Journal
CELL
Volume 183, Issue 2, Pages 429-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.09.007
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Funding
- University of Pittsburgh Medical Center
- NIH [F32 AI152296, AI132178, AI108197, P30CA016086]
- Burroughs Wellcome Fund Postdoctoral Enrichment Program Award
- NIH NIAID [T32 AI007151]
- Canada Excellence Research Chair Award
- Genome BC, Canada
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Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody V-H domain library from which we identified a high-affinity V-H binder ab8. Bivalent V-H, V-H-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. V-H-Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of V-H-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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