Gcg-XTEN: an improved glucagon capable of preventing hypoglycemia without increasing baseline blood glucose.
Gcg-XTEN: an improved glucagon capable of preventing hypoglycemia without increasing baseline blood glucose.
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DOI：
10.1371/journal.pone.0010175
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发表时间：
2010-04-14
期刊：
影响因子：
3.7
通讯作者：
Silverman J
中科院分区：
文献类型：
--
作者：
Geething NC;To W;Spink BJ;Scholle MD;Wang CW;Yin Y;Yao Y;Schellenberger V;Cleland JL;Stemmer WP;Silverman J
虽然目前大多数糖尿病治疗的重点是降低血糖水平，但胰岛素治疗会导致低血糖。胰高血糖素在体内控制低血糖中起着重要的调节作用，但其半衰期短和高血糖作用使其不能用于非急性应用。本研究的目的是确定一种改良形式的胰高血糖素，适用于预防性治疗低血糖而不增加基线血糖水平。通过应用XTEN技术，我们报道了具有扩展暴露谱的胰高血糖素融合蛋白（gg -XTEN）的构建。通过食蟹猴的设计和测试，调整了该结构的体内半衰期，以支持夜间给药。在比格犬中使用胰岛素刺激诱导低血糖，评估了该结构的有效性。gg - xten在禁食的比格犬体内的剂量范围表明，该化合物具有生物活性，其药效学特征与设计的半衰期一致。在给药后6小时，预防性给药0.6 nmol/kg gg - xten可使狗抵抗低血糖挑战，而不影响基线血糖水平。与设计的药代动力学特征一致，给药后12小时未观察到低血糖抵抗。重要的是，通过与XTEN融合，胰高血糖素肽的溶解度和稳定性也得到了显著提高。数据显示，gg - xten可有效预防低血糖，而不会出现未修饰胰高血糖素预期的相关高血糖。虽然这种gg - xten的血浆清除率已针对夜间给药进行了优化，特别是针对夜间低血糖的治疗，但明显延长暴露时间的结构是可行的。这种结构可能有多种应用，例如允许更积极的胰岛素治疗方案，治疗胰岛素分泌肿瘤引起的低血糖，在与长效GLP1类似物联合治疗中提供协同疗效，以及作为治疗肥胖的食欲抑制剂。gg - xten分子的物理性质的改进也可能允许新的递送系统目前不可能与天然胰高血糖素。
While the majority of current diabetes treatments focus on reducing blood glucose levels, hypoglycemia represents a significant risk associated with insulin treatment. Glucagon plays a major regulatory role in controlling hypoglycemia in vivo, but its short half-life and hyperglycemic effects prevent its therapeutic use for non-acute applications. The goal of this study was to identify a modified form of glucagon suitable for prophylactic treatment of hypoglycemia without increasing baseline blood glucose levels. Through application of the XTEN technology, we report the construction of a glucagon fusion protein with an extended exposure profile (Gcg-XTEN). The in vivo half-life of the construct was tuned to support nightly dosing through design and testing in cynomolgus monkeys. Efficacy of the construct was assessed in beagle dogs using an insulin challenge to induce hypoglycemia. Dose ranging of Gcg-XTEN in fasted beagle dogs demonstrated that the compound was biologically active with a pharmacodynamic profile consistent with the designed half-life. Prophylactic administration of 0.6 nmol/kg Gcg-XTEN to dogs conferred resistance to a hypoglycemic challenge at 6 hours post-dose without affecting baseline blood glucose levels. Consistent with the designed pharmacokinetic profile, hypoglycemia resistance was not observed at 12 hours post-dose. Importantly, the solubility and stability of the glucagon peptide were also significantly improved by fusion to XTEN. The data show that Gcg-XTEN is effective in preventing hypoglycemia without the associated hyperglycemia expected for unmodified glucagon. While the plasma clearance of this Gcg-XTEN has been optimized for overnight dosing, specifically for the treatment of nocturnal hypoglycemia, constructs with significantly longer exposure profiles are feasible. Such constructs may have multiple applications such as allowing for more aggressive insulin treatment regimens, treating hypoglycemia due to insulin-secreting tumors, providing synergistic efficacy in combination therapies with long-acting GLP1 analogs, and as an appetite suppressant for treatment of obesity. The improved physical properties of the Gcg-XTEN molecule may also allow for novel delivery systems not currently possible with native glucagon.
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