Cited by 285SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesMonoclonal and Polyclonal Antibodies Research

Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail

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Dong, Jinhui, Zost, Seth J., Greaney, Allison J., Starr, Tyler N., Dingens, Adam S., Chen, Elaine C., Chen, Rita E., Case, James Brett +24 more·2021·Nature Microbiology

Abstract

Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies-AZD8895 and AZD1061-which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an 'aromatic cage' at the heavy/light chain interface using germ line-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 individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.

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  • The Omicron pseudovirus spike did not contain R346K.

    “Importantly, our spike did not contain R346K, which has been observed at relatively low frequency (<10%) within the Omicron lineage, but which is known to mediate escape from class 3 neutralizing monoclonal antibodies such as AZD1061/cilgavimab (Barnes et al., 2020; Dong et al., 2021; Greaney et al., 2021b).”

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  1. [68]van Dorp L Recurrent mutations in SARS-CoV-2 genomes isolated from mink point to rapid host-adaptation. bioRxiv, 2020.2011.2016.384743, (2020).

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Authors
Dong, J., Zost, S. J., Greaney, A. J., Starr, T. N., Dingens, A. S., Chen, E. C., Chen, R. E., Case, J. B., Sutton, R. E., Gilchuk, P., Rodriguez, J., Armstrong, E., Gainza, C., Nargi, R. S., Binshtein, E., Xie, X., Zhang, X., Shi, P.-Y., Logue, J., Weston, S., McGrath, M. E., Frieman, M. B., Brady, T., Tuffy, K. M., Bright, H., Loo, Y.-M., McTamney, P. M., Esser, M. T., Carnahan, R. H., Diamond, M. S., Bloom, J. D., & Crowe, J. E.
Affiliations
  • Vanderbilt University Medical Center (US)
  • University of Washington (US)
  • Fred Hutch Cancer Center (US)
  • Washington University in St. Louis (US)
  • The University of Texas Medical Branch at Galveston (US)
  • University of Maryland, College Park (US)
  • AstraZeneca (United States) (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Crowe, James E.
Venue
Nature Microbiology
Published
2021-09-21
Volume
6
Issue
10
Pages
1233-1244
ISSN
2058-5276 (ISSN-L)
OpenAlex
W3199394546
Cited by
285
References
84
Citations by year
2026: 12 · 2025: 17 · 2024: 43 · 2023: 72 · 2022: 107 · 2021: 33 · 2020: 1
FWCI
20.13
Type
journal article
Language
en
Open access
Locations
  • Nature Microbiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI095202, 75N93019C00062, AI157155, AI141707, 75N93019C00074, AI150739)
  • U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1TR001439)
  • United States Department of Defense | Defense Advanced Research Projects Agency (HR0011-18-3-0001, HR0011-18-2-0001)
  • Merck KGaA (Future Insight Prize 2019)
  • DOE | LDRD | Argonne National Laboratory (DE-AC02-06CH11357)
  • Michigan Economic Development Corporation (085P1000817)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Keywords
SARS-CoV-2, spike protein, receptor binding domain, monoclonal antibodies, antibody neutralization, antibody-antigen complex structure, hypervariable region, HCDR3, neutralization escape, variants of concern, deep mutational scanning
MeSH terms
Protein Domains, COVID-19, SARS-CoV-2, Antibodies, Monoclonal, Antibodies, Viral, Antigenic Variation, Binding Sites, Humans, Mutation, Complementarity Determining Regions, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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