Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies.
Antibodies, Neutralizing
/ immunology
Antibodies, Viral
/ immunology
Binding Sites
/ immunology
Broadly Neutralizing Antibodies
/ immunology
COVID-19
/ immunology
Cross Reactions
Epitopes
/ metabolism
Humans
Protein Binding
Protein Interaction Domains and Motifs
Receptors, Virus
/ metabolism
SARS-CoV-2
/ immunology
Spike Glycoprotein, Coronavirus
/ chemistry
SARS-CoV-2
Spike trimer: structural biology
coronavirus
cryo-EM
neutralizing antibody
receptor-binding domain
sarbecovirus
virology: X-ray crystallography
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
28 09 2021
28 09 2021
Historique:
received:
28
04
2021
revised:
05
08
2021
accepted:
01
09
2021
pubmed:
18
9
2021
medline:
13
10
2021
entrez:
17
9
2021
Statut:
ppublish
Résumé
Many anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) neutralizing antibodies target the angiotensin-converting enzyme 2 (ACE2) binding site on viral spike receptor-binding domains (RBDs). Potent antibodies recognize exposed variable epitopes, often rendering them ineffective against other sarbecoviruses and SARS-CoV-2 variants. Class 4 anti-RBD antibodies against a less-exposed, but more-conserved, cryptic epitope could recognize newly emergent zoonotic sarbecoviruses and variants, but they usually show only weak neutralization potencies. Here, we characterize two class 4 anti-RBD antibodies derived from coronavirus disease 2019 (COVID-19) donors that exhibit breadth and potent neutralization of zoonotic coronaviruses and SARS-CoV-2 variants. C118-RBD and C022-RBD structures reveal orientations that extend from the cryptic epitope to occlude ACE2 binding and CDRH3-RBD main-chain H-bond interactions that extend an RBD β sheet, thus reducing sensitivity to RBD side-chain changes. A C118-spike trimer structure reveals rotated RBDs that allow access to the cryptic epitope and the potential for intra-spike crosslinking to increase avidity. These studies facilitate vaccine design and illustrate potential advantages of class 4 RBD-binding antibody therapeutics.
Identifiants
pubmed: 34534459
pii: S2211-1247(21)01214-6
doi: 10.1016/j.celrep.2021.109760
pmc: PMC8423902
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Antibodies, Viral
0
Broadly Neutralizing Antibodies
0
Epitopes
0
Receptors, Virus
0
Spike Glycoprotein, Coronavirus
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, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
109760Subventions
Organisme : NIAID NIH HHS
ID : P01 AI138938
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM133894
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI078788
Pays : United States
Organisme : NIAID NIH HHS
ID : R01AI640511
Pays : United States
Commentaires et corrections
Type : UpdateOf
Type : ErratumIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The Rockefeller University has filed provisional patent applications in connection with this work on which M.C.N. (US patent 63/021,387) is listed as an inventor.
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