Optimal site-specific PEGylation of mutant TNF-α improves its antitumor potency
| Autor: | Toshihide Nishibata, Yuriko Yamagata, Hiroko Shibata, Yoko Yamamoto, Takayuki Okamoto, Shinsaku Nakagawa, Yasuhiro Abe, Satoshi Nagata, Tadanori Mayumi, Madoka Taniai, Yasuo Tsutsumi, Yasuo Yoshioka, Yohei Mukai, Maki Kawamura, Shinji Ikemizu |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Fibrosarcoma Lysine Mutant Biophysics Antineoplastic Agents Pharmacology Protein Engineering Biochemistry Polyethylene Glycols Mice Necrosis Structure-Activity Relationship In vivo PEG ratio Animals Humans Structure–activity relationship Potency Molecular Biology Mice Inbred BALB C Binding Sites Tumor Necrosis Factor-alpha Chemistry Remission Induction Neoplasms Experimental Cell Biology Recombinant Proteins In vitro PEGylation Female Protein Binding |
| Zdroj: | Biochemical and Biophysical Research Communications. 315:808-814 |
| ISSN: | 0006-291X |
| Popis: | Recently, we created a lysine-deficient mutant tumor necrosis factor-alpha [mTNF-alpha-Lys(-)] with full bioactivity in vitro compared with wild-type TNF-alpha (wTNF-alpha), and site-specific PEGylation of mTNF-alpha-Lys(-) was found to selectively enhance its in vivo antitumor activity. In this study, we attempted to optimize this PEGylation of mTNF-alpha-Lys(-) to further improve its therapeutic potency. mTNF-alpha-Lys(-) was site-specifically modified at its N-terminus with linear polyethylene glycol (LPEG) or branched PEG (BPEG). While randomly mono-PEGylated wTNF-alpha (ran-LPEG5K-wTNF-alpha) with 5 kDa of LPEG (LPEG5K) had about only 4% in vitro bioactivity of wTNF-alpha, mono-PEGylated mTNF-alpha-Lys(-) [sp-PEG-mTNF-alpha-Lys(-)] with LPEG5K, LPEG20K, BPEG10K, and BPEG40K had 82%, 58%, 93%, and 65% bioactivities of mTNF-alpha-Lys(-), respectively. sp-LPEG-mTNF-alpha-Lys(-) and sp-BPEG10K-mTNF-alpha-Lys(-) had much superior antitumor activity to those of both unmodified TNF-alphas and ran-LPEG5K-wTNF-alpha, though sp-BPEG40K-mTNF-alpha-Lys(-) did not show in vivo antitumor activity. Thus, the molecular shape and weight of PEG may strongly influence the in vivo antitumor activity of sp-PEG-mTNF-alpha-Lys(-). |
| Databáze: | OpenAIRE |
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