Summary
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-IgGl level in a dose-dependent manner. MPEG-IL-6 showed
about 500 times higher thrombopoietic potency than native IL-6. Further, in comparison
to native IL-6, MPEG-IL-6 did not enhance IgGl 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 halflife 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.
