The Race Is On to Find the Holy Grail of Covid-19 Antibodies
Lab-made antibodies could be our best hope against the pandemic — and future ones
Carl Hansen was in the middle of running a pandemic simulation at AbCellera, the Vancouver biotech company where he is CEO, when the first reports of a mysterious respiratory disease trickled out of China.
It was mid-January, and the Canadian company was testing how quickly it could find promising antibodies against the coronaviruses that cause MERS and SARS. Its goal was to identify and reproduce these antibodies — proteins produced by the immune system in response to an infection — within 60 days. But when the first U.S. case of Covid-19 was detected on January 21 in Washington state, Hansen cut that simulation short to focus on the new threat.
“Then the missing piece was to find a blood sample,” he tells OneZero. After AbCellera got its hands on a small vial of blood from an early U.S. Covid-19 patient on February 28, Hansen and his team immediately started looking for antibodies in it.
Now, he and other scientists are racing to find potent antibodies in the blood of human Covid-19 survivors, in lab mice, and in other animals. The hope is that the most effective ones — known as neutralizing antibodies — could be used to both treat people who are sick with the disease and also act as a kind of temporary vaccine for those who are at high risk of contracting it. Though one drug for Covid-19, remdesivir, was granted emergency use authorization from the Food and Drug Administration, experts say it’s not a knockout punch against the virus. With a vaccine at least a year away, more treatments will be needed.
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In the absence of a vaccine, some think lab-produced antibodies that mimic the real thing are the best hope for beating back the coronavirus, as well as any new infectious pathogens that could emerge in the future. When the body detects a foreign invader, like SARS-CoV-2, it mounts an immune response and starts making a host of antibodies that are specific to the invader. Neutralizing antibodies are particularly good at helping the body fight off infection.
Scientists want to use one or a few of these neutralizing antibodies as a drug to help those hospitalized with Covid-19 recover more quickly, or prevent people who are exposed to the virus from getting sick in the first place.
The trick, though, is finding the right antibodies. Singling them out and analyzing them used to take years of research. But new technology is speeding up the process so much that it now takes days or weeks. Now, a handful of companies are already manufacturing SARS-CoV-2 antibodies and plan to start testing them in people by summer.
The notion of using antibodies to treat infections dates back more than a hundred years. In the 1890s, scientists started treating people with serum, or plasma — the clear part of the blood that contains antibodies — taken from horses that had been immunized against diseases like diphtheria and tetanus. It proved to be a life-saving approach, and it earned the scientist who spearheaded its use, Emil von Behring, the first Nobel Prize for Medicine in 1901.
During the 2014-2015 Ebola outbreak, doctors used plasma from survivors to treat patients with the disease. Now, this approach is being tried for coronavirus patients in the United States and elsewhere.
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But, the process has its downsides. Collecting plasma from Covid-19 survivors and getting it to all the people who are sick or have been exposed to the disease is difficult to scale. Plasma also contains molecules other than antibodies that might not be helpful in treating disease. Those pursuing antibody therapies think they can make a more potent treatment by singling out the powerful antibodies and producing them en masse.
Identifying neutralizing antibodies is like searching for a needle in a haystack. “If somebody is infected with a virus, they make hundreds of thousands of different antibodies,” says Christos Kyratsous, vice president for infectious disease research at Regeneron, a New York-based biotech company developing antibody drugs for Covid-19. “Some of them are extremely good at blocking the virus. Some of them are horrible.”
The huge range of antibodies produced by the immune response explains why there are still a lot of unknowns about how immunity to the coronavirus works. The mere presence of antibodies in the blood doesn’t necessarily mean a person is immune. Rather, immunity likely comes down to what kind of antibodies and how many of those antibodies a person has — and even then, it isn’t clear how long immunity lasts.
Scientists are now looking for antibodies that can neutralize the virus by binding to the so-called “spike” protein on the virus’s surface. This spike has been a major focus of Covid-19 research because it’s instrumental in helping the virus attach to human cells, allowing it to get inside. But it’s still unproven whether a drug that binds to the spike protein will prevent infection in people or help them recover faster.
“It’s not enough to say you found an antibody against the virus,” Hansen says. “You have to find one that binds to it — and strongly — so that it can neutralize that virus at a very low concentration.”
After the blood sample arrived at AbCellera’s headquarters on February 28, the company immediately began screening the 5 million immune cells it contained. Less than two weeks later, its lab had identified 500 different neutralizing SARS-CoV-2 antibodies. Since then, the list of promising candidates has been narrowed down to 24.
Hansen and his team used a “lab-on-a-chip” device that can isolate 200,000 single human immune cells into tiny reaction chambers. Those immune cells pump out antibodies, which are then analyzed with machine learning algorithms to determine whether they have properties that would make for a good drug.
In mid-March, AbCellera partnered with pharma giant Eli Lilly to further develop and manufacture the antibodies. They hope to begin testing an antibody drug in human clinical trials by July or possibly sooner.
Meanwhile, at Regeneron, Kyratsous and his team turned to a strain of genetically engineered mice to discover antibodies. The mice are bred to have certain human genes that provide instructions to make antibodies; that way, when the mice are deliberately infected with a virus or other pathogen, they produce human antibodies. The company then looked for the most potent antibodies in these mice. To be sure they had found the right antibodies, they compared the mouse-derived antibodies to those from blood samples of real Covid-19 patients.
“As expected, we saw that the antibodies from humanized mice and the antibodies from the previously infected humans are very similar in terms of properties,” says Kyratsous. “So we chose the best antibodies out of those.”
Regeneron has selected two antibodies for a drug cocktail and expects to begin clinical trials in June to test it in people infected with Covid-19. Other biotech and pharma companies like Amgen and Vir Biotechnology are also racing to produce antibody drugs that could be tested on Covid-19 patients as soon as this summer.
Academic scientists are aiding in the search for antibodies, too. Researchers at Vanderbilt University led by immunologist James Crowe used technology developed by California-based Berkeley Lights to identify 500 unique SARS-CoV-2 antibodies in a single day. The $2 million system uses small, fluid-filled microchips and fluorescent light to guide and separate thousands of immune cells at time so that they can be analyzed. Vanderbilt has since teamed up with AstraZeneca to advance the most promising of those antibodies.
“Nobody should be super confident at this point that they’ve found the right antibody,” says Eric Hobbs, CEO of Berkeley Lights. “The more patient samples we can get, the more unique antibodies we can find and the better chance that the world has at having a therapy,” he says. The company, along with Vanderbilt, Emory University, and the La Jolla Institute for Immunology, have formed a consortium to discover and develop antibodies for the coronavirus, as well as new pathogens that could emerge in the future.
Scientists hope to use antibodies in two ways: as a treatment for hospitalized patients and as a short-term vaccine for frontline health care workers. Using it as a temporary vaccine would prime the immune system, so that when it encounters the virus, the antibodies needed to fight it are already there. This approach could potentially prevent infection entirely, or at least lessen a person’s symptoms if they do get sick.
For those who are already sick with Covid-19, experts aren’t yet sure which people will benefit most from antibody drugs. “At the later stages of disease, it’s yet unknown if a really potent antibody would be able to change the course of disease,” says Hansen. “It’s highly likely that early in disease, or even before disease, an antibody could either prevent someone from getting sick or prevent them from getting very sick.”
Researchers also don’t know what dose of the drug to give to patients. The amount of antibody needed to treat someone who’s already sick will probably be much higher than the dose required to prevent someone from getting sick, explains Hansen, because “the virus has not yet taken a toehold and so it’s not as hard to fight it off.”
Phyllis Kanki, a professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, says the work on antibodies looks promising but thinks a combination of therapies that includes antibodies and other drugs might be the best approach to treating patients with severe Covid-19 symptoms.
“Antibodies in general have been very effective at bringing virus [levels] down if you’ve had a high burden of infection,” she says. But she notes that the effects appear to be temporary. “There are limitations to how much you can give and for how long.”
She points to an antibody drug for Ebola patients, which was effective at reducing the risk of death but seemed to require long intravenous infusions to keep the virus at bay. The drug, a cocktail of three antibodies, was developed by Regeneron.
Even if these antibody drugs work in upcoming trials, however, it’s possible that SARS-CoV-2 could mutate in a way that renders them ineffective. Each time the virus replicates, its sequence changes a little bit. An antibody would be virtually useless if it targets a particular place on the virus that ends up mutating. That’s where an antibody cocktail, like the one Regeneron is developing, could come in handy. If the virus changes slightly and evades one antibody, the second one is “basically an insurance policy,” says Kyratsous.
Another way to mitigate the potential for mutation is to look for broadly neutralizing antibodies, which can block multiple strains of a virus, but are much harder to find. These antibodies have been of considerable interest in HIV research because that virus mutates rapidly, but they come with a downside. Hansen says these antibodies tend to be less potent, meaning you’d likely need a lot more of them to make an effective treatment.
Antibody drugs are also difficult to manufacture. It takes months to grow the cells needed to produce a large volume of antibodies. This complex manufacturing process means antibody drugs are also expensive. A 2018 study that compared prices of antibody therapies from 1997 to 2016 found that the average annual price was $96,731.
If antibody drugs work, they could stem the tide of coronavirus infections and provide short-term immunity to people who need it until an effective vaccine is available. But that means manufacturers will need to figure out a way to produce the millions of doses that could be needed to treat patients and protect at-risk healthcare workers in the coming months and years.
Hansen says the process of finding and testing antibodies will get even quicker in the future. With technology that could rapidly identify effective antibody drugs and manufacturing capabilities to produce them on demand, the world could be ready for the next coronavirus or other infectious disease outbreak.
“We will see more pandemics,” he says. “And there will certainly be a day where we can go much faster than we can today.”