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A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

Authors :
Robert J. Watson
Oliver Carnell
Jordan J. Clark
Francisco J. Salguero
Tessa Prince
William James
Michael J. Elmore
Miriam Weckener
Philip N. Ward
Audrey Le Bas
Chelsea Norman
Susan A. Fotheringham
Raymond J. Owens
Yper Hall
Parul Sharma
James H. Naismith
Adam Harding
Karen R. Buttigieg
Andrew Owen
Peter J. Harrison
Lucile MoyniƩ
Jiandong Huo
Anja Kipar
Miles W. Carroll
Daniel K. Clare
James P. Stewart
Didier Ngabo
H. Mikolajek
Daniel Knott
Maud Dumoux
Joshua Dormon
Julia A. Tree
Julian A. Hiscox
Source :
Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021), Nature Communications
Publication Year :
2021
Publisher :
Nature Portfolio, 2021.

Abstract

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.<br />Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

Details

Language :
English
ISSN :
20411723
Volume :
12
Issue :
1
Database :
OpenAIRE
Journal :
Nature Communications
Accession number :
edsair.doi.dedup.....88bfe2f67b6c2ee50cd8f27682defac4