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. [Display omitted] •A high-affinity human antibody domain, VH ab8, specific for SARS-CoV-2 was selected•VH ab8 bound to all three S protomers competing with ACE2•Bivalent VH, VH-Fc ab8, potently neutralized SARS-CoV-2 in vitro and in animals•Small size and bivalency contribute to the high ab8 SARS-CoV-2 neutralizing potency A high-affinity human antibody domain, VH ab8, specific for SARS-CoV-2, bound to all three S protomers competing with ACE2. The relatively small size and bivalency of VH-Fc ab8 contributed to its high potency in two animal models of infection.