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.
%0 Journal Article
%1 Schneider2010
%A Schneider, B.
%A Münkel, S.
%A Krippner-Heidenreich, A.
%A Grunwald, I.
%A Wels, W. S.
%A Wajant, H.
%A Pfizenmaier, K.
%A Gerspach, J.
%D 2010
%J Cell Death and Disease
%K 2010 izi pfizenmaier
%N 8
%P e68
%R 10.1038/cddis.2010.45
%T Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins
%U https://www.ncbi.nlm.nih.gov/pubmed/21364672
%V 1
%X 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.
%7 2011/03/03
%@ 2041-4889 (Electronic)
@article{Schneider2010,
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. },
added-at = {2023-06-29T13:07:55.000+0200},
author = {Schneider, B. and M{\"{u}}nkel, S. and Krippner-Heidenreich, A. and Grunwald, I. and Wels, W. S. and Wajant, H. and Pfizenmaier, K. and Gerspach, J.},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/285a84c4864759f09c5fc7ec9231e03ff/fabian},
doi = {10.1038/cddis.2010.45},
edition = {2011/03/03},
interhash = {04c92723044e0570a10247020d089565},
intrahash = {85a84c4864759f09c5fc7ec9231e03ff},
isbn = {2041-4889 (Electronic)},
issn = {20414889},
journal = {Cell Death and Disease},
keywords = {2010 izi pfizenmaier},
number = 8,
pages = {e68},
pmid = {21364672},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Potent antitumoral activity of TRAIL through generation of tumor-targeted single-chain fusion proteins}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21364672},
volume = 1,
year = 2010
}
