Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains

Chuan Chen; James W Saville; Michelle M Marti; Alexandra Schäfer; Mary Hongying Cheng; Dhiraj Mannar; Xing Zhu; Alison M Berezuk; Anupam Banerjee; Michele D Sobolewski; Andrew Kim; Benjamin R Treat; Priscila Mayrelle Da Silva Castanha; Nathan Enick; Kevin D McCormick; Xianglei Liu; Cynthia Adams; Margaret Grace Hines; Zehua Sun; Weizao Chen; Jana L Jacobs; Simon M Barratt-Boyes; John W Mellors; Ralph S Baric; Ivet Bahar; Dimiter S Dimitrov; Sriram Subramaniam; David R Martinez; Wei Li

doi:10.1016/j.isci.2022.104798

Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains

iScience. 2022 Aug 19;25(8):104798. doi: 10.1016/j.isci.2022.104798. Epub 2022 Jul 20.

Authors

Chuan Chen¹, James W Saville², Michelle M Marti³, Alexandra Schäfer⁴, Mary Hongying Cheng⁵, Dhiraj Mannar², Xing Zhu², Alison M Berezuk², Anupam Banerjee⁵, Michele D Sobolewski⁶, Andrew Kim¹, Benjamin R Treat³, Priscila Mayrelle Da Silva Castanha³, Nathan Enick⁶, Kevin D McCormick⁶, Xianglei Liu¹, Cynthia Adams¹, Margaret Grace Hines¹, Zehua Sun¹, Weizao Chen⁷, Jana L Jacobs⁶, Simon M Barratt-Boyes³, John W Mellors^{6

7}, Ralph S Baric⁴, Ivet Bahar⁵, Dimiter S Dimitrov^{1

7}, Sriram Subramaniam^{2

8}, David R Martinez⁴, Wei Li¹

Affiliations

¹ Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
² Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
³ Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁷ Abound Bio, Pittsburgh, PA, USA.
⁸ Gandeeva Therapeutics, Inc., Vancouver, BC, Canada.

Abstract

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human V_H domain, F6, which we generated by sequentially panning large phage-displayed V_H libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V_H domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.

Keywords: Immunology; Virology.

Abstract

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