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

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 journal › Article › peer-review

7 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 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.

Original language	English
Article number	110905
Journal	Cell Reports
Volume	39
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2022.110905
State	Published - 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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10.1016/j.celrep.2022.110905

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

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.",

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

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doi = "10.1016/j.celrep.2022.110905",

language = "English",

volume = "39",

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AU - Miersch, Shane

AU - Sharma, Nitin

AU - Saberianfar, Reza

AU - Chen, Chao

AU - Caccuri, Francesca

AU - Zani, Alberto

AU - Caruso, Arnaldo

AU - Case, James Brett

AU - Diamond, Michael S.

AU - Amarasinghe, Gaya K.

AU - Novelli, Giuseppe

AU - Sidhu, Sachdev S.

PY - 2022/5/31

Y1 - 2022/5/31

N2 - 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.

AB - 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.

KW - CP: Immunology

KW - CP: Microbiology

KW - RBD

KW - S protein

KW - SARS-CoV-2

KW - antibody

KW - bi-paratopic

KW - bispecific

KW - mutational escape

KW - neutralization

KW - passive immunotherapy

KW - virus variant

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

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Keywords

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