Cell Reports
Volume 39, Issue 9, 31 May 2022, 110905
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Article
Ultrapotent and broad neutralization of SARS-CoV-2 variants by modular, tetravalent, bi-paratopic antibodies

https://doi.org/10.1016/j.celrep.2022.110905Get rights and content
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Highlights

  • Modular design enables facile generation of tetravalent antibody formats

  • Biophysical properties of tetravalent antibodies are similar to those of IgG drugs

  • Diabody-Fc-Fab format enables systematic exploration for optimal paratope pairing

  • Bispecific tetravalent antibodies neutralize virus variants that resist bivalent IgGs

Summary

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.

Keywords

antibody
SARS-CoV-2
neutralization
passive immunotherapy
bispecific
bi-paratopic
virus variant
S protein
RBD
mutational escape

Research topics

CP: Immunology
CP: Microbiology

Data and code availability

  • All data reported in this paper will be shared by the lead contact upon reasonable request.

  • This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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