Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin Germany.
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg Germany.
J Pharm Sci. 2022 Jun;111(6):1642-1651. doi: 10.1016/j.xphs.2021.10.032. Epub 2021 Oct 30.
Polymer conjugation to biologics is of key interest to the pharmaceutical industry for the development of potent and long acting biotherapeutics, with poly(ethylene glycol) (PEG) being the gold standard. Within the last years, unwanted PEG-related side effects (immunological reactions, antibody formation) arose, therefore creating several attempts to establish alternative polymers with similar potential to PEG. In this article, we synthesized N-terminal bioconjugates of the potential therapeutic human interleukin-4 (hIL-4 WT) with linear polyglycerol (LPG) of 10 and 40 kDa and compared it with its PEG analogs of same nominal weights. Polyglycerol is a highly hydrophilic polymer with good biocompatibility and therefore represents an alternative polymer to PEG. Both polymer types resulted in similar conjugation yields, comparable hydrodynamic sizes and an unaltered secondary structure of the protein after modification. LPG- and PEG-bioconjugates remained stable in human plasma, whereas binding to human serum albumin (HSA) decreased after polymer modification. Furthermore, only minor differences in bioactivity were observed between LPG- and PEG-bioconjugates of same nominal weights. The presented findings are promising for future pharmacokinetic evaluation of hIL-4-polymer bioconjugates.
聚合物与生物制剂的缀合对于制药行业来说是开发有效且长效生物疗法的关键关注点，其中聚乙二醇（PEG）是金标准。在过去的几年中，出现了一些与 PEG 相关的不良副作用（免疫反应、抗体形成），因此，人们进行了多次尝试以建立具有类似 PEG 潜力的替代聚合物。在本文中，我们合成了潜在治疗性人白细胞介素-4（hIL-4 WT）的 N 端生物缀合物，其与 10 kDa 和 40 kDa 的线性聚甘油（LPG）缀合，并将其与相同标称重量的 PEG 类似物进行了比较。聚甘油是一种具有良好生物相容性的高度亲水聚合物，因此是 PEG 的替代聚合物。两种聚合物类型均导致相似的缀合产率、相当的流体力学尺寸以及修饰后蛋白质二级结构不变。LPG 和 PEG 缀合物在人血浆中稳定，而修饰后与人血清白蛋白（HSA）的结合减少。此外，相同标称重量的 LPG 和 PEG 缀合物的生物活性仅略有差异。这些发现为未来 hIL-4-聚合物缀合物的药代动力学评估提供了希望。
