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High Potency of a Bivalent Human V(H) Domain in SARS-CoV-2 Animal Models #MMPMID32941803
Li W; Schafer A; Kulkarni SS; Liu X; Martinez DR; Chen C; Sun Z; Leist SR; Drelich A; Zhang L; Ura ML; Berezuk A; Chittori S; Leopold K; Mannar D; Srivastava SS; Zhu X; Peterson EC; Tseng CT; Mellors JW; Falzarano D; Subramaniam S; Baric RS; Dimitrov DS
Cell 2020[Oct]; 183 (2): 429-441.e16 PMID32941803show ga
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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Cell 2020 ; 183 (2): 429-441.e16
