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

DOI: 10.1038/s41467-021-25480-z DOI Help

Authors: Jiandong Huo (Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell) , Halina Mikolajek (Diamond Light Source) , Audrey Le Bas (Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell) , Jordan J. Clark (University of Liverpool) , Parul Sharma (University of Liverpool) , Anja Kipar (University of Liverpool; University of Zurich) , Joshua Dormon (The Rosalind Franklin Institute; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell) , Chelsea Norman (The Rosalind Franklin Institute; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell) , Miriam Weckener (The Rosalind Franklin Institute) , Daniel K. Clare (Diamond Light Source) , Peter J. Harrison (Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell; Diamond Light Source) , Julia A. Tree (Public Health England) , Karen R. Buttigieg (Public Health England) , Francisco J. Salguero (Public Health England) , Robert Watson (Public Health England) , Daniel Knott (Public Health England) , Oliver Carnell (Public Health England) , Didier Ngabo (Public Health England) , Michael J. Elmore (Public Health England) , Susan Fotheringham (Public Health England) , Adam Harding (University of Oxford) , Lucile Moynie (The Rosalind Franklin Institute) , Philip N. Ward (The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell) , Maud Dumoux (The Rosalind Franklin Institute) , Tessa Prince (Diamond Light Source) , Yper Hall (Public Health England) , Julian A. Hiscox (Diamond Light Source; Northwest A&F University; Infectious Diseases Horizontal Technology Centre (ID HTC), A*STAR) , Andrew Owen (University of Liverpool) , William James (University of Oxford) , Miles W. Carroll (Public Health England; University of Oxford) , James P. Stewart (Diamond Light Source; Northwest A&F University; University of Georgia) , James Naismith (The Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell) , Raymond Owens (The Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford; Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 27031

Open Access Open Access

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.

Journal Keywords: Antibody fragment therapy

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 24/09/2021 15:54

Documents:
s41467-021-25480-z.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)