Abstract
BackgroundProstate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 and CD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa.MethodsBinding characteristics of the antibody were determined by ELISA and flow cytometry. In vitro degranulation was determined by the release of β-hexosaminidase from effector cells. In vivo degranulation was monitored in human FcεRIα transgenic mice using the passive cutaneous anaphylaxis assay. These mice were also used for a vaccination study to determine the in vivo anti-cancer effects of this antibody. Significant differences in survival were determined using the Log Rank test. In vitro T-cell activation was studied using human dendritic cells and autologous T cells.ResultsThe anti-PSA IgE, expressed in murine myeloma cells, is properly assembled and secreted, and binds the antigen and FcεRI. In addition, this antibody is capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis. Importantly, the anti-PSA IgE combined with PSA also triggers immune activation in vitro and in vivo and significantly prolongs the survival of human FcεRIα transgenic mice challenged with PSA-expressing tumors in a prophylactic vaccination setting.ConclusionsThe anti-PSA IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection. Further studies on this antibody as a potential PCa therapy are warranted.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States
PCa is attractive as a target for immunotherapy for multiple reasons: 1) the presence of organ-specific tumor-associated antigens, 2) the initial slow-growing nature of the disease allowing for adequate time for an anti-immune response to develop, and 3) immunotherapy is relatively safe given the dispensable nature of the organ [5,6]
The antiPSA IgE was shown by ELISA to bind the full-length prostate-specific antigen (PSA) protein (Figure 1A), as well as the known epitope bound by AR47.47, which maps to the region of amino acids 137–144 of PSA (Figure 1B) [15]
Summary
Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. PCa is attractive as a target for immunotherapy for multiple reasons: 1) the presence of organ-specific tumor-associated antigens, 2) the initial slow-growing nature of the disease allowing for adequate time for an anti-immune response to develop, and 3) immunotherapy is relatively safe given the dispensable nature of the organ [5,6] This suggestion is supported by the fact that an immunotherapeutic strategy (sipuleucel T) was approved by the FDA in 2010 for the treatment of metastatic, castration-resistant PCa [7]. Another experimental vaccination strategy (Prostvac-VF) consisting of a recombinant vaccinia virus expressing the prostatespecific antigen (PSA) and other co-stimulatory molecules has shown promise in clinical trials of PCa [4,5,8] Despite these significant advances, the continued high rate of relapse and absence of a cure for metastatic disease highlights the need for additional treatments for PCa
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