Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern

• Type of Material: Article
• Authors: Hyeseon Cho, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Kristina K Gonzales-Wartz, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Deli Huang, Scripps Research Institute; Meng Yuan, Scripps Research Institute; Mary Peterson, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Janie Liang, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick; Nathan Beutler, Scripps Research Institute; Jonathan L Torres, Scripps Research Institute; Yu Cong, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick; Elena Postnikova, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick; Sandhya Bangaru, Scripps Research Institute; Chloe Adrienna Talana, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Wei Shi, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Eun Sung Yang, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Yi Zhang, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Kwanyee Leung, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Lingshu Wang, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Linghang Peng, Scripps Research Institute; Jeff Skinner, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Shanping Li, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Nicholas C Wu, Scripps Research Institute; Hejun Liu, Scripps Research Institute; Cherrelle Dacon, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Thomas Moyer, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Melanie Cohen, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Ming Zhao, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Frances Lee, Emory University; Rona S Weinberg, New York Blood Center; Iyadh Douagi, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Robin Gross, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick; Connie Schmaljohn, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick; Amarendra Pegu, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; John R Mascola, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Michael Holbrook, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick; David Nemazee, Scripps Research Institute; Thomas F Rogers, Scripps Research Institute; Andrew B Ward, Scripps Research Institute; Ian A Wilson, Scripps Research Institute; Peter D Crompton, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville; Joshua Tan, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville
• Language: English
• Date: 2021-10-20
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.abj5413
• Title of Journal or Parent Work: SCIENCE TRANSLATIONAL MEDICINE
• Volume: 13
• Issue: 616
• Start Page: eabj5413
• End Page: eabj5413
• Grant/Funding Information: This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272201800013C (to R.G., J.L., M.H., and E.P.). R.G., J.L., and M.H. performed this work as employees of Laulima Government Solutions LLC, and E.P. performed this work as an employee of Tunnell Government Services.; This study was partially supported by the Bill & Melinda Gates Foundation, grants OPP1170236 and INV-004923 (to I.A.W.), and the National Institutes of Health under grant R01AI132317 (to D.N., D.H., and L.P.) and grant R01AI121252 (to F.E.-H.L.).; This work was supported by the Division of Intramural Research, the Vaccine Research Center, and the Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
• Keywords: CENTER B-CELLS; Cell Biology; Science & Technology; Research & Experimental Medicine; Medicine, Research & Experimental; EXPRESSION; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional 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 collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. 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 angiotensin- converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain-RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.