期刊
INTERNATIONAL JOURNAL OF CANCER
卷 109, 期 2, 页码 281-290出版社
WILEY
DOI: 10.1002/ijc.11702
关键词
single-chain variable fragment; TNF-related apoptosis-inducing ligand; targeting; apoptosis; epithelial glycoprotein 2
类别
The apparent tumor selective apoptosis-inducing activity of recombinant soluble TNF-related apoptosis-inducing ligand (TRAIL) has aroused much interest for use in clinical application. However, to exploit fully its therapeutic potential, the characteristics of both the TRAIL receptor system and soluble TRAIL (sTRAIL) should be taken into account: first, the widespread expression of the various TRAIL receptors throughout the human body; second, the differential binding affinities and crosslinking requirements of the agonistic receptors TRAIL-RI and TRAIL-R2; and third, the solution behavior of particular sTRAIL preparations. Therefore, we constructed a novel TRAIL fusion protein, designated scFvC54:sTRAIL, comprising the human scFv antibody fragment C54 genetically linked to the N-terminus of human sTRAIL. The scFvCS4:sTRAIL fusion protein was designed to induce apoptosis by crosslinking of agonistic TRAIL receptors only after specific binding of scFvCS4:sTRAIL to the abundantly expressed carcinoma-associated cell surface antigen EGP2 (alias EpCAM). Target antigen-restricted apoptosis induction was demonstrated for various EGP2-positive tumor cells and could be inhibited by an EGP2 competing antibody. Target antigen binding converted soluble scFvCS4: sTRAIL into a membrane-bound form of TRAIL that was capable of signaling apoptosis not only through TRAIL-R1 but also through TRAIL-R2. Size-exclusion fast protein liquid chromatography (FPLC) indicated that scFvCS4:sTRAIL was produced as stable and homogeneous trimers in the absence of detectable TRAIL aggregates. The favorable characteristics of the scFvCS4:sTRAIL fusion protein potentially reduce the amount of sTRAIL required for antitumor activity and may be of value for the treatment of various human carcinomas. (C) 2003 Wiley-Liss, Inc.
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