Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations.
Angiotensin-Converting Enzyme 2
Animals
Antibodies, Neutralizing
/ chemistry
Antibodies, Viral
/ chemistry
Antiviral Agents
/ therapeutic use
Binding Sites
COVID-19
/ immunology
Chlorocebus aethiops
HEK293 Cells
Humans
Immunoglobulin G
Models, Molecular
Mutation
Protein Binding
Protein Engineering
SARS-CoV-2
/ genetics
Spike Glycoprotein, Coronavirus
/ immunology
Vero Cells
COVID-19 Drug Treatment
RBD-binding
anti-viral
neutralizing
synthetic
tetravalent
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
17 09 2021
17 09 2021
Historique:
received:
18
05
2021
revised:
17
07
2021
accepted:
21
07
2021
pubmed:
31
7
2021
medline:
29
9
2021
entrez:
30
7
2021
Statut:
ppublish
Résumé
Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.
Identifiants
pubmed: 34329642
pii: S0022-2836(21)00410-1
doi: 10.1016/j.jmb.2021.167177
pmc: PMC8316672
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Antibodies, Viral
0
Antiviral Agents
0
Immunoglobulin G
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
ACE2 protein, human
EC 3.4.17.23
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
167177Commentaires et corrections
Type : UpdateOf
Informations de copyright
Copyright © 2021. Published by Elsevier Ltd.
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