Omicron Evades Most But Fortunately Not All Monoclonal Antibodies

The Omicron variant of SARS-CoV-2 has rapidly ricocheted around the world. Reported cases are at their highest since May 2021. There is a growing need for effective monoclonal antibody treatments to prevent and treat Omicron infections. Unfortunately, most approved anti-SARS-CoV-2 antibodies have a diminished potency or are ineffective against Omicron. The Omicron mutations which render the virus resistant to antibodies induced either by natural infection or vaccine also render them resistant to most monoclonal antibody treatments. Most does not mean all. At present, there are at least five well-characterized antibodies that retain potency against most variants of SARS-CoV-2 including Omicron.

S2K146

S2K146 is a monoclonal antibody developed jointly by Vir and GSK. Isolated from the memory B cells of a symptomatic Covid-19 patient, S2K146 bind the SARS-CoV-2 S protein, as well those of SARS-CoV-1, bat coronavirus WIV-1. Additionally, the antibody-bound and potently neutralized a number of variants of concern or interest, including Alpha, Beta, Gamma, Delta, Epsilon, and Lambda. Structurally, the antibody locks two of the trimer’s three receptor-binding domains in the open configuration while the remaining binding domains remain closed.

As outlined by Park et al., the S2K146 antibody footprint mimics that of the ACE2 binding sites. As many as 21 of the amino acids of the receptor binding site of the virus’s spike protein also bind the S2K146 antibody (Figure 1). These amino acids include heavily mutated sites in variants of concern, including N501, E484, and K417. Mutations of these mutations normally reduce antibody binding. The research speculates that neutralization is preserved as the interaction between the antibody and the receptor occurs over so many contacts. To me, it makes sense that an antibody has a structured surface that closely mimics that of the ACE2 neutralizers most variants. However much it may mutate, the spike protein must bind to ACE2 itself to initiate infection. I expect to see many more such ACE2 antibodies in the future, some with binding affinities that exceed that of S2K146.

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Originally published on December 23, 2021 

© William A. Haseltine, PhD. All Rights Reserved.