Anti-hIAPP for the preservation of pancreatic function in Type 2 Diabetes

项目摘要 根据美国糖尿病协会的数据，2型糖尿病(T2D)至少影响3000万人 它是一个主要的未得到满足的公共卫生问题，在美国每年的成本超过300美元 十亿美元。此外，近25%的美国人口已经被认为是糖尿病前期，或处于患糖尿病的高危状态 开发T2D。由于胰岛素抵抗，这些个体的特点是血糖控制不佳。 再加上对葡萄糖刺激的胰岛素分泌减少。在糖尿病前期或早期糖尿病 在各个阶段，胰岛素不足通常通过刺激胰腺分泌的药物来治疗，这是 伴随着人类胰岛淀粉样多肽(HIAPP)水平的升高。ITS中的原生hIAPP 单体形式是一种荷尔蒙，它抑制高血糖素的分泌，延缓胃排空，起到饱腹感的作用。 探员。然而，当hIAPP错误折叠时，这在产量增加时很常见，它会导致结构被称为 原纤维。这些原纤维是可溶的、剧毒的，能够诱导细胞死亡。受刺激的协同- HIAPP与胰岛素一起分泌导致hIAPP升高的病理循环，包括错误折叠的hIAPP， 导致糖尿病前期患者和糖尿病患者的β细胞毒性。随之而来的β细胞功能缺陷导致 需要胰岛素分泌，这伴随着hIAPP的进一步分泌。从这个意义上说，T2D是一种淀粉样蛋白- 90%以上的胰腺中存在hIAPP斑块沉积，证明为诱发性疾病 T2D患者。开发针对有毒的hIAPP原纤维的新治疗策略，抑制它们的沉积 作为有毒的胰淀素纤维，并最终保持β细胞的健康是解决这一主要未得到满足的需求的优先事项 T2D。 目前T2D的标准护理能够提供一些血糖水平的控制，但它未能解决 细胞衰退及其在T2D进展中的作用。在这项申请中，我们提出了一种新的 治疗平台和我们来自该平台的主导产品CM-TS1。CM-TS1是一种单抗 特异性靶向原纤维、可溶构象的hIAPP，以便在斑块沉积之前快速清除 细胞破坏。我们已经证明了CM-TS1能够与这些可溶性原纤维结合 在T2D小鼠模型的外周血液和胰腺中。我们将通过以下方式继续治疗开发 首先，通过证明CM-TS1可以在行业标准的临床前阶段清除hIAPP来验证我们的初步发现 模型导致T2D病理改变减少。在此活体概念验证之后，我们将推进CM- TS1通过人性化并进入早期临床前开发，包括可制造性，稳定的细胞系 构建和非GLP药代动力学和毒性研究最终导致前IND B型 与食品和药物管理局会面。最终成功的里程碑将是在未来推出这一前景光明的产品 支持IND的研究，以便成功地接触到最需要它的患者。

Project Summary According to the American Diabetes Association, Type 2 diabetes mellitus (T2D) affects at least 30 million Americans and is a major unmet public health concern with an annual cost in the United States of over $300 billion dollars. Additionally, nearly 25% of the U.S. population is already considered prediabetic, or at high risk of developing T2D. These individuals are characterized by poor glycemic control as a result of insulin resistance combined with reduced insulin secretion in response to glucose stimulation. At the prediabetic or early diabetic stages, insulin insufficiency is frequently managed by medications that stimulate pancreatic secretion, which is accompanied by increased levels of human islet amyloid polypeptide, hIAPP (amylin). Native hIAPP in its monomeric form is a hormone that inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. However, when hIAPP misfolds, which is common at elevated production, it results in structures called protofibrils. These protofibrils are soluble, highly toxic, and capable of inducing cell death. The stimulated co- secretion of hIAPP with insulin leads to a pathologic cycle of increased hIAPP, including misfolded hIAPP, that leads to β cell toxicity in prediabetics and diabetics. The ensuing deficits in β cell function drive an increased need for insulin secretion, which is accompanied by further hIAPP secretion. In this sense, T2D is an amyloid- induced disease as evidenced by the presence of hIAPP plaque deposits in the pancreata of more than 90% of T2D patients. Developing new therapeutic strategies that target toxic hIAPP protofibrils, inhibit their deposition as toxic amylin fibrils, and ultimately preserve β cell health is a priority for addressing this major unmet need in T2D. Current standard-of-care in T2D is able to provide some control of blood glucose levels, but it fails to address the  cell decline and its contribution to T2D progression. In this application we propose to advance a novel therapeutic platform and our lead product from that platform, CM-TS1. CM-TS1 is a monoclonal antibody that specifically targets protofibrils, soluble conformations of hIAPP for rapid clearance prior to plaque deposition and  cell destruction. We have already demonstrated that CM-TS1 is capable of binding to these soluble protofibrils in peripheral blood and in the pancreata of a T2D murine model. We will continue therapeutic development by first validating our initial finding by demonstrating that CM-TS1 can clear hIAPP in an industry standard preclinical model leading to a reduction of T2D pathology. Following this in vivo proof-of-concept, we will then advance CM- TS1 through humanization and into early preclinical development including manufacturability, stable cell line construction, and non-GLP pharmacokinetic and toxicity studies ultimately culminating in a pre-IND Type B meeting with the FDA. The milestone of ultimate success will be launching this promising product into future IND-enabling studies in order to successfully reach the patients that need it the most.