Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail.
Antibodies, Monoclonal
/ chemistry
Antibodies, Neutralizing
/ chemistry
Antibodies, Viral
/ chemistry
Antigenic Variation
Binding Sites
COVID-19
/ immunology
Complementarity Determining Regions
/ chemistry
Humans
Mutation
Protein Domains
SARS-CoV-2
/ immunology
Spike Glycoprotein, Coronavirus
/ chemistry
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
02
07
2021
accepted:
01
09
2021
pubmed:
23
9
2021
medline:
9
10
2021
entrez:
22
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34548634
doi: 10.1038/s41564-021-00972-2
pii: 10.1038/s41564-021-00972-2
pmc: PMC8543371
mid: NIHMS1737710
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Neutralizing
0
Antibodies, Viral
0
Complementarity Determining Regions
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1233-1244Subventions
Organisme : NIAID NIH HHS
ID : 75N93019C00074
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI095202
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI157155
Pays : United States
Organisme : NIH HHS
ID : S10 OD028685
Pays : United States
Organisme : NIAID NIH HHS
ID : 75N93019C00062
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI150739
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI083203
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001439
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141707
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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