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

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


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

    Wei Li1*#, Alexandra Schäfer2#, Swarali S. Kulkarni3#, Xianglei Liu1#, David R. Martinez2#, Chuan Chen1 , Zehua Sun1 , Sarah R. Leist2 , Aleksandra Drelich4 , Liyong Zhang1 , Marcin L. Ura5 , Alison Berezuk6 , Sagar Chittori6 , Karoline Leopold6 , Dhiraj Mannar6 , Shanti S. Srivastava6 , Xing Zhu6 , Eric C. Peterson5 , Chien-Te Tseng4 , John W. Mellors1,5, Darryl Falzarano3 , Sriram Subramaniam6 , Ralph S. Baric2 and Dimiter S. Dimitrov1,5,7*

    Abstract

    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 SARSCoV-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.

    https://www.cell.com/cell/pdf/S0092-...showall%3Dtrue


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