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: 5.01). 09/2005; 116(3):415-21. DOI: 10.1002/ijc.21014
Source: PubMed

ABSTRACT 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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    11/2013; 1:20. DOI:10.1186/2051-1426-1-20
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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; 2014:104248. DOI:10.1155/2014/104248
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    ABSTRACT: Introduction: The advent of cancer immunotherapy is going to profoundly transform the therapy of cancer. In this context, therapeutic cancer vaccines will offer significant opportunities, provided an efficient and robust technology is developed. Areas covered: Targeting tumor-associated antigens via immunization with homologous immunogens derived from other species, an approach called xeno vaccination, combined with gene delivery is believed to be a viable strategy. Xenogene vaccination has demonstrated to be more efficient than vaccination with 'self' antigens in rodent models in prophylactic and therapeutic settings against cancer. Depending upon the targeted antigen, the mechanism of action of xeno vaccines has been shown to depend upon the development of antibody and/or cytotoxic T-cell responses. More importantly, xenogene vaccination has been shown to reproducibly affect cancer growth and to improve survival in veterinary cancer patients, mainly in dogs affected by spontaneous disease. One of these vaccines against dog melanoma has been approved by regulatory authorities in USA. Finally, several xenogene vaccines have been advanced to early Phase I/II human clinical trials where they have shown to be safe, well tolerated and capable to induce detectable immune responses against human tumor antigens. Expert opinion: Based on this compendium of results we believe that xenogene vaccination may soon become a well-established weapon in the fight against cancer.
    Expert Opinion on Biological Therapy 07/2014; 14(10):1-16. DOI:10.1517/14712598.2014.927433 · 3.65 Impact Factor

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