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

新型“锌钉”长效胰岛素类似物

• 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
• 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' 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

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)：临床前开发的第一阶段SBIR计划被提出，重点是一种新的长效胰岛素类似物，用于糖尿病的基础治疗。我们的产品命名为Insulin-ZN，是人胰岛素的衍生物，在胰岛素六聚体的外围含有新的锌结合位点。非经典锌结合位点是由A链上成对的(I，I+4)组氨酸取代(GluA4.His和ThrA8.His)所介导的。与目前长效胰岛素产品(Lantus(R))中的市场领先者不同，Insulin-ZN与促有丝分裂的1型IGF受体(IGF-1R)的交叉结合可以忽略不计。胰岛素-ZN为患者提供了一天一次剂量的潜在优势，而无需担心与IGF-1R的交叉结合增强可能会导致与IGF-1R相关的癌症(如乳腺癌、结肠癌、胰腺癌和前列腺癌)风险增加。最近，在使用LANTUS(R)治疗14万名德国2型糖尿病患者的研究中提出了这样的担忧。Insulin-ZN对IGF-1R的亲和力至少比Lantus(R)的活性成分甘精胰岛素低30倍。胰岛素-ZN改善的受体结合选择性对于需要更高剂量的胰岛素来影响血糖控制的胰岛素抵抗患者可能特别重要。我们试图测试胰岛素-ZN的候选配方，并在动物模型中评估其体内效力和药代动力学。胰岛素-ZN是由凯斯西储大学发明的，目前正在Thermarin糖尿病公司的许可下进行开发。首席研究员将40年来胰岛素制剂的药学研究经验带到了这一应用中，他是胰岛素Lispro的共同发明者。 公共卫生相关性：糖尿病在全球的患病率正在上升。为了提供更大的便利、改善的血糖控制和更少的副作用(所有这些都导致更好的依从性和更低的医疗成本)，我们发明了一种新型的长效胰岛素类似物(命名为Insulin-ZN)，与Lantus(R)不同，它与有丝分裂素1型IGF受体的交叉结合可以忽略不计，从而在理论上降低了癌症风险。Insulin-ZN的创新设计利用了在胰岛素六聚体中引入非经典的依赖于pH的锌结合位点来创建一个长效的皮下储存库。该项目将完成胰岛素-ZN的临床前概念验证。