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Cell
. 2024 Oct 4:S0092-8674(24)01084-5.
doi: 10.1016/j.cell.2024.09.026. Online ahead of print. A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification
Laura E Rosen 1 , M Alejandra Tortorici 2 , Anna De Marco 3 , Dora Pinto 3 , William B Foreman 4 , Ashley L Taylor 4 , Young-Jun Park 5 , Dana Bohan 1 , Tyson Rietz 1 , John M Errico 1 , Kevin Hauser 1 , Ha V Dang 1 , Justin W Chartron 6 , Martina Giurdanella 3 , Giuseppe Cusumano 3 , Christian Saliba 3 , Fabrizia Zatta 3 , Kaitlin R Sprouse 2 , Amin Addetia 2 , Samantha K Zepeda 2 , Jack Brown 2 , Jimin Lee 2 , Exequiel Dellota Jr 1 , Anushka Rajesh 1 , Julia Noack 1 , Qiqing Tao 1 , Yvonne DaCosta 1 , Brian Tsu 1 , Rima Acosta 1 , Sambhavi Subramanian 1 , Guilherme Dias de Melo 7 , Lauriane Kergoat 7 , Ivy Zhang 8 , Zhuoming Liu 9 , Barbara Guarino 3 , Michael A Schmid 3 , Gretja Schnell 1 , Jessica L Miller 1 , Florian A Lempp 10 , Nadine Czudnochowski 1 , Elisabetta Cameroni 3 , Sean P J Whelan 9 , Hervé Bourhy 7 , Lisa A Purcell 1 , Fabio Benigni 3 , Julia di Iulio 1 , Matteo Samuele Pizzuto 3 , Antonio Lanzavecchia 3 , Amalio Telenti 1 , Gyorgy Snell 1 , Davide Corti 11 , David Veesler 12 , Tyler N Starr 13
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.
Keywords: SARS-CoV-2; broadly neutralizing antibody; monoclonal antibody; sarbecovirus; viral antibody escape.
. 2024 Oct 4:S0092-8674(24)01084-5.
doi: 10.1016/j.cell.2024.09.026. Online ahead of print. A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification
Laura E Rosen 1 , M Alejandra Tortorici 2 , Anna De Marco 3 , Dora Pinto 3 , William B Foreman 4 , Ashley L Taylor 4 , Young-Jun Park 5 , Dana Bohan 1 , Tyson Rietz 1 , John M Errico 1 , Kevin Hauser 1 , Ha V Dang 1 , Justin W Chartron 6 , Martina Giurdanella 3 , Giuseppe Cusumano 3 , Christian Saliba 3 , Fabrizia Zatta 3 , Kaitlin R Sprouse 2 , Amin Addetia 2 , Samantha K Zepeda 2 , Jack Brown 2 , Jimin Lee 2 , Exequiel Dellota Jr 1 , Anushka Rajesh 1 , Julia Noack 1 , Qiqing Tao 1 , Yvonne DaCosta 1 , Brian Tsu 1 , Rima Acosta 1 , Sambhavi Subramanian 1 , Guilherme Dias de Melo 7 , Lauriane Kergoat 7 , Ivy Zhang 8 , Zhuoming Liu 9 , Barbara Guarino 3 , Michael A Schmid 3 , Gretja Schnell 1 , Jessica L Miller 1 , Florian A Lempp 10 , Nadine Czudnochowski 1 , Elisabetta Cameroni 3 , Sean P J Whelan 9 , Hervé Bourhy 7 , Lisa A Purcell 1 , Fabio Benigni 3 , Julia di Iulio 1 , Matteo Samuele Pizzuto 3 , Antonio Lanzavecchia 3 , Amalio Telenti 1 , Gyorgy Snell 1 , Davide Corti 11 , David Veesler 12 , Tyler N Starr 13
Affiliations
- PMID: 39383863
- DOI: 10.1016/j.cell.2024.09.026
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.
Keywords: SARS-CoV-2; broadly neutralizing antibody; monoclonal antibody; sarbecovirus; viral antibody escape.