W. Li, A. Schäfer, Swarali S Kulkarni, Xianglei Liu, D. R. Martinez, Chuan Chen, Zehua Sun, S. Leist, Aleksandra K. Drelich, Liyong Zhang, Marcin Ura, A. Berezuk, S. Chittori, K. Leopold, D. Mannar, S. S. Srivastava, Xing Zhu, E. Peterson, C. Tseng, J. Mellors, D. Falzarano, S. Subramaniam, R. Baric, D. Dimitrov
Cell, 2020
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.
Cited by 36 publications.
Field of study: Biology