Bispecific antibodies against the hepatitis C virus E1E2 envelope glycoprotein
Abstract
Hepatitis C virus (HCV) currently causes about one million infections and 240,000 deaths worldwide each year. To reach the goal set by the World Health Organization of global HCV elimination by 2030, it is critical to develop a prophylactic vaccine. Broadly neutralizing antibodies (bNAbs) target the E1E2 envelope glycoproteins on the viral surface, can neutralize a broad range of the highly diverse circulating HCV strains, and are essential tools to inform vaccine design. However, bNAbs targeting a single E1E2 epitope might be limited in neutralization breadth, which can be enhanced by using combinations of bNAbs that target different envelope epitopes. We have generated 60 immunoglobulin G (IgG)-like bispecific antibodies (bsAbs) that can simultaneously target two distinct epitopes on E1E2. We combine non- or partially overlapping E1E2 specificities into three types of bsAbs, each containing a different hinge length. The majority of bsAbs shows retained or increased potency and breadth against a diverse panel of HCV pseudoparticles and HCV produced in cell culture compared to monospecific and cocktail controls. Additionally, we demonstrate that changes in the hinge length of bsAbs can alter the binding stoichiometry to E1E2. These results provide insights into the binding modes and the role of avidity in bivalent targeting of diverse E1E2 epitopes.This study illustrates how potential cooperative effects of HCV bNAbs can be utilized by strategically designing bispecific constructs. These HCV bsAbs can guide vaccine development and unlock novel therapeutic and prophylactic strategies against HCV and other (flavi)viruses.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Laura Radić
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Anna Offersgaard
Copenhagen Hepatitis C Program, Department of Infectious Diseases, Copenhagen University Hospital–Hvidovre
Tereza Kadavá
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Ian Zon
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Joan Capella-Pujol
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Fabian Mulder
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Sylvie Koekkoek
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Vera Spek
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Ana Chumbe
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Jens Bukh
Copenhagen Hepatitis C Program, Department of Infectious Diseases, Copenhagen University Hospital–Hvidovre
Marit J. van Gils
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Rogier W. Sanders
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Victor C. Yin
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Albert J. R. Heck
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands
Judith M. Gottwein
Copenhagen Hepatitis C Program, Department of Infectious Diseases, Copenhagen University Hospital–Hvidovre
Kwinten Sliepen
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam
Janke Schinkel
Department of Medical Microbiology and Infection Prevention, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, University of Amsterdam