@article{9bfc75e71a934c5683354897fe7818fc,
title = "Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses",
abstract = "SARS-CoV-2 variants evade current monoclonal antibody therapies. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies taking advantage of the avidity and synergy provided by targeting different epitopes. Here we used controlled Fab-arm exchange to produce bsAbs that neutralize SARS-CoV and SARS-CoV-2 variants, including Omicron and its subvariants, by combining potent SARS-CoV-2-specific neutralizing antibodies with broader antibodies that also neutralize SARS-CoV. We demonstrated that the parental antibodies rely on avidity for neutralization using bsAbs containing one irrelevant Fab arm. Using mass photometry to measure the formation of antibody:spike complexes, we determined that bsAbs increase binding stoichiometry compared to corresponding cocktails, without a loss of binding affinity. The heterogeneous binding pattern of bsAbs to spike, observed by negative-stain electron microscopy and mass photometry provided evidence for both intra- and inter-spike crosslinking. This study highlights the utility of cross-neutralizing antibodies for designing bivalent agents to combat circulating and future SARS-like coronaviruses.",
keywords = "Immunology, Structural biology, Virology",
author = "Laura Radi{\'c} and Kwinten Sliepen and Victor Yin and Mitch Brinkkemper and Joan Capella-Pujol and Schriek, {Angela I.} and Torres, {Jonathan L.} and Sandhya Bangaru and Burger, {Judith A.} and Meliawati Poniman and Ilja Bontjer and Bouhuijs, {Joey H.} and David Gideonse and Dirk Eggink and Ward, {Andrew B.} and Heck, {Albert J. R.} and {van Gils}, {Marit J.} and Sanders, {Rogier W.} and Janke Schinkel",
note = "Funding Information: We thank Yoann Aldon and Tom Caniels for providing spike proteins and helpful discussions, Sylvie Koekkoek for help with cloning the antibodies, and Wouter Olijhoek and Jacqueline van Rijswijk for help with the pseudovirus neutralization assays. L.R. was funded by the AMC as part of the local scientific research incentive policy. J.S. is a recipient of a Vidi and Aspasia grant from the Netherlands Organization for Scientific Research ( NWO , grant numbers 91719372 and 015.015.042 ). R.W.S. is a recipient of a Vici grant from the Netherlands Organization for Scientific Research ( NWO , grant number 91818627 ). This research was supported by an Amsterdam institute for Infection and Immunity Postdoctoral grant (K.S.). A.J.R.H. acknowledges funding by the Netherlands Organization for Scientific Research ( NWO ) through the Spinoza Award SPI.2017.028. This work was supported by the Fondation Dormeur, Vaduz (R.W.S. and (M.J.v.G.). Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = apr,
day = "21",
doi = "https://doi.org/10.1016/j.isci.2023.106540",
language = "English",
volume = "26",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier",
number = "4",
}