title: TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice.
abstract: OBJECTIVE
  To assess a new adenovirus-based immunotherapy as a novel treatment approach to chronic hepatitis B (CHB).
  
  
  METHODS
  TG1050 is a non-replicative adenovirus serotype 5 encoding a unique large fusion protein composed of a truncated HBV Core, a modified HBV Polymerase and two HBV Envelope domains. We used a recently described HBV-persistent mouse model based on a recombinant adenovirus-associated virus encoding an over length genome of HBV that induces the chronic production of HBsAg, HBeAg and infectious HBV particles to assess the ability of TG1050 to induce functional T cells in face of a chronic status.
  
  
  RESULTS
  In in vitro studies, TG1050 was shown to express the expected large polyprotein together with a dominant, smaller by-product. Following a single administration in mice, TG1050 induced robust, multispecific and long-lasting HBV-specific T cells detectable up to 1 year post-injection. These cells target all three encoded immunogens and display bifunctionality (i.e., capacity to produce both interferon γ and tumour necrosis factor α as well as cytolytic functions). In addition, control of circulating levels of HBV DNA and HBsAg was observed while alanine aminotransferase levels remain in the normal range.
  
  
  CONCLUSIONS
  Injection of TG1050 induced both splenic and intrahepatic functional T cells producing cytokines and displaying cytolytic activity in HBV-naïve and HBV-persistent mouse models together with significant reduction of circulating viral parameters. These results warrant clinical evaluation of TG1050 in the treatment of CHB.
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Martin
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Dubois
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Jacquier
authors.affiliation: Laboratoire de pathogénèse des virus de l'hépatite B Paris and INSERM U994, Institut Pasteur, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dion
authors.affiliation: Laboratoire de pathogénèse des virus de l'hépatite B Paris and INSERM U994, Institut Pasteur, Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Mancini-Bourgine
authors.affiliation: Laboratoire de pathogénèse des virus de l'hépatite B Paris and INSERM U994, Institut Pasteur, Paris, France.
authors.forename: Ophélie
authors.initials: O
authors.lastname: Godon
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Kratzer
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Lelu-Santolaria
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Alexei
authors.initials: A
authors.lastname: Evlachev
authors.affiliation: Virology Unit, Cochin Hospital, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Meritet
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Schlesinger
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Villeval
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique, Strasbourg University, UMR 7178, Strasbourg, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Strub
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique, Strasbourg University, UMR 7178, Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Marchand
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Geist
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Renée
authors.initials: R
authors.lastname: Brandely
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Findeli
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Boukhebza
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Menguy
authors.affiliation: Department of Vectors, Transgene SA, Strasbourg, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Silvestre
authors.affiliation: Laboratoire de pathogénèse des virus de l'hépatite B Paris and INSERM U994, Institut Pasteur, Paris, France.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Michel
authors.affiliation: Department of Infectious Diseases, Transgene SA, Lyon, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Inchauspé
mesh_terms: D000256:Adenoviridae / Q000145:classification / Q000378:metabolism*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D004279:DNA, Viral / Q000097:blood*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors; D015789:HLA-A2 Antigen / Q000235:genetics; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000628:therapy*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000097:blood; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*; D019562:Viral Load
chemical_list: D004279:DNA, Viral; D015686:Gene Products, env; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D014409:Tumor Necrosis Factor-alpha; D014760:Viral Fusion Proteins; D007371:Interferon-gamma; D000410:Alanine Transaminase; D004259:DNA-Directed DNA Polymerase
keywords: CELLULAR IMMUNOLOGY; CHRONIC VIRAL HEPATITIS; HEPATITIS B; IMMUNOTHERAPY