%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 }