| Autor: |
Thomas A. Desautels, Kathryn T. Arrildt, Adam T. Zemla, Edmond Y. Lau, Fangqiang Zhu, Dante Ricci, Stephanie Cronin, Seth J. Zost, Elad Binshtein, Suzanne M. Scheaffer, Bernadeta Dadonaite, Brenden K. Petersen, Taylor B. Engdahl, Elaine Chen, Laura S. Handal, Lynn Hall, John W. Goforth, Denis Vashchenko, Sam Nguyen, Dina R. Weilhammer, Jacky Kai-Yin Lo, Bonnee Rubinfeld, Edwin A. Saada, Tracy Weisenberger, Tek-Hyung Lee, Bradley Whitener, James B. Case, Alexander Ladd, Mary S. Silva, Rebecca M. Haluska, Emilia A. Grzesiak, Christopher G. Earnhart, Svetlana Hopkins, Thomas W. Bates, Larissa B. Thackray, Brent W. Segelke, Antonietta Maria Lillo, Shivshankar Sundaram, Jesse Bloom, Michael S. Diamond, James E. Crowe, Robert H. Carnahan, Daniel M. Faissol |
| Rok vydání: |
2022 |
| Zdroj: |
bioRxiv : the preprint server for biology. |
| Popis: |
The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1–3, but also revealed how quickly viral escape can curtail effective options4, 5. With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including EvusheldTMand its constituent, cilgavimab4, 6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4and 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 protectionin vivoagainst 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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