How Regeneron's COVID-19 antibody cocktail cuts the risk of resistance

When Regeneron said in March that it would speed an antibody treatment into clinical trials for COVID-19, its scientists insisted a cocktail of two antibodies would be more effective than one alone. Now they're explaining why they chose the two antibodies that moved into human trials last week.

The reason, in short, was to thwart the ability of SARS-CoV-2, the virus at the heart of the pandemic, to mutate and cause patients to become resistant to treatment. The two antibodies Regeneron selected, REGN10933 and REGN10987, were less likely to generate “escape mutants” than individual antibodies or other cocktails the company’s scientists tested, they reported (PDF) in the journal Science.

Regeneron started the antibody selection process by using mouse models and B cells from people who contracted COVID-19 to generate a large library of antibodies that could neutralize the virus by targeting the spike protein on its surface. They narrowed down the selection to eight of the most potent antibodies.

From there, they used a “pseudo” SARS-CoV-2 virus to test the eight antibodies at various concentrations, waiting for escape mutations to develop. That’s when they discovered that the only way to stop the mutations from forming was to use a cocktail of antibodies that did not try to bind to the same region of the spike protein in order to neutralize the virus.

REGN10933 and REGN10987 bind to non-overlapping regions of the target protein, the Regeneron team reported, which “may provide enhanced protection against loss of efficacy,” they wrote in the study.

RELATED: Regeneron starts testing COVID-19 antibody cocktail in humans

Regeneron’s human trial of its anti-COVID cocktail, called REGN-COV2, is an adaptive phase 1/2/3 program involving both hospitalized and nonhospitalized patients. The company will use data generated in phase 1 and 2 to fine-tune the phase 3 portion of the study and determine how large it should be, the company said.   

The scientists noted in the Science study that because SARS-CoV-2 is an RNA virus, the risk that it can become mutated over time is high. Using two antibodies instead of one holds value because for the virus to escape treatment, it would “require the unlikely occurrence of simultaneous mutations at two distinct genetic sites,” they argued.

Regeneron has not let up on its effort to develop an antibody cocktail against COVID-19 in spite of the U.S. government’s push for a vaccine to come to market this year. Regeneron Chief Scientific Officer George Yancopoulos has said that he believes an antibody treatment could be developed more quickly than a vaccine and could still be useful in the long run to protect certain patient groups.

In fact, Regeneron is simultaneously testing REGN-COV2 in a trial designed to determine if it can prevent infection in people who are exposed to COVID-19 patients, such as healthcare workers.

Regeneron has plenty of competition in the COVID antibody race. Eli Lilly launched a phase 1 trial of its AbCellera-partnered LY-CoV555 earlier than expected. AstraZeneca is planning to start clinical trials of a two-antibody combo it developed with the help of Vanderbilt University researchers. And GlaxoSmithKline is working with Vir Biotechnology to quickly advance two antibodies into a phase 2 trial.