A Novel "Zinc-Stapled" Long-Acting Insulin Analog

新型“锌钉”长效胰岛素类似物

基本信息

批准号：
7999732
负责人：
Bruce Hill Frank
金额：
$ 42.36万
依托单位：
THERMALIN DIABETES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-28 至 2012-09-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7999732
关键词：
Adverse effects Affect Affinity Albumins Animal Model Animals Binding Binding Sites Biochemical Biological Assay Blood Glucose Breast Breast Cancer Cell Breast Carcinoma Budgets Buffers Cancer cell line Carboxypeptidase B Case-Control Studies Cell Line Cells Centrifugation Charge Chemicals Clinical Colon Coombs&apos Test Cresol Cresols Development Diabetes Mellitus Disulfides Dose Drug Carriers Drug Formulations Drug Kinetics Employee Strikes Engineering Escherichia coli Exhibits Family suidae Gel Chromatography Generations German population Glycosylated hemoglobin A Grant Growth Hand Health Care Costs Histidine Human Human Cell Line Hybrids Incidence Indiana Influentials Insulin Insulin Receptor Insulin Resistance Insulin, Lispro, Human Insulin-Dependent Diabetes Mellitus Insulin-Like Growth Factor Receptor Insulin-Like-Growth Factor I Receptor Investigation Ions Isoelectric Point Knowledge Lantus Lead Levemir Licensing Life Link Logic Long-Acting Insulin MCF7 cell Malignant Neoplasms Marketing Mass Spectrum Analysis Measurement Mediating Methods Modeling Molecular National Institute of Diabetes and Digestive and Kidney Diseases Nature Non-Insulin-Dependent Diabetes Mellitus Pancreas Patient Care Patients Pharmacodynamics Pharmacologic Substance Pharmacology Phase Physicians Physiological Polymers Precipitation Prevalence Principal Investigator Production Proinsulin Property Prostate Proteins Proteolytic Processing Proteomics Protocols documentation Rattus Recombinants Replacement Therapy Risk Safety Sampling Serum Side Signal Transduction Site Small Business Innovation Research Grant Solubility Sprague-Dawley Rats Streptozocin Structure Techniques Testing Time TimeLine Trypsin Universities Withdrawal X-Ray Crystallography Zinc absorption analog base blood glucose regulation cancer cell cancer risk carcinogenesis chemical stability chemical synthesis deamidation design diabetic rat experience fast protein liquid chromatography glargine glycemic control improved in vivo innovation interest novel polypeptide pre-clinical programs protein function public health relevance receptor receptor binding residence response subcutaneous theories three dimensional structure type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): A Phase 1 SBIR program of pre-clinical development is proposed focusing on a novel long-acting insulin analog for the basal treatment of diabetes mellitus. Designated Insulin-ZN, our product is a derivative of human insulin containing novel zinc-binding sites at the periphery of the insulin hexamer. The non-classical zinc-binding sites are mediated by paired (i, i +4) histidine substitutions in the A-chain (substitutions GluA4.His and ThrA8.His). Unlike the current market leader among long-acting insulin products (Lantus(R)), Insulin-ZN exhibits negligible cross-binding to the mitogenic Type 1 IGF receptor (IGF-1R). Insulin-ZN offers to patients the potential advantages of once-a-day dosing without concern that enhanced cross-binding to IGF-1R may lead to elevated risk of IGF-1R-related cancers (e.g., of the breast, colon, pancreas, and prostate). Such concerns have recently been raised in studies of > 140,000 German patients with Type 2 diabetes mellitus being treated with Lantus(R). The affinity of Insulin-ZN for IGF-1R is at least 30- fold lower than that of insulin glargine, the active ingredient of Lantus(R). The improved receptor-binding selectivity of Insulin-ZN may be especially important in patients with insulin resistance requiring higher doses of insulin to affect glycemic control. We seek to test candidate formulations of Insulin-ZN and to assess its in vivo potency and pharmacokinetics in animal models. Insulin-ZN was invented at Case Western Reserve University and is being developed under license to Thermalin Diabetes, Inc. The principal investigator, who brings to this application four decades of experience in pharmaceutical studies of insulin formulations, was co-inventor of insulin lispro. PUBLIC HEALTH RELEVANCE: Diabetes is increasing in global prevalence. To provide greater convenience, improved glycemic control, and fewer adverse side-effects (all of which result in greater compliance and lower healthcare costs), we have invented a novel long-acting insulin analog (designated Insulin-ZN) that, unlike Lantus(R), exhibits negligible cross-binding to the mitogenic Type 1 IGF receptor, thereby in theory reducing cancer risk. The innovative design of Insulin-ZN exploits the introduction of non-classical pH-dependent zinc-binding sites into the insulin hexamer to create a long-acting subcutaneous depot. This project will complete the pre-clinical proof of concept for Insulin-ZN.

描述（由申请人提供）：提出了临床前开发的 1 期 SBIR 计划，重点关注用于糖尿病基础治疗的新型长效胰岛素类似物。我们的产品被命名为 Insulin-ZN，是人胰岛素的衍生物，在胰岛素六聚体的外围含有新型锌结合位点。非经典锌结合位点由 A 链中成对 (i, i +4) 组氨酸取代（取代 GluA4.His 和 ThrA8.His）介导。与目前市场领先的长效胰岛素产品 (Lantus(R)) 不同，Insulin-ZN 与促有丝分裂 1 型 IGF 受体 (IGF-1R) 的交叉结合可以忽略不计。胰岛素-ZN 为患者提供了每日一次给药的潜在优势，而无需担心与 IGF-1R 交叉结合的增强可能会导致 IGF-1R 相关癌症（例如乳腺癌、结肠癌、胰腺癌、和前列腺）。最近对超过 140,000 名接受来得时 (R) 治疗的德国 2 型糖尿病患者的研究提出了这种担忧。 Insulin-ZN 对IGF-1R 的亲和力比Lantus 的活性成分甘精胰岛素低至少30 倍。 Insulin-ZN 改善的受体结合选择性对于需要更高剂量胰岛素来影响血糖控制的胰岛素抵抗患者尤其重要。我们寻求测试 Insulin-ZN 的候选制剂并评估其在动物模型中的体内效力和药代动力学。 Insulin-ZN 是凯斯西储大学发明的，并在 Thermalin Diabetes, Inc. 的许可下进行开发。首席研究员是赖脯胰岛素的共同发明人，他在胰岛素制剂的药物研究方面拥有四十年的经验，为该应用带来了四十年的经验。公共卫生相关性：糖尿病的全球患病率正在上升。为了提供更大的便利性、改善血糖控制并减少不良副作用（所有这些都可以提高依从性并降低医疗成本），我们发明了一种新型长效胰岛素类似物（指定为胰岛素-ZN），与来得时不同（ R) 与促有丝分裂 1 型 IGF 受体的交叉结合可以忽略不计，因此理论上可以降低癌症风险。 Insulin-ZN 的创新设计利用在胰岛素六聚体中引入非经典 pH 依赖性锌结合位点来创建长效皮下储库。该项目将完成 Insulin-ZN 的临床前概念验证。