Hexalog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

描述(由申请人提供)：我们寻求开发一种用于2型糖尿病和1型糖尿病(T2 DM和T1 DM)患者的快速作用的U-500胰岛素类似物配方。这种新产品将在两种情况下改善治疗：(I)对于有明显胰岛素抵抗的T2 DM患者(如皮质类固醇治疗后的“糖尿病”，线粒体糖尿病综合征MIDD，或脂肪营养不良)，快速作用的U-500制剂将增强进食或泵治疗的安全性、便利性和有效性，并可以通过减少注射量相关的疼痛，改善患者的依从性；(Ii)对于没有胰岛素抵抗的患者(即大多数T1 DM患者)或T2 DM患者 对于那些想要补丁泵的便利性的人来说，一种快速起作用的U-500配方将把目前一次性泵的蓄水器寿命延长五倍，和/或使这些一次性泵能够在不降低蓄水器寿命的情况下实现小型化。在“静电工程”的基础上，提出了一种创新的结构方法。目前只有一种U-500产品可供使用(礼来公司的Humlin R U-500，含有野生型人胰岛素)；其药代动力学和药效学(PK/PD)特性延长，类似于U-100 NPH胰岛素。实验U-500版本的Humalog同样表现出更长的PK/PD，因此不太适合用餐或泵用。设计快速作用的U-500配方的关键障碍是浓度依赖的六聚体-六聚体相互作用。这种相互作用延缓了胰岛素六聚体在皮下储存库的分解，从而阻碍了毛细血管的吸收。胰岛素六聚体呈甜甜圈状。连续六聚体(晶体堆积的主要模式)的线性堆积是由甜甜圈顶部和底部与三聚体相关的蛋白质表面调节的。我们发现，一种快速作用的U-500配方(指定为Hexalog-1)是通过结合Humalog？的“lispro”取代而成为可能的。具有B链的两个残基的酸性延伸：残基GluB31和GluB32。这些负电荷与天然电势相容，定位在相对的六角体表面之间产生静电斥力。作为另一个潜在的好处，酸性延伸(与ArgB31-ArgB32延伸相反，据报道是有丝分裂的基础类似物甘精胰岛素；Lantus？)减少与促有丝分裂的IGF受体的交叉结合。通过在PheB24(Hexalog-Cl)的对位选择性地进行氯芳烃取代，可以进一步提高拆解速度。B.Frank博士(PI)是Humalog的共同发明者？在他之前在礼来公司的职业生涯中。Thermarin糖尿病有限责任公司拥有与U500相关的IP的独家许可证，该IP由CWRU拥有。项目说明

DESCRIPTION (provided by applicant): We seek to develop a rapid-acting U-500 insulin analog formulation for patients with Type 2 and Type 1 diabetes mellitus (T2DM and T1DM). Such a novel product would improve treatment in two contexts: (i) for T2DM patients with marked insulin resistance (as associated with "diabesity," secondary to corticosteroid treatment, the mitochondrial diabetes syndrome MIDD, or lipodystrophies), a rapid-acting U-500 formulation would enhance safety, convenience, and efficacy of prandial or pump therapy and could, by reducing injection volume- associated pain, improve patient compliance; (ii) for patients without insulin resistance (i.e., the majority of patients with T1DM) or for T2DM patients who want the convenience of a patch-pump, a rapid acting U-500 formulation would extend by fivefold the reservoir life of current disposable pumps and/or would enable miniaturization of these disposable pumps without decreasing reservoir life. An innovative structural approach is proposed based on "electrostatic engineering." Only a single U-500 product is currently available (Lilly Humulin R U-500, containing wild-type human insulin); its pharmacokinetic and pharmacodynamic (PK/PD) properties are so prolonged that they resemble U- 100 NPH insulin. Experimental U-500 versions of Humalog likewise exhibit prolonged PK/PD and so are suboptimal for prandial or pump use. The key barrier to design of a rapid-acting U-500 formulation is posed by concentration-dependent hexamer-hexamer interactions. Such interactions retard disassembly of insulin hexamers in the subcutaneous depot and so block capillary absorption. The insulin hexamer is doughnut-shaped. Linear stacking of successive hexamers (the predominant mode of crystal packing) is mediated by trimer-related protein surfaces at the top and bottom of the doughnut. We have discovered that a rapid-acting U-500 formulation (designated Hexalog-1) is made possible by combining the "lispro" substitutions of Humalog? with a two-residue acidic extension of the B-chain: residues GluB31 and GluB32. Compatible with native potency, these negative charges are positioned to cause electrostatic repulsion between opposing hexamer surfaces. As a further potential benefit, the acidic extension (opposite in charge from the ArgB31-ArgB32 extension in the reportedly mitogenic basal analog insulin glargine; Lantus?) reduces cross-binding to the mitogenic IGF receptor. Speed of disassembly may be further enhanced by an optional chloro-aromatic substitution at the para position of PheB24 (Hexalog-Cl). Dr. B. Frank (PI) was co-inventor of Humalog? during his prior career at Eli Lilly. Thermalin Diabetes, LLC has an exclusive license to U500- related IP, which is owned by CWRU. Project Description