Novel Design of a Fast-On/Fast-Off Insulin Analog for Closed-Loop Systems

描述（由申请人提供）：胰岛素输送闭环系统-包括胰岛素泵，连续血糖监测仪和基于反馈的控制算法-提供了一种有前途的技术，可以在1型糖尿病患者中实现严格的血糖控制，提高患者的便利性和依从性。这种耦合装置（也被称为“人工胰腺”）的安全性和有效性将通过新型胰岛素模拟制剂的发展得到提高，该制剂将快速吸收与胰岛素信号的及时“关闭”相结合。虽然目前正在研究多种加速吸收的技术（基于药代动力学的方法；PK），但目前尚不清楚一旦在靶组织中形成了具有生产能力的激素受体复合物，如何提前缩短胰岛素信号的内在细胞持续时间（基于药效学的方法；PD）。因为闭环系统的一个关键挑战是从瞬态的过度交付事件中恢复。一种理想的泵胰岛素将结合快速的PK和缩短的PD。我们发明的双PK-PD优化胰岛素类似物配方的灵感来自于最近对胰岛素如何与胰岛素受体（IR）结合的分子基础的结构见解。一个国际学术调查小组，共同领导

DESCRIPTION (provided by applicant): Close-loop systems of insulin delivery-comprising an insulin pump, continuous glucose monitor, and feedback-based control algorithm-provide a promising technology to enable tight glycemic control in Type 1 diabetes mellitus with improved patient convenience and compliance. The safety and efficacy of such coupled devices (also known as an "artificial pancreas") would be enhanced by the development of novel insulin analog formulations that coupled rapid absorption with prompt "turn off" of insulin signaling. Whereas multiple technologies are under investigation to accelerate absorption (approaches based on pharmacokinetics; PK), it is not known how to foreshorten the intrinsic cellular duration of insulin signaling once a productive hormone- receptor complex has been formed in target tissues (approaches based on pharmacodynamics; PD). Because a key challenge in closed-loop systems is recovery from transient over-delivery events. An ideal pump insulin would combine rapid PK with foreshortened PD. Our invention of a dual PK-PD optimized insulin analog formulation was inspired by recent structural insights into the molecular basis of how insulin binds to the insulin receptor (IR). An international team of academic investigators, co-led by the laboratory of M. A. Weiss at Case Western Reserve University School of Medicine, has defined how insulin binds to its primary binding site (designated Site 1) in the IR ectodomain (in press in Nature (2013)). Elucidation of Site 1 coupled with biochemical probes of ancillary Site 2 enabled design of novel insulin analogs with abbreviated PD duration in a rodent model of Type 1 diabetes (streptozotocin- treated Sprague-Dawley rats). Dual Site 1/Site 2 co-optimization provides an innovative paradigm for insulin analog design. Our product is designated Tryptolog as an essential element is substitution of leucine position A13 (a non- conserved residue on the back surface of insulin adjoining Site 2) by tryptophan. We hypothesize that this bulkier aromatic residue foreshortens molecular communication between the hormone-triggered IR ectodomain and its intracellular tyrosine-kinase domains, in turn abbreviating the insulin signal. In this Phae 1 SBIR application we seek support for (i) the further optimization and characterization of Tryptolog products by co- modification of Site 1 sites A8 and B24 and (ii) their comparative validation in a pig model more relevant to human patients than Sprague-Dawley rats. Pig studies will be conducted at Legacy Health Systems (Portland, OR) by Dr. W. K. Ward, an expert on closed-loop systems and experienced pig investigator.