Tumor necrosis factor (TNF) prodrugs are fusion proteins comprised of an N-terminal single-chain antibody variable fragment (scFv) targeting a TNF effector and a C-terminal TNF receptor (TNFR)1-derived inhibitor module. Introduction of matrix metalloproteinase (MMP)-2 recognition motifs between TNF and the TNFR1 fragment allowed activation by recombinant MMP-2 and MMP-expressing HT1080 cells. Processing by endogeneous MMPs required specific membrane binding of the TNF prodrug via the targeting scFv, ensuring strictly antigen-dependent activation. Interestingly, TNF bioactivity of the processed prodrug was approximately 1000-fold higher upon scFv-mediated targeting, and signaled juxtatropic cell death also to antigen-negative cells. Microscopical analyses of TNFR2 clustering and TNF receptor-associated factor 2 recruitment at contact sites to adjacent cells revealed the formation of stable TNFR complexes by target-bound, processed prodrug, resembling the increased signal capacity of natural, membrane-expressed TNF. MMP-2-sensitive TNF prodrugs represent novel cytokine-based reagents for targeted cancer therapy, which should be exploitable for MMP-overexpressing tumors.
Gerspach, J
Muller, D
Munkel, S
Selchow, O
Nemeth, J
Noack, M
Petrul, H
Menrad, A
Wajant, H
Pfizenmaier, K
eng
Research Support, Non-U.S. Gov't
England
Cell Death Differ. 2006 Feb;13(2):273-84. doi: 10.1038/sj.cdd.4401735.
%0 Journal Article
%1 Gerspach2006
%A Gerspach, J.
%A Müller, D.
%A Münkel, S.
%A Selchow, O.
%A Nemeth, J.
%A Noack, M.
%A Petrul, H.
%A Menrad, A.
%A Wajant, H.
%A Pfizenmaier, Klaus
%D 2006
%J Cell Death and Differentiation
%K 2006 izi mueller pfizenmaier
%N 2
%P 273--284
%R 10.1038/sj.cdd.4401735
%T Restoration of membrane TNF-like activity by cell surface targeting and matrix metalloproteinase-mediated processing of a TNF prodrug
%U https://www.ncbi.nlm.nih.gov/pubmed/16052236
%V 13
%X Tumor necrosis factor (TNF) prodrugs are fusion proteins comprised of an N-terminal single-chain antibody variable fragment (scFv) targeting a TNF effector and a C-terminal TNF receptor (TNFR)1-derived inhibitor module. Introduction of matrix metalloproteinase (MMP)-2 recognition motifs between TNF and the TNFR1 fragment allowed activation by recombinant MMP-2 and MMP-expressing HT1080 cells. Processing by endogeneous MMPs required specific membrane binding of the TNF prodrug via the targeting scFv, ensuring strictly antigen-dependent activation. Interestingly, TNF bioactivity of the processed prodrug was approximately 1000-fold higher upon scFv-mediated targeting, and signaled juxtatropic cell death also to antigen-negative cells. Microscopical analyses of TNFR2 clustering and TNF receptor-associated factor 2 recruitment at contact sites to adjacent cells revealed the formation of stable TNFR complexes by target-bound, processed prodrug, resembling the increased signal capacity of natural, membrane-expressed TNF. MMP-2-sensitive TNF prodrugs represent novel cytokine-based reagents for targeted cancer therapy, which should be exploitable for MMP-overexpressing tumors.
%Z Gerspach, J
Muller, D
Munkel, S
Selchow, O
Nemeth, J
Noack, M
Petrul, H
Menrad, A
Wajant, H
Pfizenmaier, K
eng
Research Support, Non-U.S. Gov't
England
Cell Death Differ. 2006 Feb;13(2):273-84. doi: 10.1038/sj.cdd.4401735.
%7 2005/07/30
%@ 1350-9047 (Print)
1350-9047 (Linking)
@article{Gerspach2006,
abstract = {Tumor necrosis factor (TNF) prodrugs are fusion proteins comprised of an N-terminal single-chain antibody variable fragment (scFv) targeting a TNF effector and a C-terminal TNF receptor (TNFR)1-derived inhibitor module. Introduction of matrix metalloproteinase (MMP)-2 recognition motifs between TNF and the TNFR1 fragment allowed activation by recombinant MMP-2 and MMP-expressing HT1080 cells. Processing by endogeneous MMPs required specific membrane binding of the TNF prodrug via the targeting scFv, ensuring strictly antigen-dependent activation. Interestingly, TNF bioactivity of the processed prodrug was approximately 1000-fold higher upon scFv-mediated targeting, and signaled juxtatropic cell death also to antigen-negative cells. Microscopical analyses of TNFR2 clustering and TNF receptor-associated factor 2 recruitment at contact sites to adjacent cells revealed the formation of stable TNFR complexes by target-bound, processed prodrug, resembling the increased signal capacity of natural, membrane-expressed TNF. MMP-2-sensitive TNF prodrugs represent novel cytokine-based reagents for targeted cancer therapy, which should be exploitable for MMP-overexpressing tumors.},
added-at = {2023-06-29T13:07:55.000+0200},
annote = {Gerspach, J
Muller, D
Munkel, S
Selchow, O
Nemeth, J
Noack, M
Petrul, H
Menrad, A
Wajant, H
Pfizenmaier, K
eng
Research Support, Non-U.S. Gov't
England
Cell Death Differ. 2006 Feb;13(2):273-84. doi: 10.1038/sj.cdd.4401735.},
author = {Gerspach, J. and M{\"{u}}ller, D. and M{\"{u}}nkel, S. and Selchow, O. and Nemeth, J. and Noack, M. and Petrul, H. and Menrad, A. and Wajant, H. and Pfizenmaier, Klaus},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2a690ea4ac41d4782cd472f2b1ccba483/fabian},
doi = {10.1038/sj.cdd.4401735},
edition = {2005/07/30},
interhash = {e4e1715ccda9122c01b0b79aaecba98b},
intrahash = {a690ea4ac41d4782cd472f2b1ccba483},
isbn = {1350-9047 (Print)
1350-9047 (Linking)},
issn = {13509047},
journal = {Cell Death and Differentiation},
keywords = {2006 izi mueller pfizenmaier},
number = 2,
pages = {273--284},
pmid = {16052236},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Restoration of membrane TNF-like activity by cell surface targeting and matrix metalloproteinase-mediated processing of a TNF prodrug}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/16052236},
volume = 13,
year = 2006
}