A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification

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. [Display omitted] •Potent anti-SARS-CoV-2 mAb VIR-7229 is derived from human memory B cells•VIR-7229 uniquely competes with ACE2 and has pan-sarbecovirus breadth•VIR-7229 is resilient to epitope variation and has a high barrier to viral escape•VIR-7229 is a strong candidate to become a next-generation medicine A monoclonal antibody VIR-7229 uniquely combines potent SARS-CoV-2 inhibition via ACE2 competition with pan-sarbecovirus and pan-variant cross-reactivity and a high barrier to viral escape. This antibody may be resilient to SARS-CoV-2 evolution, with potential to be a next-generation COVID-19 medicine and a key component of pandemic preparedness in the event of a novel emerging sarbecovirus.