RT Journal Article
SR Electronic
T1 Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.27.428529
DO 10.1101/2021.01.27.428529
A1 Jinhui Dong
A1 Seth J. Zost
A1 Allison J. Greaney
A1 Tyler N. Starr
A1 Adam S. Dingens
A1 Elaine C. Chen
A1 Rita E. Chen
A1 James Brett Case
A1 Rachel E. Sutton
A1 Pavlo Gilchuk
A1 Jessica Rodriguez
A1 Erica Armstrong
A1 Christopher Gainza
A1 Rachel S. Nargi
A1 Elad Binshtein
A1 Xuping Xie
A1 Xianwen Zhang
A1 Pei-Yong Shi
A1 James Logue
A1 Stuart Weston
A1 Marisa E. McGrath
A1 Matthew B. Frieman
A1 Tyler Brady
A1 Kevin Tuffy
A1 Helen Bright
A1 Yueh-Ming Loo
A1 Patrick McTamney
A1 Mark Esser
A1 Robert H. Carnahan
A1 Michael S. Diamond
A1 Jesse D. Bloom
A1 James E. Crowe, Jr.
YR 2021
UL http://biorxiv.org/content/early/2021/03/01/2021.01.27.428529.abstract
AB 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.Competing Interest StatementT.B., K.T., H.B., Y.M-L., P.M., and M.E. are employees of and may own stock in AstraZeneca. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. All other authors declare no competing interests. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. Vanderbilt University has applied for patents concerning antibodies that are related to this work.