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: Perrine Martin, Clarisse Dubois, Emilie Jacquier, Sarah Dion, Maryline Mancini-Bourgine, Ophélie Godon, Roland Kratzer, Karine Lelu-Santolaria, Alexei Evlachev, Jean-François Meritet, Yasmin Schlesinger, Dominique Villeval, Jean-Marc Strub, Alain Van Dorsselaer, Jean-Baptiste Marchand, Michel Geist, Renée Brandely, Annie Findeli, Houda Boukhebza, Thierry Menguy, Nathalie Silvestre, Marie-Louise Michel, Geneviève Inchauspé
• Journal: Gut (Gut) Vol. 64 Issue 12 Pg. 1961-71 (Dec 2015) ISSN: 1468-3288 [Electronic] England
• PMID: 25429051 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Chemical References

• DNA, Viral
• Gene Products, env
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• Hepatitis B Core Antigens
• Hepatitis B Surface Antigens
• Tumor Necrosis Factor-alpha
• Viral Fusion Proteins
• Interferon-gamma
• Alanine Transaminase
• DNA-Directed DNA Polymerase

Topics

• Adenoviridae (classification, metabolism)
• Alanine Transaminase (blood)
• Animals
• CD8-Positive T-Lymphocytes (metabolism)
• DNA, Viral (blood)
• DNA-Directed DNA Polymerase (genetics, immunology)
• Disease Models, Animal
• Gene Products, env (genetics, immunology)
• Genetic Vectors
• HLA-A2 Antigen (genetics)
• Hepatitis B Core Antigens (genetics, immunology)
• Hepatitis B Surface Antigens (blood)
• Hepatitis B virus (immunology)
• Hepatitis B, Chronic (blood, therapy)
• Immunotherapy (methods)
• Interferon-gamma (blood)
• Lymphocyte Count
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Time Factors
• Tumor Necrosis Factor-alpha (blood)
• Viral Fusion Proteins (genetics, immunology)
• Viral Load