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

描述（由申请方提供）：拟定了一项临床前开发的I期SBIR项目，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的锌结合位点。非经典锌结合位点由A链中成对的（i，i +4）组氨酸取代（取代GluA4.His和ThrA8.His）介导。与目前市场上的长效胰岛素产品（来得时（R））不同，Insulin-ZN与促有丝分裂的1型IGF受体（IGF-1 R）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-1 R的交叉结合增强可能导致IGF-1 R相关癌症的风险升高（例如，乳腺、结肠、胰腺和前列腺）。最近，在对14万多名接受来得时（R）治疗的德国2型糖尿病患者进行的研究中提出了这种担忧。Insulin-ZN对IGF-1 R的亲和力至少比来得时（R）的活性成分甘精胰岛素低30倍。胰岛素锌的受体结合选择性的改善可能对需要更高剂量胰岛素以影响血糖控制的胰岛素抵抗患者特别重要。我们试图测试候选配方的胰岛素锌，并评估其在体内的效力和药代动力学在动物模型。Insulin-ZN是在凯斯西储大学发明的，目前正在Thermalin Diabetes，Inc.的许可下开发。主要研究者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40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保健成本），我们发明了一种新型长效胰岛素类似物（命名为Insulin-ZN），与来得时不同（R），与促有丝分裂的1型IGF受体的交叉结合可以忽略不计，从而在理论上降低癌症风险。Insulin-ZN的创新设计利用了将非经典pH依赖性锌结合位点引入胰岛素六聚体中以产生长效皮下储库。本项目将完成Insulin-ZN的临床前概念验证。

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.