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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
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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
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Date Issued |
2022-08-19
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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.
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Genre | |
Type | |
Language |
eng
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Date Available |
2022-12-13
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution 4.0 International
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DOI |
10.14288/1.0422510
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URI | |
Affiliation | |
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.
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Publisher DOI |
10.1016/j.isci.2022.104798
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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Rights URI | |
Aggregated Source Repository |
DSpace
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Item Citations and Data
Rights
Attribution 4.0 International