HLA-DQ-derived RTLs for Treatment of Celiac Disease

描述（由申请方提供）：本I期STTR的具体目标是设计、生产和表征一组治疗工具，这些工具可以控制介导乳糜泻的致病性CD 4 + T细胞。所提出的方法是基于专利重组T细胞受体配体（RTL）技术（美国专利#6，270，772），其中病毒基因组学持有独家许可。RTL技术的治疗效果首先在多发性硬化的动物模型EAE（实验性自身免疫性脑脊髓炎）中描述。RTLs可抑制病原性T细胞的活化，可用于预防和治疗EAE。这些分子在治疗其它人类自身免疫疾病中的潜力为开发用于治疗乳糜泻的HLADQ衍生的人类RTL提供了强有力的理论基础。乳糜泻是一种炎性自身免疫性疾病，其中CD 4 + 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麸质，麸质是一种在小麦，黑麦和大麦中发现的蛋白质，这种使人衰弱的疾病影响每120- 300人中的1人。仅在美国，这意味着大约220万人的市场规模。为了生产和测试HLA-DQ衍生的RTL并制备这些用于商业化的治疗剂，提出了以下具体目标： 具体目标1. HLA-DQ衍生的重组TCR配体（“RTL”）的产生和生物物理表征。 具体目标2.谷蛋白肽与HLA-DQ衍生的RTL的结合相互作用的生物化学表征。

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.