A multispecific antibody prevents immune escape and confers pan-SARS-CoV-2 neutralization.

• Type of Material: Article
• Authors: John Misasi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Ronnie R Wei, Modex Therapeutics Inc; Lingshu Wang, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Amarendra Pegu, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.; Chih-Jen Wei, Modex Therapeutics Inc; Olamide K Oloniniyi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Tongqing Zhou, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Juan I Moliva, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Bingchun Zhao, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Misook Choe, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Eun Sung Yang, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Yi Zhang, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Marika Boruszczak, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Man Chen, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Kwan Leung, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Juan Li, Modex Therapeutics Inc.; Zhi-Yong Yang, Modex Therapeutics Inc.; Hanne Andersen, Bioqual, Inc., Rockville; Kevin Carlton, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Sucheta Godbole, National Institute of Allergy and Infectious Diseases, NIH, Bethesda; Darcy R Harris, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Amy R Henry, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Vera B Ivleva, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Paula Lei, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Cuiping Liu, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Lindsay Longobardi, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.; Jonah S Merriam, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Danielle Nase, Bioqual, Inc., Rockville; Adam S Olia, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.; Laurent Pessaint, Bioqual, Inc., Rockville; Maciel Porto, Bioqual, Inc., Rockville; Wei Shi, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Jeremy J Wolff, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Daniel C Douek, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Mehul Suthar, Emory University; Jason Gall, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda; Richard A Koup, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.; Peter D Kwong, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.; John R Mascola, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.; Gary J Nabel, Modex Therapeutics Inc., an OPKO Health Company, Natick, MA 01760, USA.; Nancy J Sullivan, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
• Language: English
• Date: 2022-11-21
• Publisher: bioRxiv
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1101/2022.07.29.502029
• Title of Journal or Parent Work: bioRxiv
• Keywords: COVID-19; SARS-CoV-2

Abstract

Despite effective countermeasures, SARS-CoV-2 persists worldwide due to its ability to diversify and evade human immunity1. This evasion stems from amino-acid substitutions, particularly in the receptor-binding domain of the spike, that confer resistance to vaccines and antibodies 2-16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18 into multispecific antibodies. Here, we describe multispecific antibodies, including a trispecific that prevented virus escape >3000-fold more potently than the most effective clinical antibody or mixtures of the parental antibodies. Despite being generated before the evolution of Omicron, this trispecific antibody potently neutralized all previous variants of concern and major Omicron variants, including the most recent BA.4/BA.5 strains at nanomolar concentrations. Negative stain electron microscopy revealed that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated inter-spike binding. An optimized trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2 and BA.5, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. Such multispecific antibodies decrease the likelihood of SARS-CoV-2 escape, simplify treatment, and maximize coverage, providing a strategy for universal antibody therapies that could help eliminate pandemic spread for this and other pathogens.