TG1050, A NOVEL IMMUNOTHERAPEUTIC TO TREAT CHRONIC HEPATITIS B, CAN CONTROL HBsAg AND PROVOKE HBsAg SEROCONVERSION IN HBV-PERSISTENT MOUSE MODELS

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1 TG1050, A NOVEL IMMUNOTHERAPEUTIC TO TREAT CHRONIC HEPATITIS B, CAN CONTROL HBsAg AND PROVOKE HBsAg SEROCONVERSION IN HBV-PERSISTENT MOUSE MODELS Karine Lélu 1, Alexei Evlachev 1, Roland Kratzer 1, Sarah Dion 2, Maryline Mancini-Bourgine 2, Ophélie Godon 1,2, Doris Schmitt 3, Clarisse Dubois 1, Jean-François Meritet 4, Yasmin Schlesinger 3, Jean-Baptiste Marchand 3, Michel Geist 3, Renée Brandely 3, Annie Findeli 3, Thierry Menguy 3, Nathalie Silvestre 3, Marie-Louise Michel 2, Geneviève Inchauspé 1, Perrine Martin 1 1 Transgene SA, Dept. of Infectious Diseases, France 2 Institut Pasteur, Laboratoire de pathogénèse des virus de l hépatite B and INSERM U994, France 3 Transgene SA, Dept. of Vectors, France 4 Virology Unit, Cochin Hospital, France EASL Liver Congress 2015, Vienna 23 th April

2 RATIONALE FOR AN IMMUNOTHERAPEUTIC IN THE TREATMENT OF CHRONIC HEPATITIS B (CHB) HBV cure (HBsAg/anti-HBsAg seroconversion) rate is low with current therapies (3 to 5%) Small molecules aiming at treating CHB do not recruit the host immune system yet: A strong correlation exists between HBV specific functional T cells and control/eradication of viremia (Bertoletti and Ferrari, Gut, 2012, Dec; 61(12): ) VIRAL PARAMETERS HBV DNA HBs Ag IMMUNE RESPONSE (leading to cure) Cytokines production (IFN, TNF ) CD8+ T cells Innate immunity : NK cells Anti-HBs Ab Cytolysis HBV CURE CD8+ T cells CD4+ T cells 2

3 TG1050: PRODUCT DESCRIPTION TG1050 Based on non-replicative E1 and E3 deleted human adenovirus serotype 5 encoding a fusion protein comprising truncated HBV Core fused to a deleted and mutated HBV polymerase and 2 selected HBsAg (Env) domains (genotype D sequence) 1 Core t Pol1 Env 1 Pol2 Env 2 Pol (37 aa) (29 aa) 832 mutations inserted in Pol3 3

4 KEY FEATURES OF TG1050 IMMUNOGENICITY IN HBV-FREE MODELS In HBV-free mice, TG1050 injected once by sc route induces High frequencies of HBV-specific T cells targeting the 3 encoded HBV antigens Being mainly CD8+ T cells (detected in spleens and/or livers) Producing cytokines (mainly IFN and/or TNF ) Displaying in vivo cytolytic activities Long-lasting (up to 400 days) and displaying mainly an effector memory phenotype (CD44+/CD62L-) Martin P, et al. Gut 2014;0:1 11. doi: /gutjnl

5 AAV-HBV : A MURINE MODEL OF HBV PERSISTENCE HLA-A2/DR1 mice OR C57BL/6J mice iv injection ( vg) AAV2/8-HBV 1.2 copies of HBV genome (genotype D) Long term persistence of viral parameters (up to 1 year) HBcAg DNA intermediates Spleen Liver Blood HBV infectious viral particles HBeAg HBsAg Immune tolerance (no detected HBV-specific T cells, no anti-hbc Ab) Main differences with human HBV infection : No detectable cccdna No de novo infection of hepatocytes with new viral particles Dion et al, J Virol, 2013 May;87(10): and unpublished data 5

6 AAV-HBV MURINE MODEL AND TG1050 IMMUNIZATION AAV-HBV and TG1050 Injections Mice (HLA-A2/DR1 or C57BL/6J) are transduced by the AAV-HBV 32 days post-transduction, mice are immunized with TG1050 (once or multiple times) Example of protocol AAV-HBV TG1050 TG1050 Day Bleeding Parameters used for read-outs Immune responses : HBV-specific T cells in spleens and/or livers (ELISPOT or ICS assays) HBV-specific antibodies : anti-hbc Ab, anti-hbs Ab in blood (ELISA assays) Viral parameters : HBV DNA (qpcr) and HBsAg (ELISA assay) in blood Martin P, et al. Gut 2014;0:1 11. doi: /gutjnl and unpublished data 6

7 Number of cytokine positive CD8 T cells / test (1/5 of intrahepatic lymphocytes) TG1050 INDUCES FUNCTIONAL T CELLS SPECIFIC OF HBV IN THE LIVER OF HBV PERSISTENT MICE IFN /TNF /IL2 ICS assays at day 47 on intrahepatic lymphocytes, after single TG1050 injection of C57BL/6J mice PBS + TG1050 AAV-HBV + Empty Ad AAV-HBV + TG1050 PBS + TG1050 AAV-HBV + Empty Ad AAV-HBV + TG1050 PBS + TG1050 AAV_HBV + Empty Ad AAV-HBV + TG1050 Negative control (medium) Adenovirus peptide HBV polymerase peptide Martin P, et al. Gut 2014;0:1 11. doi: /gutjnl and unpublished data 7

8 Anti-HBc (OD 450nm, Mean +/- SEM) TG1050 INDUCES ANTI-HBV CORE ANTIBODIES IN HBV PERSISTENT MICE 4 Anti-HBc antibodies (ELISA) Days post AAV-HBV injection AAV-HBV C57BL/6J mice immunized at day D32, D54, D62, D68 with TG1050 (2x10 9 vp) Empty Ad (2x10 9 vp) Immunization (TG1050 or empty Ad) p<0,05 for comparison of AAV-HBV +TG1050 and AAV-HBV + Empty Ad C57BL/6J mice immunized at day D32, D54, D62, D68 with TG1050 (2x10 9 vp) Cut-off (0.25 OD 450 ) Plasma dilution : 1/2000 Martin P, et al. Gut 2014;0:1 11. doi: /gutjnl and unpublished data 8

9 TG1050 HAS A SUSTAINED ANTIVIRAL EFFECT IN HBV PERSISTENT MICE : Significant decrease of HBV DNA and HBsAg levels HBV DNA Fold Change (Mean +/- SEM) HBsAg Fold Change (Mean +/- SEM) HBV DNA (viral load) Mean viral load at D28 : 1.4x10 6 copies/ml Circulating HBsAg Mean HBsAg titers at D28 : 20µg/mL Days post AAV-HBV injection Days post AAV-HBV injection AAV-HBV C57BL/6J mice immunized at day D32, D54, D62, D68 with TG1050 (2x10 9 vp) Empty Ad (2x10 9 vp) Immunization (TG1050 or empty Ad) p<0.05 for comparison of Empty Ad with TG1050 (statistical analysis based on a mixed model and post-hoc tests with multiplicity correction) Martin P, et al. Gut 2014;0:1 11. doi: /gutjnl and unpublished data 9

10 TG1050 INDUCES HBV DNA AND HBSAG DECLINE AS WELL AS HBSAG SEROCONVERSION IN SOME HBV PERSISTENT MICE HBsAG log (ng/ml) HBV-DNA (log (copies/ml)) C57BL/6J mice 3.1 to 3.8 were HBV persistent and injected with TG1050 at days 32, 54, 62 and 68 (vertical dotted line) LoQ LoD days LoD days Anti HBs OD 450 LoD Anti-HBsAg Ab : Plasma dilution 1/400 Martin P, et al. Gut 2014;0:1 11. doi: /gutjnl and unpublished data 10 days

11 SUMMARY In the AAV-HBV model in C57BL/6J mice, TG1050 in stand alone was shown to be able to induce : HBV-specific functional T cells detected in the liver and producing cytokines an antiviral activity, detected as soon as after the 1rst injection and which is sustained overtime 100% of treated mice display a HBV DNA decrease 43% of treated mice display a strong (>1log) HBsAg decrease 30% of treated mice display appearance of anti-hbsag antibodies 11

12 CONCLUSION In a context of HBV persistence, TG1050 is immunogenic, exerts an antiviral activity and triggers HBsAg seroconversion TG1050 is capable of capturing key features required to acheive clinical cure A Phase 1/1b (First-In-Man and dose finding) study is underway, with recruitment expected in mid

13 ACKNOWLEDGEMENTS TRANSGENE HBV Research Team (Strasbourg and Lyon, France) Smart Virus Lab and Smart Data Lab Nathalie Silvestre Renée Brandely Annie Findeli Michel Geist Murielle Klein Yasmin Schlesinger Doris Schmitt Jean-Baptiste Marchand Thierry Menguy Benoit Sansas Infectious Diseases Dpt Geneviève Inchauspé Clarisse Dubois Alexei Evlachev Roland Kratzer Karine Lélu-Santolaria Perrine Martin INSTITUT PASTEUR, Paris, France, (HBV pathogenesis, INSERM U994) Maryline Bourgine Sarah Dion Ophélie Godon Marie-Louise Michel HOPITAL COCHIN, Paris, France (Virology department) Jean François Meritet 13

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