Discovering the Mechanism of Action of a peptide drug, OPT101, that targets CD40 mediated inflammation in type 1 diabetes

翻译后摘要：控制自身免疫性炎症在1型糖尿病（T1 D）已被证明是困难的。 目前有临床试验试图控制T1 D，但效果甚微。 期望的主要结果包括C肽的增加，作为β细胞恢复的标志物， 胰岛素需求减少，HbA 1c降低，作为全身炎症的指标， 维持外周血淋巴细胞计数。目前的治疗方法减缓了C肽 轻微亏损但未停止或逆转亏损。其他主要目标尚未实现 在目前的任何临床试验中实现。我们创造了一种新的方法来控制发病机制 在T1 D中使用小肽来调节CD 40介导的炎症。我们完成了临床前 小鼠研究，包括肽的毒理学/药效学/药代动力学研究 预防NOD小鼠的糖尿病发作，并逆转60%的糖尿病NOD小鼠的高血糖 小鼠我们已经开始了一项兽医临床试验，数据显示，与目前的临床试验不同， 试验治疗，这种方法随着时间的推移增加C肽，减少高达90%的胰岛素， 要求，减少糖化果糖胺，HbA 1c的兽医等效物， 导致免疫抑制或淋巴细胞丢失。我们收到了“安全通行”通知 FDA将开始使用该药物进行人体1a/1b期临床试验。本补助金申请是为了 对该药物进行作用机制研究。我们假设药物KGYY 15 （OPT 101用于FDA）结合β细胞CD 40以防止β细胞损伤。我们进一步假设 KGYY 15结合外周血T细胞（我们具体定义的TH 40细胞）、B细胞和 巨噬细胞/树突细胞耐受，从而防止进一步的损伤。我们还将探索 开发这种用于胰岛移植的药物方法。成功完成这项赠款将提供 关于这种药物在T1 D期间如何发挥作用的重要信息。

Abstract: Controlling the autoimmune inflammation in type 1 diabetes (T1D) has proven difficult. Currently there are clinical trials to attempt controlling T1D that are having only marginal impact. Desired primary outcomes include increasing of C-peptide, as a marker for beta cell restoration, decrease insulin requirements, decreases in HbA1c, as a measure of systemic inflammation and maintenance of peripheral blood lymphocyte counts. Current therapies have slowed C-peptide loss marginally but not halted or reversed loss. None of the other primary goals have yet been achieved in any of the current clinical trials. We created a novel approach to control pathogenesis in T1D using a small peptide to modulate CD40 mediated inflammation. We completed pre-clinical studies in mice that include toxicology/pharmacodynamic/pharmacokinetic studies on a peptide that prevents diabetes onset in NOD mice and reverses hyperglycemia in 60% of diabetic NOD mice. We have begun a veterinary clinical trial generating data that show, unlike current clinical trial treatments, this approach increases C-peptide over time, reduces, by up to 90%, insulin requirements, reduces glycated fructosamine, the veterinary equivalent of HbA1c, and does not cause immune suppression or lymphocyte loss. We were granted a “Safe-to-Proceed” notice from the FDA to begin Phase 1a/1b clinical trials in humans using this drug. This grant application is to perform mechanism of action studies on this drug. We hypothesize that the drug, KGYY15 (OPT101 for FDA) binds to beta cell CD40 to prevent beta cell damage. We further hypothesize that KGYY15 binds to peripheral blood T cells (TH40 cells specifically defined by us), B cells and macrophages/dendritic cells to tolerize thus preventing further damage. We also will explore developing this drug approach for islet transplants. Successful completion of this grant will provide important information about how this drug works specifically during T1D.