Article

Preclinical evaluation of a monoclonal antibody (3C6) specific for prostate-specific membrane antigen.

Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1088.
Current radiopharmaceuticals 01/2009; 2(1):9-17. DOI: 10.2174/1874471010902010009
Source: PubMed

ABSTRACT Better tumor markers are needed for early diagnosis and staging of prostate cancer, and for monitoring therapeutic response than the currently used prostate specific antigen (PSA). Prostate specific membrane antigen (PSMA) is highly expressed on the surface of prostatic epithelial cells making it a good target for prostate cancer. In this study, mAb 3C6, specific for the extracellular epitope of PSMA, was evaluated both in vitro and in vivo for PSMA-targeting. Immunoreactivity and specificity of mAb 3C6 was evaluated by flow cytometry using prostate cell lines expressing PSMA such as LNCaP and 22Rv1 and a cell line, DU145, that expresses very little PSMA. 3C6 was conjugated with the acyclic CHX-A" DTPA chelate, radiolabeled with (111)In, and its in vitro and in vivo properties were assessed. The biodistribution of the radioimmunoconjugate evaluated in athymic mice bearing xenografts of three human prostate carcinoma cell lines shows high uptake after 72 hr in LNCaP tumors (%ID/g 22.93 +/- 6.32) and 22Rv1 (%ID/g 10.44 +/- 2.32) in contrast to low uptake by the DU145 tumors (%ID/g 4.27 +/- 0.37). Planar gamma-scintigraphic images obtained for xenografted tumor bearing mice demonstrated targeting for PSMA positive tumors suggesting possible applications in imaging and for targeted radiation therapy.

0 Bookmarks
 · 
83 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.
    BioMed Research International 01/2013; 2013:460546. · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose:  The success of antibody drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualise target expression in normal tissues could reveal causes for target mediated clearance observed in pharmacokinetic characterisation. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. Experimental approach:  A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by noninvasive SPECT-CT imaging and immunohistochemistry. Key results:  The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As proof-of-concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. Conclusions and implications:  Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues. © 2012 Genentech, Inc. British Journal of Pharmacology © 2012 The British Pharmacological Society.
    British Journal of Pharmacology 08/2012; · 5.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the hormone-refractory stage of prostate cancer (PC), the expression of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) often remains highly active. Accumulating studies have demonstrated that these two proteins are attractive targets for specific delivery of functional molecules to advanced PC, not merely as potential sensitive markers for PC detection. In this study, we constructed a dual-modified liposome that incorporated PSA-responsive and PSMA-mediated liposomes and potentially offers double selectivity for PC. The folate moiety binds quickly to PSMA-positive tumors, and the PSA-responsive moiety is cleaved by PSA that was enriched in tumor tissues. The activated liposomes (folate and cell-penetrating peptides dual-modifications) are subsequently taken up by the tumor cells via polyarginine's penetrating effects and receptor-mediated endocytosis. To corroborate these assumptions, a series of experiments were conducted, including PSA-responsive peptide hydrolysis kinetics, cellular uptake, internalization mechanism and escape from endosomes in PC-3 and/or 22Rv1 cells, biodistribution and antitumor activity of siRNA-loaded liposomes after systemic administration, gene silencing and cell apoptosis in vitro and in vivo. The results reveal that multivalent interactions play a key role in enhancing PC cell recognition and uptake while reducing nonspecific uptake. The dual-modified liposomes carrying small interfering RNA (siRNA) have significant advantages over the control liposomes, including single-modified (folate, CPP, PSA-responsive only) and non-modified liposomes. The dual-modified liposomes elevated cellular uptake, downregulated expression of polo-like kinase 1 (PLK-1) and augmented cell apoptosis in prostate tumor cells. The entry of the dual-modified liposomes into 22Rv1 cells occurred via multiple endocytic pathways, including clathrin-mediated endocytosis and macropinocytosis, followed by an effective endosomal escape of the entrapped siRNA into the cytoplasm. In vivo studies conducted on a 22Rv1 xenograft murine model demonstrated that the dual-modified liposomes demonstrated the maximized accumulation, retention and knockdown of PLK-1 in tumor cells, as well as the strongest inhibition of tumor growth and induction of tumor cell apoptosis. In terms of targeting capacity and therapeutic potency, the combination of a PSA-responsive and PSMA-mediated liposome presents a promising platform for therapy and diagnosis of PSMA/PSA-positive PC.
    Biomaterials 06/2013; · 7.60 Impact Factor

Full-text

View
0 Downloads
Available from