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

Jiandong Huo, Halina Mikolajek, Audrey Bas, Jordan J. Clark, Parul Sharma, Anja Kipar, Joshua Dormon, Chelsea Norman, Miriam Weckener, Daniel K. Clare, Peter J. Harrison, Julia A. Tree, Karen R. Buttigieg, Francisco J. Salguero, Robert Watson, Daniel Knott, Oliver Carnell, Didier Ngabo, Michael J. Elmore, Susan Fotheringham, Adam Harding, Lucile Moynié, Philip N. Ward, Maud Dumoux, Tessa Prince, Yper Hall, Julian A. Hiscox, Andrew Owen, William James, Miles W. Carroll, James P. Stewart, James H. Naismith () and Raymond J. Owens ()
Additional contact information
Jiandong Huo: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Halina Mikolajek: Diamond Light Source Ltd, Harwell Science Campus
Audrey Bas: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Jordan J. Clark: Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Parul Sharma: Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Anja Kipar: Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Joshua Dormon: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Chelsea Norman: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Miriam Weckener: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Daniel K. Clare: Diamond Light Source Ltd, Harwell Science Campus
Peter J. Harrison: Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell, Science Campus
Julia A. Tree: National Infection Service, Public Health England, Porton Down
Karen R. Buttigieg: National Infection Service, Public Health England, Porton Down
Francisco J. Salguero: National Infection Service, Public Health England, Porton Down
Robert Watson: National Infection Service, Public Health England, Porton Down
Daniel Knott: National Infection Service, Public Health England, Porton Down
Oliver Carnell: National Infection Service, Public Health England, Porton Down
Didier Ngabo: National Infection Service, Public Health England, Porton Down
Michael J. Elmore: National Infection Service, Public Health England, Porton Down
Susan Fotheringham: National Infection Service, Public Health England, Porton Down
Adam Harding: Sir William Dunn School of Pathology, University of Oxford
Lucile Moynié: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Philip N. Ward: Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford
Maud Dumoux: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Tessa Prince: Diamond Light Source Ltd, Harwell Science Campus
Yper Hall: National Infection Service, Public Health England, Porton Down
Julian A. Hiscox: Diamond Light Source Ltd, Harwell Science Campus
Andrew Owen: Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool
William James: Sir William Dunn School of Pathology, University of Oxford
Miles W. Carroll: National Infection Service, Public Health England, Porton Down
James P. Stewart: Diamond Light Source Ltd, Harwell Science Campus
James H. Naismith: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
Raymond J. Owens: Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25480-z

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