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


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.

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    • "Several other novel mAbs targeting PSMA have been developed for molecular imaging. Among these, four new IgG mAbs (3/F11, 3/A12, 3C6, and 3/E7) with strong affinity for three different extracellular PSMA epitopes [40, 41] have been developed. The 3/A12 antibody labeled with 64Cu (64Cu-3/A12) demonstrated a good tumor-to-background ratio in preclinical models [42]. "
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    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 10/2013; 2013:460546. DOI:10.1155/2013/460546 · 2.71 Impact Factor
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    • "Prostate cancer represents one quarter of newly diagnosed cancer cases in men and is associated with a high mortality rate surpassed only by lung cancer (Jemal et al., 2010). Despite significant efforts towards improving the diagnosis (Hricak et al., 2007; Ravizzini et al., 2009; Regino et al., 2009) and therapy (Feldman and Feldman, 2001; Denmeade and Isaacs, 2002; Michaelson et al., 2008; Lin GA et al., 2009a; Shepard and Raghavan, 2009; Rosenthal and Sandler, 2010) for this disease, few treatment options exist for metastatic prostate cancer, and developing effective treatments remains a critical priority. One promising molecular target for prostate cancer therapy is a chondroitin sulphate proteoglycan known as TENB2 (Glynne-Jones et al., 2001), a transmembrane protein containing an EGF-like motif and two follistatin-like domains. "
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    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 visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. 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 non-invasive single photon emission computed tomography - X-ray computed tomography 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 a 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.
    British Journal of Pharmacology 08/2012; 168(2). DOI:10.1111/j.1476-5381.2012.02138.x · 4.84 Impact Factor
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    • "Results of a recent study, using 64 Cu-3/A12 for PET imaging of prostate cancer xenografts, showed good tumor-tobackground ratio (Elsasser-Beile et al., 2009b). Another new mAb, 3C6, targeting the extracellular epitope of PSMA has been labelled with 111 In for imaging of prostate cancer (Regino et al., 2009). "
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    ABSTRACT: Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer.
    Discovery medicine 01/2010; 9(44):55-61. · 3.63 Impact Factor
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