Fusion proteins combining hexavalent TRAIL with antibody fragments allow for a targeted delivery and efficient apoptosis induction in tumor cells. Here, we analyzed scFv-Fc-scTRAIL molecules directed against EGFR, HER2, HER3, and EpCAM as well as an untargeted Fc-scTRAIL fusion protein for their potentials to induce cell death bothin vitroand in a xenograft tumor modelin vivo. The scFv-Fc-scTRAIL fusion protein directed against EGFR as well as the fusion protein directed against EpCAM showed targeting effects on the two tested colorectal carcinoma cell lines Colo205 and HCT116, while a fusion protein targeting HER3 was more effective than untargeted Fc-scTRAIL only on Colo205 cells. Interestingly, another anti-HER3 scFv-Fc-scTRAIL fusion protein exhibiting approximately 10-fold weaker antigen binding as well as the HER2-directed molecule were unable to increase cytotoxicity compared to Fc-scTRAIL. A comparison of EC50values of cell death induction and antigen binding supports the assumption that high affinity antigen binding is one of the requirements forin vitrotargeting effects. Furthermore, a minimal number of expressed target antigens might be required for increased cytotoxicity of targeted compared to non-targeted molecules. In a Colo205 s.c. xenograft tumor model, strongest antitumor activity was observed for the anti-HER3 scFv-Fc-scTRAIL fusion protein based on antibody 3-43, with complete tumor remissions after six twice-weekly injections. Surprisingly, a similarin vivoactivity was also observed for untargeted Fc-scTRAIL in this tumor model, indicating that additional factors contribute to the potent efficacy of targeted as well as untargeted hexavalent Fc-scTRAIL fusion proteinsin vivo.
%0 Journal Article
%1 Hutt2018
%A Hutt, Meike
%A Fellermeier-Kopf, Sina
%A Seifert, Oliver
%A Schmitt, Lisa C.
%A Pfizenmaier, Klaus
%A Kontermann, Roland E.
%D 2018
%J Oncotarget
%K 2018 izi kontermann pfizenmaier
%N 13
%P 11322--11335
%R 10.18632/oncotarget.24379
%T Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells
%U http://www.ncbi.nlm.nih.gov/pubmed/29541416
%V 9
%X Fusion proteins combining hexavalent TRAIL with antibody fragments allow for a targeted delivery and efficient apoptosis induction in tumor cells. Here, we analyzed scFv-Fc-scTRAIL molecules directed against EGFR, HER2, HER3, and EpCAM as well as an untargeted Fc-scTRAIL fusion protein for their potentials to induce cell death bothin vitroand in a xenograft tumor modelin vivo. The scFv-Fc-scTRAIL fusion protein directed against EGFR as well as the fusion protein directed against EpCAM showed targeting effects on the two tested colorectal carcinoma cell lines Colo205 and HCT116, while a fusion protein targeting HER3 was more effective than untargeted Fc-scTRAIL only on Colo205 cells. Interestingly, another anti-HER3 scFv-Fc-scTRAIL fusion protein exhibiting approximately 10-fold weaker antigen binding as well as the HER2-directed molecule were unable to increase cytotoxicity compared to Fc-scTRAIL. A comparison of EC50values of cell death induction and antigen binding supports the assumption that high affinity antigen binding is one of the requirements forin vitrotargeting effects. Furthermore, a minimal number of expressed target antigens might be required for increased cytotoxicity of targeted compared to non-targeted molecules. In a Colo205 s.c. xenograft tumor model, strongest antitumor activity was observed for the anti-HER3 scFv-Fc-scTRAIL fusion protein based on antibody 3-43, with complete tumor remissions after six twice-weekly injections. Surprisingly, a similarin vivoactivity was also observed for untargeted Fc-scTRAIL in this tumor model, indicating that additional factors contribute to the potent efficacy of targeted as well as untargeted hexavalent Fc-scTRAIL fusion proteinsin vivo.
@article{Hutt2018,
abstract = {Fusion proteins combining hexavalent TRAIL with antibody fragments allow for a targeted delivery and efficient apoptosis induction in tumor cells. Here, we analyzed scFv-Fc-scTRAIL molecules directed against EGFR, HER2, HER3, and EpCAM as well as an untargeted Fc-scTRAIL fusion protein for their potentials to induce cell death bothin vitroand in a xenograft tumor modelin vivo. The scFv-Fc-scTRAIL fusion protein directed against EGFR as well as the fusion protein directed against EpCAM showed targeting effects on the two tested colorectal carcinoma cell lines Colo205 and HCT116, while a fusion protein targeting HER3 was more effective than untargeted Fc-scTRAIL only on Colo205 cells. Interestingly, another anti-HER3 scFv-Fc-scTRAIL fusion protein exhibiting approximately 10-fold weaker antigen binding as well as the HER2-directed molecule were unable to increase cytotoxicity compared to Fc-scTRAIL. A comparison of EC50values of cell death induction and antigen binding supports the assumption that high affinity antigen binding is one of the requirements forin vitrotargeting effects. Furthermore, a minimal number of expressed target antigens might be required for increased cytotoxicity of targeted compared to non-targeted molecules. In a Colo205 s.c. xenograft tumor model, strongest antitumor activity was observed for the anti-HER3 scFv-Fc-scTRAIL fusion protein based on antibody 3-43, with complete tumor remissions after six twice-weekly injections. Surprisingly, a similarin vivoactivity was also observed for untargeted Fc-scTRAIL in this tumor model, indicating that additional factors contribute to the potent efficacy of targeted as well as untargeted hexavalent Fc-scTRAIL fusion proteinsin vivo.},
added-at = {2023-06-29T13:07:55.000+0200},
author = {Hutt, Meike and Fellermeier-Kopf, Sina and Seifert, Oliver and Schmitt, Lisa C. and Pfizenmaier, Klaus and Kontermann, Roland E.},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2b630318652693bfbc08c16e93313462d/fabian},
doi = {10.18632/oncotarget.24379},
interhash = {ac6afb6e651c5efcbf3e6bef52996d4e},
intrahash = {b630318652693bfbc08c16e93313462d},
issn = {1949-2553},
journal = {Oncotarget},
keywords = {2018 izi kontermann pfizenmaier},
month = feb,
number = 13,
pages = {11322--11335},
pmid = {29541416},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/29541416},
volume = 9,
year = 2018
}