Induction of autoantibodies to syngeneic prostate-specific membrane antigen by xenogeneic vaccination

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
International Journal of Cancer (Impact Factor: 5.09). 09/2005; 116(3):415-21. DOI: 10.1002/ijc.21014
Source: PubMed


Prostate-specific membrane antigen (PSMA) is a prototypical differentiation antigen expressed on normal and neoplastic prostate epithelial cells, and on the neovasculature of many solid tumors. Monoclonal antibodies specific for PSMA are in development as therapeutic agents. Methodologies to actively immunize against PSMA may be limited by immunologic ignorance and/or tolerance that restrict the response to self-antigens. Our studies have previously shown that xenogeneic immunization with DNA vaccines encoding melanosomal differentiation antigens induces immunity in a mouse melanoma model. Here we apply this approach to PSMA to establish proof of principle in a mouse model. Immunization with xenogeneic human PSMA protein or DNA induced antibodies to both human and mouse PSMA in mice. Monoclonal antibodies specific for mouse PSMA were generated to analyze antibody isotypes and specificity for native and denatured PSMA at the clonal level. Most antibodies recognized denatured PSMA, but C57BL/6 mice immunized with xenogeneic PSMA DNA followed by a final boost with xenogeneic PSMA protein yielded autoantibodies that reacted with native folded mouse PSMA. Monoclonal antibodies were used to confirm the expression of PSMA protein in normal mouse kidney. These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth.

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    • "YC-27 800CW fluorescence was most prominent in the renal cortex, particularly in the brush border housing the proximal tubules. Several reports have found PSMA expressed in mouse kidneys [38, 39], but the implications for clinical use are unknown. Basal PSMA expression is also reported in salivary gland, brain, and small intestine [40]. "
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    ABSTRACT: Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections.
    04/2014; 2014(7):104248. DOI:10.1155/2014/104248
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    • "We used the cell model of C4-2B cells described above. Gold nanospheres (NSP) of 60 nm, PNB excitation peak at 532 nm, and silica-gold nanoshells (NS) of 110 nm, PNB excitation peak at 787 nm, were conjugated to target-specific antibodies against PSMA [81] and non-specific antibody against EGFR (C225) as NSP-PSMA (spheres) and NS-C225 (shells), respectively. The target cells were incubated in three different combinations using identical nanoparticle concentration and incubation time. "
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    ABSTRACT: The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano-agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level.
    PLoS ONE 04/2012; 7(4):e34537. DOI:10.1371/journal.pone.0034537 · 3.23 Impact Factor
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    • "Therefore, it may be affected by a manner unrelated to the effect of the therapy on tumor, and is the cause of the patients' great anxiety or overstated diagnostic expectations [29] [30]. The prostate-specific membrane antigen (PSMA) is expressed in both the benign and the neoplastic prostatic epithelial cells and in other tissues, such as kidney, liver, and brain [31]. It is upregulated in hormone-resistant states and in metastatic disease. "

    Molecular Imaging, 03/2012; , ISBN: 978-953-51-0359-2
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