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

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. VH-Fc 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.
Mesh Terms:
Angiotensin-Converting Enzyme 2, Animals, Antibodies, Neutralizing, Antibodies, Viral, Antibody Affinity, COVID-19, COVID-19 Drug Treatment, Coronavirus Infections, Cricetinae, Female, Humans, Immunoglobulin Fc Fragments, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Mice, Mice, Inbred BALB C, Mutation, Pandemics, Peptide Library, Peptidyl-Dipeptidase A, Pneumonia, Viral, Protein Domains, Spike Glycoprotein, Coronavirus
Cell
Date: Oct. 15, 2020
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