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Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins

 
: Schneider, B.; Münkel, S.; Krippner-Heidenreich, A.; Grunwald, I.; Wels, W.S.; Wajant, H.; Pfizenmaier, K.; Gerspach, J.

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Cell death & disease. Online journal 1 (2010), Art. e68, 10 pp.
http://www.nature.com/cddis/index.htm
ISSN: 2041-4889
English
Journal Article
Fraunhofer IFAM ()

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.

: http://publica.fraunhofer.de/documents/N-146489.html