@techreport{84ec32001d984f599cb48d0f9a3bbcab,
title = "Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants",
abstract = "The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of lt;1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was gt;100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.Competing Interest StatementA patent application has been submitted on the antibodies described in this manuscript. R.G., J.L., and M.R.H. performed this work as employees of Laulima Government Solutions, LLC while E.P performed this work as an employee of Tunnell Government Services. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. All other authors declare no competing interests.",
keywords = "Coronavirus, COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Novel coronavirus, Pandemic, 2019-nCoV",
author = "Hyeseon Cho and Gonzales-Wartz, {Kristina Kay} and Deli Huang and Meng Yuan and Mary Peterson and Janie Liang and Nathan Beutler and Torres, {Jonathan L.} and Yu Cong and Elena Postnikova and Sandhya Bangaru and Talana, {Chloe Adrienna} and Wei Shi and Yang, {Eun Sung} and Yi Zhang and Kwanyee Leung and Lingshu Wang and Linghang Peng and Jeff Skinner and Shanping Li and Wu, {Nicholas C.} and Hejun Liu and Cherrelle Dacon and Thomas Moyer and Melanie Cohen and Ming Zhao and Lee, {F. Eun-Hyung} and Weinberg, {Rona S.} and Iyadh Douagi and Robin Gross and Connie Schmaljohn and Amarendra Pegu and Mascola, {John R.} and Michael Holbrook and David Nemazee and Rogers, {Thomas F.} and Ward, {Andrew B.} and Wilson, {Ian A.} and Crompton, {Peter D.} and Joshua Tan",
year = "2021",
month = apr,
day = "1",
doi = "10.1101/2021.04.01.437942",
language = "English (US)",
series = "bioRxiv",
publisher = "Cold Spring Harbor Laboratory Press",
type = "WorkingPaper",
institution = "Cold Spring Harbor Laboratory Press",
}