The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In the present study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of epidermal growth factor receptor (EGFR)-targeting dimeric scTRAIL fusion proteins (Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL) as well as two non-targeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on anti-tumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective non-targeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent anti-tumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable anti-tumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the non-targeting Fc-scTRAIL in vivo.
%0 Journal Article
%1 Hutt2017
%A Hutt, Meike
%A Marquardt, Lisa
%A Seifert, Oliver
%A Siegemund, Martin
%A Müller, Ines
%A Kulms, Dagmar
%A Pfizenmaier, Klaus
%A Kontermann, Roland E.
%D 2017
%J Molecular Cancer Therapeutics
%K 2017 izi kontermann pfizenmaier
%N 12
%P molcanther.0551.2017
%R 10.1158/1535-7163.MCT-17-0551
%T Superior properties of Fc-comprising scTRAIL fusion proteins
%U http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT-17-0551
%V 16
%X The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In the present study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of epidermal growth factor receptor (EGFR)-targeting dimeric scTRAIL fusion proteins (Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL) as well as two non-targeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on anti-tumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective non-targeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent anti-tumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable anti-tumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the non-targeting Fc-scTRAIL in vivo.
@article{Hutt2017,
abstract = {The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In the present study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of epidermal growth factor receptor (EGFR)-targeting dimeric scTRAIL fusion proteins (Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL) as well as two non-targeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on anti-tumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective non-targeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent anti-tumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable anti-tumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the non-targeting Fc-scTRAIL in vivo.},
added-at = {2018-02-01T14:30:30.000+0100},
author = {Hutt, Meike and Marquardt, Lisa and Seifert, Oliver and Siegemund, Martin and M{\"{u}}ller, Ines and Kulms, Dagmar and Pfizenmaier, Klaus and Kontermann, Roland E.},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2daed4e8693e38e7033a9f762b171836b/cristiano},
doi = {10.1158/1535-7163.MCT-17-0551},
interhash = {3147bec607ded66d7208d8a7bc8e5aa9},
intrahash = {daed4e8693e38e7033a9f762b171836b},
issn = {1535-7163},
journal = {Molecular Cancer Therapeutics},
keywords = {2017 izi kontermann pfizenmaier},
month = dec,
number = 12,
pages = {molcanther.0551.2017},
pmid = {28904131},
timestamp = {2019-01-17T12:30:02.000+0100},
title = {{Superior properties of Fc-comprising scTRAIL fusion proteins}},
url = {http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT-17-0551},
volume = 16,
year = 2017
}