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Adv Ther (Weinh)
. 2021 Aug;4(8):2100099.
doi: 10.1002/adtp.202100099. Epub 2021 Aug 2.
Engineered Multivalent Nanobodies Potently and Broadly Neutralize SARS-CoV-2 Variants
Jennifer M Zupancic 1 2 , John S Schardt 1 2 3 , Alec A Desai 1 2 , Emily K Makowski 2 3 , Matthew D Smith 1 2 , Ghasidit Pornnoppadol 2 3 , Mayara Garcia de Mattos Barbosa 4 , Marilia Cascalho 4 5 , Thomas M Lanigan 6 , Peter M Tessier 1 2 3 7
Affiliations
- PMID: 34514086
- PMCID: PMC8420545
- DOI: 10.1002/adtp.202100099
Abstract
The COVID-19 pandemic continues to be a severe threat to human health, especially due to current and emerging SARS-CoV-2 variants with potential to escape humoral immunity developed after vaccination or infection. The development of broadly neutralizing antibodies that engage evolutionarily conserved epitopes on coronavirus spike proteins represents a promising strategy to improve therapy and prophylaxis against SARS-CoV-2 and variants thereof. Herein, a facile multivalent engineering approach is employed to achieve large synergistic improvements in the neutralizing activity of a SARS-CoV-2 cross-reactive nanobody (VHH-72) initially generated against SARS-CoV. This synergy is epitope specific and is not observed for a second high-affinity nanobody against a non-conserved epitope in the receptor-binding domain. Importantly, a hexavalent VHH-72 nanobody retains binding to spike proteins from multiple highly transmissible SARS-CoV-2 variants (B.1.1.7 and B.1.351) and potently neutralizes them. Multivalent VHH-72 nanobodies also display drug-like biophysical properties, including high stability, high solubility, and low levels of non-specific binding. The unique neutralizing and biophysical properties of VHH-72 multivalent nanobodies make them attractive as therapeutics against SARS-CoV-2 variants.
Keywords: COVID‐19; antibody; antibody fragment; camelid; polyvalency; polyvalent; protein engineering.