A COVID-19 treatment from Regeneron Pharmaceuticals that consists of a pair of monoclonal antibodies sometimes fails to bind to antigens produced by the concerning B.1.351 variant of SARS-CoV-2, according to a preprint posted February 19 to bioRxiv.
In lab experiments, the researchers found that nine times fewer antibodies within the cocktail bind to B.1.351’s antigens than to antigens from the most common circulating version of the virus. This means that a treatment for B.1.351 would need to be nine times as large to yield the same level of viral neutralization.
“It certainly raises a concern,” says Nathaniel (Ned) Landau, a microbiologist at the New York University Grossman School of Medicine and the lead author of the study. “When the titer goes down ninefold, it could make it not work as well.” Given that his study was conducted in vitro, Landau notes that the only way to know this for sure is to determine the clinical effects of the cocktail on patients infected with the B.1.351 variant, which first emerged in South Africa.
“One could treat patients with 9-fold more antibody, but it becomes too expensive and very unhealthy to inject such a large amount of a protein,” Landau adds in a follow-up email.
Regeneron’s drug is a one-time infusion of a combination of the antibodies REGN10987 (casirivimab) and REGN10933 (imdevimab). It received emergency use authorization (EUA) in November 2020 for people with mild to moderate COVID-19 who are at risk of progression to severe disease. In the clinical trial that supported the EUA, which included 799 patients, 3 percent of those who received the infusion ended up in the hospital, compared to 9 percent of patients on a placebo.
If one antibody in a two-antibody cocktail can neutralize SARS-CoV-2, then the overall effect will be neutralization, although with less potency.—Pamela Bjorkman, Caltech
On February 25, Regeneron halted the placebo arm of its outpatient trial of the cocktail’s effectiveness after an independent review committee’s declaration that the intervention protects well against different SARS-CoV-2 variants. The company’s announcement did not include specific details about B.1.351. The trial is taking place in the United States, where B.1.351 has not been widely detected.
The treatment is based on earlier forms of SARS-CoV-2, and new variants raise the question of how effective the cocktail will continue to be. Landau and colleagues tested how well the Regeneron antibodies, either separately or in combination, controlled the infectiousness of multiple SARS-CoV-2 variants.
They developed artificial viruses containing the spike proteins, the projections on the outside of the virus that grab hold of cells’ receptors to initiate infection, of five different variants, including B.1.351 and the benchmark variant D614G, one of the first mutations to emerge in the pandemic that quickly dominated. In cell culture, they exposed the viruses to the same antibodies as those included in the Regeneron cocktail, and measured the antibody serum concentration needed to reduce viral activity by 50 percent.
REGN10987 held its own against all variants, although with somewhat less success against B.1.351’s spike. Its companion REGN10933 had a much harder time neutralizing this variant, requiring a serum concentration 76 times higher than it needed to neutralize D614G. In tandem, the two were nine times less effective as they were against D614G.
“If one antibody in a two-antibody cocktail can neutralize SARS-CoV-2, then the overall effect will be neutralization, although with less potency,” Pamela Bjorkman, a structural biologist at Caltech who was not involved in either study, writes in an email to The Scientist.
Landau and colleagues attribute REGN10933’s drop in effectiveness to two different point mutations in the spike protein that could help the virus evade the antibody, namely K417N and E484K.
The results are supported by Bjorkman’s work. Her group used 3-D models to categorize the results of different antibody/spike protein combinations. In a study published last fall in Nature, she and her colleagues predicted that SARS-CoV-2 variants with point mutations such as those in B.1.351 would successfully evade antibodies like REGN10933—just as Landau’s team observed in the lab.
In an email to The Scientist, Regeneron spokesperson Alexandra Bowie says, “The values reported in this paper seem inconsistent with other results seen to date, both from Regeneron’s internal data and publications from outside researchers.”
The study Bowie cites does find that the antibodies within the Regeneron cocktail bind to B.1.351’s antigens with sufficient potency to reduce its viral activity by 50 percent. Its authors report that one part of the two-part cocktail maintained its capacity to neutralize B.1.351’s antigens, while the other did not. Landau’s team reached a similar conclusion about the potency of the different parts of the cocktail, and says that the cocktail does offer some protection against B.1.351, but not as much as against other variants. So there is not much disagreement between the two studies.
Adapting treatments as the pandemic wears on will be critical, and Bowie says Regeneron is aware of the risks of emerging variants and that the company has more antibodies on deck. “There’s never an antibody that just protects against everything,” Landau says. But over time it is possible, he adds, to “make it harder and harder for the virus to find a way out.”