PRE-CLINICAL PROOF-OF-CONCEPT STUDIES EXPLORING SCHEDULES OF ADMINISTRATION OF AN ADENOVIRUS- BASED HBV IMMUNOTHERAPEUTIC SHOW WIDE POTENTIAL FOR INDUCTION OF ROBUST AND LONG-LASTING T-CELL RESPONSES Move back Print add this item to your Itinerary
H. Boukhebza1, C. Dubois1, Y. Schlesinger2, V. Koerper2, R. Brandely2, M. Geist2, T. Menguy2, N. Silvestre2, R. Schirmbeck3, G. Inchauspé1, P. Martin1*
1Infectious Diseases Department, TRANSGENE SA, Lyon, 2Molecular Immunology Department, TRANSGENE SA, Illkirch-Graffenstaden, France, 3Ulm University Hospital, Ulm, Germany. *[email protected]
Background/aim: In the context of chronic Hepatitis B Virus infection, active immunotherapies aiming at inducing robust T cells are attracting as a tight correlation was established between host's effective T cell responses and viral control. It is anticipated that an immunotherapeutic product will need to be administered several times to sustain the induced HBV-specific T cell responses and allow the cure of HBV infected hepatocytes along time. We explored using an adenovirus-based prototype HBV immunotherapeutic both conventional or unconventional (highly intensive) homologous prime/boost administration schedules with respect to their capacity to induce specific T cell responses.
Methods: The prototype immunotherapeutic is based on a human Adenovirus serotype 5 encoding 2 HBV antigens (Core and Polymerase). Conventional schedules of immunization (1, 2 or 3 injections at 2 or 4 months interval) and unconventional schedules of immunization (1, 3 or 6 times at one week apart) were evaluated in HLA-A2 transgenic mice and/or HBV transgenic mice. Induced T cell responses were monitored at 2 weeks or 2 months after last injection using Elispot IFN-gamma and ICS assays. Memory and activation markers displayed by induced T cells were also explored.
Results: Robust and multispecific T cell responses were detected whatever the tested schedule at 2 weeks after last injection. Following conventional schedules, HBV-specific IFN-gamma CD8+ T cells were mainly effector memory cells (CD44+/CD62L-), some of them expressing CD27+ and CD43+ activation markers. Following 6 injections performed one week apart, a robust HBV-specific IFN-gamma T cell response was also detected (spot means/106 cells/epitope ranging from 544 to 1126) in spite of robust humoral and cellular immune responses targeting the adenovirus vector. Two months after the 6 injections, HBV-specific T cells are still clearly detectable. One third of the detected cells are positive for KLRG1 while two third are KLRG1- cells, 1/3 of them displaying the activation markers CD27+/CD43+.
Conclusions: These data show that a variety of immunization schedules can be contemplated for an Ad5-based HBV immunotherapeutic that result in robust and multispecific T-cells displaying attractive features in the context of a therapeutic application to HBV chronic carriers.
Assigned speakers:
Dr. Perrine Martin, TRANSGENE SA , Lyon , France
Assigned in sessions:
25.04.2013, 09:00-18:00, Poster Session, P01-07a, Category 07a: Viral Hepatitis B & D: Experimental, Poster Area 作者: StephenW 时间: 2013-4-13 20:56
Transgene Presents Promising Pre-Clinical Data on TG1050 to Treat Chronic HBV at EASL 2013
Initiation of a Phase I study in 2014New first in class immunotherapeutic to treat CHB
STRASBOURG, France --
Regulatory News:
Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and chronic infectious diseases, announced pre-clinical data obtained with its novel immunotherapeutic, TG1050, to treat chronic hepatitis B infection (CHB). These results were presented in an oral session (Hepatitis B and D Experimental) at this year’s European Association for the Study of the Liver Conference (Amsterdam, Netherlands, April 24-28, 2013).
Philippe Archinard, Chairman and Chief Executive Officer of Transgene, stated: “We are excited that TG1050 was selected for an oral presentation at EASL. We hope that this presentation will trigger interest in the scientific community as well as discussions with potential partners. We expect to start a first-in-human/phase 1 clinical trial in 2014 and we believe that TG1050 is currently the most promising direct active immunotherapeutic in development for the treatment of CHB, an area of unmet medical need and high worldwide prevalence.”
The selection process from 32 promising product candidates of TG1050 was endorsed and approved by different panels of key opinion leaders in the viral hepatitis field. TG1050 is based on a non-replicative Adenovirus 5 vector that encodes three HBV (Hepatitis B Virus) antigens or related domains. The clinical candidate has demonstrated potent immunogenicity in pre-clinical mouse models as well as genetic stability. Immunogenic properties include induction of potent, multi-specific, functional and cross-reactive T cell responses, including both cytokines production (IFNγ/TNFα) and in vivo cytolysis; all important characteristics that have been associated with viral clearance during natural infection.
Today’s presentation provided updated and more recent data that demonstrated the capacity of TG1050 to induce long-lasting HBV-specific memory T cells. Experiments in two murine models based on hepatic expression of the full length HBV genome, a HBV transgenic mouse model (University of Ulm) and a model using a recombinant adenovirus associated virus encoding HBV (AAV-HBV, Institute Pasteur) showed that a single injection of TG1050 had the capacity to educate HBV-specific functional T cells within a tolerant environment without inducing liver inflammation, whilst displaying antiviral activities, which were particularly shown in the AAV model.
“TG1050 is to my knowledge the most comprehensive HBV immunotherapeutic currently under development that will be delivered by a single vector. Viral vectors and adenovirus-based vectors in particular, remain today the most efficient delivery platform when it comes to inducing strong cellular immune responses which play a central role in the control of HBV infection. A strong inverse correlation exists between HBV specific functional T-cells and control/eradication of viremia; immunotherapeutic for the treatment of CHB may provide a significant increased cure rate to the existing antiviral drugs” stated Dr Fabien Zoulim, Medical Director of the Liver Department at the Hospices Civils de Lyon and Scientific Director of the Hepatitis Research Laboratory at INSERM Unit 1052. He added further: “This type of approach provides new hope towards the development of a treatment with limited duration either alone or in combination with nucleoside analogues.”
About TG1050
The novel immunotherapeutic product TG1050 developed by Transgene to treat chronic infection by hepatitis B is based on a recombinant non-replicative human adenovirus serotype 5, expressing multiple specific HBV antigens (Core, Polymerase and Envelope) from genotype D. The product has been designed to prime de novo and/or stimulate functional T cells expected to control the HBV replication and to elicit viral clearance.
According to the World Health Organization’s (“WHO”) estimates, 350 million people are chronic carriers (WHO, 2009) of HBV. Hepatitis B is more common in some parts of the world than others. In China and other parts of Asia, up to 10% of the population is believed to be chronically infected. In addition to the significant burden of disease, CHB is responsible for 1 million deaths each year due to related complications such as liver failure, cirrhosis or hepatocellular carcinoma (liver cancer).
About Transgene
Transgene (NYSE-Euronext: TNG), a member of the Institut Mérieux Group, is a biopharmaceutical company. We create, develop and manufacture targeted immunotherapeutics for the treatment of cancers and infectious diseases. Our products are major technological breakthroughs that use well tolerated viruses to indirectly or directly kill infected or cancerous cells. Our four most advanced products have generated proof of concept data in randomized clinical studies: in lung cancer (TG4010), liver cancer (Pexa-Vec), hepatitis C (TG4040) and HPV-related cervical lesions (TG4001). We have concluded strategic agreements for the development of three of these products: an option agreement with Novartis for the development of TG4010, an in-licensing agreement with US-based Jennerex, Inc. to develop and market Pexa-Vec and a strategic collaboration with EORTC to develop TG4001 in cancer of the oropharynx. We also have a non-exclusive agreement with Sanofi/Genzyme for the future commercial production of our products. Most of our 280 employees are based in Strasbourg, France, and we have operations in Lyon, China and the USA. Additional information about Transgene is available at www.transgene.fr.
Transgene Forward Looking Statements
This press release contains forward-looking statements notably referring to the future development of TG1050 as a treatment against chronic hepatitis B. Such anticipated development is based on the results obtained in preclinical models. These results are not necessarily predictive of the results that we may obtain in future clinical testing on Man. We could never be able to develop, manufacture or sell TG1050 in the future. For further information on the risks and uncertainties involved in the testing and development of Transgene’s product candidates, see Transgene’s Document de Référence on file with the French Autorité des marchés financiers on its website at http://www.amf-france.org and on Transgene’s website at www.transgene.fr.
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A MULTIVALENT ADENOVIRUS-BASED IMMUNOTHERAPEUTIC FOR TREATMENT OF CHRONIC HEPATITIS B INDUCES BROAD, ROBUST AND POLYFUNCTIONAL T CELLS IN NAIVE AND HBV TOLERANT MICE Move back Print add this item to your Itinerary
P. Martin1*, C. Dubois1, E. Jacquier1, A. Evlachev1, H. Boukhebza1, S. Dion2,3, M. Mancini-Bourgine2,3, O. Godon2,3, A. Findeli4, Y. Schlesinger4, R. Brandely4, J.-B. Marchand4, T. Menguy4, N. Silvestre4, R. Schirmbeck5, M.-L. Michel2,3, G. Inchauspé1
1Infectious Diseases Department, TRANSGENE SA, Lyon, 2Institut Pasteur, 3INSERM U 845, Paris, 4Molecular Immunology Department, TRANSGENE SA, Illkirch-Graffenstaden, France, 5Ulm University Hospital, Ulm, Germany. *[email protected]
Background and aims: Current therapies for chronic hepatitis B (CHB) virus infection seldom achieve cure. Cohort studies have shown that cellular-based immunity is crucial for control and/or cure of infection suggesting that T-cell driven immunotherapies represent an attractive novel treatment approach to CHB offering the likelihood of increasing cure rate. We engineered 32 HBV immunotherapeutics based on different antigenic designs and viral platforms. One Ad5-based candidate (labelled TG1050) was selected.
Methods: TG1050, encoding a unique fusion protein composed of a truncated Core, a modified Polymerase and HBsAg (Env) domains was in vitro characterized by sequencing and Western Blotting. TG1050 immunogenicity was assessed quantitatively and qualitatively, following single or multiple injections, in five different mouse models : three naïve mouse strains (BALB/c, C57BL/6J, HLA-A2 transgenic mice) together with two HBV models of tolerance (full-length genome HBV transgenic mice and a model based on Associated Adenovirus expressing the full length genome of HBV (AAV-HBV)). Monitoring of induced immune responses was performed using IFN-gamma ELISPOT, Intracellular Cytokine Staining, in vivo CTL assays and staining of memory markers.
Results: TG1050 expresses the expected HBV fusion protein and was shown to be genetically stable (over 9 passages). TG1050, injected subcutaneously, once or multiple times, is highly immunogenic in all three naïve mouse models. It induces robust and multispecific T cell responses, targeting Core, Polymerase and HBsAg domains with high frequencies of IFN-gamma and/or TNF-alpha producing T cells (up to 2000 IFN-gamma spots/106 cells/epitope) and displays vigorous in vivo cytolytic functions (up to 70% of in vivo cytolysis). These cells are long-lasting, display an effector memory phenotype (CD44+/CD62L-) and markers of good recall potential (CD27+/CD43-). Strikingly, TG1050 was in addition shown to induce in the two tolerant mouse models, functional T cells producing IFN-gamma and TNF-alpha as well as robust cytolytic functions.
Conclusions: We have developed a novel immunotherapeutic that has the particularity to encode multiple HBV key antigens in a single vector and to induce T-cell responses displaying features reported in resolved/controlled HBV infection. This immunotherapeutic has moved to clinical development.
Assigned speakers:
Dr. Perrine Martin, TRANSGENE SA , Lyon , France
Assigned in sessions:
27.04.2013, 15:30-17:30, Parallel Session, PS15, Parallel Session: HEPATITIS B & D EXPERIMENTAL, Hall 21