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
  • 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: [email protected].
  • 12. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
  • 13. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: [email protected].
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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