Ultrapotent and broad neutralization of SARS-CoV-2 variants by modular, tetravalent, bi-paratopic antibodies

Shane Miersch, Nitin Sharma, Reza Saberianfar, Chao Chen, Francesca Caccuri, Alberto Zani, Arnaldo Caruso, James Brett Case, Michael S. Diamond, Gaya K. Amarasinghe, Giuseppe Novelli, Sachdev S. Sidhu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Neutralizing antibodies (nAbs) that target the SARS-CoV-2 spike protein have received emergency use approval for treatment of COVID-19. However, with the emergence of variants of concern, there is a need for new treatment options. We report a format that enables modular assembly of bi-paratopic tetravalent nAbs with antigen-binding sites from two distinct nAbs. The tetravalent nAb purifies in high yield and exhibits biophysical characteristics that are comparable to those of clinically used therapeutic antibodies. The tetravalent nAb binds to the spike protein trimer at least 100-fold more tightly than bivalent IgGs (apparent KD < 1 pM) and neutralizes a broad array of SARS-CoV-2 pseudoviruses, chimeric viruses, and authentic viral variants with high potency. Together, these results establish the tetravalent diabody-Fc-Fab as a robust, modular platform for rapid production of drug-grade nAbs with potencies and breadth of coverage that greatly exceed those of conventional bivalent IgGs.

Original languageEnglish
Article number110905
JournalCell Reports
Volume39
Issue number9
DOIs
StatePublished - May 31 2022

Keywords

  • CP: Immunology
  • CP: Microbiology
  • RBD
  • S protein
  • SARS-CoV-2
  • antibody
  • bi-paratopic
  • bispecific
  • mutational escape
  • neutralization
  • passive immunotherapy
  • virus variant

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