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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.
Chen, Chuan; Saville, James W; Marti, Michelle M; Schäfer, Alexandra; Cheng, Mary Hongying; Mannar, Dhiraj; Zhu, Xing; Berezuk, Alison M; Banerjee, Anupam; Sobolewski, Michele D; Kim, Andrew; Treat, Benjamin R; Da Silva Castanha, Priscila Mayrelle; Enick, Nathan; McCormick, Kevin D; Liu, Xianglei; Adams, Cynthia; Hines, Margaret Grace; Sun, Zehua; Chen, Weizao; Jacobs, Jana L; Barratt-Boyes, Simon M; Mellors, John W; Baric, Ralph S; Bahar, Ivet; Dimitrov, Dimiter S; Subramaniam, Sriram; Martinez, David R; Li, Wei.
  • Chen C; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Saville JW; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Marti MM; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Schäfer A; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Cheng MH; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Mannar D; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Zhu X; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Berezuk AM; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Banerjee A; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Sobolewski MD; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Kim A; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Treat BR; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Da Silva Castanha PM; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Enick N; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • McCormick KD; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Liu X; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Adams C; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Hines MG; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Sun Z; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Chen W; Abound Bio, Pittsburgh, PA, USA.
  • Jacobs JL; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Barratt-Boyes SM; Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • Mellors JW; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Baric RS; Abound Bio, Pittsburgh, PA, USA.
  • Bahar I; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Dimitrov DS; Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Subramaniam S; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
  • Martinez DR; Abound Bio, Pittsburgh, PA, USA.
  • Li W; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
iScience ; 25(8): 104798, 2022 Aug 19.
Article in English | MEDLINE | ID: covidwho-1936592
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 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.
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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Journal: IScience Year: 2022 Document Type: Article Affiliation country: J.isci.2022.104798

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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Journal: IScience Year: 2022 Document Type: Article Affiliation country: J.isci.2022.104798