Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections.
Animals
Antibodies, Monoclonal
/ chemistry
Antibodies, Neutralizing
/ immunology
Antibodies, Viral
/ chemistry
Cryoelectron Microscopy
Epitope Mapping
Epitopes
Female
Mice
Mice, Inbred BALB C
Models, Molecular
Protein Binding
/ drug effects
Protein Conformation
SARS-CoV-2
/ drug effects
Spike Glycoprotein, Coronavirus
/ chemistry
COVID-19 Drug Treatment
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 01 2021
11 01 2021
Historique:
received:
25
08
2020
accepted:
03
12
2020
entrez:
12
1
2021
pubmed:
13
1
2021
medline:
20
1
2021
Statut:
epublish
Résumé
The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen-antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections.
Identifiants
pubmed: 33431876
doi: 10.1038/s41467-020-20465-w
pii: 10.1038/s41467-020-20465-w
pmc: PMC7801428
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Neutralizing
0
Antibodies, Viral
0
Epitopes
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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