A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection

Lucas J. Adams; Laura A. VanBlargan; Zhuoming Liu; Pavlo Gilchuk; Haiyan Zhao; Rita E. Chen; Saravanan Raju; Zhenlu Chong; Bradley M. Whitener; Swathi Shrihari; Prashant N. Jethva; Michael L. Gross; James E. Crowe; Sean P.J. Whelan; Michael S. Diamond; Daved H. Fremont

doi:10.1016/j.xcrm.2023.101305

A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection

Lucas J. Adams, Laura A. VanBlargan, Zhuoming Liu, Pavlo Gilchuk, Haiyan Zhao, Rita E. Chen, Saravanan Raju, Zhenlu Chong, Bradley M. Whitener, Swathi Shrihari, Prashant N. Jethva, Michael L. Gross, James E. Crowe, Sean P.J. Whelan, Michael S. Diamond, Daved H. Fremont

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4 Scopus citations

Abstract

Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape.

Original language	English
Article number	101305
Journal	Cell Reports Medicine
Volume	4
Issue number	12
DOIs	https://doi.org/10.1016/j.xcrm.2023.101305
State	Published - Dec 19 2023

Keywords

B cell epitope mapping
SARS-CoV-2
cryo-EM
neutralizing antibodies
variants of concern

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10.1016/j.xcrm.2023.101305

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Adams, L. J., VanBlargan, L. A., Liu, Z., Gilchuk, P., Zhao, H., Chen, R. E., Raju, S., Chong, Z., Whitener, B. M., Shrihari, S., Jethva, P. N., Gross, M. L., Crowe, J. E., Whelan, S. P. J., Diamond, M. S., & Fremont, D. H. (2023). A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection. Cell Reports Medicine, 4(12), Article 101305. https://doi.org/10.1016/j.xcrm.2023.101305

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title = "A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection",

abstract = "Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape.",

keywords = "B cell epitope mapping, SARS-CoV-2, cryo-EM, neutralizing antibodies, variants of concern",

author = "Adams, {Lucas J.} and VanBlargan, {Laura A.} and Zhuoming Liu and Pavlo Gilchuk and Haiyan Zhao and Chen, {Rita E.} and Saravanan Raju and Zhenlu Chong and Whitener, {Bradley M.} and Swathi Shrihari and Jethva, {Prashant N.} and Gross, {Michael L.} and Crowe, {James E.} and Whelan, {Sean P.J.} and Diamond, {Michael S.} and Fremont, {Daved H.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = dec,

day = "19",

doi = "10.1016/j.xcrm.2023.101305",

language = "English",

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Adams, LJ, VanBlargan, LA, Liu, Z, Gilchuk, P, Zhao, H, Chen, RE, Raju, S, Chong, Z, Whitener, BM, Shrihari, S, Jethva, PN, Gross, ML, Crowe, JE, Whelan, SPJ , Diamond, MS & Fremont, DH 2023, 'A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection', Cell Reports Medicine, vol. 4, no. 12, 101305. https://doi.org/10.1016/j.xcrm.2023.101305

TY - JOUR

T1 - A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection

AU - Adams, Lucas J.

AU - VanBlargan, Laura A.

AU - Liu, Zhuoming

AU - Gilchuk, Pavlo

AU - Zhao, Haiyan

AU - Chen, Rita E.

AU - Raju, Saravanan

AU - Chong, Zhenlu

AU - Whitener, Bradley M.

AU - Shrihari, Swathi

AU - Jethva, Prashant N.

AU - Gross, Michael L.

AU - Crowe, James E.

AU - Whelan, Sean P.J.

AU - Diamond, Michael S.

AU - Fremont, Daved H.

PY - 2023/12/19

Y1 - 2023/12/19

N2 - Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape.

AB - Most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) target the receptor binding domain (RBD) of the spike (S) protein. Here, we characterize a panel of mAbs targeting the N-terminal domain (NTD) or other non-RBD epitopes of S. A subset of NTD mAbs inhibits SARS-CoV-2 entry at a post-attachment step and avidly binds the surface of infected cells. One neutralizing NTD mAb, SARS2-57, protects K18-hACE2 mice against SARS-CoV-2 infection in an Fc-dependent manner. Structural analysis demonstrates that SARS2-57 engages an antigenic supersite that is remodeled by deletions common to emerging variants. In neutralization escape studies with SARS2-57, this NTD site accumulates mutations, including a similar deletion, but the addition of an anti-RBD mAb prevents such escape. Thus, our study highlights a common strategy of immune evasion by SARS-CoV-2 variants and how targeting spatially distinct epitopes, including those in the NTD, may limit such escape.

KW - B cell epitope mapping

KW - SARS-CoV-2

KW - cryo-EM

KW - neutralizing antibodies

KW - variants of concern

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U2 - 10.1016/j.xcrm.2023.101305

DO - 10.1016/j.xcrm.2023.101305

M3 - Article

C2 - 38039973

AN - SCOPUS:85180354711

SN - 2666-3791

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 12

M1 - 101305

ER -

A broadly reactive antibody targeting the N-terminal domain of SARS-CoV-2 spike confers Fc-mediated protection

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