医薬価値に優れた機能性変異蛋白質の網羅的作製とそのDDSへの応用
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概要
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Tumor necrosis factor-alpha (TNF-a) has been expected to be a promising new antitumor agent, but toxic side effects by the systemic administration of TNF-a limit its clinical application. In this study, we attempted to improve the therapeutic potency of TNF-a by using our protein-drug innovation systems. Among phage libraries displaying various mutant TNF-as, we isolated some lysine-deficient super mutant TNF-as, typified by mTNF-a-KQOR, with higher TNF-receptor affinities and stronger bioactivity in vitro, in spite of the importance of lysine residues for trimer formation and receptor binding. mTNF-a-K90R showed more than 10 times stronger in vivo antitumor effects and 1.3 times less toxicity than wild-type TNF-a (wTNF-a). Site-specifically mono-PEGylated mTNF-a-K90R (sp-PEG-mTNF-a-K90R) at TV-ter-minus showed higher in vitro bioactivity than unmodified wTNF-a, whereas randomly mono-PEGylated wTNF-a at a lysine residue (ran-PEG-wTNF-a) had less than 6% of the bioactivity of wTNF-a. The antitumor therapeutic window of sp-PEG-mTNF-a-K90R was extended by about 5 times, 60 times and 18 times compared with those of mTNF-a-K90R, wTNF-a and ran-PEG-wTNF-a, respectively. sp-PEG-mTNF-a-K90R may, thus, be a potential systemic anti-tumor therapeutic agent. These data suggested that our fusion protein-drug innovation system composed of a creation system of functional mutant proteins based on phage display technique and a site-specific PEGylation system may open up a new avenue to the optimal protein therapy.
- 公益社団法人日本薬学会の論文
- 2004-08-01