Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Naveenchandra Suryadevara; Swathi Shrihari; Pavlo Gilchuk; Laura A. VanBlargan; Elad Binshtein; Seth J. Zost; Rachel S. Nargi; Rachel E. Sutton; Emma S. Winkler; Elaine C. Chen; Mallorie E. Fouch; Edgar Davidson; Benjamin J. Doranz; Rita E. Chen; Pei Yong Shi; Robert H. Carnahan; Larissa B. Thackray; Michael S. Diamond; James E. Crowe

doi:10.1016/j.cell.2021.03.029

Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Naveenchandra Suryadevara, Swathi Shrihari, Pavlo Gilchuk, Laura A. VanBlargan, Elad Binshtein, Seth J. Zost, Rachel S. Nargi, Rachel E. Sutton, Emma S. Winkler, Elaine C. Chen, Mallorie E. Fouch, Edgar Davidson, Benjamin J. Doranz, Rita E. Chen, Pei Yong Shi, Robert H. Carnahan, Larissa B. Thackray, Michael S. Diamond, James E. Crowe

Biochemistry & Molecular Biology

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

6 Scopus citations

Abstract

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

Original language	English (US)
Pages (from-to)	2316-2331.e15
Journal	Cell
Volume	184
Issue number	9
DOIs	https://doi.org/10.1016/j.cell.2021.03.029
State	Published - Apr 29 2021

Keywords

N-terminal domain
SARS-CoV-2
coronavirus
monoclonal antibodies
neutralizing antibodies
viral antibodies

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2021.03.029

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Suryadevara, N., Shrihari, S., Gilchuk, P., VanBlargan, L. A., Binshtein, E., Zost, S. J., Nargi, R. S., Sutton, R. E., Winkler, E. S., Chen, E. C., Fouch, M. E., Davidson, E., Doranz, B. J., Chen, R. E., Shi, P. Y., Carnahan, R. H., Thackray, L. B., Diamond, M. S., & Crowe, J. E. (2021). Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein. Cell, 184(9), 2316-2331.e15. https://doi.org/10.1016/j.cell.2021.03.029

Suryadevara, N, Shrihari, S, Gilchuk, P, VanBlargan, LA, Binshtein, E, Zost, SJ, Nargi, RS, Sutton, RE, Winkler, ES, Chen, EC, Fouch, ME, Davidson, E, Doranz, BJ, Chen, RE, Shi, PY, Carnahan, RH, Thackray, LB, Diamond, MS & Crowe, JE 2021, 'Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein', Cell, vol. 184, no. 9, pp. 2316-2331.e15. https://doi.org/10.1016/j.cell.2021.03.029

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title = "Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein",

abstract = "Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.",

keywords = "N-terminal domain, SARS-CoV-2, coronavirus, monoclonal antibodies, neutralizing antibodies, viral antibodies",

author = "Naveenchandra Suryadevara and Swathi Shrihari and Pavlo Gilchuk and VanBlargan, {Laura A.} and Elad Binshtein and Zost, {Seth J.} and Nargi, {Rachel S.} and Sutton, {Rachel E.} and Winkler, {Emma S.} and Chen, {Elaine C.} and Fouch, {Mallorie E.} and Edgar Davidson and Doranz, {Benjamin J.} and Chen, {Rita E.} and Shi, {Pei Yong} and Carnahan, {Robert H.} and Thackray, {Larissa B.} and Diamond, {Michael S.} and Crowe, {James E.}",

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doi = "10.1016/j.cell.2021.03.029",

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AU - Suryadevara, Naveenchandra

AU - Shrihari, Swathi

AU - Gilchuk, Pavlo

AU - VanBlargan, Laura A.

AU - Binshtein, Elad

AU - Zost, Seth J.

AU - Nargi, Rachel S.

AU - Sutton, Rachel E.

AU - Winkler, Emma S.

AU - Chen, Elaine C.

AU - Fouch, Mallorie E.

AU - Davidson, Edgar

AU - Doranz, Benjamin J.

AU - Chen, Rita E.

AU - Shi, Pei Yong

AU - Carnahan, Robert H.

AU - Thackray, Larissa B.

AU - Diamond, Michael S.

AU - Crowe, James E.

PY - 2021/4/29

Y1 - 2021/4/29

N2 - Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

AB - Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.

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KW - neutralizing antibodies

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JO - Cell

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ER -

Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

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ASJC Scopus subject areas

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