The race for the antibodies that stop the new coronavirus begins | Science

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By Jon CohenMay. 5, 2020, 6:10 PM

Science’s COVID-19 reports are supported by the Pulitzer Center.

One of the first people to be diagnosed with COVID-19 in the United States hopes that the legacy of her nightmare, the antibodies she left in her blood, will lead to a medication that can help others infected with the new coronavirus who has now killed more. 250,000 people worldwide.

Earlier this year, the woman had just learned of the outbreak in Wuhan, China when she flew to Beijing to celebrate the Lunar New Year with her older parents and extended family. A brother from Wuhan joined the meeting on January 23, taking one of the last flights before the city closed. Days later, her father developed a fever, but the family was not worried. “My father always has some fever in the winter,” says the woman, an investigator who asked to be called Dr. X to protect her privacy.

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On January 28, her brother also developed a fever.

The next day, on her scheduled flight home, a nervous doctor X wore a mask, brought disinfectant wipes, and cleaned everything she touched, and did not accept any food or drink from flight attendants. “I treated myself as a possible infectious source.”

Her husband picked her up from the airport wearing a mask. With the car windows down, they drove to an emergency room to request a coronavirus test. “I didn’t have a fever, so they really didn’t take me seriously,” she says. But coincidentally, his brother texted him while waiting to be seen: he had COVID-19. Then she received a test. Days later, after she was quarantined, developed mild symptoms of COVID-19, and then recovered, the result was positive.

By then, her brother and father had been hospitalized. The brother recovered after 12 days, but his father, a retired scientist in his 80s, went from a ventilator to extracorporeal membrane oxygenation, a type of artificial lung. The new coronavirus, SARS-CoV-2, finally infected the seven family members who had gathered for the New Year celebration.

Dr. X was unable to help her sick relatives, but her eagerness to do so something She grew up. She knew that in China, the plasma of recovered people, which contains antibodies against the virus, seemed promising as a treatment. Her doctor told her about a project, a collaboration between Vanderbilt University and AstraZeneca, to develop something safer and more powerful. Its objective is to go beyond the mixture of antibodies in the convalescent plasma and extract the equivalent of a guided missile: an antibody that “neutralizes” the infectivity of SARS-CoV-2 by binding to the so-called spike protein that allows it to enter cells Human Once one or more neutralizing antibodies have been identified, antibody-producing B cells can be engineered to produce them in quantity. These so-called monoclonal antibodies could treat or even prevent COVID-19.

The Vanderbilt-AstraZeneca team is far from the only group trying to identify or design monoclonal against SARS-CoV-2. Unlike the many reused drugs now being tested in patients with COVID-19, including moderately effective remdesivir, immune proteins specifically target this virus. While some groups hope to screen a neutralizing antibody (a “walnut”) from the blood of a survivor like Dr. X, others are trying to produce a walnut in mice by injecting them with the spike protein. Others aim to redesign an existing antibody or even create one directly from DNA sequences.

Many researchers are optimistic that the antibodies, relatively quickly, will prove their worth as a preventative or world-time remedy until a vaccine arrives, if at all. “We have at least 50, and probably more than we don’t know, academic companies and labs that are all racehorses,” says immunologist Erica Ollmann Saphire of the La Jolla Institute of Immunology, who is leading an effort to coordinate and evaluate These candidates, Regeneron Pharmaceuticals, who developed a cocktail of three monoclonal antibodies that worked against the Ebola virus, a notoriously difficult disease to treat, may walk out the door first with a candidate monoclonal drug entering clinical trials as early as next month.

Saphire says there are many questions left. “We need an idea of ​​the big picture: what are the most effective antibodies against this virus? If we need a cocktail of two, what is the most effective combination? she asks. “And you may want a very different type of antibody to prevent infection compared to treating an established one.”

John Mascola, immunologist at the US National Institute of Allergy and Infectious Diseases. USA (NIAID) adds that the antibodies may also have non-neutralizing and stimulatory properties of the immune system. “The field doesn’t know much about protective immunity against SARS-CoV-2,” says Mascola. “So there are some scientific guesses here.”

On a practical level, monoclonals are relatively difficult to make and manage; they must be given intravenously or injected, and traditionally high-cost specialty drugs have been available mainly in wealthy countries. “Monoclonals can play a huge role,” says Jeremy Farrar, director of the Wellcome Trust charity and an infectious disease specialist. “The big questions will be the ability to scale, distribute and cost.”

On March 7, Dr. X visited the Vanderbilt Laboratory run by James Crowe to donate blood. “I really couldn’t help my dad,” says the woman. “It was too late. So I want to make sure that fewer people have to go through what my family went through.”

Her father died 9 days later.

From Ebola to COVID-19

Although monoclonal antibodies for treating cancer and autoimmune diseases are a booming business, so far few have made it to the market for infectious diseases. One prevents respiratory syncytial virus in babies, two prevent and treat anthrax, and the other helps HIV-infected people for whom standard medications have failed. But Regeneron’s monoclonal cocktail for Ebola offers an example of its power. It proved its worth in a study conducted in the Democratic Republic of the Congo (DRC) last year and could be approved by the US Food and Drug Administration. USA Within 6 months. And a single monoclonal antibody developed by a NIAID team that included Mascola prevented the Ebola virus in the same DRC study. No other treatment, including medications and convalescent plasma, had worked against Ebola.

Crowe says treating millions of people around the world with a monoclonal is not far-fetched. “In the past, fully human antibodies were difficult to isolate and expensive to produce,” he notes. But it is getting easier and cheaper. “Over the next 5 years, antibodies will become the primary tool used as a medical countermeasure in the event of an epidemic,” he predicts.

First, however, Crowe and others need to find potent monoclonal against SARS-CoV-2. It usually takes several weeks for an infected person’s B cells to start pumping nuts. For the delay. Crowe’s team, one of four funded by the Pentagon’s Defense Advanced Research Projects Agency (DARPA) to discover monoclonal for emerging infectious threats, searched for the first people in the United States to confirm SARS-CoV infections- 2, including Dr. X. The team isolated the antibody-producing B cells from their volunteers and used the spike protein, attached to a magnetic bead, as bait for the small percentage nut production against SARS-CoV-2.

When Dr. X initially bled, about 6 weeks after she became infected, those special B cells were only barely detectable. On the way to the airport on a Sunday morning to fly home from Nashville, Dr. X stopped by the lab for another hemorrhage, and they eventually found gold.

A second DARPA-funded group, AbCellera Biologics of Canada, uses a herringbone version that Mascola and her coworkers carefully designed as walnut bait. To isolate individual B cells, the AbCellera group places copies of this peak in 200,000 liquid-filled chambers in a device the size of a credit card. From the blood of an early case of US COVID-19. USA In Seattle who had severe illness, AbCellera initially found 500 candidate antibodies against the spike. The company reduced them to 24 leads, selecting those that retain their shape when mass produced and stick to the viral protein longer. (Antibodies bounce off and on their targets.)

Regeneron has also bled patients recovered from COVID-19, but is also testing an alternative strategy: injecting a peak into mice equipped with human genes for antibody production. From a group of antibodies derived from humans and mice, the company plans to select two that neutralize a wide range of SARS-CoV-2 variants. Regeneron targets a pair of antibodies that also bind to non-overlapping sites on the spike, says Christos Kyratsous, Regeneron’s vice president of research. This type of antibody cocktail provides an insurance policy against the appearance of mutant strains of SARS-CoV-2 that resist treatment. “It is unlikely that both sites [on spike] they are going to change at the same time, “says Kyratsous.

Although Regeneron designed a three-antibody cocktail for Ebola, Kyratsous says the company decided to limit its COVID-19 cocktail for practical and strategic reasons. The more antibodies needed, the more difficult manufacturing problems will be and the higher the price. And the probable Achilles heel of the spike, a region at its tip known as the receptor binding domain (RBD), is so small that a third antibody could be wasted. “It can accommodate approximately two antibodies independently of each other,” says Kyratsous.

AstraZeneca, in addition to testing the blood of recovered patients and spike-injected mice, is reviewing a massive library of essentially randomized antibodies created with a method involving viruses called phages. Most groups assume that effective antibodies should be directed at RBD. But Mark Esser, vice president of AstraZeneca, says: “We have found interesting antibodies that bind to other parts of the spike protein.” Mene Pangalos, executive vice president of pharmaceutical R&D at AstraZeneca, says they, too, want to make a cocktail. “And it may end up being a cocktail that includes antibodies from other companies.”

Virtual antibody fishing

Research groups are also looking for clues to coronavirus diseases such as severe acute respiratory syndrome (SARS) and respiratory syndrome in the Middle East. Vir Biotechnology, for example, has found an antibody in a recovered SARS survivor from 2003 that neutralizes SARS-CoV-2. This antibody binds to a region of the RBD that is “highly conserved” between the two coronaviruses, their researchers report in a preprint published online on bioRxiv on April 9. The company went on to modify the antibody to make it more potent. A modification slows down the degradation of the antibody to give it a longer effective life; Another improves the so-called vaccine effect, which calls up T cells, another arm of the immune system, to help destroy infected cells.

Jacob Glanville, an immunologist and computer scientist who runs Distributed Bio, has engineered nuts for SARS-CoV-2 on a computer, based on genetic sequences and structures known to frustrate the SARS virus in cells and even cells. mice. “Basically I can get a free ride on [past] investigate in a very short time, “says Glanville.

With molecular modeling software, Glanville mutates antibodies to the SARS virus in billions of variants. And using phages as well, Glanville’s group created an even larger library of antibodies that could work. The researchers then analyzed what Glanville calls “this vast mutational gap” for the antibodies that bind to the SARS-CoV-2 peak, they identify 50 leads that they are testing in vitro. They hope to select the best 13 candidates soon.

Glanville says the goal is to find antibodies that can potently neutralize a wide range of coronaviruses. “The exercise here is to approve a medication that will protect us from this current outbreak, but also allow us to have a tool at our disposal immediately when the next coronavirus outbreak occurs.” That way, he says, “We don’t have to play this game every time.”

The burden of choice.

With so many monoclonal COVID-19s in development, “How do you know what’s best and why?” Saphire asks. The $ 1.7 million Coronavirus immunotherapy consortium he leads, funded by the Bill & Melinda Gates Foundation, is organizing a large-scale, blind, parallel evaluation of monoclonal candidates in test-tube studies evaluating their ability to thwart SARS-CoV -2 infection of human cells. The consortium also plans to compare top candidates in animal models, but needs funds for that costly effort.

A doctor in northern Italy who recovered from COVID-19 and who, like Dr. X, contributed his own plasma to the search for AstraZeneca antibodies, emphasizes that it is far from a fact that monoclonal drugs will work. “We don’t know the role of neutralizing antibodies in this disease,” says the doctor, who asked not to be identified because of his hospital’s concerns about the publicity. He is also personally familiar with the cost and scarcity of existing monoclonal drugs – his hospital has already struggled to obtain calming immune monoclonal drugs for COVID-19 patients who were having dangerously strong immune reactions to the virus.

An effective COVID-19 vaccine could, in the long run, eliminate the global need for monoclonal antibodies against SARS-CoV-2. But Pangalos says that perspective does not concern his company. That would be “fantastic,” he says, stressing that AstraZeneca did not start this project for strictly commercial reasons. “It is important for one of us to resolve this pandemic so that we can all return to normal.”