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Ab8 COVID-19 Drug Breakthrough: Tiny Antibody Component Completely Neutralizes the SARS-CoV-2 Virus
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https://scitechdaily.com/ab8-covid-19-drug-breakthrough-tiny-antibody-component-completely-neutralizes-the-sars-cov-2-virus/
High potency of a bivalent human VH domain in SARS-CoV-2 animal models
Wei Li, Alexandra Schäfer, Swarali S. Kulkarni, Xianglei Liu, David R. Martinez, Chuan Chen, Zehua Sun, Sarah R. Leist, Aleksandra Drelich, Liyong Zhang, Marcin
L. Ura, Alison Berezuk, Sagar Chittori, Karoline Leopold, Dhiraj Mannar, Shanti S. Srivastava, Xing Zhu, Eric C. Peterson, Chien-Te Tseng, John W. Mellors, Darryl Falzarano, Sriram Subramaniam, Ralph S. Baric, Dimiter S. Dimitrov
Highlights
•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
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 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.
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