HLA-DQ-derived RTLs for Treatment of Celiac Disease

HLA-DQ 衍生的 RTL 用于治疗乳糜泻

• 批准号: 6832733
• 负责人: GREGORY George BURROWS
• 金额: $ 10.28万
• 依托单位: VIROGENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832733
• 关键词: MHC class II antigen; T cell receptor; autoimmune disorder; biotechnology; celiac disease; cellular immunity; chemical models; drug design /synthesis /production; enzyme linked immunosorbent assay; helper T lymphocyte; immunologic substance development /preparation; immunotherapy; leukocyte activation /transformation; plant proteins; protein binding; receptor binding; recombinant proteins; site directed mutagenesis; synthetic antigens

DESCRIPTION (provided by applicant): The specific goals of this Phase I STTR are to design, manufacture, and characterize a set of therapeutic tools that can control the pathogenic CD4+ T cells that mediate celiac disease. 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 EAE (experimental autoimmune encephalomyelitis), an animal model of multiple sclerosis. RTLs inhibited activation of pathogenic T cells and could be used to prevent and treat EAE. The potential of these molecules in the treatment of other human autoimmune diseases provides strong rationale to develop HLADQ- derived human RTLs for treatment of celiac disease. Celiac disease is a inflammatory autoimmune disease in which CD4+ T cells target, damage and eventually destroy the villous tissue structures of the small intestine, interfering with the absorption of nutrients from food. People who have celiac disease cannot tolerate gluten, a protein found in wheat, rye and barley, and this debilitating disease affects 1 of every 120- 300 people. In the United States alone this translates to a market size of roughly 2.2 million people. To produce and test HLA-DQ-derived RTLs and prepare these therepeutic agents for commercialization, the following specific aims are proposed: SPECIFIC AIM 1. Production and biophysical characterization of HLA-DQ-derived Recombinant TCR Ligands ("RTLs"). SPECIFIC AIM 2. Biochemical characterization of the binding interaction of gluten peptides with HLA-DQ derived RTLs.

描述(由申请人提供)：这一第一阶段STTR的具体目标是设计、制造和表征一套能够控制介导乳糜泻的致病CD4+T细胞的治疗工具。提出的方法是基于病毒基因组学拥有独家许可证的专利重组T细胞受体配基(RTL)技术(美国专利#6,270,772)。RTL技术的治疗效果首次在多发性硬化症的动物模型EAE(实验性自身免疫性脑脊髓炎)中被描述。RTLS可抑制致病T细胞的活化，可用于防治EAE。这些分子在治疗其他人类自身免疫性疾病方面的潜力为开发HLADQ来源的人类RTL用于治疗乳糜泻提供了强有力的理论基础。乳糜泻是一种炎症性自身免疫性疾病，在这种疾病中，CD4+T细胞靶向、损害并最终破坏小肠的绒毛组织结构，干扰从食物中吸收营养。患有乳糜泻的人不能耐受面筋，面筋是一种在小麦、黑麦和大麦中发现的蛋白质，这种虚弱的疾病每120-300人中就有1人受到影响。仅在美国，这就意味着大约有220万人的市场规模。为了生产和测试人类白细胞抗原-DQ衍生的RTL，并为商业化准备这些试剂，提出了以下具体目标： 特定目的1.人类白细胞抗原-DQ衍生的重组TCR配体的制备及其生物物理特性。 特定目的2.面筋蛋白多肽与人类白细胞抗原DQ来源的RTL结合作用的生化特征。