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

用于持续递送肽药物治疗 2 型糖尿病的可注射 PEG 样缀合物

• 批准号: 10520019
• 负责人: Ashutosh Chilkoti
• 金额: $ 46.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-10 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10520019
• 关键词: Address; Age; Allergic Reaction; American; Antibodies; Behavior; Binding; Biological Availability; Biological Products; Blood Circulation; Blood Glucose; Breathing; Clinical; Data; Diabetes Mellitus; Diabetic mouse; Dose; Drug Delivery Systems; Drug Industry; Drug Kinetics; FDA approved; Formulation; GLP-I receptor; Glucagon; Glycosylated Hemoglobin; Goals; Half-Life; Hemoglobin concentration result; Hour; Individual; Injectable; Injections; Islet Cell; Islets of Langerhans; Kidney; Kinetics; Length; Life; Marketing; Medicine; Methacrylates; Methodology; Methyl Ethers; Molecular Weight; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oligonucleotides; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase III Clinical Trials; Phase Transition; Plasma; Polyethylene Glycols; Polymers; Property; Proteins; Research; Reticuloendothelial System; Sampling; Site; Skin; Specificity; Structure; Subcutaneous Injections; System; Technology; Temperature; Testing; Therapeutic; Transition Temperature; United States National Institutes of Health; Vertebral column; blood glucose regulation; copolymer; design; diabetic; drug candidate; drug efficacy; drug market; drug withdrawal; ethylene glycol; immunogenicity; improved; in vitro activity; in vivo; insulin secretion; islet; new technology; next generation; peptide drug; pharmacokinetics and pharmacodynamics; pharmacologic; side effect; subcutaneous

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.

摘要 NIH R01提案目的是开发一种非免疫原性的、可注射的聚乙二醇样物质储存库 用于全身给药的多肽药物的结合物。这一提议的动机是许多肽 蛋白质类药物的血浆半衰期很短，大约在几分钟到几小时之间。聚乙二醇化-- 将聚乙二醇(PEG)部分偶联到生物制品上-通常用于克服这些问题 限制。不幸的是，聚乙二醇是抗原性的，这导致提前终止了一项 聚乙二醇化候选药物和几种聚乙二醇化药物因严重中毒而退出市场 部分患者出现过敏反应。这些问题被追踪到循环中的抗聚乙二醇抗体，这些抗体 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，在这方面的改进 聚乙二醇酯及其分支衍生物的药代动力学(PK)和药效学(PD)现已在 一条渐近线。这项建议解决了开发下一代聚乙二醇化的迫切、未得到满足的需求 这克服了这些限制。我们假设我们可以解决聚乙二醇酯的免疫原性问题 通过下一代的类聚乙二醇型“隐形”聚合物对聚乙二醇偶联物进行偶联并进一步延长其半衰期， 聚[低聚(乙二醇甲基醚)甲基丙烯酸酯](POEGMA) (OEG)主干上的侧链。我们的初步数据证实了这一假设，该数据表明， 通过将OEG侧链长度缩短到≤3来消除患者来源的抗聚乙二醇抗体，而不需要 折衷PK或Pd，并且具有两个和三个EG长侧链混合物的共聚物也允许 POEGMA在25-37℃之间可逆地从溶液转变为不可溶的凝聚体，从而实现 建立一个持续释放库。我们将演示这种非免疫原性的、可注射的 通过合成临床批准的强效但短效的exendin的POEGMA结合物来建立药物仓库 治疗2型糖尿病的多肽药物-并表明Exendin-POEGMA结合物具有药理活性， 在皮下(S.C.)上形成仓库糖尿病小鼠体内注射，表现为零级释药动力学 来自仓库的血流，导致糖尿病(db/db)小鼠持续的血糖控制，同时 消除聚乙二醇的免疫原性和抗原性。这项研究的总体意义在于它将解决 聚乙二醇抗原性问题，并将通过创建一种 形成S.C.的可注射的聚乙二醇偶联物。药物持续释放的仓库。通过这样做，它将呼吸 为一项成熟的药物输送技术注入新的生命，这项技术现在开始显示出它的年龄。更具体地说，它 还将改善约3000万美国糖尿病患者的2型糖尿病管理。因为 POEGMA结合技术很可能应用于许多疗法--超越Exendin-- 血浆半衰期短，在抗聚乙二醇抗体令人担忧的地方，它具有广泛的潜力 冲击力。