Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses.
%0 Journal Article
%1 Muller2008b
%A Müller, Dafne
%A Frey, Katharina
%A Kontermann, Roland E.
%D 2008
%J Journal of Immunotherapy
%K 2008 izi kontermann mueller
%N 8
%P 714--722
%R 10.1097/CJI.0b013e31818353e9
%T A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy
%U https://www.ncbi.nlm.nih.gov/pubmed/18779748
%V 31
%X Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses.
%Z Muller, DafneFrey, KatharinaKontermann, Roland EengResearch Support, Non-U.S. Gov'tJ Immunother. 2008 Oct;31(8):714-22. doi: 10.1097/CJI.0b013e31818353e9.
%7 2008/09/10
%@ 1537-4513 (Electronic)$\backslash$r1524-9557 (Linking)
@article{Muller2008b,
abstract = {Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses.},
added-at = {2023-06-29T13:07:55.000+0200},
annote = {Muller, DafneFrey, KatharinaKontermann, Roland EengResearch Support, Non-U.S. Gov'tJ Immunother. 2008 Oct;31(8):714-22. doi: 10.1097/CJI.0b013e31818353e9.},
author = {M{\"{u}}ller, Dafne and Frey, Katharina and Kontermann, Roland E.},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2d55fc50c1990a01d7035a48d29e09b69/fabian},
doi = {10.1097/CJI.0b013e31818353e9},
edition = {2008/09/10},
interhash = {b66204619f50db27333edd3e204114fb},
intrahash = {d55fc50c1990a01d7035a48d29e09b69},
isbn = {1537-4513 (Electronic)$\backslash$r1524-9557 (Linking)},
issn = {15249557},
journal = {Journal of Immunotherapy},
keywords = {2008 izi kontermann mueller},
number = 8,
pages = {714--722},
pmid = {18779748},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18779748},
volume = 31,
year = 2008
}
