts, growth capital, venture capitalRevenue US$2.931 billion (2019)[1] US$ 1.407 billion (2019)[1] US$ 1.536 billion (2019)[1]AUM US$ 414 billion (June 2020[2] Total assets US$8.542 billion (2019)[1] Total equity US$ 3.038 billion (2019)[1]Number of employees
1,600 (2020)[3]Website www.apollo.com The firm specializes in investing across credit, private equity, and real assets.[7][8]
Apollo Global Management reported $414B of assets under management at the end of June 2020. Around 72% of assets are in the credit business ($300.4B as of last quarter close). Around 18% of assets ($73.3B as of last quarter close) are in private equity. The remaining 10% of assets are in real assets ($39.9B as of last quarter close).[9] Around 66% of assets are in the credit business ($209.7B as of last quarter close). Around 21% of assets ($67.7B as of last quarter close) are in private equity. The remaining assets are in real assets ($39.9B as of last quarter close).[9][failed verification ]
Among the most notable companies Apollo has an investment in are ADT, CareerBuilder, Cox Media Group, Intrado, Rackspace, Redbox, Shutterfly, Smart & Final, and University of Phoenix.
In March 2021, Apollo Global Management announced plans to merge with Athene Holding, the life insurance company. The merger values Athene at $11 billion. Since it was founded in 2009, Athene has been backed by Apollo.[10] Athene went public in 2016 and had a market capitalization of just over $10 billion. Prior to the merger announcement, Apollo already owned 35% of Athene.[11] The deal is expected to close in January 2022.[12] The combined entity will have a market cap of $29 billion, making it eligible for inclusion in the S&P 500 index.[13]
In March 2021, Apollo announced that Leon Black had stepped down as CEO and chairman after revelations that he paid Jeffrey Epstein $158 million for personal tax-related advice over the period from 2012 to 2017.[14][15] Marc Rowan became CEO after Black stepped down.[16]
History Edit Apollo, originally referred to as Apollo Advisors, was founded in 1990, on the heels of the collapse of Drexel Burnham Lambert in February 1990, by Leon Black, the former head of Drexel's mergers and acquisitions department, along with other Drexel alumni.[17] Among the most notable founders are John Hannan, Drexel's former co-director of international finance; Craig Cogut, a lawyer who worked with Drexel's high-yield division in Los Angeles; and Arthur Bilger, the former head of the corporate finance department. Other founding partners included Marc Rowan, Josh Harris, and Michael Gross, who both worked under Black in the mergers and acquisitions department, and Antony Ressler, who worked as a senior vice president in Drexel's high yield department with responsibility for the new issue/syndicate desk.[18][19][20]
Less than six months after the collapse of Drexel, the founders of Apollo had already begun a series of ventures. Apollo Investment Fund L.P., the first of its private equity investment funds, was formed to make investments in distressed companies. Apollo's first fundraised approximately $400 million of investor commitments on the strength of Black's reputation as a prominent lieutenant of Michael Milken and a key player in the buyout boom of the 1980s.[18] Lion Advisors was set up to provide investment services to Credit Lyonnais, which was seeking to profit from depressed prices in the high yield market.[21]
1990s Edit At the time of Apollo's founding, there was little financing for new leveraged buyouts and Apollo turned instead to a strategy of distressed-to-control takeovers.[22][23] Apollo would purchase distressed securities which could be converted into a controlling interest in the equity of the company through a bankruptcy reorganization or other restructuring. Apollo used distressed debt as an entry point, enabling the firm to invest in such firms as Vail Resorts,[24] Walter Industries,[25][26] Culligan, and Samsonite.[27]
Early on, Apollo made a name for itself by acquiring interests in companies that Drexel had helped finance by purchasing high-yield bonds from failed savings and loans and insurance companies. Apollo acquired several large portfolios of assets from the U.S. government's Resolution Trust Corporation.[28] One of Apollo's earliest and most successful deals involved the acquisition of Executive Life Insurance Company's bond portfolio. Using this vehicle, Apollo would purchase the Executive Life portfolio, generating tremendous profits[clarification needed ] when the value of high yield bonds recovered, but also resulting in a variety of state regulatory issues for Apollo and Credit Lyonnais over the purchase.[29] More than a decade after the purchase, in 2002, California Attorney General Bill Lockyer accused Apollo, Leon Black, and an investor group led by French bank Credit Lyonnais of illegally acquiring the assets and bond portfolio of Executive Life Insurance Co. in 1991. According to the State of California, Credit Lyonnais allegedly violated a California law that prohibited foreign government-owned banks from owning California insurance companies.[30]
AREA Property Partners logo
In 1993, Apollo Real Estate Advisers was founded in collaboration with William Mack to seek opportunities in the U.S. property markets.[31] Apollo Real Estate Investment Fund, L.P., the first in a family of real estate "opportunity funds", was closed in April 1993 with $500 million of investor commitments. In 2000, Apollo exited the partnership, which continued to operate as Apollo Real Estate Advisers until changing its name to AREA Property Partners, effective January 15, 2009. That firm is owned and controlled by its remaining principals, who include William Mack, Lee Neibart, William Benjamin, John Jacobsson, Stuart Koenig, and Richard Mack.[32] As of 2008, the firm was investing out of three funds: Apollo Real Estate Investment Fund V, Apollo European Real Estate Fund II, and Apollo Value Enhancement Fund VII. In 2004, Apollo Real Estate acquired the Value Enhancement Funds family of investment vehicles to broaden its offerings in the "value-added" segment of the real estate investment spectrum. Apollo also operates a real estate mezzanine lending program and real estate securities hedge fund called Claros Real Estate Securities Fund, L.P.[33]
In 1995, Apollo raised its third private equity fund, Apollo Investment Fund III, with $1.5 billion of investor commitments from investors that included CalPERS and the General Motors pension fund.[34][35] Unlike its first two funds and later funds, Fund III would ultimately prove only an average performer for private equity funds of its vintage. Among the investments made in Fund III (invested through 1998) were: Alliance Imaging, Allied Waste Industries, Breuners Home Furnishings, Levitz Furniture,[36] Communications Corporation of America,[37] Dominick's, Ralphs (acquired Apollo's Food-4-Less),[38] Move.com, NRT Incorporated,[39] Pillowtex Corporation,[40] Telemundo,[41] and WMC Mortgage Corporation.[42]
Apollo invested in
AMC in 2001 and would buy out the company in 2004
Also in 1995, Apollo founding partner Craig Cogut left the firm to found a smaller competitor Pegasus Capital Advisors. Since inception Pegasus has raised $1.8 billion in four private equity funds focused on investments in middle-market companies in financial distress. In 1997, Apollo co-founder Tony Ressler founded Ares Management as the successor to its Lion Advisors business which would manage collateralized debt obligation vehicles.[43]
In 1998, Apollo raised its fourth private equity fund, Apollo Investment Fund IV, with $3.6 billion of investor commitments.[34] Among the investments made in Fund IV (invested through 2001) were: Allied Waste Industries,[44] AMC Entertainment,[45] Berlitz International,[46] Clark Retail Enterprises,[47] Corporate Express (Buhrmann), Encompass Services Corporation, National Financial Partners, Pacer International,[48] Rent-A-Center, Resolution Performance Products, Resolution Specialty Materials, Sirius Satellite Radio, SkyTerra Communications, United Rentals, and Wyndham Worldwide.[49]
2000''2005 Edit Apollo deployed its fourth fund during the booming markets of the late 1990s, only to experience difficulties with the collapse of the Internet bubble and the onset of the recession. Amid the turmoil of collapsing markets, Apollo was able to raise its fifth private equity fund in 2001, Apollo Investment Fund V, with $3.7 billion of investor commitments.[citation needed ] Among the investments made in Fund V (invested through 2006) were Affinion Group, AMC Entertainment, Berry Plastics, Cablecom, Compass Minerals, General Nutrition Centers (GNC), Goodman Global, Hexion Specialty Chemicals (Borden), Intelsat, Linens 'n Things, Metals USA, Nalco Investment Holdings, Sourcecorp, Spectrasite Communications, and Unity Media.
Meanwhile, Ares profited significantly from investments made after the collapse of the high yield market in 2000 and 2001.[citation needed ] Although the founders of Ares had completed a spin-out with the formation of the firm in 1997, they had initially maintained a close relationship with Apollo and operated as the West Coast affiliate of Apollo.[50][citation needed ] By 2002, when Ares raised its first corporate opportunities fund, the firm announced that it would separate from its former parent company. The timing of this separation also coincided with Apollo's legal difficulties with the State of California over its purchase of Executive Life Insurance Company in 1991.[51]
Following the spin-off of Ares in 2002, Apollo developed two new affiliates to continue its investment activities in the capital markets. The first of these new affiliates, founded in 2003, was Apollo Distressed Investment Fund (DIF) Management a credit opportunity investment vehicle.[52] The following year, in April 2004, Apollo raised $930 million through an initial public offering (IPO) for a listed business development company, Apollo Investment Corporation (Nasdaq: AINV)). Apollo Investment Corporation was formed to invest primarily in middle-market companies in the form of mezzanine debt and senior secured loans, as well as by making certain direct equity investments in companies. The company also invests in the securities of public companies.[53][54]
2005''2010 Edit Between 2005 and 2007 the private equity market was booming, with new "largest buyout" records set and surpassed several times in an 18-month window.[55] Although Apollo was involved in a number of notable and large buyouts, the firm avoided the very largest transactions during the time. Among Apollo's most notable investments during this period included Harrah's Entertainment, a leading US gaming and casino company; Norwegian Cruise Line, the cruise line operator; Claire's Stores, the retailer of costume jewelry; and Realogy, the real estate franchisor.[56]
In August 2006, Apollo launched a $2 billion publicly traded private equity vehicle in Europe, AP Alternative Assets (ENXTAM:AAA).[54] The IPO of this new vehicle followed in the footsteps of Kohlberg Kravis Roberts, which raised $5 billion for its KKR Private Equity Investors vehicle in May 2006.[57] Apollo initially attempted to raise $2.5 billion for the public vehicle but fell short when it offered the shares in June, raising only $1.5 billion. Apollo raised an additional $500 million via private placements in the weeks following that sale.[58]
Between 2006 and 2007, as the private equity industry expanded, several of the largest private equity firms, most notably The Blackstone Group and Kohlberg Kravis Roberts, announced plans to realize value from their firms through the sale of shares in the public equity markets. Apollo Management chose a different path and completed a private placement of shares in its management company in July 2007. By pursuing a private placement rather than a public offering, Apollo was able to avoid much of the public scrutiny applied to Blackstone and KKR.[54][59] In November 2007, Apollo was able to realize additional value from the sale of a 9% ownership interest in its management company to the Abu Dhabi Investment Authority (ADIA).[60] Ultimately, in April 2008, Apollo filed with the U.S. Securities and Exchange Commission (SEC)[61] to permit some holders of its privately traded stock to sell their shares on the New York Stock Exchange. That same year, the firm opened an office in India, marking their first push into Asia.[62]
As the deterioration of the financial markets worsened into 2008, Apollo saw several of its investments come under pressure. Apollo's 2005 investment in the struggling US retailer Linens 'n Things suffered from a significant debt burden and softening consumer demand. In May 2008, Linens filed for bankruptcy protection, costing Apollo all of its $365 million investment in the company.[63][64] At the same time, Apollo's investment in Claire's, Realogy and Harrah's Entertainment came under pressure.[56] Apollo responded to its investment difficulties by seeking to exchange a portion of the existing debt at Harrah's and Realogy to more favorable securities.[65] At Claire's, Apollo exercised its "PIK toggle" option to shut off cash interest payments to its bondholders and instead issue more debt, in order to provide the company with additional financial flexibility.[66]
In December 2008, Apollo completed fundraising for its latest fund, Apollo Investment Fund VII, with approximately $14.7 billion of investor commitments.[67] Apollo had been targeting $15 billion, but had been in fundraising for more than 16 months, with the bulk of the capital raised in 2007.[68]
In December 2009, it was announced that Apollo would acquire Cedar Fair Entertainment Company shares and the company would become private underneath the management group.[69] The deal includes a cash payment of $635 million and assumed debt which gives the transaction a value of $2.4 billion.[70] It was later announced in April 2010 that the deal was pulled due to poor shareholder response.[71]
2011''2017 Edit In January 2011, Apollo acquired 51% of Alcan Engineered Products from Rio Tinto.[72]
In March 2011, Apollo completed its initial public offering (NYSE: APO).[73]
In March 2012, Apollo made a second attempt to acquire an amusement park operator with a $225.7 million offer for Great Wolf Resorts.[74] In November 2012, Apollo acquired The McGraw-Hill Companies' education division ("McGraw-Hill Education") in a deal totaling $2.5 billion.[75]
On March 11, 2013, Apollo Global Management made the only bid for the snacks business of Hostess Brands, including Twinkies, for $410 million.[76] Apollo bought a portfolio of Irish home loans from Lloyds Bank in December 2013 for '‚¬307m, less than half their nominal £610m ('‚¬367m) value.[clarification needed ] The shares were bought by an Apollo Global Management subsidiary, Tanager Limited. The portfolio made a £33m loss last year.[77]
In January 2014, Apollo and CEC Entertainment, the parent company of Chuck E. Cheese's, announced that Apollo bought the company and its brand for about $1 billion.[78]
In October 2014, Apollo finalized the merger of its Endemol television studio with 21st Century Fox's Shine Group. The merged company became Endemol Shine Group, with AGM and Fox each owning half of the studio.[79]
On March 24, 2015, Centerbridge Partners reached an agreement with Apollo to acquire the Great Wolf chain from them for $1.35 billion.[80] The acquisition was finalized on May 12, 2015.[81]
In June 2015, Apollo Global Management made a successful offer of around $1.03 billion in cash to privatize OM Group.[82] Also that month, Apollo won the bidding during an auction for Saint-Gobain's Verallia glass bottle manufacturing unit for a rumored fee of around 2.95 billion.[83]
In February 2016, ADT Corporation agreed to be acquired by Apollo Global Management.[84] Apollo Education Group[85] shareholders approved a merger with Apollo Global Management in May 2016. Apollo Education is the parent company of the University of Phoenix. In June 2016, Apollo Global Management made a successful offer to purchase Diamond Resorts International.[86] Apollo made a successful offer to purchase Rackspace in August 2016.[87]
In May 2017, Apollo announced that it had entered into an agreement to acquire West Corp for approximately $2 billion.[88] In December, Apollo agreed to acquire Mexican restaurant chain Qdoba from Jack in the Box.[89]
In November 2017, Apollo Global Management loaned $184 million to Kushner Companies.[90]
2018''2019 Edit AGM was in talks to buy Nexstar Media Group for over $1 billion.[91] However, on February 14, 2019, Cox Media Group announced that it was selling its 14 television stations to AGM.[92] In March 2019 filings with the Federal Communications Commission (FCC), Apollo disclosed that, through the newly formed Terrier Media, the Cox stations would be acquired for $3.1 billion (to be reduced by the value of a minority equity stake in Terrier that will be retained by Cox Enterprises); Terrier will also concurrently acquire Northwest Broadcasting, giving the company 25 television stations.[93] On June 26, 2019, Cox announced that its 60 radio stations, as well as its national advertising business CoxReps, and local OTT advertising agency Gamut, would also be acquired by the new company, which concurrently announced that it would retain the Cox Media Group name instead of Terrier Media.[94] On February 10, 2020, Cox Enterprises bought back the Ohio newspapers it sold to AGM. The FCC required Apollo to reduce the daily newspapers to three days or sell them.[95]
On April 16, 2019, AGM announced that it would once again acquire Smart & Final for $1.1 billion.[96] On June 10, 2019, AGM announced that it would acquire Shutterfly for $2.7 billion, as well as its competitor Snapfish in a separate transaction valued at around $300 million. Apollo plans to merge both companies into a single entity, with Snapfish parent company District Photo as a minority stakeholder.[97] In August, AGM agreed to provide approximately $1.8 billion of debt financing to support New Media Investment Group Inc.'s acquisition of Gannett.[98] On October 23, 2019, AGM announced it signed agreements to take a 48.6% stake in Italian gambling group Gamenet SPA.[99][100] On October 26, 2019, Apollo and The Walt Disney Company agreed to sell Endemol Shine Group to French studio Banijay Group.[101] The sale was completed on July 3, 2020.[102]
2020''present Edit At the end of March 2020, Apollo Global Managed reported $315.5 billion of assets under management.[103][104] In April 2020, AGM announced that it would invest $300 million in Cimpress, an Irish-domiciled printing group that owns Vistaprint.[105] In May, AGM announced the purchase of $1.75 billion of preferred stock in Albertsons Companies.[106] In July 2020, it was reported that the company totalled around $100 billion in investments for war chest in the second quarter of 2020. The sum was double the company's previous record despite the effects of the COVID-19 pandemic.[107]
In March 2021, Apollo managed a $110 million mezzanine credit facility between LendingPoint and MidCap Financial Trust.[108]
On May 3, 2021, Apollo announced its intention to acquire Verizon Media (which includes AOL, Yahoo!, and Verizon Digital Media Services properties) from Verizon for $5 billion. Verizon will retain a 10% stake in the new company, which will be named Yahoo.[109]
Operations Edit Apollo is operated by its managing partners, Leon Black, Joshua Harris, and Marc Rowan and a team of more than 400 investment professionals, as of June 30, 2019. The firm's headquarters are located in the Solow Building at 9 West 57th Street[110] in New York City, with offices in Purchase, New York, Los Angeles, San Diego, El Segundo, Woodland Hills, Houston, Bethesda, London, Frankfurt, Luxembourg, Madrid, Singapore, Hong Kong, New Delhi, Powai, Shanghai, Tokyo, and Mumbai.[6]
Apollo's executive committee includes: Leon Black, chairman, and chief executive officer; Josh Harris, Co-Founder and Senior Managing Director; Marc Rowan, Co-Founder, and Senior Managing Director; Scott Kleinman, Co-President and Lead Partner, Private Equity; James Zelter, Co-President and Chief Investment Officer, Credit; and Gary Parr, Senior Managing Director.[111]
Apollo operates three business lines in an integrated manner:
Private equity: The private equity business is the cornerstone of Apollo's investment activities. Apollo invests through a variety of private equity strategies, most notably leveraged buyouts and distressed buyouts and debt investments. This business operates primarily through the firm's family of private equity investment funds (See: Investment funds).[61]Credit: Apollo invests through a variety of credit strategies to complement its core private equity business. Apollo invests through a variety of investment vehicles including mezzanine funds, hedge funds, European non-performing loan funds and senior credit opportunity funds.[112]Real Estate: Apollo Global Real Estate (AGRE) was established in 2008 to build upon Apollo's history of investing in real estate-related sectors such as hotels and lodging, leisure and logistics. AGRE manages a number of debt and equity-oriented real estate investment funds.[112]Investment vehicles Edit Private equity funds Edit Apollo has historically relied primarily on private equity funds, pools of committed capital from pension funds, insurance companies, endowments, fund of funds, high-net-worth individuals, family offices, sovereign wealth funds and other institutional investors. Since 2014, Apollo has begun investing its eighth private equity fund, Apollo Investment Fund VIII, which raised approximately $18 billion of investor commitments. In 2017, Apollo raised $24.6 billion for its ninth flagship private equity fund, making it the largest in history.[113] Since its inception in 1990, Apollo has raised a total of nine private equity funds, including:[34]
FundVintageYearCommittedCapital ($m)Apollo Investment Fund IX2017$24,600Apollo Investment Fund VIII2014$18,400Apollo Investment Fund VII[68]2008$14,700Apollo Investment Fund VI2005$10,200Apollo Investment Fund V2001$3,700Apollo Investment Fund IV1998$3,600Apollo Investment Fund III1995$1,500Apollo Investment Fund II1992$500Apollo Investment Fund I1990$400Apollo Investment Corporation Edit Apollo Investment Corporation is a US-domiciled publicly traded private equity closed-end fund and an affiliate of Apollo. AIC was formed to invest primarily in middle-market companies in the form of mezzanine debt and senior secured loans, as well as by making certain direct equity investments in companies. The company also invests in the securities of public companies.[53][54]
AIC is structured as a business development company, a type of publicly traded private equity vehicle that is designed to generate interest income and long-term capital appreciation. AIC historically has not invested in companies controlled by Apollo's private equity funds.[116]
AP Alternative Assets Edit AP Alternative Assets (Euronext: AAA) is a Guernsey-domiciled publicly traded private equity closed-end limited partnership, managed by Apollo Alternative Assets, an affiliate of Apollo Management. AAA was formed to invest alongside Apollo's main private equity funds and hedge funds.[53][54]
AAA was launched in August 2006, shortly after Kohlberg Kravis Roberts completed a $5 billion initial public offering for its KKR Private Equity Investors vehicle in May 2006.[54][57] Apollo raised a total of $2 billion for AAA including the vehicle's $1.5 billion IPO and a subsequent private placement.[58]
AAA's investment portfolio is made up of a mix of private equity and capital markets investments.[117]
Portfolio investments Edit Apollo has been an active private equity investor through the mid-2000s buyout boom. The following is a list of Apollo's most recent and currently active private equity investments. The bulk of these investments are held in Apollo Investment Fund V, VI, and VII.
InvestmentYearCompany DescriptionRef.Cox Media Group2019In December 2019, it was announced that Apollo closed the $3 billion deal which acquired the majority share of Cox Media Group. This deal entails Cox's 13 television stations, 54 radio stations, 3 newspapers, national television advertising business '' CoxReps, and local OTT advertising business '' Gamut. Smart Media from Cox.[118][119][120][121]Tech Data Corp.2019In November 2019, it was announced that Apollo acquired Florida-based Tech Data Corp. in a deal worth $5.4 billion, snatching it from Warren Buffett's Berkshire Hathaway.[122][123]GE Capital Energy Financial Services2018In October 2018, Apollo announced to have acquired a portfolio of $1 billion in energy investments of GE Capital's Energy Financial Services unit.[124]Apollo Education Group2017In February 2017, Apollo announced the acquisition of Apollo Education, the parent company of University of Phoenix, for $1.14 billion.[125][126]Diamond Resorts2016On June 29, 2016, Apollo Global Management made a successful offer to purchase Diamond Resorts International.[127]Berry Plastics2006In June 2006, Apollo and Graham Partners announced the acquisition of Berry Plastics Corporation, a maker of plastic containers, for $2.25 billion from Goldman Sachs Capital Partners and JPMorgan Partners.[128]Chuck E. Cheese's2014In 2014, Apollo bought CEC Entertainment, the parent of Chuck E. Cheese's Restaurants.Claire's2007In March 2007, Apollo announced the $3.1 billion leveraged buyouts of costume jewelry retailer, Claire's Stores. In 2008, Claire's experienced financial difficulty amid the slump in consumer spending.[129][130]Constellis2016Apollo bought Constellis Holdings in 2016 for $1 billion. Constellis is a private military contractor that was created as a result of a merger between rival contractors Triple Canopy and Academi in 2014. Academi, founded by Erik Prince and formerly known as Blackwater USA, is best known for its role in the Nisour Square Massacre, where Blackwater guards killed 17 Iraqi civilians and injured 20.[131][132][133][134]Countrywide plc2007In May 2007, Apollo acquired Countrywide plc, the leading provider of residential property related services in the UK, formerly known as Hambro Countrywide (1988) and Countrywide Assured Group (1998) for $1.05 billion (not related to Countrywide Financial).[135]CEVA Logistics2006In August 2006, TNT N.V. announced that it had agreed to the sale of its logistics division to Apollo for $1.9 billion. The business was re-branded as CEVA in November 2007.[136]Debt investments2008''2009Since the beginning of 2008, Apollo has been a significant acquirer of senior secured loans from investment banks and other financial institutions. In April 2008, Apollo, TPG Capital, and The Blackstone Group completed the acquisition of $12.5 billion of bank loans from Citigroup. The portfolio comprised primarily senior secured leveraged loans that had been made to finance leveraged buyout transactions at the peak of the market. Citigroup had been unable to syndicate the loans before the onset of the credit crunch. The loans were reported to have been sold in the "mid-80 cents on the dollar" relative to face value. In late 2008, it was reported that Apollo had received margin calls associated with the financing of its purchase of certain loan portfolios as the price of the loans decreased.[137][138][139]Great Wolf Resorts2012In March 2012 Apollo announced plans to acquire the resort's chain for $703 million. Reports indicated the chain had not turned a profit since 2008.[140]Harrah's Entertainment2006On December 19, 2006, Apollo and TPG Capital announced an agreement to acquire the gaming company for $27.4 billion, including the assumption of existing debt.[141]Hexion Specialty Chemicals2005Hexion was formed in 2005 through the merger of Borden Chemical, Inc., Resolution Performance Products LLC, and Resolution Specialty Materials LLC, and the acquisition of Bakelite AG. Hexion announced in July 2007 that it was acquiring Huntsman Corporation, a major specialty chemicals company, in a $6.5 billion leveraged buyout. Hexion announced in June 2008 it would refuse to close the deal, prompting a series of legal actions. The transaction was officially terminated on December 14 after a settlement between Hexion and Huntsman, wherein they were required to pay Huntsman $1 billion to drop fraud charges that would have potentially sent the CEO of Apollo to prison.[142][143]Jacuzzi Brands2006In October 2006, Apollo announced a $990 million leveraged buyout of Jacuzzi Brands, the manufacturer of whirlpool baths.[144]McGraw-Hill Education2012In November 2012, McGraw Hill announced that it had agreed to the sale of its education division to Apollo for $2.5 billion.[145]Momentive Performance Materials2006In June 2006, Apollo acquired General Electric's Advanced Materials (Silicones & Quartz) business in a deal valued at approximately $3.8 billion.[146]Noranda Aluminum2007In April 2007, Apollo acquired the US aluminum business of the mining company Xstrata for $1.15 billion. The aluminum business, Noranda Aluminum, includes a primary smelter and three rolling mills in Tennessee, North Carolina, and Arkansas along with other operations.[147]Norwegian Cruise Line2008In January 2008, Apollo completed a $1 billion investment in the cruise line operator to support a recapitalization of the company's balance sheet.[148]Novitex Enterprise Solutions2013In 2013, Apollo acquired Pitney Bowes Management Services (PBMS) for $400 million. From PBMS, Apollo formed Novitex Enterprise Solutions. Novitex is a document outsourcing provider that manages business-critical services for over 500 companies across ten industries. Many of its clients are Fortune 500 companies.[149][150]Oceania Cruises2007In February 2007, Apollo acquired the luxury cruise line and provided additional capital to fund the expansion of the company with the purchase of two new cruise ships.[151][152]Philips Lumileds2017In June 2017, Apollo bought 80.1% of Philips Lumileds division for $1.5 billion.[153][154]Realogy:Coldwell BankerSotheby's International RealtyCentury 21 Real Estate2006In December 2006, Apollo announced an $8.5 billion buyout of the real estate franchisor that owns Coldwell Banker, Century 21 and Sotheby's International Realty. The transaction closed in April 2007 and was delisted from the New York Stock Exchange. As the housing market crash accelerated in 2008, Realogy faced financial pressures relating to its debt load. In November 2008, Realogy launched an exchange offer for a portion of its debt to provide additional flexibility, prompting a lawsuit from Carl Icahn.[65][155][156][157]Regent Seven Seas Cruises2008In February 2008, Apollo purchased the luxury cruise line from Carlson Companies for $1 billion. Following the purchase, Apollo made public its plans to order a new ship for Regent.[158]Rexnord Corporation2006In May 2006, Apollo announced the acquisition of the manufacturer of precision motion technology products, primarily focused on power transmission, from private equity firm The Carlyle Group for $1.825 billion.[144][159]Smart & FinalHenry's MarketplaceSprouts Farmers Market2007In February 2007, Apollo announced the acquisition of the Smart & Final chain of warehouse-style food and supply stores. In June 2007, Smart & Final completed the acquisition of the Henry's Marketplace chain of "farmers market" style food retailers from Wild Oats Markets as part of that company's acquisition by Whole Foods Market. In 2011, the Henry's chain was merged with Sprouts Farmers Market, which, like the Henry's markets, had been founded by Henry Boney.[160][161][162][163]
Thai Ornament Resorts2016In January 2016, Apollo announced the acquisition of Thai Ornament Resorts, an upscale destination resort developing firm, for $75.8 million from Tri-Cities Partnership and The Pool Trust.[164]Vantium Management2008In May 2008, Apollo invested in Vantium, a company that buys residential mortgage assets as part of a strategy to profit from the housing market crash.[165]Verso Paper2006In 2006, Apollo acquired International Paper's coated and supercalendered paper business for $1.4 billion, renaming the business, Verso Paper. Verso has been the second-largest producer for the North American magazine publishing and catalog/commercial print markets. In May 2008, Verso was able to complete an initial public offering of stock.[166][167]Other investments include Connections Academy and Unity Media GMBH.
Affiliated businesses Edit From its inception, Apollo was built as part of a network of affiliated businesses focusing on private equity and a variety of distressed investment strategies.
Lion Advisors Edit Lion Advisors (or Lion Capital), which was founded at the same time as Apollo in 1990, focused on investment management and consulting services to foreign institutional accounts targeting investments in public and private high yield debt securities in the US. In 1992, Lion entered into a more formal arrangement to manage the $3 billion high-yield portfolio for Credit Lyonnais which together with a consortium of other international investors provided the capital for Lion's investment activities. The Lion business would ultimately be replaced by Ares Management.[168]
Ares Management Edit Ares Management, founded in 1997, was initially established to manage a $1.2 billion market value collateralized debt obligation vehicle. Ares would grow to manage a family of collateralized loan obligation (CLO) vehicles that would invest in capital markets-based securities including senior bank loans and high-yield and mezzanine debt. Ares was founded by Antony Ressler and John H. Kissick, both partners at Apollo as well as Bennett Rosenthal, who joined the group from the global leveraged finance group at Merrill Lynch.[169]
Ares I and II which were raised were structured as market value CLOs. Ares III though Ares X was structured as cash flow CLOs. In 2002, Ares completed a spinout from Apollo management. Although technically, the founders of Ares had completed a spinout with the formation of the firm in 1997, they had maintained a close relationship with Apollo over its first five years and operated as the West Coast affiliate of Apollo. Shortly thereafter, Ares completed fundraising for Ares Corporate Opportunities Fund, a special situations investment fund with $750 million of capital under management.[168][169]
In 2004, Ares debuted a publicly traded business development company, Ares Capital Corporation (NASDAQ:ARCC).[170] In 2006, Ares raised a $2.1 billion successor special situations fund (Ares Corporate Opportunities Fund II).[169]
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"Opening Private Equity's Door, at Least a Crack, to Public Investors." The New York Times, May 4, 2006. ^ a b Apollo equity fund IPO falls short of its target. International Herald Tribune, June 9, 2006 ^ Sorkin, Andrew Ross and De La Merced, Michael J. "Buyout Firm Said to Seek a Private Market Offering." The New York Times, July 18, 2007. ^ Apollo chief says sold nine percent of firm to Abu Dhabi. Reuters, November 7, 2007 ^ a b Apollo Global Management, LLC, Form S-1, Securities And Exchange Commission, April 8, 2008 ^ Forget slowdown, PEs still heading to India. The Economic Times, August 8, 2008 ^ a b Bankruptcy Protection for Retailer. New York Times, May 3, 2008 ^ Apollo Struggles to Keep Debt From Sinking Linens 'n Things. The New York Times, April 14, 2008 ^ a b An End Run Around Realogy's Lenders. The New York Times, November 27, 2008 ^ PIK and Roll: Companies Seize On Perks of Loose Lending. 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Retrieved July 1, 2020 . ^ Vandevelde, Mark (July 30, 2020). "Apollo adds $100bn to war chest in second quarter". Financial Times . Retrieved July 30, 2020 . ^ "LendingPoint Closes $110MM Mezzanine Facility with Midcap Financial Trust and Apollo". ABL Advisor. March 10, 2021. ^ "Verizon offloads Yahoo and AOL in $5 billion deal". CNN. May 3, 2021. ^ Business People; Taking Tyco's View. The New York Times, February 29, 2004 ^ "About Apollo Global Management". www.apollo.com . Retrieved January 13, 2019 . ^ a b Amendment No. 8 to Form S-1 ^ Dasha Afanasieva (July 27, 2017). "Apollo raises $24.6 billion for largest private equity fund ever". Reuters. ^ a b Apollo Investment (AINV) annual SEC income statement filing via Wikinvest. ^ a b Apollo Investment (AINV) annual SEC balance sheet filing via Wikinvest. ^ Apollo Investment Corporation: Portfolio Companies Archived February 27, 2009, at the Wayback Machine (company website) ^ Apollo Alternative Assets: Investment Strategy (company website) Archived January 29, 2009, at the Wayback Machine ^ "Cox Enterprises Announces Close of Cox Media Group Sale to Affialiates of Apollo Global Management". PR NEWSWIRE . Retrieved May 26, 2020 . ^ "Cox Enterprises to Sell Majority Stake in TV Stations to Apollo". The Atlanta Journal Constitution . Retrieved May 26, 2020 . ^ "It's Official: Cox Radio, Gamut, CoxReps Going to Apollo". Radio+Television Business Report . Retrieved May 26, 2020 . ^ "It's Official: Cox, Apollo Agree to Private Company". Dayton Daily News . Retrieved May 26, 2020 . ^ Coffey, Lauren (November 13, 2019). "Tech Data acquired in $5.4 billion deal". 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"Harrah's Is Said to Be in Talks to Accept $16.7 Billion Buyout." The New York Times, December 18, 2006. ^ Manufacturer of Chemicals Agrees to Bid From Apollo. The New York Times, July 13, 2007 ^ Huntsman Settles With Apollo, The New York Times, December 14, 2008 ^ a b Jacuzzi Brands Is Going Private. Reuters, October 12, 2006 ^ "McGraw-Hill to Sell Education Unit to Apollo for $2.5 Billion". The New York Times. November 26, 2012. ^ Apollo Management to buy GE Advanced Materials Business. AltAssets, September 18, 2006 Archived June 8, 2008, at the Wayback Machine ^ Mine Company Sells U.S. Unit. The New York Times, April 12, 2007 ^ Closes $1 Billion Investment by Apollo Archived February 26, 2009, at the Wayback Machine. Reuters, January 7, 2008 ^ Apollo Global Management to Acquire Management Services Business from Pitney Bowes. Pitney Bowes Inc, July 30, 2013 ^ "News & Insights '' Document Outsourcing '' Novitex" (PDF) . Archived from the original on June 17, 2014 . Retrieved July 4, 2016 . ^ Oceania Cruises sold to new owners. USA Today, February 27, 2007 Archived September 5, 2007, at the Wayback Machine ^ Oceania Cruises Closes A Transaction With Apollo Management: Completes $850 Million Strategic Partnership. Oceania Cruises press release, April 30, 2007 Archived December 5, 2008, at the Wayback Machine ^ "Philips completes sale of 80.1% interest in Lumileds to funds managed by affiliates of Apollo Global Management". August 10, 2017. [permanent dead link ] ^ "Philips to Sell Lumileds to Apollo". Bloomberg Technology . Retrieved August 10, 2017 . ^ Latest Deal in Real Estate for $9 Billion. The New York Times, December 18, 2006 ^ "Apollo Management, L.P. Completes Acquisition Of Realogy Corporation". Realogy. Archived from the original on September 27, 2007 . Retrieved June 5, 2007 . ^ Icahn Sues Real Estate Company Over Debt. The New York Times, December 2, 2008 ^ Apollo to buy cruise company Regent Seven Seas Cruises. AltAssets, December 12, 2007 Archived December 2, 2008, at the Wayback Machine ^ Carlyle to sell Rexnord Corporation to Apollo for $1.8bn. AltAssets, May 25, 2006 Archived March 7, 2008, at the Wayback Machine ^ Smart & Final sells to Apollo Management affiliate in $813.9M deal. Los Angeles Business, February 20, 2007 ^ Whole Foods Deal. Bloomberg, June 21, 2007 ^ Hamstra, Mark (February 16, 2011). "Apollo Combines Sprouts, Henry's". Supermarket News. Penton Media, Inc . Retrieved December 4, 2011 . ^ Crabtree, Penni (February 27, 2011). "Merger of Henry's, Sprouts is latest in Boney family's retail saga". SignOn San Diego. The San Diego Union-Tribune . Retrieved December 4, 2011 . ^ "Cotton ornaments, 'Happy Thai Horses' (set of 4)" . Retrieved July 4, 2016 . ^ Apollo Management Invests in Buyer of Mortgage Assets. The New York Times, May 28, 2008 ^ Verso Paper turns a page with IPO; President & CEO Mike Jackson credits a foundation document, focused strategies, and talented employees for company's success. Paper360, Oct 2008 ^ Verso Paper Sets I.P.O. Range. The New York Times, April 29, 2008 ^ a b Ares Enhanced Loan Investment Strategy IR, Ltd. Prospectus. September 22, 2008 [dead link ] ^ a b c Ares Management to Take New Fund Public. Los Angeles Times, April 22, 2004 ^ Ares Capital IPO Raises $165 Million. Los Angeles Times, October 6, 2004 External links Edit Media related to Apollo Global Management at Wikimedia Commons Official website Cox Media GroupGamut. Smart Media from Cox.McGraw-Hill EducationQdoba Mexican EatsADT Inc.Business data for Apollo Global Management, LLC:
Who is Boris Nikolic? Epstein-named executor is former Bill Gates adviser | Fox Business
Wed, 02 Jun 2021 17:38
One of the men named in Jeffrey Epstein's will as potentially being responsible for carrying it out says he was unaware he was included.
Epstein, the financier and convicted sex offender, signed a will detailing nearly $600 million in assets just two days before he killed himself in a Manhattan jail cell. In the will, he named biotech venture capitalist Boris Nikolic as ''successor executor,'' the person who would take control of the estate if the two named executors are unable or unwilling to.
Nikolic, 49, said in a statement that he was ''shocked'' that he was included.
A spokesperson for Nikolic confirmed to FOX Business that he "was never consulted on these matters and has no intent to fulfill these duties, whatsoever."
Court records show the two executors, Darren K. Indyke and Richard D. Kahn, each signed an oath confirming their willingness to serve as executor. But no such oath was filed by Nikolic.
Nikolic is a physician who completed postdoctoral training at Harvard Medical School, where he also served as an assistant professor. He previously served as chief advisor for science and technology to Bill Gates.
WASHINGTON, DC - JULY 21: Bill Gates and Boris Nikolic attend Together To End AIDS: An Evening To Benefit amfAR and GBCHealth at John F. Kennedy Center for the Performing Arts on July 21, 2012 in Washington, DC. (Photo by Paul Morigi/Getty Images)
As co-founder and managing director of health care and life sciences venture investing firm Biomatics Capital, Nikolic sits on the boards of directors for several of its portfolio companies.
A spokesperson for Nikolic told FOX Business that he and Epstein had no business ties. Nikolic has a broad network in the scientific world that overlapped with Epstein's at points.
Both men were clients of the private bank at JPMorgan Chase & Co., where several people familiar with the matter told Bloomberg Epstein helped bankers attract lucrative new clients.
FILE - This March 28, 2017, file photo, provided by the New York State Sex Offender Registry shows Jeffrey Epstein. A judge denied bail for jailed financier Jeffrey Epstein on sex trafficking charges Thursday, July 18, 2019, saying the danger to the
The executors of Epstein's will receive $250,000. The document tallies cash and investments he said he had just before his death, which were then organized into a trust. The only potential beneficiary named is Epstein's brother, Mark.
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For Billionaire Glenn Dubin, the Epstein Saga Isn't Over | Vanity Fair
Wed, 02 Jun 2021 17:32
Many secrets died with Jeffrey Epstein, the high-society pedophile, philanthropist, and financier whose inner circle included princes, a former prime minister, and a former president. But the search for answers continues in New York, where Epstein held court for years before hanging himself in federal prison. One of Epstein's more puzzling relationships was the one he had with Glenn Dubin, the billionaire hedge fund manager, and his wife, Dr. Eva Andersson-Dubin, the founder of the Dubin Breast Center of the Tisch Cancer Institute at the Mount Sinai Medical Center. Could one of Manhattan's most prominent power couples know more about the Epstein mystery?
The three were close, after all. Andersson-Dubin, a former Miss Sweden, dated Epstein for years before she and Dubin married in 1994. Even after Epstein's conviction in 2008, the couple stayed in contact with the registered sex offender, inviting him to Thanksgiving dinner at their home in Palm Beach the following year. Andersson-Dubin also wrote an email to Epstein's probation officer, asserting that she was ''100% comfortable with Jeffrey Epstein around my children,'' who were then all minors. Multiple sources told me last month that Epstein was the godfather to the Dubins' three children, although a spokesman for Dubin disputed that assertion. (''The Dubins are Jewish and Jewish people do not typically do godparents,'' he said.)
Epstein and Dubin had business ties as well. Epstein introduced Dubin to Jes Staley, then a senior executive at JPMorganChase & Co. and now the CEO of Barclays, the big British bank. After JPMorganChase bought control of Highbridge Capital, Dubin's hedge fund, in stages, starting in 2004, Epstein reportedly received a $15 million fee. Dubin also directed some of Epstein's money, for which Epstein was a fiduciary, to at least two hedge fund managers'--Dan Zwirn and Joseph Kusnan'--who once worked at Highbridge before starting their own firms. ''Glenn Dubin introduced me to Epstein as a new manager that he was familiar with and thought highly of,'' Kusnan wrote me in an email, though he and Epstein met only once, he said, and never communicated again beyond Kusnan delivering ''a good rate of return on his modest investment.''
The relationship between Epstein and Dubin also ventured into more controversial realms, if one believes the depositions recently unsealed in an old court case between one of Epstein's alleged victims, Virginia Giuffre, and Epstein's longtime companion and alleged madam, Ghislaine Maxwell. According to Giuffre's May 2016 deposition, Dubin was the ''first'' powerful person that Maxwell sent her to have sex with ''after my training.'' She also said that she was instructed by Maxwell to have sex with, among others, Alan Dershowitz, the Harvard Law professor; George Mitchell, the former U.S. senator; Bill Richardson, the former New Mexico governor; and Jean-Luc Brunel, a French model scout. ''My whole life revolved around just pleasing these men and keeping Ghislaine and Jeffrey happy,'' Giuffre said in her deposition. ''[Maxwell and Epstein's] whole entire lives revolved around sex. They call massages sex. They call modeling sex.'' She said Maxwell told her to give Dubin ''a massage.'' (The Dubins categorically deny Giuffre's allegations. Their spokesperson also provided evidence they say disproves Giuffre's account. Dershowitz, Mitchell, Richardson, and Brunel have also denied her allegations.)
Then there is Rinaldo Rizzo's June 2016 deposition, which was also recently unsealed. Rizzo and his wife, Debra, worked for the Dubins, primarily as their full-time chefs, but they did other work for the Dubins too, such as tagging their luggage for the private jet trips and generally being helpful with travel to and between the Dubins' various homes in Palm Beach; Westchester County; Gothenburg, Sweden; Manhattan; and a sprawling ranch in Gunnison, Colorado. According to the deposition, Rizzo and his wife were preparing dinner for the Dubins in the kitchen of one of their homes when Andersson-Dubin brought in a 15-year-old Swedish girl who had accompanied Epstein and Maxwell on this visit to the Dubins' home.
Rizzo testified that in late 2004 or early 2005, Andersson-Dubin told the unnamed girl to sit on a barstool in the kitchen. She seemed to be ''distraught'' and ''upset,'' Rizzo said, ''and she was shaking.'' She didn't want to talk, her head was down, and Rizzo thought she was ''on the verge of crying.'' According to the deposition, the girl told him and his wife that she worked for Epstein as his ''executive personal assistant,'' and when Rizzo expressed shock that such a young girl could have that job, ''she just breaks down hysterically.'' Rizzo stated that the girl told him she was involved in some forced sexual activity at Epstein's Caribbean island and was told by Maxwell and Epstein not to discuss it. Rizzo said he and his wife were dumbfounded. ''We hear people approach and she just shuts up,'' Rizzo testified. ''Eva comes in and tells her that she will be working for Eva in the city as a nanny.''
But about a month later, according to Rizzo, the Dubins, along with the girl and the Rizzos, were on Dubin's private jet back to Sweden and the girl was returned home. ''We flew to Sweden,'' Rizzo said in his deposition, ''we stopped at an airport we didn't usually stop at and she got off the plane.'' The Rizzos left the Dubins' employ in October 2005, following those events, he said in his deposition. ''My wife and I had discussed these incidents, and this last one was just, we couldn't deal with it,'' he said.
The Dubins vehemently deny that any such incident had taken place. ''There was never a 15-year-old Swedish nanny in the Dubins' home and flight records for trips to Sweden on the Dubins' plane do not include any minors other than family members,'' said the spokesperson, who shared the records. The Dubins also provided the testimony of their longtime live-in nanny, who attested ''with certainty'' that the couple had never employed an underage nanny. (Attempts to reach the Rizzos were unsuccessful.)
The spokesperson did confirm, however, that Dubin and his family traveled with Epstein on his private jet. Flight records show that Dubin and his family occasionally flew on Epstein's planes, often between Palm Beach and New York, where they both had homes. Ghislaine Maxwell also hitched a ride on Dubin's plane, twice, alongside Dubin's children, on that same route'--once in 2004 and again in 2010, after Epstein was a convicted sex offender. ''Epstein was not on either flight,'' Dubin's spokesman said. Jim Dowd, who piloted jets for both Dubin and Epstein, told me the men were ''friends'' and liked ''vacationing together.'' (The Dubin spokesperson disputed that characterization.) The private jets, Dowd said, gave the two men a way to avoid the delays and tedium of commercial travel. ''The only thing money cannot buy is time,'' he explained. ''These planes are time machines. They save lots of time.''
The Dubins' social circle overlapped with Epstein in New York, too. A source with knowledge of the matter said that Andersson-Dubin was ''friendly'' with Lana Pozhidaeva, the Russian model who was recently in the news for having received a $55,000 donation from Epstein for her New York-based nonprofit, Education Advance. (The Dubin spokesperson insisted the Dubins don't know her.) Pozhidaeva worked for Brunel's modeling agency, MC2 Model Management, and appeared to live in an Upper East Side apartment building where Epstein had been accused of housing underage models. (Pozhidaeva did not respond to multiple emailed requests for comment.)
And then there is the Dubins' link to Leslie Wexner, the billionaire founder and CEO of L Brands'--a retail empire that includes Victoria's Secret'--who was Epstein's only known financial client. It's not unusual, of course, for billionaires to flock together. Wexner's infamous ties to Epstein have been well documented by now, although his friendship with the Dubins has never before been reported. Yes, it was true, Dubin's spokesman told me, that Wexner had allowed the Dubins and their three children the exclusive use of Limitless, Wexner's $100 million, 316-foot private yacht, for a Mediterranean vacation. (Wexner's wife, Abigail, ''graciously invited the Dubins to use their boat for four days while Eva Dubin was recovering from breast cancer surgery,'' Dubin's spokesperson explained.) But according to one source, it was quite unusual for Wexner to let anyone use Limitless when he was not on board.
The source recalled talking to Debra Rizzo, the Dubins' onetime chef, about the trip. ''She was telling me how magnificent this thing was,'' this person said, ''and she said that the captain came over to her and she said he goes, 'I've got to ask you, what does your boss do? Who is he?' And she's like, 'Well, it's Glenn Dubin. He runs a hedge fund.' He's like, 'Oh. I'm just baffled because nobody is allowed on this boat. Nobody. We've never had anybody on this boat other than the owner.' So she said it was like a really, really big deal to them and they were shocked that Dubin was on this thing.'' (A spokesperson for Wexner declined to comment.)
Spike Protein
The Spike Protein is the weapon - Peter McCullough
Zombie Preparedness | CDC
Tue, 01 Jun 2021 14:51
Wonder why zombies, zombie apocalypse, and zombie preparedness continue to live or walk dead on a CDC web site? As it turns out what first began as a tongue-in-cheek campaign to engage new audiences with preparedness messages has proven to be a very effective platform. We continue to reach and engage a wide variety of audiences on all hazards preparedness via ''zombie preparedness''.
Zombie Preparedness BlogThere are all kinds of emergencies out there that we can prepare for.Take a zombie apocalypse for example.
Zombie Preparedness for EducatorsLooking to teach preparedness in the classroom?We've got full lesson plans and activities for you to use or adapt with your students.
Zombie Preparedness Graphic NovelLooking for an entertaining way to introduce emergency preparedness?Check out our graphic novella which uses the idea of a zombie apocalypse to demonstrate the importance of preparedness.Included is a personal preparedness checklist so you can take action once you're done reading.
SCIENCE!
NACI recommends mixing AstraZeneca, Pfizer, Moderna COVID-19 vaccines - National | Globalnews.ca
Tue, 01 Jun 2021 18:56
WATCH: NACI recommends mixing AstraZeneca, Pfizer, Moderna COVID-19 vaccines, Tam says
Canada's National Advisory Committee on Immunization (NACI) has updated its guidance, recommending that approved COVID-19 vaccines can be safely mixed and matched in most scenarios.
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Under the new recommendations released June 1, people who received a first dose of the AstraZeneca vaccine may receive an mRNA vaccine '-- Pfizer-BioNTech or Moderna '-- for their second dose, unless contraindicated.
But it is not recommending AstraZeneca after a first shot of Pfizer or Moderna.
Read more: 2nd COVID-19 shots should be offered 'as soon as possible': NACI
People who have received a first dose of an mRNA vaccine should be offered the same vaccine for their second dose, NACI said. But mRNA vaccines can be interchangeable if the same product is not readily available for the second dose, it added.
In either case, the previous dose should be counted, and the series need not be restarted, the guidance stated.
Advice on mixing vaccine shots based on goal of not wanting vaccine doses to go to waste
The non-binding recommendations were based on a range of factors '-- from safety concerns to vaccine supply, Theresa Tam, Canada's chief public health officer, said during a news conference Tuesday.
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''The interchangeability of vaccines means that you can receive one vaccine product for your first dose and then safely receive a different vaccine for your second dose to complete your two-dose vaccine series for optimal protection from COVID-19,'' Tam said.
''This advice provides provinces and territories with effective options to manage their vaccine programs,'' she added.
''It is good news that people now have the choice.''
Will B.C.'mix and match' COVID-19 vaccines?
Early data from studies in Europe suggests that mixing doses of COVID-19 vaccines is safe and effective.
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Preliminary results from a University of Oxford study published on May 12 found that mixing the Pfizer-BioNtech and AstraZeneca COVID-19 vaccines may increase the frequency of mild to moderate side effects. But these symptoms were short-lived '-- lasting no longer than a few days '-- and there were no hospitalizations or other safety concerns.
Trending Stories
Read more: Mixing COVID-19 vaccines appears safe '-- but no data on whether it works, U.K. study says
Meanwhile, a Spanish study released on May 18 showed that the presence of neutralizing antibodies rose sevenfold after people who already received a first shot of AstraZeneca vaccine were given the Pfizer dose, significantly more than the doubling effect observed after a second AstraZeneca shot.
A nationwide study was also launched in Canada last month to look at the safety and effectiveness of mixing and matching different types of shots.
Albertans being sought for national study on mixing COVID-19 vaccines '' May 20, 2021
Amid concerns of reports of rare blood clots linked with the AstraZeneca vaccine, NACI said several European countries had begun offering an mRNA vaccine as the second dose to those who received a first shot of AstraZeneca.
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The risk of the new blood-clotting syndrome, known as vaccine-induced thrombotic thrombocytopenia, or VITT, was among the considerations for NACI's updated guidance.
''This is not a new concept,'' NACI said.
''Similar vaccines from different manufacturers are used when vaccine supply or public health programs change.''
Read more: 'No A, B list of COVID vaccines': Experts weigh in on NACI's 'mixed messages'
Tania Watts, an immunologist and professor at the University of Toronto, said NACI's new recommendation was ''great news,'' making it easier to get the second dose into people's arms.
While NACI makes recommendations for the use of vaccines approved for use by Health Canada, it is ultimately up to the provinces and territories to implement that advice.
The National advisory Committee on immunization changes to vaccine mixing and matching
Some experts fear that this could lead to wastage of Canada's AstraZeneca supply.
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''It may now be more challenging to get a second dose of the AstraZeneca vaccine into people who remain overly concerned about side effects, despite the fact that VITT, which is quite uncommon, is even less common amongst second-dose recipients,'' said Gerald Evans, an infectious disease specialist at Queen's University in Kingston, Ont.
Study shows COVID-19 vaccine mixing produces 'robust immune response': Dr. Tam
Tam said it remains to be seen what the actual uptake of AstraZeneca will be following the new guidance.
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''We don't want to be ordering vaccines if we're not using it, but it can only be ascertained in a more granular way when we see what the vaccine uptake looks like in the coming days,'' she said.
'-- With files from Global News' Abigail Bimman
(C) 2021 Global News, a division of Corus Entertainment Inc.
Gary Chappell on Twitter: "Indian Bar Association serves legal notice on WHO Chief Scientist Dr Soumya Swaminathan. They claim she "deliberately suppressed the data regarding effectiveness of the drug Ivermectin, with an intent to dissuade the people of I
Mon, 31 May 2021 11:47
Gary Chappell : Indian Bar Association serves legal notice on WHO Chief Scientist Dr Soumya Swaminathan. They claim she "deliberate'... https://t.co/fWjyFImW9s
Sun May 30 19:05:56 +0000 2021
🌸🌸🌸MULUC9🇬🇧🌸🌸 : @GaryChappellDE @pepelep48542643 Good on them!!!
Mon May 31 09:21:22 +0000 2021
Bill Sadler : @GaryChappellDE @MainPerth Bloody awesome the truth is coming out
Mon May 31 09:13:59 +0000 2021
Alan Leonard : @GaryChappellDE @JoHamLew This could be the first 'real' nail in the coffin of this virus.
Mon May 31 09:10:59 +0000 2021
Catherine 🇬🇧 : @GaryChappellDE Good, hopefully many more to come!
Mon May 31 07:45:29 +0000 2021
avcobe : @GaryChappellDE @SharpieDj This has been a part of the active and intense suppression of treatment alternatives to'... https://t.co/IZ7coUmZMe
Mon May 31 07:34:51 +0000 2021
Tim and the Hidden People : @GaryChappellDE https://t.co/Zx3ClBOmyZ
Mon May 31 06:26:19 +0000 2021
VAERS
CDC caught removing Covid vaccine injury reports from VAERS '' NaturalNews.com
Thu, 03 Jun 2021 13:45
(Natural News) Last month, Great Game India published a report about a two-year-old child who died after receiving a Wuhan coronavirus (Covid-19) ''vaccine'' from Pfizer. The case was reported in the Vaccine Adverse Event Reporting System (VAERS), only to later be removed by the U.S. Centers for Disease Control and Prevention (CDC).
Since only children between the ages of five and 11 are ''authorized'' to receive a Chinese Virus injection from Pfizer, Great Game India wanted to know why a two-year-old baby received it, calling on the CDC to fully investigate the situation. Instead, the CDC ignored the request and proceeded to remove the VAERS entry without explanation.
The two-year-old girl in question passed almost immediately after receiving her second dose of Pfizer's experimental mRNA (messenger RNA) injection, instantly developing severe reactions. She ended up dead within just a few days.
News started to spread and many were calling on the CDC to take action, seeing as how it is supposed to act in the best interests of public health. Since the CDC is actually a private corporation that works for Big Pharma, however, nothing was done and the girl's death was quickly scrubbed from the government database.
The fake news media quickly swooped in to defend Big Pharma as well, falsely claiming that children under the age of five were not receiving Wuhan Flu shots at the time. Three ''fact checkers'' from Newsweek all made this patently false claim.
''Vaccine trials for babies as young as six months are underway at least since March,'' reported Great Game India about the facts.
CDC says removal of young girl's death entry was an oopsieMore than 10,000 babies as young as six months old, in fact, were receiving mRNA injections from Pfizer and Moderna as far back as mid-March, which is right around the time the two-year-old girl died from her injection.
Pfizer itself admits this to be true, which makes the Newsweek ''fact check'' laughable. In what way and using what evidence did these ''fact checkers'' come to the conclusion that babies were not yet receiving Pfizer injections as of mid-March, we would like to know?
Right on their website, Pfizer and BioNTech admit that the first doses of Chinese Virus injection administered to children as young as six months old began in March 2021, constituting a three-phase continuous study to learn how the shots are tolerated by babies.
Once the ''fact checkers'' were challenged with the actual facts, they moved on to blaming VAERS for the ''error,'' as the entry showing that a baby had died was removed by the CDC.
Newsweek actually reported on the entry's removal, claiming that the CDC took a ''rare step'' in axing it from the VAERS system. Hilariously, Newsweek's excuse for the CDC action is that the entry must have been '' since the CDC never lies, according to the fake news media '' because it was ''completely made up.''
No further details were provided by Newsweek about how it was determined that the entry was ''made up.'' Somehow, we are all just supposed to believe whatever the fake news and fake science says on any given day about a matter, even if it makes no sense and contradicts itself.
The latest claim is that VAERS is ''unreliable'' and ''noisy,'' and is not to be trusted '' even though it is supposed to be monitored by the federal government. These ''errors'' are to be expected, the establishment claims, because technology is just too hard to get right.
''The good news for a very rare event is it will pop up on VAERS,'' stated Dr. Jesse Goodman, a former chief scientist at the U.S. Food and Drug Administration (FDA), attempting to provide cover for the CDC.
More related news about the mass genocide being invoked by Chinese Virus injections can be found at ChemicalViolence.com.
Sources for this article include:
GreatGameIndia.com
GreatGameIndia.com
NaturalNews.com
The Purge
Russia Monitoring Biden's "Persecution" Of Capitol Hill Rioters & Their "Opposition Rights" | ZeroHedge
Wed, 02 Jun 2021 22:28
Moscow had some stinging words for Washington which were also hilariously ironic on Monday, as both Putin and Biden look ahead to their in-person summit set for June 16 in Geneva. Warning of "uncomfortable" signals to come, the Kremlin indicated that high on the agenda would be a range of human rights and free speech issues in the United States, particularly the "persecution" of those behind the January 6 Capitol riot by the Biden administration.
The words appear Moscow's ultimate trolling response to Biden remarks on Sunday wherein he vowed to confront Putin on egregious human rights abuses: "Of course, we will be ready to discuss everything, including problems that exist in the United States," Lavrov told reporters Monday following Biden's statements. According to AFP:
He said Russia was monitoring the "persecution" of those behind the January 6 riot at the US Capitol.
How an American reacts to something like this is a superb Rorschach Test to measure so many important attributes: https://t.co/lQyTry3VcF
'-- Glenn Greenwald (@ggreenwald) May 31, 2021Lavrov then sarcastically adopted the language and tone of US officials when they frequently lecture foreign adversaries around the world from Russia to Syria to China to Venezuela to Iran, or to any country the US doesn't like. This included Lavrov talking about the US "opposition" and their "rights" while referencing the prior pro-Trump protests and unrest inundating the Capitol.
Lavrov continued:
"A lot of interesting things are happening there," he said, adding that Russia wanted to discuss "protection of opposition rights" in the United States.
The Biden administration has over the past two months heavily focused scathing criticism on the Alexei Navalny saga - frequently holding up the now jailed anti-Kremlin activist (stemming from a prior parole violation and embezzlement case) as leading the "democratic opposition" to Putin's rule, despite before last August's alleged 'nerve agent poisoning' ordeal not having much name recognition at all inside Russia.
Here's what Biden had said in his speech ahead of Memorial Day:
In a speech marking the Memorial Day holiday, Biden said: "I'm meeting with President Putin in a couple weeks in Geneva, making it clear we will not stand by and let him abuse those rights."
He also said that the moment was right to show the world, and namely China, that the US was ready to lead again after four years of a largely inward-looking foreign policy under Donald Trump.
"It's time to remind everybody who we are," he said.
So it appears Russia is ready to punch bad just as hard with its own criticisms, focusing heavily on US double standards and hypocrisy (the Snowden and Assange situations topping the list lately).
The US has also of late focused heavy criticism on Belarus' Lukeshenko and his apparently close relationship with Putin in the wake of the Ryanair incident. The Kremlin has dismissed the West's reaction (which has included expanded sanctions against Belarus) as more "fits of hysteria" - with Putin days ago telling his Belarusian counterpart directly that this is nothing but the latest "emotional outburst" coming from the West.
Great Reset
JBS Ransomware - Cyber - Bitcoin - War on meat
Dean Banks resigns as Tyson Foods president and CEO; Donnie King named successor (UPDATED) - Talk Business & Politics
Wed, 02 Jun 2021 17:50
Springdale-based Tyson Foods said Wednesday (June 2) that president and CEO Dean Banks has resigned from the company and board for personal reasons. Donnie King, the company's chief operating officer, has been named as his successor, effective immediately.
''The board and I know that Donnie has a deep understanding of our business, values and culture and the solid leadership skills needed to continue to implement our strategy and deliver strong results,'' John H. Tyson, chairman of the board, said in a company news release. ''We want to express our appreciation to Dean for his contributions as a board member and executive.''
Banks joined the company as president in 2017 and added the CEO title in October 2020.
''Upon deep personal reflection, and discussions with my family, the board, and my colleagues, I believe that stepping down and concentrating on my family is the right decision at this time,'' Banks said in a statement.
King has more than 36 years of experience in the protein business, holding a variety of executive leadership positions involving virtually all facets of the company including poultry, beef, pork, prepared foods and international. He has also provided executive oversight of other important areas, such as food safety and quality assurance, health and safety, continuous improvement, engineering, and supply chain.
King was promoted to COO earlier this year.
''I'm humbled but excited about leading Tyson Foods, a company that feeds millions of people and means so much to me personally,'' King said in a statement. ''I believe we need to be sharply focused on operating with excellence, executing our strategies, and continuing to innovate across our businesses throughout the world. With our strong leadership team, we are committed to winning with our customers and delivering an outstanding team member experience.''
ANALYSTS REACTTyson Foods' leadership change was unexpected, but Stephens Inc. analyst Ben Bienvenu said King is well suited to fill the role given his industry experience and company knowledge.
''King is very well regarded among investors and has more than three decades of experience in the protein business, having held executive leadership positions in poultry, beef, pork, prepared foods and international. He has increasingly become more visible in the public markets with his responsibilities as COO, and we expect the company's strategic and operational priorities will remain the same following this transition,'' Bienvenu said.
Bienvenu expects to see steady improving results at Tyson Foods in the coming months. Stephens Inc. reiterated its ''buy'' rating on the shares with a price target of $90.
Analysts with Bank of America are not surprised to see Donnie King selected to replace Banks as CEO. The firm thinks King's priority remains a chicken turnaround, as Tyson's chicken segment profitability lags the industry. King recently told Wall Street that the performance in the chicken segment has not been acceptable. His goal is to restore the profits by better serving customers and resolving the hatch issues of last year after a new male used in breeding resulted in less supply.
Peter Galbo at Bank of America said King has a successful track record in the past by improving chicken margins. As a result, Bank of America remains neutral on Tyson Foods, with a target price of $84.
Tyson Foods plans to host an investor meeting this fall, and the company will release more details later.
Shares of Tyson Foods (NYSE: TSN) were unfazed Wednesday morning by the leadership transition, trading at $80.31 up 11 cents. For the past 52 weeks, shares of Tyson Foods have traded between $55.28 and $81.79. The share value is up about 25% year to date.
Talk Business & Politics senior analyst Kim Souza contributed to this report.
The latest magnetic theory
Dr Pierre Gilbert
Le Gouvernement Mondial (Conference 1995)
English translation
In the biological destruction there are the organized tempests on the magentic fields. What will follow is the contamination of the bloodstreams of mankind creating intentional infections. This will be enforced via laws that will make vaccination mandatory. And these vaccines will make it possible to control people. The vaccines will have liquid crystals that will become hosted in the brain cells, which will become micro receivers of electromagnetic fields where waves of very very low frequencies will be sent. And through these low frequency waves people will be unable to think. You'll be turned into a zombie. Don't think of this as an hypothesis... this has been done. Think of Ruanda.
Ship Carrying Auto Parts Sinks Off Japan Coast | ZeroHedge
Tue, 01 Jun 2021 15:27
By Kim Link-Wills of American Shipper
A search is ongoing for three crew members reported missing from a roll-on/roll-off (ro/ro) vessel that sank off the coast of Japan early Friday morning. The MV Byakko sank at about 2:40 a.m. local time after colliding with the chemical tanker Ulsan Pioneer just before midnight in the Seto Inland Sea, Reuters reported. The Byakko reportedly sank about 2.5 miles off the coast of Imabari.
Nine of the Byakko's 12 crew members were said to have been rescued by the Japanese coast guard and nearby ships.
Built just last year, the roll-on/roll-off vessel Byakko sank off the coast of Japan on FridayKyodo News reported that the ship's captain, 66-year-old Tamotsu Sato, was among the missing. Responders also are searching for two of the Byakko's engineers, Japanese men in their 20s.
The 557-foot-long Byakko is operated by Kobe, Japan-based Prince Kaiun Co. According to Kyodo News, the Byakko was carrying auto parts and left Kobe at 4:30 p.m. Thursday bound for Kanda, Japan. The Ulsan Pioneer reportedly departed a port in China on Tuesday and was scheduled to arrive in Osaka, Japan, on Friday afternoon.
There was no word on what types of auto parts the Byakko was carrying. Denso is the largest automotive parts manufacturer in Japan and specializes in electronic systems and powertrain control modules, according to Japan Industry News, which lists the other major suppliers in the country as Aisin Seiki, Yazaki, JTEKT and Hitachi Automotive Systems.
Sebastian Blanco, who follows the automotive industry for FreightWaves, said Toyota has a plant in Kanda and Nissan has one in the region.
On its website, Prince Kaiun lists its primary clients as Nissan Motor Co., Mitsubishi Logistics, Vantec Corp., Sea Link, Tatsumi Shokai, Zero Co. and Koshin Shoun.
The website says the 11,454-ton Byakko was built just last year and that it can carry ''809 commercial vehicles, 113 trailer chassis.'' Byakko is the Japanese word for white tiger.The Ulsan Pioneer, which flies under the flag of the Marshall Islands, was built in 2016.
A cause of the collision has not been reported. According to FreightWaves meteorologist Nick Austin, there were no indications of unusual weather at the time of the accident.
From ''Event 201'' to ''Cyber Polygon'': The WEF's Simulation of a Coming ''Cyber Pandemic'' - unlimitedhangout.com
Mon, 31 May 2021 11:46
On Wednesday, the World Economic Forum (WEF), along with Russia's Sberbank and its cybersecurity subsidiary BI.ZONE announced that a new global cyberattack simulation would take place this coming July to instruct participants in ''developing secure ecosystems'' by simulating a supply-chain cyberattack similar to the recent SolarWinds hack that would ''assess the cyber resilience'' of the exercise's participants. On the newly updated event website, the simulation, called Cyber Polygon 2021, ominously warns that, given the digitalization trends largely spurred by the COVID-19 crisis, ''a single vulnerable link is enough to bring down the entire system, just like the domino effect,'' adding that ''a secure approach to digital development today will determine the future of humanity for decades to come.''
The exercise comes several months after the WEF, the ''international organization for public-private cooperation'' that counts the world's richest elite among its members, formally announced its movement for a Great Reset, which would involve the coordinated transition to a Fourth Industrial Revolution global economy in which human workers become increasingly irrelevant. This revolution, including its biggest proponent, WEF founder Klaus Schwab, has previously presented a major problem for WEF members and member organizations in terms of what will happen to the masses of people left unemployed by the increasing automation and digitalization in the workplace.
New economic systems that are digitally based and either partnered with or run by central banks are a key part of the WEF's Great Reset, and such systems would be part of the answer to controlling the masses of the recently unemployed. As others have noted, these digital monopolies, not just financial services, would allow those who control them to ''turn off'' a person's money and access to services if that individual does not comply with certain laws, mandates and regulations.
The WEF has been actively promoting and creating such systems and has most recently taken to calling its preferred model ''stakeholder capitalism.'' Though advertised as a more ''inclusive'' form of capitalism, stakeholder capitalism would essentially fuse the public and private sectors, creating a system much more like Mussolini's corporatist style of fascism than anything else.
Yet, to usher in this new and radically different system, the current corrupt system must somehow collapse in its entirety, and its replacement must be successfully marketed to the masses as somehow better than its predecessor. When the world's most powerful people, such as members of the WEF, desire to make radical changes, crises conveniently emerge'--whether a war, a plague, or economic collapse'--that enable a ''reset'' of the system, which is frequently accompanied by a massive upward transfer of wealth.
In recent decades, such events have often been preceded by simulations that come thick and fast before the very event they were meant to ''prevent'' takes place. Recent examples include the 2020 US election and COVID-19. One of these, Event 201, was cohosted by the World Economic Forum in October 2019 and simulated a novel coronavirus pandemic that spreads around the world and causes major disruptions to the global economy'--just a few weeks before the first case of COVID-19 appeared. Cyber Polygon 2021 is merely the latest such simulation, cosponsored by the World Economic Forum. The forum's current agenda and its past track record of hosting prophetic simulations demands that the exercise be scrutinized.
Though Cyber Polygon 2021 is months off, it was preceded by Cyber Polygon 2020, a similar WEF-sponsored simulation that took place last July in which speakers warned of a coming deadly ''pandemic'' of cyberattacks that would largely target two economic sectors, healthcare and finance. Cyber Polygon 2020 was officially described as ''international online training for raising global cyber resilience'' and involved many of the world's biggest tech companies and international authorities, from IBM to INTERPOL. There were also many surprising participants at the event, some of whom have been traditionally seen as opposed to Western imperial interests. For example, the person chosen to open the Cyber Polygon event was the prime minister of the Russian Federation, Mikhail Mishustin, and its main host, BI.ZONE, was a subsidiary of the Russian-government-controlled Sberbank. This suggests that the overused ''Russian hacker'' narrative may be coming to an end or will soon be switched out for another boogeyman more suitable in light of current political realities.
Aside from Mishustin, WEF executive director Klaus Schwab and former UK prime minister Tony Blair participated in the Cyber Polygon 2020 event, which is due to be repeated annually and bears many similarities to 2019's Event 201. Rather than preparing for a potential medical pandemic, Cyber Polygon 2020 focused on preparing for a ''cyberpandemic,'' one that mainstream media outlets like the New Yorker claim is ''already underway.'' Given the WEF's recent simulations, powerful billionaire business owners and bankers appear to be poised to use both physical and digital pandemics to reform our societies according to their own design and for their own benefit.
The Architects of Cyber Polygon According to Russian cybersecurity firm BI.ZONE, 120 organizations spread over twenty-nine countries took part in the two scenarios that were simulated at Cyber Polygon 2020, with as many as five million people allegedly having watched the livestream in over fifty-seven countries. Like many events that took place in 2020, the Cyber Polygon simulations were conducted online due to COVID-19 restrictions. Together with the World Economic Forum, BI.ZONE, a subsidiary of Sberbank, manages the Cyber Polygon project. Sberbank's largest shareholder, as of last year, is the Russian government, and it is thus often described by English-language media outlets as a state-controlled bank.
The 2020 event was launched with an address from the prime minister of the Russian Federation Mishustin, who has a history of courting Western tech companies prior to entering politics. In 1989, Mishustin graduated from Moscow State Technological University (generally known as Stankin) with a qualification in systems engineering. During the 1990s, he worked at the International Computer Club, a nonprofit organization with the goal of ''attracting Western advanced information technologies'' to Russia. Between 1996 and 1998, Mishustin was the chairman of the board of the ICC, but the company was liquidated in 2016. Between 2010 and 2020, he served as head of the Federal Taxation Service of the Russian Federation. Even though he had never shown any previous political ambitions, on January 16, 2020, he was appointed prime minister of the Russian Federation by an executive order issued by President Putin.
During Mishustin's welcoming remarks at the WEF's Cyber Polygon 2020, the Russian PM warned of the need to create public policy to ''strengthen the digital security of critical activities without undermining the benefits from digital transformation in critical sectors that would unnecessarily restrict the use and openness of digital technology.'' The statement suggests that ''unnecessary restrictions'' could become seen as necessary in time.
Mishustin goes on to explain that Russia's post-COVID economic recovery will be based on the ''increasing digitalization of that economy and government,'' adding that ''we will drastically increase the number of available digital public services and introduce fundamentally new support measures for digital businesses.'' He also stated that ''Russia has developed a common national system for identification and the prevention of cyberattacks with the government agency's information systems linked in the system.'' He also addressed the Cyber Polygon audience about the international community needing to come together to prevent a ''global cyberfraud pandemic.''
Sberbank, the largest Russian banking institution and former Soviet savings monopoly, which was originally founded by Nicholas I, was an official host of the Cyber Polygon 2020 event alongside the World Economic Forum. As reported in the Economist in January 2021, the Russian banking giant has begun to reimagine its business in an effort to become a consumer-technology giant. Sberbank has spent around $2 billion on technology and acquisitions, including the acquisition of internet media group Rambler, which it fully acquired in 2020. As late as December 30, 2020, Sberbank acquired Doma.ai, which describes itself as ''a convenient real estate management platform.'' On June 15, 2020, Sberbank bought 2GIS, a map, navigator, and business directory with over 42 million monthly active users. Sberbank's twenty-two investments, eleven as the lead investor, include some of the most used services in Russia, and its clear intention is to become a one-stop digital shop for all services. The bank also became the owner of one of the largest data-processing centers in Europe when the South Port data-processing center opened in November 2011, replacing the existing thirty-six regional data centers. Sberbank is set to be the world's first bank to launch its own cryptocurrency, Sbercoin, and digital finance ''ecosystem'' this March. It notably announced the coming Sbercoin, a ''stablecoin'' tied to the Russian ruble, just a few weeks after the Cyber Polygon 2020 exercise.
Sberbank's alliance with the WEF and prominence at Cyber Polygon 2020 was underscored at the event during the welcoming remarks delivered by Klaus Schwab. Schwab gave special thanks to Herman Gref, a member of the board of trustees of the World Economic Forum and Sberbank's CEO and also issued the following dire warning:
We all know, but still pay insufficient attention to, the frightening scenario of a comprehensive cyberattack which would bring to a complete halt to the power supply, transportation, hospital services, our society as a whole. The COVID-19 crisis would be seen in this respect as a small disturbance in comparison to a major cyberattack. We have to ask ourselves, in such a situation, how could we let this happen despite the fact we had all the information about the possibility and seriousness of a risk attack. Cybercrime and global cooperation should be on the forefront of the global agenda.
Similar warnings were heard at a 2019 simulation that was also cosponsored by the World Economic Forum, Event 201. Event 201, which simulated a global pandemic just months before the COVID-19 crisis, presciently warned in its official documentation: ''The next severe pandemic will not only cause great illness and loss of life but could also trigger major cascading economic and societal consequences that could contribute greatly to global impact and suffering.'' In contrast to similar simulations conducted in the past, Event 201 championed a ''public-private partnership'' approach to combatting pandemics, with a focus on engaging ''the private sector in epidemic and outbreak preparedness at the national or regional level.'' The WEF is, among other things, a major evangelist for the merging of the public and private sectors globally, describing itself as the ''international organization for private-public cooperation.'' It is thus unsurprising that their latest disaster simulation, which focuses on cyberattacks, would promote this same agenda.
The Speakers at Cyber Polygon 2020Aside from Schwab and Mishustin, twenty others took part in Cyber Polygon 2020, including some big names from the top echelons of the political elite. First off, Herman Gref engaged in discussion with former UK prime minister Tony Blair, who has been pushing for digital identity systems for decades. Blair straightforwardly told the CEO of Sberbank that biometric digital identity systems will ''inevitably'' be the tools that most governments will use to deal with future pandemics. Blair, discussing the coronavirus pandemic with Gref, advocated the harshest of lockdown measures, saying the only alternative to biometric digital identities is to ''lockdown the economy.''
Next, Sebastian Tolstoy, Ericsson's general director for Eastern Europe, Central Asia, and Russia and current chairman of the Tolstoy Family Foundation in Sweden, dialogued with Alexey Kornya. Kornya is president, CEO, and chairman of the management board of Mobile TeleSystems. He previously worked for PricewaterhouseCoopers and AIG-Brunswick Capital Management at North-West Telecom. Tolstoy and Kornya presented a segment at Cyber Polygon 2020 entitled ''Building a Secure Interconnected World: What Is the Role of the Telecom Sector?'' in which they discussed the importance of digital communication and connectivity to our modern way of living.
In the next segment, Nik Gowing, BBC World News presenter between 1996 and 2014 and founder and director of Thinking the Unthinkable, spoke with Vladimir Pozner, journalist and broadcaster, on the subject of ''fake news'' in a conversation that was actually somewhat refreshing in its arguments and approach.
St(C)phane Duguin, the CEO of the CyberPeace Institute, a Geneva-based company that describes itself as ''citizens who seek peace and justice in cyberspace,'' then gave a talk to the millions of viewers watching the simulation. The CyberPeace Institute, funded by Microsoft, Facebook, Mastercard, and the Hewlett Foundation, among others, claims to help their customers ''increase digital resilience and the capacity to respond to and recover from cyberattacks.'' The core backers of the CyberPeace Institute are also among the top backers of the Global Cyber Alliance, which unites the public sectors of the US, UK, and France with multinational corporations and intelligence-linked cybersecurity firms, employing ''a coordinated approach and nontraditional collaboration'' to ''reduce cyber risk.''
Duguin, who is also on the advisory board of the Global Forum on Cyber Expertise, recently launched the Cyber4Healthcare initiative, a ''free'' cybersecurity service to healthcare providers fighting the COVID-19 pandemic. The Cyber4Healthcare initiative includes as its main partners BI.ZONE as well as Microsoft and the Global Cyber Alliance. This is yet another suspicious Microsoft-linked free cybersecurity service currently being pitched to and adopted by healthcare providers around the world at a time when warnings of a coming cyberattack on healthcare systems globally are becoming more public.
Dhanya Thakkar, senior vice president of AMEA at Trend Micro, who advertises himself online as a top ASEAN LinkedIn ''cybersecurity influencer,'' and Wendi Whitmore, vice president of IBM X-Force Threat Intelligence, next discussed the topic ''Know Your Enemy: How Is the Crisis Changing the Cyberthreat Landscape?'' IBM's presence is notable due to the company's longstanding relationship with the CIA, dating back to the early Cold War. The company has become so entrenched that the CIA recently recruited their chief information officer directly from IBM Federal. Before joining IBM, Whitmore held executive positions at California-based cybersecurity technology companies CrowdStrike and Mandiant, the latter acquired by FireEye in a stock and cash deal worth in excess of $1 billion. Whitmore was responsible for ''professional services.'' Notably, both CrowdStrike and Mandiant/FireEye are the key organizations leading the investigation into the recent SolarWinds hack, which US intelligence has blamed on a ''Russian hacker'' without providing any evidence. Whitmore began her career as a special agent conducting computer crime investigations with the Air Force Office of Special Investigations.
Jacqueline Kernot, the Australian ''partner in cybersecurity'' for Ernst and Young, and Hector Rodriguez, senior vice president and regional risk officer for Visa, next discussed how to prepare for cyberattacks. Kernot worked for over twenty-five years as a military officer for the Australian Intelligence Corps and spent two years working at IBM's Defence|Space|Intelligence for Tivoli Software in the UK with ''international responsibilities within the UK Ministry of Defence, Defence Primes, and NATO.'' Ernst and Young and Visa, alongside other WEF-linked corporations such as Salesforce, are well represented on the Vatican's exclusive Council for Inclusive Capitalism. The Council, like the WEF, calls for the reconstruction of the economic system to be more ''sustainable,'' ''inclusive,'' and ''dynamic'' by ''harnessing the power of the private sector.''
Troels rting J¸rgensen , chairman of the advisory board of the World Economic Forum's Centre for Cybersecurity, and J¼rgen Stock, the Danish secretary general of INTERPOL, also spoke together at Cyber Polygon regarding the changes in global cybercrime over the course of the previous year. A few months after appearing at Cyber Polygon, the Danish Financial Supervisory Authority announced in an official statement that ''Troels rting has notified the Ministry of Business Affairs that he is resigning from the Danish Financial Supervisory Authority's board.'' Citing unnamed sources, Danish financial news service FinansWatch reported that during the time between 2015 and 2018, when he was employed as head of security at Barclays bank, rting had been a key figure in the hunt for a whistleblower who had exposed the same criminal activity rting railed against at Cyber Polygon.
The man speaking alongside rting, J¼rgen Stock, is a former German police officer, criminologist, and lawyer. He was elected for a second term as secretary general of INTERPOL in 2019, a term that generally lasts for five years. Craig Jones, the cybercrime director at INTERPOL, also joined the discussion at Cyber Polygon 2020. The New Zealander spent twenty-seven years in law enforcement and is considered an expert in cybercrime investigations. He previously held several senior-management positions in UK law enforcement, most recently at the National Crime Agency.
Petr Gorodov and John Crain were briefly interviewed at the Cyber Polygon 2020 event. Gorodov is head of the General Directorate for International Relations and Legal Assistance of the Prosecutor General's Office of the Russian Federation and also sits on the Commission for the Control of INTERPOL's files. He is on the Requests Chamber of INTERPOL, which examines and decides on requests for access to data as well as requests for correction and/or deletion of data processed in the INTERPOL information system. John Crain is chief security, stability, and resiliency officer at ICANN, the nonprofit internet security corporation. He is currently responsible for the management of the L-Root server, one of the internet's thirteen root servers, making his inclusion at the simulation particularly notable. At Cyber Polygon 2020 he promoted a ''long-term solution of working together in the cybersecurity community.''
The final word at Cyber Polygon 2020 was delivered by Stanislav Kuznetsov, deputy chairman of the executive board at Sberbank. He is also a board member for the Sberbank charity foundation Contribution to the Future, a project that seeks to get Russian schoolchildren from grades seven through eleven interested in AI (artificial intelligence), machine learning, and data analysis and to help them develop math and programming skills. Kuznetsov studied at the Law Institute of the Ministry of Internal Affairs of the Russian Federation.
The Main Event: Enter the PolygonParticipants in the Cyber Polygon 2020 event, Source: https://cyberpolygon.com/The simulation component of Cyber Polygon 2020 saw 120 teams from twenty-nine countries take part in the cybersecurity technical simulation. During the online event, participants ''exercise[d] the actions of the response team in a targeted attack aimed at stealing confidential data and thus resulting in damage to the company reputation.'' Two teams, the Red and the Blue, went head-to-head in the simulations where the Red Team, made up of the training organizers from BI.ZONE, simulated cyberattacks and the Blue Team members attempted to protect their segments of the training infrastructure. The actual simulation was made up of two scenarios in which the various subgroups making up the teams could gain points.
The first scenario, called Defence, made the Cyber Polygon participants practice repelling an active APT (advanced persistent threat) cyberattack. The scenario's objective was stated as being to ''develop skills for repelling targeted cyberattacks on a business-critical system.'' The simulation's fictional organization's virtual infrastructure included a service that processes confidential client information. This service became the subject of interest to an APT group that planned to steal confidential user data and resell it on the ''darknet'' to financially benefit and damage the company's reputation. The APT group studied the target system in advance and discovered several critical vulnerabilities. In the scenario, the cyber ''gang'' plans to attack on the day of the exercise. The participants involved were judged on their ability to cope with the attack as fast as possible, to minimize the amount of information stolen, and to maintain service availability. Blue Team participants could apply any applications and tools to protect the infrastructure and were also allowed to fix system vulnerabilities by improving the service code.
In the second scenario, called Response, the teams had to investigate the incident using ''classic forensics and threat hunting techniques.'' Based on the information gathered, participants had to compose a dossier that would help law enforcement agencies locate the criminals. The second scenario's objective was to develop skills in incident investigation using the scenario in which cybercriminals gained access to a privileged account through a successful phishing attack.
When the BI.ZONE team released the results of the simulation they intentionally avoided using the real names of the organizations so as not to ''set off a competition between the participants and keep their results confidential.'' However, the teams could later compare their results with the others by using a basic scoreboard, and the hosts could analyse the crucial data showing various organizational weaknesses of each of the participating teams/institutions.
The final report states that the results showed that ''banks and companies from the IT industry demonstrated the highest resilience. Security assessment expertise in these sectors is quite well developed, with classic forensics and threat hunting widely applied.'' In lay terms, the teams from banks and the IT industry seemed to be better prepared than most other sectors for investigating and hunting down threats. However, all the teams involved proved to be less than able when it came to the initial defense from a cyberattack, with the BI.ZONE report stating that ''27% of the teams had difficulties earning points for the first scenario, which allows us to conclude that some of the team members lack or have insufficient expertise in security assessment and protection of web applications.'' On the subject of threat hunting, the report goes on to say that ''21% of the teams could not earn a single point for the second round of the second scenario. This was attributed to 'Threat Hunting' being a relatively novel approach and the majority of organisations lacking experience of applying its techniques in practice.''
The Cyber Polygon 2020 event revealed the weakness in human-led defensive response and resilience as it relates cyberdefense. This outcome is convenient for hi-tech cybersecurity companies like BI.ZONE that wish to highlight the superiority of AI-driven cybersecurity products in comparison to ''inefficient'' human workers. Also, it should be noted that BI.ZONE's gaining knowledge of global institutional weaknesses through cyberdefense training could be useful intelligence for their parent company, Sberbank, and in turn the largest shareholder of Sberbank, the Russian government.
Bringing Russia in from the Cold?Although Russian Federation authorities are quite used to being out in the cold both politically and physically, there appears to be a change in the usual order of nations. Russia's inclusion as the leader in such an important global cybersecurity initiative is a bit surprising, especially after Russia has been the scapegoat of choice for any cyberattack committed against any Western power for several years, most recently with the SolarWinds hack in the US. Yet, there was no outcry in the West over Cyber Polygon 2020, in which a company that is majority owned by the Russian government was able to gain direct knowledge of the cyberdefense weaknesses of major global institutions, banks, and corporations through their hosting of the exercise.
The complete absence of the ''Russian hacker'' narrative at Cyber Polygon as well as Russia's leadership role at the event suggests either that a geopolitical shift has taken place or that the Russian hacker narrative commonly deployed by intelligence agencies in the US and Europe is mainly meant for the general public and not for the elite figures and policymakers in attendance at Cyber Polygon.
Another possibility for Russia no longer being treated as the perpetual enemy of cyberspace is that it is entirely on board with both the official coronavirus narrative and the allegedly imminent cyberpandemic. Cyber Polygon 2020 appeared, in part, to be a Russian charm offensive that was welcomed by the powerful elite. Tony Blair, who once held out the hand of false reconciliation on behalf of the international community to Colonel Gaddafi, has often been involved in these exercises of international diplomacy on behalf of the elites in the years since he left public office. His involvement in the exercise may have been meant to facilitate support among Western WEF-aligned governments for even greater Russian inclusion in the Great Reset. Part of this is due to the WEF-led effort to bring BRICS nations like China and Russia into the Great Reset fold because it is essential for their agenda's success on a global scale. Now, Russia is pioneering this new model of supposedly national finance systems that the WEF supports through Sberbank's creation of a digital monopoly not only of financial services but all services within the Russian Federation.
Cyber Polygon 2020 was both an ad for pro-Russian relations and a promotional exercise for Klaus Schwab and the World Economic Forum's Great Reset. Some of the people who took part and supported the Cyber Polygon event are involved at the highest levels of cyber intelligence; some may have even been unofficial representatives of their national state intelligence apparatus. The decisions of several national governments to participate directly in the WEF-led Great Reset is no ''conspiracy theory.'' For instance, the incoming Biden administration sent its climate envoy, John Kerry, to the WEF annual meeting last month, where Kerry underscored the US commitment to the Great Reset agenda and the associated Fourth Industrial Revolution that seeks to automate most jobs being currently performed by humans. With the governments of Russia, China, the US, the UK, Israel, Canada, and India, among others, on board with this transnational agenda, it becomes deeply unsettling that high-ranking operatives in both the public and private sectors joined the WEF to conduct a simulation of a crisis that would clearly benefit the Great Reset agenda.
As previously mentioned, the WEF cosponsored a simulation of a coronavirus pandemic just months before the actual event. Soon after the COVID-19 crisis began in earnest last March, Schwab noted that the pandemic crisis was just what was needed to launch the Great Reset as it served as a convenient catalyst to begin overhauling economies, governance, and social society on a global scale. If the destabilizing events simulated at Cyber Polygon do come to pass, it will likely be similarly welcomed by the WEF, given that a critical failure in the current global financial system would allow the introduction of new public-private ''digital ecosystem'' monopolies such as those being built in Russia by Sberbank.
This effort by Sberbank to both digitize and monopolize access to all services, both private and public, may be appealing to some because of its apparent convenience. However, it will also be emblematic of what we can expect from Schwab's Great Reset'--monopolies of fused public- and private-sector entities disguised by the term ''stakeholder capitalism.'' What the general public does not realize yet is that they themselves will not be included among these ''stakeholders,'' as the Great Reset has been designed by the bankers and wealthy elite for the bankers and the wealthy elite.
As for the Cyber Polygon 2020 event, the coming cyberpandemic is being prophetically thrown in our faces just as the pandemic exercise was prior to the actual disease's appearance. Such prophetic warnings are coming not only from the WEF, however. For instance, the head of Israel's National Cyber Directorate, Yigal Unna, warned last year that a ''cyber winter'' of cyberattacks ''is coming and coming faster than even I suspected.'' In the cyber directorate, Unna works closely with Israeli intelligence agencies, including the infamous Unit 8200, which has a long history of electronic espionage targeting the US and other countries and which has been responsible for several devastating hacks, including the Stuxnet virus that damaged Iran's nuclear program. Israeli intelligence is also poised to be among the greatest beneficiaries of the Great Reset due to the strength of the nation's hi-tech sector. In addition, last month saw the UAE's central bank following Cyber Polygon's lead by conducting its first-ever cyberattack simulation in coordination with the Emirati private-finance sector. Corporate media outlets, for their part, began this year by claiming that ''cyberattacks may trigger the next crisis for banks'' and, as of February 1, that ''the next cyberattack is already underway.''
Some will say that a ''cyberpandemic'' is an inevitable consequence of the quickly developing hi-tech world in which we live, but it still fair to point out that 2021 is the year that many have been predicting for the financial destruction of big institutions that will lead to new economic systems that align with the Great Reset. The inevitable collapse of the global banking system, resulting from the off-the-charts corruption and fraud that has run rampant for decades, is likely to be conducted through a controlled collapse, one that would allow wealthy bankers and elites, such as those that participated in Cyber Polygon, to avoid responsibility for their economic pillaging and criminal activity.
This is especially true for Cyber Polygon participant Deutsche Bank, whose inevitable collapse has been openly discussed for years due to the bank's extreme corruption, fraud, and massive exposure to derivatives. In late 2019, months before the COVID-19 crisis began, the CEO of Deutsche Bank warned that central banks no longer had tools that could adequately respond to the next ''economic crisis.'' It is certainly telling that entirely new banking systems, such as Sberbank's soon-to-be-launched digital monetary monopoly, began to be developed just as it began to be publicly acknowledged that central banks' traditional means of responding to economic calamities were no longer viable.
A massive cyberattack, such as that simulated at Cyber Polygon 2020, would allow faceless hackers to be blamed for economic collapse, thus absolving the real financial criminals of responsibility. Furthermore, due to the difficult nature of investigating hacks and the ability of intelligence agencies to frame other nation states for hacks they in fact committed themselves, any boogeyman of choice can be blamed, whether a ''domestic terror'' group or a country unaligned with the WEF (for now, at least) like Iran or North Korea. Between the well-placed warnings, simulations, and the clear benefit for the global elite intent on a Great Reset, Cyber Polygon 2020 appears to have served not only its publicly stated purpose but its own ulterior motives.
Statement from the U.S. Department of Agriculture on JBS USA Ransomware Attack | USDA
Wed, 02 Jun 2021 05:08
Skip to main content Release & Contact InfoStatement
Release No. 0120.21
Contact: USDA PressEmail: press@usda.gov
WASHINGTON, June 1, 2021 '-- As noted earlier today by the White House, USDA is aware of the ransomware attack against JBS, which is affecting the company's operations, including its facilities in the United States. USDA continues to work closely with the White House, Department of Homeland Security, JBS USA and others to monitor this situation closely and offer help and assistance to mitigate any potential supply or price issues. As part of that effort, USDA has reached out to several major meat processors in the United States to ensure they are aware of the situation, encouraging them to accommodate additional capacity where possible, and to stress the importance of keeping supply moving.
USDA has also been in contact with several food, agriculture and retail organizations to underscore the importance of maintaining close communication and working together to ensure a stable, plentiful food supply. USDA will continue to encourage food and agriculture companies with operations in the United States to take necessary steps to protect their IT and supply chain infrastructure so that it is more durable, distributed and better able to withstand modern challenges, including cybersecurity threats and disruptions.
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Biden to suspend oil leases in Alaska Arctic refuge...
Tue, 01 Jun 2021 23:52
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Battle Brews Over Banning Natural Gas to Homes
Battle Brews Over Banning Natural Gas to Homes - WSJ
Mon, 31 May 2021 12:44
A growing fight is unfolding across America as cities concerned about climate change consider phasing out natural gas for home cooking and heating.
Major cities including San Francisco, Seattle, Denver and New York have either enacted or proposed measures to ban or discourage the use of the fossil fuel in new homes and buildings, two years after Berkeley, Calif., passed the first such prohibition in the U.S. in 2019.
The bans in turn have led Arizona, Texas, Oklahoma, Tennessee, Kansas and Louisiana to enact laws outlawing such municipal prohibitions in their states before they can spread. Ohio is considering a similar measure.
The outcome of the battle has the potential to reshape the future of the utility industry, and demand for natural gas, which the U.S. produces more of than any other country.
Proponents of phasing out natural gas say their aim is to reduce planet-warming emissions over time by fully electrifying new homes and buildings as wind and solar farms proliferate throughout the country, making the power grid cleaner.
Homes and businesses account for about 13% of the nation's annual greenhouse gas emissions, according to the Environmental Protection Agency, mostly because natural gas is used in cooking, heating, and washers and dryers. Climate activists say reducing that percentage is critical for states with goals to slash carbon emissions in the coming decades.
Opponents in the gas industry counter by citing the higher costs of making many homes fully electric, and pointing to the added security of having a second home energy source to heat and cook with during extreme weather events. They also highlight the preference many home and professional chefs have for using gas-fired stoves.
New all-electric homes are cost-competitive with those that use gas in many parts of the country, but retrofits can be considerably more expensive, depending on the existing heating and cooking systems and the cost of effectively converting them. A recent study by San Francisco found that retrofitting all housing units that now use natural gas would cost between $3.4 billion and $5.9 billion, costs that would fall on residents, the city or both.
Induction ranges, which use magnets to heat pots and pans directly, can be more expensive to buy than gas ranges, especially in professional kitchens. Restaurant associations across the nation have raised concerns about going electric.
Utilities that supply both electricity and natural gas could face more muted impacts if the shift accelerates. But those that supply only natural gas face the prospect of slower growth or even a reversal of demand, especially if momentum builds to electrify both new and existing homes.
Greater reliance on electricity raises the possibility that parts of the natural-gas delivery system will become stranded assets, facilities that retire before they pay for themselves. The Environmental Defense Fund, a nonprofit environmental advocacy group, in 2019 warned that in California, where gas utilities spend billions of dollars on their systems each year, stranded assets could complicate efforts to move away from gas by saddling customers with higher costs over time.
President Biden's $1.7 trillion infrastructure plan calls for greater adoption of all-electric heat pumps and induction stoves, giving proponents hope that the government will do more to incentivize their adoption.
Panama Bartholomy, director of the Building Decarbonization Coalition, which supports efforts to electrify buildings throughout California, said the organization is pushing for the state to cut emissions from homes and businesses by 40% by 2030, and to adopt zero-emission building codes for each within the next few years.
''All of a sudden there's a conversation happening that wasn't happening two years ago,'' Mr. Bartholomy said. ''It's the fastest-growing trend we've ever seen.''
Industry pushback has been swift, with many utilities and businesses voicing opposition to local gas bans.
Arizona last year became the first state to pass pre-emptive legislation barring municipalities from banning new gas hookups. The Arizona Chamber of Commerce helped lead a coalition of businesses that pushed for the legislation, even though no bans were under consideration in the state at the time. Garrick Taylor, the chamber's interim chief executive, said the legislation was born of concerns that bans would result in higher electricity costs and reduced energy choices for residents and businesses.
''If you see something next door in California, there's a chance that a municipality in your state is likely going to consider it,'' Mr. Taylor said.
The American Gas Association, a national lobbying group, has been pushing for state laws prohibiting local bans. President Karen Harbert said an indiscriminate approach to widespread electrification could put strain on the grid, resulting in either higher electricity prices or greater reliance on gas-fired power plants.
''You have to do the math,'' she said. ''We can't just say if we electrify everything, we're going to solve the challenge of climate change.''
State agencies in California, Colorado, Massachusetts and New York have launched efforts to assess how the role of gas utilities may change in the coming years if demand plateaus or declines. Utilities across the country are beginning to ask the same question as they consider new gas investments.
Jan Berman, director of energy strategy and innovation at PG&E Corp. , which serves 16 million people in Northern and Central California, said it may eventually shrink its gas distribution system, if more homes are retrofitted to run entirely on electricity.
''We welcome the opportunity to avoid investments in new gas assets that might later prove to be underutilized as decarbonization efforts progress here in California,'' she said.
Southern California Gas Co., a unit of Sempra Energy that is the nation's largest gas utility, opposes bans on new hookups, arguing that customers should have the right to choose. The California Public Utilities Commission recently determined that SoCalGas misused ratepayer money to advocate against such bans and other energy efficiency measures, and ordered the company to refund customers for those efforts.
SoCalGas said it appreciates the agency's finding that no violations, fines or penalties are warranted.
SoCalGas recently set a goal to achieve net-zero emissions by 2045. The utility is working to expand its use of renewable natural gas made from landfill waste and green hydrogen, which is produced using electricity from renewable energy sources. CEO Scott Drury said he envisions a future where the company's existing infrastructure is used to augment wind and solar power, especially during periods of peak demand.
''What is flowing through those pipes will be different in 2045 than it is today,'' he said. ''How do you take the infrastructure that's there, and use it in the most thoughtful way as a tool to enable what we're collectively trying to pursue?''
Write to Katherine Blunt at Katherine.Blunt@wsj.com
Return to Office: Employees Are Quitting Instead of Giving Up Work From Home - Bloomberg
Tue, 01 Jun 2021 14:09
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Dog are People too
The hidden reason processed pet foods are so addictive - BBC Future
Thu, 03 Jun 2021 13:52
The hidden reason processed pet foods are so addictive
(Image credit: ; Getty Images)
From potently smelly additives to offal concentrates, pet food companies turn to some surprising ingredients in the quest to make kibble delicious.
T
The cue might be a hand in a pocket, the opening of a cupboard door, or even a word said carelessly aloud '' "dinner". Before you know it, you're tripping over a pet excitedly awaiting a portion of... dull-brown dried pellets. What's in these mysterious morsels, that makes them as delectable as roasted chicken, wild salmon, or bundles of fresh herbs?
Take my flatmate, a small black rabbit. For a large part of every day, he can be found sitting attentively with his paws on his empty food bowl, awaiting his next portion of kibble '' even though it looks like his droppings and smells equally unappetising. He used to have an automatic dispenser with a timer, but he learnt to throw it across the room to access its contents prematurely. No matter what delicacies I place before him '' home-grown parsley, soft-cut hay, fresh carrot-tops, organic kale '' he would always rather eat processed pet food.
It seems that this is not unusual. Anecdotes abound about pets whose thoughts are largely preoccupied with kibble, such as the cat that has a daily panic attack when it realises it has eaten all its pellets and the pragmatic German shepherd found carrying a bag of dog food around the streets of Houston after Hurricane Harvey.
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How changing our food may have changed usThe food that lasts 2,000 yearsThe hidden risks of cooking your foodAs it happens, this addictive quality is carefully engineered. Big Pet Food is a multi-billion-dollar industry which invests heavily in research into "palatants" '' ingredients that make our pets want to eat their products. And from potently smelly chemicals usually found in rotting meat to an additive commonly added to potatoes to stop them discolouring, the quest to make the most scrumptious pet food has led to some surprising insights.
"Big [pet food] companies have huge departments that make palatants," says Darren Logan, head of research at the Waltham Petcare Science Institute, part of the company Mars Petcare. "Just like we make them for humans, we make them for pets as well."
Upper-class dogs
The first pet food was invented in 1860 by James Spratt, an enterprising lightning-rod salesman from the US state of Ohio. Legend has it that he had travelled to England for his business, and was looking out over the docks of Liverpool one day when he noticed stray dogs knocking back leftover hardtack biscuits.
This was a revelation for two reasons.
Rabbits eat fresh vegetables in the wild, but many kept as pets feast instead on processed pellets (Credit: Getty Images)
Firstly, hardtack were famously unappealing '' loathed by generations of the soldiers and sailors who ate them, these simple slabs of baked flour and water were tougher than wood and sometimes hard enough to break your teeth. Their nicknames included "sheet iron" and "worm castles", the latter because of the high proportion that were infested with maggots and weevils. The oldest piece of surviving hardtack was baked just nine years before Spratt's dock visit, and still looks suspiciously well-preserved 170 years later.
Secondly, until that moment it hadn't occurred to anyone to check what their pets would like to eat '' or that this could be monetised. For as long as we had kept domesticated animals, they had been fed more or less the same food as humans, or expected to fend for themselves.
One striking example is the husky. In their native territory of Arctic Greenland, Canada and Alaska, Inuit hunter-gatherers have traditionally fed these dogs on seal meat, which comprises the majority of their own diet. Sled-dogs are so well-adapted to this that when the British Antarctic Survey brought them to Antarctica as a form of transport in 1945, they found that they struggled to digest commercial dog food. In the end, they had to kill a number of local seals each year, just to feed the dogs, before they were largely replaced with skidoos in the 1960s and 70s.
Meanwhile in Victorian London, dogs that were lucky enough to be looked after were either given table scraps or gruel. Even specialist exotic animals were fed everyday human food '' the 20,000 or tortoises imported from Morocco each year were mostly expected to survive on ordinary garden vegetables or bread soaked in water. Cats were considered street animals and rarely fed.
But Spratt had hit upon something entirely new. Over the coming months he developed the "Meat Fibrine Dog Cake", a biscuit-like concoction of beetroot, vegetables, grains and beef of dubious origins that claimed to meet all the nutritional needs of his customers' hounds. (While its packaging implied that it was the finest prairie beef, what it was actually made from was a secret he took to his grave.)
Spratt's innovation coincided with a cultural revolution in the way people saw their pets '' dogs and cats went from being viewed as mere utility animals or borderline-vermin to beloved family members to be coddled. Consequently, the Meat Fibrine Dog Cake was marketed as a luxury food for aristocratic pets.
The husky dogs taken on early Antarctic voyages had to be fed with freshly killed seals (Credit: Ozge Elif Kizil/Anadolu Agency/Getty Images)
The adverts labelled them "Dog's Delight" and included gushing testimonials from wealthy customers. Ironically, Spratt's also promoted the fact that they were chosen to feed the sled dogs on Captain Scott's 1901 trip to the Antarctic, though we now know they would much rather have eaten seal.
Eventually the company branched out into cat food '' "Spratt's puts pussy into fine form!", they said '' and the rest is history. However, the science of pet food palatants still had some way to go.
Disgusting smells
Today it's possible to buy specialised kibble for almost any kind of pet, from frogs to sugar gliders (a small marsupial). Most follow roughly the same formula '' they usually contain some kind of base carbohydrate, assorted proteins and fats, sugars, a source of fibre, antioxidants or other preservatives, emulsifiers (which keep the fat in the food and prevent it from separating), vitamins and minerals, and colouring agents.
More sophisticated versions may also contain probiotics or digestibility enhancers '' such as chicory, which is often added to dog food '' as well as enzymes, anti-parasitic compounds and minerals to prevent the build-up of tartar on teeth.
To turn these ingredients into a dry pet food, it's formed into a paste and "extruded" via a process that involves heating it up and forcing it through a plate with holes in it, to form an aerated product that matches the shape of the holes. It's the same process that's used to make puffed snack foods, with flavourings added in the final step '' in the case of pet food, they're either sprayed on or added as a powder.
Oddly, there is very little relationship between how healthy a pet food is and its inherent deliciousness. That's because in the US, the EU and many other parts of the world, in order to describe one as "complete" '' containing everything the body needs to be healthy '' it must meet certain nutritional standards. These set out acceptable ranges for most ingredients, so manufacturers can't just load up on sugar and fat to make it compelling.
"From my standpoint as a nutritionist, all pet foods are the same," says Marion Nestle, professor emerita of nutrition, food studies, and public health at New York University.
The first processed dog foods were luxury products which ushered in the idea of the "pampered pet" (Credit: Kirn Vintage Stock/Corbis via Getty Images)
Instead, companies turn to chemistry.
Many animals rely heavily on smell to navigate the world around them, and this is often the main sense that's targeted. While human noses contain around 50 million olfactory receptors, cats have 67 million, rabbits have 100 million and dogs have around 220 million. On the other hand, their sense of taste is generally less discriminating than ours '' our relatively high density of taste receptors is thought to have evolved to help us cope with our diverse omnivorous diets.
The catch is that appealing to animals that find the smell of roadkill, sweaty socks, and vomit utterly enchanting '' as carnivorous pets often do '' while not making their human companions feel violently ill, is extremely tricky. "There is a slight paradox there, because the smells that cats particularly but also dogs seem to like are often the opposite of what humans like," says Logan.
Nestle puts it more bluntly '' "animals eat faeces", she says. "They like strong animal odours and pet food manufacturers have a really difficult time, because they have to make it disgusting enough so that the animal will eat it, but not so disgusting that the owners won't buy it."
Examples include putrescine and cadaverine, colourless chemicals produced naturally by the breakdown of proteins. They're largely responsible for the revolting smell of rotting flesh '' and cats love them. While in human food, their levels are sometimes closely monitored as a way of ensuring the freshness and safety of meat, they're often actively added to cat and dog food, either as offal extracts or lab-made additives.
In the case of naturally vegan animals, such as rabbits and guinea pigs, irresistible smells such as mint and oregano are sometimes added in the form of concentrates.
Japanese-inspired cuisine
Other insights are arguably more surprising. A recent study identified nine volatile compounds in common pet food flavourings that are linked to how delicious they are to dogs, including heptanal, nonanal, and octanal, which all have strong, fruity odours.
However, taste is also important '' and here the preferences of carnivorous pets are not so different from ours.
One of the most popular additives in human food is the enigmatic "hydrolysed protein", which is formed by breaking down the long strands of proteins into their constituent amino acids, usually using enzymes or hydrochloric acid. It imparts a flavour similar to that achieved by meat or vegetable stock, and often comes with MSG, which is produced as a by-product of the same reaction and is responsible for the savoury taste of tomatoes, cheese and Iberico ham.
Though hydrolysed proteins are produced artificially, the process is similar to what happens when you cook food for a long period of time '' it's a kind of pre-digestion, and is thought to contribute to the enticing smell of many brands of kibble.
Early processed dog food resembled the tooth-challenging hard-tack biscuits often taken on long sea voyages (Credit: Getty Images)
"The understanding of cat palatability is very similar to Japanese or Asian cuisine, where there's a lot of focus on umami and another taste modality called kokumi," says Logan.
Kokumi was discovered in Japan in 1989, and has been proposed as the sixth taste in humans, after sweetness, saltiness, bitterness, sourness and umami. It's described as a kind of mouth-feel rather than a flavour per se '' a texture that imparts richness and "thickness" to foods. Unlike the others, kokumi hasn't yet been linked to a specific set of compounds, but foods that conjure this sensory experience include scallops, soy sauce, shrimp paste, yeast and beer.
The sixth taste is thought to be particularly popular with carnivorous animals, which may discern it via receptors in their mouths that evolved to detect calcium. And as you would expect, pet food companies have already begun targeting it with cocktails of flavour-enhancing chemicals.
But there are some flavours that you will never find in certain pet foods.
For example, most wild carnivorous animals lack the receptors for tasting sugar or carbohydrates. And unlike dogs, which have been living around humans and feasted off our scraps for up to 40,000 years, domestic cats have only been around for about 4,300. For the majority of that time, they were considered a kind of free pest-control that could fend for themselves.
So, while cats are particularly drawn to Japanese food, which is rich in meat and seafood, you're unlikely to find them stealing ice-creams or doughnuts '' unlike dogs, they simply haven't been around humans for long enough to have evolved the ability to taste sugar.
Cats are irresistibly drawn to the chemical compounds found in rotting fish (Credit: Getty Images)
On the other hand, because vegan animals eat exclusively vegetable matter, which is often rich in fibre and carbohydrates, they tend to prefer sweeter pet food.
Finally, no list of palatants would be complete without pyrophosphate, described in Popular Science as "cat crack". This common additive performs a number of roles in human food, such as preventing potato products from going dark after they're cooked '' none of which involve improving its taste. Nevertheless, cats go nuts for it, possibly because it intensifies the flavour of amino acids.
Pet food companies are now so successful at making food delicious that they're increasingly encountering a dilemma '' it's almost too good. "The danger for cats and dogs today is the same as for people, it's overconsumption," says Andrew Knight, a professor of animal welfare and ethics at the University of Winchester.
Pet obesity is a growing problem in the developed world, with one survey of veterinary professionals at a vet show in London suggesting that around 51% of dogs, 44% of cats and 29% of small mammals are now overweight or obese.
According to Logan, this is not down to the way pet food is formulated, but humans succumbing to their beloved pets' pleading gazes. "The reason we make pet food palatable is that if they don't eat all the food that we give them, it won't meet the nutritional needs that they require," he says. "The real problem is owners feeding them too much '' pets can't open the packets themselves."
However, there is an upside. There are mounting concerns about the environmental impact of pet food, too '' in 2009, two New Zealand scientists estimated the planetary cost of keeping a dog as roughly twice that of having a medium-sized SUV.
Pets given too much calorific processed food may, just like humans, put on extra weight (Credit: Getty Images)
This is where palatants come in. Because most pet foods comprise a fairly tasteless base that is spruced up with delicious flavourings and smells, pet foods made from more sustainable ingredients such as insects or soya are generally just as acceptable to carnivorous pets as the real deal. (Though cats cannot be fed a diet that is meat free.)
"According to this really large-scale study that we've just finished, the animals on vegan pet foods seem to be just as happy as animals on meat ones," says Knight, who is hopeful about their future potential.
"There is a broad recognition that the need to be more sustainable will have a big impact on the pet food business," says Logan, who explains that the pet food company he works for has just released its own brand of insect-based pet food.
So, why do our pets find pet food so addictive? Well, because it's been made that way. Just like us, our pets find it hard to say no to the food we have designed to be tasty.
* Zaria Gorvett is a senior journalist for BBC Future and tweets at @ZariaGorvett
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Freedom Passpoert
The passports will be used to identify the VAXXED!!
Big Pharma
Viagra for young men - ADD and SSRI's
I just wanted to throw this into the conversation. I heard about this a few years back from my buddy who was recently married to a beautiful woman who he couldn't get hard for. He is under 30. His doctor found out it was due to his hormone levels out of whack from 20+ years of prescribed adderall use.
I bet we could do a study and see how many ADHD kids are also heavy into porn. Chicken or the egg? Do they watch so much porn because they can't get hard/get off because they are hopped up on meds that numb them? Or can they not get hard/get off because they watch too much porn?
PCR
Netherlands Drops Negative PCR-RT Test Requirement From Transit Passengers Effective Today (June 1, 2021) - LoyaltyLobby
Thu, 03 Jun 2021 13:16
Netherlands was one of the first countries to introduce PCR-RT test requirements for transit passengers (often you needed two) that some other countries followed with less time-consuming and cheaper tests.
The Netherlands has removed the negative test requirement from transit passengers effective today. However, you need to ensure that you fulfill the destination country's entry requirements, including possible test(s).
You can access the Netherlands page for Covid-19 and travel here.
Here's the information (Google translate from English):
As a traveler, you must be able to show a negative COVID-19 test result before traveling or returning to the Netherlands. This applies to most countries and to anyone aged 13 or older. The test result is mandatory for departures by plane, ship, international train and international bus. From 1 June, the negative test result is also mandatory for travelers with their own transport, such as the car or motorcycle.
Changes from June 1:
Negative NAAT(PCR) test result also mandatory for travelers with a car or motorcycle unless the travelers have been in the Netherlands for less than 12 hours . Transfer passengers except for the mandatory tests Rapid test only mandatory for travelers from countries with a worrying virus variantAND
Negative COVID-19 test result: rules when switching
As a traveler, you must be able to show a negative COVID-19 test result before traveling or returning to the Netherlands. The rules for switching differ per situation.
You start your journey in a safe country and you have a transfer in a high-risk area
If you stayed at the airport, you do not need a negative COVID-19 test result.If you leave the airport during the transfer, this counts as a new journey. In that case, the obligation applies to the negative COVID-19 test result .You start your journey in a high-risk area and you have a transfer in a non-high-risk area
The rules for the negative COVID-19 test result from a high-risk area also apply to you.You present a negative NAAT(PCR) test result of up to 72 hours old upon boarding;The test result remains valid during the transfer and possible delay. You start your journey in a high-risk area and you have a transfer in the Netherlands
You do not need to be able to show a negative NAAT(PCR) test result or rapid test result upon arrival in the Netherlands. A transfer is understood to mean: traveling on directly, within a few hours, but no later than 1 day, without leaving the transfer point. Conclusion
This is a welcomed change, and it has been rather unusual that the transit point may have required you to have a PCR-RT test when the destination country doesn't, and this has even included intra-Schengen and EU/EEA travel.
Now that the EU is opening up for first internal travel and later for more widespread international visitors, having a PCR-RT test requirement for merely a transit would have disadvantaged Netherlands, Schiphol, and KLM over other countries and airlines.
I had to take an unnecessary PCR-RT test in Barcelona last month (read more here) when I was transiting the Netherlands to Mexico City. I am back at Schiphol in four weeks and need to check a couple of days before the entry requirements to Spain and Greece and whether I need another test or two.
Trump
Are the Military and Trump in control? '' News With Views
Wed, 02 Jun 2021 13:20
Dr. Laurie Roth, Ph.D
I just got off the phone with a high up and trusted, military source I know. He comfirmed a few things for me.
Regarding, the speculation/confusion as to whether President Trump signed the Insurrection Act or not, he did. He signed it on Jan 14th, 2021. The act of signing it immediately gave him 2 more months as President according to the very directives of the Act itself. I was then told that the military gave him 2 more months as President. The second extension was over on May 20th and most likely extended again by the military who is now in control per the signed Insurrection Act.
Now, with Manhattan Attorney Cy Vance convening a Grand Jury against President Trump, regarding his taxes and business practices, the Trump which hunt continues. The only problem they may have is that they cannot arrest a sitting President and I am assured that he still is President. Once again, the liberal, legal crazies are desperately trying all they can to stop Trump.
It was confirmed today that many Generals approached Trump to run for office to take out the deep state, criminal cabal. They have been making arrests since the Biden '' fake inauguration. The military support is all around Trump and continues under the Insurrection Act.
I was told that the military goes through the FISA court and already did their own investigation, determining that there was international and domestic voter fraud They have long known the real election and voting numbers and have acted accordingly.
Our military is bound by the constitution, their duty and the signed insurrection act to be in control, do what they have to do, make arrests and make things right. They are supporting a new election in August and the return of President Trump . I am told he will be returning very soon.
My source shared much more with me that gave me real hope that justice was unfolding in a big way and the truth would soon come out in spite of the sellout media and ego-laden politicians.
Hold on to your hat. Pray for President Trump and our military as the truth really comes out.
God bless America.
(C) 2021 Laurie Roth '' All Rights Reserved
E-Mail Laurie Roth: drljroth@aol.com
Dr. Laurie Roth earned a black belt in Tae Kwon Do. In the late 90's, Laurie hosted and produced a successful PBS television show called "CD Highway" that aired nationally on 130 TV stations.Tune in to The Roth Show, Weeknights from 7:00 to 10:00 pm PAC and find out for yourself! You can listen live on cable radio network (live on the internet) channel 6 or visit The Roth Show web site and click on "where to listen" www.therothshow.com Call the Roth Show at: 1-866-388-9093 E-Mail: Rsintaro@aol.com
Insurrection Act of 1807 - Wikipedia
Wed, 02 Jun 2021 13:19
United States law
The Insurrection Act of 1807 is a United States federal law[1] that empowers the President of the United States to deploy U.S. military and federalized National Guard troops within the United States in particular circumstances, such as to suppress civil disorder, insurrection, or rebellion.
The act provides a "statutory exception" to the Posse Comitatus Act of 1878, which limits the use of military personnel under federal command for law enforcement purposes within the United States.[2][3]
Before invoking the powers under the Act, 10 U.S.C. § 254 requires the President to first publish a proclamation ordering the insurgents to disperse. As part of the Posse Comitatus Act of 1878, these provisions are now codified as amended.
There are Constitutional exceptions to Posse Comitatus restrictions rooted in the President's own constitutional authority. Defense Department guidelines describe "homeland defense" as a "constitutional exception" to Posse Comitatus restriction, meaning that measures necessary to guarantee National Security from external threats are not subject to the same limitations.
Purpose and content [ edit ] The Act empowers the U.S. president to call into service the U.S. Armed Forces and the National Guard:
when requested by a state's legislature, or governor if the legislature cannot be convened, to address an insurrection against that state (§ 251),to address an insurrection, in any state, which makes it impracticable to enforce the law (§ 252), orto address an insurrection, domestic violence, unlawful combination or conspiracy, in any state, which results in the deprivation of constitutionally secured rights, and where the state is unable, fails, or refuses to protect said rights (§ 253).The 1807 Act replaced the earlier Calling Forth Act of 1792, which had allowed for federalization of state militias, with similar language that allowed either for federalization of state militias or use of the regular armed forces in the case of rebellion against a state government.[4]: 60
The 1807 Act has been modified twice. In 1861, a new section was added allowing the federal government to use the National Guard and armed forces against the will of the state government in the case of "rebellion against the authority of the government of the United States," in anticipation of continued unrest after the Civil War.[5] In 1871, the Third Enforcement Act revised this section (§ 253) to protect Black Americans from attacks by the Ku Klux Klan. The language added at that time allows the federal government to use the act to enforce the Equal Protection Clause of the Fourteenth Amendment to the United States Constitution.[4]: 63''64 This section of the act was invoked during the Reconstruction era, and again during desegregation fights during the Civil Rights Era.[6]
The chief clause of the Insurrection Act, in its original 1807 wording (which has been thoroughly updated since to reflect modern legalese), reads:[7]
An Act authorizing the employment of the land and naval forces of the United States, in cases of insurrectionsBe it enacted by the Senate and House of Representatives of the United States of America in Congress assembled, That in all cases of insurrection, or obstruction to the laws, either of the United States, or of any individual state or territory, where it is lawful for the President of the United States to call forth the militia for the purpose of suppressing such insurrection, or of causing the laws to be duly executed, it shall be lawful for him to employ, for the same purposes, such part of the land or naval force of the United States, as shall be judged necessary, having first observed all the pre-requisites of the law in that respect.[8][9]
In 2016, Public Law 114-328 was amended to include Guam and the US Virgin Islands under Ch. 13 jurisdiction. §252: "Use of militia and armed forces to enforce Federal authority" currently reads:
Whenever the President considers that unlawful obstructions, combinations, or assemblages, or rebellion against the authority of the United States, make it impracticable to enforce the laws of the United States in any State by the ordinary course of judicial proceedings, he may call into Federal service such of the militia of any State, and use such of the armed forces, as he considers necessary to enforce those laws or to suppress the rebellion.[10][7]
Application [ edit ] The Insurrection Act has been invoked throughout American history. In the 19th century, it was invoked during conflicts with Native Americans. In the late 19th and early 20th centuries, it was invoked during labor conflicts. Later in the 20th century, it was used to enforce federally mandated desegregation,[11] with Presidents Dwight D. Eisenhower and John F. Kennedy invoking the Act in opposition to the affected states' political leaders to enforce court-ordered desegregation.[12] More recently, governors have requested and received support following looting in the aftermath of Hurricane Hugo in 1989 and during the 1992 Los Angeles riots.[13]
In 2006, the George W. Bush administration considered intervening in the state of Louisiana's response to Hurricane Katrina despite the refusal from Louisiana's governor, but this was inconsistent with past precedent, politically difficult, and potentially unconstitutional.[4]: 73''75 A provision of the John Warner National Defense Authorization Act for Fiscal Year 2007, added by an unidentified sponsor, amended the Insurrection act to permit military intervention without state consent, in case of an emergency that hindered the enforcement of laws.[2] Bush signed this amendment into law, but some months after it was enacted, all fifty state governors issued a joint statement against it, and the changes were repealed in January 2008.[2]
On June 1, 2020, President Donald Trump warned that he would invoke the Act in response to the George Floyd protests following the murder of George Floyd.[14][15][16] In his official statement, Trump urged "every governor to deploy the National Guard in sufficient numbers" to re-establish civil law and order "until the violence has been quelled".[17]
Invocations [ edit ] Date of invocationInvoking PresidentState requested?Affected areaOccasionApril 19, 1808Thomas JeffersonLake ChamplainEmbargo Act violations[12]August 23, 1831Andrew JacksonYesNorfolk, VirginiaNat Turner's slave rebellion[18]January 28, 1834Andrew JacksonYesWilliamsport, MarylandLabor dispute by workers on Chesapeake and Ohio Canal[19]April 15, 1861Abraham LincolnSouth Carolina, Georgia, Alabama, Florida, Mississippi, Louisiana, Texas, Virginia, North Carolina, Tennessee, and ArkansasCivil war[20]October 17, 1871Ulysses S. GrantNoSouth CarolinaSuppression of Ku Klux Klan[21]September 15, 1872Ulysses S. GrantNoNew Orleans, LouisianaUnrest following 1872 Louisiana gubernatorial election[22]May 13, 1874Ulysses S. GrantYesLittle Rock, ArkansasBrooks''Baxter War [23]October 7, 1878Rutherford B. HayesYesLincoln County, New Mexico TerritoryLincoln County War[24]July 7, 1894Grover ClevelandYesChicago, IllinoisPullman Strike[25][26]April 28, 1914Woodrow WilsonYesColoradoColorado Coalfield War[27]July 28, 1932Herbert HooverYesWashington, D.C.Conflict with Bonus Army[28]July 22, 1943Franklin D. RooseveltYesDetroit, Michigan1943 Detroit race riot[29]September 24, 1957Dwight D. EisenhowerNoLittle Rock, ArkansasTo protect Little Rock Nine[30]September 30, 1962John F. KennedyNoOxford, MississippiOle Miss riot of 1962[12]: 13 June 11, 1963John F. KennedyNoTuscaloosa, AlabamaStand in the Schoolhouse Door[31]September 10, 1963John F. KennedyNoAlabamaEnforce desegregation orders on Alabama public schools[12]March 20, 1965Lyndon B. JohnsonYesAlabamaProvide protection to marchers during the Selma to Montgomery Marches[32] [33]July 24, 1967Lyndon B. JohnsonYesDetroit, Michigan1967 Detroit riot[34]April 5, 1968Lyndon B. JohnsonYesWashington, D.C.1968 Washington, D.C., riots[35]April 7, 1968Lyndon B. JohnsonYesBaltimore, MarylandBaltimore riot of 1968[36]April 7, 1968Lyndon B. JohnsonYesChicago, Illinois1968 Chicago riots[37]September 20, 1989George H. W. BushYesSaint Croix, United States Virgin IslandsDisorder following Hurricane Hugo[38]May 1, 1992George H. W. BushYesLos Angeles County, California1992 Los Angeles riots[39]See also [ edit ] Martial law in the United StatesList of national emergencies in the United StatesReferences [ edit ] ^ (10 U.S.C. §§ 251''255; prior to 2016, 10 U.S.C. §§ 331''335; amended 2006, 2007) ^ a b c Hoffmeister, Thaddeus (2010). "An Insurrection Act for the Twenty-First Century". Stetson Law Review. 39: 898. Once finalized, the Enforcement Act was quietly tucked into a large defense authorization bill: the John Warner Defense Authorization Act of 2007. Very few people, including many members of Congress who voted on the larger defense bill, actually knew they were also voting to modify the Insurrection Act. The secrecy surrounding the Enforcement Act was so pervasive that the actual sponsor of the new legislation remains unknown to this day. ^ Magsamen, Kelly (June 12, 2020). "4 Ways Congress Can Amend the Insurrection Act". Center for American Progress . Retrieved June 18, 2020 . ^ a b c Banks, William C. (2009). "Providing Supplemental Security '' The Insurrection Act and the Military Role in Responding to Domestic Crises" (PDF) . Journal of National Security Law & Policy. 3. Archived (PDF) from the original on August 8, 2017 . Retrieved June 2, 2020 . ^ Coakley, Robert (1988). The role of federal military forces in domestic disorders: 1789''1878. Washington: Center of Military History, US Army. p. 228. ^ "The Posse Comitatus Act and Related Matters: The Use of the Military to Execute Civilian Law" (PDF) . Congressional Research Service. 2018. Archived (PDF) from the original on June 2, 2020 . Retrieved June 2, 2020 . ^ a b Moore, Cortney (June 1, 2020). "What is the Insurrection Act?". FOXBusiness . Retrieved June 18, 2020 . ^ Ninth Congress. Sees. H. Ch. 37, 39, 40, 41. 1807. ^ "What Is The Insurrection Act That Trump Is Threatening To Invoke?". NPR.org . Retrieved June 18, 2020 . ^ "[USC02] 10 USC Ch. 13: Insurrection". uscode.house.gov . Retrieved June 18, 2020 . ^ Hauser, Christine (June 2, 2020). "What Is the Insurrection Act of 1807, the Law Behind Trump's Threat to States?". The New York Times. ISSN 0362-4331. Archived from the original on June 3, 2020 . Retrieved June 3, 2020 . ^ a b c d Beckler, Mark M. (2008). Insurrection Act Restored: States Likely to Maintain Authority Over National Guard in Domestic Emergencies (PDF) . Fort Leavenworth, Kansas: School of Advanced Military Studies United States Army Command and General Staff College. Archived (PDF) from the original on June 2, 2020 . Retrieved June 2, 2020 . ^ Elsea, Jennifer K. (August 14, 2006). "The Use of Federal Troops for Disaster Assistance: Legal Issues" (PDF) . Congressional Research Service. Archived (PDF) from the original on June 2, 2020 . Retrieved June 1, 2020 . ^ "Trump says he will deploy military if state officials can't contain protest violence". NBC News. Archived from the original on June 3, 2020 . Retrieved June 2, 2020 . ^ Carney, Jordain (June 1, 2020). "Cotton: Trump should use Insurrection Act to deploy active-duty military to cities". The Hill. Archived from the original on June 3, 2020 . Retrieved June 2, 2020 . ^ MDParadis (June 3, 2020). "Can Trump Use the Insurrection Act to Deploy Troops to American Streets?". Lawfare . Retrieved June 18, 2020 . ^ "Statement by the President". whitehouse.gov . Retrieved June 18, 2020 '' via National Archives. ^ Coakley, Robert (1988). The role of federal military forces in domestic disorders : 1789''1878. Washington: Center of Military History, US Army. p. 93. ^ Coakley, Robert (1988). The role of federal military forces in domestic disorders : 1789''1878. Washington: Center of Military History, US Army. p. 93. ^ "A Proclamation" (PDF) . ^ Coakley, Robert (1988). The role of federal military forces in domestic disorders : 1789''1878. Washington: Center of Military History, US Army. p. 312. ^ Coakley, Robert (1988). The role of federal military forces in domestic disorders : 1789''1878. Washington: Center of Military History, US Army. p. 326. ^ Coakley, Robert (1988). The role of federal military forces in domestic disorders : 1789''1878. Washington: Center of Military History, US Army. p. 333. ^ Laurie; Cole (1997). The Role of Federal Military Forces in Domestic Disorders, 1877''1945. Washington: Center of Military History, United States Army. p. 68. ^ Eric Arnesen (2004). The Human Tradition in American Labor History. Rowman & Littlefield. p. 96. ISBN 978-0842029872. Archived from the original on April 24, 2016. ^ Laurie; Cole (1997). The Role of Federal Military Forces in Domestic Disorders, 1877''1945. Washington: Center of Military History, United States Army. p. 138. ^ Laurie; Cole (1997). The Role of Federal Military Forces in Domestic Disorders, 1877''1945. Washington: Center of Military History, United States Army. p. 208. ^ Laurie; Cole (1997). The Role of Federal Military Forces in Domestic Disorders, 1877''1945. Washington: Center of Military History, United States Army. p. 374. ^ Laurie; Cole (1997). The Role of Federal Military Forces in Domestic Disorders, 1877''1945. Washington: Center of Military History, United States Army. p. 414. ^ Scheips (2012). The Role of Federal Military Forces in Domestic Disorders, 1945''1992. Washington: Center of Military History. p. 46. ^ Scheips (2012). The Role of Federal Military Forces in Domestic Disorders, 1945''1992. Washington: Center of Military History. p. 150. ^ "Executive Order 11207 '' Providing Federal Assistance in the State of Alabama | The American Presidency Project". www.presidency.ucsb.edu . Retrieved July 28, 2020 . ^ Scheips, Paul (2012). The Role of Federal Military Forces in Domestic Disorders, 1945''1992. Center of Military History, U.S. Army. p. 163. ^ Scheips (2012). The Role of Federal Military Forces in Domestic Disorders, 1945''1992. Washington: Center of Military History. p. 46. ^ Scheips (2012). The Role of Federal Military Forces in Domestic Disorders, 1945''1992. Washington: Center of Military History. p. 284. ^ Scheips. The role of Federal Military Forces in Domestic Disorders, 1945''1992. United States Army Center of Military History. p. 333. ^ Janson, Donald (April 7, 1968). "MORE SOLDIERS SENT TO CONTROL WASHINGTON AND CHICAGO RIOTS;; 5,000 Troops Are Flown To Chicago for Riot Duty 5,000 U.S. Troops Sent as Chicago Riots Spread; Death Toll Is 9, and 300 Are Hurt A YOUTH CURFEW ORDERED BY DALEY 7,500 Guard Troops Help to Patrol the City '' 800 Persons Seized". The New York Times. Archived from the original on June 3, 2020 . Retrieved June 1, 2020 . ^ Scheips (2012). The Role of Federal Military Forces in Domestic Disorders, 1945''1992. Washington: Center of Military History. p. 441. ^ "Operation Garden Plot, JTF-LA Joint Task Force Los Angeles". GlobalSecurity.org. Archived from the original on December 28, 2019 . Retrieved June 1, 2020 . External links [ edit ] Proclamation 157 '' Declaring that Peace, Order, Tranquillity, and Civil Authority Now Exists in and Throughout the Whole of the United States of America (20 August 1866)Proclamation On The Embargo '' President Thomas Jefferson (19 April 1808)Proclamation 3204 '' Obstruction of Justice in the State of Arkansas, President Dwight Eisenhower (invoking the Insurrection Act to send troops to Little Rock, Arkansas, to enforce school desegregation orders)(23 September 1957)Executive Order 11,053 '' Providing Assistance for the Removal of Unlawful Obstructions of Justice in the State of Mississippi, President John F. Kennedy (September 30, 1962)"The Posse Comitatus Act and Related Matters: The Use of the Military to Execute Civilian Law," Updated November 6, 2018, Congressional Research Service. https://fas.org/sgp/crs/natsec/R42659.pdf
Noodle Gun
Bill gates common core
AGENDER - A Guide to Understanding Gender Identity and Pronouns : NPR
Thu, 03 Jun 2021 11:47
"Pronouns are basically how we identify ourselves apart from our name. It's how someone refers to you in conversation," says Mary Emily O'Hara, a communications officer at GLAAD. "And when you're speaking to people, it's a really simple way to affirm their identity." Kaz Fantone for NPR hide caption
toggle caption Kaz Fantone for NPR "Pronouns are basically how we identify ourselves apart from our name. It's how someone refers to you in conversation," says Mary Emily O'Hara, a communications officer at GLAAD. "And when you're speaking to people, it's a really simple way to affirm their identity."
Kaz Fantone for NPR Issues of equality and acceptance of transgender and nonbinary people '-- along with challenges to their rights '-- have become a major topic in the headlines. These issues can involve words and ideas and identities that are new to some.
That's why we've put together a glossary of terms relating to gender identity. Our goal is to help people communicate accurately and respectfully with one another.
Proper use of gender identity terms, including pronouns, is a crucial way to signal courtesy and acceptance. Alex Schmider, associate director of transgender representation at GLAAD, compares using someone's correct pronouns to pronouncing their name correctly '' "a way of respecting them and referring to them in a way that's consistent and true to who they are."
Glossary of gender identity termsThis guide was created with help from GLAAD. We also referenced resources from the National Center for Transgender Equality, the Trans Journalists Association, NLGJA: The Association of LGBTQ Journalists, Human Rights Campaign, InterAct and the American Psychological Association. This guide is not exhaustive, and is Western and U.S.-centric. Other cultures may use different labels and have other conceptions of gender.
One thing to note: Language changes. Some of the terms now in common usage are different from those used in the past to describe similar ideas, identities and experiences. Some people may continue to use terms that are less commonly used now to describe themselves, and some people may use different terms entirely. What's important is recognizing and respecting people as individuals.
Jump to a term: Sex, gender, gender identity, gender expression, cisgender, transgender, nonbinary, agender, gender-expansive, gender transition, gender dysphoria, sexual orientation, intersex
Jump to Pronouns: questions and answers
Sex refers to a person's biological status and is typically assigned at birth, usually on the basis of external anatomy. Sex is typically categorized as male, female or intersex.
Gender is often defined as a social construct of norms, behaviors and roles that varies between societies and over time. Gender is often categorized as male, female or nonbinary.
Gender identity is one's own internal sense of self and their gender, whether that is man, woman, neither or both. Unlike gender expression, gender identity is not outwardly visible to others.
For most people, gender identity aligns with the sex assigned at birth, the American Psychological Association notes. For transgender people, gender identity differs in varying degrees from the sex assigned at birth.
Gender expression is how a person presents gender outwardly, through behavior, clothing, voice or other perceived characteristics. Society identifies these cues as masculine or feminine, although what is considered masculine or feminine changes over time and varies by culture.
Cisgender, or simply cis, is an adjective that describes a person whose gender identity aligns with the sex they were assigned at birth.
Transgender, or simply trans, is an adjective used to describe someone whose gender identity differs from the sex assigned at birth. A transgender man, for example, is someone who was listed as female at birth but whose gender identity is male.
Cisgender and transgender have their origins in Latin-derived prefixes of "cis" and "trans" '-- cis, meaning "on this side of" and trans, meaning "across from" or "on the other side of." Both adjectives are used to describe experiences of someone's gender identity.
Nonbinary is a term that can be used by people who do not describe themselves or their genders as fitting into the categories of man or woman. A range of terms are used to refer to these experiences; nonbinary and genderqueer are among the terms that are sometimes used.
Agender is an adjective that can describe a person who does not identify as any gender.
Gender-expansive is an adjective that can describe someone with a more flexible gender identity than might be associated with a typical gender binary.
Gender transition is a process a person may take to bring themselves and/or their bodies into alignment with their gender identity. It's not just one step. Transitioning can include any, none or all of the following: telling one's friends, family and co-workers; changing one's name and pronouns; updating legal documents; medical interventions such as hormone therapy; or surgical intervention, often called gender confirmation surgery.
Gender dysphoria refers to psychological distress that results from an incongruence between one's sex assigned at birth and one's gender identity. Not all trans people experience dysphoria, and those who do may experience it at varying levels of intensity.
Gender dysphoria is a diagnosis listed in the Diagnostic and Statistical Manual of Mental Disorders. Some argue that such a diagnosis inappropriately pathologizes gender incongruence, while others contend that a diagnosis makes it easier for transgender people to access necessary medical treatment.
Sexual orientation refers to the enduring physical, romantic and/or emotional attraction to members of the same and/or other genders, including lesbian, gay, bisexual and straight orientations.
People don't need to have had specific sexual experiences to know their own sexual orientation. They need not have had any sexual experience at all. They need not be in a relationship, dating or partnered with anyone for their sexual orientation to be validated. For example, if a bisexual woman is partnered with a man, that does not mean she is not still bisexual.
Sexual orientation is separate from gender identity. As GLAAD notes, "Transgender people may be straight, lesbian, gay, bisexual or queer. For example, a person who transitions from male to female and is attracted solely to men would typically identify as a straight woman. A person who transitions from female to male and is attracted solely to men would typically identify as a gay man."
Intersex is an umbrella term used to describe people with differences in reproductive anatomy, chromosomes or hormones that don't fit typical definitions of male and female.
Intersex can refer to a number of natural variations, some of them laid out by InterAct. Being intersex is not the same as being nonbinary or transgender, which are terms typically related to gender identity.
Pronouns: questions and answersWhat is the role of pronouns in acknowledging someone's gender identity?
Everyone has pronouns that are used when referring to them '' and getting those pronouns right is not exclusively a transgender issue.
"Pronouns are basically how we identify ourselves apart from our name. It's how someone refers to you in conversation," says Mary Emily O'Hara, a communications officer at GLAAD. "And when you're speaking to people, it's a really simple way to affirm their identity."
"So, for example, using the correct pronouns for trans and nonbinary youth is a way to let them know that you see them, you affirm them, you accept them and to let them know that they're loved during a time when they're really being targeted by so many discriminatory anti-trans state laws and policies," O'Hara says.
"It's really just about letting someone know that you accept their identity. And it's as simple as that."
Getting the words right is about respect and accuracy, says Rodrigo Heng-Lehtinen, deputy executive director of the National Center for Transgender Equality. Kaz Fantone for NPR hide caption
toggle caption Kaz Fantone for NPR Getting the words right is about respect and accuracy, says Rodrigo Heng-Lehtinen, deputy executive director of the National Center for Transgender Equality.
Kaz Fantone for NPR What's the right way to find out a person's pronouns?
Start by giving your own '' for example, "My pronouns are she/her."
"If I was introducing myself to someone, I would say, 'I'm Rodrigo. I use him pronouns. What about you?' " says Rodrigo Heng-Lehtinen, deputy executive director of the National Center for Transgender Equality.
O'Hara says, "It may feel awkward at first, but eventually it just becomes another one of those get-to-know-you questions."
Should people be asking everyone their pronouns? Or does it depend on the setting?
Knowing each other's pronouns helps you be sure you have accurate information about another person.
How a person appears in terms of gender expression "doesn't indicate anything about what their gender identity is," GLAAD's Schmider says. By sharing pronouns, "you're going to get to know someone a little better."
And while it can be awkward at first, it can quickly become routine.
Heng-Lehtinen notes that the practice of stating one's pronouns at the bottom of an email or during introductions at a meeting can also relieve some headaches for people whose first names are less common or gender ambiguous.
"Sometimes Americans look at a name and are like, 'I have no idea if I'm supposed to say he or she for this name' '-- not because the person's trans, but just because the name is of a culture that you don't recognize and you genuinely do not know. So having the pronouns listed saves everyone the headache," Heng-Lehtinen says. "It can be really, really quick once you make a habit of it. And I think it saves a lot of embarrassment for everybody."
Might some people be uncomfortable sharing their pronouns in a public setting?
Schmider says for cisgender people, sharing their pronouns is generally pretty easy '' so long as they recognize that they have pronouns and know what they are. For others, it could be more difficult to share their pronouns in places where they don't know people.
But there are still benefits in sharing pronouns, he says. "It's an indication that they understand that gender expression does not equal gender identity, that you're not judging people just based on the way they look and making assumptions about their gender beyond what you actually know about them."
How is "they" used as a singular pronoun?
"They" is already commonly used as a singular pronoun when we are talking about someone, and we don't know who they are, O'Hara notes. Using they/them pronouns for someone you do know simply represents "just a little bit of a switch."
"You're just asking someone to not act as if they don't know you, but to remove gendered language from their vocabulary when they're talking about you," O'Hara says.
"I identify as nonbinary myself and I appear feminine. People often assume that my pronouns are she/her. So they will use those. And I'll just gently correct them and say, hey, you know what, my pronouns are they/them just FYI, for future reference or something like that," they say.
O'Hara says their family and friends still struggle with getting the pronouns right '-- and sometimes O'Hara struggles to remember others' pronouns, too.
"In my community, in the queer community, with a lot of trans and nonbinary people, we all frequently remind each other or remind ourselves. It's a sort of constant mindfulness where you are always catching up a little bit," they say.
"You might know someone for 10 years, and then they let you know their pronouns have changed. It's going to take you a little while to adjust, and that's fine. It's OK to make those mistakes and correct yourself, and it's OK to gently correct someone else."
What if I make a mistake and misgender someone, or use the wrong words?
Simply apologize and move on.
"I think it's perfectly natural to not know the right words to use at first. We're only human. It takes any of us some time to get to know a new concept," Heng-Lehtinen says. "The important thing is to just be interested in continuing to learn. So if you mess up some language, you just say, 'Oh, I'm so sorry,' correct yourself and move forward. No need to make it any more complicated than that. Doing that really simple gesture of apologizing quickly and moving on shows the other person that you care. And that makes a really big difference."
Why are pronouns typically given in the format "she/her" or "they/them" rather than just "she" or "they"?
The different iterations reflect that pronouns change based on how they're used in a sentence. And the "he/him" format is actually shorter than the previously common "he/him/his" format.
"People used to say all three and then it got down to two," Heng-Lehtinen laughs. He says staff at his organization was recently wondering if the custom will eventually shorten to just one pronoun. "There's no real rule about it. It's absolutely just been habit," he says.
But he notes a benefit of using he/his and she/her: He and she rhyme. "If somebody just says he or she, I could very easily mishear that and then still get it wrong."
What does it mean if a person uses the pronouns "he/they" or "she/they"?
"That means that the person uses both pronouns, and you can alternate between those when referring to them. So either pronoun would be fine '-- and ideally mix it up, use both. It just means that they use both pronouns that they're listing," Heng-Lehtinen says.
Schmider says it depends on the person: "For some people, they don't mind those pronouns being interchanged for them. And for some people, they are using one specific pronoun in one context and another set of pronouns in another, dependent on maybe safety or comfortability."
The best approach, Schmider says, is to listen to how people refer to themselves.
Why might someone's name be different than what's listed on their ID?
Heng-Lehtinen notes that there's a perception when a person comes out as transgender, they change their name and that's that. But the reality is a lot more complicated and expensive when it comes to updating your name on government documents.
"It is not the same process as changing your last name when you get married. There is bizarrely a separate set of rules for when you are changing your name in marriage versus changing your name for any other reason. And it's more difficult in the latter," he says.
"When you're transgender, you might not be able to update all of your government IDs, even though you want to," he says. "I've been out for over a decade. I still have not been able to update all of my documents because the policies are so onerous. I've been able to update my driver's license, Social Security card and passport, but I cannot update my birth certificate."
"Just because a transgender person doesn't have their authentic name on their ID doesn't mean it's not the name that they really use every day," he advises. "So just be mindful to refer to people by the name they really use regardless of their driver's license."
NPR's Danny Nett contributed to this report.
Rijksmuseum Slavery Exhibit Revisits 'Golden Age' | Smart News | Smithsonian Magazine
Wed, 02 Jun 2021 20:57
Smart News Keeping you current A Rijksmuseum exhibition explores the legacy of colonialism and misleading nature of the term ''Dutch Golden Age'' Anonymous, Enslaved Men Digging Trenches, c. 1850 (Courtesy of the Rijksmuseum) smithsonianmag.com June 1, 2021
Historians studying the Netherlands' history sometimes refer to the 17th century as the ''Dutch Golden Age.'' The term refers to an era of unprecedented wealth in the Dutch Republic, when artists such as Rembrandt van Rijn and Johannes Vermeer painted masterpieces and intellectual life flourished in cities like Amsterdam and Delft.
But this glittery phrase obscures a dark truth: Many of the republic's wealthiest residents made their fortunes through the enslavement, sale and exploitation of African people. The dissonance between the ''Golden Age'' descriptor and this horrific reality is such that in 2019, the Amsterdam Museum announced plans to remove the term from its galleries'--a major step in nationwide efforts to explain and contextualize Dutch citizens' role in the transatlantic slave trade.
Now, a major exhibition at the Rijksmuseum in Amsterdam is examining this period in all its brutality. ''Slavery,'' which debuted online last month and is set to welcome in-person visitors when the museum reopens this summer, traces the global history of colonialism through the stories of ten individuals, including those who suffered enslavement and those who profited from it.
All told, reports Daniel Boffey for the Guardian, Dutch traders enslaved and forcibly transported some 600,000 African people to the Americas and between 660,000 and 1.1 million people around the Indian Ocean during the so-called ''Golden Age.''
As Valika Smeulders, head of the museum's history department, tells Mike Corder of the Associated Press (AP), organizers aimed to create a show that emphasizes how this legacy has shaped the lives of all Dutch residents'--not just the descendants of the enslaved.
''We wanted to make the case, that this is a history that speaks to anybody in the Netherlands,'' she says. ''It belongs to all of us, so that's why we chose a personal approach.''
Speaking with Emi Eleode of the Art Newspaper, Smeulders adds that the museum also revised the wall text for about 70 objects with previously undisclosed relationships to the slave trade.
For the exhibition, curators united more than 140 artifacts that trace the history of Dutch involvement in the slave trade between the early 1600s and 1863, when the practice was outlawed in Suriname and the Antilles, per the Guardian. (At the time, the former was a Dutch plantation colony known as Surinam; the latter refers to a group of Caribbean islands, some of which were then under Dutch control.) These include items cherished by enslaved people, such as blue sparkling glass beads that were once used as currency on the Dutch island of Sint Eustatius. Local legend holds that at the moment of emancipation, people threw these beads into the ocean in an expression of joy, reports the Art Newspaper.
Curators also included works that are rarely explicitly linked to slavery: For instance, two Rembrandt portraits in the exhibition depict wealthy elites who profited from enslavement. Another display case holds a richly decorated brass collar that researchers once thought belonged to a family dog. As it turns out, the collar was actually designed to be worn by enslaved Black people who worked in some of the Netherland's wealthiest households, according to the Guardian.
Ten individual narratives anchor the show. One is the story of Wally, an enslaved man who was forced to work on a sugar plantation in Suriname in the early 18th century. In 1707, Wally fled captivity after arguing with his enslavers; later, he was recaptured, tortured and burned to death for attempting to escape.
An audio guide for the show includes the rarely heard oral history of Ma Chichi, a woman born into slavery in 1853. In the recording, which was made when she was 105 years old in 1958, Chichi relates her grandmothers' experiences living as an enslaved woman in 18th-century Cura§ao, notes the Guardian.
The show also features the story of Oopjen Coppit, the wealthy Dutch widow of Marten Soolmans, whose family owned the largest sugar refinery in Amsterdam. Per the AP, men and women enslaved in South America harvested the crops processed at the refinery under brutal conditions. In 1634, Oopjen sat for a portrait by Rembrandt, who rendered the material evidence of her slave-derived wealth in sharp detail: Pearls, lace, gold jewelry and other finery abound.
Though the exhibition focuses on individual narratives specific to Dutch colonial history, curators hope that its major themes resonate far and wide.
''Colonial history is international history that binds Europe, the transatlantic world and the world around the Indian Ocean together,'' Smeulders tells the Art Newspaper.
'' Slavery '' will be on view at the Rijksmuseum in Amsterdam through August 29. Materials from the show are available to peruse online.
Editor of JAMA Leaves After Outcry Over Colleague's Remarks on Racism - The New York Times
Wed, 02 Jun 2021 20:53
Dr. Howard Bauchner will step down after another editor suggested ''taking racism out of the conversation'' on a journal podcast.
Dr. Howard Bauchner during a C-Span appearance in September. He will step down from JAMA at the end of June. Credit... C-Span.org June 1, 2021
Following an outcry over comments about racism made by an editor at JAMA, the influential medical journal, the top editor, Dr. Howard Bauchner, will step down from his post effective June 30.
The move was announced on Tuesday by the American Medical Association, which oversees the journal. Dr. Bauchner, who had led JAMA since 2011, had been on administrative leave since March because of an ongoing investigation into comments made on the journal's podcast.
Dr. Edward Livingston, another editor at JAMA, had claimed that socioeconomic factors, not structural racism, held back communities of color. A tweet promoting the podcast had said that no physician could be racist. It was later deleted.
''I remain profoundly disappointed in myself for the lapses that led to the publishing of the tweet and podcast,'' Dr. Bauchner said in a statement. ''Although I did not write or even see the tweet, or create the podcast, as editor in chief, I am ultimately responsible for them.''
Last month, the A.M.A.'s leaders admitted to serious missteps and proposed a three-year plan to ''dismantle structural racism'' within the organization and in medicine. The announcement on Tuesday did not mention the status of the investigation at JAMA. The journal declined further comment.
''This is a real moment for JAMA and the A.M.A. to recreate themselves from a founding history that was based in segregation and racism to one that is now based on racial equity,'' said Dr. Stella Safo, a Black primary care physician at the Icahn School of Medicine at Mount Sinai in New York.
Dr. Safo and her colleagues started a petition, now signed by more than 9,000 people, that had called on JAMA to restructure its staff and hold a series of town hall conversations about racism in medicine. ''I think that this is a step in the right direction,'' she said of the announcement.
But other critics said they were withholding judgment to see how the organization addressed what they saw as pervasive neglect of covering racism's impact on health in its journals.
''In the entire history of all the JAMA network journals, there's only been one non-white editor,'' noted Dr. Raymond Givens, a cardiologist at Columbia University in New York. In October, Dr. Givens wrote to Dr. Bauchner, noting that editors at the JAMA journals were overwhelmingly white and male. Dr. Bauchner did not respond, according to Dr. Givens.
''This is not cause to celebrate,'' he said of the announcement, adding that he had not intended to jeopardize Dr. Bauchner's job. Nor will appointing a top editor of color resolve the issues, Dr. Givens said.
''Looking for just a person of color misses the point,'' he added. ''I'm more interested in a bold voice. I want somebody who is willing to take a stand, push to move things forward.''
The podcast that set the events in motion aired on Feb. 24 and did not include any Black researchers or experts on racism in medicine.
''Structural racism is an unfortunate term,'' Dr. Livingston, who is white, said on the podcast. ''Personally, I think taking racism out of the conversation will help. Many people like myself are offended by the implication that we are somehow racist.''
The podcast was promoted with a tweet from the journal that said, ''No physician is racist, so how can there be structural racism in health care?'' Following widespread protest in the medical community, the journal took down the podcast and deleted the tweet.
''Comments made in the podcast were inaccurate, offensive, hurtful and inconsistent with the standards of JAMA,'' Dr. Bauchner said in a statement released a week later. ''We are instituting changes that will address and prevent such failures from happening again.''
Dr. Livingston later resigned, and the A.M.A. placed Dr. Bauchner on administrative leave on March 25.
The JAMA family of journals added four new titles under Dr. Bauchner's leadership, and expanded to include podcasts, videos and new, shorter article types. But critics noted that the journals rarely addressed structural racism in medicine, and more often published papers linking health disparities to socioeconomic or biological factors.
Dr. Bauchner's exit offered the journals a chance to improve, said Dr. Mary Bassett, professor of the practice of health and human rights at Harvard University.
''Medical journals have helped build the racist idea that races have intrinsic differences that have a bearing on health,'' Dr. Bassett said. Journals are ''challenged to embrace, not only accept, racism as a health issue.''
Dr. Bauchner told The New York Times last month that JAMA had published ''more than 100 articles on issues such as social determinants of health, health care disparities and structural racism over just the last five years.'' He also noted that JAMA accepted only a tiny fraction of the manuscripts it had received.
He said in the statement on Tuesday that the journal would be better served by his resignation. ''The best path forward for the JAMA Network, and for me personally, is to create an opportunity for new leadership at JAMA,'' he said.
In an editorial published in JAMA on Tuesday, colleagues at the journal lauded Dr. Bauchner's leadership, saying he ''has left an indelible legacy of progress, innovation and excellence in medical journalism.''
The A.M.A. said it has begun a search for Dr. Bauchner's replacement. The journal's executive editor, Dr. Phil Fontanarosa, will serve as interim editor in chief.
Whoever the new editor may be, he or she will need to acknowledge the profound impact of structural racism on health outcomes for communities of color, Dr. Bassett said.
''Racism works in ways that are structural and not simply as the result of ignorant, misguided or even racist individuals,'' she added. ''As a new editor in chief is sought, there will be a chance for JAMA to lead in dismantling this idea. I hope they grab it.''
BTC
AMC, GameStop Bets Put Short Sellers Down More Than $3 Billion on Wednesday | Barron's
Thu, 03 Jun 2021 11:13
AMC Entertainment's market capitalization eclipsed GameStop, its peer in the so-called meme stock trade, on Wednesday. But any way you slice the incredible rallies in these stocks, short sellers betting against them are down big.
AMC stock climbed 95% to $62.55 on Wednesday, bringing its market cap to $28.17 billion. GameStop jumped 13% to $282.24, hitting a $19.97 billion market cap. Shares of both companies have rallied amid heightened short interest, options volume, and enthusiasm from retail traders.
Ihor...
AMC Entertainment 's market capitalization eclipsed GameStop , its peer in the so-called meme stock trade, on Wednesday. But any way you slice the incredible rallies in these stocks, short sellers betting against them are down big.
AMC stock climbed 95% to $62.55 on Wednesday, bringing its market cap to $28.17 billion. GameStop jumped 13% to $282.24, hitting a $19.97 billion market cap. Shares of both companies have rallied amid heightened short interest, options volume, and enthusiasm from retail traders.
Ihor Dusaniwsky, managing director at the short selling analytics firm S3 Partners, told Barron's he estimates AMC's short interest was recently at 90.87 million shares, or about 18% of shares available for trading. He pegs GameStop's short interest at 11.31 million shares or 19.8% of the float.
Dusaniwsky said short sellers betting against AMC were down $2.77 billion on Wednesday alone, bringing year-to-date losses to more than $5.22 billion. For GameStop, he estimates a loss of $375.7 million on Wednesday, and $7.15 billion in 2021.
Other meme stocks, including Bed Bath & Beyond (BBBY) and BlackBerry (BB), surged on Wednesday too.
The recent resurgence of meme stocks has once again brought mainstream attention to Wall Street. On Reddit investing forums such as WallStreetBets and AMCStock, the recent action has been celebrated as a win for the average person. But not everyone has been so enthused.
''I never would have believed it, but the recklessness of a segment of retail investors appears to have no bounds in this market,'' Whitney Tilson of Empire Financial Research wrote in a note Wednesday. ''This type of short-term rally is to be expected, and for stocks like these, this is an opportunity to add to a short or put position because it's clearly a dead-cat bounce.''
David Trainer, CEO of investment research firm New Constructs, wrote that AMC's business was trending in the wrong direction before the pandemic. Since then, he noted that AMC has diluted existing shares via millions in stock sales, adding that the stock is worthless considering its debt load and weak earnings prospects.
''The surge in shares of AMC Entertainment is yet another sign of the reckless meme stock-driven investing landscape that we find ourselves in today,'' Trainer said. ''Wall Street insiders are preying on the naivete of retail meme stock traders. There is no fundamental reason to be buying shares of AMC Entertainment.''
What's ahead for investors is anyone's guess. Calling a top for meme stocks has been a fool's errand this year. But eventually, the fundamentals will need to catch up to the valuation.
Write to Connor Smith at connor.smith@barrons.com
COVID-20-26
Explainer: So far, low risk of human spread of H10N3 bird flu | Reuters
Thu, 03 Jun 2021 11:03
Workers vaccinate chicks with the H9 bird flu vaccine at a farm in Changfeng county, Anhui province, April 14, 2013. REUTERS/Stringer/File Photo
A 41-year-old man in China's eastern province of Jiangsu has been confirmed as the first human case of infection with a rare strain of bird flu known as H10N3, Beijing's National Health Commission (NHC) has said.
The man, a resident of the city of Zhenjiang, was hospitalized on April 28 and diagnosed with H10N3 on May 28, the health commission said on Tuesday, adding that his condition is stable.
It did not give details on how the man was infected but said investigation of his close contacts found no other cases and the risk of spread was very low.
WHAT DO WE KNOW ABOUT H10N3?
Little is known about the virus, which appears to be rare in birds, according to the Food and Agriculture Organisation (FAO), and does not cause severe disease.
The World Health Organization (WHO) said while the source of the patient's exposure to the H10N3 virus was not known and no other cases were found among the local population, there was no indication of human-to-human transmission yet.
Yet avian influenza viruses that have little impact on birds can be much more serious in people, such as the H7N9 strain that killed almost 300 people in China during the winter of 2016-2017. The WHO has said there had been only rare instances of person-to-person spread of the H7N9 virus.
WHAT ARE THE RISKS?
The risk of further infection with H10N3 is currently believed to be very low, with experts describing the case as "sporadic".
Such cases occur occasionally in China which has huge populations of both farmed and wild birds of many species.
And with growing surveillance of avian influenza in the human population, more infections with bird flu viruses are being picked up.
In February, Russia reported the first human infection with the H5N8 virus that caused huge damage on poultry farms across Europe, Russia and East Asia last winter.
Seven people infected with the virus were asymptomatic, authorities said.
Experts will be on alert for any clusters of H10N3 cases, but for now, a single case is not much of a concern.
"As long as avian influenza viruses circulate in poultry, sporadic infection of avian influenza in humans is not surprising, which is a vivid reminder that the threat of an influenza pandemic is persistent," the WHO told Reuters in a statement.
The strain is "not a very common virus," and only around 160 isolates of the virus were reported in the 40 years to 2018, according to Filip Claes, regional laboratory coordinator of the FAO's Emergency Centre for Transboundary Animal Diseases at the regional office for Asia and the Pacific.
Still, flu viruses can mutate rapidly and mix with other strains circulating on farms or among migratory birds, known as "reassortment," meaning they could make genetic changes that pose a transmission threat to humans.
WHAT DO WE STILL NEED TO KNOW?
The genetic sequence of the virus that infected the patient has not yet been published, and will be needed to fully assess its risk.
Scientists will want to know how easily H10N3 can infect human cells to determine if it could become a greater risk.
For example, the H5N1 variant that first infected people in 1997 has been the most deadly, killing 455 people globally so far.
It would only take a few mutations before the H5N1 variant gains the ability to spread easily from person-to-person, said Ben Cowling, professor at the School of Public Health at the University of Hong Kong, making it a high priority for surveillance.
Having the genetic information for the H10N3 variant would help assess if it was "close to being the type of virus we should be worried about", he said.
Our Standards: The Thomson Reuters Trust Principles.
Israel
Netanyahu opponents reach coalition deal to oust Israeli PM
Thu, 03 Jun 2021 11:04
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VIDEO - Joshua Kop ðŸ‡...🇺 ðŸ‡"🇱 on Twitter: "@altern8ending ooohhh another for the collection @adamcurry" / Twitter
Thu, 03 Jun 2021 11:00
Joshua Kop ðŸ‡...🇺 ðŸ‡"🇱 : @altern8ending ooohhh another for the collection @adamcurry
Thu Jun 03 10:04:41 +0000 2021
VIDEO - Roberto Wakerell-Cruz '''¸ on Twitter: "Trudeau describes the euphoria of getting a COVID vaccine, tells Canadians to shame their ''crusty uncle who resists'' into getting their shots. What a lunatic. https://t.co/LaXhaQlyT7" / Twitter
Thu, 03 Jun 2021 04:03
Roberto Wakerell-Cruz '''¸ : Trudeau describes the euphoria of getting a COVID vaccine, tells Canadians to shame their ''crusty uncle who resists'... https://t.co/q5XfxHiZdX
Wed Jun 02 15:37:57 +0000 2021
Maverick-Visionaries : @Robertopedia Sophie Trudeau pulled a Melania Trump and refused to hold Justin's hand during the covid 19 vaccinati'... https://t.co/DnjaunNgVv
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A : @Robertopedia Can't believe these are the people who run countries
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CJ Bracky : @Robertopedia People still listening to Prime Minister Blackface?@JustinTrudeau
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The Immortal 🇨ðŸ‡... Christus Vincit : @Robertopedia He's taking Fentanyl for his frisbee injury.
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Guimbo OG : @Robertopedia Would sound better with a black face on
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Jesse : @Robertopedia @TheLastRefuge2 COVID VAX SPIKE PROTEIN TOXIChttps://t.co/dOpJtCn8Lehttps://t.co/lvhIjX4UGh
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Sean Pelette : @Robertopedia Lunatic is a mild description for the moral malady that is @JustinTrudeau
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Star : @Robertopedia Vote him out already, would ya
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@ linny306🁠: @Robertopedia What the fcuck in hell is wrong with his mouth, teeth or tongue. ? Watch it if you can stomach it . S'... https://t.co/ceBTwBmt2F
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Time For Truth! : @Robertopedia @TheLastRefuge2 It's time to arrest these control freaks!
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Dave Doleman 🇨ðŸ‡...🇨ðŸ‡...🇨ðŸ‡... : @Robertopedia Looks more like the euphoria of a nice little sativa buzz.
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BajasKSmith : @Robertopedia GFY @JustinTrudeau
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604Terry - PROTECT GOD and GUNS : @Robertopedia This is EMBARRASSING
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sub_commandante : @Robertopedia @TheLastRefuge2 https://t.co/rKbmaWSekI
Thu Jun 03 03:35:51 +0000 2021
Dave Erickson : @Robertopedia Nuremberg Code article 1 violation by a politician so dumb he allows himself to be filmed doing it: n'... https://t.co/ZNgexVNNEI
Thu Jun 03 03:33:58 +0000 2021
Vaccine Passports Are the Gateway to Fascism : @Robertopedia @TheLastRefuge2 He's a good marionette for his Davos, WEF, CoFR puppetmasters
Thu Jun 03 03:33:54 +0000 2021
VIDEO - razorback1111 on Twitter: "Acting premier @JamesMerlinoMP finally speaks the truth, ''The vaccine is our Enemy '' https://t.co/U0F2e76AG6" / Twitter
Thu, 03 Jun 2021 04:02
razorback1111 : Acting premier @JamesMerlinoMP finally speaks the truth, ''The vaccine is our Enemy '' https://t.co/U0F2e76AG6
Thu Jun 03 02:31:48 +0000 2021
caterina catzella : @razorback11111 @JamesMerlinoMP so what happens when Covaxxed people start testing positive! Do these morons even t'... https://t.co/KWlYH8q6a7
Thu Jun 03 03:50:32 +0000 2021
TrumpSavesTheWorld : @razorback11111 @JamesMerlinoMP https://t.co/trpwQdgzkH
Thu Jun 03 03:49:57 +0000 2021
Michael Smith News : @razorback11111 @JanSummersalt @JamesMerlinoMP Was he on My Favourite Martian?
Thu Jun 03 03:42:50 +0000 2021
JB ðŸ‡...🇺 : @razorback11111 @JanSummersalt @JamesMerlinoMP Ha! When you are so caught up in govt lies and you let this slipðŸ¤...🏼''¸ #COVID19Vic #springst
Thu Jun 03 03:38:29 +0000 2021
Aaron Ashley : @razorback11111 @JamesMerlinoMP "bad acting" Premier lol..
Thu Jun 03 03:21:17 +0000 2021
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Thu Jun 03 03:15:48 +0000 2021
Earthgift2 : @razorback11111 @JamesMerlinoMP https://t.co/W7yJ7iXsRL
Thu Jun 03 03:09:57 +0000 2021
Anastasios (Taso) Manolakis (ðŸ'...ðŸ'...ðŸ'... : @razorback11111 @troothmonstah @JamesMerlinoMP The @ScottMorrisonMP govt is our enemy James#auspol #qt
Thu Jun 03 03:07:12 +0000 2021
Con Spiracy : @razorback11111 @JamesMerlinoMP Maybe he has to finish 'the job'. Bring ALP down. Morrisons plug pull on federal fu'... https://t.co/UOw8QyEiih
Thu Jun 03 03:05:07 +0000 2021
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Thu Jun 03 02:56:07 +0000 2021
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Thu Jun 03 02:50:05 +0000 2021
Land cruiser : @razorback11111 @JamesMerlinoMP https://t.co/dKfPFvBGP8
Thu Jun 03 02:48:51 +0000 2021
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Thu Jun 03 02:47:29 +0000 2021
Aaron Ashley : @razorback11111 @JamesMerlinoMP Sucking agenda here.Incompence to think 'theres' only 1 way out of this pandemic''... https://t.co/XYajKbZGPG
Thu Jun 03 02:41:37 +0000 2021
something's fu''Œky in victoria, australia : @razorback11111 @JamesMerlinoMP Is he referring to supply, rollout or other?
Thu Jun 03 02:38:49 +0000 2021
Aaron Ashley : @razorback11111 @JamesMerlinoMP hahaha its hard to hold down continual bullshitting lies, at some point ya slip up'... https://t.co/GloMkSCHxR
Thu Jun 03 02:37:12 +0000 2021
VIDEO - Sackler Family, Owner Of Purdue Pharma, Set To Win Immunity From Opioid Lawsuits : NPR
Thu, 03 Jun 2021 00:02
Members of the Sackler family who own Purdue Pharma, the maker of Oxycontin, moved a step closer to winning immunity from opioid lawsuits. Erik McGregor/LightRocket via Getty Images hide caption
toggle caption Erik McGregor/LightRocket via Getty Images Members of the Sackler family who own Purdue Pharma, the maker of Oxycontin, moved a step closer to winning immunity from opioid lawsuits.
Erik McGregor/LightRocket via Getty Images After more than a year of high stakes negotiations with billions of dollars on the line, a bankruptcy plan for Purdue Pharma, the maker of Oxycontin, cleared a major hurdle late Wednesday.
Federal Judge Robert Drain in White Plains, N.Y., moved the controversial deal forward despite objections from dozens of state attorneys general, setting the stage for a final vote by the company's creditors expected this summer.
The drug maker filed for Chapter 11 protection in 2019 facing an avalanche of lawsuits tied to its aggressive opioid sales practices.
Public health experts and many government officials say the introduction of Oxycontin fueled the nation's deadly opioid epidemic.
This development brings members of the Sackler family, some of whom own Purdue Pharma and served on the company's board of directors, a step closer to winning immunity from future opioid lawsuits.
According to legal documents filed as part of the case, that immunity would extend to dozens of family members, more than 160 financial trusts, and at least 170 companies, consultants and other entities associated with the Sacklers.
"The Sacklers are paying $4.275 billion and they very much plan and expect to be done with this chapter," said Marshall Huebner, an attorney representing Purdue Pharma, during a hearing last week.
One of the firms that would secure protection from future opioid lawsuits under the deal is Luther Strange & Associates, founded by former U.S. Sen. Luther Strange (R-Alabama) who helped Purdue Pharma pitch the bankruptcy plan to Republican state attorneys general.
While Purdue Pharma has twice pleaded guilty to federal crimes relating to its opioid marketing schemes, no member of the Sackler family has faced criminal charges.
Appearing before a congressional panel last December, members of the Sackler family said they had done nothing wrong. "The family and the board acted legally and ethically," testified David Sackler, who served on Purdue Pharma's board for six years.
In addition to contributing money from their personal fortunes, the Sacklers have agreed to give up control of Purdue Pharma. They will, however, retain ownership of other companies, admit no wrongdoing and will remain one of the wealthiest families in America.
Two dozen states still oppose the bankruptcy deal that's been negotiated largely behind closed doors. They argue it would improperly strip them of authority to sue members of the family for alleged wrongdoing.
"I don't believe ... at this point the plan is confirmable," said Andrew Troop, an attorney representing a coalition of "non-consenting" states, during a hearing last week.
But Judge Drain said this stage of the bankruptcy process wasn't focused on final approval of the plan.
Instead, the court evaluated whether Purdue Pharma and the Sacklers had provided enough information and transparency to allow creditors to make an informed decision on the deal's financial merits.
Despite a significant veil of secrecy surrounding the proceedings '-- which included an expansive investigation of the Sacklers that will likely never be made public '-- Drain signaled the so-called "disclosure statement" was adequate.
"I found the disclosure statement to contain adequate information," he said Wednesday.
Attorneys representing Purdue Pharma and other parties in the bankruptcy process said negotiations continue.
"We are mediating as we speak with the non-consenting states," Huebner said on Wednesday. "We continue to be open and listen as hard as we can to all other remaining objectors between now and confirmation."
A vote and final approval expected by August
In the coming weeks, more than 600,000 individuals, companies and governments with claims against Purdue Pharma will vote on the package, described by attorneys involved in the process as one of the most complicated and controversial bankruptcies ever.
A final confirmation hearing is scheduled for Aug. 9. Judge Drain has indicated he believes this plan offers the best chance at financial relief for those harmed by Purdue Pharma's Oxycontin business.
Supporters of the bankruptcy deal say the alternative would be a chaotic scrum of risky and expensive litigation. "Billions would be spent on legal fees," Huebner said last week. "It would be years until claimants might get a recovery."
The reorganization plan also includes a detailed formula that would be used to distribute hundreds of millions of dollars each year in aid to communities and individuals harmed by opioids.
A growing number of government officials have signaled they expect to vote in favor of the deal.
But critics, including more than 20 mostly Democratic state attorneys general, say the Sacklers are improperly piggybacking on their company's bankruptcy without actually filing for bankruptcy themselves.
"The bankruptcy system should not be allowed to shield non-bankrupt billionaires," said Massachusetts Attorney General Maura Healey in an interview with NPR last month.
More and more legal scholars have also questioned whether bankruptcy court is the proper venue for a case that involves a addiction crisis that has killed hundreds of thousands of Americans.
"[T]he most socially important chapter 11 case in history will be determined through a process that does not comport with basic notions of due process," wrote Adam Levitin, who teaches law at Georgetown University, in an article published last month in the Texas Law Review.
In a legal brief filed with the bankruptcy court on Tuesday, Jonathan Lipson, a legal scholar at Temple University who also represents a client with a claim against Purdue Pharma, noted this case is complicated by allegations of criminal conduct leveled against the Sacklers by the Justice Department last October.
"These cases have been overshadowed by a single, critical question: who is responsible for [Purdue Pharma's] confessed crimes and the harm they caused?" Lipson wrote in his motion.
Lipson requested an independent examiner be appointed to review whether the Chapter 11 process has been handled appropriately.
Again, the Sacklers have denied any wrongdoing, have never been charged with crimes. As part of their settlement with the DOJ, members of the Sackler family paid $225 million while denying the allegations.
Sackler family pushes back against "false allegations"
During last week's hearing an attorney representing the Raymond Sackler branch of the family said they have created a website designed to offer a rebuttal to critics of the Sacklers.
"Raymond Sackler family members have consistently expressed their regret that OxyContin, which continues to help patients suffering from chronic pain, unexpectedly became part of the opioid crisis," the family said in a statement.
In civil lawsuits already filed against the Sacklers, government officials allege some family members had direct knowledge of the highly addictive nature of Oxycontin but continued to push Purdue Pharma's sales team to maximize profits.
The DOJ settlement with the Sacklers also included the allegation some family members engaged in "fraudulent" transfers of wealth and approved a marketing plan that focused on pushing Oxycontin sales to "extreme, high-volume prescribers."
According to the Justice Department statement, that program led "health care providers to prescribe opioids for uses that were unsafe, ineffective, and medically unnecessary, and that often led to abuse and diversion."
The Sacklers maintain they did nothing wrong and acted ethically. If this bankruptcy plan is approved and upheld on appeal, it's unlikely the allegations will ever be tested in court.
More than 400 civil cases already filed against members of the Sackler family for alleged wrongdoing would be halted.
VIDEO - FRANTIC MSNBC Cries: How Can Feds Overturn State Election Laws? | Newsbusters
Wed, 02 Jun 2021 23:26
While most Americans were enjoying their Memorial Day weekend by spending time with family and paying tribute to our brave men and women who gave their lives for our country, MSNBC decided to continue vile and vitriolic rants against its political enemies in the Republican Party.
On Monday night, MSNBC's 11th Hour anchor Brian Williams led the segment by playing a clip of President Biden's Memorial Day speech in which he claimed ''democracy itself is in peril.'' The left-wing host then brought on a panel which consisted of New York Times Correspondent Peter Baker, Texas Tribune Washington Bureau Chief Abby Livingston, and Neal Katyal, Obama's former acting Solicitor General.
Baker started off the insanity by making the preposterous claim that American democracy is under attack in much the same way as other third world countries around the world. ''I spent four years living in Moscow, where I was a correspondent for the Washington Post,'' he recalled. Baker warned that the U.S. was no better than such authoritarian regimes: ''I traveled and reported from the Middle East, I traveled from countries all around the world, and we've seen, I think, in recent times, stories here I would have only imagined we would have covered as foreign correspondents.''
That comment is laughable on its face. Especially coming from a putative reporter who claims he's been to the Middle East, which throughout its history has seen no shortages of fraudulent elections, including not allowing women to vote.
Later in the segment, Williams wailed that the federal government should be able to cancel state election laws at will: "What power does the federal government have? What power does the Department of Justice have when states, when Republicans in legislatures are working so hard, and in some cases, passing laws signed by the governor to restrict voting?"
Not to be out done by Peter Baker, Neal Katyal decided to go even lower into the leftist sewer by claiming the Republican Party is an ''anti-democracy party.'' Katyal even decided to re-write history with this eyebrow-raising quote: ''And when the Democratic Party was named and originated, I don't think anyone thought that to be controversial, to be like, in favor of democracy. Who would be against that? But now we know, you have to view this Texas vote in light of so much else that the Republican Party has been doing, like a concerted effort in Georgia and other states to roll back voting, a slavish devotion to a filibuster that bears no relationship to the filibuster our founders knew that's totally empowering of a small minority.''
It's truly startling that Katyal's knowledge of history is so poor that he would ignore the Democratic Party's dismal legacy of supporting slavery, armed insurrection, and Jim Crow-era racism.
MSNBC can't even give the political attacks a day off. Even on a solemn occasion like Memorial Day, the far-left cable channel can't help itself.
This appalling display of left-wing media bias was brought to you by Verizon and Applebee's. Contact them at the Conservatives Fight Back page here
Read the transcript below by clicking "expand:"
The 11th Hour
5/31/2021
11:05 PM
BRIAN WILLIAMS: Peter, I would like to begin with you, given the life you have led in this country and overseas, given all the stories you have chronicled as a journalist, how bracing, how striking was it to hear an American president declare our democracy in peril on this Memorial Day 2021?
PETER BAKER [NEW YORK TIMES WHITE HOUSE CORRESPONDENT]: Well, I think what we have learned in recent times, is that the democracy we all thought was pretty well cemented is in fact fragile. The institutions, the norms, the standards, the traditions that we believed were rock solid in the United States have their vulnerabilities, just as we have seen in other countries around the world. I spent four years living in Moscow, where I was a correspondent for the Washington Post, I traveled and reported from the Middle East, I traveled from countries all around the world, and we've seen, I think, in recent times, stories here I would have only imagined we would have covered as foreign correspondents, and I think that's why you're right today had a certain poignancy because the people who fought and died to protect this country, whose memories we honor today, did so with the idea that they were, you know, defending a robust and healthy democratic system, one I think we do need to continue to protect and guard, whether it be on the battlefields or in our society today. That's why I think, one thing we all focus on today no matter what party we're in, whether in journalism or in government or politics, we give thanks for those who have stood up for us and we think about the role we ourselves have to play, making this a more perfect nation, as they say.
WILLIAMS: Abby, to Peter's last point, that somehow brings this story to you because it brings the story to Texas, and the prong of this, that Republicans in that state are busy and trying to achieve. Tell us how long Democrats can stave this off, how long can the impact from a walk-out last and what power the governor and Republicans have regarding a special session.
ABBY LIVINGSTON [WASHINGTON BUREAU CHIEF, TEXAS TRIBUNE]: Well a special session is called by the governor, otherwise he, Texas actually has an incredibly weak executive. But the how long is really not the specific question. It's when. So the governor, there will be a special session in the fall almost no matter what to count for redistricting and the census delay of that. But the Lt. Governor Dan Patrick is urging him to call one in June. So it's a matter of when did they pick it up again? In June or the fall? And it's very unlikely Democrats will in the end be able to override this. In some ways this bill could get worse for them and so it's very much up in the air but I think it did inject some enthusiasm into the state party and to national Democrats to have a cause specific on this voting rights issue to jump on to.
WILLIAMS: I want to return to this topic with you in a moment after we hear from Neal, and Neal we asked 30 different versions of this question to you and the former feds who we rely on during times like this. What power does the federal government have? What power does the Department of Justice have when states, when Republicans in legislatures are working so hard, and in some cases, passing laws signed by the governor to restrict voting?
NEAL KATYAL [FMR. ACTING SOLICITOR GENERAL UNDER OBAMA]: So before getting to that Brian. I think there is a bigger point here, there is a forest and this forest I think unites a lot of what we're talking about tonight, not just Texas, and this state but the January 6th commission, Biden's remarks you just averted to, and the name of it is the Republican Party has become an anti-democracy party. And when the Democratic Party was named and originated, I don't think anyone thought that to be controversial, to be like, in favor of democracy. Who would be against that? But now we know, you have to view this Texas vote in light of so much else that the Republican Party has been doing, like a concerted effort in Georgia and other states to roll back voting, a slavish devotion to a filibuster that bears no relationship to the filibuster our founders knew that's totally empowering of a small minority. You've got a party who's scared, you know, heaven forbid to have people vote in Washington, D.C. and Puerto Rico. You've got a party who's hellbent on getting their nominees to the Supreme Court to strike down legislation that they don't like, that's been passed by a majority of people. This is an anti-majority party in the end, and it's a collapsed party. It's a party that lost its moral ground. Ah, you know, It's like the USSR in the Cold War. Yes, they've bluster and strength and insults but they don't have any purpose anymore. And to answer your question, because of the Supreme Court decision in 2013, the federal government is fairly limited in the powers it has. I argued the case in 2009 that saved that part of the Voting Rights Act, but it was reversed in 2013 by a five to four vote. And so right now, pending in Congress is the John Lewis Voting Rights Act which would restore that act. So when Texas tries to pass a bill like this, it would require pre-clearance in Washington, D.C. by a court or by the Justice Department. That's the way stuff operated since 1965 but now it isn't because of that new Supreme Court decision. So we need that law passed. Without it I do fear we will have more and more antics like this from a party that is bent on these antics.
VIDEO - (263) Watch Brianna Keilar eat dead cicadas on live TV - YouTube
Wed, 02 Jun 2021 22:31
VIDEO - (263) The Blue's Clues Pride Parade ðŸ"¸'ðŸŒ Sing-Along Ft. Nina West! - YouTube
Wed, 02 Jun 2021 22:20
VIDEO - kingbaal: "now we better understand who and why Beirut port '..." - No Agenda Social
Wed, 02 Jun 2021 21:47
@ kingbaal @ adam @ Johncdvorak Well, when I was in Lebanon, they weren't too happy that Israel was stealing their oil reserves off their coastline. So I would peg it more to Israel.
VIDEO - (262) Help kids learn that bodies are private [with Scoops & Friends] - YouTube
Wed, 02 Jun 2021 19:20
VIDEO - Dr. McCullough Sounds the Alarm on Covid Jabs: All Covid-19 Vaccines Produce the Dangerous Wuhan Spike Protein (AUDIO)
Wed, 02 Jun 2021 18:25
Dr. Peter A. McCullough sounded the alarm on the Covid-19 vaccines and explained how they all make the dangerous Wuhan spike protein.
Dr. McCullough is an Internist, Cardiologist, Epidemiologist and testified to the Senate Committee on Homeland Security and Governmental Affairs in November 2020.
''It's alarming right now '' we have had over 4400 deaths and 14,000 hospitalizations'....That is probably only the tip of the iceberg,'' Dr. McCullough said in an interview with Rose Unplugged on 1320 AM WJAS.
Dr. McCullough said people who have been infected with Covid-19 should not get the vaccine.
TRENDING: HAPPENING NOW: Pennsylvania Legislative Delegation Sits Down with Arizona Lawmakers to Discuss Election Integrity And Replicating the Audit
The doctor also said pregnant women, women of child-bearing years, children or healthy people under 50 should not get the Covid jab.
Dr. McCullough explained how all Covid-19 vaccines produce the dangerous Wuhan spike protein and what that does to a person's body.
AUDIO:
Check out Rose Unplugged on WJAS 1320 AM '' The Talk of Pittsburgh 1320 AM
DOCTOR SOUNDS THE ALARM ON COVID JABS https://t.co/75fp5szJW6
'-- roseunplugged (@roseunplugged2) June 2, 2021
VIDEO - Mark Stevens on Twitter: "Yep, this is serious. Don't touch that ball! Adelaide's Covid Sherrin crackdown. '...@7NewsMelbourne'(C) @7afl https://t.co/8BvnU0kHUB" / Twitter
Wed, 02 Jun 2021 18:24
Mark Stevens : Yep, this is serious.Don't touch that ball!Adelaide's Covid Sherrin crackdown.'...@7NewsMelbourne'(C) @7afl https://t.co/8BvnU0kHUB
Wed Jun 02 05:48:48 +0000 2021
saffyishere : @Stevo7AFL @7NewsMelbourne @7AFL I suggest if there's so much concern , don't let spectators into the ground!
Wed Jun 02 16:39:46 +0000 2021
MechaRandom42, Professional Smart-A$$🉠: @Stevo7AFL @7NewsMelbourne @7AFL Most people who go out in public have already been vaxxed or don't care about germ'... https://t.co/nq0clbm8rh
Wed Jun 02 16:26:25 +0000 2021
Praz Silva : @Stevo7AFL @7NewsMelbourne @7AFL ðŸ
Wed Jun 02 16:25:08 +0000 2021
Craig Taylor : @Stevo7AFL @7NewsMelbourne @7AFL This is the same govt thought that you could receive the coronavirus off a pizza box!
Wed Jun 02 15:28:04 +0000 2021
Footy Head : @Stevo7AFL @7NewsMelbourne @7AFL I have watched this about 10 times today and laughed just as hard every time 🂠https://t.co/t8WG0da8tn
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KGS : @Stevo7AFL @7NewsMelbourne @7AFL The high paid brainpower making the decisions'... amazing advice'...
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Anthony Anf Brown : @Stevo7AFL @7NewsMelbourne @7AFL Sums up Adelaide's take on this Pandemic!
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Wed Jun 02 14:03:34 +0000 2021
VIDEO - CNBC on Twitter: "Leon Black will retire as CEO of Apollo Global Management by the end of July, but will remain chairman. @LesliePicker has the details. https://t.co/3EiZt5R8rn https://t.co/NDKeZv0cF0" / Twitter
Wed, 02 Jun 2021 18:13
CNBC : Leon Black will retire as CEO of Apollo Global Management by the end of July, but will remain chairman.'... https://t.co/pRCi7v0WjQ
Mon Jan 25 21:56:40 +0000 2021
VIDEO - (262) Anti-Biden flags with profanity going up in the front yards of homes in Cape Coral - YouTube
Wed, 02 Jun 2021 18:01
VIDEO - BREKKIE VON BITCOIN 2021 on Twitter: "@skwp @nntaleb It's never too late to apologize @nntaleb https://t.co/owtwByXQa4" / Twitter
Wed, 02 Jun 2021 16:58
BREKKIE VON BITCOIN 2021 : @skwp @nntaleb It's never too late to apologize @nntaleb https://t.co/owtwByXQa4
Mon May 31 05:00:28 +0000 2021
VIDEO - Shooting in Springfield, Virginia: Police searching for suspects | wusa9.com
Wed, 02 Jun 2021 13:41
Ronnie Marshall, 20, and D'Angelo Strand, 19, are both facing two counts of second-degree murder and two counts of use of a firearm in a commission of a felony.
SPRINGFIELD, Va. '-- Fairfax County Police say two suspects are now in custody in connection with the murder of a husband and wife, both military veterans, in Springfield. Fairfax County Police Chief Kevin Davis said the victims were "viciously shot and killed up close at point-blank range" on their front lawn Wednesday morning.
On Thursday, Fairfax County police released a photo of one of the men responsible: 20-year-old Ronnie Keandre Marshall. The other suspect that was arrested was later identified by authorities as 19-year-old D'Angelo Strand. Both men are facing two counts of second-degree murder along with two counts of use of a firearm in a commission of a felony.
The two men went before a Fairfax County judge Friday and were ordered held without bond.
"It is outrageous, and it is a real aberration for our community," Fairfax County Commonwealth's Attorney Steve Descano said.
Police said they believe the deaths are connected to a dispute or burglary at the house that they were called to just two days earlier.
.@FairfaxCountyPD announce two suspects arrested for murder of two veterans in Springfield yesterday morning. @wusa9 pic.twitter.com/WGZIlue7tc
'-- Tom Dempsey (@KCTomDempsey) May 27, 2021Police identified the man and woman killed as 55-year-old Edward McDaniel Jr., and his 63-year-old wife, Brenda McDaniel. Edward McDaniel was currently an active duty full-bird colonel in the U.S. Army. It is not known at this time which branch of the military Brenda McDaniel served in. Major Ed O'Carroll of Fairfax Police described both victims as "physicians" and "honorable soldiers."
The shooting happened just after 9 a.m. in the 8000 block of Flint Street, police said. There were family members inside the home when the shooting happened, Davis said. Everyone that was in the home has been relocated to a safe place.
Davis said one of the people inside the home may be the son of the victims. Investigators with the Fairfax County Police Department tell WUSA9 that the suspects and one of the victims' family members are believed to be co-workers.
The motive for the shooting remains unknown, but police said they believe both Marshall and Strand are connected to Monday's burglary at the home committed before Wednesday's double murder.
Neighbors said friends of the son have been involved in trouble in the neighborhood before.
"The teenage kids, their friends are bad people," Carlos Buendia, who lives just a few doors down from where the shooting happened, said. "They bring weapons into the neighborhood."
Neighbor Juliana Buendia said she was shocked this incident happened in her neighborhood but said she's sadly not surprised at where the crime happened.
"You never really see people coming and going," she said. "It's the only house where we don't know anybody who lives here.''
Chief Davis and @edocarroll updated the community tonight on this mornings tragic double homicide in Springfield. BOLO light colored 2018 Nissan Altima MD:1EF1479. If seen call 911. https://t.co/nR59ZVSeOb #FCPD pic.twitter.com/ltoiLACqLT
'-- Fairfax County Police (@FairfaxCountyPD) May 27, 2021Police said some neighbors witnessed the shooting, while others reported seeing the couple walking their dog right before the shooting.
"Nice people," neighbor Frank Breen said. "We used to talk every time they come around walking with the dogs.''
The murders of the McDaniels are the ninth and tenth murders of the year in Fairfax County.
A probable cause hearing is scheduled for Aug. 9, at which point prosecutors will have to detail the case against Marshall and Strand, and possibly outline what could have allegedly motivated them to murder the mother and father in the front yard of their house in the prosperous Newington Forest neighborhood.
"We are going to work non-stop until we get the person or persons to justice," Davis said.
Police are offering a $10,000 reward for information in regards to this case. If you have any additional information, please contact the Fairfax County Police Department at 1-866-411-TIPS (866-411-8477).
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VIDEO - (7) Axios on Twitter: "Biden on the anniversary of the Tulsa Race Massacre: ''Terrorism from white supremacy is the most lethal threat to the homeland today.'' https://t.co/5F7lGI7Dv6" / Twitter
Tue, 01 Jun 2021 23:43
Axios : Biden on the anniversary of the Tulsa Race Massacre: ''Terrorism from white supremacy is the most lethal threat to t'... https://t.co/tA9TxrbpAD
Tue Jun 01 21:16:30 +0000 2021
Chuck Mabbott : @axios Not sure what he is trying to prove, just pandering for votes
Tue Jun 01 23:42:37 +0000 2021
Angela Downing : @axios You mean like what you were maybe still are. I haven't heard you apologize for all your past white privilege'... https://t.co/VUwFD0hovL
Tue Jun 01 23:42:25 +0000 2021
If The Shoe Fitz.... : @axios The left will do anything to keep us divided. Power is in numbers. Cut it in half. Keep em divided, keep th'... https://t.co/7w3crSVoA0
Tue Jun 01 23:41:41 +0000 2021
Mr.Ugly : @axios Joe lies again!
Tue Jun 01 23:41:32 +0000 2021
Odds : @axios Biden living still in the 50s
Tue Jun 01 23:41:20 +0000 2021
Wes Morehead : @axios pandering again...white supremacy supporters are no significant threat to USA..we can squash in 5 minutes...'... https://t.co/IME5fAxUD5
Tue Jun 01 23:41:07 +0000 2021
walleye perch : @axios Good when will the founding party of the white supremacists/slave owners/KKK founders, be barred from servi'... https://t.co/SHCx0piFnD
Tue Jun 01 23:40:04 +0000 2021
Todd Szymanski : @axios https://t.co/uPJhYKSxra
Tue Jun 01 23:37:52 +0000 2021
kevvpanther : @axios Pedo joe really talking about blm and antifa
Tue Jun 01 23:37:37 +0000 2021
Hammers are good : @axios Does anyone really believe this? I mean I know there is a constant flow of anti-white propaganda but deep do'... https://t.co/DaE8s2IyBm
Tue Jun 01 23:37:01 +0000 2021
VIDEO - Meat Supplier JBS Shuts Down Slaughterhouses After Cyberattack - YouTube
Tue, 01 Jun 2021 20:33
VIDEO - UN Live United Nations Web TV - A Pandemic Treaty to Make the World Safer
Tue, 01 Jun 2021 20:13
A Pandemic Treaty to Make the World Safer
5 Apr 2021 - The World Health Organization (WHO) chief hailed support for an international pandemic treaty to shield the world from future health crises. Twenty-five heads of government and international agencies have endorsed the treaty, which would signal high-level political action needed to protect the world from future health crisesThe international community should work together ''towards a new international treaty for pandemic preparedness and response'' to build a more robust global health architecture that will protect future generations, world leaders said in a commentary published today in several newspapers around the world.''There will always be new pathogens with pandemic potential,'' said WHO Director-General Dr. Tedros Adhanom Ghebreyesus. ''It's not a matter of if but when.''
VIDEO - Cyberattack hits world's largest meat supplier
Tue, 01 Jun 2021 16:11
CANBERRA, Australia '-- Thousands of meat workers had no work for a second day on Tuesday after a cyberattack crippled the world's largest meat processing company. A government minister said it might be days before production resumes.
JBS is also Australia's largest meat and food processing company, with 47 facilities across the country including abattoirs, feedlots and meat processing sites. JBS employs around 11,000 people.
JBS USA said in a statement from Greeley, Colorado, on Monday that it was the target on Sunday of an ''organized cybersecurity attack'' affecting some of its servers supporting its North American and Australian IT systems.
''The company's backup servers were not affected and it is actively working with an Incident Response firm to restore its systems as soon as possible,'' the statement said.
Australian Agriculture Minister David Littleproud said the government and Australian Federal Police were working with JBS to resolve the problems and to pursue those responsible.
''Despite the fact that JBS accounts for around 20 percent of our processing production here in Australia, we're not expecting there to be significant impacts on exports so long as this isn't a protracted shutdown,'' Littleproud said on Tuesday.
''We're also working with JBS right here in Australia to make sure that we can get some limited capacity up and going in the next couple of days. JBS have been very proactive in that,'' he said.
Littleproud said it was too early to say whether it was a ransomware attack or who might be responsible.
Australian staff learned of the attack when they were turned away from their workplaces on Monday.
JBS exports about 70 percent of what it produces in Australia. But Australia and New Zealand account for only 4 percent of the company's global revenue.
Several consignments of cattle in Queensland state were canceled at short notice and cattle trucks were turned around, Australian Broadcasting Corp. reported.
''We had to send them up on Sunday afternoon and then we got the message in the morning that they'd have to cancel the train because the meat works was going to be shutting for an indefinite amount of time,'' Queensland cattle rancher Colin Baker told ABC.
''We had a wasted day . . . because mustering the cattle, sorting them out and then trucking them up there and then we had to bring them home today and let them all go again,'' Baker added.
VIDEO - IS COVID-19 A BIO-WEAPON?
Tue, 01 Jun 2021 15:29
Rumble '-- IS COVID-19 A BIO-WEAPON?
The origins of #Covid19 are becoming increasingly clear, and Dr. Richard Fleming, cardiologist and researcher walks Del through a shocking paper trail surrounding the SARS-CoV2 virus and its link to Tony Fauci and US funded gain-of-function research.
#FireFauci #GainOfFunction #GOF #FlemingProtocol #Covid19 #LabCreated #WuhanLab #CovidOrigins #TheHighwire #DelBigtree
POSTED: May 13, 2021
VIDEO - (255) THE TOMORROW WAR Official Trailer (2021) - YouTube
Tue, 01 Jun 2021 13:47
VIDEO - Reporters admit dismissing Wuhan lab leak theory in part because Republicans proposed it | Fox News
Tue, 01 Jun 2021 12:53
'Some things may be true even if Donald Trump said them,' ABC's Jonathan Karl saidJournalists continued to acknowledge Sunday that the media's longstanding dismissal of the Wuhan "lab-leak" theory was in part due to Republicans pitching it.
Once widely cast aside as a racist "conspiracy theory" and "fringe" nonsense, the possibility that the coronavirus accidentally leaked from the Wuhan Institute of Virology has gained increasing credence in recent weeks. The saga has led to yet another reckoning for mainstream media journalists about groupthink and bias in the industry. Faced with criticism that they blasted the theory last year for political reasons, some reporters have admitted its Republican origins with figures like Sen. Tom Cotton, R-Ark., former President Donald Trump, and former Secretary of State Mike Pompeo played into why they disparaged it.
ABC News Washington correspondent Jonathan Karl suggested on ABC's "This Week" Sunday that figures like Trump and Pompeo were not taken seriously by members of the media, saying "now serious people are saying it needs a serious inquiry."
REPORTERS BLAME TRUMP FOR NOT INITIALLY FINDING WUHAN LAB THEORY CREDIBLE
"Yes, I think a lot of people have egg on their face," Karl said. "This was an idea that was first put forward by Mike Pompeo, secretary of state, Donald Trump, and look some things may be true even if Donald Trump said them. Because Trump was saying so much else, that was just out of control, and because he was, you know, making a frankly racist appeal talking about Kung Flu, and the China virus, he said flatly this came from that lab, and it was widely dismissed ... but now serious people are saying it needs a serious inquiry."
New York Times reporter David Leonhardt also conceded Sunday many journalists dismissed the lab-leak theory solely because Cotton, a Trump ally and longtime critic of China, proposed it.
"I think people made this mistake. I think a lot of people on the political left and a lot of people in the media made the mistake. They said, 'wow if Tom Cotton is saying something, it can't be true.' Or they assumed that. And that's not right," he said on CNN.
CNN'S SMERCONISH COMPLAINS OF COVID LAB LEAK THEORY 'POLITICS,' DESPITE NETWORK DISMISSING IT FOR MONTHS
NBC's Chuck Todd addressed the issue on "Meet The Press" Sunday, saying that "for many," the lab leak theory got "tangled up in politics" and was conflated with one theory that the Chinese released the virus deliberately.
While interviewing former Trump Deputy National Security Adviser Matthew Pottinger, Todd repeatedly suggested anti-China rhetoric was to blame for media dismissals of the virus.
"Did in some ways, the sort of irrational attacks on China, did that slow down efforts of the intelligence community to actually do some fact-finding?" Todd asked.
"Well, look, I think what slowed down efforts more than anything else were the early statements that were published by a few scientists dismissing the idea that it could have come out of a lab," Pottinger said. "And in fact, caricaturing people who thought that it might have come out of a lab."
"Do you think your former boss' statements contributed to that a little bit?" Todd asked.
WAPO COLUMNIST ROASTS MEDIA ON COVID-19 LAB THEORY ABOUT-FACE: 'ZERO SELF AWARENESS'
"Well, you know, there are political mistakes that lead to, to, you know, trouble in government. And then there are institutional shortcomings," Pottinger said.
The language mirrored that of figures like the New York Times' Maggie Haberman and the Washington Post's Glenn Kessler last week.
"I think it is important to remember that part of the issue is when this was first being reported on and discussed back a few months after the pandemic had begun, was that then President Trump and Mike Pompeo, secretary of state, suggested they've seen evidence that this was formed in a lab and they also suggested that is was not released on purpose. But they refused to release the evidence showing what it was and so because of that made this instantly political," Haberman said on CNN last week.
In a new fact-check timeline that declared the lab theory was "suddenly" credible, Kessler wrote, "The Trump administration's messaging was often accompanied by anti-Chinese rhetoric that made it easier for skeptics to ignore its claims."
Washington Post reporter Aaron Blake wrote an analysis titled, "The vexing 'lab leak' theory on China and the coronavirus," in which he defended reporters dismissing the Trump administration claims that there was a high probability the virus originated in a lab.
FORMER STATE DEPARTMENT OFFICIAL: PROBE INTO COVID ORIGINS FOUND ALMOST NO EVIDENCE SUPPORTING NATURAL ORIGIN
"Given everything we know about how Trump handled such things, caution and skepticism were invited. That (very much warranted) caution and skepticism spilled over into some oversimplification, particularly when it came to summarizing the often more circumspect reporting," Blake wrote.
The Washington Post's Josh Rogin blasted reporters on Saturday for their sudden about-face, saying the facts on the ground had not changed out of the blue, and accusing them of bias, "general incompetence" and even "TDS," short for Trump Derangement Syndrome.
President Biden ordered the intelligence community last week to investigate the origins of the virus and report back in 90 days.
Outlets from the Washington Post and New York Times to CNN and NPR have gone from outright mockery of the idea to taking it seriously, and "fact checks" have been updated with editor's notes about why the theory is no longer necessarily "debunked." Former Centers for Disease Control and Prevention Director Robert Redfield is among the proponents of the theory, pointing to the virus' efficient transmission among humans and the "gain of function" research at the Wuhan lab.
CLICK HERE TO GET THE FOX NEWS APP
The virus' true origins are still unknown.
Fox News' Thomas Barrabi and Andrew Kugle contributed to this report.
VIDEO - TODAY on Twitter: "Naomi Osaka withdrew from the French Open on Monday, a day after she was fined $15,000 by tournament officials for skipping post-match press conferences, citing her mental health. @mollymhunter reports. https://t.co/ZYfYjXArs3"
Tue, 01 Jun 2021 12:49
TODAY : Naomi Osaka withdrew from the French Open on Monday, a day after she was fined $15,000 by tournament officials for'... https://t.co/RbG6Th6uvo
Tue Jun 01 12:07:04 +0000 2021
Zarathustra : @TODAYshow @mollymhunter Naomi Osaka doesn't want to be interviewed because she hears racist comments from Japanese journalists.
Tue Jun 01 12:37:31 +0000 2021
Michelle : @TODAYshow @mollymhunter Leave her alone!! She is asking for support with her mental health and the media is making'... https://t.co/FLgW0HVPOp
Tue Jun 01 12:32:26 +0000 2021
Dave : @TODAYshow @mollymhunter Suggestion. Use that money to get help with your anxiety. Hire a professional spokes perso'... https://t.co/j9GUgR1c5q
Tue Jun 01 12:18:35 +0000 2021
marianne kimball : @TODAYshow @mollymhunter Fined for trying to look out for her mental health? Really? Better re-think that one.
Tue Jun 01 12:18:33 +0000 2021
StikeDCicada ðŸ...—🌲 ðŸ...— : @TODAYshow @mollymhunter She made $55 million last year, maybe she could plunk down 2 grand for media training. 🤷🏽''¸
Tue Jun 01 12:15:22 +0000 2021
Christine Haller : @TODAYshow @mollymhunter I don't understand why it is mandatory to talk to the media. They shouldn't have to if the'... https://t.co/MaA1bfOP1i
Tue Jun 01 12:12:49 +0000 2021
Jenny Sampangwongse : @TODAYshow @mollymhunter Good riddance #NaomiOsaka; Quit trying to move up the intersectional oppressed hierarchy.'... https://t.co/fFnwYYCCf7
Tue Jun 01 12:11:27 +0000 2021
VIDEO - Keith Olbermann on Twitter: "NEW VIDEO: As Texas @GOP votes to end democracy and education there, it's time to take power away from such Failed States. These are bullies. Bullies stop only when THEY are hurt more than they CAN hurt. The Anti-Democ
Tue, 01 Jun 2021 12:12
Keith Olbermann : NEW VIDEO: As Texas @GOP votes to end democracy and education there, it's time to take power away from such Failed'... https://t.co/55J4L0j0Bv
Sun May 30 21:21:40 +0000 2021
MajorBear640 🇺🇲 : @KeithOlbermann @GOP You look like you're about to cry.
Tue Jun 01 12:10:42 +0000 2021
FakeXero : @KeithOlbermann @GOP I hope you're in therapy.
Tue Jun 01 12:09:54 +0000 2021
Saratoga Fan : @KeithOlbermann @GOP What do you consider a failed state?
Tue Jun 01 12:08:32 +0000 2021
A J Burton : @KeithOlbermann @GOP Keith somewhere there is a village short of an idiot the jobs yours.
Tue Jun 01 12:07:51 +0000 2021
VIDEO - TikTok: COVID-19 'Lone Survivor' Fantasy Is Anti-Vax Movement's New Myth
Mon, 31 May 2021 04:13
Unvaccinated TikTokers are fantasizing they'll be the "lone survivors" of the COVID-19 pandemic. Videos show TikTokers performing to the soundtrack from "The Transformers." Vaccine misinformation has been spreading on TikTok since the start of the pandemic. Visit Insider's homepage for more stories. Unvaccinated TikTokers are rallying together by pretending they're the "lone survivors" of the coronavirus pandemic.
In more than a dozen videos seen by Insider, TikTok users are falsely claiming those who have not been vaccinated will be the last remaining survivors on earth.
Some of the videos involve TikTokers facing away from the camera, with their hands on their hips, as audio from the 2007 "The Transformers" plays in the background.
Read more: TikTok and YouTube influencers reveal the wild gifts they've received from fans and brands, including fake thongs, spicy peppers, and antique dolls
"I am Optimus Prime," the audio says "and I send this message to any surviving Autobots taking refuge among the stars. We are here. We are waiting." The videos are accompanied by hashtags including #unvaccinated and #wearehere.
One video in this format, which shows two men standing in their garden with their hands on their hips, has almost half a million views.
Other formats of the "lone survivor" videos include people whistling to the "Hunger Games" theme song alongside the caption: "Calling out all my unvaccinated Americans."
A TikToker, who made one of these videos, told Insider: "It's not like I believe everyone will die from the vaccine but I liked this format and am a 'Transformers' fan."
The person, aged 21, also said they don't plan to get the vaccine because they believe "it can harm young people" and said they think it's "unfair that the government is making people take them." They did not want to be named for this article.
The Pfizer, Moderna, and Johnson & Johnson vaccines have all been authorized by the Food and Drug Administration (FDA) and have very good safety records.
In October last year, Insider identified more than two dozen videos in which people were pretending to experience painful or sinister side-effects after taking a COVID-19 vaccine.
Many of the videos were fictional or joking in nature, however, experts told Insider they can still help spread anti-vaccine sentiment.
The lone survivor videos also come as the demand for COVID-19 vaccinations is slowing down across the US '-- a trend that has some experts concerned.
Kolina Koltai, a postdoctoral fellow at the Center for an Informed Public at The University of Washington, told Insider she's "not a fan of the videos" because they "can encourage vaccine hesitancy."
However, Koltai believes that while they promote anti-vaccine sentiment, they are "not doing anything that would fall under vaccine misinformation ... They don't make any claims about the vaccine, like if it is dangerous or that it is unnecessary."
"Expressing your opinion or sentiment on vaccines is something that should be allowed on platforms, even at the expense that it may encourage others to be more vaccine-hesitant," she added. "The bigger issue is vaccine misinformation on social media platforms and the persistent anti-vaccination narratives being promoted."
A TikTok spokesperson told Insider: "Our Community Guidelines prohibit content that's false or misleading, including medical misinformation related to COVID-19, and anti-vaccine disinformation more broadly ... In addition to removing content, we redirect searches associated with vaccine or COVID-19 disinformation to our Community Guidelines and do not autocomplete anti-vaccine hashtags in search."
The company did not include their COVID-19 tags on any of the "lone survivor" videos.
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VIDEO - The late veteran conspiracy researcher Eustace Mullins talks vaccines & how the Rockefellers own and control the pharmaceutical industry '' great information '' David Icke
Mon, 31 May 2021 04:10
Copyright (C) 2021 David Icke Books Limited. All Rights Reserved.
VIDEO - Rabbit Hole
Sun, 30 May 2021 20:36
Zombie ApocalypseEveryone injected with zombie juice is going to become a zombie because it's the intended purpose. FEMA camps are ready to house the zombies because they're walking, talking biohazards that are breeding mutant variants. It's genocide science. The information presented here is part of an ordered sequence. Take your time with it, go in order, and be patient while the videos load.
Death is not the end of life. Souls are simply being re-organized during the Great Reset. It's also necessary for the Great Awakening so that people see they can't let others decide their fate for them. The pathogen is the path of awakening. Crisis awakens the Christ.
When we align with Truth above all else, we transcend duality and elevate our world to triality.
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The Satanic Overlords ensure the cure is always censored.
These videos were removed even from alternative platforms, but truth always prevails.Save them to your computer, and share them widely.
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The mRNA technology is turning people into walking, talking biohazards that are spawning the mutant variations and creating a zombie apocalypse for operation depopulation.
Anyone injected with mRNA technology is probably going to die very quickly. The science is simple. The pathogen is equated with self, so the body stops fighting it. No fight means no symptoms. You won't get sick. You'll die. The rationale is obvious. The clinical studies demonstrate the obvious. The real-world results prove the point.
In addition, the RNA is reverse-transcribed into the DNA turning people into mutant chimeras. The body may or may not accept the modification. If it's rejected, it will either be purged or the body will destroy itself in an attempt to get rid of it.
The science is conclusive.
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There's countless videos circulating of magnets sticking to the injection site, light bulbs illuminating at the touch of the injection site, bluetooth activating as people walk nearby.
People are being injected with classified Star Trek technology to assimilate them into a 5G network for surveillance and mind control. 5G is a Trojan Horse. It's the silent killer. 5G prevents 5D and fundamentally alters the electromagnetics of our planet leading to multiple species extinction and the gradual deteroration of all that's organic.
At the same time, they're using molecular mimicry to sterilize the population by fooling the immune system into attacking the sexual organs. This Frankenstein created by morons with power may annihilate the human race.
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Free speech is humanity's only chance of survivalIf we don't put our differences aside and come together as a people to seek win-win solutions, our civilization will fall. Just as Atlantis was destroyed by Gaia who ushered in a great flood to purge the morons with power, we're now once again at the Precipice of Evolution. We've crossed a line of no return. If we don't unite now, we self-destruct.
My title as Messiah is not ego or grandiosity. It's reality. It's cold hard mathematics. I understand that most people will react in shock and disbelief at this information. I don't need you to believe me. I request that we put our differences aside and work in partnership for the highest good of our world.
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This loveable darling who invented PCR, Kary Mullis, was murdered in 2019 to prevent the world from learning about the "number lies" that currently has everyone chasing their tails in futility.
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Excessive amplification cycles is one of the strategies of the scamdemic.The test is meaningless.
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Our legal system is owned and operated by a Satanic-Luciferian elite that doesn't care about the welfare of the people.
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Michael Yeadon, former VP of Pfizer, understands the situation. Those who can be silenced don't need to be murdered. Unfortunately, there's something wrong with this video.The important quote "not my crime" appears to be unwatchable.
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He's now working with LiberalSpring to help save humanity.
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The Age of the Black Sun fades at the dawning of Age of the Gold Sun as a stepping stone to the Age of the White Sun. I'm the new Adam Weishaupt, not by choice, but by divine inheritence. I don't seek power. It's bestowed onto me. I accept my position with grace and honor.
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EMF emissions at the injection site are from the Star Trek nanotechnology used to assimilate the world into a hive mind collective.
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Satan aka Bill Gates is a moron with power who will doom our species to extinction. After the famine depopulation backup plan, autonomous regions independent of legal oversight will implement descending spirals of hell in a new form of feudalism called technocracy. Government by science. You'll own nothing and be happy while the Satanic Overlords consolidate power by assimilating the unweary into Satan's Paradise.
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In order for Satan to maintain control over the matter realm, it's necessary to disconnect it from the spirit realm. The Corona Hoax is designed to disconnect the Crown Chakra from the Mother of God by intercepting the divine transmission in the left year and replacing it with the AI Red Wave frequency of the Dark Mother. The Vagina Crown of the Lunar Matrix prevents us from uniting with our spiritual parents. Big Brother is an abusive parent.
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Chelsea Handler found out too late. Her daemon has already been removed.
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The technology spreads throughout the body. Since the vaccinated are guinea pigs, it's possible that some people are in control groups and may have been injected with a placebo.
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In the inverted system of the Satanic hell realm, ignorance and incompetence is promoted while dissenting voices are silenced by any means necessary.
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Many of our most trusted leaders are complete lies.
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Bluetooth is just the beginning. Soon, 5G-compatible robots will be able to hunt you down and exterminate you if you think about unapproved topics.
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I've said it before, and I'll say it again. Mythology is more accurate than causality as a model for reality. Materialistic science is a dead-end road to species extinction. The era of spirit science is upon us. Klaus Schwab, the current head of the snake, replacing former head Satan (Bill Gates), is Dr Evil from Austin Powers.
Stroke your hairless cat while you still can.The powers of Austin are coming for you.
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Our emerging global society is bifurcating into two factions - Transhumanism and Enlightenment. Choose your side before you get assimilated by the Borg. Transhumanism merges man with machine in order to redirect our organic ascension process into an artificial trap. Satan's Paradise is the descending path. The Mark of the Beast is the vaccine. Deny our spiritual reality to your peril. This materialistic hologram is an illusion. Our immortal souls can be trapped for harvesting in phantom worlds.
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Medbeds are highly classified alien Star Trek technology that use electromagnetism to heal our DNA. Lucifer is hiding them because Satan wants to depopulate the planet. This husband and wife pairing is cannibalistic. Their 20 year mating cycle is finally giving birth to a third. Uranus claims the throne because this is the dawning of the Age of Aquarius.
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As our society graduates to galactic citizenship, we must educate ourselves on our new rights. Knowledge is power.
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The pathogen is the path of awakening. Crisis awakens the Christ.
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This is her final performance before being gently escorted to the slaughterhouse.
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Informed consent is the difference between penetration and violation. The former is benevolent while the latter is malevolent. If you cannot think and reason for yourself, you may not survive the New World Order.
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STORIES
FireEye selling products business and name for $1.2 billion
Thu, 03 Jun 2021 13:19
The FireEye logo is seen outside the company's offices in Milpitas, California, December 29, 2014.
Beck Diefenbach | Reuters
FireEye said Wednesday it's selling its products business, including the FireEye name, to a consortium led by private-equity firm Symphony Technology Group for $1.2 billion in cash.
The U.S. cybersecurity firm said the sale will split Mandiant Solutions, its cyber forensics unit, from its cloud security, network and email products.
Shares of FireEye were relatively flat after hours. The company said the deal is expected to close by the end of the fourth quarter.
FireEye was the subject of a cyberattack in December of last year, which it believes was state-sponsored. Microsoft in February credited the company's transparency about the breach in helping it discover that had also been attacked.
FireEye CEO Kevin Mandia said the sale will help it grow its Mandiant Solutions business.
"After closing, we will be able to concentrate exclusively on scaling our intelligence and frontline expertise through the Mandiant Advantage platform, while the FireEye Products business will be able to prioritize investment on its cloud-first security product portfolio," Mandia added.
The sale is just the latest example of a big-dollar tech deal going to private equity.
With the exception of special purpose acquisition companies, seven of the 12 largest tech acquisitions in the U.S. in 2021 have been carried out by private equity firms, according to data from FactSet.
In Wednesday's announcement, FireEye also said its board approved a share buyback program of up to $500 million.
United States Patent: 11021532
Thu, 03 Jun 2021 11:44
This disclosure provides superhuman antibodies and antigen-binding fragments that can be administered to an individual that is infected or suspected of being infected with a virus. Superhuman antibodies and antigen-binding fragments provided herein can be capable of treating or curing the virus, and which may provide protection against the virus for up to at least several weeks. Superhuman antibodies and antigen-binding fragments provided herein can be used to diagnose a SARS Cov-2 infection.
Wilson Sonsini Goodrichh & Rosati Parent Case Text CROSS-REFERENCE
This application claims the benefit of U.S. Provisional Application No. 63/014,948, filed on Apr. 24, 2020; 63/013,485, filed Apr. 21, 2020; and 62/993,630, filed Mar. 23, 2020, all of which are incorporated herein by reference in their entireties for all purposes. Claims
What is claimed is:
1. An antibody or an antigen-binding fragment that selectively binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that comprises a variable heavy chain(VH) complementarity determining region 1 (CDR1) having an amino acid sequence of SEQ ID NO: 214; a VH CDR2 having an amino acid sequence of SEQ ID NO: 262; a VH CDR3 having an amino acid sequence of SEQ ID NO: 310; a variable light chain (VL) CDR1having an amino acid sequence of SEQ ID NO: 46; a VL CDR2 having an amino acid sequence of SEQ ID NO: 94; and a VL CDR3 having an amino acid sequence of SEQ ID NO: 142.
2. The antibody or the antigen-binding fragment of claim 1, that comprises a VH having an amino acid sequence that is at least 90% identical to SEQ ID NO: 358 and a VL having an amino acid sequence that is at least 90% identical to SEQ ID NO:382.
3. The antibody or the antigen-binding fragment of claim 2, wherein the antibody is an IgG, an IgM, an IgE, an IgA, or an IgD, or is derived therefrom.
4. The antibody or the antigen-binding fragment of claim 2, that comprises a binding affinity of less than 70 nanomolar (nM).
5. The antibody or the antigen-binding fragment of claim 2, wherein the antigen-binding fragment comprises a Fab, a Fab', a F(ab').sub.2, a variable fragment (Fv), a triabody, a tetrabody, a minibody, a bispecific F(ab').sub.2, a trispecificF(ab').sub.2, a diabody, a bispecific diabody, a single chain variable fragment (scFv), a scFv-Fc, a Fab-Fc, a VHH, or a bispecific scFv.
6. A method of preventing or treating a SARS-CoV-2 viral infection or COVID19 in a subject in need thereof, comprising administering to the subject the antibody or the antigen-binding fragment of claim 1.
7. The method of claim 6, that further comprises administering one or more additional therapies or drugs to the subject.
8. A method of diagnosing a subject as being infected with a SARS-CoV-2 virus or suspected of being infected with a SARS-CoV-2 virus, the method comprising contacting a sample obtained from the subject with the antibody or the antigen-bindingfragment of claim 1; detecting the presence or absence of an antibody/SARS-CoV-2 virus complex or an antigen-binding fragment/SARS-CoV-2 virus complex; and diagnosing the subject as being infected with a SARS-CoV-2 virus when the presence of theantibody/SARS-CoV-2 virus complex or the antigen-binding fragment/SARS-CoV-2 virus complex is detected.
9. The method of claim 8, wherein the sample comprises a nasal swab, a tissue sample, saliva, or blood.
10. The method of claim 8, wherein detecting the presence or absence of the antibody/SARS-CoV-2 virus complex or the antigen-binding fragment/SARS-CoV-2 virus complex comprises an enzyme linked immunosorbent assay (ELISA), an immunospot assay,a lateral flow assay, flow cytometry, immunohistochemistry, or a western blot.
11. The antibody or the antigen-binding fragment of claim 2, that selectively binds to a receptor binding domain (RBD) of SARS-CoV-2, wherein the RBD comprises an amino acid sequence of SEQ ID NO: 494.
12. An antibody or an antigen-binding fragment that selectively binds to a SARS-CoV-2, that comprises: (i) a VH CDR1 having an amino acid sequence of SEQ ID NO: 200, a VH CDR2 having an amino acid sequence of SEQ ID NO: 248, a VH CDR3 having anamino acid sequence of SEQ ID NO: 296, a VL CDR1 having an amino acid sequence of SEQ ID NO: 32, a VL CDR2 having an amino acid sequence of SEQ ID NO: 80, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 128; (ii) a VH CDR1 having an amino acidsequence of SEQ ID NO: 430, a VH CDR2 having an amino acid sequence of SEQ ID NO: 431, a VH CDR3 having an amino acid sequence of SEQ ID NO: 429, a VL CDR1 having an amino acid sequence of SEQ ID NO: 432, a VL CDR2 having an amino acid sequence of SEQ IDNO: 433, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 441; or (iii) a VH CDR1 having an amino acid sequence of SEQ ID NO: 215, a VH CDR2 having an amino acid sequence of SEQ ID NO: 263, a VH CDR3 having an amino acid sequence of SEQ ID NO:311, a VL CDR1 having an amino acid sequence of SEQ ID NO: 47, a VL CDR2 having an amino acid sequence of SEQ ID NO: 95, and a VL CDR3 having an amino acid sequence of SEQ ID NO: 143.
13. An antibody or an antigen-binding fragment that selectively binds to a SARS-CoV-2, that comprises a VH having an amino acid sequence of SEQ ID NO: 358 and a VL having an amino acid sequence of SEQ ID NO: 382.
14. The antibody or the antigen-binding fragment of claim 1, that selectively binds to a receptor binding domain (RBD) of SARS-CoV-2, wherein the RBD comprises an amino acid sequence of SEQ ID NO: 494.
15. The antibody or the antigen-binding fragment of claim 1, that comprises a binding affinity of less than 70 nanomolar (nM).
16. The antibody or the antigen-binding fragment of claim 1, wherein the antibody is an IgG, an IgM, an IgE, an IgA, or an IgD, or is derived therefrom.
17. The antibody or the antigen-binding fragment of claim 1, wherein the antigen-binding fragment comprises a Fab, a Fab', a F(ab').sub.2, a variable fragment (Fv), a triabody, a tetrabody, a minibody, a bispecific F(ab').sub.2, a trispecificF(ab').sub.2, a diabody, a bispecific diabody, a single chain variable fragment (scFv), a scFv-Fc, a Fab-Fc, a VHH, or a bispecific scFv. Description
SEQUENCE LISTING
The instant application contains a Sequence Listing which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 22, 2020, is named 44561-724_201_SL.txt and is184,726 bytes in size.
BACKGROUND OF THE INVENTION
Viruses are small infectious agents that can enter a living cell of an organism. Genetic information from a virus can be injected into the living cell, and can replicate inside the living cell, and be released. Viruses can cause disease in theorganism and can spread between organisms. The mechanism by which a virus can cause disease can vary between viruses and can include cell lysis and/or cell death.
Coronaviruses are a group of related viruses that can cause disease, for example in mammals and birds. Coronaviruses can cause respiratory tract infections, such as those causing pneumonia-like diseases, that can range from mild to lethal.
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is a coronavirus responsible for a pandemic of a respiratory disease, COVID19. An outbreak of this virus was first identified in Wuhan, Hubei, China, and a pandemic was recognized bythe World Health Organization on Mar. 11, 2020. The range of the severity of COVID19 is large, and ranges from asymptomatic to death. Approximately 20% of infected individuals can require hospitalization. The mortality rate of COVID19 appears to bebetween 1% and 4%. COVID19 is transmitted between people, for example through respiratory droplets, and can be spread by symptomatic and asymptomatic individuals, including during an extended incubation period. Social distancing has been appliedworldwide to decrease the spread of COVID19.
Currently, there is no vaccine or treatment for COVID19. There is an urgent need for new compositions that can be used for treating or preventing SARS-Cov-2 infection and for diagnosing an exposure to SARS-Cov-2 virus.
SUMMARY OF THE INVENTION
Provided herein is a superhuman (SH) antibody or antigen-binding fragment that is derived from 2dd8, 2ghw, 3bgf, 6nb6, or CR3022, and that selectively binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In some embodiments,the SH antibody or antigen-binding fragment has a binding affinity of less than 50 nanomolar (nM). In further embodiments, the SH antibody or antigen-binding fragment selectively binds to a receptor binding domain (RBD) of severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2). In further embodiments, the SH antibody or antigen-binding fragment comprises an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to a VH CDR3 comprising an amino acid sequence of any one ofany one of SEQ ID NOS: 293-316 and 429. In further embodiments, the SH antibody or antigen-binding fragment comprises further comprise an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to one or more of a VH CDR1 comprisingan amino acid sequence of any one of SEQ ID NOS: 197-220 and 430 and a VH CDR2 comprising an amino acid sequence of any one of SEQ ID NOS: 245-268 and 431.
Provided herein is an SH antibody or antigen-binding fragment as described herein, that comprises a VH chain that comprises: a. a VH CDR1 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ IDNOS: 197-220 and 430; b. a VH CDR2 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 245-268 and 431; and c. a VH CDR3 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100%identical to any one of SEQ ID NOS: 293-316 and 429.
Provided herein is an SH antibody or antigen-binding fragment as described herein, that comprises a VL chain that comprises: a. a VL CDR1 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 29-52and 432; b. a VL CDR2 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 77-100 and 433; and
a VL CDR3 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 125-148 and 441.
Provided herein is an SH antibody or antigen-binding fragment that comprises (i) a VH CDR3 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 296; (ii) a VH CDR1 having an amino acid sequence thatis at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 200; (ii) a VH CDR2 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 248; (iv) a VL CDR1 having an amino acid sequence that is at least 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 32; (v) a VL CDR2 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 80; and (vi) a VL CDR3 having an amino acid sequence that is at least 90%, 95%, 98%, 99%,or 100% identical to SEQ ID NO: 128. Further provided herein is an SH antibody or antigen-binding fragment that comprises (i) a VH CDR3 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 310; (ii) a VHCDR1 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 214; (ii) a VH CDR2 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 262; (iv) a VL CDR1 having anamino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 46; (v) a VL CDR2 having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 94; and (vi) a VL CDR3 having an amino acidsequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 142. Further provided herein is an SH antibody or antigen-binding fragment that comprises an amino acid sequence of any one of SEQ ID NOS: 5-28, a FW-L2 comprising an aminoacid sequence of any one of SEQ ID NOS: 53-76, a FW-L3 comprising an amino acid sequence of any one of any one of SEQ ID NOS: 101-124, a FW-L4 comprising amino acid of any one of SEQ ID NOS: 149-172, 435, a FW-H1 comprising an amino acid sequence of anyone of SEQ ID NOS: 173-196, a FW-H2 comprising amino acid sequence of any one of SEQ ID NOS: 221-244, a FW-H3 comprising an amino acid sequence of any one of SEQ ID NOS: 269-292, and a FW-H4 comprising an amino acid sequence of any one of SEQ ID NOS:317-340. Further provided herein is an SH antibody or antigen-binding fragment that comprises a VH chain having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 341-364 and 436. Further providedherein is an SH antibody or antigen-binding fragment that comprises a VL chain having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 365-388 and 437. Further provided herein is an SH antibody orantigen-binding fragment that comprises a VL having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 365-388 and 437, and a VH having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or100% identical to any one of SEQ ID NOS: 341-364 and 436. Further provided herein is an SH antibody or antigen-binding fragment that comprises a VH having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 344and a VL having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 368. Further provided herein is an SH antibody or antigen-binding fragment that comprises a VH having an amino acid sequence that is at least90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 358 and a VL having an amino acid sequence that is at least 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 382. Further provided herein is an SH antibody, wherein the antibody is an IgG, an IgM,an IgE, an IgA, or an IgD, or is derived therefrom.
Provided herein is an SH antibody as described herein, wherein the binding affinity is less than 50 nM, 49 nM, 48 nM, 47 nM, 46 nM, 45 nM, 44 nM, 43 nM, 42 nM, 41 nM, 40 nM, 39 nM, 38 nM, 37 nM, 36 nM, 35 nM, 34 nM, 33 nM, 32 nM, 31 nM, 30 nM,29 nM, 28 nM, 27 nM, 26 nM, 25 nM, 24 nM, 23 nM, 22 nM, 21 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920pM, 910 pM, 900 pM, 890 pM, 880 pM, 870 pM, 860 pM, 850 pM, 840 pM, 830 pM, 820 pM, 810 pM, 800 pM, 790 pM, 780 pM, 770 pM, 760 pM, 750 pM, 740 pM, 730 pM, 720 pM, 710 pM, 700 pM, 690 pM, 680 pM, 670 pM, 660 pM, 650 pM, 640 pM, 630 6M, 620 pM, 610 pM,600 pM, 590 pM, 580 pM, 570 pM, 560 pM, 550 pM, 540 pM, 530 pM, 520 pM, 510 pM, 500 pM, 490 pM, 480 pM, 470 pM, 460 pM, 450 pM, 440 pM, 430 pM, 420 pM, 410 pM, 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290pM, 280 pM, 270 pM, 260 pM, 250 pM, 240 pM, 230 pM, 220 pM, 210 pM, 200 pM, 190 pM, 180 pM, or any integer therebetween. Further provided herein is an SH antibody or antigen-binding fragment, wherein the antibody's antigen-binding domain or theantigen-binding fragment comprises a Fab, a Fab', a F(ab')2, a variable fragment (Fv), a triabody, a tetrabody, a minibody, a bispecific F(ab')2, a trispecific F(ab')2, a diabody, a bispecific diabody, a single chain variable fragment (scFv), a scFv-Fc,a Fab-Fc, a VHH, or a bispecific scFv.
Provided herein is a method of preventing or treating a SARS-CoV-2 viral infection or COVID19 in a subject in need thereof, comprising administering to the subject one or more of the SH antibodies or antigen-binding fragments as describedherein. Further provided herein is a method, that further comprises administering one or more additional therapies or drugs to the subject. Further provided herein is a method of diagnosing a subject as being infected with a SARS-Cov-2 virus orsuspected of being infected with a SARS-Cov-2 virus, the method comprising contacting a sample obtained from the subject with a SH antibody or antigen-binding fragment as described herein; detecting the presence or absence of the SH antibody orantigen-binding fragment; and diagnosing the subject as being infected with a SARS-CoV-2 virus when the presence of the SH antibody or antigen-binding fragment is detected. Further provided herein is a method, wherein the sample comprises a nasal swab,a tissue sample, saliva, or blood. Further provided herein is a method, wherein detecting the presence or absence of the SH antibody or antigen-binding fragment comprises an enzyme linked immunosorbent assay (ELISA), an immunospot assay, a lateral flowassay, flow cytometry, immunohistochemistry, or a western blot.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individuallyindicated to be incorporated by reference.
BRIEF DISCLOSURE OF THE DRAWINGS
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed descriptionthat sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:
FIG. 1 provides representative viral antigen sequences.
DETAILED DESCRIPTION OF THE INVENTION
In view of the ongoing pandemic, there is a great need for therapeutic and diagnostic antibodies that selectively bind to severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2).
"2dd8" is a SARS-Cov-1 spike protein receptor binding domain. A "parental clone" or a "parental clone 2dd8" as used herein refers to an antibody that selectively binds to SARS-Cov-1 and which has the following combination of complementaritydetermining regions (CDRs), or the following variable heavy chain (VH), and variable light chain (VL).
TABLE-US-00001 2dd8 Parental CDR Sequences SEQ ID NO VH CDR1 GTFSSYTIS 389 VH CDR2 MGGITPILGIANYA 390 VH CDR3 CARDTVMGGMDV 391 VL CDR1 GGNNIGSKSVH 392 VL CDR2 DDSDRPS 393 VL CDR3 QVWDSSSDYV 394
TABLE-US-00002 Clone VH/VL Parental CDR Sequences SEQ ID NO 2dd8 VH QVQLQQSGAEVKKPGSSVKVSCK 395 ASGGTFSSYTISWVRQAPGQGLEW MGGITPILGIANYAQKFQGRVTITT DESTSTAYMELSSLRSEDTAVYYC ARDTVMGGMDVWGQGTTVTVSS 2dd8 VL SYELTQPPSVSVAPGKTARITCGGN 396NIGSKSVHWYQQKPGQAPVLVVYD DSDRPSGIPERFSGSNSGNTATLTISR VEAGDEADYYCQVWDSSSDYVFGT GTKVTVL
"2ghw" is a SARS-Cov-1 spike protein receptor binding domain. A "parental clone" or a "parental clone 2ghw" as used herein refers to an antibody that selectively binds to SARS-Cov-1 and which has the following combination of CDRs, or thefollowing variable heavy chain (VH), and variable light chain (VL).
TABLE-US-00003 2ghw Parental CDR Sequences SEQ ID NO VH CDR1 FAFSSYAMH 397 VH CDR2 AVISYDGSNKYYA 398 VH CDR3 CARDRSYYLDY 399 VL CDR1 RASQSVRSNLA 400 VL CDR2 DASTRAT 401 VL CDR3 CQQRSNWPPT 402
TABLE-US-00004 Clone VH/VL Parental CDR Sequences SEQ ID NO 2ghw VH EVQLVQ SGGGVVQPGKSLRLSCAAS 403 GFAFSSYAMHWVRQAPGKGLEWVA VISYDGSNKYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARD RSYYLDYWGQGTLVTVSS 2ghw VL ETTLTQSPATLSLSPGERATLSCRASQ 404SVRSNLAWYQQKPGQAPRPLIYDAST RATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQRSNWPPTFGQGTKVEVK
"3bgf" is a Middle East Respiratory Syndrome Coronavirus (MERS) spike protein receptor binding domain. A "parental clone" or a "parental clone 3bgf" as used herein refers to an antibody that selectively binds to MERS and which has the followingcombination of CDRs, or the following variable heavy chain (VH), and variable light chain (VL).
TABLE-US-00005 3bgf Parental CDR Sequences SEQ ID NO VH CDR1 YTFTTYRMH 405 VH CDR2 GAIYPGNSDTTYN 406 VH CDR3 CTREGIPQLLRTLDY 407 VL CDR1 RASQEISGYLS 408 VL CDR2 AASTLDS 409 VL CDR3 CLQYVSYPWT 410
TABLE-US-00006 Clone VH/VL Parental CDR Sequences SEQ ID NO 3bgf VH EVQLEESGTVLARPGASVKMSCKASGYTFTTYRM 411 HWIKQRPGQGLEWIGAIYPGNSDTTYNQKFKDKA KLTAVTSTSSAYMELSSLTNEDSAVYFCTREGIPQL LRTLDYWGQGTSVTVSS 3bgf VL DILMTQSPSSLSASLGERVSLTCRASQEISGYLSWL 412QEKPDGTIKRLIYAASTLDSGVPKRFSGSRSGSDYS LTISSLESEDFADYYCLQYVSYPWTFGGGTKLEIK
"6nb6" is a SARS-Cov-1 spike protein receptor binding domain. A "parental clone" or a "parental clone 6nb6" as used herein refers to an antibody that selectively binds to SARS-Cov-1 and which has the following combination of CDRs, or thefollowing variable heavy chain (VH), and variable light chain (VL).
TABLE-US-00007 6nb6 Parental CDR Sequences SEQ ID NO VH CDR1 FTFRNYAMH 413 VH CDR2 AVITSDGRNKFYA 414 VH CDR3 CVTQRDNSRDYFPHYFHDMDV 415 VL CDR1 RSSQSLVYSDGDTYLN 416 VL CDR2 QVSNRDS 417 VL CDR3 CMQGSHWPPT 418
TABLE-US-00008 Clone VH/VL Parental CDR Sequences SEQ ID NO 6nb6 VH QVQLVESGGALVQPGRSLRLSCAASGFTFRNYAMH 419 WVRQAPATGLQWLAVITSDGRNKFYADSVKGRFTI SREDSKNTLYLQMDSLRGEDTAVYYCVTQRDNSR DYFPHYFHDMDVWGQGTLVTVSS 6nb6 VLDVVLTQSPLSLPVTLGQPASISCRSSQSLVYSDGDT 420 YLNWFQQRPGQSPRRLIYQVSNRDSGVPDRFSGSG SGTDFTLKISRVEAEDVGVYYCMQGSHWPPTFGQG TKVEIK
"CR3022" as referenced herein refers to an antibody that selectively binds to SARS-Cov-1 and which has the following combination of complementarity determining regions (CDRs), or the following variable heavy chain (VH), and variable light chain(VL).
TABLE-US-00009 CR3022 Parental CDR Sequences SEQ ID NO VH CDR1 YGFITYWIG 421 VH CDR2 GIIYPGDSETRYS 422 VH CDR3 CAGGSGISTPMDV 423 VL CDR1 KSSQSVLYSSINKNYLA 424 VL CDR2 WASTRES 425 VL CDR3 CQQYYSTPYT 426
TABLE-US-00010 Clone VH/VL Parental CDR Sequences SEQ ID NO CR3022 VH QMQVQSGTEVKKPGESLKISCKGSGYGFITYWIGW 427 VRQMPGKGLEWMGIIYPGDSETRYSPSFQGQVTISA DKSINTAYLQWSSLKASDTAIYYCAGGSGISTPMDV WGQGTTVTVSS CR3022 VL DIQLTQSPDSLAVSLGERATINCKSSQSVLYSSINKN428 YLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGS GTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTK VEIK
The present disclosure describes superhuman (SH) antibodies and antigen-binding fragments herein that selectively bind to SARS-Cov-2.
A SH antibody or antigen-binding fragment herein that is "derived from" these parental clones and which selectively bind to SARS-Cov-1 or MERS refers to an antibody or antigen-binding fragment that does not comprise amino acid sequences that are100% identical to the combination of CDRs of the parental clones, or that does not comprise amino acid sequences that are 100% identical to amino acid sequences of the VH and the VL sequences of the parental clones. Instead, such SH antibodies orantibody-binding fragments can have some degree of sequence identity to the parental clones.
In one instance, SH antibodies and antigen-binding fragments herein do not contain amino acid sequences that are 100% identical to the following combination of CDRs of the parental clone 2dd8 of SEQ ID NOS: 389-394, or amino acid sequences thatare 100% identical to the VH/VL combination of SEQ ID NOS: 395 and 396.
In one instance, SH antibodies and antigen-binding fragments herein do not contain amino acid sequences that are 100% identical to the following combination of CDRs of the parental clone 2ghw of the CDRs of SEQ ID NOS: 397-402, or amino acidsequences that are 100% identical to the VH/VL combination of SEQ ID NOS: 403 and 404.
In one instance, SH antibodies and antigen-binding fragments herein do not contain amino acid sequences that are 100% identical to the following combination of CDRs of the parental clone 3bgf of the CDRs of SEQ ID NOS: 405-410, or amino acidsequences that are 100% identical to the VH/VL combination of SEQ ID NOS: 411 and 412.
In one instance, SH antibodies and antigen-binding fragments herein do not contain amino acid sequences that are 100% identical to the following combination of CDRs of the parental clone 6nb6 of the CDRs of SEQ ID NOS: 413-418, or amino acidsequences that are 100% identical to the VH/VL combination of SEQ ID NOS: 419 and 420.
In one instance, SH antibodies and antigen-binding fragments herein do not contain amino acid sequences that are 100% identical to the following combination of CDRs of the parental clone CR3022 of the CDRs of SEQ ID NOS: 421-426, or amino acidsequences that are 100% identical to the VH/VL combination of SEQ ID NOS: 427 and 428.
As used herein, the terms "SH antibody or antigen-binding fragment" and "SH antibody or antigen-binding fragment herein which selectively binds to the SARS-Cov-2" are synonymous.
A SH antibody or antigen-binding fragment herein also refers to an antibody or antigen-binding fragment that selectively binds to SARS-Cov-2, and which has a greater binding affinity for SARS-Cov-2 than to SARS-Cov-1. A SH antibody orantigen-binding fragment herein that is derived from the parental clone also refers to a SH antibody or antigen-binding fragment that is capable of neutralizing the activity of SARS-Cov-2. A SH antibody or antigen-binding fragment herein can selectivelybind to the receptor binding domain (RBD) of SARS-Cov-2. In one instance, a SH antibody or antigen-binding fragment herein selectively binds solely to SARS-Cov-2, and not to SARS1, SARS2, and/or Middle East Respiratory Syndrome (MERS).
Binding affinity of a SH antibody or antigen-binding fragment herein can be determined by any suitable means including, but not limited to, high-throughput surface plasmon resonance (SPR) kinetic experiments. Briefly, a SH antibody orantigen-binding fragment herein is immobilized to a solid surface using an anti-V5 antibody. Different concentrations of antigen (SARS-Cov-2, SARS-Cov-1, SARS2, or MERS RBD proteins) are flowed over the immobilized SH antibodies or antigen-bindingfragments to characterize the interactions to the immobilized SH antibodies or antigen-binding fragments. The SPR signal originates from changes in the refractive index at the surface of a gold sensor chip. An increase in mass associated with a bindingevent between an antibody or antigen-binding fragment and the antigen causes a proportional increase in the refractive index, which is observed as a change in response. These changes are measured as changes in the resonance angle (.delta..theta.) ofrefracted light when the antigen, flowing in a microfluidic channel, binds to the immobilized antibody and increases in density at the sensor chip. For antibody-antigen interactions, the change in refractive index on the surface is linearly related tothe number of antigens bound to an immobilized antibody. The response signal (the SPR signal) is quantified in resonance units (RU). When a steady-state is achieved (all binding sites occupied), the maximum RU is determined (n: number of binding sitesin ligand). Monitoring the change in the SPR signal over time produces a sensorgram, a plot of the binding response (RU) versus time which allows different stages of a binding event to be visualized and evaluated. During the injection of an antigen,the binding response increase is due to the formation of antigen-antibody complexes at the surface and the sensorgram is dominated by the association phase. After a certain time of injection, a steady state is reached, in which binding and dissociatingmolecules are in equilibrium. The decrease in response after analyte injection is terminated is due to dissociation of the complexes, defining the dissociation phase. Depending on the dissociation rate of the tested antibody, some assays may require aregeneration step in order to reach the baseline again. Fitting the sensorgram data to an appropriate kinetic binding model allows calculation of kinetic parameters such as the association (k.sub.d) and dissociation (k.sub.d) rate constants, and thebinding affinity of the tested interactions.
Preferably, a SH antibody or antigen-binding fragment herein selectively binds to SARS-Cov-2 with a binding affinity of less than 50 nM. In one instance, a SH antibody or antigen-binding fragment herein can selectively bind to SARS-Cov-2 with abinding affinity of from about 0.26 nM (e.g., 260 pM) to about 50 nM. In one instance, a SH antibody or antigen-binding fragment herein can selectively bind to SARS-Cov-2 with a binding affinity of less than 50 nM, 49 nM, 48 nM, 47 nM, 46 nM, 45 nM, 44nM, 43 nM, 42 nM, 41 nM, 40 nM, 39 nM, 38 nM, 37 nM, 36 nM, 35 nM, 34 nM, 33 nM, 32 nM, 31 nM, 30 nM, 29 nM, 28 nM, 27 nM, 26 nM, 25 nM, 24 nM, 23 nM, 22 nM, 21 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM,7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920 pM, 910 pM, 900 pM, 890 pM, 880 pM, 870 pM, 860 pM, 850 pM, 840 pM, 830 pM, 820 pM, 810 pM, 800 pM, 790 pM, 780 pM, 770 pM, 760 pM, 750 pM, 740 pM, 730pM, 720 pM, 710 pM, 700 pM, 690 pM, 680 pM, 670 pM, 660 pM, 650 pM, 640 pM, 630 6M, 620 pM, 610 pM, 600 pM, 590 pM, 580 pM, 570 pM, 560 pM, 550 pM, 540 pM, 530 pM, 520 pM, 510 pM, 500 pM, 490 pM, 480 pM, 470 pM, 460 pM, 450 pM, 440 pM, 430 pM, 420 pM,410 pM, 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290 pM, 280 pM, 270 pM, 260 pM, 250 pM, 240 pM, 230 pM, 220 pM, 210 pM, 200 pM, 190 pM, or 180 pM, or any integer therebetween.
In any of the embodiments herein, a SH antibody or antigen-binding fragment herein can neutralize the activity of SARS-Cov-2. Neutralization ability of a SH antibody or antigen-binding fragment herein can be assessed using any suitable meansincluding, but not limited to, an in vitro pseudovirus assay. For example, spike genes from a SARS-Cov-2 virus are codon-optimized for human cells and cloned into eukaryotic expression plasmids to generate envelope recombinant plasmids; mammalian cellsare then transfected with the plasmids. The transfected mammalian cells are contacted with a SH antibody or antigen-binding fragment herein and trypsinization is determined as a measure of neutralization. In some instances, a SH antibody orantigen-binding fragment herein neutralize SARS-Cov-2 by at least 5%, 10%, 15%, 20%, 25%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more compared to a non-specific antibody, or compared to an antibody that selectively binds toSARS-Cov-1 or MERS. Neutralization ability of a SH antibody or antigen-binding fragment herein can also be assessed using, for example, an in vivo hamster animal model. For example, hamsters can be injected with either saline or a SH antibody orantigen-binding fragment herein. Body weight and viable signs (e.g., ruffled hair and movement) are recorded. Viral titers are assessed in homogenates of lung tissues and/or by immunohistochemistry of lung tissue. A SH antibody or antigen-bindingfragment herein reduces viral titers compared to controls.
Competition assay of the interaction of SARS-Cov-2 with angiotensin-converting enzyme 2 (ACE2) can be assessed using an assay including, but not limited to, a classical sandwich and premix assay format. For example, anti-V5 tag antibodies arebiotinylated and loaded onto streptavidin sensor tips. For a classical sandwich assay format, a SH antibody or antigen-binding fragment herein is loaded onto the anti-V5 sensor tips. Following establishment of a baseline, SARS-Cov-2 is added, followedby sandwiching of ACE2 or buffer. Dissociation in buffer is measured. Capture of biotinylated ACE2 is included as a self-blocking control. Alternatively, for a premix assay format, a SH antibody or antigen-binding fragment herein are loaded onto theanti-V5 sensor tips. Following establishment of a baseline, a premix complex of SARS-Cov-2+ACE2, or a SARS-Cov-2 alone are added to the antibodies or antigen-binding fragments. Dissociation in buffer is measured. Capture of biotinylated ACE2 isincluded as a self-blocking control.
Representative CDR Sequences that Selectively Bind to SARS-Cov-2
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-Cov-2 can comprise an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%identical to a VH CDR3 comprising an amino acid sequence of any one of any one of SEQ ID NOS: 293-316 and 429-320.
In some instances, a SH antibody or antigen-binding fragment herein that selectively binds to SARS-Cov-2 can further comprise an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,98%, 99%, or 100% identical to one or more of a VH CDR1 comprising an amino acid of any one of SEQ ID NOS: 197-220 and 431-432; and a VH CDR2 comprising an amino acid sequence of any one of SEQ ID NOS: 245-268 and 433-434.
In some instances, a SH antibody or antigen-binding fragment herein that selectively binds to SARS-Cov-2 can further comprise an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,98%, 99%, or 100% identical to one or more of a VL CDR1 comprising an amino acid of any one of SEQ ID NOS: 29-52 and 435-436, a VL CDR2 comprising an amino acid sequence of any one of SEQ ID NOS: 77-100 and 437-438, and a VL CDR3 comprising an amino acidsequence of any one of SEQ ID NOS: 125-148 and 439-440.
In other instances, a SH antibody or antigen-binding fragment that specifically binds to a Sars-Cov-2 virus, that comprises an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,98%, 99%, or 100% identical to a VH CDR1, a VH CDR2, a VH CDR3, a VL CDR1, a VL CDR2, and a VL CDR3; wherein the VH CDR1 has an amino acid sequence of any one of SEQ ID NOS: 197-220 and 431-432; the VH CDR2 has an amino acid sequence of any one of SEQ IDNOS: 245-268 and 433-434; the VH CDR3 has an amino acid sequence of any one of SEQ ID NOS: 293-316 and 429-420; a VL CDR1 has an amino acid sequence of any one of SEQ ID NOS: 29-52 and 435-436; a VL CDR2 has an amino acid sequence of any one of SEQ IDNOS: 77-100 and 437-438; and a VL CDR3 has an amino acid sequence of any one of SEQ ID NOS: 125-148 and 441.
Representative VH CDR3 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00011 Clone ID VH CDR3 SEQ ID NO: COVID19_P23_F10 CAIGTTVVTPFGYW 293 COVID19_P24_H06 CARGQVRGSGPQVVVMDVW 294 COVID19_P24_F11 CAKDGTLITTTLDYW 295 COVID19_P23_G11 CARAGYSSSSGYYYYGMDVW 296 COVID19_P24_D09 CARVRGSAAIAMMDVW 297COVID19_P11_H02 CASFERFGELVPETFDYW 298 COVID19_P24_C06 CARDRGSYDTDAFDIW 299 COVID19_P12_B07 CASAHSSSWYSDWFDPW 300 COVID19_P24_H04 CAGMGMGRDGYNSRAFDIW 301 COVID19_P23_G10 CARVDYGDYGRLEDYW 302 COVID19_P24_A09 CARLEGGSYWTGYFDLW 303 COVID19_P11_D12CAKTRYGGNSRSRYYYYGMDVW 304 COVID19_P24_A11 CARDLMDIVVVPWLGGMDVW 305 COVID19_P24_C10 CARD SGVDTATLRYYYYGMDVW 306 COVID19_P11_D08 CARDSGVDTATLRYYYYGMDVW 307 COVID19_P24_E02 CAKDVQNYYGSGSSFDYW 308 COVID19_P23_H10 CARGSSGYYFGW 309 COVID19_P24_G06CTTDPVLEWFGYSIW 310 COVID19_P24_C01 CAKGAPHDYIWGSYRPDAFDIW 311 COVID19_P24_G09 CAKGAPHDYIWGSYRPDAFDIW 312 COVID19_P24_D08 CATVTPGYGMDVW 313 COVID19_P11_H07 CARGWMAYDAFDIW 314 COVID19_P11_G03 CARDRGYSYDHDQIYYYYGMDVW 315 COVID19_P24_B09 CARDRGDTIDYW 316COVID19_P23_G12 CARDRGSYDTDAFDIW 429 Representative VH CDR1 sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00012 Clone ID VH CDR1 SEQ ID NO: COVID19_P23_F10 DTFSNYGIS 197 COVID19_P24_H06 FSFSNYDMH 198 COVID19_P24_F11 FTFSGSAMH 199 COVID19_P23_G11 GTFRSTAIS 200 COVID19_P24_D09 GTFSSYAIS 201 COVID19_P11_H02 GTFTSYHMH 202 COVID19_P24_C06YIFTSYPIH 203 COVID19_P12_B07 YTFINYDIN 204 COVID19_P24_H04 YTFTDYHMH 205 COVID19_P23_G10 YTFTDYYIQ 206 COVID19_P24_A09 YTFTDYYMQ 207 COVID19_P11_D12 YTFTENEMH 208 COVID19_P24_A11 YTFTENEMH 209 COVID19_P24_C10 YTFTENEMH 210 COVID19_P11_D08 YTFTENEMH 211COVID19_P24_E02 YTFTGNYIH 212 COVID19_P23_H10 YTFTGSYAIS 213 COVID19_P24_G06 YTFTNYGIS 214 COVID19_P24_C01 YTFTRYYIH 215 COVID19_P24_G09 YTFTRYYIH 216 COVID19_P24_D08 YTFTSYDIN 217 COVID19_P11_H07 YTFTSYDIN 218 COVID19_P11_G03 YTFTSYEIN 219COVID19_P24_B09 YTFTSYGIS 220 COVID19_P23_G12 YIFTSYPIH 430
Representative VH CDR2 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a VH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00013 Clone ID VH CDR2 SEQ ID NO: COVID19_P23_F10 GWMNPNSGGTNYA 245 COVID19_P24_H06 AVISYDGGFKLYA 246 COVID19_P24_F11 SAISRNGGTTYYA 247 COVID19_P23_G11 GWMNPNSGNTGYA 248 COVID19_P24_D09 GIVNPSSGSTTYA 249 COVID19_P11_H02 GWMNPNSGNTGYA250 COVID19_P24_C06 GWMNPNSGNTGYA 251 COVID19_P12_B07 GVINPSAGSTSYA 252 COVID19_P24_H04 GWMNPNSGNTSYA 253 COVID19_P23_G10 GWINPNSGGPNYA 254 COVID19_P24_A09 GWIDPHSGATNYA 255 COVID19_P11_D12 GIINPSGGSTSYA 256 COVID19_P24_A11 GIINPSGGSTSYA 257COVID19_P24_C10 GIINPSGGSTSYA 258 COVID19_P11_D08 GIINPSGGSTSYA 259 COVID19_P24_E02 GWMNPNSGNTGYA 260 COVID19_P23_H10 GWINPKTGDTNYA 261 COVID19_P24_G06 GWISARNGNTNYA 262 COVID19_P24_C01 GIINPSGGSTTYA 263 COVID19_P24_G09 GIINPSGGSTTYA 264 COVID19_P24_D08GIIDPSGGSTSYA 265 COVID19_P11_H07 GWMNSNSGSTGYA 266 COVID19_P11_G03 GIINPSDGSSTYA 267 COVID19_P24_B09 GGIIPMFGTTNYA 268 COVID19_P23_G12 GWMNPNSGNTGYA 431
Representative VL CDR1 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a VL CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00014 Clone ID VL CDR1 SEQ ID NO: COVID19_P23_F10 RASESVSSRYLA 29 COVID19_P24_H06 QASQGIRNDLG 30 COVID19_P24_F11 RAS QSIGYYLN 31 COVID19_P23_G11 RASQGISNNLN 32 COVID19_P24_D09 RASQDIRNELG 33 COVID19_P11_H02 RASQGIRNDLA 34COVID19_P24_C06 RASQDISNYLN 35 COVID19_P12_B07 RASQSISSYLN 36 COVID19_P24_H04 RASQSISTYLN 37 COVID19_P23_G10 RASQSIYSWLA 38 COVID19_P24_A09 RASQSVSSNYLA 39 COVID19_P11_D12 RASQHISSYLN 40 COVID19_P24_A11 RASQAITNYLA 41 COVID19_P24_C10 QASQDISKYLN 42COVID19_P11_D08 QASQDISKYLN 43 COVID19_P24_E02 RASQGIRNYLA 44 COVID19_P23_H10 RASQSISSYLN 45 COVID19_P24_G06 KSSQSVFSSSNNKNYLA 46 COVID19_P24_C01 RASENIDSWLA 47 COVID19_P24_G09 RASENIDSWLA 48 COVID19_P24_D08 RASQTIYSYLN 49 COVID19_P11_H07 QASQSIYNYLN 50COVID19_P11_G03 RVSQGISSYLN 51 COVID19_P24_B09 RASQGISNNLN 52 COVID19_P23_G12 RASQDISNYLN 432
Representative VL CDR2 sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00015 Clone ID VL CDR2 SEQ ID NO: COVID19_P23_F10 GASTRAT 77 COVID19_P24_H06 DASRLQS 78 COVID19_P24_F11 AASSLQS 79 COVID19_P23_G11 AASSLQS 80 COVID19_P24_D09 AASSLQS 81 COVID19_P11_H02 AASSLQS 82 COVID19_P24_C06 AASNLQS 83COVID19_P12_B07 AASSLQS 84 COVID19_P24_H04 AASTLQS 85 COVID19_P23_G10 DASSLES 86 COVID19_P24_A09 AVSSRAT 87 COVID19_P11_D12 AASALQS 88 COVID19_P24_A11 AASSLQS 89 COVID19_P24_C10 GASTLSD 90 COVID19_P11_D08 GASTLSD 91 COVID19_P24_E02 AASTLQS 92COVID19_P23_H10 AASRLQS 93 COVID19_P24_G06 WASTRES 94 COVID19_P24_C01 EASTLES 95 COVID19_P24_G09 EASTLES 96 COVID19_P24_D08 DASNLET 97 COVID19_P11_H07 DASNLET 98 COVID19_P11_G03 AASILQS 99 COVID19_P24_B09 AASSLES 100 COVID19_P23_G12 AASNLQS 433
Representative VL CDR3 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00016 Clone ID VL CDR3 SEQ ID NO: COVID19_P23_F10 CQQGYKNPPTF 125 COVID19_P24_H06 CQQYYSTPPLTF 126 COVID19_P24_F11 CQQSYTTPLTF 127 COVID19_P23_G11 CQQYDTFPLTF 128 COVID19_P24_D09 CQQSYSTPPWTF 129 COVID19_P11_H02 CQQSYSTPPTF 130COVID19_P24_C06 CQQANSFPSTF 131 COVID19_P12_B07 CQQSYSTPLTF 132 COVID19_P24_H04 CQQSYSMPLTF 133 COVID19_P23_G10 CQQLNSYPYTF 134 COVID19_P24_A09 CQQYGSSPLTF 135 COVID19_P11_D12 CQQGYGTPYTF 136 COVID19_P24_A11 CQQYYSYPPTF 137 COVID19_P24_C10 CQQGYSTPYSF138 COVID19_P11_D08 CQQGYSTPYSF 139 COVID19_P24_E02 CQQSYSPPLTF 140 COVID19_P23_H10 CQQSYSTPLTF 141 COVID19_P24_G06 CQQYYSTPLTF 142 COVID19_P24_C01 CHQYLSSPETF 143 COVID19_P24_G09 CHQYLSSPETF 144 COVID19_P24_D08 CQQAISFPLTF 145 COVID19_P11_H07CQQAISFPLTF 146 COVID19_P11_G03 CQQGYSTPFTF 147 COVID19_P24_B09 CQQGNGFPLTF 148 COVID19_P23_G12 CQQANSFPSTF 441
Representative CDR Combinations
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 293; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 197; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 245; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 29; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 77; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 125.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 294; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 198; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 246; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 30; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 78; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 126.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 295; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 199; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 247; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 31; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 79; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 127.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 296; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 200; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 248; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 32; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 80; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 128.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 297; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 201; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 249; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 33; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 81; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 129.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 298; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 202; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 250; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 34; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 82; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 130.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 299; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 203; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 251; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 35; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 83; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 131.
In one instance, the antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 300; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 204; (ii) a VHCDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 252; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 36; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 84; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 132.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 301; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 205; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 253; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 37; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 85; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 133.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 302; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 206; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 254; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 38; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 86; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 134.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 303; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 207; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 255; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 39; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 87; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 135.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 304; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 208; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 256; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 40; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 88; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 136.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 305; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 209; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 257; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 41; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 89; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 137.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 306; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 210; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 258; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 42; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 90; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 138.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 307; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 211; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 259; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 43; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 91; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 139.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 308; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 212; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 260; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 44; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 92; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 140.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 309; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 213; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 261; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 45; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 93; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 141.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 310; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 214; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 262; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 46; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 94; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 142.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 311; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 215; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 263; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 47; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 95; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 143.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 312; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 216; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 264; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 48; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 96; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 144.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 313; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 217; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 265; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 49; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 97; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 145.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 314; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 218; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 266; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 50; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 98; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 146.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 315; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 219; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 267; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 51; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 99; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 147.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 316; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 220; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 268; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 52; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 100; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 148.
In one instance, the SH antibody or antigen-binding fragment that selectively binds to SARS-Cov-2 can comprise (i) a VH CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 429; (ii) a VH CDR1 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 430; (ii) aVH CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 431; (iv) a VL CDR1 having an amino acid sequence that is at least 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 432; (v) a VL CDR2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 98%, 99%, or 100% identical to SEQ ID NO: 433; and (vi) a VL CDR3 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 441.
Representative Superhuman (SH) Frameworks (FW) of Antibodies and Antigen-Binding Fragments that Selectively Bind to SARS-CoV-2
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-Cov-2 can comprise an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%identical to one or more of a FW-L1 comprising an amino acid sequence of any one of SEQ ID NOS: 5-28, a FW-L2 comprising an amino acid sequence of any one of SEQ ID NOS: 53-76, a FW-L3 comprising an amino acid sequence of any one of any one of SEQ IDNOS: 101-124, a FW-L4 comprising amino acid of any one of SEQ ID NOS: 149-172, 435, a FW-H1 comprising an amino acid sequence of any one of SEQ ID NOS: 173-196, a FW-H2 comprising amino acid sequence of any one of SEQ ID NOS: 221-244, a FW-H3 comprisingan amino acid sequence of any one of SEQ ID NOS: 269-292, and a FW-H4 comprising an amino acid sequence of any one of SEQ ID NOS: 317-340.
Representative FW-L1 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a (FW-L1) having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00017 Clone ID FW-L1 SEQ ID NO: COVID19_P23_F10 EIVMTQSPATLSVSPGERATLSC 5 COVID19_P24_H06 DIQMTQSPSSLSASVGDRVTITC 6 COVID19_P24_F11 DIQMTQSPSSLSASVGDRVTITC 7 COVID19_P23_G11 DIQMTQSPSSLSASVGDRVTITC 8 COVID19_P24_D09DIQMTQSPSSLSASVGDRVTITC 9 COVID19_P11_H02 DIQMTQSPSSLSASVGDRVTITC 10 COVID19_P24_C06 DIQMTQSPSSLSASVGDRVTITC 11 COVID19_P12_B07 DIQMTQSPSSLSASVGDRVTITC 12 COVID19_P24_H04 DIQMTQSPSSLSASVGDRVTITC 13 COVID19_P23_G10 DIQMTQSPSSLSASVGDRVTITC 14COVID19_P24_A09 EIVMTQSPATLSVSPGERATLSC 15 COVID19_P11_D12 DIQMTQSPSSLSASVGDRVTITC 16 COVID19_P24_A11 DIQMTQSPSSLSASVGDRVTITC 17 COVID19_P24_C10 DIQMTQSPSSLSASVGDRVTITC 18 COVID19_P11_D08 DIQMTQSPSSLSASVGDRVTITC 19 COVID19_P24_E02 DIQMTQSPSSLSASVGDRVTITC20 COVID19_P23_H10 DIQMTQSPSSLSASVGDRVTITC 21 COVID19_P24_G06 DIVMTQSPDSLAVSLGERATINC 22 COVID19_P24_C01 DIQMTQSPSSLSASVGDRVTITC 23 COVID19_P24_G09 DIQMTQSPSSLSASVGDRVTITC 24 COVID19_P24_D08 DIQMTQSPSSLSASVGDRVTITC 25 COVID19_P11_H07DIQMTQSPSSLSASVGDRVTITC 26 COVID19_P11_G03 DIQMTQSPSSLSASVGDRVTITC 27 COVID19_P24_B09 DIQMTQSPSSLSASVGDRVTITC 28 COVID19_P23_G12 DIQMTQSPSSLSASVGDRVTITC 28
Representative FW-L2 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a FW-L2 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00018 Clone ID FW-L2 SEQ ID NO: COVID19_P23_F10 WYQQKPGQAPRLLIY 53 COVID19_P24_H06 WYQQKPGKAPKLLIY 54 COVID19_P24_F11 WYQQKPGKAPKLLIY 55 COVID19_P23_G11 WYQQKPGKAPKLLIY 56 COVID19_P24_D09 WYQQKPGKAPKLLIY 57 COVID19_P11_H02WYQQKPGKAPKLLIY 58 COVID19_P24_C06 WYQQKPGKAPKLLIY 59 COVID19_P12_B07 WYQQKPGKAPKLLIY 60 COVID19_P24_H04 WYQQKPGKAPKLLIY 61 COVID19_P23_G10 WYQQKPGKAPKLLIY 62 COVID19_P24_A09 WYQQKPGQAPRLLIY 63 COVID19_P11_D12 WYQQKPGKAPKLLIY 64 COVID19_P24_A11WYQQKPGKAPKLLIY 65 COVID19_P24_C10 WYQQKPGKAPKLLIY 66 COVID19_P11_D08 WYQQKPGKAPKLLIY 67 COVID19_P24_E02 WYQQKPGKAPKLLIY 68 COVID19_P23_H10 WYQQKPGKAPKLLIY 69 COVID19_P24_G06 WYQQKPGQPPKLLIY 70 COVID19_P24_C01 WYQQKPGKAPKLLIY 71 COVID19_P24_G09WYQQKPGKAPKLLIY 72 COVID19_P24_D08 WYQQKPGKAPKLLIY 73 COVID19_P11_H07 WYQQKPGKAPKLLIY 74 COVID19_P11_G03 WYQQKPGKAPKLLIY 75 COVID19_P24_B09 WYQQKPGKAPKLLIY 76 COVID19_P23_G12 WYQQKPGKAPKLLIY 76
Representative FW-L3 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a FW-L3 having an amino acid sequence o that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00019 Clone ID FW-L3 SEQ ID NO: COVID19_P23_F10 GIPARFSGSGSGTEFTLTISSLQSEDFAVYY 101 COVID19_P24_H06 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 102 COVID19_P24_F11 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 103 COVID19_P23_G11 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY104 COVID19_P24_D09 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 105 COVID19_P11_H02 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 106 COVID19_P24_C06 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 107 COVID19_P12_B07 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 108 COVID19_P24_H04GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 109 COVID19_P23_G10 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 110 COVID19_P24_A09 GIPARFSGSGSGTEFTLTISSLQSEDFAVYY 111 COVID19_P11_D12 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 112 COVID19_P24_A11 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 113COVID19_P24_C10 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 114 COVID19_P11_D08 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 115 COVID19_P24_E02 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 116 COVID19_P23_H10 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 117 COVID19_P24_G06GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY 118 COVID19_P24_C01 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 119 COVID19_P24_G09 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 120 COVID19_P24_D08 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 121 COVID19_P11_H07 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 122COVID19_P11_G03 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 123 COVID19_P24_B09 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 124 COVID19_P23_G12 GVPSRFSGSGSGTDFTLTISSLQPEDFATYY 124
Representative FW-L4 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise FW-L4 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or100% identical to any one of the following sequences:
TABLE-US-00020 Clone ID FW-L4 SEQ ID NO: COVID19_P23_F10 GQGTKVEIKR 149 COVID19_P24_H06 GQGTKVEIKR 150 COVID19_P24_F11 GGGTKVEIKR 151 COVID19_P23_G11 GQGTKLEIKR 152 COVID19_P24_D09 GQGTKLEIKR 153 COVID19_P11_H02 GQGTKLEIKR 154 COVID19_P24_C06GQGTKLEIKR 155 COVID19_P12_B07 GGGTKVEIKR 156 COVID19_P24_H04 GQGTKVEIKR 157 COVID19_P23_G10 GQGTKVEIKR 158 COVID19_P24_A09 GGGTKVEIKR 159 COVID19_P11_D12 GQGTKLEIKR 160 COVID19_P24_A11 GQGTKLEIKR 161 COVID19_P24_C10 GQGTKLEIKR 162 COVID19_P11_D08GQGTKLEIKR 163 COVID19_P24_E02 GQGTKVEIKR 164 COVID19_P23_H10 GGGTKVEIKR 165 COVID19_P24_G06 GGGTKVEIKR 166 COVID19_P24_C01 GQGTKVEIKR 167 COVID19_P24_G09 GQGTKVEIKR 168 COVID19_P24_D08 GGGTKLEIKR 169 COVID19_P11_H07 GGGTKVEIKR 170 COVID19_P11_G03GPGTKVDIKR 171 COVID19_P24_B09 GPGTKVDIKR 172 COVID19_P23_G12 GQGTKLEIKR 435
Representative FW-H1 Sequences
A SH antibody or antigen-binding fragment herein can comprise a VH framework (FW) 1 (FW-H1) having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%identical to any one of the following sequences:
TABLE-US-00021 SEQ ID Clone ID FW-H1 NO: COVID19_P23_F10 QVQLVQSGAEVKKPGASVKVSCKASG 173 COVID19_P24_H06 EVQLLESGGGLVQPGGSLRLSCAASG 174 COVID19_P24_F11 EVQLLESGGGLVQPGGSLRLSCAASG 175 COVID19_P23_G11 QVQLVQSGAEVKKPGASVKVSCKASG 176 COVID19_P24_D09QVQLVQSGAEVKKPGASVKVSCKASG 177 COVID19_P11_H02 QVQLVQSGAEVKKPGASVKVSCKASG 178 COVID19_P24_C06 QVQLVQSGAEVKKPGASVKVSCKASG 179 COVID19_P12_B07 QVQLVQSGAEVKKPGASVKVSCKASG 180 COVID19_P24_H04 QVQLVQSGAEVKKPGASVKVSCKASG 181 COVID19_P23_G10QVQLVQSGAEVKKPGSSVKVSCKASG 182 COVID19_P24_A09 QVQLVQSGAEVKKPGASVKVSCKASG 183 COVID19_P11_D12 QVQLVQSGAEVKKPGASVKVSCKASG 184 COVID19_P24_A11 QVQLVQSGAEVKKPGASVKVSCKASG 185 COVID19_P24_C10 QVQLVQSGAEVKKPGASVKVSCKASG 186 COVID19_P11_D08QVQLVQSGAEVKKPGASVKVSCKASG 187 COVID19_P24_E02 QVQLVQSGAEVKKPGASVKVSCKASG 188 COVID19_P23_H10 QVQLVQSGAEVKKPGASVKVSCKASG 189 COVID19_P24_G06 QVQLVQSGAEVKKPGASVKVSCKASG 190 COVID19_P24_C01 QVQLVQSGAEVKKPGASVKVSCKASG 191 COVID19_P24_G09QVQLVQSGAEVKKPGASVKVSCKASG 192 COVID19_P24_D08 QVQLVQSGAEVKKPGASVKVSCKASG 193 COVID19_P11_H07 QVQLVQSGAEVKKPGASVKVSCKASG 194 COVID19_P11_G03 QVQLVQSGAEVKKPGASVKVSCKASG 195 COVID19_P24_B09 QVQLVQSGAEVKKPGSSVYVSCKASG 196 COVID19_P23_G12QVQLVQSGAEVKKPGASVKVSCKASG 194
Representative FW-H2 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a FW-112 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00022 Clone ID FW-H2 SEQ ID NO: COVID19_P23_F10 WVRQAPGQGLEWM 221 COVID19_P24_H06 WVRQAPGKGLEWV 222 COVID19_P24_F11 WVRQAPGKGLEYV 223 COVID19_P23_G11 WVRQAPGQGLEWM 224 COVID19_P24_D09 WVRQAPGQGLEWM 225 COVID19_P11_H02 WVRQAPGQGLEWM 226COVID19_P24_C06 WVRQAPGQGLEWM 227 COVID19_P12_B07 WVRQAPGQGLEWM 228 COVID19_P24_H04 WVRQAPGQGLEWM 229 COVID19_P23_G10 WVRQAPGQGLEWM 230 COVID19_P24_A09 WVRQAPGQGLEWM 231 COVID19_P11_D12 WVRQAPGQGLEWM 232 COVID19_P24_A11 WVRQAPGQGLEWM 233 COVID19_P24_C10WVRQAPGQGLEWM 234 COVID19_P11_D08 WVRQAPGQGLEWM 235 COVID19_P24_E02 WVRQAPGQGLEWM 236 COVID19_P23_H10 WVRQAPGQGLEWM 237 COVID19_P24_G06 WVRQAPGQGLEWM 238 COVID19_P24_C01 WVRQAPGQGLEWM 239 COVID19_P24_G09 WVRQAPGQGLEWM 240 COVID19_P24_D08 WVRQAPGQGLEWM241 COVID19_P11_H07 WVRQAPGQGLEWM 242 COVID19_P11_G03 WVRQAPGQGLEWM 243 COVID19_P24_B09 WVRQAPGQGLEWM 244 COVID19_P23_G12 WVRQAPGQGLEWM 244
Representative FW-H3 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a FW-113 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00023 Clone ID FW-H3 SEQ ID NO: COVID19_P23_F10 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 269 COVID19_P24_H06 DSVKGRFTISRDNAKNSLYLRMNSLRSEDTAVYY 270 COVID19_P24_F11 DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYY 271 COVID19_P23_G11QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 272 COVID19_P24_D09 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 273 COVID19_P11_H02 LKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 274 COVID19_P24_C06 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 275 COVID19_P12_B07 HKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY276 COVID19_P24_H04 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 277 COVID19_P23_G10 QKFQGRVTITADESTSTAYMELSSLRSEDTAVYY 278 COVID19_P24_A09 HSFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 279 COVID19_P11_D12 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 280 COVID19_P24_A11QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 281 COVID19_P24_C10 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 282 COVID19_P11_D08 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 283 COVID19_P24_E02 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 284 COVID19_P23_H10 QEFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY285 COVID19_P24_G06 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 286 COVID19_P24_C01 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 287 COVID19_P24_G09 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 288 COVID19_P24_D08 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 289 COVID19_P11_H07QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 290 COVID19_P11_G03 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 291 COVID19_P24_B09 QKFQGRVTITADKSTSTAYMELSSLRSEDTAVYY 292 COVID19_P23_G12 QKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYY 291
Representative FW-H4 Sequences
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise a FW-114 having an amino acid sequence that is at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%,or 100% identical to any one of the following sequences:
TABLE-US-00024 Clone ID FW-H4 SEQ ID NO: COVID19_P23_F10 GQGTLVNVSS 317 COVID19_P24_H06 GKGTTVTVSS 318 COVID19_P24_F11 GQGTLVTVSS 319 COVID19_P23_G11 GKGTTVTVSS 320 COVID19_P24_D09 GQGTTVTVSS 321 COVID19_P11_H02 GQGTLVTVSS 322 COVID19_P24_C06GQGTMVTVSS 323 COVID19_P12_B07 GQGTLVTVSS 324 COVID19_P24_H04 GQGTMVTVSS 325 COVID19_P23_G10 GQGTLVTVSS 326 COVID19_P24_A09 GRGTLVTVSS 327 COVID19_P11_D12 GQGTTVTVSS 328 COVID19_P24_A11 GQGTTVTVSS 329 COVID19_P24_C10 GQGTTVTVSS 330 COVID19_P11_D08GQGTTVTVSS 331 COVID19_P24_E02 GQGTLVTVSS 332 COVID19_P23_H10 GQGTLVTVSS 333 COVID19_P24_G06 GQGTMVTVSS 334 COVID19_P24_C01 GQGTMVTVSS 335 COVID19_P24_G09 GQGTMVTVSS 336 COVID19_P24_D08 GQGTTVTVSS 337 COVID19_P11_H07 GQGTMVTVSS 338 COVID19_P11_G03GQGTTVTVSS 339 COVID19_P24_B09 GQGTLVTVSS 340 COVID19_P23_G12 GQGTMVTVSS 338
Representative SH VH and VL Sequences that Bind to SARS-CoV-2
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise an VH amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to any one of the following sequences:
TABLE-US-00025 SEQ ID Clone ID VH NO: COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGDTFSNYGISWVRQAPGQGLEWM 341 P23_F10 GWMNPNSGGTNYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCA IGTTVVTPFGYWGQGTLVNVSS COVID19_ EVQLLESGGGLVQPGGSLRLSCAASGFSFSNYDMHWVRQAPGKGLEWVA 342P24_H06 VISYDGGFKLYADSVKGRFTISRDNAKNSLYLRMNSLRSEDTAVYYCARG QVRGSGPQVVVMDVWGKGTTVTVSS COVID19_ EVQLLESGGGLVQPGGSLRLSCAASGFTFSGSAMHWVRQAPGKGLEYVS 343 P24_F11 AISRNGGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD GTLITTTLDYWGQGTLVTVSS COVID19_QVQLVQSGAEVKKPGASVKVSCKASGGTFRSTAISWVRQAPGQGLEWMG 344 P23_G11 WMNPNSGNTGYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR AGYSSSSGYYYYGMDVWGKGTTVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGGTFSSYAISWVRQAPGQGLEWMG 345 P24_D09IVNPSSGSTTYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARV RGSAAIAMMDVWGQGTTVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGGTFTSYHMHWVRQAPGQGLEWM 346 P11_H02 GWMNPNSGNTGYALKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCA SFERFGELVPETFDYWGQGTLVTVSS COVID19_QVQLVQSGAEVKKPGASVKVSCKASGYIFTSYPIHWVRQAPGQGLEWMG 347 P24_C06 WMNPNSGNTGYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR DRGSYDTDAFDIWGQGTMVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFINYDINWVRQAPGQGLEWM 348 P12_B07GVINPSAGSTSYAHKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAS AHSSSWYSDWFDPWGQGTLVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYHMHWVRQAPGQGLEW 349 P24_H04 MGWMNPNSGNTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYC AGMGMGRDGYNSRAFDIWGQGTMVTVSS COVID19_QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYIQWVRQAPGQGLEWM 350 P23_G10 GWINPNSGGPNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR VDYGDYGRLEDYWGQGTLVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMQWVRQAPGQGLEW 351 P24_A09 MGWIDPHSGATNYAHSFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLEGGSYWTGYFDLWGRGTLVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTENEMHWVRQAPGQGLEWM 352 P11_D12 GIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKT RYGGNSRSRYYYYGMDVWGQGTTVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTENEMHWVRQAPGQGLEWM 353 P24_A11GIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARD LMDIVVVPWLGGMDVWGQGTTVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTENEMHWVRQAPGQGLEWM 354 P24_C10 GIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARD SGVDTATLRYYYYGMDVWGQGTTVTVSS COVID19_QVQLVQSGAEVKKPGASVKVSCKASGYTFTENEMHWVRQAPGQGLEWM 355 P11_D08 GIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARD SGVDTATLRYYYYGMDVWGQGTTVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTGNYIHWVRQAPGQGLEWM 356 P24_E02GWMNPNSGNTGYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCA KDVQNYYGSGSSFDYWGQGTLVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTGSYAISWVRQAPGQGLEWM 357 P23_H10 GWINPKTGDTNYAQEFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCA RGSSGYYFGWGQGTLVTVSS COVID19_QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGISWVRQAPGQGLEWM 358 P24_G06 GWISARNGNTNYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCT TDPVLEWFGYSIWGQGTMVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYYIHWVRQAPGQGLEWM 359 P24_C01GIINPSGGSTTYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKG APHDYIWGSYRPDAFDIWGQGTMVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYYIHWVRQAPGQGLEWM 360 P24_G09 GIINPSGGSTTYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAKG APHDYIWGSYRPDAFDIWGQGTMVTVSS COVID19_QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQAPGQGLEWM 361 P24_D08 GIIDPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCATV TPGYGMDVWGQGTTVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQAPGQGLEWM 362 P11_H07 GWMNSNSGSTGYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGWMAYDAFDIWGQGTMVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQAPGQGLEWM 363 P11_G03 GIINPSDGSSTYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARD RGYSYDHDQIYYYYGMDVWGQGTTVTVSS COVID19_ QVQLVQSGAEVKKPGSSVYVSCKASGYTFTSYGISWVRQAPGQGLEWMG 364 P24_B09GIIPMFGTTNYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARDR GDTIDYWGQGTLVTVSS COVID19_ QVQLVQSGAEVKKPGASVKVSCKASGYIFTSYPIHWVRQAPGQGLEWMG 436 P23_G12 WMNPNSGNTGYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR DRGSYDTDAFDIWGQGTMVTVSS
A SH antibody or antigen-binding fragment herein that selectively binds to SARS-CoV-2 can comprise an VL amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to any one of the following sequences
TABLE-US-00026 SEQ ID CloneID VL NO: COVID19_ EIVMTQSPATLSVSPGERATLSCRASESVSSRYLAWYQQKPGQAPRLLIYG 365 P23_F10 ASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQGYKNPPTFGQGT KVEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCQASQGIRNDLGWYQQKPGKAPKLLIYDA 366 P24_H06SRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPPLTFGQGT KVEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQSIGYYLNWYQQKPGKAPKLLIYAA 367 P24_F11 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPLTFGGGTK VEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQGISNNLNWYQQKPGKAPKLLIYAA368 P23__G11 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYDTFPLTFGQZTK VEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQDIRNELGWYQQKPGKAPKLLIYAA 369 P24_D09 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPWTFGQGT KLEIKR COVID19_DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLAWYQQKPGKAPKLLIYAA 370 P11_H02 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKL EIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYAA 371 P24_C06 SNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPSTFGQGTK LEIKRCOVID19_ DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAS 372 P12_B07 SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKV EIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQSISTYLNWYQQKPGKAPKLLIYAAS 373 P24_H04TLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSMPLTFGQGTKV EIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQSIYSWLAWYQQKPGKAPKLLIYDA 374 P23_G10 SSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLNSYPYTFGQGTK VEIKR COVID19_ EIVMTQSPATLSVSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYA 375P24_A09 VSSRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYGSSPLTFGGGT KVEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQHISSYLNWYQQKPGKAPKLLIYAA 376 P11_D12 SALQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYGTPYTFGZZTK VEIKR COVID19_DIQMTQSPSSLSASVGDRVTITCRASQAITNYLAWYQQKPGKAPKLLIYAA 377 P24_A11 SSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSYPPTFGQGTK LEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCQASQDISKYLNWYQQKPGKAPKLLIYGA 378 P24_C10 STLSDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYSTPYSFGQGTK LEIKRCOVID19_ DIQMTQSPSSLSASVGDRVTITCQASQDISKYLNWYQQKPGKAPKLLIYGA 379 P11_D08 STLSDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYSTPYSFGZGTK LEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQGIRNYLAWYQQKPGKAPKLLIYAA 380 P24_E02STLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSPPLTFGQGTK VEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAS 381 P23_H10 RLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKV EIKR COVID19_ DIVMTQSPDSLAVSLGERATINCKSSQSVFSSSNNKNYLAWYQQKPGQPPK382 P24_G06 LLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPL TFGGZTKVEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASENIDSWLAWYQQKPGKAPKLLIYEA 383 P24_C01 STLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYLSSPETFGQGTK VEIKR COVID19_DIQMTQSPSSLSASVGDRVTITCRASENIDSWLAWYQQKPGKAPKLLIYEA 384 P24_G09 STLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYLSSPETFGQGTK VEIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQTIYSYLNWYQQKPGKAPKLLIYDA 385 P24_D08 SNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAISFPLTFGGGTKL EIKRCOVID19_ DIQMTQSPSSLSASVGDRVTITCQASQSIYNYLNWYQQKPGKAPKLLIYDA 386 P11_H07 SNLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAISFPLTFGGGTKV EIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRVSQGISSYLNWYQQKPGKAPKLLIYAA 387 P11_G03SILQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYSTPFTFGPGTKV DIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQGISNNLNWYQQKPGKAPKLLIYAA 388 P24_B09 SSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNGFPLTFGPGTK VDIKR COVID19_ DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYAA437 P23_G12 SNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPSTFGQGTK LEIKR
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 341and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 365.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 342and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 366.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 343and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 367.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 344and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 368.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 345and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 369.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 346and an VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 370.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 347and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 371.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 348and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 372.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 349and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 373.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 350and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 374.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 351and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 375.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 352and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 376.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 353and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 377.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 354and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 378.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 355and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 379.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 356and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 380.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 357and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 381.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 358and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 382.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 359and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 383.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 360and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 384.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 361and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 385.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 362and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 386.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 363and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 387.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 364and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 388.
In one instance, a SH antibody or antigen-binding fragment, herein that selectively binds to SARS-Cov-2 can comprise a VH having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 436and a VL having an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to SEQ ID NO: 437.
Modified Antibodies
The present disclosure provides for modified antibodies. Modified antibodies can comprise antibodies which have one or more modifications which can enhance their activity, binding, specificity, selectivity, or another feature. In one aspect,the present disclosure provides for modified antibodies (which can be heteromultimers) that comprise an anti-SARS-Cov-2 antibody as herein. Reference to a modified antibody herein also refers to a modified antigen-binding fragment.
A modified antibody can comprise a bispecific modified antibody, a trispecific modified antibody or antigen-binding fragment, or a tetraspecific modified antibody or antigen-binding fragment. A bispecific modified antibody can be able tospecifically bind to 2 targets. In some cases, one of the targets a bispecific modified antibody can specifically bind to can be a SARS-CoV-2. A trispecific modified antibody can be able to specifically bind to 3 targets. In some cases, one of thetargets a trispecific modified antibody can specifically bind to can be a SARS-CoV-2. A tetraspecific modified antibody can be able to specifically bind to 4 targets. In some cases, one of the targets a tetraspecific modified antibody can specificallybind to can be a SARS-CoV-2.
A modified antibody can comprise a human modified antibody. Also included herein are amino acid sequence variants of the modified antibody which can be prepared by introducing appropriate nucleotide changes into the modified antibody DNA, or bysynthesis of the desired modified antibody polypeptide. Such variants include, for example, deletions from, or insertions or substitutions of, residues within the amino acid sequences of the first and second polypeptides forming the modified antibody. Any combination of deletion, insertion, and substitution is made to arrive at the final construct, provided that the final construct possesses the desired antigen-binding characteristics. The amino acid changes also may alter post-translationalprocesses of the modified antibody, such as changing the number or position of glycosylation sites.
"Alanine scanning mutagenesis" can be a useful method for identification of certain residues or regions of the modified antibody polypeptides that might be preferred locations for mutagenesis. Here, a residue or group of target residues areidentified (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) and replaced by a neutral or negatively charged amino acid (for example, alanine or polyalanine) to affect the interaction of the amino acids with the surrounding aqueous environmentin or outside the cell. Those domains demonstrating functional sensitivity to the substitutions then are refined by introducing further or other variants at or for the sites of substitution. Thus, while the site for introducing an amino acid sequencevariation is predetermined, the nature of the mutation per se need not be predetermined.
Normally the mutations can involve conservative amino acid replacements in non-functional regions of the modified antibody. Exemplary mutations are shown below.
TABLE-US-00027 Original Preferred Residue Exemplary Substitutions Substitutions Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His; Lys; Arg Gln Asp (D) Glu Glu Cys (C) Ser Ser Gln (Q) Asn Asn Glu (E) Asp Asp Gly (G) Pro; AlaAla His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; Norleucine Leu Leu (L) Norleucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Leu; Val; Ile; Ala; Tyr Leu Pro (P) Ala Ala Ser (S) Thr Thr Thr(T) Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; Norleucine Leu
Covalent modifications of antibody, antigen-binding fragment, or modified antibody polypeptides are included within the scope of this disclosure. Covalent modifications of the modified antibody can be introduced into the molecule by reactingtargeted amino acid residues of the modified antibody or fragments thereof with an organic derivatizing agent that can be capable of reacting with selected side chains or the N- or C-terminal residues. Another type of covalent modification of themodified antibody polypeptide can comprise altering the native glycosylation pattern of the polypeptide. Herein, "altering" can mean deleting one or more carbohydrate moieties found in the original modified antibody, and/or adding one or moreglycosylation sites that are not present in the original modified antibody. Addition of glycosylation sites to the modified antibody polypeptide can be accomplished by altering the amino acid sequence such that it contains one or more N-linkedglycosylation sites. The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the original modified antibody sequence (for O-linked glycosylation sites). For ease, the modified antibody aminoacid sequence can be altered through changes at the DNA level, particularly by mutating the DNA encoding the modified antibody polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids. Anothermeans of increasing the number of carbohydrate moieties on the modified antibody polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Removal of carbohydrate moieties present on the modified antibody can be accomplishedchemically or enzymatically.
Another type of covalent modification of modified antibody comprises linking the modified antibody polypeptide to one of a variety of non-proteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes.
Methods for complexing binding agents or the antibody or antigen-binding fragments thereof herein with another agent are known in the art. Such methods may utilize one of several available heterobifunctional reagents used for coupling orlinking molecules.
In one instance, Fc portions of antibodies can be modified to increase half-life of the molecule in the circulation in blood when administered to a subject.
Additionally, antibodies may be produced or expressed so that they do not contain fucose on their complex N-glycoside-linked sugar chains to increase effector functions. Similarly, antibodies can be attached at their C-terminal end to all orpart of an immunoglobulin heavy chain derived from any antibody isotype, e.g., IgG, IgA, IgE, IgD, and IgM and any of the isotype subclasses, e.g., IgG1, IgG2b, IgG2a, IgG3, and IgG4.
Glycosylation of immunoglobulins has been shown to have significant effects on their effector functions, structural stability, and rate of secretion from antibody-producing cells. Antibodies and antigen-binding fragments herein may beglycosylated. Glycosylation at a variable domain framework residue can alter the binding interaction of the antibody with antigen. The present disclosure includes criteria by which a limited number of amino acids in the framework or CDRs of animmunoglobulin chain can be chosen to be mutated (e.g., by substitution, deletion, and/or addition of residues) in order to increase the affinity of an antibody.
Linkers for conjugating antibodies to other moieties are within the scope of the present disclosure. Associations (binding) between antibodies and labels include, but are not limited to, covalent and non-covalent interactions, chemicalconjugation, as well as recombinant techniques.
Antibodies, or antigen-binding fragments thereof, can be modified for various purposes such as, for example, by addition of polyethylene glycol (PEG). PEG modification (PEGylation) can lead to one or more of improved circulation time, improvedsolubility, improved resistance to proteolysis, reduced antigenicity and immunogenicity, improved bioavailability, reduced toxicity, improved stability, and easier formulation.
An antibody or antigen-binding fragment can be conjugated to, or recombinantly engineered with, an affinity tag (e.g., a purification tag). Affinity tags such as, for example, His6 tags (His-His-His-His-His-His) (SEQ ID NO: 442) have beendescribed.
Since it is often difficult to predict in advance the characteristics of a variant modified antibody, it will be appreciated that some screening of the recovered variants may be needed to select an optimal variant. Exemplary methods ofscreening the recovered variants are described below in the Examples.
Methods of Expressing Antibodies
Also provided herein are methods of making any of these antibodies or polypeptides. The polypeptides can be produced by proteolytic or other degradation of the antibodies, by recombinant methods (i.e., single or fusion polypeptides) asdescribed above, or by chemical synthesis. Polypeptides of the antibodies, especially shorter polypeptides up to about 50 amino acids, can be made by chemical synthesis. Methods of chemical synthesis are commercially available. For example, anantibody could be produced by an automated polypeptide synthesizer employing a solid phase method.
Antibodies may be made recombinantly by first isolating the antibodies and antibody producing cells from host animals, obtaining the gene sequence, and using the gene sequence to express the antibody recombinantly in host cells (e.g., CHOcells). Another method which may be employed is to express the antibody sequence in plants (e.g., tobacco) or transgenic milk. Methods for expressing antibodies recombinantly in plants or milk have been disclosed. Methods for making derivatives ofantibodies, e.g., single chain, etc. are also within the scope of the present disclosure.
As used herein, "host cell" includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may notnecessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected with a polynucleotide(s) of this disclosure.
DNA encoding an antibody may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonalantibodies). Hybridoma cells may serve as a source of such DNA. Once isolated, the DNA may be placed into one or more expression vectors (such as expression vectors disclosed in PCT Publication No. WO 87/04462), which are then transfected into hostcells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also may bemodified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences, or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence fora non-immunoglobulin polypeptide. In that manner, "chimeric" or "hybrid" antibodies are prepared that have the binding specificity of an antibody herein.
Contemplated herein are vectors that encode the one or more antibodies or antigen-binding fragments herein. As used herein, "vector" means a construct, which is capable of delivering, and possibly expressing, one or more gene(s) or sequence(s)of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors; naked DNA or RNA expression vectors; plasmid, cosmid, or phage vectors; DNA or RNA expression vectors associated with cationic condensing agents; DNA or RNAexpression vectors encapsulated in liposomes; and certain eukaryotic cells, such as producer cells.
As used herein, "expression control sequence" means a nucleic acid sequence that directs transcription of a nucleic acid. An expression control sequence can be a promoter, such as a constitutive or an inducible promoter, or an enhancer. Theexpression control sequence is operably linked to the nucleic acid sequence to be transcribed. An expression vector can be used to direct expression of an antibody. Expression vectors can be administered to obtain expression of an exogenous protein invivo.
For high level production, a widely used mammalian expression system is one which utilizes Lonza's GS Gene Expression System.TM.. This system uses a viral promoter and selection via glutamine metabolism to provide development of high-yieldingand stable mammalian cell lines.
For alternative high-level production, a widely used mammalian expression system is one which utilizes gene amplification by dihydrofolate reductase deficient ("dhfr") Chinese hamster ovary cells. The system is based upon the dihydrofolatereductase "dhfr" gene, which encodes the DHFR enzyme, which catalyzes conversion of dihydrofolate to tetrahydrofolate. In order to achieve high production, dhfr-CHO cells are transfected with an expression vector containing a functional DHFR gene,together with a gene that encodes a desired protein. In this case, the desired protein is recombinant antibody heavy chain and/or light chain.
By increasing the amount of the competitive DHFR inhibitor methotrexate (MTX), the recombinant cells develop resistance by amplifying the dhfr gene. In standard cases, the amplification unit employed is much larger than the size of the dhfrgene, and as a result the antibody heavy chain is co-amplified.
When large scale production of the protein, such as the antibody chain, is desired, both the expression level and the stability of the cells being employed are taken into account.
The present application provides one or more isolated polynucleotides (nucleic acids) encoding an antibody or an antigen-binding fragment herein, vectors containing such polynucleotides, and host cells and expression systems for transcribing andtranslating such polynucleotides into polypeptides.
The present application also provides constructs in the form of plasmids, vectors, transcription or expression cassettes which comprise at least one polynucleotide as above.
The present application also provides a recombinant host cell which comprises one or more constructs as above. A nucleic acid encoding any antibody herein forms an aspect of the present application, as does a method of production of theantibody, which method comprises expression from encoding nucleic acid therefrom. Expression can be achieved by culturing under appropriate conditions recombinant host cells containing the nucleic acid. Following production by expression, an antibodyor a portion thereof can be isolated and/or purified using any suitable technique, then used as appropriate. Systems for cloning and expression of a polypeptide in a variety of different host cells are contemplated for use herein.
A further aspect provides a host cell containing nucleic acid as disclosed herein using any suitable method. A still further aspect provides a method comprising introducing such nucleic acid into a host cell. The introduction can be followedby causing or allowing expression from the nucleic acid, e.g., by culturing host cells under conditions for expression of the gene.
One or more polynucleotides encoding an antibody or an antigen-binding fragment can be prepared recombinantly/synthetically in addition to, or rather than, cloned. In a further embodiment, the full DNA sequence of the recombinant DNA moleculeor cloned gene(s) of an antibody or antigen-binding fragment herein can be operatively linked to an expression control sequence which can be introduced into an appropriate host using any suitable method.
Nucleic acid sequences can be expressed by operatively linking them to an expression control sequence in an appropriate expression vector and employing that expression vector to transform an appropriate host cell. Any of a wide variety ofexpression control sequences--sequences that control the expression of a nucleic acid sequence operatively linked to it--can be used in these vectors to express the nucleic acid sequences.
A wide variety of host/expression vector combinations can be employed in expressing the nucleic acid sequences of this disclosure. It will be understood that not all vectors, expression control sequences, and hosts will function equally well toexpress the nucleic acid sequences. Neither will all hosts function equally well with the same expression system. In some embodiments, in selecting a vector, the host is considered such that the vector can function in it. The vector's copy number, theability to control that copy number, and the expression of any other proteins encoded by the vector, such as antibiotic markers, may also be considered. In certain embodiments, in selecting a vector, the host is considered such that the vector functionsin it. The vector's copy number, the ability to control that copy number, and the expression of any other proteins encoded by the vector, such as antibiotic markers, can also be considered.
The present application also provides a method which comprises using a construct as stated above in an expression system in order to express the antibodies (or portions thereof) as above. Considering these and other factors, a variety ofvector/expression control sequence/host combinations can be constructed that can express the nucleic acid sequences on fermentation or in large scale animal culture.
Simultaneous incorporation of the antibody (or portion thereof)-encoding nucleic acids and the selected amino acid position changes can be accomplished by a variety of suitable methods including, for example, recombinant and chemical synthesis.
Provided herein are methods of expressing an antibody or antigen-binding fragment antigen-binding that can selectively bind to SARS-Cov-2 in a subject comprising administering to the subject a composition comprising one or more polynucleotides(e.g., mRNA) encoding the antibody or antigen-binding fragment.
In some cases, administering the one or more polynucleotides to the subject can comprise enteral, gastroenteral, oral, transdermal, epicutaneous, intradermal, subcutaneous, nasal administration, intravenous, intraperitoneal, intraarterial,intramuscular, intraosseous infusion, transmucosal, insufflation, or sublingual administration. In some cases, a polynucleotide can be administered via more than one route.
Antibodies or antigen-binding fragments can be synthesized in the subject based at least in part on the polynucleotide encoding the antibody or antigen-binding fragment. For example, a polynucleotide can enter a cell of the subject, and theantibody or antigen-binding fragment can be synthesized at least in part by using the subject's cellular transcription and/or translation machinery. In some cases, for example where the polynucleotide is an mRNA molecule, the antibody or antigen-bindingfragment can be synthesized at least in part by using the subject's cellular translation machinery (e.g., ribosomes, tRNA, etc.). In some cases, antibody or antigen-binding fragments can be transported from a cell to the plasma of the subject aftertranslation.
Compositions
Compositions comprising a SH antibody or antigen-binding fragment herein may be prepared for storage by mixing an antibody or antigen-binding fragment having the desired degree of purity with optional pharmaceutically acceptable carriers,excipients or stabilizers (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000)), in the form of lyophilized formulations or aqueous solutions.
As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with thesubject's immune system. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Preferreddiluents for aerosol or parenteral administration are phosphate buffered saline or normal (0.9%) saline. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18thedition, A. Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1990; and Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).
Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidantsincluding ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol,trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG).
The compositions to be used for in vivo administration may be sterilized. This may be accomplished by, for example, filtration through sterile filtration membranes, or any other art-recognized method for sterilization. Antibody compositionsare generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. Other methods for sterilization and filtration are known in the art andare contemplated herein.
In one embodiment of the present invention, the compositions are formulated to be free of pyrogens such that they are acceptable for administration to a subject.
The compositions according to the present invention may be in unit dosage forms such as solutions or suspensions, tablets, pills, capsules, powders, granules, or suppositories, etc., for intravenous, oral, parenteral or rectal administration, oradministration by inhalation or insufflation.
The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, whenadministered to a subject.
In some instances, an antibody or antigen-binding fragment can be bound to one or more carriers. Carriers can be active and/or inert. Examples of well-known carriers include polypropylene, polystyrene, polyethylene, dextran, nylon, amylases,glass, natural and modified celluloses, polyacrylamides, agaroses and magnetite. The nature of the carrier can be either soluble or insoluble for purposes of the invention. Those skilled in the art will know of other suitable carriers for bindingantibodies, or will be able to ascertain such, using routine experimentation.
One embodiment contemplates the use of the antibodies and antigen-binding fragments to manufacture a medicament for treating a condition, disease or disorder described herein. Medicaments can be formulated based on the physical characteristicsof the subject needing treatment, and can be formulated in single or multiple formulations based on the stage of the condition, disease or disorder. Medicaments can be packaged in a suitable package with appropriate labels for the distribution tohospitals and clinics wherein the label is for the indication of treating a subject having a disease described herein. Medicaments can be packaged as a single or multiple units. Instructions for the dosage and administration of the compositions can beincluded with the packages as described below. The invention is further directed to medicaments of an antibody or antigen-binding fragment and a pharmaceutically acceptable carrier.
Kits
Provided herein are kits that comprise one or more SH antibodies or antigen-binding fragments herein. Provided herein is a container means comprising one or more SH antibodies or antigen-binding fragments herein. The container means may be anysuitable container which may house a liquid or lyophilized composition including, but not limited to, a vial, a syringe, a bottle, an intravenous (IV) bag, an ampoule, or any other suitable container. A syringe may be able to hold any volume of liquidsuitable for injection into a subject including, but not limited to, 0.5 cc, 1 cc, 2 cc, 5 cc, 10 cc or more. In some embodiments, the SH antibody or antigen-binding fragment is lyophilized, and the kit comprises one or more suitable buffers forreconstitution prior to injection.
The kit may comprise one or more instruction sheets describing the use of the one or more SH antibodies or antigen-binding fragments. The kit may include one or more labels describing the contents and use of the one or more SH antibodies.
Methods of Treatment
The present disclosure provides methods of preventing or treating a subject infected with SARS-Cov-2 (COVID) or suspected of being infected with SARS-Cov-2 in a subject in need thereof, comprising administering to the subject an antibody herein. In one instance, the subject to be treated is symptomatic prior to administration of the antibody. In another instance, the subject to be treated is asymptomatic prior to administration of the antibody.
The present disclosure provides methods of prophylactically treating (e.g., preventing) a subject having one or more co-morbidities or having an increased or high risk of infection.
A "subject" as herein, includes, but is not limited to, a human, a rodent, a primate, etc. In some instances, the subject to be treated exhibits one or more underlying conditions that exacerbate the infection such as, for example, high bloodpressure, heart problems, diabetes, immunocompromised, lung disease, cancer, clots, thrombosis, or a combination thereof.
A subject can be administered a SH antibody or antigen-binding fragment herein in an amount that achieves at least partially a partial or complete reduction of one or more symptoms. Reduction can be, for example, a decrease of one or moresymptoms by about 5% or more compared to prior to treatment. For the administration to human patients, the compositions can be formulated by methodology known by one in the art. The amount of an antibody necessary to bring about therapeutic treatmentof COVID19 is not fixed per se. The amount of antibody administered may vary with the extensiveness of the disease, and size of the human suffering from COVID19. Treatment, in one instance, lowers infection rates in a population of subjects. Treatmentmay also result in a shortened recovery time, in fewer symptoms, or in less severe symptoms, or a combination thereof compared to an untreated subject who has COVID19.
The SH antibodies and antigen-binding fragments herein may be used to treat a COVID19 infection (an infection caused by SARS-Cov-2) in a subject in need thereof, thereby reducing one or more symptoms of the infection. The one or more symptomsto be treated include, but are not limited to, a fever of over 100.4.degree. F., fatigue, coughing (e.g., a dry cough), aches, pains, runny nose, stuffy nose, sore throat, diarrhea, headaches, shortness of breath, or any combination thereof. In someinstances, treatment of a subject includes a reduction by at least 5% in 1 symptom, 2 symptoms, 3 symptoms, 4 symptoms, 5 symptoms, 6 symptoms, 7 symptoms, 8 symptoms, 9 symptoms, 10 symptoms, or 11 symptoms. During at least a portion of this timeperiod the SH antibody or antigen-binding fragment can protect the subject from infection by SARS-Cov-2. Protecting can comprise for example reducing an infection rate of SARS-Cov-2 or reducing or preventing reproduction of SARS-Cov-2. Treatment cancomprise for example reducing symptoms of COVID-19, reducing a death rate, or reducing or preventing reproduction of SARS-Cov-2.
"Administering" is referred to herein as providing one or more compositions to a patient in a manner that results in the composition being inside the patient's body. Such an administration can be by any route including, without limitation,locally, regionally, or systemically, by subcutaneous, intradermal, intravenous, intra-arterial, intraperitoneal, or intramuscular administration (e.g., injection). In one instance, administration is via intradermal injection. In another instance,administration is via subcutaneous injection. In one embodiment, a subject is administered one of the antibodies or antigen-binding fragments herein one or more times. In another embodiment, a subject is administered two of the antibodies orantigen-binding fragments herein one or more times. In another embodiment, a subject is administered three of the antibodies or antigen-binding fragments herein one or more times. In another embodiment, a subject is administered four of the antibodiesor antigen-binding fragments herein one or more times. A SH antibody or antigen-binding fragment herein to be administered to the subject exhibits a nM or a pM binding affinity, e.g., between 180 pM and 50 nM.
The present disclosure provides methods of reducing the death rate of infection by SARS-Cov-2 by administering to a subject in need thereof a composition comprising one or more polynucleotides (e.g., mRNA) encoding an antibody or antigen-bindingfragment that can specifically bind to SARS-Cov-2. Reduction in death rate can be determined for example by comparing the rate of death of subjects infected by SARS-Cov-2 between a cohort that receives the composition and a cohort that does not receivethe composition. Death rate can be determined for example by determining the number of infected subjects of a cohort wherein infection by SARS-Cov-2 results in death. In some cases, the death rate can be reduced compared with subjects not administereda composition comprising an mRNA molecule provided herein by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some cases, the death rate can be reducedcompared with subjects not administered a composition comprising an mRNA molecule provided herein by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two foregoing values.
The present disclosure also provides methods for reducing the infection rate of SARS-Cov-2 by administering to a subject non infected with SARS-Cov-2 a composition comprising one or more polynucleotides (e.g., mRNA) encoding an antibody orantigen-binding fragment that can specifically bind to SARS-CoV-2. Reduction in infection rate can be determined for example by comparing the rate of infection of subjects exposed to SARS-Cov-2 between a cohort that receives the composition and a cohortthat does not receive the composition. Infection of a subject can be determined by analyzing a sample from the subject for the presence or absence of SARS-Cov-2 after suspected or confirmed exposure to SARS-Cov-2, or after an elapsed time in whichexposure to SARS-Cov-2 is likely. In some cases, the infection rate can be reduced compared with subjects not administered a composition comprising an mRNA molecule provided herein by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%,at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some cases, the infection rate can be reduced compared with subjects not administered a composition comprising an mRNA molecule provided herein by about 10%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two foregoing values.
The present disclosure also provides methods for slowing or preventing reproduction of SARS-Cov-2 in a subject by administering to a subject infected with SARS-Cov-2 a composition comprising one or more polynucleotides (e.g., mRNA) encoding anantibody or antigen-binding fragment that can specifically bind to SARS-Cov-2. Slowing or preventing reproduction of SARS-Cov-2 can be determined for example by comparing the rate of reproduction of the virus in subjects infected SARS-Cov-2 between acohort that receives the composition and a cohort that does not receive the composition. Replication of SARS-Cov-2 can be determine for example by determining (directly or indirectly) the amount of SARS-Cov-2 in a sample acquired from the subject atdifferent time points. Assays that can be used to determine amount of SARS-Cov-2 in a sample can include a plaque assay, a focus forming assay, an endpoint dilution assay, a protein assay (e.g., a bicinchoninic acid assay or a single radialimmunodiffusion assay), transmission electron microscopy, tunable resistive pulse sensing, flow cytometry, qPCR, ELISA, or another acceptable method. An assay can be performed on a whole sample or a fraction of a sample, or SARS-Cov-2 can be isolatedfrom the sample prior to performing an assay. In some cases, the reproduction of SARS-Cov-2 can be slowed compared with subjects not administered a composition comprising an mRNA molecule provided herein by at least 5%, at least 10%, at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some cases, the reproduction of SARS-Cov-2 can be slowed compared with subjects not administered a composition comprising an mRNA molecule providedherein by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or a range between any two foregoing values.
The present disclosure also provides methods of activating T cells in a subject comprising administering to a subject a composition comprising one or more polynucleotides (e.g., mRNA) encoding an antibody or antigen-binding fragment that canspecifically bind to SARS-CoV-2. In some cases, T cell activation can be elevated compared with subjects not administered the composition. Activation of T cells can be determined for example by comparing the activation of T cells in subjects infectedSARS-Cov-2 between a cohort that receives the composition and a cohort that does not receive the composition. In one aspect, the activation of T cells in the subject can be directed to an anti-SARS-Cov-2 response in the subject. Activated T cells inthe subject can reduce severity of COVID-19 symptoms, death rate, time to recovery, or viral reproduction in the subject. Activation of T cells can be measured for example by measuring T cell proliferation, measuring cytokine production (e.g., viaenzyme-linked immunosorbent assays or enzyme-linked immunospot assays), or detection of cell-surface markers associated with T cell activation (e.g., CD69, CD40L, CD137, CD25, CD71, CD26, CD27, CD28, CD30, CD154, or CD134) for example by flow cytometry. In some cases, the T cell activation can be elevated compared with subjects not administered a composition comprising an mRNA molecule provided herein by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, or at least 90%. In some cases, the T cell activation can be elevated compared with subjects not administered a composition comprising an mRNA molecule provided herein by about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, about 70%, about 80%, about 90%, or a range between any two foregoing values.
The present disclosure also provides methods for inducing T cell proliferation in a subject comprising administering to a subject a composition comprising one or more polynucleotides (e.g., mRNA) encoding an antibody or antigen-binding fragmentthat can specifically bind to SARS-CoV-2. In some cases, T cell proliferation can be elevated compared with subjects not administered the composition. In some cases, T cell proliferation can be directed to an anti-SARS-Cov-2 response in the subject. In some cases, T cell proliferation in the subject can reduce or decrease severity of COVID-19 symptoms, death rate, time to recovery, or viral reproduction in the subject. T cell proliferation can be determined for example by cell counting, viabilitystaining, optical density assays, or detection of cell-surface markers associated with T cell activation (e.g., CD69, CD40L, CD137, CD25, CD71, CD26, CD27, CD28, CD30, CD154, or CD134) for example by flow cytometry. In some cases, T cell proliferationcan be elevated compared with subjects not administered a composition comprising an mRNA molecule provided herein by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least90%. In some cases, T cell proliferation can be elevated compared with subjects not administered a composition comprising an mRNA molecule provided herein by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about90%, or a range between any two foregoing values.
The present disclosure also provides methods for inducing a memory T cell response in a subject comprising administering to a subject a composition comprising one or more polynucleotides (e.g., mRNA) encoding an antibody or antigen-bindingfragment that can specifically bind to SARS-CoV-2. In some cases, a memory T cell response can be elevated compared with subjects not administered the composition. In some cases, a memory T cell response in the subject can reduce or decrease i severityof COVID-19 symptoms, death rate, time to recovery, or viral reproduction in the subject. A memory T cell response can be directed to an anti-SARS-Cov-2 response in the subject. A memory T cell response can be determined for example by measuring T cellmarkers associated with memory T cells, measuring local cytokine production related to memory immune response, or detecting memory T cell-surface markers for example by flow cytometry. In some cases, the memory T cell response can be elevated comparedwith subjects not administered a composition comprising an mRNA molecule provided herein by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some cases, thememory T cell response can be elevated compared with subjects not administered a composition comprising an mRNA molecule provided herein by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or a rangebetween any two foregoing values.
A polynucleotide (e.g., mRNA) herein can be administered in any route available, including, but not limited to, enteral, gastroenteral, oral, transdermal, epicutaneous, intradermal, subcutaneous, nasal administration, intravenous,intraperitoneal, intraarterial, intramuscular, intraosseous infusion, transmucosal, insufflation, or sublingual administration. In some cases, mRNA of the present disclosure can be administered parenterally (e.g., includes subcutaneous, intravenous,intraperitoneal, intratumoral, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and injection or infusion techniques), intraventricularly, orally, by inhalation spray, topically, rectally, nasally,buccally, or via an implanted reservoir.
Actual dosage levels of antibody can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response without being toxic to the patient. The selected dosage level will depend upon avariety of factors including the activity of the particular antibody employed, the route of administration, the time of administration, the rate of excretion of the particular antibody being employed, the duration of the treatment, other drugs, compoundsand/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
The antibodies herein can be administered to a subject in various dosing amounts and over various time frames.
A physician or veterinarian can readily determine and prescribe the effective amount (ED50) of the antibody required. For example, the physician or veterinarian could start doses of the antibody employed in the composition at levels lower thanthat required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Alternatively, a dose can remain constant.
The antibody can be administered to a patient by any convenient route such as described above. Regardless of the route of administration selected, the antibodies of the present invention, which can be used in a suitable hydrated form, and/orthe compositions, are formulated into acceptable dosage forms.
Toxicity and therapeutic efficacy of compounds can be determined by standard procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED.sub.50 (the dosetherapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. While compounds that exhibit toxic side effects may be used, care shouldbe taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to healthy cells and, thereby, reduce side effects.
Data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 withlittle or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound, a therapeutically effective dose can be estimated initially from cell culture assays. Adose can be formulated in animal models to achieve a circulating plasma concentration arrange that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition) as determined in cell culture. Levels in plasmacan be measured, for example, by high performance liquid chromatography. Such information can be used to more accurately determine useful doses in humans.
It will be understood that administration of one or more of the antibodies or antigen-binding fragments herein can be supplemented by one or more additional therapies or drugs such as, for example, respiratory therapy; one or more blood thinnersor anti-coagulants; statins, intubation; hydroxy chloroquine; one or more antibiotics (e.g., doxycycline, Azithromycin, etc.); one or more decongestants (e.g., Mucinex, Sudafed, etc.); one or more anti-histamines and/or glucocorticoids (e.g., Zyrtec,Claritin, Allegra, fluticasone luroate, etc.); one or more pain relievers (e.g., acetominophen); one or more zinc-containing medications (e.g., Zycam, etc.); Azithromycin, hydroquinolone, or a combination thereof; one or more integrase inhibitors (e.g.,Bictegravir, dolutegravir (Tivicay), elvitegravir, raltegravir, or a combination thereof); one or more nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; e.g., abacavir (Ziagen), emtricitabine (Emtriva), lamivudine (Epivir), tenofoviralafenamide fumarate (Vemlidy), tenofovir disoproxil fumarate (Viread), zidovudine (Retrovir), didanosine (Videx, Videx EC), stavudine (Zerit), or a combination thereof); a combination of NRTIs (e.g., (i) abacavir, lamivudine, and zidovudine (Trizivir),(ii) abacavir and lamivudine (Epzicom), (iii) emtricitabine and tenofovir alafenamide fumarate (Descovy), (iv) emtricitabine and tenofovir disoproxil fumarate (Truvada), (v) lamivudine and tenofovir disoproxil fumarate (Cimduo, Temixys), (vi) lamivudineand zidovudine (Combivir), etc.); a combination of Descovy and Truvada; one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., doravirine (Pifeltro), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune, Viramune XR),rilpivirine (Edurant), delavirdine (Rescriptor), or a combination thereof); one or more Cytochrome P4503A (CYP3A) inhibitors (e.g., cobicistat (Tybost), ritonavir (Norvir), etc.); one or more protease inhibitors (PIs; e.g., atazanavir (Reyataz),darunavir (Prezista), fosamprenavir (Lexiva), lopinavir, ritonavir (Norvir), tipranavir (Aptivus), etc.); one or PIs in combination with cobicistat, ritonavir, Lopinavir, Tipranavir, Atazanavir, fosamprenavir, indinavir (Crixivan), nelfinavir (Viracept),saquinavir (Invirase), or a combination thereof; Atazanavir; fosamprenavir; a combination of Atazanavir, darunavir and cobicistat; one or more fusion inhibitors (e.g., enfuvirtide (Fuzeon); one or more post-attachment inhibitors (e.g., ibalizumab-uiyk(Trogarzo)); one or more Chemokine coreceptor antagonists (CCR5 antagonists; e.g., maraviroc (Selzentry)); and one or more viral entry inhibitors (e.g., enfuvirtide (Fuzeon), ibalizumab-uiyk (Trogarzo), maraviroc (Selzentry), etc.); or a combinationthereof.
Non-limiting examples of combinations include one or more of the antibodies or antigen-binding fragments herein to be administered with one or more of the following: (1) Azithromycin, hydroquinolone, or a combination thereof, (2) darunavir andcobicistat (Prezcobix), (3) lopinavir and ritonavir (Kaletra), (4) abacavir, lamivudine, and zidovudine (Trizivir), (5) abacavir and lamivudine (Epzicom), (6) emtricitabine and tenofovir alafenamide fumarate (Descovy), (7) emtricitabine and tenofovirdisoproxil fumarate (Truvada), (8) lamivudine and tenofovir disoproxil fumarate (Cimduo, Temixys), (9) lamivudine and zidovudine (Combivir), (10), atazanavir and cobicistat (Evotaz), (11) doravirine, lamivudine, and tenofovir disoproxil fumarate(Delstrigo), (12) efavirenz, lamivudine, and tenofovir disoproxil fumarate (Symfi), (13) efavirenz, lamivudine, and tenofovir disoproxil fumarate (Symfi Lo), (14) efavirenz, emtricitabine, and tenofovir disoproxil fumarate (Atripla), (15) emtricitabine,rilpivirine, and tenofovir alafenamide fumarate (Odefsey), (16) emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (Complera), (17) elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (Stribild), (18) elvitegravir,cobicistat, emtricitabine, and tenofovir alafenamide fumarate (Genvoya), (19) abacavir, dolutegravir, and lamivudine (Triumeq), (20) bictegravir, emtricitabine, and tenofovir alafenamide fumarate (Biktarvy), (21) dolutegravir and lamivudine (Dovato),(22) dolutegravir and rilpivirine (Juluca), (23) darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (Symtuza).
Non-limiting examples of combinations include one or more of the antibodies or antigen-binding fragments herein to be administered with one or more blood thinners. Blood thinners to be co-administered include, but are not limited to,anti-platelet, and anti-coagulation medications. Antiplatelet medications are those such as, for example, aspirin, clopidogrel (PLAVIX.RTM.); prasugrel (EFFIENT.RTM.); ticlopidine (TICLID.RTM.); ticagrelor (BRILINTA.RTM.); and combinations thereof. Anticoagulants include, but are not limited to, Warfarin (COUMADIN.RTM., JANTOVEN.RTM.); Heparin (e.g., FRAGMIN.RTM., INNOHEP.RTM., and LOVENOX.RTM.); Eabigatran (PRADAXA.RTM.); Epixaban (ELIQUIS.RTM.); Non-vitamin K antagonist oral anticoagulants(NOACs) such as, for example, Rivaroxaban (XARELTO.RTM.); Factor Xa inhibitors such as, for example, Edoxaban (SAVAYSA.RTM.), Fondaparinux (ARIXTRA.RTM.); and combinations thereof.
Diagnostics
Provided herein are methods of diagnosing a subject suspected of being infected with SARS-Cov-2 by contacting a sample obtained from the subject with one or more antibodies or antigen-binding fragments herein.
A "sample" from a subject to be tested utilizing one or more of the assays herein includes, but is not limited to, a nasal swab, a tissue sample, saliva, blood, etc. In some instances, the sample is treated prior to use in a diagnostic assay. For example, a nasal swab may be flushed with phosphate buffered saline (PBS); a fluid sample may be centrifuged to concentrate the sample components; blood may be treated with heparin to prevent coagulation, etc.
Samples may be tested in any suitable assay including, but not limited to, an enzyme linked immunosorbent assay (ELISA), an immunospot assay, a lateral flow assay, immunohistochemistry (IHC), western blot, flow cytometry, etc. The sample iscontacted with an antibody herein, and when the presence of the antibody bound to a SARS-CoV-2 is detected, the subject is diagnosed as being infected with SARS-Cov-2 and/or having a COVID-19 infection.
In one instance, a sample obtained from a subject is contacted with a SH antibody or antigen-binding fragment herein that selectively binds to SARS-Cov-2 and the presence or absence of the antibody or antigen-binding fragment is determined. Thesubject is diagnosed as being infected with SARS-Cov-2 when the presence of the antibody or antigen-binding fragment is detected.
Exemplary Definitions
The term "about" as used herein, generally refers to a range that is 2%, 5%, 10%, 15% greater than or less than (.+-.) a stated numerical value within the context of the particular usage. For example, "about 10" would include a range from 8.5to 11.5. As used herein, the terms "about" and "approximately," when used to modify a numeric value or numeric range, indicate that deviations of up to about 0.2%, about 0.5%, about 1%, about 2%, about 5%, about 7.5%, or about 10% (or any integerbetween about 1% and 10%) above or below the value or range remain within the intended meaning of the recited value or range.
As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, references to "a method" include one or more methods,and/or steps of the type herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.
Polypeptides (e.g., proteins) and polynucleotides (e.g., nucleic acids) herein can be isolated and/or purified from their natural environment in substantially pure or homogeneous form. Methods of purifying proteins and nucleic acids arecontemplated for use herein. "Isolated" (used interchangeably with "substantially pure") when applied to polypeptides means a polypeptide or a portion thereof which, by virtue of its origin or manipulation: (i) is present in a host cell as theexpression product of a portion of an expression vector; (ii) is linked to a protein or other chemical moiety other than that to which it is linked in nature; or (iii) does not occur in nature, for example, a protein that is chemically manipulated byappending, or adding at least one hydrophobic moiety to the protein so that the protein is in a form not found in nature. By "isolated" it is further meant a protein that is: (i) synthesized chemically or (ii) expressed in a host cell and purified awayfrom associated and contaminating proteins. The term generally means a polypeptide that has been separated from other proteins and nucleic acids with which it naturally occurs. The polypeptide may also be separated from substances such as antibodies orgel matrices (polyacrylamide) which are used to purify it. As used herein, substantially pure, isolated," or purified refers to material which is at least 50% pure (e.g., free from contaminants), at least 60% pure, at least 70% pure, at least 80% pure,at least 85% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, or at least 99% pure.
Polypeptides can be isolated and purified from culture supernatant or ascites by saturated ammonium sulfate precipitation, an euglobulin precipitation method, a caproic acid method, a caprylic acid method, ion exchange chromatography (DEAE orDE52), or affinity chromatography using anti-Ig column or a protein A, protein G, or protein L column such as described in more detail below. In one aspect, reference to a binding agent, an antibody or an antigen-binding fragment also refers to an"isolated binding agent," an "isolated antibody," or an "isolated antigen-binding fragment." In another aspect, reference to a binding agent, an antibody, or an antigen-binding fragment also refers to a "purified binding agent," a "purified antibody," ora "purified antigen-binding fragment."
Antibodies can be "isolated" and "purified" from the culture supernatant or ascites mentioned above by saturated ammonium sulfate precipitation, euglobulin precipitation method, caproic acid method, caprylic acid method, ion exchangechromatography (DEAE or DE52), or affinity chromatography using anti-Ig column or a protein A, G or L column using art-recognized conventional methods.
As used herein, the term "antibody" refers to an immunoglobulin (Ig), polypeptide, or a protein having a binding domain which is, or is homologous to, an antigen-binding domain. The term further includes "antigen-binding fragments" and otherinterchangeable terms for similar binding fragments as described below. Native antibodies and native immunoglobulins (Igs) are generally heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light chains and two identicalheavy chains. Each light chain is typically linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularlyspaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain ("VH") followed by a number of constant domains ("C.sub.H"). Each light chain has a variable domain at one end ("VL") and a constant domain ("CL") at its other end;the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form aninterface between the light- and heavy-chain variable domains. In some instances, an antibody or an antigen-binding fragment comprises an isolated antibody or antigen-binding fragment, a purified antibody or antigen-binding fragment, a recombinantantibody or antigen-binding fragment, a modified antibody or antigen-binding fragment, or a synthetic antibody or antigen-binding fragment.
Antibodies and antigen-binding fragments herein can be partly or wholly synthetically produced. An antibody or antigen-binding fragment can be a polypeptide or protein having a binding domain which can be, or can be homologous to, anantigen-binding domain. In one instance, an antibody or an antigen-binding fragment can be produced in an appropriate in vivo animal model and then isolated and/or purified. It would be understood that the antibodies herein can be modified as describedbelow or as known in the art.
Antibodies useful in the present invention encompass, but are not limited to, monoclonal antibodies, polyclonal antibodies, antibody fragments (e.g., Fab, Fab', F(ab').sub.2, Fv, Fc, scFv, scFv-Fc, Fab-Fc, scFv-zipper, scFab, crossFab, camelids(VHH), etc.), chimeric antibodies, bispecific antibodies, multispecific antibodies, heteroconjugate antibodies, single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion (e.g., a domain antibody), humanized antibodies, humanantibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, andcovalently modified antibodies.
Depending on the amino acid sequence of the constant domain of its heavy chains, immunoglobulins (Igs) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these maybe further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. An Ig or portion thereof can, in some cases, be a human Ig. In some instances, a C.sub.H3 domain can be from an immunoglobulin. In some cases, a chain or apart of an antibody or antigen-binding fragment, a modified antibody or antigen-binding fragment, or a binding agent can be from an Ig. In such cases, an Ig can be IgG, an IgA, an IgD, an IgE, or an IgM. In cases where the Ig is an IgG, it can be asubtype of IgG, wherein subtypes of IgG can include IgG1, an IgG2a, an IgG2b, an IgG3, and an IgG4. In some cases, a C.sub.H3 domain can be from an immunoglobulin selected from the group consisting of an IgG, an IgA, an IgD, an IgE, and an IgM.
The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa or (".kappa." or "K") and lambda or (".lamda."), based on the amino acid sequences of theirconstant domains.
As used herein, a "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally-occurringmutations that may be present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a singledeterminant on the antigen (epitope). The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody byany particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, 1975, Nature, 256:495, or may be made by recombinant DNAmethods such as described in U.S. Pat. No. 4,816,567. The monoclonal antibodies may also be isolated from phage libraries generated using the techniques described in McCafferty et al., 1990, Nature, 348:552-554, for example. Other methods are knownin the art and are contemplated for use herein.
A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable regions of the heavy and light chain each consist offour framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute tothe formation of the antigen-binding site of antibodies. Amino acid residues of CDRs and framework regions are as herein for the provided sequences.
With respect to antibodies, the term "variable domain" refers to the variable domains of antibodies that are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenlydistributed throughout the variable domains of antibodies. Rather, it is concentrated in three segments called hypervariable regions (also known as CDRs) in both the light chain and the heavy chain variable domains. More highly conserved portions ofvariable domains are called the "framework regions," "FWs," or "FRs." The variable domains of unmodified heavy and light chains each contain four FRs (FR1, FR2, FR3, and FR4), largely adopting a .beta.-sheet configuration interspersed with three CDRswhich form loops connecting and, in some cases, part of the .beta.-sheet structure. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen-binding siteof antibodies.
A "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.
"Epitope" refers to that portion of an antigen or other macromolecule capable of forming a binding interaction with the variable region binding pocket of an antibody. Such binding interactions can be manifested as an intermolecular contact withone or more amino acid residues of one or more CDRs. Antigen-binding can involve, for example, a CDR3 or a CDR3 pair or, in some cases, interactions of up to all six CDRs of the VH and VL chains. An epitope can be a linear peptide sequence("continuous") or can be composed of noncontiguous amino acid sequences ("conformational" or "discontinuous"). An antibody can recognize one or more amino acid sequences; therefore, an epitope can define more than one distinct amino acid sequence. Epitopes recognized by antibodies can be determined by peptide mapping and sequence analysis techniques well known to one of skill in the art. Binding interactions are manifested as intermolecular contacts between an epitope on an antigen and one ormore amino acid residues of a CDR. An epitope provided herein can refer to an amino acid sequence on a receptor binding domain or a spike domain.
An antibody selectively binds to a target if it binds with greater affinity, avidity, more readily, and/or with greater duration than it binds to other substances. For example, an antibody or antigen-binding fragment that selectively binds to aSARS-Cov-2 epitope is an antibody or antigen-binding fragment that binds this epitope with greater affinity, avidity, more readily, and/or with greater duration than it binds to SARS-Cov-1 or MERS. The term "Fc region" is used to define a C-terminalregion of an immunoglobulin heavy chain. The "Fc region" may be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usuallydefined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3.
The terms "hypervariable region" and "CDR" when used herein, refer to the amino acid residues of an antibody which are responsible for antigen-binding. The CDRs comprise amino acid residues from three sequence regions which bind in acomplementary manner to an antigen and are known as CDR1, CDR2, and CDR3 for each of the VH and VL chains. It is understood that the CDRs of different antibodies may contain insertions, thus the amino acid numbering may differ. CDR sequences of theantibodies and antigen-binding fragments thereof have been provided herein below.
As used herein, "framework region" or "FR" or "FW" refers to framework amino acid residues that form a part of the antigen-binding pocket or groove. In some embodiments, the framework residues form a loop that is a part of the antigen-bindingpocket or groove and the amino acids residues in the loop may or may not contact the antigen. Framework regions generally comprise the regions between the CDRs. Framework regions of the antibodies and antigen-binding fragments thereof have beenprovided herein below.
The loop amino acids of a FR can be assessed and determined by inspection of the three-dimensional structure of an antibody heavy chain and/or antibody light chain. The three-dimensional structure can be analyzed for solvent accessible aminoacid positions as such positions are likely to form a loop and/or provide antigen contact in an antibody variable domain. Some of the solvent accessible positions can tolerate amino acid sequence diversity and others (e.g., structural positions) are,generally, less diversified. The three-dimensional structure of the antibody variable domain can be derived from a crystal structure or protein modeling.
In the present disclosure, the following abbreviations (in the parentheses) are used in accordance with the customs, as necessary: heavy chain (H chain), light chain (L chain), heavy chain variable region (VH), light chain variable region (VL),complementarity determining region (CDR), first complementarity determining region (CDR1), second complementarity determining region (CDR2), third complementarity determining region (CDR3), heavy chain first complementarity determining region (VH CDR1),heavy chain second complementarity determining region (VH CDR2), heavy chain third complementarity determining region (VH CDR3), light chain first complementarity determining region (VL CDR1), light chain second complementarity determining region (VLCDR2), and light chain third complementarity determining region (VL CDR3).
In some instances, an anti-SARS-Cov-2 antibody is a monoclonal antibody. As used herein, a "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodiescomprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against differentdeterminants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen (epitope). The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population ofantibodies and is not to be construed as requiring production of the antibody by any particular method, including the Tumbler methods described below.
In some instances, an anti-SARS-Cov-2 antibody or antigen-binding fragment is a humanized antibody or a humanized antigen-binding fragment. As used herein, "humanized" antibodies refer to forms of non-human (e.g., murine) antibodies that arespecific chimeric immunoglobulins, immunoglobulin chains, or fragments thereof that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residuesfrom a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and biological activity. In someinstances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may comprise residues that are found neither in the recipient antibody nor in the imported CDRor framework sequences, but are included to further refine and optimize antibody performance. In general, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRregions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulinconstant region or domain (Fc), typically that of a human immunoglobulin. Antibodies may have Fc regions modified as described in, for example, WO 99/58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, or six)which are altered with respect to the original antibody, which are also termed one or more CDRs "derived from" one or more CDRs from the original antibody.
If needed, an antibody or an antigen-binding fragment herein can be assessed for immunogenicity and, as needed, be deimmunized (i.e., the antibody is made less immunoreactive by altering one or more T cell epitopes). As used herein, a"deimmunized antibody" means that one or more T cell epitopes in an antibody sequence have been modified such that a T cell response after administration of the antibody to a subject is reduced compared to an antibody that has not been deimmunized. Analysis of immunogenicity and T-cell epitopes present in the antibodies and antigen-binding fragments herein can be carried out via the use of software and specific databases. Exemplary software and databases include iTope.TM. developed by Antitope ofCambridge, England. iTope.TM., is an in silico technology for analysis of peptide binding to human MEW class II alleles. The iTope.TM. software predicts peptide binding to human MEW class II alleles and thereby provides an initial screen for thelocation of such "potential T cell epitopes." iTope.TM. software predicts favorable interactions between amino acid side chains of a peptide and specific binding pockets within the binding grooves of 34 human MHC class II alleles. The location of keybinding residues is achieved by the in silico generation of 9mer peptides that overlap by one amino acid spanning the test antibody variable region sequence. Each 9mer peptide can be tested against each of the 34 MHC class II allotypes and scored basedon their potential "fit" and interactions with the MHC class II binding groove. Peptides that produce a high mean binding score (>0.55 in the iTope.TM. scoring function) against >50% of the MHC class II alleles are considered as potential T cellepitopes. In such regions, the core 9 amino acid sequence for peptide binding within the MHC class II groove is analyzed to determine the MHC class II pocket residues (P1, P4, P6, P7, and P9) and the possible T cell receptor (TCR) contact residues (P-1,P2, P3, P5, P8). After identification of any T-cell epitopes, amino acid residue changes, substitutions, additions, and/or deletions can be introduced to remove the identified T-cell epitope. Such changes can be made so as to preserve antibodystructure and function while still removing the identified epitope. Exemplary changes can include, but are not limited to, conservative amino acid changes.
An anti-SARS-Cov-2 antibody or antigen-binding fragment can be a human antibody or human antigen-binding fragment. As used herein, a "human antibody" means an antibody having an amino acid sequence corresponding to that of an antibody producedby a human and/or that has been made using any suitable technique for making human antibodies. This definition of a human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody comprising murine light chain and human heavy chain polypeptides. In one embodiment, the human antibody is selected from a phage library, where that phage library expresses human antibodies (Vaughan et al., 1996, NatureBiotechnology, 14:309-314; Sheets et al., 1998, PNAS USA, 95:6157-6162; Hoogenboom and Winter, 1991, J. Mol. Biol., 227:381; Marks et al., 1991, J. Mol. Biol., 222:581). Human antibodies can also be made by introducing human immunoglobulin loci intotransgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. This approach is described in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016. Alternatively, the human antibody may be prepared by immortalizing human B lymphocytes that produce an antibody directed against a target antigen (such B lymphocytes may be recovered from an individual or may have been immunized in vitro). See, e.g.,Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., 1991, J. Immunol., 147 (1):86-95; and U.S. Pat. No. 5,750,373.
Any of the anti-SARS-Cov-2 antibodies, or antigen-binding fragments herein can be bispecific. Bispecific antibodies are antibodies that have binding specificities for at least two different antigens or different affinities for the same antigen. Bispecific antibodies can be prepared using the antibodies or antigen-binding fragments disclosed herein. Methods for making bispecific antibodies are described (see, e.g., Suresh et al., 1986, Methods in Enzymology 121:210). Traditionally, therecombinant production of bispecific antibodies was based on the co-expression of two immunoglobulin heavy chain-light chain pairs, with the two heavy chains having different specificities (Millstein and Cuello, 1983, Nature, 305, 537-539). Bispecificantibodies can be composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure,with an immunoglobulin light chain in only one half of the bispecific molecule, facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations. Bispecific antibody fragments may be connected via a linker. This approach is described in PCT Publication No. WO 94/04690.
According to one approach to making bispecific antibodies, antibody variable domains with the desired binding specificities (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. The fusion can be with animmunoglobulin heavy chain constant domain, comprising at least part of the hinge, CH2 and CH3 regions. The first heavy chain constant region (CH1), containing the site necessary for light chain binding, can be present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. This provides for great flexibility in adjustingthe mutual proportions of the three polypeptide fragments in embodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yields. It is, however, possible to insert the coding sequences for two or allthree polypeptide chains in one expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios are of no particular significance.
Heteroconjugate antibodies, comprising two covalently joined antibodies, are also within the scope of the disclosure. Such antibodies have been used to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980). Heteroconjugateantibodies may be made using any suitable cross-linking methods. Suitable cross-linking agents and techniques are described, for example, in U.S. Pat. No. 4,676,980.
In some instances, an anti-SARS-Cov-2 antibody herein is a chimeric antibody. "Chimeric" forms of non-human (e.g., murine) antibodies include chimeric antibodies which contain minimal sequence derived from a non-human Ig. For the most part,chimeric antibodies are murine antibodies in which at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, is inserted in place of the murine Fc. Chimeric or hybrid antibodies also may be prepared in vitrousing suitable methods of synthetic protein chemistry, including those involving cross-linking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents forthis purpose include iminothiolate and methyl-4-mercaptobutyrimidate.
Provided herein are antibodies and antigen-binding fragments thereof, modified antibodies and antigen-binding fragments thereof, and binding agents that specifically bind to one or more epitopes on one or more target antigens. In one instance,a binding agent selectively binds to an epitope on a single antigen. In another instance, a binding agent is bivalent and either selectively binds to two distinct epitopes on a single antigen or binds to two distinct epitopes on two distinct antigens. In another instance, a binding agent is multivalent (i.e., trivalent, quatravalent, etc.) and the binding agent binds to three or more distinct epitopes on a single antigen or binds to three or more distinct epitopes on two or more (multiple) antigens.
Functional fragments of any of the antibodies herein are also contemplated. The terms "antigen-binding portion of an antibody," "antigen-binding fragment," "antigen-binding domain," "antibody fragment," or a "functional fragment of an antibody"are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. Representative antigen-binding fragments include, but are not limited to, a Fab, a Fab', a F(ab').sub.2, a Fv, ascFv, a dsFv, a variable heavy domain, a variable light domain, a variable NAR domain, bi-specific scFv, a bi-specific Fab.sub.2, a tri-specific Fab.sub.3, an AVIMER.RTM., a minibody, a diabody, a maxibody, a camelid, a VHH, an intrabody, fusion proteinscomprising an antibody portion (e.g., a domain antibody), a single chain binding polypeptide, a scFv-Fc, or a Fab-Fc.
"F(ab').sub.2" and "Fab'" moieties can be produced by treating an Ig with a protease such as pepsin and papain, and include antibody fragments generated by digesting immunoglobulin near the disulfide bonds existing between the hinge regions ineach of the two heavy chains. For example, papain cleaves IgG upstream of the disulfide bonds existing between the hinge regions in each of the two heavy chains to generate two homologous antibody fragments in which an light chain composed of V.sub.Land C.sub.L (light chain constant region), and a heavy chain fragment composed of V.sub.H and C.sub.H.gamma.1 (.gamma.1) region in the constant region of the heavy chain) are connected at their C terminal regions through a disulfide bond. Each of thesetwo homologous antibody fragments is called Fab'. Pepsin also cleaves IgG downstream of the disulfide bonds existing between the hinge regions in each of the two heavy chains to generate an antibody fragment slightly larger than the fragment in whichthe two above-mentioned Fab' are connected at the hinge region. This antibody fragment is called F(ab').sub.2.
The Fab fragment also contains the constant domain of the light chain and the first constant domain (C.sub.H1) of the heavy chain. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavychain C.sub.H1 domain including one or more cysteine(s) from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab').sub.2 antibody fragmentsoriginally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
A "Fv" as used herein refers to an antibody fragment which contains a complete antigen-recognition and antigen-binding site. This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent orcovalent association (disulfide linked Fvs have been described, see, e.g., Reiter et al. (1996) Nature Biotechnology 14:1239-1245). It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on thesurface of the V.sub.H-V.sub.L dimer. Collectively, a combination of one or more of the CDRs from each of the V.sub.H and V.sub.L chains confer antigen-binding specificity to the antibody. For example, it would be understood that, for example, theCDRH3 and CDRL3 could be sufficient to confer antigen-binding specificity to an antibody when transferred to V.sub.H and V.sub.L chains of a recipient antibody or antigen-binding fragment and this combination of CDRs can be tested for binding,specificity, affinity, etc. using any of the techniques herein. Even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although likely at a lower specificity oraffinity than when combined with a second variable domain. Furthermore, although the two domains of a Fv fragment (V.sub.L and V.sub.H) are coded for by separate genes, they can be joined using recombinant methods by a synthetic linker that enables themto be made as a single protein chain in which the V.sub.L and V.sub.H regions pair to form monovalent molecules (known as single chain Fv (scFv); Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883;and Osbourn et al. (1998) Nat. Biotechnol. 16:778). Such scFvs are also intended to be encompassed within the term "antigen-binding portion" of an antibody. Any V.sub.H and V.sub.L sequences of specific scFv can be linked to an Fc region cDNA orgenomic sequences in order to generate expression vectors encoding complete Ig (e.g., IgG) molecules or other isotypes. V.sub.H and V.sub.L can also be used in the generation of Fab, Fv, or other fragments of Igs using either protein chemistry orrecombinant DNA technology.
"Single-chain Fv" or "sFv" antibody fragments comprise the V.sub.H and V.sub.L domains of an antibody, wherein these domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptidelinker between the V.sub.H and V.sub.L domains which enables the sFv to form the desired structure for antigen-binding. For a review of sFvs, see, e.g., Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994).
The term "AVIMER.RTM." refers to a class of therapeutic proteins of human origin, which are unrelated to antibodies and antibody fragments, and are composed of several modular and reusable binding domains, referred to as A-domains (also referredto as class A module, complement type repeat, or LDL-receptor class A domain). They were developed from human extracellular receptor domains by in vitro exon shuffling and phage display (Silverman et al., 2005, Nat. Biotechnol. 23:1493-1494; Silvermanet al., 2006, Nat. Biotechnol. 24:220). The resulting proteins can contain multiple independent binding domains that can exhibit improved affinity and/or specificity compared with single-epitope binding proteins. Each of the known 217 human A-domainscomprises .about.35 amino acids (.about.4 kDa); and these domains are separated by linkers that average five amino acids in length. Native A-domains fold quickly and efficiently to a uniform, stable structure mediated primarily by calcium binding anddisulfide formation. A conserved scaffold motif of only 12 amino acids is required for this common structure. The end result is a single protein chain containing multiple domains, each of which represents a separate function. Each domain of theproteins binds independently, and the energetic contributions of each domain are additive.
Antigen-binding polypeptides also include heavy chain dimers such as, for example, antibodies from camelids and sharks. Camelid and shark antibodies comprise a homodimeric pair of two chains of V-like and C-like domains (neither has a lightchain). Since the V.sub.H region of a heavy chain dimer IgG in a camelid does not have to make hydrophobic interactions with a light chain, the region in the heavy chain that normally contacts a light chain is changed to hydrophilic amino acid residuesin a camelid. V.sub.H domains of heavy-chain dimer IgGs are called V.sub.HH domains. Shark Ig-NARs comprise a homodimer of one variable domain (termed a V-NAR domain) and five C-like constant domains (C-NAR domains). In camelids, the diversity ofantibody repertoire is determined by the CDRs 1, 2, and 3 in the V.sub.H or V.sub.HH regions. The CDR3 in the camel V.sub.HH region is characterized by its relatively long length, averaging 16 amino acids (Muyldermans et al., 1994, Protein Engineering7(9): 1129). This is in contrast to CDR3 regions of antibodies of many other species. For example, the CDR3 of mouse V.sub.H has an average of 9 amino acids. Libraries of camelid-derived antibody variable regions, which maintain the in vivo diversityof the variable regions of a camelid, can be made by, for example, the methods disclosed in U.S. Patent Application Ser. No. 20050037421.
As used herein, a "maxibody" refers to a bivalent scFv covalently attached to the Fc region of an immunoglobulin, see, e.g., Fredericks et al., Protein Engineering, Design & Selection, 17:95-106 (2004) and Powers et al., Journal of ImmunologicalMethods, 251:123-135 (2001).
As used herein, a "dsFv" can be a Fv fragment obtained by introducing a Cys residue into a suitable site in each of a heavy chain variable region and a light chain variable region, and then stabilizing the heavy chain variable region and thelight chain variable region by a disulfide bond. The site in each chain, into which the Cys residue is to be introduced, can be determined based on a conformation predicted by molecular modeling. In the present disclosure, for example, a conformationis predicted from the amino acid sequences of the heavy chain variable region and light chain variable region of the above-described antibody, and DNA encoding each of the heavy chain variable region and the light chain variable region, into which amutation has been introduced based on such prediction, is then constructed. The DNA construct is incorporated then into a suitable vector and prepared from a transformant obtained by transformation with the aforementioned vector.
Single chain variable region fragments ("scFv") of antibodies are herein. Single chain variable region fragments may be made by linking light and/or heavy chain variable regions by using a short linking peptide. Bird et al. (1988) Science242:423-426. The single chain variants can be produced either recombinantly or synthetically. For synthetic production of scFv, an automated synthesizer can be used. For recombinant production of scFv, a suitable plasmid containing polynucleotide thatencodes the scFv can be introduced into a suitable host cell, either eukaryotic, such as yeast, plant, insect, or mammalian cells, or prokaryotic, such as E. coli. Polynucleotides encoding the scFv of interest can be made by routine manipulations suchas ligation of polynucleotides. The resultant scFv can be isolated using any suitable protein purification techniques.
Diabodies can be single chain antibodies. Diabodies can be bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domainson the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see, e.g., Holliger, P., et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993); and Poljak, R. J., et al.,Structure, 2:1121-1123 (1994)).
As used herein, a "minibody" refers to a scFv fused to CH3 via a peptide linker (hingeless) or via an IgG hinge has been described in Olafsen, et al., Protein Eng. Des. Sel., April 2004; 17(4):315-23.
As used herein, an "intrabody" refers to a single chain antibody which demonstrates intracellular expression and can manipulate intracellular protein function (Biocca, et al., EMBO J. 9:101-108, 1990; Colby et al., Proc Natl Acad. Sci. USA. 101:17616-21, 2004). Intrabodies, which comprise cell signal sequences which retain the antibody construct in intracellular regions, may be produced as described in Mhashilkar et al., (EMBO J., 14:1542-51, 1995) and Wheeler et al. (FASEB J. 17:1733-5. 2003). Transbodies are cell-permeable antibodies in which a protein transduction domains (PTD) is fused with single chain variable fragment (scFv) antibodies Heng et al. (Med Hypotheses. 64:1105-8, 2005).
A "scFv-Fc" fragment as herein refers to an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains inthe scFv (i.e., VH-VL or VL). Any suitable Fc domain known in the art or herein may be used. In some cases, the Fc domain comprises an IgG1 Fc domain or an IgG4 Fc domain. A scFv-Fc format allows for rapid characterization of candidate scFvs isolatedfrom phage display libraries before conversion into a full-length IgG. This format offers several advantages over the phage display-derived scFv, including bivalent binding, longer half-life, and Fc-mediated effector functions. Here, a detailed methodis presented, which describes the cloning, expression, and purification of an scFv-Fc fragment, starting from scFv fragments obtained from a phage display library. This method facilitates the rapid screening of candidate antibodies, prior to a moretime-consuming conversion into a full IgG format. In one instance, a single-chain Fv (scFv) includes the heavy and light chains in the Fv of an anti-SARS-Cov-2 antibody herein joined with a flexible peptide linker (e.g., of about 10, 12, 15 or moreamino acid residues) in a single peptide chain. The single chain antibody may be monovalent, if only a single VH and VL are used, bivalent, if two VH and VL are used, or polyvalent, if more than two VH and VL are used. In some instances, the entire Fcregion is attached to the scFv. In other instances, only the CH3 region of a Fc is attached to the scFv (a "scFv-CH).
A "scFab" as herein refers to an antigen-binding domain that specifically binds to SARS-Cov-2 is fused via a peptide linker to the C-terminus to one of the heavy chains.
A "scFv zipper" as herein refers to constructs of leucine zipper-based dimerization cassettes for the conversion of recombinant monomeric scFv antibody fragments to bivalent and bispecific dimers. A truncated murine IgG3 hinge region and a Fosor Jun leucine zipper are cloned into four scFv fragments. Cysteine residues flanking the zipper region are introduced to covalently link dimerized scFv fragments. The secreted fusion proteins form stable Fos Fos or Jun Jun homodimers.
A "cross-Fab fragment" or "xFab fragment" or "crossover Fab fragment" as herein refers to a Fab fragment, wherein either the variable regions or the constant regions of the heavy and light chain are exchanged. Two different chain compositionsof a crossover Fab molecule are possible and comprised within the scope of bispecific antibodies and antigen-binding fragments herein. On the one hand, the variable regions of the Fab heavy and light chain are exchanged, i.e. the crossover Fab moleculecomprises a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1), and a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL). This crossover Fabmolecule is also referred to as CrossFab VLVH. On the other hand, when the constant regions of the Fab heavy and light chain are exchanged, the crossover Fab molecule comprises a peptide chain composed of the heavy chain variable region (VH) and thelight chain constant region (CL), and a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1). This crossover Fab molecule is also referred to as CrossFab CLCH1.
A "Fab-Fc" fragment as herein refers to a Fab fragment that is attached to a CH1, CH2, and/or a CH3 region of a Fc, where the molecule does not contain all of a CH1, CH2, and CH3.
The terms "single domain antibody" and "sdAb" refer to a single-chain antibody polypeptide consisting of a single monomeric variable antibody domain. The term "VHH" as used herein refers to molecules engineered from heavy-chain antibodies foundin camelids. The terms "shark new antigen receptor", "VNAR" and "IgNAR" as used herein refer to molecules obtained from the heavy-chain antibodies of cartilaginous fish, such as sharks. Single-domain antibodies can also be obtained by splitting dimericvariable domains from common immunoglobulin G (IgG) into monomers. Single-domain antibodies are typically about 110 amino acids long and have a typical molecular weight in the region of from about 12 to about 15 kDa. As such, single-domain antibodiesare much smaller than common antibodies (150-160 kDa), and even smaller than Fab fragments (which consist of one light chain and half a heavy chain and have a molecular weight of about 50 kDa) and single-chain variable fragments (which consist of twovariable domains, one from a light and one from a heavy chain, and have a molecular weight of about 25 kDa).
Suitable linkers may be used to link various parts of recombinant or synthetic antibodies or antigen-binding fragments thereof or to multimerize binding agents. A non-limiting example of a linking peptide is (GGGGS).sub.n, where n=3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more (SEQ ID NO: 443) and which bridges approximately 3.5 nm between the carboxy terminus of one variable region and the amino terminus of the other variable region. Linkers of other sequences havebeen designed and used. Methods of producing such antibodies are described in for instance U.S. Pat. No. 4,946,778, Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315(1994), Bird et al., Science 242, 423-426 (1988), Huston et al., PNAS USA 85, 5879-5883 (1988) and McCafferty et al., Nature 348, 552-554 (1990). Linkers can in turn be modified for additional functions, such as attachment of drugs or attachment tosolid supports. Fab and scFab fragments may be stabilized via natural disulfide bonds between the CL domain and the CH1 domain. Antigen-binding fragments comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), such as theFab, crossFab, scFv and scFab fragments as herein might be further stabilized by introducing interchain disulfide bridges between the VH and the VL domain. Accordingly, in one embodiment, the Fab fragment(s), the crossFab fragment(s), the scFvfragment(s) and/or the scFab fragment(s) comprised in the antigen-binding receptors according to the invention might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues. Such stabilized antigen-bindingmoieties are referred to by the term "ds". Cysteine engineered antibodies, in some embodiments, are made reactive for conjugation with linker-degrader intermediates herein, by treatment with a reducing agent such as DTT (Cleland's reagent,dithiothreitol) or TCEP (tris(2-carboxyethyl)phosphine hydrochloride; Getz et al. (1999) Anal. Biochem. Vol 273:73-80; Soltec Ventures, Beverly, Mass.) followed by re-formation of the inter-chain disulfide bonds (re-oxidation) with a mild oxidant suchas dehydroascorbic acid.
Also provided herein are affinity matured antibodies. For example, affinity matured antibodies can be produced by any suitable procedure (see, e.g., Marks et al., 1992, Bio/Technology, 10:779-783; Barbas et al., 1994, Proc Nat. Acad. Sci, USA91:3809-3813; Schier et al., 1995, Gene, 169:147-155; Yelton et al., 1995, J. Immunol., 155:1994-2004; Jackson et al., 1995, J. Immunol., 154(7):3310-9; Hawkins et al, 1992, J. Mol. Biol., 226:889-896; and WO2004/058184). The following methods may beused for adjusting the affinity of an antibody and for characterizing a CDR. One way of characterizing a CDR of an antibody and/or altering (such as improving) the binding affinity of a polypeptide, such as an antibody, is termed "library scanningmutagenesis." Generally, library scanning mutagenesis works as follows. One or more amino acid position in the CDR is replaced with two or more (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) amino acids. This generatessmall libraries of clones (in some embodiments, one for every amino acid position that is analyzed), each with a complexity of two or more members (if two or more amino acids are substituted at every position). Generally, the library also includes aclone comprising the native (unsubstituted) amino acid. A small number of clones, for example, about 20-80 clones (depending on the complexity of the library), from each library can be screened for binding specificity or affinity to the targetpolypeptide (or other binding target), and candidates with increased, the same, decreased, or no binding are identified. Binding affinity may be determined using Biacore surface plasmon resonance analysis, which detects differences in binding affinityof about 2-fold or greater. Biacore can be particularly useful when the starting antibody already binds with a relatively high affinity, for example, a K.sub.D of about 10 nM or lower.
In some instances, an antibody or antigen-binding fragment is bi-specific or multi-specific and can specifically bind to more than one antigen. In some cases, such a bi-specific or multi-specific antibody or antigen-binding fragment canspecifically bind to 2 or more different antigens. In some cases, a bi-specific antibody or antigen-binding fragment can be a bivalent antibody or antigen-binding fragment. In some cases, a multi specific antibody or antigen-binding fragment can be abivalent antibody or antigen-binding fragment, a trivalent antibody or antigen-binding fragment, or a quatravalent antibody or antigen-binding fragment.
An antibody or antigen-binding fragment herein can be an isolated, purified, recombinant, or synthetic.
As used herein, the term "affinity" refers to the equilibrium constant for the reversible binding of two agents and is expressed as K.sub.D. The binding affinity (K.sub.D) of a SH antibody or antigen-binding fragment herein can be less than 50nM, 49 nM, 48 nM, 47 nM, 46 nM, 45 nM, 44 nM, 43 nM, 42 nM, 41 nM, 40 nM, 39 nM, 38 nM, 37 nM, 36 nM, 35 nM, 34 nM, 33 nM, 32 nM, 31 nM, 30 nM, 29 nM, 28 nM, 27 nM, 26 nM, 25 nM, 24 nM, 23 nM, 22 nM, 21 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 990 pM, 980 pM, 970 pM, 960 pM, 950 pM, 940 pM, 930 pM, 920 pM, 910 pM, 900 pM, 890 pM, 880 pM, 870 pM, 860 pM, 850 pM, 840 pM, 830 pM, 820 pM, 810 pM, 800 pM, 790 pM,780 pM, 770 pM, 760 pM, 750 pM, 740 pM, 730 pM, 720 pM, 710 pM, 700 pM, 690 pM, 680 pM, 670 pM, 660 pM, 650 pM, 640 pM, 630 6M, 620 pM, 610 pM, 600 pM, 590 pM, 580 pM, 570 pM, 560 pM, 550 pM, 540 pM, 530 pM, 520 pM, 510 pM, 500 pM, 490 pM, 480 pM, 470pM, 460 pM, 450 pM, 440 pM, 430 pM, 420 pM, 410 pM, 400 pM, 390 pM, 380 pM, 370 pM, 360 pM, 350 pM, 340 pM, 330 pM, 320 pM, 310 pM, 300 pM, 290 pM, 280 pM, 270 pM, 260 pM, 250 pM, 240 pM, 230 pM, 220 pM, 210 pM, 200 pM, 190 pM, 180 pM, or any integertherebetween.
Binding affinity may be determined using surface plasmon resonance (SPR), Kinexa Biocensor, scintillation proximity assays, enzyme linked immunosorbent assay (ELISA), ORIGEN immunoassay (IGEN), fluorescence quenching, fluorescence transfer,yeast display, or any combination thereof. Binding affinity may also be screened using a suitable bioassay.
As used herein, the term "avidity" refers to the resistance of a complex of two or more agents to dissociation after dilution. Apparent affinities can be determined by methods such as an enzyme linked immunosorbent assay (ELISA) or any othertechnique familiar to one of skill in the art. Avidities can be determined by methods such as a Scatchard analysis or any other technique familiar to one of skill in the art.
An antibody or antigen-binding fragment can be modified by making one or more substitutions in the amino acid sequence using a conservative or a non-conservative substitution such that the resulting modified antibody exhibits about 80% homologyto a sequence herein.
The phrase "conservative amino acid substitution" refers to grouping of amino acids on the basis of certain common properties. A functional way to define common properties between individual amino acids is to analyze the normalized frequenciesof amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and R. H. Schirmer, Principles of Protein Structure, Springer-Verlag). According to such analyses, groups of amino acids may be defined where amino acids withina group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure. Examples of amino acid groups defined in this manner include:
(i) a charged group, consisting of Glu and Asp, Lys, Arg and His;
(ii) a positively-charged group, consisting of Lys, Arg and His;
(iii) a negatively-charged group, consisting of Glu and Asp;
(iv) an aromatic group, consisting of Phe, Tyr and Trp;
(v) a nitrogen ring group, consisting of His and Trp;
(vi) a large aliphatic non-polar group, consisting of Val, Leu and Ile;
(vii) a slightly-polar group, consisting of Met and Cys;
(viii) a small-residue group, consisting of Ser, Thr, Asp, Asn, Gly, Ala, Glu, Gln and Pro;
(ix) an aliphatic group consisting of Val, Leu, Ile, Met and Cys; and
(x) a small hydroxyl group consisting of Ser and Thr.
In addition to the groups presented above, each amino acid residue may form its own group, and the group formed by an individual amino acid may be referred to simply by the one and/or three letter abbreviation for that amino acid commonly usedin the art as described above.
A "conserved residue" is an amino acid that is relatively invariant across a range of similar proteins. Often conserved residues will vary only by being replaced with a similar amino acid, as described above for "conservative amino acidsubstitution."
The letter "x" or "xaa" as used in amino acid sequences herein is intended to indicate that any of the twenty standard amino acids may be placed at this position unless specifically noted otherwise.
As used herein, "identity" means the percentage of identical nucleotide or amino acid residues at corresponding positions in two or more sequences when the sequences are aligned to maximize sequence matching, i.e., taking into account gaps andinsertions. Identity can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects,Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; andSequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48: 1073 (1988). Methods to determine identity are designed to give the largest match between thesequences tested. Moreover, methods to determine identity are codified in publicly available computer programs. Computer program methods to determine identity between two sequences include, but are not limited to, the GCG program package (Devereux, J.,et al., Nucleic Acids Research 12(1): 387 (1984)), BLASTP, BLASTN, and FASTA (Altschul, S. F. et al., J. Molec. Biol. 215: 403-410 (1990) and Altschul et al. Nuc. Acids Res. 25: 3389-3402 (1997)). The BLAST X program is publicly available from NCBIand other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol. 215: 403-410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity. Ranges of desireddegrees of sequence identity across a CDR, a FR, a VH, and/or a VL, a fragment, etc. are from about 80% to about 100% and integer values therebetween. In general, this disclosure encompasses sequences with about 80%, about 81%, about 82%, about 83%,about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity with any sequence provided herein. The letter "X" or theterm "Xaa" as used in an amino acid sequence herein is intended to indicate that any of the twenty standard amino acids may be placed at this position, unless specifically noted otherwise.
"Polynucleotide" or "nucleic acid," as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/ortheir analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structuremay be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps," substitution of one or more of the naturally-occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates,phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides,ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomericnucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protectinggroups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbonatoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclicsugar analogs, alpha-anomeric sugars, epimeric sugars such as arabinose, xyloses, or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkagesmay be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR.sub.2 ("amidate"), P(O)R, P(O)OR', CO, orCH.sub.2 ("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (--O--) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages in a polynucleotideneed be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.
In one aspect, provided herein is one or more RNA molecules that encode one or more of the antibodies or antigen-binding fragments herein. Such one or more RNA molecules may be present in a vector for administration to a subject.
Provide herein are polynucleotides (such as RNA, for example mRNA) encoding antibodies or antigen-binding fragments that can specifically bind to SARS-CoV-2. Antibody or antigen-binding fragments encoded by polynucleotides can includeantibodies or antigen-binding fragments. Polynucleotides can be administered to a subject to prevent infection of the subject by SARS-Cov-2 or to treat a subject infected by SARS-CoV-2. In some cases, antibodies or antigen-binding fragments can beproduced in a subject that has been administered a polynucleotide herein.
Polynucleotides can comprise genetic material encoding an antibody or antigen-binding fragment (e.g., DNA or mRNA). In some cases, polynucleotides can be in a vector, such as a viral vector or an artificial chromosome such as a human artificialchromosome. In some cases, polynucleotides can additionally comprise a promoter, a terminator, a sequence encoding a tag, a sequence encoding a second antibody or antigen-binding fragment, or a sequence encoding a molecule that can aid in folding orfunction of the antibody or antigen-binding fragment.
In some cases, polynucleotides can be used to prevent and/or treat disease caused by SARS-Cov-2 or a similar virus (e.g., COVID-19); i.e., polynucleotides can have prophylactic or therapeutic uses, or both prophylactic and therapeutic uses. Accordingly, the present disclosure provides methods to prevent and/or treat infection by SARS-CoV-2. In some cases, such methods can comprise administering to a subject one or more mRNA molecules encoding a antibody or antigen-binding fragment that canspecifically bind to SARS-CoV-2.
An antibody library herein can comprise a plurality of antibodies and/or antigen-binding fragments. The plurality of antibodies and/or antigen-binding fragments can be at least 1.0.times.10.sup.6, 1.0.times.10.sup.7, 1.0.times.10.sup.8,1.0.times.10.sup.9, 1.0.times.10.sup.10, 2.0.times.10.sup.10, 3.0.times.10.sup.10, 4.0.times.10.sup.10, 5.0.times.10.sup.10, 6.0.times.10.sup.10, 7.0.times.10.sup.10, 8.0.times.10.sup.10, 9.0.times.10.sup.10, or 10.0.times.10.sup.10.
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skillof the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in MolecularBiology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell andTissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); GeneTransfer Vectors for Mammalian Cells (J. M. Miller and M. P. Cabs, eds., 1987); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology(J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989);Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); and The Antibodies (M. Zanetti and J. D.Capra, eds., Harwood Academic Publishers, 1995).
EXAMPLES
The application may be better understood by reference to the following non-limiting examples, which are provided as exemplary embodiments of the application. The following examples are presented in order to more fully illustrate embodiments andshould in no way be construed, however, as limiting the broad scope of the application.
Example 1: Kinetics and Affinity Determination of an Anti-SARS-Cov-2scFv by Surface Plasmon Resonance
High-throughput surface plasmon resonance (SPR) kinetic experiments were performed on Carterra LSA Array SPR instrument (Carterra, Salt Lake City, Utah) equipped with HC200M sensor chip (catalog No. 4287, Carterra, Salt Lake City, Utah) at25.degree. C. Anti-SARS-Cov-2 scFv constructs were expressed with a V5 epitope tag to enable capture via immobilized anti-V5 antibody. Surfaces were prepared in HBSTE (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.01% (v/v) Tween-20) as running buffer. The capture surface was prepared by standard amine-coupling of anti-V5 tag antibody (catalog No. ab27671, Abcam, Cambridge, Mass.) on the entire chip surface as follows. The chip was activated with a 10-min injection of a freshly prepared 1:1:1 (v/v/v)mixture of 0.4 M 1-Ethyl-3-(3-Dimethylaminopropyl) carbodiimide hydrochloride (EDC)+0.1 M N-hydroxysulfosuccinimide (sNHS)+0.1 M 2-(N-morpholino) ethanesulfonic acid (MES) pH 5.5. Then, anti-V5 tag antibody was diluted to 50 .mu.g/ml in 10 mM sodiumacetate pH 4.3 and coupled for 14 min. Excess reactive esters were blocked with a 10-min injection of 1 M ethanolamine HCl pH 8.5. A library of anti-COVID-19 scFv clones was supplied as plates of crude bacterial periplasmic extracts (PPE) and diluted2-fold in running buffer. ScFv samples were flow printed for 15-min in batches of 96 PPE's in parallel using the 96 channel printhead to generate a 384-ligand array comprising 1 spot per scFv. For the interaction analysis, the running buffer HBST (10mM HEPES pH 7.4, 150 mM NaCl, 0.01% (v/v) Tween-20) was supplemented with 0.5 mg/ml BSA. Surfaces were stabilized with seven to eight buffer analyte injections. SARS-CoV-2, SARS-CoV-1, and MERS Receptor Binding Domain (RBD) proteins were prepared atconcentrations of 0, 3.7, 11.1, 33.3, 100, 37, and 300 nM and these samples were injected as analyte for 5 min, allowing a 15-min dissociation time. Samples were injected in ascending concentration without any regeneration in between them. Binding datafrom the local reference spots were subtracted from the active spots and the nearest buffer blank analyte responses were subtracted to double-reference the data. The double-referenced data were fitted to a simple 1:1 Langmuir binding model in Carterra'sKinetic Inspection Tool to give kinetics (k.sub.d, k.sub.d), affinity (K.sub.D), and R.sub.max value for each interaction.
TABLE-US-00028 Captures RL ka KD Rmax Clone ID (RU) (M-1 s-1) kd (s-1) (nM) (RU) COVID19_P23_F10 1552 9.80E+04 7.70E-04 7.86 65.79 COVID19_P24_H06 1709 1.20E+05 5.70E-05 0.5 21 COVID19_P24_F11 1531 6.16E+05 2.80E-04 0.46 18 COVID19_P23_G11 18722.94E+04 1.08E-04 3.67 20.39 COVID19_P24_D09 1825 1.14E+05 5.70E-05 0.5 19 COVID19_P11_H02 1609 3.20E+05 7.10E-04 2.2 25 COVID19_P24_C06 1514 2.28E+05 5.70E-05 0.3 31 COVID19_P12_B07 1641 1.78E+05 5.70E-05 0.32 17.8 COVID19_P24_H04 2116 1.70E+05 6.80E-044 91 COVID19_P23_G10 1629 1.54E+05 5.70E-05 0.37 8.72 COVID19_P24_A09 1432 1.52E+05 2.29E-04 1.51 51 C0V1D19_P11_D12 1756 7.90E+04 3.40E-04 4.3 74 C0V1D19_P24_A11 1435 1.58E+05 3.08E-04 1.95 20 C0V1D19_P24_C10 1356 5.53E+05 4.87E-04 0.88 48C0V1D19_P11_D08 1294 1.10E+05 5.30E-04 4.7 41 C0V1D19_P24_E02 1507 2.09E+05 8.36E-04 4.01 109 C0V1D19_P23_H10 2025 5.53E+04 5.70E-05 1.03 9.63 C0V1D19_P24_G06 1742 3.70E+05 1.92E-04 0.52 35 COVID19_P24_C01 1478 3.28E+05 3.22E-04 0.98 18 COVID19_P24_G091708 3.29E+05 5.12E-04 1.56 33 COVID19_P24_D08 1532 5.65E+05 4.10E-04 0.73 31 COVID19_P11_H07 1734 1.10E+05 5.70E-05 0.5 39 COVID19_P11_G03 1532 9.90E+04 6.40E-04 6.45 40 COVID19_P24_B09 1467 5.08E+05 1.39E-02 27.47 47.99 COVID19_P23_G12 0.37
The described clones each had a superior binding affinity of less than 50 nM. Moreover, some clones were found to not only bind to Sars-Cov-2, but also to MERS and/or SARS-Cov-1.
TABLE-US-00029 Clone ID Binding Affinity For: COVID19_P23_F10 COV2 COVID19_P24_H06 COV2 COVID19_P24_F11 COV2 COVID19_P23_G11 COV2+SARS1+SARS2 COVID19_P24_D09 COV2 COVID19_P11_H02 COV2 COVID19_P24_C06 COV2 COVID19_P12_B07 COV2 COVID19_P24_H04COV2 COVID19_P23_G10 COV2 COVID19_P24_A09 COV2 COVID19_P11_D12 COV2 COVID19_P24_A11 COV2 COVID19_P24_C10 COV2 COVID19_P11_D08 COV2 COVID19_P24_E02 COV2 COVID19_P23_H10 COV2+SARS1+SARS2 COVID19_P24_G06 COV2 COVID19_P24_C01 COV2 COVID19_P24_G09 COV2COVID19_P24_D08 COV2 COVID19_P11_H07 COV2+SARS1+SARS2+MERS COVID19_P11_G03 COV2 COVID19_P24_B09 COV2 COVID19_P23_G12
Example 2: In Vitro Neutralization Assay for Sars-Cov-2 Virus
Production and Titration of Pseudoviruses
For pseudovirus construction, spike genes from a SARS CoV-2 virus strain, a specific were codon-optimized for human cells and cloned into eukaryotic expression plasmid to generate the envelope recombinant plasmids. The pseudoviruses wereproduced and titrated using methods similar, as described previously in Nie J. et al. (Emerg Microbes Infect. 2020 December; 9(1):680-686), 293T cells were transfected with Pseudo virus vector using Lipofectamine system (ThermoFisher) following themanufacturer's instruction. Twenty-four hours later, new media was replaced and after 48 h from the beginning of transfection SARS-CoV-2 pseudoviruses containing culture supernatants were harvested, filtered (0.45-.mu.m pore size, Millipore, SLHP033RB)and stored at -80.degree. C. in aliquots until use. The 50% tissue culture infectious dose (TCID50) of SARS-CoV-2 pseudovirus was determined using a single-use aliquot from the pseudovirus bank; all stocks were used only once to avoid inconsistenciesthat could have resulted from repeated freezing-thawing cycles. For titration of the SARS-CoV-2 pseudovirus, a 2-fold initial dilution was made in triplicates wells of 96-well culture plates followed by serial 3-fold dilutions (8 dilutions in total). The last column served as the cell control without the addition of pseudovirus. Then, the 96-well plates were seeded with trypsin-treated Vero E6 mammalian transfectable cells adjusted to a pre-defined concentration. After 24 h incubation in a 5%CO.sub.2 environment at 37.degree. C., the culture supernatant was aspirated gently to leave 100 .mu.l in each well; then, 100 .mu.l of luciferase substrate was added to each well. Two min after incubation at room temperature, 150 .mu.l of lysate wastransferred to white solid 96-well plates for the detection of luminescence using a microplate luminometer (PerkinElmer). The positive well was determined as ten-fold relative luminescence unit (RLU) values higher than the cell background. The 50%tissue culture infectious dose (TCID50) was calculated using the Reed-Muench method, as described in Nie J et al. Id. In some cases the pseudovirus included a GFP reporter instead of Luciferase; in these cases, GFP fluorescence is measured by flowcytometry.
Pseudovirus Based Neutralization Assay
Neutralization is measured by the reduction in luciferase gene expression or GFP gene expression as described previously Nie J et al. Id. The 50% inhibitory dilution (EC50) is defined as the dilution of the tested antibodies at which therelative light units (RLUs) were reduced by 50% compared with the virus control wells (virus+ cells) after subtraction of the background RLUs in the control groups with cells only. In brief, pseudovirus in the TCID50 determined above is incubated withserial dilutions of the test samples (six dilutions in a 3-fold step-wise manner) in duplicate for 1 h at 37.degree. C., together with the virus control and cell control wells in triplicate. Then, freshly trypsinized cells were added to each well. Following 24 h of incubation in a 5% CO.sub.2 environment at 37.degree. C., the luminescence or fluoresce (depending on the reporter gene used) is measured as described above (relating to pseudovirus titration). The EC50 values were calculated withnon-linear regression, i.e., log (inhibitor) vs. response (four parameters), using GraphPad Prism 8 (GraphPad Software, Inc., San Diego, Calif., USA).
Results
Neutralization was observable for the clones tested: Average Tm1 (.degree. C.) and IC50 data for a subset of the clones was provided below:
TABLE-US-00030 Average IC50 IC50 [.mu.g/mL] IC50 Tm1 [.mu.g/mL] pseudotyped [.mu.g/mL] Clone ID (.degree. C.) plaque lenti neut neut COVID19_P24_H06 62 - COVID19_P24_F11 74.5 + COVID19_P23_G11 74.1 0.26 COVID19_P24_D09 62.6 + COVID19_P23_G1273.7 + 15.9 COVID19_P12_B07 73.4 + COVID19_P24_C10 59.2 + COVID19_P23_H10 63.1 COVID19_P24_G06 72.8 <3 0.16 <1:16 COVID19_P24_C01 68.5 + 0.92 COVID19_P24_D08 59.6 + 17 - COVID19_P11_H07 60.9 COVID19_P23_G10 65.9 -
Example 3: Competition of SARS-CoV-2/ACE2 Interaction with Anti-SARS-Cov-2 scFv by Biolayer Interferometry
Competition assay of the interaction of SARS-CoV-2 with ACE2 is conducted in a classical sandwich and a premix assay format using a ForteBio Octet HTX biolayer interferometry instrument (Molecular Devices ForteBio LLC, Fremont, Calif.) at25.degree. C. with running buffer HBST (10 mM HEPES pH 7.4, 150 mM NaCl, 0.01% (v/v) Tween-20, pH 7.4) supplemented with 1 mg/mL BSA.
An Anti-V5 tag antibody (catalog No. ab27671, Abcam, Cambridge, Mass.) is biotinylated with a 5:1 molar ratio of sulfo-NHS-LC-LC-biotin (catalog No. 21338, ThermoFisher Scientific, Waltham, Mass.) and buffer exchanged into PBS using ThermoFisherZeba 7K MWCO columns (catalog No. 89883, ThermoFisher Scientific, Waltham, Mass.).
Streptavidin sensor tips (catalog no. 18-5021, Molecular Devices ForteBio LLC, Fremont, Calif.) are equilibrated in buffer for 10-min before the run. Sample plates are agitated at 1000 rpm. At the start of the run, sensors are exposed tobuffer for 60 sec to establish a baseline. The biotinylated anti-V5 tag antibody at 7 .mu.g/mL are loaded onto the sensors for 5-min to prepare an anti-V5 surface. To block remaining free biotin binding sites, all sensors are exposed for 5-min with 20.mu.M amine-PEG2-biotin (catalog No. 21346, ThermoFisher Scientific, Waltham, Mass.) followed by two alternating 30-sec cycles of 10 mM glycine-HCl pH1.7 and buffer to precondition the sensors.
For the classical sandwich assay format, a baseline in buffer is established for 60-sec and anti-SARS-Cov-2 scFv clones as PPE undiluted are captured for 2-min onto the anti-V5 sensor tips. Baseline in buffer is recorded for 60-sec followed byassociation of SARS-Cov-2 at 100 nM for 2-min, a quick wash in buffer for 15-sec, and sandwiching of 500 nM ACE2 or buffer for 2-min. After each classical sandwich cycle, sensors are regenerated with two alternating 30-sec cycles of 10 mM glycine-HClpH1.7 and buffer.
For the premix assay format, a baseline in buffer is established for 60-sec and anti-SARS-Cov-2 scFv clones as PPE undiluted are captured for 2-min onto the anti-V5 sensor tips. Baseline in buffer is recorded for 60-sec followed by associationof buffer, a premixed complex of 100 nM SARS-Cov-2+500 nM ACE2, or 100 nM SARS-Cov-2. Dissociation in buffer is measured for 30-sec. After each binding cycle, sensors are regenerated with two alternating 30-sec cycles of 10 mM glycine-HCl pH1.7 andbuffer. Capture of biotinylated ACE2 at 10 .mu.g/mL is included as a self-blocking control in both assays.
Example 4: In Vivo Hamster Model for Sars-COV2 Infections
Competent 6-8 weeks old Syrian golden hamsters females (Charles River Laboratories or Harlan Laboratories) are housed three per cage in a biosafety level 3-4 animal facility in UTMB Galveston. Animals will be acclimatized in the BSL-3-4biosafety containment 3-5 days before the experiment begins. Animal will be housed and treated as recommended by Institutional Biosafety and the Institutional Animal Care and Use Committees.
Animals are injected IP with 0.5-1 mL of either saline, a therapeutic antibody at 10 mg/Kg (as disclosed herein), or an isotype control antibody at 10 mg/Kg, 24 h before viral infection. Animals are acclimatized in the ABSL-3 biosafetycontainment. On the day of infection, hamsters (5 per group) will be inoculated with PBS or 10E5 (1.times.10.sup.5) virus load via nasal cavity in a total volume of 100 .mu.L (50 .mu.L into each naris).
Hamsters' bodyweight and viable signs (such as ruffled hair and lack of movement) will be monitored and recorded twice daily for 3 days and virus titers will be measured from a nasal swab on day 2. Hamsters will be sacrificed on day 3 and virustiters in homogenates of lung tissues will be determined.
H&E-stained lung tissues will be evaluated by a suitable scientist, medical professional, or veterinary professional (e.g., trained in pathology) to determine the severity of infection and amount of protection provided by the neutralizingantibodies. To determine the TCID50 in the lungs, tissues will be homogenized and spun down and the supernatants will be removed and analyzed by a TCID50 assay as described in a previous Example, above.
Example 5: Generation of a SuperHuman Library (SHL) 2.0
A superhuman library is generated using the following steps: 1. The best 4 VH and best 4 VK frameworks from a human repertoire of 3500 combinations (IGHV1-46, IGHV1-69, IGHV3-15, IGHV3-23 for heavy and IGKV1-39, IGKV2-28, IGKV3-15, IGKV4-1 forlight) are selected based on a combination of 1) previous demonstrated safety in human mAbs, 2) thermostability, 3) not aggregation prone, 4) a single dominant allele in the frameworks at the amino acid level across all human populations (i.e., not aracist medicine), 5) different canonical topologies of the CDRs, and/or 6) express well in bacteria and display well on phage. 2. Blood is obtained from 140 subjects. 3. Naive (CD27-/IgM+) cells and memory (CD27+/IgG+) cells are sorted from theblood. 4. Pools are checked for quality using next generation sequencing (NGS), and pools with problematic diversity or biochemical liabilities are rejected. 5. VH CDR3 sequences from naive cells are PCR amplified with universal primers. 6. VHCDR1, VH CDR2, VL CDR1, VL CDR2, and VL CDR3 sequences from memory cells are PCR amplified with framework specific primers. 7. Order frameworks as synthetically produced germline segments. 8. Nucleic acid libraries are assembled using PCR-OE. 9. The assemblies from step 8 are checked for quality using NGS sequencing. 10. Light chains are cloned into a vector with a stuffer VH. 11. In-frame material is selected by protein A or protein L after thermal pressure. 12. Heavy chains are clonedinto the vector to replace the stuffer VH. 13. Microbes are transformed with the vectors generated at the end of step 12 using electroporation.
Example 6: Screening for Affinity to SARS CoV-2 Receptor Binding Domain
A primary screen of two 96-well plates of clones randomly selected after round 4 SuperHuman panning of SARS CoV-2.
Samples are immediately assayed on Carterra high-throughput kinetics instrument, bypassing ELISA screening. A majority of the hits are positive and sequenced, unique sequences are obtained.
Clones showing affinity to SARS CoV-2 are confirmed against human and cynomolgus monkey.
Example 7: SARS CoV-2 ELISA and Sanger Screening of 2 Plates of Antibody Clones
An ELISA panning antibody clones from two plates against SARS CoV-2 is carried out.
Sanger sequencing of these clones is also carried out. Extreme diversity of round 3 outputs ensured that hits against any epitope can be recovered by screening a few 96-well plates of clones.
Diversity is found not only in the VH CDR3 sequences, but also in the VH CDR1 and VH CDR2 sequences.
Example 8: Combining Design and Selection Processes to Produce an Antibody Library with Diverse VII and VK Sequences
Functional selection for expression and thermostability during construction is applied to produce a library with over 95% functional diversity across 40 million light chains. The antibody library is created with 7.6.times.10.sup.10transformants.
First, a VK (kappa light chain) library is produced by cloning into a vector the desired light chain and temporary stuffer VH sequence. The VK library is displayed and subjected to a heat stress at over 65.degree. C. In-frame material isselected using protein A/L. The stuffer VH sequence in the library resulting from the protein A/L, selection is replaced with the target VH sequence.
Example 9: Generation of a SuperHuman Library (SHL) 3.0
A superhuman library is generated using the following steps: 1. Six antibody frameworks (IGHV1-46, IGHV3-23, IGKV1-39, IGKV2-28, IGKV3-15, and IGKV4-1) are selected based on a combination of 1) previous demonstrated safety in human mAbs, 2)thermostability, 3) not aggregation prone, 4) a single dominant allele in the frameworks at the amino acid level across all human populations (i.e. not a racist medicine), 5) different canonical topologies of the CDRs, and/or 6) express well in bacteriaand display well on phage. 2. Blood is obtained from 50-100 subjects. 3. Naive (CD27-/IgM+ or CD27-/IgD+) cells and memory cells are sorted from the blood. 4. Pools are checked for quality using next generation sequencing (NGS), and pools withproblematic diversity or biochemical liabilities are rejected. 5. VH CDR3 sequences from naive cells are PCR amplified with universal primers. 6. Favorable VH CDR1, VH CDR2, VL CDR1, VL CDR2, and VL CDR3 sequences without liabilities are selected byDNA synthesis based on (1) being observed present in human natural antibodies, (2) being observed not under-performing under selection of SuperHuman 2.0 against a variety of antigens, (3) being free of biochemical liabilities (C, exposed M, deaminationsites, acid hydrolysis sites, N-linked glycosylation sites, amber stop codons, opal stop codons, highly positively charged), (4) not being more mutated than a threshold (e.g., no more than 3 amino acid mutations per CDR). Stated differently, VH CDR1,VHCDR2, VL CDR1, VL CDR2, and VL CDR3 sequences are synthesized if they meet the following criteria: a. have no more than 4 amino acid mutations away from the respective germline CDR for the respective framework used; and b. are identified as present inat least 2 of the subjects during NGS and are enriched without a fitness disadvantage when evaluating a pool of 55,000 hits against 11 antigens from SuperHuman 2.0, or have not been observed in a person but to have heavily enriched during panning in thesame SuperHuman 2.0 pool; and c. do not contain any biochemical liabilities (N-linked glycosylation, deamination, acid hydrolysis, positive charge endopeptidic cleavage, free cysteines, free methionines, alternative stop codons, cryptic splice sites, tevcleavage sites, or overly positively charged CDRs). 7. Order frameworks as synthetically produced 100% germline segments with no mutations. 8. Nucleic acid libraries are assembled using PCR-OE or another method for DNA assembly. 9. The assembliesfrom step 8 are checked for quality using NGS sequencing. 10. Light chains are cloned into a vector with a stuffer VH 11. In-frame material is selected by protein A or protein L after thermal pressure. 12. Heavy chains are cloned into the vector toreplace the stuffer VH. 13. Microbes are transformed with the vectors generated at the end of step 12 using electroporation.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutionswill now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention herein may be employed in practicing the invention. It is intended that the followingclaims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
SEQUENCE LISTINGS
1
SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 443 <210> SEQ IDNO 1 <211> LENGTH: 208 <212> TYPE: PRT <213> ORGANISM: Middle East respiratory syndrome-related coronavirus <400> SEQUENCE: 1 Val Glu Cys Asp Phe Ser Pro Leu Leu Ser Gly Thr Pro Pro Gln Val 1 5 10 15 Tyr Asn Phe Lys Arg Leu ValPhe Thr Asn Cys Asn Tyr Asn Leu Thr 20 25 30 Lys Leu Leu Ser Leu Phe Ser Val Asn Asp Phe Thr Cys Ser Gln Ile 35 40 45 Ser Pro Ala Ala Ile Ala Ser Asn Cys Tyr Ser Ser Leu Ile Leu Asp 50 55 60 Tyr Phe Ser Tyr Pro Leu Ser Met Lys Ser Asp Leu Ser Val Ser Ser65 70 75 80 Ala Gly Pro Ile Ser Gln Phe Asn Tyr Lys Gln Ser Phe Ser Asn Pro 85 90 95 Thr Cys Leu Ile Leu Ala Thr Val Pro His Asn Leu Thr Thr Ile Thr 100 105 110 Lys Pro Leu Lys Tyr Ser Tyr Ile Asn Lys Cys Ser Arg Leu Leu Ser 115 120 125 Asp Asp Arg ThrGlu Val Pro Gln Leu Val Asn Ala Asn Gln Tyr Ser 130 135 140 Pro Cys Val Ser Ile Val Pro Ser Thr Val Trp Glu Asp Gly Asp Tyr 145 150 155 160 Tyr Arg Lys Gln Leu Ser Pro Leu Glu Gly Gly Gly Trp Leu Val Ala 165 170 175 Ser Gly Ser Thr Val Ala Met Thr GluGln Leu Gln Met Gly Phe Gly 180 185 190 Ile Thr Val Gln Tyr Gly Thr Asp Thr Asn Ser Val Cys Pro Lys Leu 195 200 205 <210> SEQ ID NO 2 <211> LENGTH: 200 <212> TYPE: PRT <213> ORGANISM: Severe acute respiratory syndrome coronavirus2 <400> SEQUENCE: 2 Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn 1 5 10 15 Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser 20 25 30 Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser 35 40 45 Thr PheLys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys 50 55 60 Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val 65 70 75 80 Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr 85 90 95 Lys Leu Pro Asp Asp Phe Thr Gly Cys ValIle Ala Trp Asn Ser Asn 100 105 110 Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu 115 120 125 Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu 130 135 140 Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn145 150 155 160 Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val 165 170 175 Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His 180 185 190 Ala Pro Ala Thr Val Cys Gly Pro 195 200 <210> SEQ ID NO 3 <211> LENGTH:202 <212> TYPE: PRT <213> ORGANISM: Human SARS coronavirus <400> SEQUENCE: 3 Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr 1 5 10 15 Lys Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Lys Ile Ser Asn Cys 20 25 30 Val Ala AspTyr Ser Val Leu Tyr Asn Ser Thr Phe Phe Ser Thr Phe 35 40 45 Lys Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser 50 55 60 Asn Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln 65 70 75 80 Ile Ala Pro Gly Gln Thr Gly Val Ile Ala AspTyr Asn Tyr Lys Leu 85 90 95 Pro Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn Thr Arg Asn Ile 100 105 110 Asp Ala Thr Ser Thr Gly Asn Tyr Asn Tyr Lys Tyr Arg Tyr Leu Arg 115 120 125 His Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe 130 135240 Ser Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu Asn Cys Tyr Trp 145 150 155 160 Pro Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly Ile Gly Tyr Gln 165 170 175 Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala 180 185 190 Thr Val Cys GlyPro Lys Leu Ser Thr Asp 195 200 <210> SEQ ID NO 4 <211> LENGTH: 202 <212> TYPE: PRT <213> ORGANISM: Human SARS coronavirus <400> SEQUENCE: 4 Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr 1 5 10 15 Thr PhePro Ser Val Tyr Ala Trp Glu Arg Lys Arg Ile Ser Asn Cys 20 25 30 Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Ser Phe Ser Thr Phe 35 40 45 Lys Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser 50 55 60 Asn Val Tyr Ala Asp Ser Phe Val Val Lys GlyAsp Asp Val Arg Gln 65 70 75 80 Ile Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu 85 90 95 Pro Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn Thr Arg Asn Ile 100 105 110 Asp Ala Thr Ser Thr Gly Asn Tyr Asn Tyr Lys Tyr Arg Ser Leu Arg 115 120125 His Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe 130 135 140 Ser Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Phe Asn Cys Tyr Trp 145 150 155 160 Pro Leu Asn Asp Tyr Gly Phe Phe Thr Thr Asn Gly Ile Gly Tyr Gln 165 170 175 Pro Tyr Arg ValVal Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala 180 185 190 Thr Val Cys Gly Pro Lys Leu Ser Thr Asp 195 200 <210> SEQ ID NO 5 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 5 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys 20 <210> SEQ ID NO 6 <211> LENGTH: 23<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 6 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser ValGly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 7 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 7 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 8
<211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 8 Asp Ile Gln Met Thr Gln SerPro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 9 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 9 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 10 <211> LENGTH: 23 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr IleThr Cys 20 <210> SEQ ID NO 11 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 11Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 12 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 12 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 13 <211> LENGTH: 23<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 13 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser ValGly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 14 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 14 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 15 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 15 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys 20 <210> SEQ IDNO 16 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 16 Asp Ile Gln Met Thr Gln SerPro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 17 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Synthetic peptide <400> SEQUENCE: 17 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 18 <211> LENGTH: 23 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 18 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr IleThr Cys 20 <210> SEQ ID NO 19 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 19Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 20 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 20 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 21 <211> LENGTH: 23<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 21 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser ValGly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20
<210> SEQ ID NO 22 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 22 AspIle Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys 20 <210> SEQ ID NO 23 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 23 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 24 <211> LENGTH: 23<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 24 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser ValGly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 25 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 25 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 26 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 26 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ IDNO 27 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 27 Asp Ile Gln Met Thr Gln SerPro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 28 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Synthetic peptide <400> SEQUENCE: 28 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> SEQ ID NO 29 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 29 Arg Ala Ser Glu Ser Val Ser Ser Arg Tyr Leu Ala 1 5 10 <210> SEQ ID NO 30 <211>LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 30 Gln Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly 1 510 <210> SEQ ID NO 31 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 31 Arg AlaSer Gln Ser Ile Gly Tyr Tyr Leu Asn 1 5 10 <210> SEQ ID NO 32 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 32 Arg Ala Ser Gln Gly Ile Ser Asn Asn Leu Asn 1 5 10 <210> SEQ ID NO 33 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 33 Arg Ala Ser Gln Asp Ile Arg Asn Glu Leu Gly 1 5 10 <210> SEQ ID NO 34 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 34 Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Ala 1 5 10 <210> SEQ ID NO 35 <211> LENGTH: 11 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 35 Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> SEQ ID NO 36 <211>LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 36 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 510 <210> SEQ ID NO 37 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 37 Arg Ala Ser Gln Ser Ile Ser Thr Tyr Leu Asn 1 5 10 <210> SEQ ID NO 38 <211> LENGTH: 11 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 38 Arg Ala Ser Gln Ser Ile Tyr Ser Trp Leu Ala 1 5 10 <210> SEQ ID NO 39 <211>LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 39 Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu Ala1 5 10 <210> SEQ ID NO 40 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 40 ArgAla Ser Gln His Ile Ser Ser Tyr Leu Asn 1 5 10 <210> SEQ ID NO 41 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 41 Arg Ala Ser Gln Ala Ile Thr Asn Tyr Leu Ala 1 5 10 <210> SEQ ID NO 42 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 42 Gln Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn 1 5 10 <210> SEQ ID NO 43 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 43 Gln Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn 1 5 10 <210> SEQ ID NO 44 <211> LENGTH: 11 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 44 Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala 1 5 10 <210> SEQ ID NO 45<211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 45 Arg Ala Ser Gln Ser Ile Ser Ser TyrLeu Asn 1 5 10 <210> SEQ ID NO 46 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:46 Lys Ser Ser Gln Ser Val Phe Ser Ser Ser Asn Asn Lys Asn Tyr Leu 1 5 10 15 Ala <210> SEQ ID NO 47 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 47 Arg Ala Ser Glu Asn Ile Asp Ser Trp Leu Ala 1 5 10 <210> SEQ ID NO 48 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 48 Arg Ala Ser Glu Asn Ile Asp Ser Trp Leu Ala 1 5 10 <210> SEQ ID NO 49 <211> LENGTH: 11 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 49 Arg Ala Ser Gln Thr Ile Tyr Ser Tyr Leu Asn 1 5 10 <210> SEQ ID NO 50 <211>LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 50 Gln Ala Ser Gln Ser Ile Tyr Asn Tyr Leu Asn 1 510 <210> SEQ ID NO 51 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 51 Arg ValSer Gln Gly Ile Ser Ser Tyr Leu Asn 1 5 10 <210> SEQ ID NO 52 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 52 Arg Ala Ser Gln Gly Ile Ser Asn Asn Leu Asn 1 5 10 <210> SEQ ID NO 53 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 53 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 1 5 10 15
<210> SEQ ID NO 54 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 54Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 55 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 55 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 56 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 56 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 57 <211> LENGTH: 15<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 57 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr1 5 10 15 <210> SEQ ID NO 58 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 58Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 59 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 59 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 60 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 60 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 61 <211> LENGTH: 15<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 61 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr1 5 10 15 <210> SEQ ID NO 62 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 62Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 63 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 63 Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 64 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 64 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 65 <211> LENGTH: 15<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 65 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr1 5 10 15 <210> SEQ ID NO 66 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 66Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 67 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 67 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 68 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 68 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 69 <211> LENGTH: 15<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 69 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr1 5 10 15 <210> SEQ ID NO 70 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 70
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 71 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Synthetic peptide <400> SEQUENCE: 71 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 72 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 72 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 73 <211> LENGTH: 15<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 73 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr1 5 10 15 <210> SEQ ID NO 74 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 74Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 75 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 75 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 76 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 76 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> SEQ ID NO 77 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 77 Gly Ala Ser Thr Arg Ala Thr 1 5 <210> SEQ ID NO 78<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 78 Asp Ala Ser Arg Leu Gln Ser 1 5<210> SEQ ID NO 79 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 79 Ala Ala SerSer Leu Gln Ser 1 5 <210> SEQ ID NO 80 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 80 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 81 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 81 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 82 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 82 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 83 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 83 Ala Ala Ser Asn Leu Gln Ser 1 5 <210> SEQ ID NO 84 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 84 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 85 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 85 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 86 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 86 Asp Ala Ser Ser Leu Glu Ser 1 5 <210> SEQ ID NO 87 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 87 Ala Val Ser Ser Arg Ala Thr 1 5 <210> SEQ ID NO 88 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 88 Ala Ala Ser Ala Leu Gln Ser 1 5 <210> SEQ ID NO 89 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 89 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 90 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 90 Gly Ala Ser Thr Leu Ser Asp 1 5 <210> SEQ ID NO 91 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 91 Gly Ala Ser Thr Leu Ser Asp 1 5 <210> SEQ ID NO 92 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 92 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> SEQ ID NO 93 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 93 Ala Ala Ser Arg Leu Gln Ser 1 5 <210> SEQ ID NO 94 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 94 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> SEQID NO 95 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 95 Glu Ala Ser Thr Leu Glu Ser1 5 <210> SEQ ID NO 96 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 96 Glu AlaSer Thr Leu Glu Ser 1 5 <210> SEQ ID NO 97 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 97 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> SEQ ID NO 98 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 98 Asp Ala Ser Asn Leu Glu Thr 1 5 <210> SEQ ID NO 99 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 99 Ala Ala Ser Ile Leu Gln Ser 1 5 <210> SEQ ID NO 100 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 100 Ala Ala Ser Ser Leu Glu Ser 1 5 <210> SEQ ID NO 101 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 101 Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr 20 2530 <210> SEQ ID NO 102 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 102Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 103 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 103
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 104 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 104 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro GluAsp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 105 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <400> SEQUENCE: 105 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 106 <211> LENGTH: 31 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 106 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 107 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic polypeptide <400> SEQUENCE: 107 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 108 <211>LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 108 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly SerGly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 109 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 109 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210>SEQ ID NO 110 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 110 Gly Val Pro SerArg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 111 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 111 Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val TyrTyr 20 25 30 <210> SEQ ID NO 112 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 112 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 113 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 113 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser LeuGln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 114 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 114 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 115 <211> LENGTH: 31 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 115 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 116 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 116 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 117 <211>LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 117
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 118 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 118 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser LeuGln Ala Glu Asp Val Ala Val Tyr Tyr 20 25 30 <210> SEQ ID NO 119 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 119 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 120 <211> LENGTH: 31 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 120 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 15 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 121 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 121 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 122 <211>LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 122 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly SerGly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 123 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 123 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210>SEQ ID NO 124 <211> LENGTH: 31 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 124 Gly Val Pro SerArg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 20 25 30 <210> SEQ ID NO 125 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 125 Cys Gln Gln Gly Tyr Lys Asn Pro Pro Thr Phe 1 5 10 <210> SEQ ID NO 126 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 126 Cys Gln Gln Tyr Tyr Ser Thr Pro Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 127 <211>LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 127 Cys Gln Gln Ser Tyr Thr Thr Pro Leu Thr Phe 1 510 <210> SEQ ID NO 128 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 128 CysGln Gln Tyr Asp Thr Phe Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 129 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 129 Cys Gln Gln Ser Tyr Ser Thr Pro Pro Trp Thr Phe 1 5 10 <210> SEQ ID NO 130 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 130 Cys Gln Gln Ser Tyr Ser Thr Pro Pro Thr Phe 1 5 10 <210> SEQ ID NO 131 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 131 Cys Gln Gln Ala Asn Ser Phe Pro Ser Thr Phe 1 5 10 <210> SEQ ID NO 132 <211> LENGTH: 11 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 132 Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe
1 5 10 <210> SEQ ID NO 133 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 133 Cys Gln Gln Ser Tyr Ser Met Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 134 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 134 Cys Gln Gln Leu Asn Ser Tyr Pro Tyr Thr Phe 1 5 10 <210> SEQ ID NO 135 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 135 Cys Gln Gln Tyr Gly Ser Ser Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 136 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 136 Cys Gln Gln Gly Tyr Gly Thr Pro Tyr Thr Phe 1 5 10 <210> SEQ ID NO 137 <211> LENGTH: 11<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 137 Cys Gln Gln Tyr Tyr Ser Tyr Pro Pro Thr Phe 1 5 10<210> SEQ ID NO 138 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 138 Cys GlnGln Gly Tyr Ser Thr Pro Tyr Ser Phe 1 5 10 <210> SEQ ID NO 139 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 139 Cys Gln Gln Gly Tyr Ser Thr Pro Tyr Ser Phe 1 5 10 <210> SEQ ID NO 140 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 140 Cys Gln Gln Ser Tyr Ser Pro Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 141 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 141 Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 142 <211> LENGTH: 11 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 142 Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 143<211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 143 Cys His Gln Tyr Leu Ser Ser Pro GluThr Phe 1 5 10 <210> SEQ ID NO 144 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 144 Cys His Gln Tyr Leu Ser Ser Pro Glu Thr Phe 1 5 10 <210> SEQ ID NO 145 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 145 Cys Gln Gln Ala Ile Ser Phe Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 146 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 146 Cys Gln Gln Ala Ile Ser Phe Pro Leu Thr Phe 1 5 10 <210> SEQ ID NO 147 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 147 Cys Gln Gln Gly Tyr Ser Thr Pro Phe Thr Phe 1 5 10 <210> SEQ ID NO 148 <211> LENGTH: 11<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 148 Cys Gln Gln Gly Asn Gly Phe Pro Leu Thr Phe 1 5 10<210> SEQ ID NO 149 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide
<400> SEQUENCE: 149 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 150 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 150 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 151 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 151 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 152 <211> LENGTH: 10 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 152 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 153 <211> LENGTH:10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 153 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10<210> SEQ ID NO 154 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 154 Gly GlnGly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 155 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 155 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 156 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 156 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 157 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 157 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 158 <211> LENGTH: 10 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 158 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 159 <211> LENGTH:10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 159 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 1 5 10<210> SEQ ID NO 160 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 160 Gly GlnGly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 161 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 161 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 162 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 162 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 163 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 163 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 164 <211> LENGTH: 10 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 164 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 165 <211> LENGTH:10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 165 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 1 5 10<210> SEQ ID NO 166 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 166 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 167 <211> LENGTH: 10 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 167 Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 168<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 168 Gly Gln Gly Thr Lys Val Glu Ile LysArg 1 5 10 <210> SEQ ID NO 169 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:169 Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 170 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 170 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 171 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 171 Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 1 5 10 <210> SEQ ID NO 172 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 172 Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 1 5 10 <210> SEQ ID NO 173 <211> LENGTH: 26 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 173 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 SerVal Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 174 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 174 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 20 25 <210> SEQ ID NO 175 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 175 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys AlaAla Ser Gly 20 25 <210> SEQ ID NO 176 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 176 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 177 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 177 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25<210> SEQ ID NO 178 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 178 Gln ValGln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 179 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 179 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO180 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 180 Gln Val Gln Leu Val Gln Ser GlyAla Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 181 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 181 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 182 <211> LENGTH: 26 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 182 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 SerVal Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 183 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 183 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 184 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 184 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys LysAla Ser Gly 20 25 <210> SEQ ID NO 185 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 185 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 186 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 186 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25<210> SEQ ID NO 187 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 187 Gln ValGln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 188 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 188 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO189 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 189 Gln Val Gln Leu Val Gln Ser GlyAla Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 190 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 190 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 191 <211> LENGTH: 26<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 191 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys ProGly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 192 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 192 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 193 <211> LENGTH: 26 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 193 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 SerVal Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 194 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 194 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 195 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 195 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQID NO 196 <211> LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 196 Gln Val Gln Leu Val GlnSer Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Tyr Val Ser Cys Lys Ala Ser Gly 20 25 <210> SEQ ID NO 197 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 197 Asp Thr Phe Ser Asn Tyr Gly Ile Ser 1 5 <210> SEQ ID NO 198 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 198 Phe Ser Phe Ser Asn Tyr Asp Met His 1 5 <210> SEQ ID NO 199 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 199 Phe Thr Phe Ser Gly Ser Ala Met His 1 5 <210> SEQ ID NO 200 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 200 Gly Thr Phe Arg Ser Thr Ala Ile Ser 1 5 <210> SEQ IDNO 201 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 201 Gly Thr Phe Ser Ser Tyr AlaIle Ser 1 5 <210> SEQ ID NO 202 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:202 Gly Thr Phe Thr Ser Tyr His Met His 1 5 <210> SEQ ID NO 203 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 203 Tyr Ile Phe Thr Ser Tyr Pro Ile His 1 5 <210> SEQ ID NO 204 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 204 Tyr Thr Phe Ile Asn Tyr Asp Ile Asn 1 5 <210> SEQ ID NO 205 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 205 Tyr Thr Phe Thr Asp Tyr His Met His 1 5 <210> SEQ ID NO 206 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 206 Tyr Thr Phe Thr Asp Tyr Tyr Ile Gln 1 5 <210> SEQ ID NO 207 <211> LENGTH: 9 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 207 Tyr Thr Phe Thr Asp Tyr Tyr Met Gln 1 5 <210> SEQ ID NO 208 <211> LENGTH: 9<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 208 Tyr Thr Phe Thr Glu Asn Glu Met His 1 5 <210> SEQ IDNO 209 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 209 Tyr Thr Phe Thr Glu Asn GluMet His 1 5 <210> SEQ ID NO 210 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:210 Tyr Thr Phe Thr Glu Asn Glu Met His 1 5 <210> SEQ ID NO 211 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 211
Tyr Thr Phe Thr Glu Asn Glu Met His 1 5 <210> SEQ ID NO 212 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 212 Tyr Thr Phe Thr Gly Asn Tyr Ile His 1 5 <210> SEQ ID NO 213 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 213 Tyr Thr Phe Thr Gly Ser Tyr Ala Ile Ser 1 5 10 <210> SEQ ID NO 214 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 214 Tyr Thr Phe Thr Asn Tyr Gly Ile Ser 1 5 <210> SEQ ID NO 215 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 215 Tyr Thr Phe Thr Arg Tyr Tyr Ile His 1 5 <210> SEQ ID NO 216 <211> LENGTH: 9 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 216 Tyr Thr Phe Thr Arg Tyr Tyr Ile His 1 5 <210> SEQ ID NO 217<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 217 Tyr Thr Phe Thr Ser Tyr Asp Ile Asn1 5 <210> SEQ ID NO 218 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 218 TyrThr Phe Thr Ser Tyr Asp Ile Asn 1 5 <210> SEQ ID NO 219 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide<400> SEQUENCE: 219 Tyr Thr Phe Thr Ser Tyr Glu Ile Asn 1 5 <210> SEQ ID NO 220 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 220 Tyr Thr Phe Thr Ser Tyr Gly Ile Ser 1 5 <210> SEQ ID NO 221 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 221 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 222 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 222 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 1 5 10 <210> SEQ ID NO 223 <211>LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 223 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu TyrVal 1 5 10 <210> SEQ ID NO 224 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:224 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 225 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 225 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 226 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 226 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 227 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 227 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 228<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 228 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 229 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 229 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 230 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 230 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 231<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 231 Trp Val Arg Gln Ala Pro Gly Gln GlyLeu Glu Trp Met 1 5 10 <210> SEQ ID NO 232 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 232 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 233 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 233 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 234 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 234 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 235 <211> LENGTH: 13 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 235 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO236 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 236 Trp Val Arg Gln Ala Pro Gly GlnGly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 237 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide<400> SEQUENCE: 237 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 238 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 238 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 239 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 239 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 240 <211> LENGTH: 13 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 240 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210>SEQ ID NO 241 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 241 Trp Val Arg Gln AlaPro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 242 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 242 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 243 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 243 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 244 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 244 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 1 5 10 <210> SEQ ID NO 245 <211>LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 245 Gly Trp Met Asn Pro Asn Ser Gly Gly Thr Asn TyrAla 1 5 10 <210> SEQ ID NO 246 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:246 Ala Val Ile Ser Tyr Asp Gly Gly Phe Lys Leu Tyr Ala 1 5 10 <210> SEQ ID NO 247 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 247 Ser Ala Ile Ser Arg Asn Gly Gly Thr Thr Tyr Tyr Ala 1 5 10 <210> SEQ ID NO 248 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 248 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala 1 5 10 <210> SEQ ID NO 249 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 249 Gly Ile Val Asn Pro Ser Ser Gly Ser Thr Thr Tyr Ala 1 5 10 <210> SEQ ID NO 250<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 250 Gly Trp Met Asn Pro Asn Ser Gly AsnThr Gly Tyr Ala 1 5 10 <210> SEQ ID NO 251 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 251 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala 1 5 10 <210> SEQ ID NO 252 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 252 Gly Val Ile Asn Pro Ser Ala Gly Ser Thr Ser Tyr Ala 1 5 10 <210> SEQ ID NO 253 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 253 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Ser Tyr Ala 1 5 10 <210> SEQ ID NO 254 <211> LENGTH: 13 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 254 Gly Trp Ile Asn Pro Asn Ser Gly Gly Pro Asn Tyr Ala 1 5 10 <210> SEQ ID NO255 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 255 Gly Trp Ile Asp Pro His Ser GlyAla Thr Asn Tyr Ala 1 5 10 <210> SEQ ID NO 256 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide<400> SEQUENCE: 256 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala 1 5 10 <210> SEQ ID NO 257 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 257 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala 1 5 10 <210> SEQ ID NO 258 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 258 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala 1 5 10 <210> SEQ ID NO 259 <211> LENGTH: 13 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 259 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala 1 5 10 <210>SEQ ID NO 260 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 260 Gly Trp Met Asn ProAsn Ser Gly Asn Thr Gly Tyr Ala 1 5 10 <210> SEQ ID NO 261 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 261 Gly Trp Ile Asn Pro Lys Thr Gly Asp Thr Asn Tyr Ala 1 5 10
<210> SEQ ID NO 262 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 262Gly Trp Ile Ser Ala Arg Asn Gly Asn Thr Asn Tyr Ala 1 5 10 <210> SEQ ID NO 263 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 263 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Thr Tyr Ala 1 5 10 <210> SEQ ID NO 264 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 264 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Thr Tyr Ala 1 5 10 <210> SEQ ID NO 265 <211> LENGTH: 13 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 265 Gly Ile Ile Asp Pro Ser Gly Gly Ser Thr Ser Tyr Ala 1 5 10 <210> SEQ ID NO 266<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 266 Gly Trp Met Asn Ser Asn Ser Gly SerThr Gly Tyr Ala 1 5 10 <210> SEQ ID NO 267 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400>SEQUENCE: 267 Gly Ile Ile Asn Pro Ser Asp Gly Ser Ser Thr Tyr Ala 1 5 10 <210> SEQ ID NO 268 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 268 Gly Gly Ile Ile Pro Met Phe Gly Thr Thr Asn Tyr Ala 1 5 10 <210> SEQ ID NO 269 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 269 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp ThrAla Val 20 25 30 Tyr Tyr <210> SEQ ID NO 270 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 270 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 1 5 10 15 Ser Leu Tyr Leu Arg Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 271 <211> LENGTH: 34 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 271 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 1 5 10 15Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 272 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 272 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQID NO 273 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 273 Gln Lys Phe Gln GlyArg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 274 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 274 Leu Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg SerGlu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 275 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <400> SEQUENCE: 275 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 276 <211> LENGTH: 34 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 276 His Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser LeuArg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 277 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 277 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 278 <211> LENGTH: 34<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 278 Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp GluSer Thr Ser 1 5 10 15 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 279 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 279 His Ser Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr<210> SEQ ID NO 280 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 280 GlnLys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 281 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 281 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser LeuArg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 282 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 282 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 283 <211> LENGTH: 34<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 283 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp ThrSer Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 284 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 284 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr<210> SEQ ID NO 285 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 285 GlnGlu Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 286 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 286 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser LeuArg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 287 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 287 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 288 <211> LENGTH: 34<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 288 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp ThrSer Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
20 25 30 Tyr Tyr <210> SEQ ID NO 289 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 289 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 290 <211> LENGTH: 34 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 290 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 291 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 291 Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser 1 5 10 15 Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQID NO 292 <211> LENGTH: 34 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 292 Gln Lys Phe Gln GlyArg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser 1 5 10 15 Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val 20 25 30 Tyr Tyr <210> SEQ ID NO 293 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 293 Cys Ala Ile Gly Thr Thr Val Val Thr Pro Phe Gly Tyr Trp 1 5 10 <210> SEQ ID NO 294 <211> LENGTH: 19<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 294 Cys Ala Arg Gly Gln Val Arg Gly Ser Gly Pro Gln Val ValVal Met 1 5 10 15 Asp Val Trp <210> SEQ ID NO 295 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide<400> SEQUENCE: 295 Cys Ala Lys Asp Gly Thr Leu Ile Thr Thr Thr Leu Asp Tyr Trp 1 5 10 15 <210> SEQ ID NO 296 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 296 Cys Ala Arg Ala Gly Tyr Ser Ser Ser Ser Gly Tyr Tyr Tyr Tyr Gly 1 5 10 15 Met Asp Val Trp 20 <210> SEQ ID NO 297 <211> LENGTH: 16 <212> TYPE:PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 297 Cys Ala Arg Val Arg Gly Ser Ala Ala Ile Ala Met Met Asp Val Trp 1 5 10 15<210> SEQ ID NO 298 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 298 Cys AlaSer Phe Glu Arg Phe Gly Glu Leu Val Pro Glu Thr Phe Asp 1 5 10 15 Tyr Trp <210> SEQ ID NO 299 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 299 Cys Ala Arg Asp Arg Gly Ser Tyr Asp Thr Asp Ala Phe Asp Ile Trp 1 5 10 15 <210> SEQ ID NO 300 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 300 Cys Ala Ser Ala His Ser Ser Ser Trp Tyr Ser Asp Trp Phe Asp Pro 1 5 10 15 Trp <210> SEQ ID NO 301 <211>LENGTH: 19 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 301 Cys Ala Gly Met Gly Met Gly Arg Asp Gly Tyr AsnSer Arg Ala Phe 1 5 10 15 Asp Ile Trp <210> SEQ ID NO 302 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 302 Cys Ala Arg Val Asp Tyr Gly Asp Tyr Gly Arg Leu Glu Asp Tyr Trp 1 5 10 15 <210> SEQ ID NO 303 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 303 Cys Ala Arg Leu Glu Gly Gly Ser Tyr Trp Thr Gly Tyr Phe Asp Leu 1 5 10 15 Trp <210> SEQ ID NO 304 <211> LENGTH: 22<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 304 Cys Ala Lys Thr Arg Tyr Gly Gly Asn Ser Arg Ser Arg TyrTyr Tyr 1 5 10 15 Tyr Gly Met Asp Val Trp 20 <210> SEQ ID NO 305 <211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 305 Cys Ala Arg Asp Leu Met Asp Ile Val Val Val Pro Trp Leu Gly Gly 1 5 10 15 Met Asp Val Trp 20 <210> SEQ ID NO 306 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 306 Cys Ala Arg Asp Ser Gly Val Asp Thr Ala Thr Leu Arg Tyr Tyr Tyr 1 5 10 15 Tyr Gly Met Asp Val Trp 20 <210> SEQ ID NO307 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 307 Cys Ala Arg Asp Ser Gly Val AspThr Ala Thr Leu Arg Tyr Tyr Tyr 1 5 10 15 Tyr Gly Met Asp Val Trp 20 <210> SEQ ID NO 308 <211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 308 Cys Ala Lys Asp Val Gln Asn Tyr Tyr Gly Ser Gly Ser Ser Phe Asp 1 5 10 15 Tyr Trp <210> SEQ ID NO 309 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 309 Cys Ala Arg Gly Ser Ser Gly Tyr Tyr Phe Gly Trp 1 5 10 <210> SEQ ID NO 310 <211> LENGTH: 15<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 310 Cys Thr Thr Asp Pro Val Leu Glu Trp Phe Gly Tyr Ser IleTrp 1 5 10 15 <210> SEQ ID NO 311 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:311 Cys Ala Lys Gly Ala Pro His Asp Tyr Ile Trp Gly Ser Tyr Arg Pro 1 5 10 15 Asp Ala Phe Asp Ile Trp 20 <210> SEQ ID NO 312 <211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 312 Cys Ala Lys Gly Ala Pro His Asp Tyr Ile Trp Gly Ser Tyr Arg Pro 1 5 10 15 Asp Ala Phe Asp Ile Trp 20 <210> SEQ ID NO 313 <211> LENGTH: 13<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 313 Cys Ala Thr Val Thr Pro Gly Tyr Gly Met Asp Val Trp 1 5 10<210> SEQ ID NO 314 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 314 Cys AlaArg Gly Trp Met Ala Tyr Asp Ala Phe Asp Ile Trp 1 5 10 <210> SEQ ID NO 315 <211> LENGTH: 23 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 315 Cys Ala Arg Asp Arg Gly Tyr Ser Tyr Asp His Asp Gln Ile Tyr Tyr 1 5 10 15 Tyr Tyr Gly Met Asp Val Trp 20 <210> SEQ ID NO 316 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 316 Cys Ala Arg Asp Arg Gly Asp Thr Ile Asp Tyr Trp 1 5 10 <210> SEQ ID NO 317 <211> LENGTH:10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 317 Gly Gln Gly Thr Leu Val Asn Val Ser Ser 1 5 10<210> SEQ ID NO 318 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 318 Gly Lys Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 319 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 319 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 320 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 320 Gly Lys Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 321 <211> LENGTH: 10 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 321 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 322<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 322 Gly Gln Gly Thr Leu Val Thr Val SerSer 1 5 10 <210> SEQ ID NO 323 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:323 Gly Gln Gly Thr Met Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 324 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 324 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 325 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 325 Gly Gln Gly Thr Met Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 326 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 326 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 327 <211> LENGTH: 10 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 327 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 328<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 328 Gly Gln Gly Thr Thr Val Thr Val SerSer 1 5 10 <210> SEQ ID NO 329 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:329 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 330 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 330 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 331 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 331 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 332 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 332 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 333 <211> LENGTH: 10 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 333 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 334<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 334 Gly Gln Gly Thr Met Val Thr Val SerSer 1 5 10 <210> SEQ ID NO 335 <211> LENGTH: 10
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 335 Gly Gln Gly Thr Met Val Thr Val Ser Ser 1 5 10<210> SEQ ID NO 336 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 336 Gly GlnGly Thr Met Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 337 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 337 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 338 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 338 Gly Gln Gly Thr Met Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 339 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 339 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 340 <211> LENGTH: 10 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 340 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> SEQ ID NO 341 <211> LENGTH:119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 341 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val LysLys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Ser Asn Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln GlyArg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ile Gly Thr Thr Val Val Thr Pro Phe Gly Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Asn Val Ser Ser 115<210> SEQ ID NO 342 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 342 GluVal Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asn Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Gly PheLys Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Arg Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gln Val Arg Gly Ser Gly Pro Gln Val Val Val Met Asp 100105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 343 <211> LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic polypeptide <400> SEQUENCE: 343 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Ser 20 25 30 Ala Met His Trp Val Arg Gln Ala ProGly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser Arg Asn Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 8590 95 Ala Lys Asp Gly Thr Leu Ile Thr Thr Thr Leu Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 344 <211> LENGTH: 125 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 344 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe ArgSer Thr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu SerSer Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Gly Tyr Ser Ser Ser Ser Gly Tyr Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 345 <211> LENGTH: 121<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 345 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys LysPro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Ile Val Asn Pro Ser Ser Gly Ser Thr Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Arg Gly SerAla Ala Ile Ala Met Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 346 <211> LENGTH: 123 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 346 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Thr Ser Tyr 20 25 30 His MetHis Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Leu Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu AspThr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Phe Glu Arg Phe Gly Glu Leu Val Pro Glu Thr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 347 <211> LENGTH: 121 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 347 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser CysLys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr 20 25 30 Pro Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr ValTyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Ser Tyr Asp Thr Asp Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 348 <211> LENGTH:122 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 348 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val LysLys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Asn Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Asn Pro Ser Ala Gly Ser Thr Ser Tyr Ala His Lys Phe 50 55 60 Gln GlyArg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Ala His Ser Ser Ser Trp Tyr Ser Asp Trp Phe Asp Pro Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val SerSer 115 120 <210> SEQ ID NO 349 <211> LENGTH: 124 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 349 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 His Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn ProAsn Ser Gly Asn Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Gly Met Gly Met Gly Arg Asp Gly Tyr Asn Ser ArgAla Phe Asp 100 105 110 Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 350 <211> LENGTH: 121 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION:Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 350 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile Gln Trp Val ArgGln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Gly Gly Pro Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val TyrTyr Cys 85 90 95 Ala Arg Val Asp Tyr Gly Asp Tyr Gly Arg Leu Glu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 351 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 351 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly TyrThr Phe Thr Asp Tyr 20 25 30 Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asp Pro His Ser Gly Ala Thr Asn Tyr Ala His Ser Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 MetGlu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Glu Gly Gly Ser Tyr Trp Thr Gly Tyr Phe Asp Leu Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 352 <211> LENGTH: 127 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 352 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 15 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Asn 20 25 30 Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys ThrArg Tyr Gly Gly Asn Ser Arg Ser Arg Tyr Tyr Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 353 <211> LENGTH: 125 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 353 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly TyrThr Phe Thr Glu Asn 20 25 30 Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 MetGlu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Met Asp Ile Val Val Val Pro Trp Leu Gly Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 354 <211> LENGTH:127 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 354 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val LysLys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Asn 20 25 30 Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln GlyArg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gly Val Asp Thr Ala Thr Leu Arg Tyr Tyr Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly ThrThr Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 355 <211> LENGTH: 127 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <400> SEQUENCE: 355 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Asn 20 25 30 Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 4045 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gly Val AspThr Ala Thr Leu Arg Tyr Tyr Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 356 <211> LENGTH: 123 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 356 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Asn20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser LeuArg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Val Gln Asn Tyr Tyr Gly Ser Gly Ser Ser Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 357 <211> LENGTH: 118 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 357 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Ser 20 25 30 Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp 35 40 45 Met Gly Trp Ile Asn Pro Lys Thr Gly Asp Thr Asn Tyr Ala Gln Glu 50 55 60 Phe Gln Gly Arg Val Thr Met Thr ArgAsp Thr Ser Thr Ser Thr Val 65 70 75 80 Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Gly Ser Ser Gly Tyr Tyr Phe Gly Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> SEQ ID NO 358 <211>LENGTH: 120 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 358 Gln Val Gln Leu Val Gln Ser Gly Ala GluVal Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Arg Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Asp Pro Val Leu Glu Trp Phe Gly Tyr Ser Ile Trp Gly Gln 100 105 110 Gly Thr Met Val Thr Val SerSer 115 120 <210> SEQ ID NO 359 <211> LENGTH: 127 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 359 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser LeuArg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ala Pro His Asp Tyr Ile Trp Gly Ser Tyr Arg Pro Asp 100 105 110 Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 360 <211> LENGTH: 127<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 360 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys LysPro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly ArgVal Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gly Ala Pro His Asp Tyr Ile Trp Gly Ser Tyr Arg Pro Asp 100 105 110 Ala Phe Asp Ile Trp Gly Gln Gly Thr MetVal Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 361 <211> LENGTH: 118 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <400> SEQUENCE: 361 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 4045 Gly Ile Ile Asp Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Val Thr Pro Gly TyrGly Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 <210> SEQ ID NO 362 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Descriptionof Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 362 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala ProGly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Ser Asn Ser Gly Ser Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 8590 95 Ala Arg Gly Trp Met Ala Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <210> SEQ ID NO 363 <211> LENGTH: 128 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 363 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr20 25 30 Glu Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Asp Gly Ser Ser Thr Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser LeuArg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Tyr Ser Tyr Asp His Asp Gln Ile Tyr Tyr Tyr 100 105 110 Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 364 <211> LENGTH: 117<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 364 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys LysPro Gly Ser 1 5 10 15 Ser Val Tyr Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Met Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly ArgVal Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Asp Thr Ile Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> SEQID NO 365 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 365 Glu Ile Val Met ThrGln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ser Ser Arg 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro AlaArg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Tyr Lys Asn Pro 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO366 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 366 Asp Ile Gln Met Thr GlnSer Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Tyr Asp Ala Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Pro 85 90 95 Leu Thr Phe Gly Gln GlyThr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 367 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <400> SEQUENCE: 367 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Tyr Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 4045 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr LysVal Glu Ile Lys Arg 100 105 <210> SEQ ID NO 368 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 368 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Asn 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr AlaAla Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu IleLys Arg 100 105 <210> SEQ ID NO 369 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 369 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Arg Asn Glu 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser SerLeu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg100 105 <210> SEQ ID NO 370 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE:370 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu GlnSer Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105<210> SEQ ID NO 371 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 371 AspIle Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Asn Leu Gln Ser GlyVal Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ser 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210>SEQ ID NO 372 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 372 Asp Ile Gln MetThr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro SerArg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO373 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 373 Asp Ile Gln Met Thr GlnSer Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg PheSer Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Met Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 374<211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:
Synthetic polypeptide <400> SEQUENCE: 374 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Tyr Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala ProLys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Tyr 85 90 95 Thr PheGly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 375 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 375 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg LeuLeu 35 40 45 Ile Tyr Ala Val Ser Ser Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln 65 70 75 80 Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly GlyGly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 376 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <400> SEQUENCE: 376 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln His Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 4045 Tyr Ala Ala Ser Ala Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Gly Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr LysVal Glu Ile Lys Arg 100 105 <210> SEQ ID NO 377 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 377 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Thr Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr AlaAla Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu IleLys Arg 100 105 <210> SEQ ID NO 378 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 378 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Lys Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser ThrLeu Ser Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Tyr 85 90 95 Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100105 <210> SEQ ID NO 379 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 379Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Lys Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Leu Ser AspGly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ser Thr Pro Tyr 85 90 95 Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105<210> SEQ ID NO 380 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 380 AspIle Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser GlyVal Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Pro Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210>SEQ ID NO 381 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 381 Asp Ile Gln MetThr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Arg Leu Gln Ser Gly Val Pro SerArg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 382 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 382 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser GlnSer Val Phe Ser Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 IleSer Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg <210> SEQ ID NO 383 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 383 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile ThrCys Arg Ala Ser Glu Asn Ile Asp Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Glu Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu GlnPro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Leu Ser Ser Pro Glu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 384 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 384 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg AlaSer Glu Asn Ile Asp Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Glu Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 7075 80 Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Leu Ser Ser Pro Glu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 385 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 385 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser GlnThr Ile Tyr Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 GluAsp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ile Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> SEQ ID NO 386 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 386 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile TyrAsn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe AlaThr Tyr Tyr Cys Gln Gln Ala Ile Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 387 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 387 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Val Ser Gln Gly Ile Ser Ser Tyr20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ile Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr TyrTyr Cys Gln Gln Gly Tyr Ser Thr Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> SEQ ID NO 388 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 388 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Asn 20 25 30 LeuAsn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys GlnGln Gly Asn Gly Phe Pro Leu 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> SEQ ID NO 389 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 389
Gly Thr Phe Ser Ser Tyr Thr Ile Ser 1 5 <210> SEQ ID NO 390 <211> LENGTH: 14 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 390 Met Gly Gly Ile Thr Pro Ile Leu Gly Ile Ala Asn Tyr Ala 1 5 10 <210> SEQ ID NO 391 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 391 Cys Ala Arg Asp Thr Val Met Gly Gly Met Asp Val 1 5 10 <210> SEQ ID NO 392 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 392 Gly Gly Asn Asn Ile Gly Ser Lys Ser Val His 1 5 10 <210> SEQ ID NO 393 <211> LENGTH: 7<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 393 Asp Asp Ser Asp Arg Pro Ser 1 5 <210> SEQ ID NO 394<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 394 Gln Val Trp Asp Ser Ser Ser Asp TyrVal 1 5 10 <210> SEQ ID NO 395 <211> LENGTH: 118 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 395 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Thr ProIle Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Thr Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Thr Val Met Gly Gly Met Asp Val Trp GlyGln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 <210> SEQ ID NO 396 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic polypeptide <400> SEQUENCE: 396 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val ValTyr 35 40 45 Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp Tyr 85 90 95 Val Phe Gly Thr GlyThr Lys Val Thr Val Leu 100 105 <210> SEQ ID NO 397 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide<400> SEQUENCE: 397 Phe Ala Phe Ser Ser Tyr Ala Met His 1 5 <210> SEQ ID NO 398 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 398 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala 1 5 10 <210> SEQ ID NO 399 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220>FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 399 Cys Ala Arg Asp Arg Ser Tyr Tyr Leu Asp Tyr 1 5 10 <210> SEQ ID NO 400 <211> LENGTH: 11 <212> TYPE: PRT <213>ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 400 Arg Ala Ser Gln Ser Val Arg Ser Asn Leu Ala 1 5 10 <210> SEQ ID NO 401 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 401 Asp Ala Ser Thr Arg Ala Thr 1 5 <210> SEQID NO 402 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 402 Cys Gln Gln Arg Ser AsnTrp Pro Pro Thr 1 5 10 <210> SEQ ID NO 403 <211> LENGTH: 117 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 403 Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Lys 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr IleSer Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Tyr Tyr Leu Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> SEQ ID NO 404<211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 404 Glu Thr Thr Leu Thr Gln SerPro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe SerGly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys 100 105 <210> SEQ ID NO 405 <211>LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 405 Tyr Thr Phe Thr Thr Tyr Arg Met His 1 5<210> SEQ ID NO 406 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 406 Gly AlaIle Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn 1 5 10 <210> SEQ ID NO 407 <211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:Synthetic peptide <400> SEQUENCE: 407 Cys Thr Arg Glu Gly Ile Pro Gln Leu Leu Arg Thr Leu Asp Tyr 1 5 10 15 <210> SEQ ID NO 408 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 408 Arg Ala Ser Gln Glu Ile Ser Gly Tyr Leu Ser 1 5 10 <210> SEQ ID NO 409 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 409 Ala Ala Ser Thr Leu Asp Ser 1 5 <210> SEQ ID NO 410 <211> LENGTH: 10 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 410 Cys Leu Gln Tyr Val Ser Tyr Pro Trp Thr 1 5 10 <210> SEQ ID NO 411<211> LENGTH: 121 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 411 Glu Val Gln Leu Glu Glu SerGly Thr Val Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Arg Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Thr Tyr Asn Gln LysPhe 50 55 60 Lys Asp Lys Ala Lys Leu Thr Ala Val Thr Ser Thr Ser Ser Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Thr Arg Glu Gly Ile Pro Gln Leu Leu Arg Thr Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr SerVal Thr Val Ser Ser 115 120 <210> SEQ ID NO 412 <211> LENGTH: 107 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 412 Asp Ile Leu Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Leu Gln Glu Lys Pro Asp Gly Thr Ile Lys Arg Leu Ile 35 40 45 Tyr AlaAla Ser Thr Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Tyr Val Ser Tyr Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu IleLys 100 105 <210> SEQ ID NO 413 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE:413 Phe Thr Phe Arg Asn Tyr Ala Met His 1 5 <210> SEQ ID NO 414 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpeptide <400> SEQUENCE: 414 Ala Val Ile Thr Ser Asp Gly Arg Asn Lys Phe Tyr Ala 1 5 10 <210> SEQ ID NO 415 <211> LENGTH: 21 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence:
Synthetic peptide <400> SEQUENCE: 415 Cys Val Thr Gln Arg Asp Asn Ser Arg Asp Tyr Phe Pro His Tyr Phe 1 5 10 15 His Asp Met Asp Val 20 <210> SEQ ID NO 416 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 416 Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asp Thr Tyr Leu Asn 1 5 10 15 <210> SEQ ID NO 417 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 417 Gln Val Ser Asn Arg Asp Ser 1 5 <210> SEQID NO 418 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 418 Cys Met Gln Gly Ser HisTrp Pro Pro Thr 1 5 10 <210> SEQ ID NO 419 <211> LENGTH: 127 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide<400> SEQUENCE: 419 Gln Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Ala Thr Gly Leu Gln Trp Leu 35 40 45 Ala ValIle Thr Ser Asp Gly Arg Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Glu Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Arg Gly Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Thr Gln Arg Asp Asn Ser Arg Asp TyrPhe Pro His Tyr Phe His 100 105 110 Asp Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> SEQ ID NO 420 <211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 420 Asp Val Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30 AspGly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45 Pro Arg Arg Leu Ile Tyr Gln Val Ser Asn Arg Asp Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val GlyVal Tyr Tyr Cys Met Gln Gly 85 90 95 Ser His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> SEQ ID NO 421 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 421 Tyr Gly Phe Ile Thr Tyr Trp Ile Gly 1 5 <210> SEQ ID NO 422 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: ArtificialSequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 422 Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser 1 5 10 <210> SEQ ID NO 423 <211> LENGTH: 13<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 423 Cys Ala Gly Gly Ser Gly Ile Ser Thr Pro Met Asp Val 1 5 10<210> SEQ ID NO 424 <211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 424 Lys SerSer Gln Ser Val Leu Tyr Ser Ser Ile Asn Lys Asn Tyr Leu 1 5 10 15 Ala <210> SEQ ID NO 425 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description ofArtificial Sequence: Synthetic peptide <400> SEQUENCE: 425 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> SEQ ID NO 426 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 426 Cys Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr 1 5 10 <210> SEQ ID NO 427 <211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 427 Gln Met Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly TyrGly Phe Ile Thr Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Asn Thr Ala Tyr 65 70 75 80 LeuGln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Gly Gly Ser Gly Ile Ser Thr Pro Met Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser
115 <210> SEQ ID NO 428 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400>SEQUENCE: 428 Asp Ile Gln Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Ile Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu LeuIle Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr LysVal Glu Ile 100 105 110 Lys <210> SEQ ID NO 429 <211> LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide<400> SEQUENCE: 429 Cys Ala Arg Asp Arg Gly Ser Tyr Asp Thr Asp Ala Phe Asp Ile Trp 1 5 10 15 <210> SEQ ID NO 430 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 430 Tyr Ile Phe Thr Ser Tyr Pro Ile His 1 5 <210> SEQ ID NO 431 <211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 431 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala 1 5 10 <210> SEQ ID NO 432 <211> LENGTH: 11 <212>TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 432 Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> SEQ IDNO 433 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide <400> SEQUENCE: 433 Ala Ala Ser Asn Leu Gln Ser 15 <210> SEQ ID NO 434 <400> SEQUENCE: 434 000 <210> SEQ ID NO 435 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 435 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 1 5 10 <210> SEQ ID NO 436 <211> LENGTH: 121 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHERINFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 436 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr 20 25 30 Pro IleHis Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu AspThr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Ser Tyr Asp Thr Asp Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> SEQ ID NO 437 <211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM:Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic polypeptide <400> SEQUENCE: 437 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile ThrCys Arg Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu GlnPro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ser 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> SEQ ID NO 438 <400> SEQUENCE: 438 000 <210> SEQ ID NO 439 <400> SEQUENCE: 439000 <210> SEQ ID NO 440 <400> SEQUENCE: 440 000 <210> SEQ ID NO 441 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of ArtificialSequence: Synthetic peptide <400> SEQUENCE: 441 Cys Gln Gln Ala Asn Ser Phe Pro Ser Thr Phe 1 5 10 <210> SEQ ID NO 442 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223>OTHER INFORMATION: Description of Artificial Sequence: Synthetic 6xHis tag <400> SEQUENCE: 442
His His His His His His 1 5 <210> SEQ ID NO 443 <211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Syntheticpolypeptide <220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(100) <223> OTHER INFORMATION: This sequence may encompass 3-20 "Gly Gly Gly Gly Ser" repeating units <220> FEATURE: <223> OTHER INFORMATION:See specification as filed for detailed description of substitutions and preferred embodiments <400> SEQUENCE: 443 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser GlyGly 20 25 30 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 35 40 45 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 50 55 60 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 65 70 75 80 Gly Gly Gly Gly SerGly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 85 90 95 Gly Gly Gly Ser 100
* * * * *
Americans are partying again. But elsewhere, the pandemic is getting worse. - The Washington Post
Thu, 03 Jun 2021 11:29
You're reading an excerpt from the Today's WorldView newsletter. Sign up to get the rest, including news from around the globe, interesting ideas and opinions to know, sent to your inbox every weekday.
In the United States, life is returning to normal. Restaurants and bars are filling up again, vacations are being booked and flights are selling out. At sporting events, maskless fans are hugging and cheering. Memorial Day weekend, the country's unofficial start to the summer, was celebrated with much more gusto and many more family barbecues than it was a year ago.
That's all for good reason: A majority of Americans have received at least one dose of a coronavirus vaccine, and daily new infections and deaths are at their lowest levels in almost a year. The pandemic is slowly receding from the daily lives of many Americans as businesses open up and local authorities ease restrictions. Britain, which on Tuesday reported no new coronavirus-related deaths for the first time since March 2020, can also see the sunlit uplands of a post-pandemic future.
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''Covid-19 won't end with a bang or a parade,'' wrote Devi Sridhar, chair of global public health at the University of Edinburgh. ''Throughout history, pandemics have ended when the disease ceases to dominate daily life and retreats into the background like other health challenges.''
But the pandemic is hardly in retreat elsewhere. The emergence of more virulent variants of the virus in countries like Brazil and India and the slowness of vaccination efforts in many places outside the West have contributed to deadly new waves. Coronavirus case counts worldwide are already higher in 2021 than they were in 2020. The death toll almost certainly will be.
Southeast Asia, once a bastion of resistance to the virus as it ravaged Western countries, is in the grip of a harrowing spike in infections. Cases in Thailand and Vietnam rose dramatically over the past month. Malaysia is now registering more new infections per million people than any medium- or large-size country in Asia, surpassing India, which remains a global hot spot. On Tuesday, the Malaysian government implemented a nationwide lockdown that will last for the next two weeks.
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''The economy will certainly suffer. The people will suffer even more, those who live. Many are dying and will die,'' wrote columnist Munir Majid in the New Straits Times. ''We are staring at the abyss.''
In Africa, concerns are growing over the possible arrival of a new wave powered by a more transmissible variant of the virus, with the health systems in many countries at risk of being quickly subsumed by a surge of infections. A recent study found that the continent has the world's highest death rate of patients critically ill with covid-19, thanks to limited intensive care facilities and reserves of vital medical supplies like oxygen.
In parts of Latin America, the virus rages on, largely unabated. Peru, according to its own government-adjusted data, now has the worst covid-19 mortality rate per capita in the world. The country is slated to stage a closely contested presidential runoff election this weekend.
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Even in East Asia, where a handful of nations set the gold standard in preventing community spread, the virus is on the march. Taiwan has seen an explosion of cases over the past month. In Japan, which still intends to host the Summer Olympics, numerous areas including Tokyo remain under a state of emergency. It's a sign, argue some public health experts, that the strict methods that kept places like Taiwan, South Korea and Singapore safer than their counterparts in the West for all of last year may not be sustainable in the long term.
For a number of reasons, the vaccine rollouts in these countries have been slow, hampered by a lack of supply. In an interview earlier this year with Today's WorldView, Koji Tomita, Japan's ambassador in Washington, described his country and other East Asian states that initially managed to clamp down on community spread '-- but built up little herd immunity '-- as ''prisoners of their own success.''
Public health advocates and international organizations recognize the main problem: The global gap in vaccinations. In the United States, there's already discussion of booster shots for the general public, while front-line medical workers in some developing countries have yet to even receive a first dose of a vaccine. In a joint statement, the heads of the International Monetary Fund, the World Bank, the World Trade Organization and the World Health Organization laid out a $50 billion plan for collective action that would accelerate vaccine distribution to poor and middle-income countries and expand and diversify production capacity throughout the world.
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''Inequitable vaccine distribution is leaving millions of people vulnerable to the virus while allowing deadly variants to emerge and ricochet back across the world,'' they wrote in an op-ed published in The Washington Post. ''As variants spread, even countries with advanced vaccination programs have been forced to reimpose stricter public health measures and travel restrictions. The ongoing pandemic is deepening divergence in economic fortunes, with negative consequences for all.''
''It would be a monumental error for any country to think the danger has passed,'' WHO Director General Tedros Adhanom Ghebreyesus said Monday at the close of the World Health Assembly. He warned that insufficient global coordination at present means that ''we will still face the same vulnerabilities that allowed a small outbreak to become a global pandemic.''
Attention now moves to this month's meeting of the Group of Seven nations, where leaders of these traditional world powers are expected to step up and deliver on the global need for vaccines. The Biden administration also opted to support negotiations at the WTO over a possible waiver of international property protections on coronavirus vaccines, which could lead to more countries being able to produce them. But the waiver is still opposed by major European governments, while advocates contend that these discussions should have taken place at a much earlier stage in the pandemic.
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Now, time is of the essence, as more transmissible variants appear to be burning rapidly through societies without much immunological protection. ''It is, of course, understandable that every nation wants to vaccinate its own first, but a country with high levels of vaccination, especially among its more vulnerable populations, can hold things off, especially if they also had big outbreaks before,'' wrote Zeynep Tufekci in the New York Times, arguing that wealthier nations like the United States should be actively prioritizing providing for other countries over its own population. ''In addition, excess stockpiles can go where they are needed without even slowing down existing vaccination programs.''
Anthony S. Fauci, the leading infectious-disease expert in the United States, appeared to recognize the broader threat. ''As long as there is some degree of activity throughout the world, there's always a danger of variants emerging and diminishing somewhat the effectiveness of our vaccines,'' he told the Guardian.
Iranian Navy ships could reach the Atlantic by Thursday
Wed, 02 Jun 2021 22:18
The Makran anchored north of Larak Island in the Persian Gulf. | Satellite image (C)2021 Maxar Technologies
The two Iranian Navy ships steaming south along the east coast of Africa are expected to round the Cape of Good Hope and reach the Atlantic Ocean as early as Thursday, according to two U.S. officials with direct knowledge.
National security officials tracking the ships do not know the ships' final destination, but believe they may be ultimately bound for Venezuela, POLITICO first reported on Saturday. The ships were still moving south on Wednesday, and at their current pace they are on track to turn west around the Cape on Thursday, said the people, who requested anonymity to discuss sensitive operations.
Advertisement''Our belief that it's heading toward Venezuela has not changed,'' one of the people said.
Iranian warships sailing into the Atlantic Ocean would present a major test for the Biden administration, which has been trying to re-engage Tehran in negotiations over its nuclear program. Iran has previously threatened to send warships into the Atlantic, but never followed through, settling for an emergency port call in South Africa in 2016.
Tehran's intent in sending the ships toward the Atlantic is not clear. But a spokesperson for the National Security Council noted that Venezuela purchased weapons from Iran over a year ago, and warned that any new delivery of weapons "would be a provocative act and a threat to our partners in this hemisphere."
"We would reserve the right to take appropriate measures '-- in concert with our partners '-- to deter the delivery or transit of such weapons," the person said, speaking on condition of anonymity to discuss a sensitive topic.
AdvertisementThe Iranian ships include a frigate and the Makran, a former oil tanker that was converted to a floating forward staging base, according to the officials.
Tehran and Caracas have previously worked together to defy the United States and to further both governments' goals. Iran has in the past sent tankers to dock in Venezuela and deliver oil, in defiance of U.S. sanctions.
''Tehran is intent on deepening its footprint in Latin America and in the Western Hemisphere more broadly. Venezuela offers Tehran a forward operating base in the region,'' said Behnam Ben Taleblu, an Iran expert at the hawkish Foundation for Defense of Democracies, whose scholars often advocate for a tough U.S. policy aimed at undermining Iran's Islamist regime. Taleblu noted that the Makran's movement, in particular, has raised eyebrows.
Top officials in Tehran have implicitly confirmed the ships' movement. In response to POLITICO's reporting, the Iranian Foreign Ministry on Monday warned U.S. officials to avoid miscalculations about the country's warships sailing in international waters.
Advertisement''Iran is always present in international waters and has this right under international law and can be present in international waters,'' Foreign Ministry spokesperson Saeed Khatibzadeh told reporters in Tehran.
''No country can violate this right,'' he said. ''Those who have sit in glass houses should be careful.''
Over the past few days, the ships have alternatively stopped and indicated they might turn around, the U.S. officials said. But since Friday they have made significant progress south along the coast.
The Biden administration updated lawmakers on the ships' progress on Tuesday, one of the people said.
After POLITICO first reported on the ships' movements, Sen. Marco Rubio (R-Fla.), the vice chair of the Senate Intelligence Committee, suggested that the U.S. should prevent the ships from reaching Venezuela.
''There are only two reasons why an Iranian warship would travel half a world away to make a port call in Venezuela,'' Rubio wrote on Twitter. ''To deliver military cargo they have sold them; to test the U.S. by conducting joint exercises with them. We should allow neither to happen.''
However, a U.S. defense official said there are currently no plans to send U.S. Navy ships to monitor or deter the Iranian task force. U.S. Southern Command typically operates two littoral combat ships in the South and Central America region.
The ships' cargo is also unknown. However, satellite photos of the Makran taken by Maxar Technologies in April and May and shared with POLITICO show the vessel leaving a port in Iran in April with seven high-speed fast attack craft on its deck. The images were first reported by USNI News. Another picture taken in May shows the Makran north of Larak Island in the Strait of Hormuz with the boats still onboard.
AdvertisementThe boats seen in the images are consistent with the fast attack craft operated by the Islamic Revolutionary Guard Corps Navy, which frequently patrol the Persian Gulf and the Strait of Hormuz. This type of boat has been used in recent months to harass U.S. ships operating in international waters.
Pentagon spokesperson John Kirby declined to comment on the ships' movement during a press briefing on Tuesday.
''I'm not going to speculate about what the Iranian Navy might or might not do,'' Kirby said. However, he noted that Adm. Craig Faller, commander of U.S. Southern Command, ''has at his disposal capabilities to help secure our interest and to meet our commitments in that part of the world.''
Taleblu noted that Iran's ship movements have created geopolitical challenges in the past, and urged the Biden administration to watch the latest development closely.
''Sanctioned Iranian and Venezuelan actors have reportedly [bartered] jet fuel for gasoline in the past and may be using the tanker trade or port calls for other purposes,'' he wrote in an email. ''As the Biden team looks to unwind sanctions on Iran, discerning where the U.S. is on such activity is getting harder, and that's a big problem.''
Also Wednesday, a major Iranian Navy vessel, the Kharg, sank after catching fire, while a huge blaze broke out at an oil refinery that serves the Iranian capital.
While the exact cause of the fires was not yet clear, various Iranian infrastructure and military assets have been damaged by explosions and fires in the past that analysts have suspected is the work of Israel, which views Iran as a major adversary and is trying to damage its nuclear program.
The Kharg went down in the Gulf of Oman near the Strait of Hormuz. Iranian media quoted a Navy spokesperson as saying there was a 20-hour battle to bring the blaze under control, but to no avail.
AdvertisementThe fire began in the vessel's engine room, according to Iran's semi-official Fars News agency, which quoted the unnamed spokesperson. The media outlet reported that the ship had been in service for 40 years and was used for both logistical and training purposes.
The fire at the oil refinery struck the state-owned Tondgooyan Petrochemical Co. to the south of Tehran, The Associated Press reported, sending up huge black plumes of smoke.
Nahal Toosi and Betsy Woodruff Swan contributed to this report.
Inside Citizen: The public safety app pushing surveillance boundaries
Wed, 02 Jun 2021 21:35
The smartphone app Citizen describes itself in simple terms: a safety network that sends alerts about nearby incidents including crime. But in recent months, its business has pushed into potentially dangerous new territory, alarming law enforcement officials and people who worked there.
In Los Angeles, the company's CEO, Andrew Frame, ordered his staff to put a $30,000 reward on the capture of a man he incorrectly thought was responsible for starting a brushfire that was threatening homes. The sheriff's office denounced the move, saying it put the man in danger, and the man was cleared of wrongdoing.
Days later, people started to see what looked like a law enforcement SUV bearing Citizen's logo driving around Los Angeles. It turned out to be a test of a private security force for people willing to pay the company a monthly fee, and it was quickly denounced on social media as a dystopian idea that could interfere with the 911 system. The company then abandoned the test.
These attempts by Citizen to branch out are causing alarm among both experts and people who have worked at Citizen, because they say the company seems to be heading in a new, more aggressive direction that may end up doing more harm than good.
"Why does Andrew Frame get to decide to put a bounty on anyone's head?" said one former Citizen employee, who said he was disgusted by the turn the company has taken, including its use of an online wanted poster not authorized by police. Like other former Citizen employees, he agreed to be interviewed about his experience at the company on the condition of anonymity, saying he feared retaliation from Citizen management for speaking against the company.
"It should make everyone afraid, because it could be anyone," the former employee said. "There's no oversight."
Citizen, which is based in New York City and initially went by the name Vigilante, got to this juncture in a roundabout journey, marked over the past two years by a major shake-up in senior management, the departure of a co-founder, the elimination of the company's growth team and what former employees called a desperate search to find a way to make money from the information it's been collecting in about 30 U.S. cities.
It's not unusual for tech startups to cycle through business ideas and focus on growth as they figure out what they want to be. But because Citizen is focused on public safety, the stakes behind each idea are higher.
"When you're dealing with public safety, it's more difficult to take risks than if you're dealing with restaurant reviews," said a second former Citizen employee.
Ben Jealous, a former president of the NAACP and a former partner at a firm that invested in Citizen, has helped to burnish the company's reputation, comparing it to street lights as a basic safety tool. In a statement Tuesday, he said he still believes in the app's ability to help vulnerable communities find missing people and avoid danger, but he also expressed concern.
"These were serious mistakes that cannot be repeated," Jealous said through a personal spokesperson. "I'm hopeful that the company will both course correct quickly as they've done in the past and put checks in place to prevent future missteps."
Citizen founder and CEO Andrew Frame speaks in San Francisco on Sept. 19, 2017. Steve Jennings / Getty images fileNBC News spoke with eight former employees of Citizen who collectively described a startup that frequently acts without thinking through consequences, and often fails to live up to its marketing themes about putting safety over other priorities such as attracting new users.
Three of the former employees said they believed Citizen was moving closer to the earlier version of the app, Vigilante, which launched in 2016 and was banned from Apple's App Store for encouraging people to rush toward violence. That version was marketed as a way for civilians to take the law into their own hands and respond to crime in progress, rather than avoid it.
Frame did not respond to a request for an interview. A spokesperson for Citizen said he had declined the request and that no one else was available for an interview.
In a statement, the company said it wants to create a network of people protecting one another, despite the fire incident in Los Angeles, which the company called a mistake.
"One of the goals when we founded the company was to create symmetry of information between the community and law enforcement '-- so nobody has to wonder why there's a police car on their corner or helicopters overhead," the company said in response to written questions. "Citizen creates an open, shared safety system where police and citizens can hold each other accountable. This is the only way to rebuild trust between community and law enforcement."
It is also "completely untrue" that there had been turmoil or high turnover within the company since the start of 2020, a spokesperson said.
From Vigilante to Citizen Citizen is one of a handful of apps that have risen in popularity in recent years as a way for people to track, report and share local news and discuss crime close to home.
"It's extending the dragnet of surveillance into residential space, and that I believe is something new," said Lauren Bridges, a doctoral candidate in critical data studies at the Annenberg School for Communication at the University of Pennsylvania. She has written about the impact of another home security tech product, Amazon's Ring cameras.
But unlike the neighborhood-focused social media network Nextdoor and the Neighbors app, which is used to share videos from Ring cameras, Citizen's focus is squarely on local crime. Opening the app brings the user to a map of their nearby area with a line sweeping around the screen reminiscent of a radar tracking system, showing incidents.
Citizen captures information about crime from several sources '-- including law enforcement radio traffic '-- and presents it to people in a localized form. Last year, it added localized information about the spread of Covid-19.
Residents can use the app to broadcast video live from the scene of a fire, car wreck, crime or other incident, and law enforcement officers can, too.
Citizen is available in about 30 cities nationwide and says on its website that it's "working to expand our coverage rapidly to more cities." The company has raised more than $130 million in funding from some of the biggest venture capital firms, including Sequoia Capital and Greycroft, according to Crunchbase, a website that tracks startups.
The app has found some success, though not the kind typically encouraged by startups backed with tens of millions of dollars in venture capital. It has been downloaded about 11.7 million times since its launch, according to Apptopia, a tech research firm. Its growth has been steady over the past two years, according to Apptopia data, though well behind the most popular consumer apps.
Citizen, a smartphone app, is designed to alert you when crimes, emergencies and other dangerous events occur in your area. CitizenAnd users tend to engage with the app consistently. Categorized in app stores as a "news" app, Citizen is in the top 20 percent for seven-day retention among Apple iOS users and the top 10 percent among Google Android users. Downloads peaked in June 2020, during nationwide protests over police violence, Apptopia research says.
Citizen said in response to written questions that it has a clear strategy and business plan, but it did not say what the plan is, other than that it does not involve selling user data or advertisements. It said it had more than doubled its user base in 2020.
But in a possible warning sign, the percentage of negative user reviews has been increasing in recent months, according to Apptopia. In January, about 23 percent of reviews were negative, steadily increasing to 37 percent in May. Some have found the app so off-putting that they decided to delete it. (Citizen noted that it still has a 4.8 rating on Apple's app store.)
At its best, the app serves as something of a neighborhood watch. Its users have been responsible for finding a missing 76-year-old man in New York, alerting a New York apartment dweller to a fire in his own building and helping a person in Atlanta avoid a nearby armed robbery, among other success stories, according to the company.
"We take great care to differentiate incidents and describe them accurately and objectively," Citizen said in a statement. The company says, for example, that it labels incidents as "unconfirmed" unless confirmed by law enforcement.
To some others, though, the information on Citizen isn't so reliable.
A third former employee said he came to doubt the accuracy of most of the information on Citizen because of what he called the lack of in-depth vetting. Citizen staff members often pass along information directly from police scanners, a notoriously unverified source, he said.
"It fuels public insanity and fear," the former employee said. "The effect of Citizen is to make everybody afraid in a community. I'm not a supporter. I tell people that."
Citizen said in a statement that it updates a post if it receives information indicating that a report was a false alarm. It also says its staff members, known as "analysts," often have backgrounds in media or law enforcement that help them filter information. They receive training and follow manuals, according to the company.
Citizen staff members generally spend most of an eight-hour shift monitoring scanner traffic from multiple cities, with different cities each night, often listening to recordings at double-speed to maximize efficiency, a fourth former employee said.
"That sounds like it can get overwhelming, and at times it can be," she said. "I had nightmares every night about either waking up to work late or, worse yet, falling really, really behind on radio clips." She said analysts discussed organizing but didn't form a union while she was there.
She said that one day last year, in the late spring or early summer, Citizen sent a celebratory-but-premature notification that "we had flattened the curve" against Covid-19, but "that was not true at all. There was no proper vetting there," she said.
Atop the company is Frame, 41, the CEO and a co-founder. A teenage prodigy as a hacker who dropped out of high school and avoided jail time as a minor after he breached NASA computer systems, he made tens of millions of dollars from early work at Facebook building network architecture, according to a 2019 profile in Forbes magazine.
Frame started Citizen in 2016 as the Vigilante app, and former employees said they fear he never lost his interest in a swashbuckling, vigilante-style network, despite Apple's veto of that idea and public statements from Citizen afterward disavowing the original ethos.
"The company was spending so much time and effort to try to get away from the Vigilante thing, when it was so clear that Frame loved the Vigilante thing," a fifth former employee said. "He would always show us videos or things related to the Vigilante days." Among the videos he would play for employees was a 2016 marketing video, by then years old, showcasing how civilians might rush toward a violent crime in progress if asked to do so, this person said.
A sixth former employee said that, on one occasion, Frame defended the original Vigilante marketing theme after a staff member in a meeting had offhandedly called it a mistake.
"Andrew was like, 'That wasn't a mistake,'" the former employee said. "He said, 'The worst thing that can befall a company is to be ignored.' He said, 'That's what put this company on the map.'"
A Citizen spokesperson did not answer a written question about whether Frame replays the old Vigilante marketing video for the staff, or whether he's interested in returning to that idea.
A seventh former employee was skeptical that Frame had done anything out of line, saying that while Frame is "definitely a passionate individual," at the same time, there was a "clear red line that he could never cross." That threshold was to not identify specific people in the app, or to start "manhunts."
"I know while I was there that the red line existed, and everyone around Frame was aware of it, and we never had to remind Frame that that line existed either, probably because the platform's entire existence depended on it," this person said.
But by last month, Frame was enthusiastically backing the idea of manhunts, according to screenshots of internal company communications seen by NBC News and first reported by Motherboard.
"We should catch a new bad guy EVERY DAY," Frame told employees via the messaging app Slack, according to the screenshots.
The context was the brushfire in Los Angeles that had forced evacuations. Citizen told people on its app that it was offering a $30,000 reward for information leading to the arrest of what it said was an "arson suspect." It showed a photograph of the person, and during a live broadcast within the app, hosts from Citizen repeatedly asked listeners to "bring this guy to justice," according to Cerise Castle, a journalist who live-tweeted the broadcast.
Frame signed off on and encouraged the reward, according to the Slack screenshots.
"FIND THIS F---," he wrote, using an expletive. "This guy is the devil. Get him," he said.
For Frame, there was a potential personal stake: He lives near the site of the fire, a Citizen spokesperson confirmed.
But it turned out the person was wanted only for questioning, not as a suspect. The company said it received information about a person of interest from a police sergeant '-- including the man's identity and a photo '-- and that its staff members concluded prematurely, on their own, that he was a suspect. The information did not come through the Los Angeles Police Department's designated public information officer, and it's not clear if a Citizen staff member spoke personally with the sergeant or how the company communicated with authorities in the case.
"Typically, we verify information with the appropriate agencies; in this case, we moved too quickly after receiving information about a person of interest, from an LAPD Sergeant, and did not follow our strict protocols for verifying information with the appropriate public safety agencies," Citizen said in a statement.
The reward was potentially "disastrous" because it could have led to someone getting hurt, the Los Angeles sheriff's office said. Sheriff's deputies eventually found the man and released him because they did not have evidence to charge him, according to Spectrum News. They later charged someone else with starting the blaze.
But Citizen isn't ruling out more rewards in the future. The company said it was evaluating the impact and usefulness of offering rewards and would move forward in a way that benefits public safety.
Private securityAnother idea to emerge at the startup recently was Citizen Protect, a $20-a-month service that would give subscribers the ability to call a Citizen staff member at any time as kind of a digital bodyguard. The staff member could video-chat during a walk home at night, for example. Two of the former employees said the idea was panned by some internally as not a product many people would pay for.
Citizen said the Protect product was still being tested, and that as of now, the company has no plans to launch its own private security force. The SUV in Los Angeles was a promotional vehicle and the only one used as part of a pilot project, according to Citizen. "We are constantly testing new ideas," the company said.
The churn of ideas coincided with a nearly wholesale turnover in senior management during 2020, according to interviews with former employees and profiles on LinkedIn.
Luis Samaniego, a Citizen co-founder, left last year to work at a company that makes retail checkout software. He declined an interview request. And others who left last year included the head of design, the head of growth and the head of product '-- accounting for many of Frame's direct reports. The senior staff members who remained included the head of engineering, the head of central operations and Frame himself.
"The upper management kept changing repeatedly, to the point where I just stopped keeping track of who had what title," said one of the former employees.