Imaging active urokinase plasminogen activator in prostate cancer

Cancer Res. 2015 Apr 1;75(7):1225-35. doi: 10.1158/0008-5472.CAN-14-2185. Epub 2015 Feb 11.


The increased proteolytic activity of membrane-bound and secreted proteases on the surface of cancer cells and in the transformed stroma is a common characteristic of aggressive metastatic prostate cancer. We describe here the development of an active site-specific probe for detecting a secreted peritumoral protease expressed by cancer cells and the surrounding tumor microenvironment. Using a human fragment antigen-binding phage display library, we identified a human antibody termed U33 that selectively inhibited the active form of the protease urokinase plasminogen activator (uPA, PLAU). In the full-length immunoglobulin form, U33 IgG labeled with near-infrared fluorophores or radionuclides allowed us to noninvasively detect active uPA in prostate cancer xenograft models using optical and single-photon emission computed tomography imaging modalities. U33 IgG labeled with (111)In had a remarkable tumor uptake of 43.2% injected dose per gram (%ID/g) 72 hours after tail vein injection of the radiolabeled probe in subcutaneous xenografts. In addition, U33 was able to image active uPA in small soft-tissue and osseous metastatic lesions using a cardiac dissemination prostate cancer model that recapitulated metastatic human cancer. The favorable imaging properties were the direct result of U33 IgG internalization through an uPA receptor-mediated mechanism in which U33 mimicked the function of the endogenous inhibitor of uPA to gain entry into the cancer cell. Overall, our imaging probe targets a prostate cancer-associated protease, through a unique mechanism, allowing for the noninvasive preclinical imaging of prostate cancer lesions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Fluorescent Antibody Technique
  • Gene Expression
  • Humans
  • Indium Radioisotopes
  • Male
  • Mice, Nude
  • Neoplasm Transplantation
  • Organ Specificity
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / enzymology*
  • Radiopharmaceuticals
  • Tomography, Emission-Computed, Single-Photon
  • Tomography, Optical
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism*


  • Indium Radioisotopes
  • Radiopharmaceuticals
  • Urokinase-Type Plasminogen Activator