Target-selective activation of a TNF prodrug by urokinase-type plasminogen activator (uPA) mediated proteolytic processing at the cell surface

Cancer Immunology, Immunotherapy : CII
Jeannette GerspachKlaus Pfizenmaier

Abstract

We have previously developed TNF prodrugs comprised of a N-terminal scFv targeting, a TNF effector and a C-terminal TNFR1-derived inhibitor module linked to TNF via a MMP-2 motif containing peptide, allowing activation by MMP-2-expressing tumor cells. To overcome the known heterogeneity of matrix metalloprotease expression, we developed TNF prodrugs that become processed by other tumor and/or stroma-associated proteases. These TNF prodrugs comprise either an uPA-selective or a dual uPA-MMP-2-specific linker which displayed efficient, target-dependent and cleavage sequence-specific activation by the corresponding tumor cell-expressed proteases. Selective pharmacologic inhibition of endogenous uPA and MMP-2 confirm independent prodrug processing by these two model proteases and indicate the functional superiority of a prodrug containing a multi-specific protease linker. Processing optimised TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.

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Citations

Jul 31, 2007·Cancer Immunology, Immunotherapy : CII·Valeska HofmeisterJürgen C Becker
Jan 18, 2011·Cancer Letters·Harald WajantKlaus Pfizenmaier
Aug 5, 2009·Protein Science : a Publication of the Protein Society·Jerry M Thomas, Patrick S Daugherty
Feb 13, 2009·Journal of Cellular and Molecular Medicine·Kerstin PapenfussHenning Walczak
Apr 24, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Gary B BraunTambet Teesalu
Dec 29, 2012·Molecular Cancer Therapeutics·Maria-Fernanda ZuluagaNorbert Lange

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