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: 10600613
• 负责人: Joana M Murad
• 金额: $ 29.99万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600613
• 关键词: Address; Affect; Affinity; American; Amyloid; Amyloid Fibrils; Amyloidosis; Animal Model; Antigens; Apoptosis; Beta Cell; Binding; Binding Proteins; Blood Glucose; Cell Death; Cell Survival; Cell physiology; Cells; Dependence; Deposition; Development; Diabetes Mellitus; Disease; Disease Progression; Dose; Drug Kinetics; Engineering; Epidemic; Evaluation; Excision; Future; Gastroparesis; Glucagon; Glucose; Guidelines; Health; Hormones; Human; In Vitro; Individual; Industry Standard; Insulin; Insulin Resistance; Islets of Langerhans; Lead; Medical; Membrane; Molecular Chaperones; Molecular Conformation; Monoclonal Antibodies; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathologic; Pathology; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Physicians; Physiological; Population; Pramlintide; Pre-Clinical Model; Prediabetes syndrome; Process; Production; Public Health; Rodent; Satiation; Schedule; Scientist; Specificity; Stress; Structure; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Time; Toxic effect; Transgenes; Transgenic Mice; Treatment Efficacy; United States; amyloid formation; analog; analytical method; biophysical properties; cell bank; cell injury; cost; diabetic; diabetic patient; efficacy study; glycemic control; high risk; improved; in vivo; insulin secretion; islet; islet amyloid polypeptide; manufacturability; meetings; mouse model; novel; novel therapeutic intervention; novel therapeutics; nucleobindin; pancreatic juice; peptide hormone; peripheral blood; preclinical development; preservation; prevent; response; stable cell line; standard of care; success; therapeutic development; tool

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.

项目概要 据美国糖尿病协会称，2 型糖尿病 (T2D) 影响至少 3000 万人 美国人，是一个未得到解决的重大公共卫生问题，在美国每年造成的费用超过 300 美元 十亿美元。此外，近 25% 的美国人口已被认为处于糖尿病前期，或处于糖尿病前期的高风险中。 发展 T2D。这些人的特点是由于胰岛素抵抗而导致血糖​​控制不佳 与响应葡萄糖刺激的胰岛素分泌减少相结合。在糖尿病前期或糖尿病早期 在各个阶段，胰岛素不足通常通过刺激胰腺分泌的药物来控制，这是 伴随着人胰岛淀粉样多肽 hIAPP（胰淀素）水平的增加。其原生 hIAPP 单体形式是一种抑制胰高血糖素分泌、延迟胃排空并起到饱腹感作用的激素 代理人。然而，当 hIAPP 错误折叠时（这在产量增加时很常见），会产生称为 原纤维。这些原纤维是可溶的、剧毒的并且能够诱导细胞死亡。受刺激的共 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， 导致糖尿病前期和糖尿病患者的 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，这伴随着进一步的 hIAPP 分泌。从这个意义上说，T2D 是一种淀粉样蛋白- 超过 90% 的胰腺中存在 hIAPP 斑块沉积物，证明了诱发疾病 T2D 患者。开发针对有毒 hIAPP 原纤维并抑制其沉积的新治疗策略 作为有毒的胰淀素原纤维，并最终保持 β 细胞健康是解决这一未满足的主要需求的首要任务 T2D。 当前 T2D 的护理标准能够对血糖水平提供一定程度的控制，但未能解决  细胞衰退及其对 T2D 进展的贡献。在此应用中，我们建议提出一种新颖的 治疗平台以及我们该平台的主导产品 CM-TS1。 CM-TS1 是一种单克隆抗体， 专门针对原纤维，hIAPP 的可溶性构象，可在斑块沉积之前快速清除，  细胞破坏。我们已经证明 CM-TS1 能够与这些可溶性原纤维结合 在 T2D 小鼠模型的外周血和胰腺中。我们将继续进行治疗开发 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 T2D 病理减少的模型。在体内概念验证之后，我们将推进 CM- TS1 通过人源化进入早期临床前开发，包括可制造性、稳定细胞系 构建、非 GLP 药代动力学和毒性研究最终形成预 IND 类型 B 与 FDA 会面。最终成功的里程碑将是将这个有前景的产品推向未来 支持 IND 的研究，以成功惠及最需要的患者。