Broadly neutralizing single-domain antibody targeting the spike NTD displays therapeutic efficacy against diverse SARS-CoV-2 variants.

The continuous evolution of SARS-CoV-2 virus has led to the emergence of multiple Omicron descendants resistant to previously approved therapeutic antibodies. Therefore, cross-reactive antibodies to conserved neutralizing epitopes are urgently needed to protect immunocompromised patients and individuals at high risk of severe COVID-19. Here we report the characterization of 1p2B5, a single-domain antibody targeting N-terminal domain (NTD) of SARS-CoV-2 S protein. 1p2B5 exerts broad neutralizing activity against diverse SARS-CoV-2 variants. The Fc-fused form of the antibody demonstrates enhanced neutralizing potency in vitro, inhibiting both the earliest and currently circulating subvariants with nanomolar activity. Systemic therapeutic administration of 1p2B5-Fc at a dose of 1 mg/kg protects Syrian hamsters and hACE2-transgenic mice from challenge with evolutionarily distant SARS-CoV-2 variants. Our findings highlight the potential of NTD-specific monoclonal antibodies for prophylaxis and therapeutic intervention.