2. Academic Validation
  3. A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification

A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification

  • Cell. 2024 Dec 12;187(25):7196-7213.e26. doi: 10.1016/j.cell.2024.09.026.
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

Affiliations

  • 1 Vir Biotechnology, San Francisco, CA 94158, USA.
  • 2 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • 3 Humabs BioMed SA, a Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
  • 4 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  • 5 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
  • 6 ProtaBody, Pasadena, CA 91105, USA.
  • 7 Institut Pasteur, Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit, F-75015 Paris, France.
  • 8 Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional PhD Program in Computational Biology and Medicine, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
  • 9 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 10 Vir Biotechnology, San Francisco, CA 94158, USA; Humabs BioMed SA, a Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
  • 11 Humabs BioMed SA, a Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland. Electronic address: dcorti@vir.bio.
  • 12 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: dveesler@uw.edu.
  • 13 Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: tyler.starr@biochem.utah.edu.
PMID: 39383863 DOI: 10.1016/j.cell.2024.09.026
Abstract

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.

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