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

doi:10.1016/j.isci.2022.104798

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

Laufer Center for Physical and Quantitative Biology

University of Pittsburgh
University of British Columbia
University of North Carolina at Chapel Hill
Galapagos NV

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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 V_H domain, F6, which we generated by sequentially panning large phage-displayed V_H 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 V_H 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.

Original language	English
Article number	104798
Journal	iScience
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.isci.2022.104798
State	Published - Aug 19 2022

Keywords

Immunology
Virology

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10.1016/j.isci.2022.104798

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Chen, C., Saville, J. W., Marti, M. M., Schäfer, A., Cheng, M. H., Mannar, D., Zhu, X., Berezuk, A. M., Banerjee, A., Sobolewski, M. D., Kim, A., Treat, B. R., Da Silva Castanha, P. M., Enick, N., McCormick, K. D., Liu, X., Adams, C., Hines, M. G., Sun, Z., ... Li, W. (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. iScience, 25(8), Article 104798. https://doi.org/10.1016/j.isci.2022.104798

@article{ff19ce776e0b43838599b243f08620b6,

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",

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.",

keywords = "Immunology, Virology",

author = "Chuan Chen and Saville, \{James W.\} and Marti, \{Michelle M.\} and Alexandra Sch{\"a}fer and Cheng, \{Mary Hongying\} and Dhiraj Mannar and Xing Zhu and Berezuk, \{Alison M.\} and Anupam Banerjee and Sobolewski, \{Michele D.\} and Andrew Kim and Treat, \{Benjamin R.\} and \{Da Silva Castanha\}, \{Priscila Mayrelle\} and Nathan Enick and McCormick, \{Kevin D.\} and Xianglei Liu and Cynthia Adams and Hines, \{Margaret Grace\} and Zehua Sun and Weizao Chen and Jacobs, \{Jana L.\} and Barratt-Boyes, \{Simon M.\} and Mellors, \{John W.\} and Baric, \{Ralph S.\} and Ivet Bahar and Dimitrov, \{Dimiter S.\} and Sriram Subramaniam and Martinez, \{David R.\} and Wei Li",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = aug,

day = "19",

doi = "10.1016/j.isci.2022.104798",

language = "English",

volume = "25",

journal = "iScience",

issn = "2589-0042",

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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 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', iScience, vol. 25, no. 8, 104798. https://doi.org/10.1016/j.isci.2022.104798

TY - JOUR

T1 - 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

AU - Chen, Chuan

AU - Saville, James W.

AU - Marti, Michelle M.

AU - Schäfer, Alexandra

AU - Cheng, Mary Hongying

AU - Mannar, Dhiraj

AU - Zhu, Xing

AU - Berezuk, Alison M.

AU - Banerjee, Anupam

AU - Sobolewski, Michele D.

AU - Kim, Andrew

AU - Treat, Benjamin R.

AU - Da Silva Castanha, Priscila Mayrelle

AU - Enick, Nathan

AU - McCormick, Kevin D.

AU - Liu, Xianglei

AU - Adams, Cynthia

AU - Hines, Margaret Grace

AU - Sun, Zehua

AU - Chen, Weizao

AU - Jacobs, Jana L.

AU - Barratt-Boyes, Simon M.

AU - Mellors, John W.

AU - Baric, Ralph S.

AU - Bahar, Ivet

AU - Dimitrov, Dimiter S.

AU - Subramaniam, Sriram

AU - Martinez, David R.

AU - Li, Wei

PY - 2022/8/19

Y1 - 2022/8/19

N2 - 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.

AB - 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.

KW - Immunology

KW - Virology

UR - https://www.scopus.com/pages/publications/85135879816

U2 - 10.1016/j.isci.2022.104798

DO - 10.1016/j.isci.2022.104798

M3 - Article

AN - SCOPUS:85135879816

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 8

M1 - 104798

ER -

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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