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; Zhiqiang An

doi:10.1038/s41467-020-20789-7

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 ShiZhiqiang An

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

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.

Original language	English (US)
Article number	469
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20789-7
State	Published - Dec 1 2021
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Ku, Z., Xie, X., Davidson, E., Ye, X., Su, H., Menachery, V. D., Li, Y., Yuan, Z., Zhang, X., Muruato, A. E., i Escuer, A. G., Tyrell, B., Doolan, K., Doranz, B. J., Wrapp, D., Bates, P. F., McLellan, J. S., Weiss, S. R., Zhang, N., ... An, Z. (2021). Molecular determinants and mechanism for antibody cocktail preventing SARS-CoV-2 escape. Nature communications, 12(1), Article 469. https://doi.org/10.1038/s41467-020-20789-7

Ku, Z, Xie, X, Davidson, E, Ye, X, Su, H, Menachery, VD, Li, Y, Yuan, Z, Zhang, X, Muruato, AE, i Escuer, AG, Tyrell, B, Doolan, K, Doranz, BJ, Wrapp, D, Bates, PF, McLellan, JS, Weiss, SR, Zhang, N, Shi, PY & An, Z 2021, 'Molecular determinants and mechanism for antibody cocktail preventing SARS-CoV-2 escape', Nature communications, vol. 12, no. 1, 469. https://doi.org/10.1038/s41467-020-20789-7

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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{\textquoteright}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.",

author = "Zhiqiang Ku and Xuping Xie and Edgar Davidson and Xiaohua Ye and Hang Su and Menachery, {Vineet D.} and Yize Li and Zihao Yuan and Xianwen Zhang and Muruato, {Antonio E.} and {i Escuer}, {Ariadna Grinyo} and Breanna Tyrell and Kyle Doolan and Doranz, {Benjamin J.} and Daniel Wrapp and Bates, {Paul F.} and McLellan, {Jason S.} and Weiss, {Susan R.} and Ningyan Zhang and Shi, {Pei Yong} and Zhiqiang An",

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

Abstract

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