TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice

Abstract

ObjectiveTo assess a new adenovirus-based immunotherapy as a novel treatment approach to chronic hepatitis B (CHB).MethodsTG1050 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.ResultsIn 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 (ie, 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.ConclusionsInjection 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.

Future therapy for hepatitis B virus infection

“…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 envelope domains [29]. TG1050 demonstrated HBsAg seroconversion in persistently infected mouse models [30].…”

Research progress of therapeutic vaccines for treating chronic hepatitis B

“…Preclinical study indicated that TG1050 could induce robust and long-lasting HBV-specific T cells and exert an antiviral effect in HBV-persistent mice. 73 The sponsor of TG1050, Transgene Tasly, is initiating a doubleblind, randomized, placebo-controlled, multi-cohort Phase 1/ 1b trial in patients to assess the safety and tolerability of TG-1050. Currently, the study is recruiting participants (ClinicalTrials.gov, Identifier: NCT02428400).…”

Vaccination contre l’hépatite B

“…Les données récentes portant sur l'immunité anti-VHB au cours de l'infection chronique suggèrent que les approches vaccinales devront prendre en compte la situation complexe d'immunotolérance qui est induite par les fortes charges antigéniques présentes dans le sérum des patients ainsi que la présence de cellules T anti-VHB dont les fonctions sont fortement altérées [39]. De nouveaux vecteurs viraux ont ainsi été déve-loppés, comme ceux utilisant l'adénovirus, et les cibles antigéniques ont été élargies afin d'inclure la protéine de capside et la polymérase virale [40]. Pour tenter de contrecarrer les mécanismes d'épuisement ou d'inhibition des cellules T, des anticorps appelés « checkpoint inhibitors » (inhibiteurs de points de blocage) ayant fait leurs preuves dans le domaine de l'immunothérapie du cancer, sont en cours d'essais dans des modèles animaux en combinaison avec des vaccins ADN [41].…”