Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, highly bioactive form of TRAIL to a wide variety of tumour antigens, enabling customized solutions for a patient-specific targeted cancer therapy with a reduced risk of side effects.
%0 Journal Article
%1 Siegemund2018
%A Siegemund, Martin
%A Schneider, Felix
%A Hutt, Meike
%A Seifert, Oliver
%A Müller, Ines
%A Kulms, Dagmar
%A Pfizenmaier, Klaus
%A Kontermann, Roland E.
%D 2018
%J Scientific Reports
%K 2018 izi kontermann pfizenmaier
%N 1
%P 7808
%R 10.1038/s41598-018-24450-8
%T IgG-single-chain TRAIL fusion proteins for tumour therapy
%U http://www.ncbi.nlm.nih.gov/pubmed/29773864
%V 8
%X Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, highly bioactive form of TRAIL to a wide variety of tumour antigens, enabling customized solutions for a patient-specific targeted cancer therapy with a reduced risk of side effects.
@article{Siegemund2018,
abstract = {Single-chain formats of TNF-related apoptosis inducing ligand (scTRAIL) can serve as effector components of tumour-associated antigen-targeted as well as non-targeted fusion proteins, being characterized by high tumour cell-specific induction of apoptosis through death receptor activation. We studied the suitability of immunoglobulin G as a scaffold for oligovalent and bispecific TRAIL fusion proteins. Thus, we developed novel targeted hexa- and dodecavalent IgG-scTRAIL molecules by fusing scTRAIL to the C-terminus of either light (LC-scTRAIL) or heavy immunoglobulin chain (HC-scTRAIL), or to both ends (LC/HC-scTRAIL) of the anti-EGFR IgG antibody hu225. The binding specificity to EGFR and death receptors was retained in all IgG-scTRAIL formats and translated into high antigen-specific bioactivity on EGFR-positive Colo205, HCT116 and WM1366 tumour cell lines, with or without sensitization to apoptosis by bortezomib. In vivo, therapeutic potential was assessed for one of the targeted variants, HC-scTRAIL, compared to the non-targeted Fc-scTRAIL. Both molecules showed a significant reduction of tumour volume and synergism with a Smac mimetic in a Colo205 xenograft tumour model. The IgG-scTRAIL format allows directing a defined, highly bioactive form of TRAIL to a wide variety of tumour antigens, enabling customized solutions for a patient-specific targeted cancer therapy with a reduced risk of side effects.},
added-at = {2023-06-29T13:07:55.000+0200},
author = {Siegemund, Martin and Schneider, Felix and Hutt, Meike and Seifert, Oliver and M{\"{u}}ller, Ines and Kulms, Dagmar and Pfizenmaier, Klaus and Kontermann, Roland E.},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/28af0a400719a70da66b2f96b7a329520/fabian},
doi = {10.1038/s41598-018-24450-8},
interhash = {9ac3e0df23c0436d4afa02cfdebeadad},
intrahash = {8af0a400719a70da66b2f96b7a329520},
issn = {2045-2322},
journal = {Scientific Reports},
keywords = {2018 izi kontermann pfizenmaier},
month = dec,
number = 1,
pages = 7808,
pmid = {29773864},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{IgG-single-chain TRAIL fusion proteins for tumour therapy}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/29773864},
volume = 8,
year = 2018
}
