Optimum bioconjugated cytokines selectively enhanced their therapeutic potency and reduces side-effects.

将聚乙二醇修饰的白细胞介素-6（MPEG-IL-6）（其中IL-6的14个赖氨酸氨基中的54%与PEG偶联）的体内血小板生成活性与天然IL-6的体内血小板生成活性进行比较。将天然IL-6和MPEG-IL-6（其显示天然IL-6的约51%的比生物活性）每2天皮下施用至小鼠，持续7天。天然IL-6不仅增加外周血小板计数，而且以剂量依赖性方式增加血浆IgG 1水平。MPEG-IL-6显示出比天然IL-6高约500倍的促血小板生成效力。此外，与天然IL-6相比，MPEG-IL-6并不像其增强血小板产生那样增强IgG 1产生。MPEG-IL-6显著刺激用5-氟尿嘧啶处理的小鼠的血小板恢复，而施用天然IL-6具有可忽略的作用。MPEG-IL-6的血浆半衰期比天然IL-6的血浆半衰期长约100倍。MPEG-IL-6的血浆清除率降低被认为部分是由于PEG链屏蔽了IL-6分子中的蛋白水解位点。网状内皮系统（如肝脏和脾脏）对IL-6的摄取明显受到PEG化的限制。IL-6的PEG化修饰显著增强了IL-6的血液驻留，从而有效地增强了其血小板生成活性并显著降低了其副作用。这些结果表明，MPEG-IL-6可能是一个潜在的候选血小板生成剂。

The in vivo thrombopoietic activity of polyethylene glycol-modified interleukin-6 (MPEG-IL-6), in which 54% of the 14 lysine amino groups of IL-6 were coupled with PEG, was compared to that of native IL-6. Native IL-6 and MPEG-IL-6, which showed about 51 % of the specific bioactivity of native IL-6, were administered subcutaneously to mice every 2 days for 7 days. Native IL-6 increased not only the peripheral platelet count, but also the plasma-IgG1 level in a dose-dependent manner. MPEG-IL-6 showed about 500 times higher thrombopojetic potency than native IL-6. Further, in comparison to native IL-6, MPEG-IL-6 did not enhance IgG1 production as much as it enhanced platelet production. MPEG-IL-6 significantly stimulated platelet recovery in mice treated with 5-fluorouracil, whereas the administration of native IL-6 had a negligible effect. The plasma half-life of MPEG-IL-6 was about 100-fold longer than that of native IL-6. The decrease in the plasma clearance of MPEG-IL-6 was thought to be due, in part, to the shielding of the proteolytic sites in the IL-6 molecule by the PEG chain. The uptake of IL-6 by the reticuloendothelial system, such as the liver and spleen, was markedly limited by PEGylation. The PEGylation of IL-6 markedly enhanced the blood-residency of IL-6, resulting in effective augmentation of its thrombopoietic activity and a marked decrease in its side-effects. These findings suggest that MPEG-IL-6 may be a potential candidate for thrombopoietic agent.