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，2型糖尿病（T2 D）影响至少3000万人 是一个主要的未得到满足的公共卫生问题，在美国每年的费用超过300美元 亿美元此外，近25%的美国人口已经被认为是前驱糖尿病，或处于高风险。 发展T2 D。这些个体的特征是由于胰岛素抵抗导致血糖控制不佳 并伴有对葡萄糖刺激的胰岛素分泌减少。在糖尿病前期或早期 阶段，胰岛素不足通常通过刺激胰腺分泌的药物来控制， 伴随着人胰岛淀粉样多肽hIAPP（胰淀素）水平的增加。原生hIAPP在其 单体形式是抑制胰高血糖素分泌、延迟胃排空和充当饱腹感的激素 剂然而，当hIAPP错误折叠时，这在产量增加时很常见，它会导致称为 原纤维这些原纤维是可溶性的，高毒性的，并且能够诱导细胞死亡。受刺激的共同- hIAPP与胰岛素的分泌导致hIAPP增加的病理循环，包括错误折叠的hIAPP， 导致糖尿病前期和糖尿病患者的β细胞毒性。随后的β细胞功能缺陷驱动了 需要胰岛素分泌，这伴随着进一步的hIAPP分泌。从这个意义上说，T2 D是一种淀粉样蛋白- 诱导的疾病，如通过在超过90%的胰腺中存在hIAPP斑块沉积所证明的， T2 D患者开发新的治疗策略，靶向毒性hIAPP原纤维，抑制其沉积 作为毒性胰淀素原纤维，并最终保持β细胞健康是解决这一主要未满足需求的优先事项， 2型糖尿病 目前的T2 D标准治疗能够提供对血糖水平的一些控制，但未能解决 胰岛细胞减少及其对T2 D进展的贡献。在本申请中，我们提出了一种新颖的 治疗平台和我们在该平台上的主导产品CM-TS 1。CM-TS 1是一种单克隆抗体， 特异性靶向原纤维，hIAPP的可溶性构象，用于在斑块沉积之前快速清除， 细胞破坏。我们已经证明CM-TS 1能够与这些可溶性原纤维结合 在T2 D鼠模型的外周血和胰腺中。我们将通过以下方式继续治疗开发： 首先通过证明CM-TS 1可以在工业标准临床前试验中清除hIAPP来验证我们的初步发现， 导致T2 D病理学减少的模型。在体内概念验证之后，我们将推进CM- TS 1通过人源化进入早期临床前开发，包括可生产性、稳定细胞系 构建和非GLP药代动力学和毒性研究，最终导致IND前B型 与FDA会面。最终成功的里程碑将是将这一有前途的产品推向未来 IND使研究能够成功地达到最需要它的患者。

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.