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

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-20789-7

2041-1723

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 Bates, Jason S. McLellan, Susan R. Weiss, Ningyan Zhang, Pei‐Yong Shi, Zhiqiang An,

Viral gastroenteritis research and epidemiology

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.