Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail

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Author Name

Jinhui Dong

Seth J. Zost

Allison J Greaney


Tyler N Starr

Adam S Dingens

Elaine C Chen

Rita E. Chen

James Brett Case

Rachel E Sutton

Pavlo Gilchuk

Jessica Rodriguez

Erica Armstrong

Christopher Gainza

Rachel S Nargi

Elad Binshtein

Xuping Xie

Xianwen Zhang

Pei-Yong Shi

James Logue

Stuart Weston

Marisa E. McGrath

Matthew B Frieman

Tyler Brady

Kevin Tuffy

Helen Bright

Yueh-Ming Loo

Patrick McTamney

Mark Esser

Robert H. Carnahan

Michael Diamond

James E. Crowe

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The SARS-CoV-2 pandemic has led to an urgent need to understand the molecular basis for immune recognition of SARS-CoV-2 spike (S) glycoprotein antigenic sites. To define the genetic and structural basis for SARS-CoV-2 neutralization, we determined the structures of two human monoclonal antibodies COV2-2196 and COV2-21301, which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor binding domain (RBD) of SARS-CoV-2. COV2-2196 forms an "aromatic cage" at the heavy/light chain interface using germline-encoded residues in complementarity determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals1-4. The structure of COV2-2130 reveals that an unusually long LCDR1 and HCDR3 make interactions with the opposite face of the RBD from that of COV2-2196. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the critical residues of both antibodies and identified positions of concern for possible viral escape. Nonetheless, both COV2-2196 and COV2-2130 showed strong neutralizing activity against SARS-CoV-2 strain with recent variations of concern including E484K, N501Y, and D614G substitutions. These studies reveal germline-encoded antibody features enabling recognition of the RBD and demonstrate the activity of a cocktail like AZD7442 in preventing escape from emerging variant viruses.

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