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Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs(1–3), but also revealed how quickly viral escape can curtail effective options(4,5). With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug pro...

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Autores principales: Desautels, Thomas A., Arrildt, Kathryn T., Zemla, Adam T., Lau, Edmond Y., Zhu, Fangqiang, Ricci, Dante, Cronin, Stephanie, Zost, Seth J., Binshtein, Elad, Scheaffer, Suzanne M., Dadonaite, Bernadeta, Petersen, Brenden K., Engdahl, Taylor B., Chen, Elaine, Handal, Laura S., Hall, Lynn, Goforth, John W., Vashchenko, Denis, Nguyen, Sam, Weilhammer, Dina R., Lo, Jacky Kai-Yin, Rubinfeld, Bonnee, Saada, Edwin A., Weisenberger, Tracy, Lee, Tek-Hyung, Whitener, Bradley, Case, James B., Ladd, Alexander, Silva, Mary S., Haluska, Rebecca M., Grzesiak, Emilia A., Earnhart, Christopher G., Hopkins, Svetlana, Bates, Thomas W., Thackray, Larissa B., Segelke, Brent W., Lillo, Antonietta Maria, Sundaram, Shivshankar, Bloom, Jesse, Diamond, Michael S., Crowe, James E., Carnahan, Robert H., Faissol, Daniel M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628197/
https://www.ncbi.nlm.nih.gov/pubmed/36324800
http://dx.doi.org/10.1101/2022.10.21.513237
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author Desautels, Thomas A.
Arrildt, Kathryn T.
Zemla, Adam T.
Lau, Edmond Y.
Zhu, Fangqiang
Ricci, Dante
Cronin, Stephanie
Zost, Seth J.
Binshtein, Elad
Scheaffer, Suzanne M.
Dadonaite, Bernadeta
Petersen, Brenden K.
Engdahl, Taylor B.
Chen, Elaine
Handal, Laura S.
Hall, Lynn
Goforth, John W.
Vashchenko, Denis
Nguyen, Sam
Weilhammer, Dina R.
Lo, Jacky Kai-Yin
Rubinfeld, Bonnee
Saada, Edwin A.
Weisenberger, Tracy
Lee, Tek-Hyung
Whitener, Bradley
Case, James B.
Ladd, Alexander
Silva, Mary S.
Haluska, Rebecca M.
Grzesiak, Emilia A.
Earnhart, Christopher G.
Hopkins, Svetlana
Bates, Thomas W.
Thackray, Larissa B.
Segelke, Brent W.
Lillo, Antonietta Maria
Sundaram, Shivshankar
Bloom, Jesse
Diamond, Michael S.
Crowe, James E.
Carnahan, Robert H.
Faissol, Daniel M.
author_facet Desautels, Thomas A.
Arrildt, Kathryn T.
Zemla, Adam T.
Lau, Edmond Y.
Zhu, Fangqiang
Ricci, Dante
Cronin, Stephanie
Zost, Seth J.
Binshtein, Elad
Scheaffer, Suzanne M.
Dadonaite, Bernadeta
Petersen, Brenden K.
Engdahl, Taylor B.
Chen, Elaine
Handal, Laura S.
Hall, Lynn
Goforth, John W.
Vashchenko, Denis
Nguyen, Sam
Weilhammer, Dina R.
Lo, Jacky Kai-Yin
Rubinfeld, Bonnee
Saada, Edwin A.
Weisenberger, Tracy
Lee, Tek-Hyung
Whitener, Bradley
Case, James B.
Ladd, Alexander
Silva, Mary S.
Haluska, Rebecca M.
Grzesiak, Emilia A.
Earnhart, Christopher G.
Hopkins, Svetlana
Bates, Thomas W.
Thackray, Larissa B.
Segelke, Brent W.
Lillo, Antonietta Maria
Sundaram, Shivshankar
Bloom, Jesse
Diamond, Michael S.
Crowe, James E.
Carnahan, Robert H.
Faissol, Daniel M.
author_sort Desautels, Thomas A.
collection PubMed
description The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs(1–3), but also revealed how quickly viral escape can curtail effective options(4,5). With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld(™) and its constituent, cilgavimab(4,6). Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination(4) and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies with a known clinical profile to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign COV2-2130 to rescue in vivo efficacy against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the contemporaneously dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and many variants of concern that subsequently emerged, and provides protection in vivo against the strains tested, WA1/2020, BA.1.1, and BA.5. Deep mutational scanning of tens of thousands pseudovirus variants reveals 2130-1-0114-112 improves broad potency without incurring additional escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Because our approach is computationally driven, not requiring experimental iterations or pre-existing binding data, it could enable rapid response strategies to address escape variants or pre-emptively mitigate escape vulnerabilities.
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spelling pubmed-96281972022-11-03 Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants Desautels, Thomas A. Arrildt, Kathryn T. Zemla, Adam T. Lau, Edmond Y. Zhu, Fangqiang Ricci, Dante Cronin, Stephanie Zost, Seth J. Binshtein, Elad Scheaffer, Suzanne M. Dadonaite, Bernadeta Petersen, Brenden K. Engdahl, Taylor B. Chen, Elaine Handal, Laura S. Hall, Lynn Goforth, John W. Vashchenko, Denis Nguyen, Sam Weilhammer, Dina R. Lo, Jacky Kai-Yin Rubinfeld, Bonnee Saada, Edwin A. Weisenberger, Tracy Lee, Tek-Hyung Whitener, Bradley Case, James B. Ladd, Alexander Silva, Mary S. Haluska, Rebecca M. Grzesiak, Emilia A. Earnhart, Christopher G. Hopkins, Svetlana Bates, Thomas W. Thackray, Larissa B. Segelke, Brent W. Lillo, Antonietta Maria Sundaram, Shivshankar Bloom, Jesse Diamond, Michael S. Crowe, James E. Carnahan, Robert H. Faissol, Daniel M. bioRxiv Article The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs(1–3), but also revealed how quickly viral escape can curtail effective options(4,5). With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld(™) and its constituent, cilgavimab(4,6). Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination(4) and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies with a known clinical profile to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign COV2-2130 to rescue in vivo efficacy against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the contemporaneously dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and many variants of concern that subsequently emerged, and provides protection in vivo against the strains tested, WA1/2020, BA.1.1, and BA.5. Deep mutational scanning of tens of thousands pseudovirus variants reveals 2130-1-0114-112 improves broad potency without incurring additional escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Because our approach is computationally driven, not requiring experimental iterations or pre-existing binding data, it could enable rapid response strategies to address escape variants or pre-emptively mitigate escape vulnerabilities. Cold Spring Harbor Laboratory 2023-04-24 /pmc/articles/PMC9628197/ /pubmed/36324800 http://dx.doi.org/10.1101/2022.10.21.513237 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Desautels, Thomas A.
Arrildt, Kathryn T.
Zemla, Adam T.
Lau, Edmond Y.
Zhu, Fangqiang
Ricci, Dante
Cronin, Stephanie
Zost, Seth J.
Binshtein, Elad
Scheaffer, Suzanne M.
Dadonaite, Bernadeta
Petersen, Brenden K.
Engdahl, Taylor B.
Chen, Elaine
Handal, Laura S.
Hall, Lynn
Goforth, John W.
Vashchenko, Denis
Nguyen, Sam
Weilhammer, Dina R.
Lo, Jacky Kai-Yin
Rubinfeld, Bonnee
Saada, Edwin A.
Weisenberger, Tracy
Lee, Tek-Hyung
Whitener, Bradley
Case, James B.
Ladd, Alexander
Silva, Mary S.
Haluska, Rebecca M.
Grzesiak, Emilia A.
Earnhart, Christopher G.
Hopkins, Svetlana
Bates, Thomas W.
Thackray, Larissa B.
Segelke, Brent W.
Lillo, Antonietta Maria
Sundaram, Shivshankar
Bloom, Jesse
Diamond, Michael S.
Crowe, James E.
Carnahan, Robert H.
Faissol, Daniel M.
Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants
title Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants
title_full Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants
title_fullStr Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants
title_full_unstemmed Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants
title_short Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants
title_sort computationally restoring the potency of a clinical antibody against sars-cov-2 omicron subvariants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628197/
https://www.ncbi.nlm.nih.gov/pubmed/36324800
http://dx.doi.org/10.1101/2022.10.21.513237
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