A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity
A brush-polymer/exendin-4 conjugate reduces blood glucose levels for up to five days and eliminates poly(ethylene glycol) antigenicity
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DOI：
10.1038/s41551-016-0002
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发表时间：
2017-01-01
影响因子：
28.1
通讯作者：
Chilkoti, Ashutosh
中科院分区：
文献类型：
--
作者：
Qi, Yizhi;Simakova, Antonina;Chilkoti, Ashutosh
治疗性肽和蛋白质的递送通常受到短半衰期和随后需要频繁注射的挑战，这限制了功效，降低了患者依从性并增加了治疗成本。在这里，我们证明了一个单一的皮下注射的位点特异性（C-末端）共轭物exendin-4（exendin）-一种治疗肽，临床上用于治疗2型糖尿病mellitus和聚[寡（乙二醇）甲基醚甲基丙烯酸酯]（POEGMA）与精确控制的分子量降低血糖高达120小时喂养小鼠。最值得注意的是，我们表明，exendin-C-POEGMA共轭物与平均9个侧链乙二醇（EG）重复表现出显着较低的反应性对患者来源的抗聚（乙二醇）（抗PEG）抗体比两个美国FDA批准的PEG化药物，并减少侧链长度为三个EG重复完全消除PEG抗原性，而不影响体内疗效。我们的研究结果确立了POEGMA的位点特异性缀合作为下一代PEG化技术，用于改善传统PEG化药物的药理学性能，其安全性和有效性受到患者中预先存在的抗PEG抗体的阻碍。
The delivery of therapeutic peptides and proteins is often challenged by short half-lives and the consequent need for frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. Here, we demonstrate that a single subcutaneous injection of site-specific (C-terminal) conjugates of exendin-4 (exendin)-a therapeutic peptide that is clinically used to treat type 2 diabetes mellitus-and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) with precisely controlled molecular weights lowered blood glucose for up to 120 h in fed mice. Most notably, we show that an exendin-C-POEGMA conjugate with an average of nine side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (anti-PEG) antibodies than two US FDA-approved PEGylated drugs, and that reducing the side-chain length to three EG repeats completely eliminates PEG antigenicity without compromising in vivo efficacy. Our findings establish the site-specific conjugation of POEGMA as a next-generation PEGylation technology for improving the pharmacological performance of traditional PEGylated drugs, whose safety and efficacy are hindered by pre-existing anti-PEG antibodies in patients.