4.4 Article

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

Journal

ADVANCED THERAPEUTICS
Volume 4, Issue 8, Pages -

Publisher

WILEY
DOI: 10.1002/adtp.202100099

Keywords

antibody; antibody fragment; camelid; COVID-19; polyvalency; polyvalent; protein engineering

Funding

  1. National Institutes of Health [RF1AG059723, R35GM136300, F32 GM137513, R01 AI 51588 01]
  2. National Science Foundation [CBET 1159943, 1605266, 1813963]
  3. Biointerfaces Institute
  4. Albert M. Mattocks Chair
  5. MICHR Education PTSP 2020 [U069943]
  6. COVID-19: CVC Impact Research Ignitor Grant Award
  7. University of Michigan MICHR Accelerating Synergy Award
  8. University of Michigan Institutional Funds

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A novel multivalent nanobody, VHH-72, has shown significant neutralizing activity against various SARS-CoV-2 variants with high biophysical stability, solubility, and specificity.
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.

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