Receptor-mimicking antibodies retain neutralization of recent SARS-CoV-2 variants

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised the efficacy of many neutralizing antibodies. Receptor-mimicking antibodies, whose binding modes partially resemble those of angiotensin-converting enzyme 2 (ACE2), are of particular interest as they recognize functionally constrained regions of the receptor-binding domain (RBD). However, whether these antibodies retain activity against newly emerged SARS-CoV-2 variants remains unclear. In this study, two representative receptor-mimicking antibodies, VIR-7229 and S2K146, were evaluated alongside S2H13, another RBD-targeting antibody. VIR-7229 and S2K146 retained neutralizing activity better than S2H13, with VIR-7229 showing the greatest retention. VIR-7229 potently neutralized the Wuhan-Hu-1, BA.1, XBB.1.5, and BA.2.86 variants and exhibited reduced yet considerable neutralizing activity against KP.3.1.1, XEC, and XEC.25.1. Enzyme-linked immunosorbent assay (ELISA) and biolayer interferometry further demonstrated that VIR-7229 maintained strong binding to spike proteins from recent variants. Computational structural analysis suggested that mutations in these variants may weaken VIR-7229 binding to the RBD but do not fully disrupt the antibody-RBD interface. These findings indicate that VIR-7229 retains considerable neutralizing activity and robust spike recognition against recent SARS-CoV-2 variants, likely through recognition of a functional interface involved in ACE2 binding. This study supports further evaluation of receptor-mimicking antibodies and may inform the design of candidate immunogens against evolving SARS-CoV-2 variants.