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

Author

Listed:
  • Jiandong Huo

    (Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
    Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell, Science Campus)

  • Halina Mikolajek

    (Diamond Light Source Ltd, Harwell Science Campus)

  • Audrey Bas

    (Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
    Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at 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
    Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich)

  • Joshua Dormon

    (Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell, Science Campus)

  • Chelsea Norman

    (Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at 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
    Diamond Light Source Ltd, 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
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell, Science Campus)

  • 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
    Northwest A&F University
    Infectious Diseases Horizontal Technology Centre (ID HTC), A*STAR)

  • 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
    Nuffield Department of Medicine, University of Oxford)

  • James P. Stewart

    (Diamond Light Source Ltd, Harwell Science Campus
    Northwest A&F University
    University of Georgia)

  • James H. Naismith

    (Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
    Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell, Science Campus)

  • Raymond J. Owens

    (Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus
    Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford
    Protein Production UK, The Rosalind Franklin Institute – Diamond Light Source, The Research Complex at Harwell, Science Campus)

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.

Suggested Citation

  • 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 & Ka, 2021. "A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25480-z
    DOI: 10.1038/s41467-021-25480-z
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    Cited by:

    1. Anna R. Mäkelä & Hasan Uğurlu & Liina Hannula & Ravi Kant & Petja Salminen & Riku Fagerlund & Sanna Mäki & Anu Haveri & Tomas Strandin & Lauri Kareinen & Jussi Hepojoki & Suvi Kuivanen & Lev Levanov &, 2023. "Intranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Dhiraj Mannar & James W. Saville & Zehua Sun & Xing Zhu & Michelle M. Marti & Shanti S. Srivastava & Alison M. Berezuk & Steven Zhou & Katharine S. Tuttle & Michele D. Sobolewski & Andrew Kim & Benjam, 2022. "SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Courtney J. Mycroft-West & Sahar Abdelkarim & Helen M. E. Duyvesteyn & Neha S. Gandhi & Mark A. Skidmore & Raymond J. Owens & Liang Wu, 2024. "Structural and mechanistic characterization of bifunctional heparan sulfate N-deacetylase-N-sulfotransferase 1," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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