Knauf M J, Bell D P, Hirtzer P, Luo Z P, Young J D, Katre N V
Department of Process/Product Development, Cetus Corporation, Emeryville, California 94608.
J Biol Chem. 1988 Oct 15;263(29):15064-70.
We have examined the effects of a variety of chemical modifications to recombinant human interleukin-2 (rIL-2) on its pharmacokinetic behavior in rats. Unmodified rIL-2 is cleared from plasma with half-lives of 3 and 44 min for the alpha and beta phases. Modification of rIL-2 with monomethoxy polyethylene glycol or polyoxyethylated glycerol increased the half-lives as much as 20-fold, although the volume of distribution remained unchanged at 88 +/- 13 ml/kg. The clearance rates correlated with the effective molecular size of the modified protein determined by size exclusion chromatography. Clearance decreased rapidly as the effective molecular size increased from 19.5 to 70 kDa, whereas above 70 kDa the clearance decreased more slowly. This abrupt change at 70 kDa may be related to the permeability threshold of the kidney glomerular membrane which retains proteins larger than albumin in the plasma. Using the relationship between clearance and effective molecular size, the clearance rates of mixtures of modified rIL-2 could be predicted based on their average effective molecular size. Since the effectiveness of rIL-2 therapy is likely to be related to its pharmacokinetic behavior, the ability to design a molecule with a predictable time course in plasma provides a means to study this relationship.
我们研究了对重组人白细胞介素-2（rIL-2）进行多种化学修饰后对其在大鼠体内药代动力学行为的影响。未修饰的rIL-2从血浆中清除，α相和β相的半衰期分别为3分钟和44分钟。用单甲氧基聚乙二醇或聚氧乙烯化甘油修饰rIL-2可使半衰期延长多达20倍，尽管分布容积保持在88±13 ml/kg不变。清除率与通过尺寸排阻色谱法测定的修饰蛋白的有效分子大小相关。随着有效分子大小从19.5 kDa增加到70 kDa，清除率迅速下降，而在70 kDa以上，清除率下降得更慢。70 kDa处的这种突然变化可能与肾小球膜的通透性阈值有关，该阈值可保留血浆中大于白蛋白的蛋白质。利用清除率与有效分子大小之间的关系，可以根据修饰的rIL-2混合物的平均有效分子大小预测其清除率。由于rIL-2治疗的有效性可能与其药代动力学行为有关，设计一种在血浆中具有可预测时间进程的分子的能力提供了一种研究这种关系的方法。
