Zwitterionic nanogel encapsulation of uricase to evade immune responses

两性离子纳米凝胶封装尿酸酶以逃避免疫反应

• 批准号: 8951361
• 负责人: SHAOYI JIANG
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951361
• 关键词: Address; Adopted; Adverse event; Anaphylaxis; Animal Model; Antibodies; Antibody Response; Attention; Biocompatible Materials; Biodistribution; Blood Circulation; Cells; Characteristics; Chemistry; Clinical Trials; Cross Syndrome; Crosslinker; Dendritic Cells; Development; Digestion; Drug Delivery Systems; Encapsulated; Enzyme-Linked Immunosorbent Assay; Epitopes; Free Radicals; Freeze Drying; Future; Gel; Generations; Gout; Harvest; Immune; Immune response; In Situ; In Vitro; Injection of therapeutic agent; Measures; Membrane Proteins; Modeling; Monitor; NanoGel; Particle Size; Peptide Hydrolases; Pharmacologic Substance; Polyethylene Glycols; Polymers; Process; Property; Proteins; Rattus; Resistance; Serum; Source; Structure; Surface; Techniques; Technology; Temperature; Testing; Therapeutic; Transmission Electron Microscopy; Trypsin; United States Food and Drug Administration; Urate Oxidase; Urea; Work; base; cytokine; immunogenic; immunogenicity; in vivo; intravenous injection; light scattering; macrophage; monomer; novel strategies; particle; patient safety; polymerization; public health relevance; research study; response; success; therapeutic protein; uptake; zeta potential

 DESCRIPTION (provided by applicant): One of the major obstacles that impede the wide application of therapeutic protein products is their potential immunological responses, especially for those obtained from non-human sources. These responses decrease the efficacy of the protein and cause adverse events such as anaphylaxis, cytokine-release syndrome, and cross-reactive neutralization of endogenous proteins, all which may threaten patient safety. Currently, the most successful strategy to mitigate immune response to foreign proteins is the surface conjugation of the amphiphilic polymer polyethylene glycol (PEG) to cover the protein surface epitopes in the "PEGylation" process. This surface coverage strategy has been shown to decrease to some extent immune responses to the underlying protein and more than ten PEGylated protein products have been approved by the Food and Drug Administration (FDA). However, recent studies have demonstrated the repeated administration of PEGylated therapeutics generating anti-PEG antibodies both in animal models and clinical trials, which directly challenges the future of the PEGylation technology. One typical example is the PEGylated version of the highly immunogenic mammalian uricase for the therapy of gout (approved by FDA in 2010), where the high rate of anti-PEG generation after administration has caused extensive attention. We believe there are two shortcomings for the current PEGylation technology: 1) the PEG polymer is immunogenic and 2) PEG forms sparse brush structures that provides inadequate surface coverage due to its existing and available chemistries. Thus, we propose here a poly(carboxybetaine) (pCB) based nanogel encapsulation technique to overcome these problems simultaneously. In prior studies, we have demonstrated that pCB is a biocompatible material with better non-fouling property and less immunogenicity than PEG. Using pCB as a shielding material, the resulting nanogel will provide 100% protein surface coverage. This new approach adopts the same principle as PEGylation in that coverage of surface epitopes can diminish protein immune responses, but utilizes a non-immunogenic base material and provides a more comprehensive surface coverage. Thus, we hypothesize that pCB-coated uricase will have better circulation profiles and less immunogenicity compared to the current PEGylated version. This hypothesis will be addressed in the experiments of the following Specific Aims: 1) Development of uricase-loaded pCB nanogels with high activity; 2) determination of nanogel stability, stealth characteristics and protease resistance; and 3) determination of circulation profiles, biodistribution, and antibody responses. Successful completion of this proposal will culminate in a new approach for the entire protein pharmaceutical field to generate alternatives to the existing, but insufficient PEGylation technology, producing safer and more effective protein therapeutics.

 描述（应用程序提供）：阻碍广泛应用治疗性蛋白质产品的主要障碍之一是它们的潜在免疫反应，尤其是对于从非人类来源获得的免疫反应。这些反应降低了蛋白质的有效性，并引起不良事件，例如过敏反应，细胞因子释放综合征和内源性蛋白质的交叉反应性中和，所有这些都可能威胁到患者的安全。当前，减轻对异物蛋白免疫增强的最成功策略是两亲聚合物聚合物聚合物甘氨酸（PEG）的表面缀合，以覆盖“ peggenation”过程中的蛋白质表面表位。该表面覆盖策略已被证明在某种程度上降低了对潜在蛋白质的免疫回报，并且已获得食品药品监督管理局（FDA）批准了十种以上的蛋白质产品。然而，最近的研究表明，在动物模型和临床试验中，一再施用了卵形理论，产生了抗PEG抗体，这直接挑战了Pegylation Technology的未来。一个典型的例子是用于治疗痛风的高度免疫原性哺乳动物尿布的pe节制版本（2010年获得FDA批准），在该治疗后，给药后，抗PEG发电的高率引起了广泛的关注。我们认为，当前的Pegylation技术存在两个缺点：1）PEG聚合物具有免疫原性和2）PEG形成稀疏的刷子结构，由于其现有和可用的化学作用，它们的表面覆盖不足。这就是我们在这里提出的基于聚（羧贝因）（PCB）的纳米凝胶封装技术，以简单地克服这些问题。在先前的研究中，我们已经证明PCB是一种生物相容性材料，其非污染特性且免疫原性较小。将PCB作为屏蔽材料，所得的纳米凝胶将提供100％蛋白质表面覆盖率。这种新方法采用与Pegylation相同的原理，因为表面表位的覆盖范围可以减少蛋白质免疫回报，但利用非免疫原性的基本材料并提供了更全面的表面覆盖率。这是我们假设与当前的Pegyperated版本相比，具有PCB涂层的尿酶的循环谱和免疫原性较低。该假设将在以下特定目的的实验中解决：1）具有较高活性的尿酶加载的PCB纳米凝胶的发展； 2）确定纳米凝胶稳定性，隐形特征和抗蛋白质耐药性； 3）确定循环谱，生物分布和抗体反应。该提案的成功完成将以新的方法为整个蛋白质药物领域的新方法达到顶峰，以生成现有的但不足的卵巢技术的替代方法，从而产生更安全，更有效的蛋白质治疗。