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.

抽象的 NIH R01 提案的目标是开发一种非免疫原性、可注射的 PEG 类药物储存库。 用于全身药物输送的肽药物缀合物。该提议的动机是许多肽 蛋白质药物的血浆半衰期较短，约为几分钟至几小时。聚乙二醇化—— 聚乙二醇 (PEG) 部分与生物制剂的缀合通常用于克服这些问题 限制。不幸的是，PEG 具有抗原性，这导致该药物的 III 期临床试验提前终止。 聚乙二醇化候选药物以及多种聚乙二醇化药物因严重的不良反应而从市场上撤出 部分患者出现过敏反应。这些问题可追溯到循环中的抗 PEG 抗体 即使在以前未接受过聚乙二醇化药物的个体中也发现了这种情况。此外，改进 PEG及其支链衍生物赋予的药代动力学（PK）和药效学（PD）现已在 渐近线。该提案解决了开发下一代聚乙二醇化的迫切且未满足的需求 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 缀合物，并通过下一代 PEG 类“隐形”聚合物进一步延长 PEG 缀合物的半衰期， 聚[低聚（乙二醇）甲醚甲基丙烯酸酯]（POEGMA），呈现短的低聚乙二醇 （OEG）主链上的侧链。我们的初步数据证实了这一假设，该数据表明反应性 通过将 OEG 侧链长度缩短至 ≤3，消除了对患者来源的抗 PEG 抗体的影响，而无需 损害 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溶性凝聚层，从而使 建立缓释库。我们将展示这种非免疫原性注射剂的实用性 通过合成 Exendin 的 POEGMA 缀合物来制备药物库 - 一种有效但短效的临床批准药物 治疗 2 型糖尿病的肽药物——并表明 exendin-POEGMA 缀合物具有药理活性， 在糖尿病小鼠皮下 (s.c.) 注射后形成储库，显示出零级释放动力学 来自储存库的血液，导致糖尿病 (db/db) 小鼠的血糖持续控制，同时 消除 PEG 的免疫原性和抗原性。这项研究的总体意义在于它将解决 PEG 抗原性问题，还将通过创建 形成皮下注射的 PEG 缀合物具有药物缓释作用的储库。这样做，它就会呼吸 为已成熟的药物输送技术注入了新的活力，但该技术现在已开始显得过时了。更具体地说，它 还将改善约 3000 万美国糖尿病患者的糖尿病管理。因为 POEGMA 缀合物技术可能适用于除毒蜥外泌肽之外的许多治疗方法 血浆半衰期短，并且在关注抗 PEG 抗体的情况下，它有可能具有广泛的应用前景 影响。