Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Developing broad-spectrum antivirals against sarbecoviruses, including SARS-CoV-2 variants and future zoonotic threats, is crucial.
• Understanding antibody responses is key to designing effective countermeasures.

Purpose of the Study:

• To isolate and characterize a human monoclonal antibody with broad neutralizing activity against SARS-CoV- and SARS-CoV-2-related sarbecoviruses.
• To evaluate the antibody's potential for clinical development and its mechanism of action.

Main Methods:

• Isolation and characterization of a human monoclonal antibody (S2K146).
• Structural and functional studies to determine the antibody-antigen interaction and mechanism of neutralization.
• In vivo studies using a hamster model to assess protection against SARS-CoV-2 Beta variant challenge.
• Viral passaging experiments to assess the emergence of escape mutants.

Main Results:

• S2K146 broadly neutralizes SARS-CoV- and SARS-CoV-2-related sarbecoviruses that use ACE2 as an entry receptor.
• The antibody targets conserved ACE2-binding residues, potently inhibiting viral entry.
• S2K146 demonstrated protection against SARS-CoV-2 Beta variant in hamsters.
• High barrier for the emergence of escape mutants was observed, indicating viral resistance.

Conclusions:

• S2K146 is a promising candidate for clinical development due to its broad neutralization and high barrier to resistance.
• Targeting conserved ACE2-binding sites offers a viable strategy for developing pan-sarbecovirus vaccines and therapeutics.