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：聚乙二醇（PEG）由于具有抵抗蛋白质吸附和减少RES清除的能力，已被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，抗 PEG 抗体 (APA) 可以通过选择诱导聚乙二醇化疗法，或已经存在，可能是由于每天不断接触聚乙二醇卫生、护肤品和食品。反过来，APA 可以显着限制 PEG 化的循环动力学治疗方法并使它们无效，甚至可能不安全。鉴于数量不断增加聚乙二醇化疗法已获得 FDA 批准或处于临床开发阶段，迫切需要可以在高 APA 滴度的患者中使用聚乙二醇化药物的干预措施。这里，通过结合通过一系列体外和体内研究，我们建立了基于生理学的药代动力学（PBPK）模型确定高分子量游离 PEG 的施用是阻断 APA 的简单、有效和安全的策略与聚乙二醇化疗法结合。事实上，注射游离 PEG 增加了循环分数与 PBS 对照相比，小鼠体内的聚乙二醇化脂质体 APA 水平高出 100 倍以上，达到水平与没有 APA 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、肝肾功能以及仔细的组织组织学检查与 PBS 对照并没有显示肾小球炎症的证据。令人惊讶的是，完全没有毒性似乎与 PEG 的高度柔性性质以及没有 PEG 锚定到基质有关具有固定构象，限制了免疫复合物的形成并触发常规效应器功能。为了充分发挥这一战略的潜力，我们提出了一项严格的研究计划，该计划结合了通过计算机、体外和体内方法评估在小鼠中使用游离 PEG 的有效性和安全性两种聚乙二醇化治疗药物 Krystexxa（用于治疗痛风的聚乙二醇尿酸酶）和 Onivyde（聚乙二醇化脂质体伊立替康，用于治疗胰腺转移性腺癌）。瞄准 1、我们将进一步开发我们的PBPK模型来指导游离PEG的使用优化（PEG MW、剂量、剂量方案等）来抑制 APA，并预测这种干预措施在小鼠和小鼠中的有效性。人类。在目标 2 中，我们将验证目标 1 的预测，以恢复 Krystexxa 的长期循环通过一系列精心设计，小鼠的 APA 滴度与人类中发现的 APA 滴度相匹配药代动力学、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 在基因工程小鼠胰腺癌模型中的有效性 APA。如果成功，我们的工作将找到一条易于翻译的途径，以恢复各种技术的使用高滴度 APA 患者的聚乙二醇化药物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Pretargeted delivery of PEG-coated drug carriers to breast tumors using multivalent, bispecific antibody against polyethylene glycol and HER2.

使用针对聚乙二醇和 HER2 的多价双特异性抗体将 PEG 涂层药物载体预靶向递送至乳腺肿瘤。

DOI：
10.1016/j.nano.2019.102076
发表时间：
2019-08-05
期刊：
Nanomedicine : nanotechnology, biology, and medicine
影响因子：
0
作者：
C. L. Parker;M. McSweeney;A. Lucas;T. Jacobs;Daniel Wadsworth;W. Zamboni;S. Lai
通讯作者：
S. Lai

Antibody-mediated trapping in biological hydrogels is governed by sugar-sugar hydrogen bonds.

生物水凝胶中抗体介导的捕获是由糖-糖氢键控制的。