On Jun. 11, 2020, Regeneron announced that Science had accepted for publication two papers describing the creation of its novel two-antibody cocktail, REGN-COV2, and its potential to diminish risk of viral escape by effectively binding to the virus’s critical spike protein in two separate, non-overlapping locations.

The first paper entitled “Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail” describes Regeneron’s parallel efforts using both humanized VelocImmune^® mice and blood samples from recovered COVID-19 patients to generate a large and diverse collection of antibodies targeting multiple different regions of the critical receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The spike protein on the virus cell surface binds to the host cell and is required for infectivity. By blocking its interaction with the host cell, antibodies are able to neutralize the virus and block infection. Regeneron scientists selected pairs of highly potent individual antibodies that simultaneously and non-competitively bind to the RBD. Regeneron pursues a multi-antibody cocktail approach for infectious diseases in order to decrease the potential for the virus to escape.

Viral escape is when, under pressure from an anti-viral therapeutic, spontaneously arising mutant forms of the virus are able to ‘escape’ or evade the therapeutic’s blocking action. These mutants are then ‘selected’ (i.e., are able to survive and proliferate despite the single therapeutic treatment) and may ultimately become the dominant strain of the virus.

The concept that drug cocktails can prevent viral escape has previously been demonstrated for traditional antiviral drugs used to treat HIV and other viruses. Regeneron now reports the fundamental realization that this can also be true for antibody-based therapies as reported in the second paper, entitled “Antibody Cocktail to SARS-Cov-2 Spike Protein Prevents Rapid Mutational Escape Seen with Individual Antibodies,” which further defines the protective value of the multiple-antibody approach against SARS-CoV-2 specifically. This research for the first time demonstrates that, under pressure from individual antibodies, mutant viruses were rapidly selected that evaded the blocking function of all individual antibodies tested, including antibodies that potently bind to highly-conserved regions on the spike protein. However, escape mutants could not be efficiently generated following exposure to the REGN-COV2 cocktail since it utilizes two antibodies that can simultaneously bind to distinct regions of the RBD.

REGN-COV2’s preclinical development and preclinical/clinical manufacturing has been funded in part with federal funds from the Biomedical Advanced Research and Development Authority
(BARDA), part of the office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, under OT number: HHSO100201700020C.