Molecular design of hybrid tumor necrosis factor-α III: polyethylene glycol-modified tumor necrosis factor-α has markedly enhanced antitumor potency due to longer plasma half-life and higher tumor accumulation
Y. Tsutsumi, T. Kihira, S. Tsunoda, H. Kamada, S. Nakagawa, Y. Kaneda, T. Kanamori and T. MayumiJournal of Pharmacology and Experimental Therapeutics (1999), Vol. 278 pages 1006-1011
We have reported that chemical modification of tumor necrosis factor-α (TNF-α) with polyethylene glycol (PEG) markedly increases its antitumor potency without any adverse side effects. MPEG-TNF-α, especially, in which 56% of the lysine amino groups of TNF-α are coupled with PEG, exhibits 100-fold more antitumor activity in vivo than native TNF-α in the Meth-A murine sarcoma model. In this study, we investigated the pharmacokinetics of PEG-modified TNF-α with various molecular sizes to clarify the mechanisms of the enhanced antitumor potency of MPEG-TNF-α. The plasma half-lives of modified TNF-α increased with increasing molecular size. The decreased plasma clearance of modified TNF-α was partially caused by the shielding effect of the proteolytic sites in TNF-α by the attached PEG and the decreased transport from blood to various tissues. Almost all native TNF-α was uniformly distributed to the kidney and reticuloendothelial system within 1 hr of an intravenous administration, and rapidly disappeared from these tissues at 3 hr. However, very little native TNF-α was transported into the tumor. The absolute distributed amount and distribution profile of modified TNF-α to tissues other than the tumor were the same as those of native TNF-α, whereas the plasma levels of the modified TNF-α were higher than plasma levels of the native TNF-α. The tumor distribution of modified TNF-α was markedly enhanced compared with native TNF-α and gradually increased over time. About 9-fold more MPEG-TNF-α was distributed to the tumor than native TNF-α. Thus, we found that the marked increase in the antitumor potency of PEG-modified TNF-α resulted from the enhanced blood residency and tumor accumulation. The antitumor effect of MPEG-TNF-α against sarcoma-180 other than Meth-A fibrosarcoma was also about 100 times greater than that of native TNF-α when systemically administered. The optimal PEGylation of TNF-α facilitated its antitumor potency and MPEG-TNF-α may be useful systemic antitumor therapeutic drug.