HLA-DR4-derived RTLs for Treating Rheumatoid Arthritis

HLA-DR4 衍生的 RTL 用于治疗类风湿关节炎

• 批准号: 7050652
• 负责人: JIANYA HUAN
• 金额: $ 10.05万
• 依托单位: VIROGENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050652
• 关键词: Escherichia coli; MHC class II antigen; RNase protection assay; T cell receptor; arthritis therapy; artificial immunosuppression; biotechnology; collagen; disease /disorder model; genetically modified animals; helper T lymphocyte; hybridomas; immune tolerance /unresponsiveness; immunoregulation; laboratory mouse; lymphocyte proliferation; nonhuman therapy evaluation; polymerase chain reaction; recombinant proteins; rheumatoid arthritis; site directed mutagenesis

DESCRIPTION (provided by applicant): The specific goal of this Phase I STTR is to design, manufacture, characterize and evaluate a set of therapeutic agents that can control the pathogenic CD4+ T cells that mediate an inflammatory autoimmune disease, rheumatoid arthritis (RA). The approach presented is based on patented Recombinant T cell receptor Ligand (RTL) technology (US Patent # 6,270,772) for which Virogenomics holds an exclusive license. The therapeutic efficacy of the RTL technology was first described in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. RTLs inhibited activation of pathogenic T cells and reversed clinical score of EAE. The potential of these molecules in the treatment of other human autoimmune diseases provides strong rationale to develop HLA-DR4-derived RTLs for treatment of RA. RA is an inflammatory autoimmune disease in which CD4+ T cells are selectively activated by the presentation of RA susceptible HLA-DR and/or -DQ class II molecules with disease associated antigens, initiating a cascade of inflammatory processes that leads to cartilage destruction and bone erosion at multiple joints. People who have RA will eventually loss work ability and quality of life. This debilitating and chronic disease affects about 1% of general population in the U.S. and around world. In the United States alone this translates to a market size of roughly 2-3 million people. To produce and evaluate HLA-DR4-derived RTLs and prepare these therapeutic agents for commercialization, the following specific aims are proposed:Specific Aim 1: Develop and characterize the recombinant peptide/MHC complexes derived from murine l-Aq and HLA-DR4 alphal and betal domain with or without a covalently linked immunodominant T cell epitope. Specific Aim 2: Evaluate the biological function of the RTLs in DBA1/J mice and humanized HLA-DR4 Transgenic mice

描述（由申请人提供）：I阶段ISTTR的具体目标是设计，制造，表征和评估一组可以控制介导炎症自身免疫性疾病的致病性CD4+ T细胞，类风湿关节炎（RA）。提出的方法基于获得专利的T细胞受体配体（RTL）技术（美国专利＃6,270,772），该技术为病毒基因组学拥有独家许可​​。 RTL技术的治疗功效首先在实验性自身免疫性脑脊髓炎（EAE）中描述，这是多发性硬化症的动物模型。 RTL抑制了致病性T细胞的激活，并逆转了EAE的临床评分。这些分子在治疗其他人类自身免疫性疾病中的潜力为开发HLA-DR4衍生的RTL提供了强大的理由来治疗RA。 RA是一种炎症自身免疫性疾病，通过呈现RA易感HLA -DR和/或-DQ II类分子与疾病相关抗原，CD4+ T细胞被选择性地激活，从而引发了一系列炎症过程，从而导致多个关节处的软骨破坏和骨落入骨骼。拥有RA的人最终将丧失工作能力和生活质量。这种衰弱和慢性疾病影响了美国和世界各地的一般人群的1％。仅在美国，这意味着大约2-3万人的市场规模。为了生产和评估HLA-DR4衍生的RTL并准备这些治疗剂以进行商业化，提出了以下具体目的：具体目的1：开发和表征源自鼠L-AQ和HLA-DR4α-DR4α-DR4α和Bet域的重组肽/MHC复合物，具有无连接的免疫谱。特定目标2：评估RTL在DBA1/J小鼠和人源化HLA-DR4转基因小鼠中的生物学功能