title: Recognition of core-derived epitopes from a novel HBV-targeted immunotherapeutic by T-cells from patients infected by different viral genotypes.
abstract: Hepatitis B virus (HBV) infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. Current therapies based on nucleos(t)ide analogs or pegylated-interferon-α lead to control of viral replication in most patients but rarely achieve cure. A potential strategy to control chronic hepatitis B is to restore or induce functional anti-HBV T-cell immune responses using HBV-specific immunotherapeutics. However, viral diversity is a challenge to the development of this class of products as HBV genotypes display a sequence diversity of up to 8%. We have developed a novel HBV-targeted immunotherapeutic, TG1050, based on a non-replicative Adenovirus vector encoding a unique and large fusion protein composed of multiple antigenic regions derived from a HBV genotype D sequence. Using peripheral blood mononuclear cells from 23 patients chronically infected by five distinct genotypes (gt A, B, C, D and E) and various sets of peptides encompassing conserved versus divergent regions of HBV core we have measured ability of TG1050 genotype D core-derived peptides to be recognized by T-cells from patients infected by various genotypes. Overall, PBMCs from 78% of genotype B or C- and 100% genotype A or E-infected patients lead to detection of HBV core-specific T-cells recognizing genotype D antigenic domains located both in conserved and variable regions. This proof-of-concept study supports the clinical development of TG1050 in large patient populations independently of infecting genotypes.
authors.affiliation: Laboratoire de Pathogenèse des virus de l'hépatite B, Département de Virologie, Institut Pasteur, 28, rue du Docteur Roux, Paris Cedex 15 75724, France.
authors.forename: Ophelie
authors.initials: O
authors.lastname: Godon
authors.affiliation: Transgene SA, Department of Infectious Diseases, Lyon, France.
authors.forename: Alexei
authors.initials: A
authors.lastname: Evlachev
authors.affiliation: Laboratoire de Pathogenèse des virus de l'hépatite B, Département de Virologie, Institut Pasteur, 28, rue du Docteur Roux, Paris Cedex 15 75724, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Bourgine
authors.affiliation: Virology Unit, Cochin Hospital, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Meritet
authors.affiliation: Transgene SA, Department of Infectious Diseases, Lyon, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Martin
authors.affiliation: Transgene SA, Department of Infectious Diseases, Lyon, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Inchauspe
authors.affiliation: Laboratoire de Pathogenèse des virus de l'hépatite B, Département de Virologie, Institut Pasteur, 28, rue du Docteur Roux, Paris Cedex 15 75724, France; INSERM U994, Département de Virologie, Institut Pasteur, Paris, France. Electronic address: marie-louise.michel@pasteur.fr.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Michel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D003429:Cross Reactions; D004337:Drug Carriers; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005838:Genotype; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000628:therapy*; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology
chemical_list: D004337:Drug Carriers; D000939:Epitopes; D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic
keywords: Core protein; Genotypes; HBV; Immunotherapy; T-cell responses; Vaccine