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

• Published in: Nature communications Vol. 12; no. 1; pp. 469 - 13
• Main Authors: Ku, Zhiqiang, Xie, Xuping, Davidson, Edgar, Ye, Xiaohua, Su, Hang, Menachery, Vineet D., Li, Yize, Yuan, Zihao, Zhang, Xianwen, Muruato, Antonio E., i Escuer, Ariadna Grinyo, Tyrell, Breanna, Doolan, Kyle, Doranz, Benjamin J., Wrapp, Daniel, Bates, Paul F., McLellan, Jason S., Weiss, Susan R., Zhang, Ningyan, Shi, Pei-Yong, An, Zhiqiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2152/2153/1291; 631/326/596/4130; 64/60; 82/1; 82/80; ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - immunology; Antibodies, Viral - genetics; Antibodies, Viral - immunology; Binding; Chlorocebus aethiops; COVID-19; COVID-19 - drug therapy; COVID-19 - virology; Determinants; Disease Models, Animal; Epitopes; Female; Humanities and Social Sciences; Humans; Immunoglobulin Fragments - genetics; Immunoglobulin Fragments - immunology; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Mice; Mice, Inbred BALB C; Models, Molecular; multidisciplinary; Mutation; Neutralizing; Phages; Protein Binding; Protein folding; Receptors; SARS-CoV-2 - drug effects; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Vero Cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20789-7

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. Antibody cocktails represent a promising approach to prevent SARS-CoV-2 escape. Here, Ku et al., identify SARS-CoV-2 neutralizing antibodies from a phage library and identify an antibody combination that prevents viral escape and protects mice from viral challenge.