Cancer Immunology, Immunotherapy

, Volume 55, Issue 12, pp 1590–1600

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

  • Jeannette Gerspach
  • Julia Németh
  • Sabine Münkel
  • Harald Wajant
  • Klaus Pfizenmaier
Original Article

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.

Keywords

Targeted TNF activation Prodrug processing uPA MMP-2 

Abbreviations

Ab

Antibody

FAP

Fibroblast activation protein

MMP

Matrix-metalloproteinase

TNF

Tumor necrosis factor

TNFR

TNF receptor

scFv 36

FAP-specific single chain variable fragment

uPA

Urokinase-type plasminogen activator

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Jeannette Gerspach
    • 1
  • Julia Németh
    • 1
  • Sabine Münkel
    • 1
  • Harald Wajant
    • 2
  • Klaus Pfizenmaier
    • 1
  1. 1.Institute of Cell Biology and Immunology University of StuttgartStuttgartGermany
  2. 2.Department of Molecular Internal Medicine, Medical Clinic and Polyclinic IIUniversity of WürzburgWurzburgGermany

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