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

• 批准号: 7136398
• 负责人: RICHARD C DUKE
• 金额: $ 29.83万
• 依托单位: GLOBEIMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136398
• 关键词: antigens; clinical research; clinical trials; hepatitis C; hepatitis C virus; human; immune response; infection; neoplasm /cancer; yeasts

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）：T细胞介导的免疫的稳健性和广度已被认为可以通过直接和间接控制病毒复制、病毒血症水平和慢性状态的进展来影响丙型肝炎病毒（HCV）感染的自然过程。因此，开发刺激幼稚和感染个体中有效 T 细胞免疫反应的疫苗和免疫治疗产品至关重要。 Globelmmune 开发了一种疫苗和免疫治疗平台，该平台使用完整的、热灭活的重组酿酒酵母作为递送载体。 Globelmmune 的产品被称为 Tarmogens(tm)（靶向分子免疫原），已被证明能够在多种动物物种中引发针对表达多种病毒和癌症抗原的靶细胞的细胞免疫反应，并且以抗原特异性、CD8+ CTL 介导的方式实现这一点。使用 Tarmogens 的两个主要优点是它们与多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（针对突变型人类 K-Ras）和 GI-5005（针对 HCV NS3 和 Core）目前正在分别针对胰腺癌、结直肠癌和肺癌患者以及慢性 HCV 感染者进行一期临床试验。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 Tarmogens； (2) 建立cGMP生产和验证协议； (3) 在小鼠中进行关键且彻底的临床前安全性和免疫原性测试； (4) 证明新的Tarmogens可以在体外刺激人HCV特异性T细胞； (5) 在与 FDA 协商后，进行 GLP 毒性研究，以期在健康、非 HCV 感染个体以及慢性 HCV 感染患者中启动临床试验。摘要：目前美国有超过 400 万人感染丙型肝炎病毒 (HCV)，数百万人面临感染风险。目前还没有疫苗，可用的药物疗法有毒，并且对许多人无效。 Globelmmune 已经发现了普通面包酵母预防和治疗 HCV 感染的新用途，目前正在感染个体中测试该产品。该项目的目标是制备第二代产品，最终将在人体中进行测试，以预防和治疗丙型肝炎病毒感染。