@article{f02f625a9eb7490bb482bb6640548221,
title = "Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations",
abstract = "Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.",
keywords = "RBD-binding, anti-viral, neutralizing, synthetic, tetravalent",
author = "Shane Miersch and Zhijie Li and Reza Saberianfar and Mart Ustav and {Brett Case}, James and Levi Blazer and Chao Chen and Wei Ye and Alevtina Pavlenco and Maryna Gorelik and {Garcia Perez}, Julia and Suryasree Subramania and Serena Singh and Lynda Ploder and Safder Ganaie and Chen, {Rita E.} and Leung, {Daisy W.} and Pandolfi, {Pier Paolo} and Giuseppe Novelli and Giulia Matusali and Francesca Colavita and Capobianchi, {Maria R.} and Suresh Jain and Gupta, {J. B.} and Amarasinghe, {Gaya K.} and Diamond, {Michael S.} and James Rini and Sidhu, {Sachdev S.}",
note = "Funding Information: This study was supported in part by contracts and grants from NIH (R01 AI157155) and the Defense Advanced Research Project Agency (HR001117S0019) to MSD, NIH grants P01AI120943 and R01AI123926 to GKA, and an NIH grant R01AI107056 to DWL. This study was also supported in part by a CIHR operating grant (COVID-19 Rapid Research Funding #OV3-170649) to JR and SSS, and by the Lazio Region (Italy, DGR n. 653 29 September 2020) and the Rome Foundation (Italy, Prot 317A/I). Additional support was generously provided by FAST grants #2161 to GKA and SSS and #2189 to SSS, from Emergent Ventures through the Thistledown Foundation (Canada) and the Mercatus Center at George Mason University. We are grateful to Daniele Lapa (INMI), for his contribution in determining the neutralizing power of the antibodies tested in Rome. We are also grateful to Carlo Tomino for his valuable help in preparing for the regulatory aspects of monoclonal antibodies in Italy. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MSD is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. SSS, SJ, SM, MU, JBG and PPP are shareholders in Virna Therapeutics. Funding Information: This study was supported in part by contracts and grants from NIH (R01 AI157155) and the Defense Advanced Research Project Agency (HR001117S0019) to MSD, NIH grants P01AI120943 and R01AI123926 to GKA, and an NIH grant R01AI107056 to DWL. This study was also supported in part by a CIHR operating grant (COVID-19 Rapid Research Funding #OV3-170649) to JR and SSS, and by the Lazio Region (Italy, DGR n. 653 29 September 2020) and the Rome Foundation (Italy, Prot 317A/I). Additional support was generously provided by FAST grants #2161 to GKA and SSS and #2189 to SSS, from Emergent Ventures through the Thistledown Foundation (Canada) and the Mercatus Center at George Mason University. We are grateful to Daniele Lapa (INMI), for his contribution in determining the neutralizing power of the antibodies tested in Rome. We are also grateful to Carlo Tomino for his valuable help in preparing for the regulatory aspects of monoclonal antibodies in Italy. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = sep,
day = "17",
doi = "10.1016/j.jmb.2021.167177",
language = "English",
volume = "433",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
number = "19",
}