Overcoming anti-PEG immunity to restore prolonged circulation and efficacy of PEGylated therapeutics

克服抗 PEG 免疫，恢复 PEG 化治疗的延长循环和功效

基本信息

批准号：
10181024
负责人：
Samuel Lai
金额：
$ 67.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181024
关键词：
Acute Adsorption Agreement Anaphylaxis Animals Antibodies Antibody titer measurement Antigen-Antibody Complex B-Lymphocytes Binding Biodistribution Biological Assay Blood Blood Circulation Brain Chronic Clinical Clinical Research Complete Blood Count Complex Control Groups Coupled Deposition Development Dose Drug Kinetics Drug Regulations Effectiveness Effectiveness of Interventions Ensure Exposure to FDA approved Factor IXa Food Genetically Engineered Mouse Gout Heart Histology Human Hygiene Hypersensitivity Immune response Immunity Immunocompetent Immunologics In Vitro Inbred BALB C Mice Inflammation Infusion procedures Injections Intervention Intervention Studies Intravenous Kidney Kinetics Lead Light Liposomes Liver Longevity Lung Measures Mediating Mediator of activation protein Metastatic Pancreatic Adenocarcinoma Methods Modeling Molecular Conformation Mononuclear Mus Nature Opsonin Parents Pathway interactions Patients Phagocytes Pharmaceutical Preparations Physiology Plasma Polyethylene Glycols Polymers Proteins RNA Radiolabeled Reaction Refractory Regimen Renal function Research Risk Safety Series Serious Adverse Event Spleen System Therapeutic Therapeutic Uses Time Tissues Toxic effect Translations Urate Oxidase Vaccinated Work aptamer base chemokine clinical development design drug development effective intervention effectiveness evaluation flexibility immunogenicity in silico in vivo irinotecan liver function mouse model nanomedicine pancreatic cancer model pharmacokinetic model phase 3 study programs therapeutic nanoparticles tumor growth

项目摘要

Abstract: Polyethylene glycol (PEG), due to its ability to resist protein adsorption and reduce RES clearance, has been widely used to extend the circulation times of protein and nanoparticle therapeutics. Unfortunately, recent animal and human studies have shown that anti-PEG antibodies (APA) can be either induced by select PEGylated therapeutics, or are pre-existing, presumably due to constant exposure to PEG in everyday hygiene, skincare and food products. In turn, APA can substantially limit the circulation kinetics of PEGylated therapeutics and render them non-efficacious, and potentially even unsafe. In light of the increasing number of PEGylated therapeutics that are either FDA approved or in clinical development, there is an urgent need for interventions that can enable the use of PEGylated drugs in patients with high APA titers. Here, by combining physiology-based pharmacokinetic (PBPK) modeling with a series of in vitro and in vivo studies, we have identified administration of high MW free-PEG to be a simple, effective and safe strategy in blocking APA binding to PEGylated therapeutics. Indeed, injection of free-PEG increased the fraction of circulating PEGylated liposomes in mice with substantial levels of APA by >100-fold compared to PBS control, reaching levels identical to mice without APA. More importantly, all toxicity studies of this intervention, including complete blood counts, liver and renal functions as well as careful tissue histology, were indistinguishable from PBS control and showed no evidence of glomeruli inflammation. The surprising, complete lack of toxicity appears related to the highly flexible nature of PEG coupled to the absence of PEG anchoring to substrates with fixed conformations, which limits the formation of immune complexes and triggering conventional effector functions. To realize the full potential of this strategy, we propose a rigorous research program that combines in silico, in vitro and in vivo approaches to evaluate the effectiveness and safety of the use of free-PEG in mice with high titers of APA for two PEGylated therapeutics, Krystexxa (PEG-uricase for treatment of gout) and Onivyde (PEGylated liposomal irinotecan for treatment of metastatic adenocarcinoma of the pancreas). In Aim 1, we will further develop our PBPK model to guide the optimization of use of free PEG (PEG MW, dose, dosing regimen, etc) to suppress APA, and to predict the effectiveness of this intervention in both mice and humans. In Aim 2, we will verify the predictions from Aim 1 for restoring prolonged circulation of Krystexxa in mouse with APA titers matching those found in humans through a series of carefully designed pharmacokinetic, biodistribution and toxicity studies. Finally, in Aim 3, we will verify the predictions from Aim 1 for restoring the effectiveness of Onivyde in a genetically engineered mouse model of pancreatic cancer with APA. If successful, our work will identify a readily translatable pathway for restoring the use of a variety of PEGylated agents in patients with high titers of APA.

抽象的：由于聚乙烯乙二醇（PEG），由于其能够抵抗蛋白质吸附和减少清除的能力，广泛用于延长蛋白质和纳米颗粒疗法的循环时间。不幸的是，最近动物和人类研究表明，可以通过选择诱导抗PEG抗体（APA）高乙二醇化的疗法，或者已经存在的治疗方法，大概是由于每天不断暴露于钉子卫生，护肤和食品。反过来，APA可以实质上限制Pegyped的循环动力学治疗和使其变得非效率，甚至可能不安全。鉴于越来越多的 FDA批准或在临床开发中，迫切需要可以在高APA滴度患者中使用类乙二醇药物的干预措施。在这里，结合基于生理学的药代动力学（PBPK）建模，通过一系列体外和体内研究，我们有确定高MW Free-PEG的管理是阻止APA的简单，有效且安全的策略结合到卵巢疗法。实际上，自由peg注入增加了循环的比例与PBS对照相比，具有大量APA水平的小鼠中的脂肪体脂质体，达到100倍水平与没有APA的小鼠相同。更重要的是，该干预措施的所有毒性研究，包括完整的血液计数，肝脏和肾功能以及仔细的组织组织学是无法区分的 PBS控制，没有显示肾小球炎症的迹象。令人惊讶的，完全缺乏毒性似乎与PEG的高度柔韧性有关，耦合到缺乏固定在底物上的PEG 具有固定构象，限制了免疫复合物的形成并触发常规效应器功能。为了实现这种策略的全部潜力，我们提出了一个严格的研究计划，将在计算机中，体外和体内方法评估小鼠使用自由peg的有效性和安全性 APA的高滴度用于两种Pegyperated Therapeutics，Krystexxa（用于治疗痛风的PEG-尿酶）和 Onivyde（用于治疗胰腺转移性腺癌的脂质体伊立替康）。目标 1，我们将进一步开发我们的PBPK模型，以指导免费使用PEG的使用（PEG MW，剂量，，给出剂量方案等）以抑制APA，并预测这种干预对小鼠和人类。在AIM 2中，我们将验证AIM 1的预测，以恢复Krystexa的延长循环通过一系列精心设计药代动力学，生物分布和毒性研究。最后，在AIM 3中，我们将验证AIM 1的预测用于恢复Onivyde在胰腺癌的基因工程小鼠模型中的有效性 APA。如果成功，我们的工作将确定一条易于翻译的途径，用于恢复各种的使用 APA滴度高的患者中的pegypated剂。