Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail

Cell Rep. 2023 Jun 27;42(6):112621. doi: 10.1016/j.celrep.2023.112621. Epub 2023 May 26.

Abstract

Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. 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 AZD1061 (COV2-2130) mAb. Here, we show that this mutation remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution.

Keywords: COVID-19; CP: Immunology; CP: Microbiology; SARS-CoV-2; cryo-EM; monoclonal antibodies; receptor binding domain; spike glycoprotein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19*
  • Combined Antibody Therapeutics
  • Humans
  • Neutralization Tests
  • SARS-CoV-2*
  • Spike Glycoprotein, Coronavirus

Substances

  • Combined Antibody Therapeutics
  • Antibodies, Viral
  • Antibodies, Neutralizing
  • Antibodies, Monoclonal
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2

Supplementary concepts

  • SARS-CoV-2 variants