Author:
Misasi John,Wei Ronnie R.,Wang Lingshu,Pegu Amarendra,Wei Chih-Jen,Oloniniyi Olamide K.,Zhou Tongqing,Moliva Juan I.,Zhao Bingchun,Choe Misook,Yang Eun Sung,Zhang Yi,Boruszczak Marika,Chen Man,Leung Kwan,Li Juan,Yang Zhi-Yong,Andersen Hanne,Carlton Kevin,Godbole Sucheta,Harris Darcy R.,Henry Amy R.,Ivleva Vera B.,Lei Paula,Liu Cuiping,Longobardi Lindsay,Merriam Jonah S.,Nase Danielle,Olia Adam S.,Pessaint Laurent,Porto Maciel,Shi Wei,Wolff Jeremy J.,Douek Daniel C.,Suthar Mehul S.,Gall Jason,Koup Richard A.,Kwong Peter D.,Mascola John R.,Nabel Gary J.,Sullivan Nancy J.
Abstract
Summary ParagraphDespite 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 antibodies2–16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18into 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.
Publisher
Cold Spring Harbor Laboratory