Key result
SARS-CoV-2 E406W mutation reduces ACE2 binding ~14-fold and escapes REGEN-COV but remains susceptible to broad mAbs.
Why the study?
The SARS-CoV-2 receptor-binding domain E406W mutation abrogates neutralization by the REGEN-CoV therapeutic monoclonal antibody cocktail and cilgavimab (AZD1061).
The SARS-CoV-2 E406W mutation escapes specific clinical monoclonal antibodies by remodeling the ACE2-binding site, but remains susceptible to broadly neutralizing sarbecovirus mAbs.
E406W escape should not alter current mAb use; leaves open in vivo activity of broadly neutralizing sarbecovirus antibodies.
The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-CoV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the cilgavimab (AZD1061) mAb. Here, we show that this residue substitution remodels the ACE2-binding site allosterically, thereby dampening receptor recognition severely and altering the epitopes recognized by these three mAbs. Although vaccine-elicited neutralizing antibody titers are decreased similarly against the E406 mutant and the Delta or Epsilon variants, broadly neutralizing sarbecovirus mAbs, including a clinical mAb, inhibit the E406W spike mutant.
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Addetia et al. (2022) studied SARS-CoV-2. SARS-CoV-2 spike E406W mutation vs. Wildtype (Wuhan-Hu-1) SARS-CoV-2 spike was evaluated on ACE2 binding affinity and neutralization escape. The SARS-CoV-2 E406W mutation allosterically remodels the receptor-binding domain, reducing ACE2 binding affinity 14-fold and escaping REGEN-COV and cilgavimab while remaining susceptible to broadly neutralizing mAbs.
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