Anti-PEG IgM production and accelerated blood clearance phenomenon after the administration of PEGylated exosomes in mice
Anti-PEG IgM production and accelerated blood clearance phenomenon after the administration of PEGylated exosomes in mice
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DOI：
10.1016/j.jconrel.2021.05.001
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发表时间：
2021-05-06
影响因子：
10.8
通讯作者：
Ishida, Tatsuhiro
中科院分区：
文献类型：
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作者：
Emam, Sherif E.;Elsadek, Nehal E.;Ishida, Tatsuhiro
最近，人们越来越关注外泌体或细胞外囊泡作为递送RNA、蛋白质、基因和抗癌剂的潜在候选物。外泌体性质的工程化作为扩展外泌体应用的手段正在迅速发展。外泌体的PEG化是一种用于改善其体内稳定性、循环半衰期，并且有时允许靶向配体结合至外泌体外部的技术。根据FDA关于PEG化蛋白质开发的指导方针，应检查对PEG化分子和颗粒的免疫应答。在这项研究中，我们制备了PEG化的外泌体，并研究了小鼠单次静脉注射后抗PEG IgM抗体的产生。此外，我们监测了在初始剂量后施用的第二剂量的PEG化外泌体的血液浓度和肿瘤蓄积。在小鼠中单次注射PEG化外泌体以T细胞依赖性方式诱导抗PEG IgM产生。当PEG化外泌体的注射剂量进一步增加时，抗PEG IgM产生减少。在C26鼠结肠直肠癌模型中，通过注射PEG化外泌体诱导的抗PEG IgM降低了第二剂量的PEG化外泌体的血液浓度，并抑制了它们的肿瘤积累。PEG化脂质体或PEG化卵清蛋白（PEG-OVA）的初始注射剂量（两者均诱导抗PEG IgM产生）也降低了PEG化外泌体的血液浓度。有趣的是，通过注射PEG化外泌体诱导的抗PEG IgM不影响PEG-OVA的血液浓度。这些结果暗示了当需要重复PEG化外泌体剂量时和/或当PEG化外泌体与其他PEG化治疗剂一起使用时监测抗PEG IgM的重要性。
Recently, there is an increasing interest in exosomes or extracellular vesicles as potential candidates for delivering RNAs, proteins, genes, and anticancer agents. Engineering of exosome properties is rapidly evolving as a means of expanding exosome applications. PEGylation of exosomes is a technique used to improve their in vivo stability, circulation half-lives, and sometimes to allow the binding targeting ligands to the exosome exterior. According to FDA guidelines for the development of PEGylated proteins, immunological responses to PEGylated molecules and particles should be examined. In this study, we prepared PEGylated exosomes and investigated the production of anti-PEG IgM antibodies after single i.v. injections in mice. In addition, we monitored blood concentrations and tumor accumulation of a second dose of PEGylated exosomes administered after the initial dose. Single injections of PEGylated exosomes in mice induced anti-PEG IgM production in a T cell-dependent manner. The anti-PEG IgM production decreased when the injection dose of PEGylated exosomes was further increased. Anti-PEG IgM induced by injection of PEGylated exosomes decreased blood concentrations of a second dose of PEGylated exosomes and suppressed their tumor accumulation in a C26 murine colorectal cancer model. Initial injection doses of either PEGylated liposomes or PEGylated ovalbumin (PEG-OVA), both of them induced anti-PEG IgM production, also decreased the blood concentration of PEGylated exosomes. Interestingly, anti-PEG IgM induced by injection of PEGylated exosomes did not affect the blood concentration of PEG-OVA. These results imply the importance of monitoring anti-PEG IgM when repeat PEGylated exosome doses are required and/or when PEGylated exosomes are used together with other PEGylated therapeutics.