Molecular determinants and mechanism for antibody cocktail preventing SARS-CoV-2 escape

Zhiqiang Ku, Xuping Xie, Edgar Davidson, Xiaohua Ye, Hang Su, Vineet D. Menachery, Yize Li, Zihao Yuan, Xianwen Zhang, Antonio E. Muruato, Ariadna Grinyo i Escuer, Breanna Tyrell, Kyle Doolan, Benjamin J. Doranz, Daniel Wrapp, Paul F. Bates, Jason S. McLellan, Susan R. Weiss, Ningyan Zhang (), Pei-Yong Shi () and Zhiqiang An ()
Additional contact information
Zhiqiang Ku: University of Texas Health Science Center at Houston
Xuping Xie: University of Texas Medical Branch
Edgar Davidson: Integral Molecular, Philadelphia
Xiaohua Ye: University of Texas Health Science Center at Houston
Hang Su: University of Texas Health Science Center at Houston
Vineet D. Menachery: University of Texas Medical Branch
Yize Li: University of Pennsylvania
Zihao Yuan: University of Texas Health Science Center at Houston
Xianwen Zhang: University of Texas Medical Branch
Antonio E. Muruato: University of Texas Medical Branch
Ariadna Grinyo i Escuer: Integral Molecular, Philadelphia
Breanna Tyrell: Integral Molecular, Philadelphia
Kyle Doolan: Integral Molecular, Philadelphia
Benjamin J. Doranz: Integral Molecular, Philadelphia
Daniel Wrapp: University of Texas at Austin
Paul F. Bates: University of Pennsylvania
Jason S. McLellan: University of Texas at Austin
Susan R. Weiss: University of Pennsylvania
Ningyan Zhang: University of Texas Health Science Center at Houston
Pei-Yong Shi: University of Texas Medical Branch
Zhiqiang An: University of Texas Health Science Center at Houston

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Antibody cocktails represent a promising approach to prevent SARS-CoV-2 escape. The determinants for selecting antibody combinations and the mechanism that antibody cocktails prevent viral escape remain unclear. We compared the critical residues in the receptor-binding domain (RBD) used by multiple neutralizing antibodies and cocktails and identified a combination of two antibodies CoV2-06 and CoV2-14 for preventing viral escape. The two antibodies simultaneously bind to non-overlapping epitopes and independently compete for receptor binding. SARS-CoV-2 rapidly escapes from individual antibodies by generating resistant mutations in vitro, but it doesn’t escape from the cocktail due to stronger mutational constraints on RBD-ACE2 interaction and RBD protein folding requirements. We also identified a conserved neutralizing epitope shared between SARS-CoV-2 and SARS-CoV for antibody CoV2-12. Treatments with CoV2-06 and CoV2-14 individually and in combination confer protection in mice. These findings provide insights for rational selection and mechanistic understanding of antibody cocktails as candidates for treating COVID-19.

Date: 2021
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DOI: 10.1038/s41467-020-20789-7

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