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

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  • Chen, Chuan
    • Other Affiliation: University of Pittsburgh Medical School
  • Saville, James W.
    • Other Affiliation: University of British Columbia
  • Marti, Michelle M.
    • Other Affiliation: University of Pittsburgh
  • Schäfer, Alexandra
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Cheng, Mary Hongying
    • Other Affiliation: University of Pittsburgh
  • Mannar, Dhiraj
    • Other Affiliation: University of British Columbia
  • Zhu, Xing
    • Other Affiliation: University of British Columbia
  • Berezuk, Alison M.
    • Other Affiliation: University of British Columbia
  • Banerjee, Anupam
    • Other Affiliation: University of Pittsburgh
  • Sobolewski, Michele D.
    • Other Affiliation: University of Pittsburgh
  • Kim, Andrew
    • Other Affiliation: University of Pittsburgh Medical School
  • Treat, Benjamin R.
    • Other Affiliation: University of Pittsburgh
  • Da Silva Castanha, Priscila Mayrelle
    • Other Affiliation: University of Pittsburgh
  • Enick, Nathan
    • Other Affiliation: University of Pittsburgh
  • McCormick, Kevin D.
    • Other Affiliation: University of Pittsburgh
  • Liu, Xianglei
    • Other Affiliation: University of Pittsburgh Medical School
  • Adams, Cynthia
    • Other Affiliation: University of Pittsburgh Medical School
  • Hines, Margaret Grace
    • Other Affiliation: University of Pittsburgh Medical School
  • Sun, Zehua
    • Other Affiliation: University of Pittsburgh Medical School
  • Chen, Weizao
    • Other Affiliation: Abound Bio
  • Jacobs, Jana L.
    • Other Affiliation: University of Pittsburgh
  • Barratt-Boyes, Simon M.
    • Other Affiliation: University of Pittsburgh
  • Mellors, John W.
    • Other Affiliation: University of Pittsburgh
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Bahar, Ivet
    • Other Affiliation: University of Pittsburgh
  • Dimitrov, Dimiter S.
    • Other Affiliation: Abound Bio
  • Subramaniam, Sriram
    • Other Affiliation: University of British Columbia
  • Martinez, David R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Li, Wei
    • Other Affiliation: University of Pittsburgh Medical School
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 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 a 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.
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  • Article
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  • In Copyright
Journal title
  • iScience
Page start
  • 104798
Language
  • English
Version
  • Postprint
ISSN
  • 2589-0042

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