Injectable PEG-like Conjugate for Sustained Delivery of a Peptide Drug for Type 2 Diabetes Treatment

摘要 该NIH R 01提案的目的是开发一种非免疫原性的PEG样多肽的可注射储库。 用于全身药物递送的肽药物缀合物。该提议的动机是许多肽 并且蛋白质药物具有短的血浆半衰期，大约为几分钟到几小时。聚乙二醇化- 通常使用聚乙二醇（PEG）部分与生物制剂的缀合来克服这些缺点。 局限性。不幸的是，PEG是抗原性的，这导致了早期终止的III期临床试验， 聚乙二醇化候选药物和几种聚乙二醇化药物因严重的 一些患者出现过敏反应。这些问题已被追溯到循环抗PEG抗体， 甚至在以前没有接受过聚乙二醇化药物的个体中也发现了这种情况。此外，改善 PEG及其支链衍生物赋予的药代动力学（PK）和药效学（PD）的研究现在在 渐近线该提案解决了开发下一代聚乙二醇化技术的迫切需求， 克服了这些限制。我们假设我们可以解决PEG的免疫原性问题 通过下一代PEG样“隐形”聚合物进一步延长PEG缀合物的半衰期， 聚[低聚（乙二醇）甲基醚甲基丙烯酸酯]（POEGMA）， (OEG)主链上的侧链。我们的初步数据证实了这一假设， 通过将OEG侧链长度缩短至≤3， 并且具有两个和三个EG长侧链的混合物的共聚物还允许 POEGMA在25-37 ºC之间可逆地从溶液转变为不溶性凝聚层，从而使 建立一个持续释放的仓库。我们将证明这种非免疫原性的，可注射的 通过合成毒蜥外泌肽的POEGMA缀合物-一种有效但短效的临床批准的药物 用于2型糖尿病的肽类药物-并显示exendin-POEGMA缀合物具有抗肿瘤活性， 在皮下（s.c.）注射在糖尿病小鼠中，显示零级释放动力学进入 血液从仓库，导致持续的血糖控制糖尿病（db/db）小鼠，而同时 消除PEG免疫原性和抗原性。这项研究的总体意义在于，它将解决 PEG抗原性的问题，并且还将通过产生 可注射PEG缀合物，其形成s.c.具有持续释放药物的贮库。通过这样做，它将呼吸 新的生命注入到一个既定的药物输送技术，现在开始显示它的年龄。更具体地说， 还将改善对约3000万美国糖尿病患者的2型糖尿病管理。因为 POEGMA结合物技术可能应用于除毒蜥外的许多治疗方法， 具有短的血浆半衰期，并且在关注抗PEG抗体的情况下，它具有广泛的潜在的 冲击

ABSTRACT The objective of this NIH R01 proposal is to develop a non-immunogenic, injectable depot of a PEG-like conjugate of a peptide drug for systemic drug delivery. This proposal is motivated by the fact that many peptide and protein drugs have a short plasma half-life on the order of minutes to a few hours. PEGylation —the conjugation of polyethylene glycol (PEG) moieties to biologics— is commonly used to overcome these limitations. Unfortunately, PEG is antigenic, which has led to the early termination of a Phase III clinical trial of a PEGylated drug candidate and withdrawal of several PEGylated drugs from the market because of severe allergic reactions in some patients. These problems have been traced to circulating anti-PEG antibodies that are found even in individuals who have not previously received a PEGylated drug. Furthermore, the improvement in pharmacokinetics (PK) and pharmacodynamics (PD) conferred by PEG and its branched derivatives are now at an asymptote. This proposal addresses the urgent, unmet need to develop the next-generation of PEGylation that overcomes these limitations. We hypothesize that we can solve the immunogenicity problem of PEG conjugates and further extend the half-life of PEG conjugates by a next generation PEG-like “stealth” polymer, poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) that presents short oligomeric ethylene glycol (OEG) side-chains on a backbone. This hypothesis is validated by our preliminary data that shows that reactivity towards patient-derived anti-PEG antibodies is eliminated by shortening the OEG side-chain length to ≤3 without compromising PK or PD, and that a copolymer with a mixture of two and three EG long side-chains also allows POEGMA to reversibly transition from a solution into an insoluble coacervate between 25-37 ºC, thereby enabling the creation of a sustained release depot. We will demonstrate the utility of this non-immunogenic, injectable drug depot by synthesizing POEGMA conjugates of exendin —a potent but short-acting clinically approved peptide drug for type 2 diabetes— and show that exendin-POEGMA conjugates are pharmacologically active, form a depot upon subcutaneous (s.c.) injection in diabetic mice, show zero-order release kinetics into the bloodstream from the depot, leading to sustained glucose control in diabetic (db/db) mice, while simultaneously eliminating PEG immunogenicity and antigenicity. The overall significance of this research is that it will solve the problem of PEG antigenicity and will also improve upon the PK and PD of PEG conjugates by creating an injectable PEG conjugate that forms a s.c. depot with sustained release of the drug. By doing so, it will breathe new life into an established drug delivery technology that is now beginning to show its age. More specifically, it will also enable improved management of type diabetes for the ~30 million Americans who are diabetic. Because the POEGMA conjugate technology can likely be applied to the many therapeutics —beyond exendin— that have a short plasma half-life and where anti-PEG antibodies are of concern, it has the potential to have broad impact.