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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.

摘要：聚乙二醇（PEG）由于其抵抗蛋白质吸附和减少RES清除的能力，已被广泛应用于临床。广泛用于延长蛋白质和纳米颗粒治疗剂的循环时间。不幸的是，最近动物和人体研究表明，抗PEG抗体（阿帕）可以通过选择性免疫抑制剂诱导， PEG化治疗剂，或预先存在，可能是由于每天持续暴露于PEG 卫生、护肤和食品。反过来，阿帕可以基本上限制聚乙二醇化的微生物制剂的循环动力学。治疗剂，并使它们无效，甚至可能不安全。鉴于越来越多的对于FDA批准或处于临床开发中的PEG化治疗剂，迫切需要这些干预措施可以使聚乙二醇化药物用于高阿帕滴度的患者。在这里，通过结合基于生理学的药代动力学（PBPK）建模与一系列的体外和体内研究，我们有经鉴定，给予高分子量游离PEG是阻断阿帕的一种简单、有效和安全的策略与PEG化治疗剂的结合。事实上，注射游离PEG增加了循环中与PBS对照相比，小鼠中的聚乙二醇化脂质体具有>100倍的阿帕实质水平，水平与没有阿帕的小鼠相同。更重要的是，这种干预措施的所有毒性研究，包括全血细胞计数、肝和肾功能以及仔细的组织组织学检查， PBS对照，未显示肾小球炎症的证据。令人惊讶的是，完全没有毒性这似乎与PEG的高度柔性性质以及PEG锚定到基底上的缺失有关具有固定的构象，这限制了免疫复合物的形成并触发常规效应物功能协调发展的为了实现这一战略的全部潜力，我们提出了一个严格的研究计划，评价小鼠中使用游离PEG的有效性和安全性的计算机模拟、体外和体内方法对于两种PEG化治疗剂，Krystexxa（用于治疗痛风的PEG-尿酸酶）和 Onivyde（聚乙二醇化脂质体伊立替康，用于治疗转移性胰腺腺癌）。在Aim中 1，我们将进一步开发我们的PBPK模型，以指导游离PEG（PEG分子量，剂量，给药方案等）来抑制阿帕，并预测这种干预在小鼠和人类在目标2中，我们将验证目标1中关于恢复Krystexxa长期循环的预测，通过一系列精心设计的实验，药代动力学、生物分布和毒性研究。最后，在目标3中，我们将验证目标1的预测用于恢复Onivyde在胰腺癌基因工程小鼠模型中的有效性，阿帕。如果成功，我们的工作将确定一个容易翻译的途径，恢复使用各种高滴度阿帕患者的PEG化药物。