A bivalent spike-targeting nanobody with anti-sarbecovirus activity

Area of Science:

• Virology
• Immunology
• Biotechnology

Background:

• Coronaviruses pose a significant zoonotic threat, necessitating broad-acting antiviral strategies.
• Nanobodies offer advantages over traditional antibodies, including smaller size and ease of engineering.

Purpose of the Study:

• To develop and characterize a novel nanobody (7F) with broad reactivity against sarbecoviruses.
• To evaluate the therapeutic potential of 7F, particularly in bivalent constructs, against SARS-CoV-2 and emerging variants.

Main Methods:

• Characterization of llama-derived nanobody 7F targeting the spike receptor-binding domain.
• Pseudovirus neutralization assays against SARS-CoV-2, SARS-CoV, and WIV16.
• Structural analysis of nanobody-spike protein interactions.
• Ex vivo efficacy studies using 3D human airway tissue models.

Main Results:

• 7F effectively neutralizes SARS-CoV-2 and exhibits cross-neutralization against SARS-CoV and SARS-like CoV WIV16.
• Structural studies reveal 7F targets a conserved region, inducing spike trimer dimers.
• Bivalent 7F constructs significantly enhance neutralization potency and breadth, including against SARS-CoV-2 variants.
• Bivalent 7F demonstrates therapeutic potential in ex vivo human airway tissue models.

Conclusions:

• Bivalent 7F nanobodies possess broad activity against sarbecoviruses and emerging variants.
• The distinct structural features and potent efficacy of bivalent 7F position it as a promising antiviral candidate for future coronavirus threats.