A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification

Affiliations

• Vir Biotechnology, San Francisco, CA 94158, USA
• Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
• Humabs BioMed SA, a Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
• Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
• Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
• ProtaBody, Pasadena, CA 91105, USA
• Institut Pasteur, Université Paris Cité, Lyssavirus Epidemiology and Neuropathology Unit, F-75015 Paris, France
• 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
• Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA

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.

SARS-CoV-2的突变进化导致病毒对获临床授权的单克隆抗体（mAbs）产品免疫逃逸，因此迫切需要开发出针对表位多样化具备中和活性的单克隆抗体。我们发现了一种人源单克隆抗体，命名为VIR-7229，能够靶向病毒受体结合模体（RBM），对所有沙贝冠状病毒谱系，包括不利用ACE2的蝙蝠沙贝冠状病毒，具有前所未有的交叉反应性，同时有效中和自2019年以来的SARS-CoV-2变异株，包括最近的EG.5、BA.2.86和JN.1。VIR-7229能够耐受极大的表位变异，这部分归因于其高结合亲和力、受体分子模拟及与RBM主链原子的相互作用。因此，VIR-7229具有选择逃逸突变的高障碍，这些突变很少出现且与病毒适应性降低相关，凸显了其对未来病毒进化的抵抗潜力。VIR-7229是下一代药物的有力候选者。