Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA.
Department of Biomedical Engineering, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA.
Acta Biomater. 2023 Oct 15;170:250-259. doi: 10.1016/j.actbio.2023.08.052. Epub 2023 Aug 31.
The interactions between polymers and the immune system remains poorly controlled. In some instances, the immune system can produce antibodies specific to polymer constituents. Indeed, roughly half of pegloticase patients without immunomodulation develop high titers of anti-PEG antibodies (APA) to the PEG polymers on pegloticase, which then quickly clear the drug from circulation and render the gout treatment ineffective. Here, using pegloticase as a model drug, we show that addition of high molecular weight (MW) free (unconjugated) PEG to pegloticase allows us to control the immunogenicity and mitigates APA induction in mice. Compared to pegloticase mixed with saline, mice repeatedly dosed with pegloticase containing different MW or amount of free PEG possessed 4- to 12- fold lower anti-PEG IgG, and 6- to 10- fold lower anti-PEG IgM, after 3 rounds of pegloticase dosed every 2 weeks. The markedly reduced APA levels, together with competitive inhibition by free PEG, restored the prolonged circulation of pegloticase to levels observed in APA-naïve animals. In contrast, mice with pegloticase-induced APA eliminated nearly all pegloticase from the circulation within just four hours post-injection. These results support the growing literature demonstrating free PEG may effectively suppress drug-induced APA, which in turn may offer sustained therapeutic benefits without requiring broad immunomodulation. We also showed free PEG effectively blocked the PEGylated protein from binding with cells expressing PEG-specific B cell receptors. It provides a template of how we may be able to tune the interactions and immunogenicity of other polymer-modified therapeutics. STATEMENT OF SIGNIFICANCE: A major challenge with engineering materials for drug delivery is their interactions with the immune system. For instance, our body can produce high levels of anti-PEG antibodies (APA). Unfortunately, the field currently lack tools to limit immunostimulation or overcome pre-existing anti-PEG antibodies, without using broad immunosuppression. Here, we showed that simply introducing free PEG into a clinical formulation of PEG-uricase can effectively limit induction of anti-PEG antibodies, and restore their prolonged circulation upon repeated dosing. Our work offers a readily translatable method to safely and effectively restore the use PEG-drugs in patients with PEG-immunity, and provides a template to use unconjugated polymers with low immunogenicity to regulate interactions with the immune system for other polymer-modified therapeutics.
聚合物与免疫系统的相互作用仍然难以控制。在某些情况下，免疫系统会产生针对聚合物成分的特异性抗体。事实上，大约一半未经免疫调节的培戈洛酶患者会产生针对培戈洛酶上聚乙二醇（PEG）聚合物的高滴度抗聚乙二醇抗体（APA），这些抗体随后会迅速从循环中清除药物，使痛风治疗无效。在这里，我们以培戈洛酶为模型药物，表明添加高分子量（MW）游离（未结合）PEG 可控制其免疫原性并减轻小鼠 APA 的诱导。与培戈洛酶混合生理盐水相比，在每两周重复给予 3 轮培戈洛酶的情况下，用含有不同 MW 或游离 PEG 量的培戈洛酶处理的小鼠，其抗聚乙二醇 IgG 降低了 4 至 12 倍，抗聚乙二醇 IgM 降低了 6 至 10 倍。APA 水平显著降低，游离 PEG 的竞争性抑制作用恢复了培戈洛酶的延长循环，使其恢复到无 APA 动物的水平。相比之下，具有培戈洛酶诱导的 APA 的小鼠在注射后仅 4 小时内就从循环中消除了几乎所有的培戈洛酶。这些结果支持越来越多的文献表明游离 PEG 可能有效地抑制药物诱导的 APA，这反过来可能提供持续的治疗益处，而无需广泛的免疫调节。我们还表明，游离 PEG 可有效地阻止与表达 PEG 特异性 B 细胞受体的细胞结合的 PEG 化蛋白。它为我们提供了一个模板，说明我们如何能够调整其他聚合物修饰治疗剂的相互作用和免疫原性。意义声明：为药物输送工程材料带来的主要挑战是它们与免疫系统的相互作用。例如，我们的身体会产生高水平的抗聚乙二醇抗体（APA）。不幸的是，目前该领域缺乏限制免疫刺激或克服预先存在的抗聚乙二醇抗体的工具，而无需使用广泛的免疫抑制。在这里，我们表明，只需将游离 PEG 引入 PEG-尿酸酶的临床制剂中，就可以有效地限制抗聚乙二醇抗体的诱导，并在重复给药时恢复其延长的循环。我们的工作提供了一种易于转化的方法，可以安全有效地恢复对具有 PEG 免疫性的患者使用 PEG 药物，并为使用低免疫原性的未结合聚合物来调节与免疫系统的相互作用提供了一个模板，用于其他聚合物修饰的治疗剂。
