High potency of a bivalent human VH domain in SARS-CoV-2 animal models

Li, Wei; Schäfer, Alexandra; Kulkarni, Swarali S.; Liu, Xianglei; Martinez, David R.; Chen, Chuan; Sun, Zehua; Leist, Sarah R.; Drelich, Aleksandra; Zhang, Liyong; Ura, Marcin L.; Berezuk, Alison; Chittori, Sagar; Leopold, Karoline; Mannar, Dhiraj; Srivastava, Shanti S.; Zhu, Xing; Peterson, Eric C.; Tseng, Chien-Te; Mellors, John W.; Falzarano, Darryl; Subramaniam, Sriram; Baric, Ralph S.; Dimitrov, Dimiter S.

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 5300 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.