iScience (Aug 2022)
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
Affiliations
- Chuan Chen
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- James W. Saville
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Michelle M. Marti
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
- Alexandra Schäfer
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Mary Hongying Cheng
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Dhiraj Mannar
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Xing Zhu
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Alison M. Berezuk
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Anupam Banerjee
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Michele D. Sobolewski
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Andrew Kim
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- Benjamin R. Treat
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
- Priscila Mayrelle Da Silva Castanha
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
- Nathan Enick
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Kevin D. McCormick
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Xianglei Liu
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- Cynthia Adams
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- Margaret Grace Hines
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- Zehua Sun
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
- Weizao Chen
- Abound Bio, Pittsburgh, PA, USA
- Jana L. Jacobs
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Simon M. Barratt-Boyes
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
- John W. Mellors
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Abound Bio, Pittsburgh, PA, USA
- Ralph S. Baric
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Ivet Bahar
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Dimiter S. Dimitrov
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA; Abound Bio, Pittsburgh, PA, USA; Corresponding author
- Sriram Subramaniam
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Gandeeva Therapeutics, Inc., Vancouver, BC, Canada; Corresponding author
- David R. Martinez
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
- Wei Li
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 8
p. 104798
Abstract
Summary: 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 VH domain, F6, which we generated by sequentially panning large phage-displayed VH 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 VH 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.
