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

Lookup NU author(s): Dr Anja Krippner-Heidenreich

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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

Publication metadata

Author(s): Schneider B, Munkel S, Krippner-Heidenreich A, Grunwald I, Wels WS, Wajant H, Pfizenmaier K, Gerspach J

Publication type: Article

Publication status: Published

Journal: Cell Death & Disease

Year: 2010

Volume: 1

Issue: 8

Print publication date: 26/08/2010

ISSN (print):

ISSN (electronic): 2041-4889

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/cddis.2010.45

DOI: 10.1038/cddis.2010.45

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