Abstract
Recently, we created a lysine-deficient mutant tumor necrosis factor-α [mTNF-α-Lys(−)] with full bioactivity in vitro compared with wild-type TNF-α (wTNF-α), and site-specific PEGylation of mTNF-α-Lys(−) was found to selectively enhance its in vivo antitumor activity. In this study, we attempted to optimize this PEGylation of mTNF-α-Lys(−) to further improve its therapeutic potency. mTNF-α-Lys(−) was site-specifically modified at its N-terminus with linear polyethylene glycol (LPEG) or branched PEG (BPEG). While randomly mono-PEGylated wTNF-α (ran-LPEG 5K-wTNF-α) with 5 kDa of LPEG (LPEG 5K) had about only 4% in vitro bioactivity of wTNF-α, mono-PEGylated mTNF-α-Lys(−) [sp-PEG-mTNF-α-Lys(−)] with LPEG 5K, LPEG 20K, BPEG 10K, and BPEG 40K had 82%, 58%, 93%, and 65% bioactivities of mTNF-α-Lys(−), respectively. sp-LPEG-mTNF-α-Lys(−) and sp-BPEG 10K-mTNF-α-Lys(−) had much superior antitumor activity to those of both unmodified TNF-αs and ran-LPEG 5K-wTNF-α, though sp-BPEG 40K-mTNF-α-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-α-Lys(−).
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