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

抗 hIAPP 用于保护 2 型糖尿病患者的胰腺功能

• 批准号: 10713060
• 负责人: Joana M Murad
• 金额: $ 99.94万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713060
• 关键词: Anti; hIAPP; preservation; pancreatic; function

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.

项目摘要 根据美国糖尿病协会的说法，2型糖尿病（T2D）至少影响3000万 美国人，是美国的主要未满足的公共卫生问题，在美国的年度费用超过300美元 十亿美元。此外，几乎25％的美国人口已经被认为是糖尿病的 开发T2D。这些个体的特征是由于胰岛素抵抗而导致血糖​​控制不良 与葡萄糖刺激响应胰岛素分泌减少的结合。在糖尿病前期或早期糖尿病患者 阶段，胰岛素不足通常是由刺激胰腺分泌的药物来管理的， 伴随着人类胰岛多肽水平升高Hiapp（淀粉酶）。本地hiapp 单体形式是抑制胰高血糖素分泌，延迟胃排空并充当饱腹感的马匹 代理人。但是，当Hiapp Missoffolds在升高生产中很常见时，它会导致称为的结构 原纤维。这些原纤维是固体，剧毒且能够诱导细胞死亡的。刺激的共同 用胰岛素分泌Hiapp会导致Hiapp增加的病理循环，包括错误折叠的Hiapp， 导致前糖尿病和糖尿病患者的β细胞毒性。确保β细胞功能的缺陷驱动增加 需要进一步的Hiapp分泌来实现胰岛素分泌。从这个意义上讲，T2D是淀粉样蛋白 诱发疾病，这是由超过90％的胰腺中的Hiapp斑块沉积物所证明的 T2D患者。制定针对有毒Hiapp原纤维的新的治疗策略，抑制其沉积 由于有毒淀粉蛋白原纤维并最终保留β细胞健康是解决这一主要未满足需求的优先事项 T2D。 T2D中当前的护理标准能够提供一些对血糖水平的控制，但无法解决 细胞下降及其对T2D进展的贡献。在此应用中，我们建议推进小说 该平台CM-TS1的治疗平台和我们的铅产品。 CM-TS1是一种单克隆抗体 特别针对原纤维，在牙菌斑沉积之前对Hiapp进行稳固的考虑，以便快速清除 细胞破坏。我们已经证明CM-TS1能够与这些固体原纤维结合 在外周血和T2D鼠模型的胰腺中。我们将继续通过 首先通过证明CM-TS1可以在行业标准临床前清除HIAPP来验证我们的初步发现 导致降低T2D病理学的模型。遵循这种体内概念验证，然后我们将促进CM- TS1通过人性化并进入早期临床前开发，包括制造，稳定的细胞系 结构，非GLP药代动力学和毒性研究最终最终达到预定B型 与FDA会面。最终成功的里程碑将是将此承诺产品推向未来 为了成功地吸引最需要它的患者，索引研究。