Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Shane Miersch; Zhijie Li; Reza Saberianfar; Mart Ustav; James Brett Case; Levi Blazer; Chao Chen; Wei Ye; Alevtina Pavlenco; Maryna Gorelik; Julia Garcia Perez; Suryasree Subramania; Serena Singh; Lynda Ploder; Safder Ganaie; Rita E. Chen; Daisy W. Leung; Pier Paolo Pandolfi; Giuseppe Novelli; Giulia Matusali; Francesca Colavita; Maria R. Capobianchi; Suresh Jain; J. B. Gupta; Gaya K. Amarasinghe; Michael S. Diamond; James Rini; Sachdev S. Sidhu

doi:10.1016/j.jmb.2021.167177

Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

Shane Miersch, Zhijie Li, Reza Saberianfar, Mart Ustav, James Brett Case, Levi Blazer, Chao Chen, Wei Ye, Alevtina Pavlenco, Maryna Gorelik, Julia Garcia Perez, Suryasree Subramania, Serena Singh, Lynda Ploder, Safder Ganaie, Rita E. Chen, Daisy W. Leung, Pier Paolo Pandolfi, Giuseppe Novelli, Giulia MatusaliFrancesca Colavita, Maria R. Capobianchi, Suresh Jain, J. B. Gupta, Gaya K. Amarasinghe, Michael S. Diamond, James Rini, Sachdev S. Sidhu

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

26 Scopus citations

Abstract

Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.

Original language	English
Article number	167177
Journal	Journal of Molecular Biology
Volume	433
Issue number	19
DOIs	https://doi.org/10.1016/j.jmb.2021.167177
State	Published - Sep 17 2021

Keywords

RBD-binding
anti-viral
neutralizing
synthetic
tetravalent

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10.1016/j.jmb.2021.167177

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Miersch, S., Li, Z., Saberianfar, R., Ustav, M., Brett Case, J., Blazer, L., Chen, C., Ye, W., Pavlenco, A., Gorelik, M., Garcia Perez, J., Subramania, S., Singh, S., Ploder, L., Ganaie, S., Chen, R. E., Leung, D. W., Pandolfi, P. P., Novelli, G., ... Sidhu, S. S. (2021). Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations. Journal of Molecular Biology, 433(19), Article 167177. https://doi.org/10.1016/j.jmb.2021.167177

@article{f02f625a9eb7490bb482bb6640548221,

title = "Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations",

abstract = "Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.",

keywords = "RBD-binding, anti-viral, neutralizing, synthetic, tetravalent",

author = "Shane Miersch and Zhijie Li and Reza Saberianfar and Mart Ustav and {Brett Case}, James and Levi Blazer and Chao Chen and Wei Ye and Alevtina Pavlenco and Maryna Gorelik and {Garcia Perez}, Julia and Suryasree Subramania and Serena Singh and Lynda Ploder and Safder Ganaie and Chen, {Rita E.} and Leung, {Daisy W.} and Pandolfi, {Pier Paolo} and Giuseppe Novelli and Giulia Matusali and Francesca Colavita and Capobianchi, {Maria R.} and Suresh Jain and Gupta, {J. B.} and Amarasinghe, {Gaya K.} and Diamond, {Michael S.} and James Rini and Sidhu, {Sachdev S.}",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = sep,

day = "17",

doi = "10.1016/j.jmb.2021.167177",

language = "English",

volume = "433",

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Miersch, S, Li, Z, Saberianfar, R, Ustav, M, Brett Case, J, Blazer, L, Chen, C, Ye, W, Pavlenco, A, Gorelik, M, Garcia Perez, J, Subramania, S, Singh, S, Ploder, L, Ganaie, S, Chen, RE, Leung, DW, Pandolfi, PP, Novelli, G, Matusali, G, Colavita, F, Capobianchi, MR, Jain, S, Gupta, JB, Amarasinghe, GK , Diamond, MS, Rini, J & Sidhu, SS 2021, 'Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations', Journal of Molecular Biology, vol. 433, no. 19, 167177. https://doi.org/10.1016/j.jmb.2021.167177

TY - JOUR

T1 - Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

AU - Miersch, Shane

AU - Li, Zhijie

AU - Saberianfar, Reza

AU - Ustav, Mart

AU - Brett Case, James

AU - Blazer, Levi

AU - Chen, Chao

AU - Ye, Wei

AU - Pavlenco, Alevtina

AU - Gorelik, Maryna

AU - Garcia Perez, Julia

AU - Subramania, Suryasree

AU - Singh, Serena

AU - Ploder, Lynda

AU - Ganaie, Safder

AU - Chen, Rita E.

AU - Leung, Daisy W.

AU - Pandolfi, Pier Paolo

AU - Novelli, Giuseppe

AU - Matusali, Giulia

AU - Colavita, Francesca

AU - Capobianchi, Maria R.

AU - Jain, Suresh

AU - Gupta, J. B.

AU - Amarasinghe, Gaya K.

AU - Diamond, Michael S.

AU - Rini, James

AU - Sidhu, Sachdev S.

PY - 2021/9/17

Y1 - 2021/9/17

N2 - Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.

AB - Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.

KW - RBD-binding

KW - anti-viral

KW - neutralizing

KW - synthetic

KW - tetravalent

UR - http://www.scopus.com/inward/record.url?scp=85112226054&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2021.167177

DO - 10.1016/j.jmb.2021.167177

M3 - Article

C2 - 34329642

AN - SCOPUS:85112226054

SN - 0022-2836

VL - 433

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

IS - 19

M1 - 167177

ER -

Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations

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Keywords

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