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Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells
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 pot...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834252/ https://www.ncbi.nlm.nih.gov/pubmed/29541416 http://dx.doi.org/10.18632/oncotarget.24379 |
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author | Hutt, Meike Fellermeier-Kopf, Sina Seifert, Oliver Schmitt, Lisa C. Pfizenmaier, Klaus Kontermann, Roland E. |
author_facet | Hutt, Meike Fellermeier-Kopf, Sina Seifert, Oliver Schmitt, Lisa C. Pfizenmaier, Klaus Kontermann, Roland E. |
author_sort | Hutt, Meike |
collection | PubMed |
description | 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 both in vitro and in a xenograft tumor model in 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 EC(50) values of cell death induction and antigen binding supports the assumption that high affinity antigen binding is one of the requirements for in vitro targeting 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 similar in vivo activity 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 proteins in vivo. |
format | Online Article Text |
id | pubmed-5834252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-58342522018-03-14 Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells Hutt, Meike Fellermeier-Kopf, Sina Seifert, Oliver Schmitt, Lisa C. Pfizenmaier, Klaus Kontermann, Roland E. Oncotarget Research Paper 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 both in vitro and in a xenograft tumor model in 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 EC(50) values of cell death induction and antigen binding supports the assumption that high affinity antigen binding is one of the requirements for in vitro targeting 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 similar in vivo activity 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 proteins in vivo. Impact Journals LLC 2018-01-31 /pmc/articles/PMC5834252/ /pubmed/29541416 http://dx.doi.org/10.18632/oncotarget.24379 Text en Copyright: © 2018 Hutt et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Hutt, Meike Fellermeier-Kopf, Sina Seifert, Oliver Schmitt, Lisa C. Pfizenmaier, Klaus Kontermann, Roland E. Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells |
title | Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells |
title_full | Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells |
title_fullStr | Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells |
title_full_unstemmed | Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells |
title_short | Targeting scFv-Fc-scTRAIL fusion proteins to tumor cells |
title_sort | targeting scfv-fc-sctrail fusion proteins to tumor cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834252/ https://www.ncbi.nlm.nih.gov/pubmed/29541416 http://dx.doi.org/10.18632/oncotarget.24379 |
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