title: Imaging active urokinase plasminogen activator in prostate cancer.
abstract: 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.
authors: Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California. alebeau@umn.edu Henry.Vanbrocklin@ucsf.edu.
authors: Aaron M
authors: AM
authors: LeBeau
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
authors: Natalia
authors: N
authors: Sevillano
authors: CytomX Therapeutics, Inc., South San Francisco, California.
authors: Kate
authors: K
authors: Markham
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
authors: Michael B
authors: MB
authors: Winter
authors: Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
authors: Stephanie T
authors: ST
authors: Murphy
authors: CytomX Therapeutics, Inc., South San Francisco, California.
authors: Daniel R
authors: DR
authors: Hostetter
authors: CytomX Therapeutics, Inc., South San Francisco, California.
authors: James
authors: J
authors: West
authors: CytomX Therapeutics, Inc., South San Francisco, California.
authors: Henry
authors: H
authors: Lowman
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
authors: Charles S
authors: CS
authors: Craik
authors: Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California. alebeau@umn.edu Henry.Vanbrocklin@ucsf.edu.
authors: Henry F
authors: HF
authors: VanBrocklin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000201:enzymology*; D019275:Radiopharmaceuticals; D015899:Tomography, Emission-Computed, Single-Photon; D041622:Tomography, Optical; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D014568:Urokinase-Type Plasminogen Activator