Engineered Multivalent Nanobodies Potently and Broadly Neutralize SARS-CoV-2 Variants

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• The COVID-19 pandemic persists, driven by SARS-CoV-2 variants that can evade existing immunity.
• Broadly neutralizing antibodies targeting conserved epitopes are crucial for effective COVID-19 therapeutics and prophylaxis.
• Nanobodies offer a potential platform for developing novel antiviral agents.

Purpose of the Study:

• To enhance the neutralizing activity of a SARS-CoV nanobody (VHH-72) against SARS-CoV-2 variants using multivalent engineering.
• To investigate the epitope specificity of synergistic neutralization improvements.
• To assess the therapeutic potential of multivalent VHH-72 nanobodies against SARS-CoV-2 variants.

Main Methods:

• A multivalent engineering strategy was applied to a SARS-CoV cross-reactive nanobody (VHH-72).
• The neutralizing activity of engineered nanobodies against SARS-CoV-2 variants (B.1.1.7, B.1.351) was evaluated.
• Biophysical properties including stability, solubility, and non-specific binding were assessed.

Main Results:

• Multivalent engineering of VHH-72 resulted in synergistic improvements in neutralizing activity.
• Hexavalent VHH-72 nanobodies effectively bound and neutralized SARS-CoV-2 variants (B.1.1.7, B.1.351).
• Engineered nanobodies exhibited favorable drug-like biophysical properties (high stability, solubility, low non-specific binding).

Conclusions:

• Multivalent VHH-72 nanobodies demonstrate potent neutralization of SARS-CoV-2 variants.
• The engineering approach yields nanobodies with improved therapeutic potential against current and emerging variants.
• These multivalent nanobodies represent promising candidates for COVID-19 therapy and prophylaxis.