A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike

  1. Ying Fu
  2. Juliana da Fonseca Rezende e Mello
  3. Bryan D. Fleming
  4. Alex Renn
  5. Catherine Z. Chen
  6. Xin Hu
  7. Miao Xu
  8. Kirill Gorshkov
  9. Quinlin Hanson
  10. Wei Zheng
  11. Emily M. Lee
  12. Lalith Perera
  13. Robert Petrovich
  14. Manisha Pradhan
  15. Richard T. Eastman
  16. Zina Itkin
  17. Thomas Stanley
  18. Allen Hsu
  19. Venkata Dandey
  20. William Gillette
  21. Troy Taylor
  22. Nitya Ramakrishnan
  23. Shelley Perkins
  24. Dominic Esposito
  25. Eunkeu Oh
  26. Kimihiro Susumu
  27. Mason Wolak
  28. Marc Ferrer
  29. Matthew D. Hall
  30. Mario J. Borgnia
  31. Anton Simeonov
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Abstract

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.

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