Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Young Jun Park; Anna De Marco; Tyler N. Starr; Zhuoming Liu; Dora Pinto; Alexandra C. Walls; Fabrizia Zatta; Samantha K. Zepeda; John E. Bowen; Kaitlin R. Sprouse; Anshu Joshi; Martina Giurdanella; Barbara Guarino; Julia Noack; Rana Abdelnabi; Shi Yan Caroline Foo; Laura E. Rosen; Florian A. Lempp; Fabio Benigni; Gyorgy Snell; Johan Neyts; Sean P.J. Whelan; Herbert W. Virgin; Jesse D. Bloom; Davide Corti; Matteo Samuele Pizzuto; David Veesler

doi:10.1126/science.abm8143

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Young Jun Park, Anna De Marco, Tyler N. Starr, Zhuoming Liu, Dora Pinto, Alexandra C. Walls, Fabrizia Zatta, Samantha K. Zepeda, John E. Bowen, Kaitlin R. Sprouse, Anshu Joshi, Martina Giurdanella, Barbara Guarino, Julia Noack, Rana Abdelnabi, Shi Yan Caroline Foo, Laura E. Rosen, Florian A. Lempp, Fabio Benigni, Gyorgy SnellJohan Neyts, Sean P.J. Whelan, Herbert W. Virgin, Jesse D. Bloom, Davide Corti, Matteo Samuele Pizzuto, David Veesler

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

40 Scopus citations

Abstract

Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta variant challenge in hamsters, and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.

Original language	English
Journal	Science
Volume	375
Issue number	6579
DOIs	https://doi.org/10.1126/science.abm8143
State	Published - Jan 28 2022

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Park, Y. J., De Marco, A., Starr, T. N., Liu, Z., Pinto, D., Walls, A. C., Zatta, F., Zepeda, S. K., Bowen, J. E., Sprouse, K. R., Joshi, A., Giurdanella, M., Guarino, B., Noack, J., Abdelnabi, R., Caroline Foo, S. Y., Rosen, L. E., Lempp, F. A., Benigni, F., ... Veesler, D. (2022). Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry. Science, 375(6579). https://doi.org/10.1126/science.abm8143

@article{c1beffab3ae04dd6b05f252133e3cbea,

title = "Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry",

abstract = "Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta variant challenge in hamsters, and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.",

author = "Park, {Young Jun} and {De Marco}, Anna and Starr, {Tyler N.} and Zhuoming Liu and Dora Pinto and Walls, {Alexandra C.} and Fabrizia Zatta and Zepeda, {Samantha K.} and Bowen, {John E.} and Sprouse, {Kaitlin R.} and Anshu Joshi and Martina Giurdanella and Barbara Guarino and Julia Noack and Rana Abdelnabi and {Caroline Foo}, {Shi Yan} and Rosen, {Laura E.} and Lempp, {Florian A.} and Fabio Benigni and Gyorgy Snell and Johan Neyts and Whelan, {Sean P.J.} and Virgin, {Herbert W.} and Bloom, {Jesse D.} and Davide Corti and Pizzuto, {Matteo Samuele} and David Veesler",

note = "Funding Information: S2K146 therefore overcomes the mutational plasticity of the RBM, which is implicated in immune evasion, by targeting residues required for binding to the ACE2 receptor. This is supported by S2K146 recognition of the reconstructed RBD ancestor of SARS-CoV and Publisher Copyright: {\textcopyright} 2022 American Association for the Advancement of Science. All rights reserved.",

year = "2022",

month = jan,

day = "28",

doi = "10.1126/science.abm8143",

language = "English",

volume = "375",

journal = "Science",

issn = "0036-8075",

number = "6579",

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Park, YJ, De Marco, A, Starr, TN, Liu, Z, Pinto, D, Walls, AC, Zatta, F, Zepeda, SK, Bowen, JE, Sprouse, KR, Joshi, A, Giurdanella, M, Guarino, B, Noack, J, Abdelnabi, R, Caroline Foo, SY, Rosen, LE, Lempp, FA, Benigni, F, Snell, G, Neyts, J, Whelan, SPJ, Virgin, HW, Bloom, JD, Corti, D, Pizzuto, MS & Veesler, D 2022, 'Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry', Science, vol. 375, no. 6579. https://doi.org/10.1126/science.abm8143

TY - JOUR

T1 - Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

AU - Park, Young Jun

AU - De Marco, Anna

AU - Starr, Tyler N.

AU - Liu, Zhuoming

AU - Pinto, Dora

AU - Walls, Alexandra C.

AU - Zatta, Fabrizia

AU - Zepeda, Samantha K.

AU - Bowen, John E.

AU - Sprouse, Kaitlin R.

AU - Joshi, Anshu

AU - Giurdanella, Martina

AU - Guarino, Barbara

AU - Noack, Julia

AU - Abdelnabi, Rana

AU - Caroline Foo, Shi Yan

AU - Rosen, Laura E.

AU - Lempp, Florian A.

AU - Benigni, Fabio

AU - Snell, Gyorgy

AU - Neyts, Johan

AU - Whelan, Sean P.J.

AU - Virgin, Herbert W.

AU - Bloom, Jesse D.

AU - Corti, Davide

AU - Pizzuto, Matteo Samuele

AU - Veesler, David

N1 - Funding Information: S2K146 therefore overcomes the mutational plasticity of the RBM, which is implicated in immune evasion, by targeting residues required for binding to the ACE2 receptor. This is supported by S2K146 recognition of the reconstructed RBD ancestor of SARS-CoV and Publisher Copyright: © 2022 American Association for the Advancement of Science. All rights reserved.

PY - 2022/1/28

Y1 - 2022/1/28

N2 - Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta variant challenge in hamsters, and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.

AB - Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2) as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta variant challenge in hamsters, and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.

UR - http://www.scopus.com/inward/record.url?scp=85123631387&partnerID=8YFLogxK

U2 - 10.1126/science.abm8143

DO - 10.1126/science.abm8143

M3 - Article

C2 - 34990214

AN - SCOPUS:85123631387

SN - 0036-8075

VL - 375

JO - Science

JF - Science

IS - 6579

ER -

Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

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