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

摘要：控制1型糖尿病(T1D)的自身免疫性炎症已被证明是困难的。 目前，有一些临床试验试图控制T1D，但效果不大。 预期的初步结果包括C-肽增加，作为β细胞恢复的标志， 减少胰岛素需求，降低HbA1c，作为全身炎症和 维持外周血淋巴细胞计数。目前的治疗方法减缓了C-肽 略有亏损，但没有止损或扭转亏损。其他主要目标还没有一个是 在目前的任何临床试验中都取得了成功。我们创造了一种控制发病机制的新方法 在T1D中，使用一个小肽来调节CD40介导的炎症。我们完成了临床前工作 对一种多肽进行毒理学/药效学/药代动力学研究的小鼠研究 预防NOD小鼠糖尿病的发生，逆转60%的NOD糖尿病小鼠的高血糖 老鼠。我们已经开始了一项兽医临床试验，产生的数据表明，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，相当于兽医的HbA1c，而不是 导致免疫抑制或淋巴细胞丧失。我们收到了一份“安全行动”通知 FDA将开始在使用该药物的人体上进行1a/1b期临床试验。这项拨款申请是为了 对该药物进行作用机理研究。我们推测这种药物KGYY15 (FDA的OPT101)与β细胞CD40结合，以防止β细胞损伤。我们进一步假设 KGYY15与外周血T细胞(TH40细胞)、B细胞和 巨噬细胞/树突状细胞耐受，从而防止进一步的损害。我们还将探索 开发这种用于胰岛移植的药物方法。成功完成这笔赠款将提供 关于这种药物在T1D期间如何起作用的重要信息。

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.