title: Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins.
abstract: In an attempt to improve TRAIL's (tumor necrosis factor-related apoptosis-inducing ligand) tumor selective activity a variant was designed, in which the three TRAIL protomers are expressed as a single polypeptide chain (scTRAIL). By genetic fusion with a single-chain antibody fragment (scFv) recognizing the extracellular domain of ErbB2, we further equipped scTRAIL with tumor-targeting properties. We studied tumor targeting and apoptosis induction of scFv-scTRAIL in comparison with non-targeted scTRAIL. Importantly, the tumor antigen-targeted scTRAIL fusion protein showed higher apoptotic activity in vitro, with a predominant action by TRAIL-R2 signaling. Pharmacokinetic studies revealed increased plasma half-life of the targeted scTRAIL fusion protein compared with scTRAIL. In vivo studies in a mouse tumor model with xenotransplanted Colo205 cells confirmed greater response to the ErbB2-specific scTRAIL fusion protein compared with non-targeted scTRAIL both under local and systemic application regimen. Together, in vitro and in vivo data give proof of concept of higher therapeutic activity of tumor-targeted scFv-scTRAIL molecules. Further, we envisage that through targeting of scTRAIL, potential side effects should be minimized. We propose that scFv-mediated tumor targeting of single-chain TRAIL represents a promising strategy to improve TRAIL's antitumoral action and to minimize potential unwanted actions on normal tissues.Cell Death and Disease (2010) 1, e68; doi:10.1038/cddis.2010.45; published online 26 August 2010.
authors.affiliation: Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schneider
authors.forename: S
authors.initials: S
authors.lastname: Münkel
authors.forename: A
authors.initials: A
authors.lastname: Krippner-Heidenreich
authors.forename: I
authors.initials: I
authors.lastname: Grunwald
authors.forename: W S
authors.initials: WS
authors.lastname: Wels
authors.forename: H
authors.initials: H
authors.lastname: Wajant
authors.forename: K
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: J
authors.initials: J
authors.lastname: Gerspach
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D000939:Epitopes; D006207:Half-Life; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000939:Epitopes; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D053221:TNF-Related Apoptosis-Inducing Ligand