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

Addetia, A.; Park, Y.-J.; Starr, T.; Greaney, A. J.; Sprouse, K.; Bowen, J. E.; Tiles, S. W.; Van Voorhis, W. C.; Bloom, J. D.; Corti, D.; Walls, A. C.; Veesler, D.

doi:10.1101/2022.01.21.477288

bioRxiv · 10.1101/2022.01.21.477288

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

Addetia, A.·Park, Y.-J.·Starr, T.·Greaney, A. J.·Sprouse, K.·Bowen, J. E.·Tiles, S. W.·Van Voorhis, W. C.·Bloom, J. D.·Corti, D.·Walls, A. C.·Veesler, D.

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Abstract

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, A., Park, Y.-J., Starr, T., Greaney, A. J., Sprouse, K., Bowen, J. E., Tiles, S. W., Van Voorhis, W. C., Bloom, J. D., Corti, D., Walls, A. C., Veesler, D.. 2022-01-25. Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail. https://doi.org/10.1101/2022.01.21.477288

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