gms | German Medical Science

27th German Cancer Congress Berlin 2006

German Cancer Society (Frankfurt/M.)

22. - 26.03.2006, Berlin

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

Meeting Abstract

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  • corresponding author presenting/speaker Jeannette Gerspach - Zellbiologie und Immunologie, Stuttgart, Deutschland
  • Julia Nemeth - Zellbiologie und Immunologie, Stuttgart
  • Sabine Münkel - Zellbiologie und Immunologie, Stuttgart
  • Harald Wajant - Innere Molekulare Medizin, Würzburg
  • Klaus Pfizenmaier - Zellbiologie und Immunologie, Stuttgart

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPE465

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dkk2006/06dkk575.shtml

Published: March 20, 2006

© 2006 Gerspach et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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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. Because of the known heterogeneity of matrix-metalloprotease expression, we exploited TNF prodrug processing by other tumor and/or stroma associated proteases by introducing peptide linkers with multiple cleavage sites. TNF prodrugs comprised of either a uPA selective or a dual specific uPA-MMP2 linker were constructed which displayed efficient, targeting dependent and cleavage sequence specific activation by 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 optimized TNF prodrugs should increase the proportion of active therapeutic within the targeted tissue and thus potentially enhance tumor response rate.