One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer
One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer
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DOI：
10.1038/s41551-017-0078
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发表时间：
2017-06-01
影响因子：
28.1
通讯作者：
Chilkoti, Ashutosh
中科院分区：
文献类型：
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作者：
Luginbuhl, Kelli M.;Schaal, Jeffrey L.;Chilkoti, Ashutosh
胰高血糖素样肽-1（GLP 1）受体的刺激是2型糖尿病的一种有用的治疗策略，因为它具有多效性，如调节胰岛激素和诱导饱腹感。然而，GLP 1受体的天然配体由于酶失活和快速清除而具有短半衰期。在这里，我们表明，皮下贮库形成后，单次注射GLP 1重组融合的热敏弹性蛋白样多肽的结果在零级释放动力学和循环时间长达10天的小鼠和17天的猴子。优化的药代动力学导致在三种不同的糖尿病小鼠模型中10天的血糖控制，以及每周一次治疗8周的ob/ob小鼠中糖化血红蛋白水平和体重增加的降低。我们的研究结果表明，优化的GLP 1制剂可以通过消除峰谷药代动力学和改善总体安全性和耐受性来提高治疗效果。我们建立的设计原则应该广泛适用于改善其他肽和蛋白质治疗剂的药理学性能。
Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes due to pleiotropic effects, such as the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-life owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics lead to 10 days of glycaemic control in three different mouse models of diabetes, as well as the reduction of glycosylated haemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.