Single-domain antibody 1p2B5-Fc broadly neutralizes SARS-CoV-2 variants, protecting hamsters and mice from infection.

The relentless evolution of SARS-CoV-2 continues to generate new variants, such as Omicron descendants, which often evade existing therapeutic antibodies. This immune escape necessitates the urgent development of cross-reactive antibodies targeting conserved viral epitopes. Such antibodies are critical for protecting immunocompromised patients and individuals at high risk of severe COVID-19. The SARS-CoV-2 spike (S) protein, particularly its N-terminal domain (NTD), presents a promising target due to its role in viral entry and its relatively conserved nature across variants, offering a potential avenue for broad-spectrum antiviral strategies.

Researchers characterized 1p2B5, a single-domain antibody specifically targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein. To enhance its neutralizing potency, an Fc-fused form, 1p2B5-Fc, was developed. The team assessed the in vitro neutralizing activity of 1p2B5-Fc against a panel of diverse SARS-CoV-2 variants, including both early and currently circulating subvariants. For in vivo efficacy, 1p2B5-Fc was administered systemically at a dose of 1 mg/kg to Syrian hamsters and hACE2-transgenic mice. These animal models were subsequently challenged with evolutionarily distant SARS-CoV-2 variants to evaluate therapeutic protection.

The single-domain antibody 1p2B5 demonstrated broad neutralizing activity against a range of SARS-CoV-2 variants. The Fc-fused version, 1p2B5-Fc, exhibited significantly enhanced neutralizing potency in vitro, effectively inhibiting both the earliest and currently circulating subvariants with nanomolar activity. This enhanced activity suggests improved binding and effector functions. Critically, systemic therapeutic administration of 1p2B5-Fc at a dose of 1 mg/kg provided robust protection in animal models. Syrian hamsters and hACE2-transgenic mice were protected from challenge with evolutionarily distant SARS-CoV-2 variants, indicating broad in vivo efficacy. This protection highlights the potential of targeting the NTD for pan-variant therapeutic strategies. The findings underscore the critical role of the NTD as a conserved epitope for developing broadly neutralizing antibodies.

Systemic administration of 1p2B5-Fc at 1 mg/kg protected Syrian hamsters and hACE2-transgenic mice from challenge with diverse SARS-CoV-2 variants.