Searching for a coronavirus cure in the blood

The blood of people who have recovered from COVID-19 may be the world’s most sought-after substance right now. It contains a stockpile of antibodies made by immune cells that have successfully mounted an attack on the invading virus, SARS-CoV-2. While multiple efforts are focusing on repurposing existing drugs, like remdesivir or chloroquine, to fight this new virus, many scientists think that the fastest route to novel therapies specifically designed to treat the infection could come by harvesting those antibodies.

These antibody-based therapies could take many forms. The simplest, and the only that is already being tested in people with COVID-19, is convalescent plasma, the antibody-rich portion of blood donated from someone who recovered from the disease. At the other end of the spectrum, companies are meticulously analyzing plasma from recovered humans or immunized animals to select the very best antibodies, which they can use to manufacture traditional monoclonal antibody therapies. These approaches, and others in between, are barreling toward the clinic at a pandemic pace.

The antibody-based therapy that could reach people with COVID-19 the fastest is convalescent plasma, the clear, yellowish, protein-filled portion of the blood collected from people who have recently recovered from an infection. Potential donors must wait at least 14 days for their symptoms of COVID-19 to clear and then must test negative for the virus and positive for antibodies for SARS-CoV-2 before donating their plasma.

“It’s an idea that goes all the way back to the Spanish flu of 1918,” says Warner Greene, a virologist at the Gladstone Institute of Virology and Immunology. It’s been used with varying degrees of success for many infectious diseases, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola virus disease. “It is not a cure,” Greene says. “It just buys you enough time to make your own antibodies.” And that could be particularly important for older people, whose immune systems don’t mount as vigorous of an immune response.

On March 27, a team of researchers at the Shenzhen Third People’s Hospital in China published a tiny observational study showing that five people with COVID-19 who received convalescent plasma improved (JAMA, J. Am. Med. Assoc. 2020, DOI: 10.1001/jama.2020.4783). Hospitals in Houston and New York City began providing convalescent plasma to people with COVID-19 the next day.

A few days later, on April 3, the US Food and Drug Administration announced a new, coordinated national effort to streamline access to convalescent plasma. The Mayo Clinic is the contact point for donors and for doctors requesting convalescent plasma, and the American Red Cross is collecting and distributing the plasma. A number of hospitals and universities in the US are planning clinical trials to assess the technique’s effectiveness.

“There will be anecdotal data from very ill patients who receive convalescent plasma over the next few weeks that may provide hints about efficacy,” says Jeffrey Henderson, an infectious disease biochemist at Washington University in St. Louis. “It is also possible that the disease will be too far advanced in many of these patients for plasma to be very helpful. There are many unknowns about COVID-19. We are gaining knowledge in a rapid, but piecemeal, manner right now.”

Other groups are collecting convalescent plasma as the base ingredient for a refined product that companies call hyperimmune globulin, in which the antibody fractions of plasma donations are isolated and pooled into a concentrated therapy. “It is much more potent than convalescent plasma,” says Christopher Morabito, head of R&D for Takeda Pharmaceutical’s Plasma-Derived Therapies Business Unit.

Takeda and CSL Behring, two companies that control about half the market for plasma-derived therapies, and four smaller companies formed an alliance at the beginning of April to begin collecting convalescent plasma to make a single, unbranded hyperimmune therapy. Emergent BioSolutions, Grifols, and SAB Biotherapeutics are all developing their own hyperimmune therapies for COVID-19 with support from the US Biomedical Advanced Research and Development Authority.

CSL, Emergent, Grifols, and Takeda all sell approved hyperimmune therapies intended to treat immunodeficiency diseases or specific pathogen infections, like anthrax and rabies, and all are banking on expedited clinical trials and regulatory reviews of their COVID-19 treatments. Morabito says Takeda plans to skip safety studies in humans and smaller studies to gauge efficacy and jump right into a Phase III trial this summer. Emergent, meanwhile, is aiming to start a Phase II trial in September, if the company can start manufacturing this summer, says Laura Saward, head of the Antibody Therapeutics Business Unit at Emergent. “The overall timeline is really dependent on getting sufficient sources of plasma,” she adds.

Although convalescent plasma can be deployed to help people with COVID-19 more quickly than hyperimmune therapy, the concentration of antibodies in the plasma that target SARS-CoV-2, and thus the plasma’s potency, will vary from donor to donor. Saward says that hyperimmune therapies, which pool antibodies from many donors, will be designed to have more consistent antibody levels and will hopefully work more predictably.

Companies say it is too soon to know how many patients can be treated from one plasma donation, but it is likely no more than a few, at best. Emergent is hoping to avoid potential delays in plasma collection by also producing hyperimmune globulins in horses vaccinated with whole or partial bits of SARS-CoV-2. SAB takes this concept a step further, fully relying on its herd of genetically engineered cattle in Sioux Falls, South Dakota, as the source of its experimental hyperimmune therapy for COVID-19, which it expects will be ready for clinical testing this summer.

Others hope to avoid any supply limitations from donors—whether human, equine, or bovine. David Johnson, CEO of GigaGen, calls the hyperimmune approach “old school.” Hyperimmune therapies are one kind of polyclonal antibody therapy, in which many different antibodies targeting a virus are produced by many different B cells. GigaGen specializes in polyclonal antibody therapies that can be manufactured at scale in bioreactors. The start-up will collect blood from about 50 to 100 people that have recovered from COVID-19, find B cells that make antibodies for SARS-CoV-2, and then copy the genes from those B cells into genetically modified cell lines that crank out these virus-targeting antibodies in bioreactors.

GigaGen’s polyclonal antibody approach is comparable to traditional monoclonal antibody production, except instead of mass production of a single antibody, GigaGen’s product would likely contain thousands of different antibodies. It’s like “re-creating the entire immune system” in a drug, Johnson says. He hopes to begin manufacturing in July and start clinical trials in early 2021. The therapeutic and manufacturing strategy is unproven, however, and its COVID-19 program could be the start-up’s first therapy tested in humans.

But convalescent plasma is useful only if there are people around who have recovered. Furthermore, scientists say that our immune system often doesn’t make its best antibodies until a couple of weeks after recovery. Amid a budding pandemic, waiting a month or more for the first samples seems too slow.

So scientists are trying to sift through the many antibodies produced by our immune cells to identify the most effective ones—the so-called neutralizing antibodies, which bind to a pathogen and keep it from infecting cells. Some combination of those in theory could be turned into a drug. And researchers already have experience identifying neutralizing antibodies from similar coronaviruses—the ones that cause SARS and MERS.

Indeed, when SARS-CoV-2 hit, some companies first turned to these SARS and MERS neutralizing antibodies. Vir Biotechnology began screening SARS and MERS antibodies in late January, and by mid-February, it found two that neutralized SARS-CoV-2. Vir has since struck partnerships to bring those to patients: a pact with WuXi Biologics and Biogen will prepare for manufacturing those antibodies, while a deal with Xencor centers on technology to make the antibodies circulate in the bloodstream longer. In April, GlaxoSmithKline made a $250 million investment in Vir and agreed to help speed up the development of Vir’s two antibodies. Vir expects clinical trials could begin this summer, as soon as July.

The rapidity of the discovery, dealmaking, and translation to the clinic highlights the urgency companies are feeling during the pandemic. And although no SARS therapy has ever been approved, Vir’s speed can be partly attributed to the fact that it had several SARS antibodies on deck.

But some scientists doubt that these old antibodies will be useful for treating COVID-19.

“I have yet to see a drug that can be used against two viruses and be efficacious,” says Christos Kyratsous, head of infectious disease research at Regeneron Pharmaceuticals. It’s possible to design drugs that target multiple coronaviruses, he says, “but the broader you get, the harder it is to discover something that is important.”

That’s why most groups are focusing on neutralizing antibodies that are designed specifically for SARS-CoV-2. Industry and academic labs are taking a variety of approaches to discover monoclonal antibodies or concoct cocktails of these antibodies to treat COVID-19. Regeneron has emerged as a leader in the monoclonal antibody race by taking a somewhat unique approach. The company uses mice that are genetically engineered to produce human antibodies when exposed to a virus. It’s the same approach Regeneron used to discover three monoclonal antibodies for the Ebola virus during the 2014 outbreak.

Those antibodies were used in an experimental treatment called REGN-EB3 during the Ebola outbreak in the Democratic Republic of the Congo in 2018 and 2019. The trial was stopped early because of overwhelming evidence that Regeneron’s therapy saved significantly more lives than ZMapp, another trio of monoclonal antibodies. Regeneron plans to submit REGN-EB3 to the FDA for review this year.

Motivated by its success with Ebola, Regeneron began a monoclonal antibody discovery program for SARS-CoV-2 soon after the virus’s genome was posted online in mid-January. Regeneron had previously worked on two antibodies for the MERS coronavirus in 2016. Like other coronaviruses, the one that causes MERS binds to the surface of human cells using its spike protein. Since some antibodies that target the spike proteins of the viruses that cause SARS and MERS can prevent the viruses from infecting cells, Kyratsous’s team decided to look for antibodies that bind the SARS-CoV-2 spike protein.

In early February, Regeneron scientists began immunizing its genetically engineered mice with the SARS-CoV-2 spike protein, produced with the genetic instructions in the virus’s genome. After the mice mounted a strong antibody response to the spike protein, the team began isolating B cells from the mice and screening them to find the most potent mouse-produced antibodies against SARS-CoV-2. “We screened 3,000 or 4,000 and ended up with a few hundred that block coronavirus entry into cells,” Kyratsous says. In late March, the team began winnowing that number down to find the top two that bind to nonoverlapping sites of the spike protein. The company will also isolate antibodies in human convalescent plasma to compare them to the best mouse antibodies.

While that work is ongoing, other scientists at Regeneron are already preparing the cell lines that will ultimately be used to manufacture its top two antibodies. The parallel work is necessary if the biotech firm is to meet its ambitious timeline of having its first batch of antibodies ready for clinical testing in June.

Kyratsous says that Regeneron is looking to study its top antibodies in mouse and monkey models of COVID-19 in late May or early June, meaning that these animal studies will likely start soon before, or at the same time as, a clinical trial. Regeneron’s urgency to get its antibodies tested in humans will reflect the severity of the pandemic at that time, Kyratsous says. “It will be a risk-benefit calculation.”

The COVID-19 pandemic is testing the limits of what rapid drug development means. Monoclonal antibody programs initiated in January or February that begin testing this summer will set records for their speed. But even with that speed, manufacturing monoclonal antibodies and scaling up to larger batches is laborious and time consuming.

Long before this pandemic began, a division of the US Department of Defense had been working with academic and industry partners to develop a plan to go from pathogen identification to human testing of a new therapy in just 60 days.

In late 2017, the Defense Advanced Research Projects Agency (DARPA) launched its 4-year Pandemic Prevention Platform (P3) program. Its mission was “to halt the spread of any infectious disease outbreak before it can escalate into a pandemic.”

Four separate teams at AbCellera Biologics, Duke University, MedImmune, and Vanderbilt University were chosen to develop tools and strategies to complete two tasks: first, rapidly identify antibodies that can neutralize a new pathogen; and second, encode the antibody in DNA or messenger RNA (mRNA) for injection into a human, where that nucleic acid code will transform an individual’s cells into a personal drug factory. DARPA P3 program manager Amy Jenkins anticipates that these nucleic acid therapies can be manufactured much more quickly than traditional antibodies.

Each year, the program has researchers put their technological developments to the test with a mock challenge. In January 2019, the groups were given convalescent plasma from survivors of the Zika virus. This January, Jenkins was visiting one of the P3 teams at the Vanderbilt Vaccine Center just as it was gearing up for a new challenge. After the first coronavirus case hit the US a few days later, the team decided to skip the trial run and try to make an antibody therapy for real.

James Crowe and Robert Carnahan, the director and associate director of the Vanderbilt Vaccine Center, respectively, began feverishly reaching out to health-care providers and local health authorities to pin down some of the earliest cases of COVID-19 in North America to identify recovering patients who might donate their plasma. The Vanderbilt team eventually got four samples that it has used to identify about 1,500 antibodies that target SARS-CoV-2. Now the researchers are working with academic collaborators to determine which of those antibodies are best at neutralizing the virus.

AbCellera, another P3 group, received its first convalescent plasma sample on Feb. 25. Within 8 days, the start-up had identified 500 unique antibodies that bind the SARS-CoV-2 spike protein. AbCellera is now screening them with its partners at the National Institutes of Health to see which ones are the best at neutralizing the virus. The pharma firm Eli Lilly and Company has committed to manufacturing the best ones for clinical trials, which may start by late July.

Jenkins says that the P3 groups will stick to making traditional antibody therapies during this pandemic rather than encoding them in DNA or mRNA. “These technologies are still fairly risky,” she says.

But even traditional monoclonal antibodies are relatively unproven as infectious disease treatments. The drugs are typically expensive to produce, and although several experimental monoclonal antibodies have been made, only one—MedImmune’s palivizumab, which prevents respiratory syncytial virus (RSV) infections in children—has demonstrated it can prevent infectious disease in humans.