Development of whole yeast-based hepatitis C vaccines and Immunotherapeutics

基于全酵母的丙型肝炎疫苗和免疫疗法的开发

基本信息

批准号：
7274291
负责人：
RICHARD C DUKE
金额：
$ 29.04万
依托单位：
GLOBEIMMUNE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7274291
关键词：
Acute Animals Antigens Binding Biological Response Modifiers CD8B1 gene Cells Cellular Immunity Chimeric Proteins Chronic Class Clinical Trials Colorectal Consultations Cyclic GMP Cytotoxic T-Lymphocytes Dendritic Cells Development Dose Engineering Generations Goals Heating Hepatitis C Hepatitis C Vaccine Hepatitis C virus Histocompatibility Antigens Class II Human Humoral Immunities Immune response Immunotherapeutic agent Immunotherapy In Vitro Individual Infection MHC Class I Genes Malignant neoplasm of lung Measures Mediating Memory Molecular Target Mus Non-Small-Cell Lung Carcinoma Pancreas Patients Pattern recognition receptor Peripheral Blood Mononuclear Cell Persons Phagocytosis Pharmacotherapy Phase I Clinical Trials Population Process Production Proteins Protocols documentation Recombinants Research Contracts Research Personnel Risk Route Saccharomyces cerevisiae Safety Schedule Support of Research System T-Lymphocyte Testing Toll-Like Receptor 2 Toll-like receptors Toxic effect Treatment Protocols United States Food and Drug Administration Vaccines Validation Viral Viral Antigens Viral Cancer Viremia Yeasts base immunogenicity in vivo killings macrophage manufacturing process mutant novel polypeptide pre-clinical prevent programs ras Proteins research clinical testing response vaccine delivery vaccine development vector

项目摘要

DESCRIPTION (provided by applicant): The robustness and breadth of T cell-mediated immunity has been suggested to influence the natural course of hepatitis C virus (HCV) infection by directly and indirectly controlling viral replication, the level of viremia, and progression to the chronic state. Hence, the development of vaccines and immunotherapeutic products that stimulate potent T cell immune responses in naive as well as infected individuals is of major importance. Globelmmune has developed a vaccine and immunotherapy platform based on the use of whole, heat-inactivated, recombinant S. cerevisiae yeast as a delivery vehicle. Globelmmune's products, termed Tarmogens(tm) (Targeted molecular immunogens), have been shown to elicit cellular immune responses against target cells expressing a variety of viral and cancer antigens, in a variety of animal species, and to do so in an antigen-specific, CD8+ CTL-mediated fashion. Two major advantages of using Tarmogens are that they bind to a variety of pattern recognition receptors including multiple Toll-like receptors on dendritic cells and do not appear to be neutralized upon repeated administration. Globelmmune's 1st generation products, GI-4000, targeting mutant human K-Ras, and GI-5005, targeting HCV NS3 and Core, are currently being investigated in phase 1 clinical trials in patients with pancreas, colorectal and lung cancer and in chronically HCV-infected individuals, respectively. The overall goals of the proposed project are: (1) to produce 2nd generation Tarmogens that target a broader array of HCV antigens; (2) to establish cGMP manufacturing and validation protocols; (3) to perform critical and thorough preclinical safety and immunogenicity testing in mice; (4) to show that the new Tarmogens can stimulate human HCV-specific T cells in vitro; and (5) to perform, following consultation with the FDA, GLP toxicity studies in anticipation of initiation of clinical trials in healthy, non-HCV-infected individuals as well as in chronically HCV-infected patients. Lay Summary: More than 4 million persons in the U.S. are currently infected with hepatitis C virus (HCV) and millions are at risk of infection. There are no vaccines and available drug therapies are toxic and are not effective in many individuals. Globelmmune has identified a novel use of ordinary Baker's yeast to prevent and treat HCV infection and is currently testing a product in infected individuals. The goal of this project is to prepare 2nd generation products that will ultimately be tested in humans to prevent and treat HCV infection.

描述（由申请人提供）：已经提出了T细胞介导的免疫力的鲁棒性和广度来影响丙型肝炎病毒（HCV）感染的自然病程，直接和间接控制病毒复制，病毒血症水平和向慢性状态发展。因此，疫苗和免疫治疗产物的发展刺激了幼稚和感染个体中有效的T细胞免疫反应。 Globelmmune基于整个，热灭活的，重组的酿酒酵母酵母作为送货车开发了一种疫苗和免疫疗法平台。 Globelmmune的产物称为破这样（TM）（TM）（靶向分子免疫原），已被证明会引起各种动物物种中表达各种病毒和癌症抗原的靶细胞的细胞免疫反应，并以抗原特异性的，CD8+ CTL介导的时尚。使用柏油碱基的两个主要优点是它们与各种模式识别受体结合，包括树突状细胞上的多个Toll样受体，并且在重复给药后似乎不会被中和。 GlobelMmune的第一代产品，GI-4000，靶向突变的人K-RAS和GI-5005，靶向HCV NS3和CORE的GI-4000，目前正在针对胰腺，结直肠癌和肺癌以及长期HCV感染的个体的1阶段临床试验进行研究。拟议项目的总体目标是：（1）生产针对更广泛的HCV抗原的第二代破梯；（2）建立CGMP制造和验证协议；（3）在小鼠中进行关键和彻底的临床前安全性和免疫原性测试；（4）证明新的盗窃金可以在体外刺激人类HCV特异性的T细胞；（5）在与FDA协商后，GLP毒性研究在预期健康的，非HCV感染的个体以及慢性HCV感染的患者中进行临床试验。 Lay摘要：美国目前有超过400万人感染了丙型肝炎病毒（HCV），数以百万计的人有感染的风险。没有疫苗，可用的药物疗法是有毒的，在许多人中无效。 Globelmmune已确定了普通贝克酵母预防和治疗HCV感染的新型使用，目前正在感染者中测试产品。该项目的目的是准备第二代产品，这些产品最终将在人类中进行测试，以预防和治疗HCV感染。