A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo.
Fiche publication
Date publication
décembre 2017
Journal
Antiviral research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas
Tous les auteurs :
Desombere I, Mesalam AA, Urbanowicz RA, Van Houtte F, Verhoye L, Keck ZY, Farhoudi A, Vercauteren K, Weening KE, Baumert TF, Patel AH, Foung SKH, Ball J, Leroux-Roels G, Meuleman P
Lien Pubmed
Résumé
Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain.
Mots clés
Animals, Antibodies, Monoclonal, immunology, Antibodies, Neutralizing, immunology, Disease Models, Animal, Epitope Mapping, Epitopes, genetics, Genotype, Hepacivirus, drug effects, Hepatitis C, drug therapy, Hepatitis C Antibodies, immunology, Humans, Liver Transplantation, Mice, Mice, SCID, Mutation, Neutralization Tests, Structure-Activity Relationship, Viral Envelope Proteins, genetics, Virus Internalization, drug effects
Référence
Antiviral Res.. 2017 Dec;148:53-64