Potent bivalent nanobody constructs that protect against the SARS-CoV-2 XBB variant

Most antibody-based therapeutics approved for SARS-CoV-2 treatment have shown greatly reduced neutralization activity against emerging Omicron variants. To target recent Omicron variants, we developed XBB-specific antibody-like therapeutics by screening a yeast surface-displayed single-domain antibody library against the receptor binding domain of the XBB spike protein. Three lead nanobodies, XNb 4.13, XNb 4.14, and XNb 4.15, were selected based on their binding affinity to the XBB spike protein and were fused to a mouse Fc domain. While all three constructs showed sub-nanomolar binding affinities to the XBB S protein, XNb 4.13-Fc and XNb 4.14-Fc also neutralized XBB in vitro. Intraperitoneal injection of XNb 4.13-Fc and XNb 4.14-Fc and intranasal delivery of XNb 4.13-Fc protected transgenic mice from a challenge with XBB virus with a significant reduction in viral lung titers post-infection. These antibody-like constructs identified using yeast surface display have potential as therapeutics that can protect against SARS-CoV-2 XBB variants.