High Potency of a Bivalent Human VH Domain in SARS-CoV-2 Animal Models

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  • Li, Wei
    • Other Affiliation: University of Pittsburgh Medical School
  • Schäfer, Alexandra
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Kulkarni, Swarali S.
    • Other Affiliation: University of Saskatchewan
  • Liu, Xianglei
    • Other Affiliation: University of Pittsburgh Medical School
  • Martinez, David R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Chen, Chuan
    • Other Affiliation: University of Pittsburgh Medical School
  • Sun, Zehua
    • Other Affiliation: University of Pittsburgh Medical School
  • Leist, Sarah R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Drelich, Aleksandra
    • Other Affiliation: Galveston National Laboratory
  • Zhang, Liyong
    • Other Affiliation: University of Pittsburgh Medical School
  • Ura, Marcin L.
    • Other Affiliation: Abound Bio
  • Berezuk, Alison
    • Other Affiliation: University of British Columbia
  • Chittori, Sagar
    • Other Affiliation: University of British Columbia
  • Leopold, Karoline
    • Other Affiliation: University of British Columbia
  • Falzarano, Darryl
    • Other Affiliation: University of Saskatchewan
  • Subramaniam, Sriram
    • Other Affiliation: University of British Columbia
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Dimitrov, Dimiter S.
    • Other Affiliation: University of Pittsburgh Medical School
Abstract
  • Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody VH domain library from which we identified a high-affinity VH binder ab8. Bivalent VH, VH-Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. VHFc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of VH-Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.
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  • Article
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  • In Copyright
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  • Cell
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  • English
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  • Postprint

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