|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30437
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
Gut 2015;64:1961-1971 doi:10.1136/gutjnl-2014-308041
Hepatology
Original article
TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice
Open Access
Perrine Martin1, Clarisse Dubois1, Emilie Jacquier1, Sarah Dion2, Maryline Mancini-Bourgine2, Ophélie Godon2, Roland Kratzer1, Karine Lelu-Santolaria1, Alexei Evlachev1, Jean-François Meritet3, Yasmin Schlesinger4, Dominique Villeval4, Jean-Marc Strub5, Alain Van Dorsselaer5, Jean-Baptiste Marchand4, Michel Geist4, Renée Brandely4, Annie Findeli4, Houda Boukhebza1, Thierry Menguy4, Nathalie Silvestre4, Marie-Louise Michel2, Geneviève Inchauspé1
+
Author Affiliations
1Department of Infectious Diseases, Transgene SA, Lyon, France
2Laboratoire de pathogénèse des virus de l'hépatite B Paris and INSERM U994, Institut Pasteur, Paris, France
3Virology Unit, Cochin Hospital, Paris, France
4Department of Vectors, Transgene SA, Strasbourg, France
5Laboratoire de Spectrométrie de Masse BioOrganique, Strasbourg University, UMR 7178, Strasbourg, France
Correspondence to Dr Geneviève Inchauspé, Transgene SA, 321 Avenue Jean Jaures, Lyon 69007, France; [email protected]
Received 15 July 2014
Revised 4 October 2014
Accepted 20 October 2014
Published Online First 26 November 2014
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 (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.
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.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
|
|
发表于 2015-11-11 13:06