Zwitterionic gel encapsulation promotes protein stability, enhances pharmacokinetics, and reduces immunogenicity
Zwitterionic gel encapsulation promotes protein stability, enhances pharmacokinetics, and reduces immunogenicity
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DOI：
10.1073/pnas.1512465112
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发表时间：
2015-09-29
影响因子：
11.1
通讯作者：
Jiang, Shaoyi
中科院分区：
文献类型：
--
作者：
Zhang, Peng;Sun, Fang;Jiang, Shaoyi
许多治疗性蛋白质的稳定性差、药代动力学 (PK) 特征不足和免疫原性阻碍了蛋白质治疗的进展。聚乙二醇缀合（PEG化）是迄今为止克服这些缺点最成功的策略，已有超过10种PEG化蛋白质被推向市场。然而，治疗诱导的抗 PEG 抗体引起了人们对 PEG 化治疗的未来的严重担忧。在这里，我们展示了一种两性离子聚合物网络封装技术，可有效增强蛋白质稳定性和 PK，同时减轻免疫反应。用全面的两性离子聚羧基甜菜碱 (PCB) 网络修饰的尿酸酶表现出卓越的稳定性和大大延长的循环半衰期。更重要的是，在大鼠模型中每周注射三周后，PK行为没有改变，并且没有检测到抗尿酸酶和抗PCB抗体。该技术适用于多种蛋白质，并开启了采用高免疫原性蛋白质进行治疗或保护应用的可能性。
Advances in protein therapy are hindered by the poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity of many therapeutic proteins. Polyethylene glycol conjugation (PEGylation) is the most successful strategy to date to overcome these shortcomings, and more than 10 PEGylated proteins have been brought to market. However, anti-PEG antibodies induced by treatment raise serious concerns about the future of PEGylated therapeutics. Here, we demonstrate a zwitterionic polymer network encapsulation technology that effectively enhances protein stability and PK while mitigating the immune response. Uricase modified with a comprehensive zwitterionic polycarboxybetaine (PCB) network exhibited exceptional stability and a greatly prolonged circulation half-life. More importantly, the PK behavior was unchanged, and neither anti-uricase nor anti-PCB antibodies were detected after three weekly injections in a rat model. This technology is applicable to a variety of proteins and unlocks the possibility of adopting highly immunogenic proteins for therapeutic or protective applications.