EASL2013:TG1050治疗性疫苗, 临床前研究

StephenW

Abstract 391
     
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

StephenW

背景/目的：建立主动免疫疗法在慢性乙型肝炎病毒感染的情况下，以强大的T细胞诱导吸引一个紧密相关的主机之间有效的T细胞反应和病毒的控制。可以预料，将需要多次给药免疫治疗产品维持诱导HBV特异性T细胞的反应，并允许沿时间的HBV感染的肝细胞的固化。我们探讨了用腺病毒为基础的原型HBV免疫常规或者非常规的（高度密集的）同源黄金/自己的能力，诱导特异性T细胞反应，提高管理计划。
方法：原型免疫治疗是根据一个人腺病毒血清型5编码2的HBV抗原（核心和聚合酶）。常规的免疫时间表（1，2或3次注射在2个或4个月的间隔）和非常规的免疫时间表（1，3或6次，间隔一周）进行了评价，在HLA-A2转基因小鼠和/或HBV转基因小鼠。诱导T细胞反应进行了监测，在最后一次注射后2周或2个月，使用酶联免疫斑点法IFN-γ和ICS分析。内存和显示的诱导T细胞活化标志物进行了探讨。
结果：检测到任何稳健和多特异性的T细胞反应，在最后一次注射后2周的测试计划。按照常规的时间表，HBV特异性IFN-γ的CD8 + T细胞为主要效应记忆细胞（CD44 + / CD62L），其中的一些表达CD27 +，CD43 +活化标志物。经过6次注射进行间隔一周，一个强大的HBV特异性IFN-γ的T细胞的反应也被检测到（现货means/106细胞/表位的范围从544到1126），尽管强大的体液和细胞免疫应答针对的腺病毒载体。 6次注射后的两个月，还清楚地检测到HBV特异性T细胞。一个第三个检测到的细胞是阳性KLRG1而两个第三种是的KLRG1-细胞，1/3，他们显示的激活标记CD27 + / CD43 +。
结论：这些数据表明，可以设想各种免疫时间表为Ad5的基于HBV免疫治疗而导致在鲁棒和多特异性T-细胞显示吸引力的功能的治疗性应用的上下文中HBV的慢性携带者。

咬牙硬挺

感谢分享

StephenW

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.

Société anonyme au capital de 72.886.317 € – R.C. Strasbourg B 317 540 581
400 boulevard Gonthier d’Andernach – Parc d’Innovation - CS80166 – 67405 ILLKIRCH GRAFFENSTADEN CEDEX (France)
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http://www.fortmilltimes.com/2013/04/29/2651444/transgene-presents-promising-pre.html

StephenW

Transgene介绍有前途的临床前数据TG1050治疗慢性HBV在EASL 2013

2014New第一类免疫治疗治疗慢性乙型肝炎的I期研究启动
法国斯特拉斯堡 -
监管新闻：

转基因SA（巴黎：TNG）（巴黎Euronext：FR0005175080），一家生物制药公司，开发有针对性的免疫治疗在癌症和慢性感染性疾病的治疗主要的未满足的医疗需求的产品，宣布临床前获得的数据，其新颖的免疫治疗，TG1050，对待慢性乙型肝炎（CHB）。这些结果发表在今年的欧洲肝脏会议研究协会的的口头会议（乙型肝炎和D实验）（阿姆斯特丹，荷兰，4月24-28日，2013年）。

主席兼行政总裁菲利普Archinard，转基因，说：“我们很高兴，TG1050被选定为在EASL口头陈述。我们希望本次的介绍，将引发了科学界的兴趣，以及与潜在的合作伙伴进行讨论。我们预计在2014年开始临床试验first-in-human/phase我们认为TG1050是目前最有前途的发展直接主动免疫治疗用于治疗慢性乙型肝炎，满足医疗需要的面积和高全世界流行。“


选择过程中，从32个有前途的候选产品TG1050赞同和认可的关键意见领袖不同的面板病毒性肝炎领域。 TG1050是根据一个非复制型腺病毒载体编码HBV（乙型肝炎病毒）抗原或相关的领域。临床候选人已表现出强大的免疫原性，在临床前小鼠模型以及遗传稳定性。免疫特性包括诱导强有力的，多功能专用，功能和交叉反应的T细胞反应，包括两种细胞因子的产生（IFNγ/TNFα）和在体内细胞溶解;已与清除病毒自然感染过程中的所有重要特征。

今天的演示提供了更新和更近期的数据表明诱导长期持久的HBV特异性记忆T细胞的能力TG1050。两种小鼠模型的基础上肝表达全长HBV基因组，HBV转基因小鼠模型（乌尔姆大学）和一个模型使用重组腺病毒相关病毒编码乙型肝炎病毒（AAV-HBV，巴斯德研究所）的实验表明，单次注射TG1050有能力教育HBV特异性T细胞功能在一个宽容的环境中，并没有引起肝脏炎症，而显示抗病毒活性，特别所示的AAV模型中。

“TG1050是据我所知，最全面的乙肝免疫治疗目前正在开发中，将交付由一个单一的载体。尤其是病毒载体和腺病毒载体，今天依然是最有效的交付平台，当它涉及到引发强烈的细胞免疫反应中发挥核心作用在HBV感染的控制。一个强大的逆相关性之间存在HBV特异性功能性T细胞和控制/消除病毒血症，用于治疗慢性乙型肝炎免疫治疗提供了显着的提高治愈率现有的抗病毒药物“法比安斯基Zoulim博士表示，医疗肝部主任收容所会议在里昂和肝炎研究实验室的在INSERM单位1052科学主任。他进一步补充说：“这种类型的方法，对限期治疗单独或与核苷类似物结合的发展提供了新的希望。”

关于TG1050

开发的转基因治疗慢性乙肝感染的新型免疫疗法产品TG1050是基于重组非复制人类腺病毒5，表示该产品已被设计为多个特定HBV抗原（核心，聚合酶和信封），D基因型首相从头和/或刺激功能性T细胞有望控制乙肝病毒的复制，并引发病毒清除。

据世界卫生组织（“世卫组织”）的估计，有3.5亿人是乙肝病毒的慢性携带者（WHO，2009）。 B型肝炎是比较常见的比其他一些世界各地。在中国和亚洲其他地区，多达10％的人口被认为是慢性感染。除了重大疾病负担，慢性乙型肝炎是负责每年100万人死亡，由于相关的并发症如肝功能衰竭，肝硬化或肝癌（肝癌）。

关于转基因

转基因梅里厄研究所集团（纽约证券交易所泛欧证券交易所：TNG）的一员，是一家生物制药公司。我们创造，开发和制造用于治疗癌症和传染性疾病的靶向免疫疗法。我们的产品是重大技术突破，使用良好的耐受性，病毒直接或间接地杀死受感染或癌变的细胞。我们的四个最先进的产品已产生的随机临床研究证明，概念数据：（TG4010）在肺癌，肝癌（Pexa-VEC），丙型肝炎（TG4040）和HPV相关的宫颈癌前病变（TG4001）。我们签订了战略合作协议，这些产品的三个发展：TG4010的发展与诺华公司的选择权协议，许可协议Jennerex，总部设在美国的公司，开发和销售Pexa-VEC和战略合作EORTC发展TG4001口咽癌。我们也有赛诺菲/ Genzyme公司的非排他性协议，为未来的商业化生产我们的产品。我们的280名员工大部分是总部设在法国的斯特拉斯堡，里昂，中国和美国，我们拥有业务。关于转基因的其他信息提供www.transgene.fr。

转基因前瞻性陈述

本新闻稿包含前瞻性陈述，尤其是指对一种治疗慢性乙型肝炎这种预期发展TG1050的未来发展的基础上所取得的成果在临床前模型。这些人在未来的临床试验的结果，我们可以得到的结果并不一定能够预测。我们可能永远无法开发，制造或销售TG1050在未来。对于测试和开发转基因的候选产品中涉及的风险和不确定性的进一步资料，请参阅法国市场管理局金融市场在其网站http://www.amf-f​​rance.org的文件和转基因的参考文献DE转基因的网站在www.transgene.fr。

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http://www.fortmilltimes.com/2013/04/29/2651444/transgene-presents-promising-pre.html

StephenW

Abstract 130
     
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

StephenW

背景和目的：目前的治疗慢性乙型肝炎（CHB）病毒感染很少达到治愈。队列研究表明，基于细胞的免疫是至关重要的，用于控制和/或感染，这表明T细胞驱动的免疫疗法是一个有吸引力的新的治疗方法，CHB提供的可能性提高治愈率治愈。我们设计了32 HBV免疫疗法根据不同的抗原的设计和病毒平台。一个基于Ad5的候选（标记为TG1050）被选中。
方法：TG1050，被截断的核心组成一个独特的融合蛋白进行编码，修改后的的聚合酶和乙肝表面抗原（ENV）域特征在体外经测序和Western印迹。 TG1050免疫原性定性和定量评估，单个或多个注射后，在五个不同的小鼠模型：三个天真的小鼠品系（BALB / c小鼠，C57BL/6J，HLA-A2转基因小鼠），连同两个HBV模型的公差（全长基因组HBV转基因小鼠和美联社腺病毒表达的全长基因组中HBV（AAV-HBV））为基础的模型。使用IFN-γ酶联免疫斑点，体内的的CTL检测和染色的内存标记细胞内细胞因子染色，诱导的免疫反应进行监测。
结果：TG1050表达HBV融合蛋白预期被证明是遗传稳定的（超过9个通道）。 TG1050，皮下注射，一次或多次在所有三个天真的小鼠模型，具有很强的免疫原性。它诱导强大和多特异性的T细胞反应，针对与IFN-γ的高频率和/或TNF-α产生的T细胞（IFN-γ高达2000 spots/106细胞/表位）显示核心，聚合酶和HBsAg域趋热体内溶细胞功能（高达70％的的体内细胞溶解）。这些细胞是持久的，显示效应记忆表型（CD44 + / CD62L）和良好的召回潜力的标记（CD27 + / CD43-）。引人注目的是，TG1050除了诱导宽容的小鼠模型，功能性T细胞产生IFN-γ和TNF-α以及强大的杀伤功能。
结论：我们已经开发了一种新的免疫治疗具有编码在一个单一的向量的多个HBV键抗原诱导T细胞应答，显示解决/控制HBV感染的报告功能的特殊性。免疫治疗已经转移到临床开发。