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

doi:10.1016/j.celrep.2022.110905

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

Cell Rep. 2022 May 31;39(9):110905. doi: 10.1016/j.celrep.2022.110905. Epub 2022 May 16.

Authors

Affiliations

¹ The Donnelly Centre, University of Toronto, Toronto, ON, Canada. Electronic address: shane.miersch@utoronto.ca.
² Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
³ The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁴ Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy.
⁵ Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁶ Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA; Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; IRCCS Neuromed, Pozzilli, Isernia, Italy; Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV, USA.
⁸ The Donnelly Centre, University of Toronto, Toronto, ON, Canada. Electronic address: sachdev.sidhu@utoronto.ca.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antibodies, Neutralizing
Antibodies, Viral
COVID-19*
Humans
Neutralization Tests
SARS-CoV-2*
Spike Glycoprotein, Coronavirus

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

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