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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; Marti, Michelle M.; Schäfer, Alexandra; Cheng, Mary Hongying; Mannar, Dhiraj; Zhu, Xing; Berezuk, Alison; Banerjee, Anupam; Sobolewski, Michele D.; Kim, Andrew; Treat, Benjamin R.; Castanha, Priscila Mayrelle Da Silva; 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

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.

Item Metadata

Title
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
Creator
Chen, Chuan; Saville, James; Marti, Michelle M.; Schäfer, Alexandra; Cheng, Mary Hongying; Mannar, Dhiraj; Zhu, Xing; Berezuk, Alison; Banerjee, Anupam; Sobolewski, Michele D.; Kim, Andrew; Treat, Benjamin R.; Castanha, Priscila Mayrelle Da Silva; 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
Date Issued
2022-08-19
Description
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.
Genre
Article
Type
Text
Language
eng
Date Available
2022-12-13
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International
DOI
10.14288/1.0422510
URI
http://hdl.handle.net/2429/83414
Affiliation
Medicine, Faculty of; Non UBC; Biochemistry and Molecular Biology, Department of
Citation
Chen C, Saville JW, Marti MM, Schäfer A, Cheng MH, Mannar D, Zhu X, Berezuk AM, Banerjee A, Sobolewski MD, Kim A, Treat BR, Da Silva Castanha PM, Enick N, McCormick KD, Liu X, Adams C, Hines MG, Sun Z, Chen W, Jacobs JL, Barratt-Boyes SM, Mellors JW, Baric RS, Bahar I, Dimitrov DS, Subramaniam S, Martinez DR, Li W. 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.
Publisher DOI
10.1016/j.isci.2022.104798
Peer Review Status
Reviewed
Scholarly Level
Faculty
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International