@article{b86b06bbfe634e6ea22a98fc356ebe8b,
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.",
keywords = "CP: Immunology, CP: Microbiology, RBD, S protein, SARS-CoV-2, antibody, bi-paratopic, bispecific, mutational escape, neutralization, passive immunotherapy, virus variant",
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.}",
note = "Funding Information: S.M. and S.S.S. are inventors on a patent application describing anti-SARS-CoV-2 antibodies and multivalent antibody formats. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Funding Information: We thank Dr. James Rini for providing biotinylated S protein, RBD, and the ACE2-expressing HEK293T cells. This study was partially supported by grants from Canadian Institutes of Health Operating Grant COVID-19 Rapid Research Funding Opportunity OV3-170649 , an Emergent Ventures/ Thistledown Foundation FAST grant, Emergent Ventures/ The Mercatus Center FAST ( #2161 and #2189 ), and Temerty Foundation Knowledge Translation Grant-Novel Antibody Tools for COVID-19. Infrastructure was supported by Canada Foundation for Innovation Infrastructure and Operating Grant #IOF-33363 , as well as grants from the Rome Foundation (Italy, Prot 317A/I) 592 , Italian Ministry of University and Research ( FISR2020IP_03161 ), Regione Lazio, and by US National Institutes of Health grants ( R01AI161374 , R01AI143292 , P01AI120943 , and R01 AI157155 ). Funding Information: We thank Dr. James Rini for providing biotinylated S protein, RBD, and the ACE2-expressing HEK293T cells. This study was partially supported by grants from Canadian Institutes of Health Operating Grant COVID-19 Rapid Research Funding Opportunity OV3-170649, an Emergent Ventures/Thistledown Foundation FAST grant, Emergent Ventures/The Mercatus Center FAST (#2161 and #2189), and Temerty Foundation Knowledge Translation Grant-Novel Antibody Tools for COVID-19. Infrastructure was supported by Canada Foundation for Innovation Infrastructure and Operating Grant #IOF-33363, as well as grants from the Rome Foundation (Italy, Prot 317A/I) 592, Italian Ministry of University and Research (FISR2020IP_03161), Regione Lazio, and by US National Institutes of Health grants (R01AI161374, R01AI143292, P01AI120943, and R01 AI157155). Conceptualization, S.M. and S.S.S.; methodology, S.M. and R.S.; investigation, S.M. N.S. R.S. C.C. J.B.C. G.K.A. A.C. F.C. A.Z. and G.N.; supervision, S.M. M.S.D. and S.S.S.; writing – original draft, S.M. M.S.D. and S.S.S.; writing – review & editing, S.M. and M.S.D.; visualization, S.M.; validation, S.M.; project administration, S.M.; funding acquisition, M.S.D. and S.S.S. S.M. and S.S.S. are inventors on a patent application describing anti-SARS-CoV-2 antibodies and multivalent antibody formats. M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = may,
day = "31",
doi = "10.1016/j.celrep.2022.110905",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
number = "9",
}