The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants.
Journal
Nature biotechnology
ISSN: 1546-1696
Titre abrégé: Nat Biotechnol
Pays: United States
ID NLM: 9604648
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
14
12
2021
accepted:
02
06
2022
pubmed:
22
7
2022
medline:
17
12
2022
entrez:
21
7
2022
Statut:
ppublish
Résumé
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).
Identifiants
pubmed: 35864170
doi: 10.1038/s41587-022-01382-3
pii: 10.1038/s41587-022-01382-3
pmc: PMC9750863
doi:
Substances chimiques
ensovibep
PV6AA88RDU
Designed Ankyrin Repeat Proteins
0
Antibodies, Monoclonal
0
Combined Antibody Therapeutics
0
Antibodies, Neutralizing
0
Types de publication
Journal Article
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
1845-1854Informations de copyright
© 2022. The Author(s).
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