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

聚乙二醇修饰的白细胞介素-6 （MPEG-IL-6）的体内血小板生成活性与天然IL-6相比，其中IL-6的14个赖氨酸氨基中有54%与PEG偶联。小鼠每2天皮下注射一次天然IL-6和MPEG-IL-6，其特异性生物活性约为天然IL-6的51%，连续7天。天然IL-6不仅增加外周血小板计数，而且以剂量依赖的方式增加血浆igg1水平。MPEG-IL-6的血小板效价比天然IL-6高约500倍。此外，与天然IL-6相比，MPEG-IL-6对IgG1产生的促进作用不如对血小板产生的促进作用那么大。MPEG-IL-6显著刺激5-氟尿嘧啶处理小鼠的血小板恢复，而天然IL-6的作用可以忽略不计。MPEG-IL-6的血浆半衰期比天然IL-6长约100倍。血浆中MPEG-IL-6清除率的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的摄取受到聚乙二醇化的明显限制。IL-6的聚乙二醇化显著增强了IL-6的血液驻留，从而有效增强了其血小板生成活性，并显著降低了其副作用。这些发现提示MPEG-IL-6可能是一种潜在的候选血小板生成药物。

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.