Abstract 2848: IgE-mediated immune activation targeting the prostate specific antigen: a potential prostate cancer therapy.

Abstract

Prostate cancer (PCa) is the second leading cause of cancer deaths among 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 is to take advantage of the unique properties of the IgE molecule in order to trigger immune activation against PCa. The properly assembled and secreted anti-PSA IgE binds the antigen and the Fc epsilon RI (FcεRI) as demonstrated by ELISA and flow cytometry, respectively. This novel IgE antibody is capable of triggering effector cell degranulation in vitro as determined by the release of β-hexosaminidase from rat basophil leukemic effector cells that express human FcεRI (RBL SX-38). Furthermore, the IgE triggered degranulation in vivo in human FcεRIα transgenic mice using the passive cutaneous anaphylaxis assay. Degranulation was only observed when the IgE was artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis in patients. Importantly, when incubated in vitro with human dendritic cells the anti-PSA IgE complexed with the antigen (PSA) triggered autologous CD4 and CD8 T-cell activation, suggesting enhancement of antigen presentation. Immune activation was also observed in vivo where a prophylactic vaccination with the anti-PSA IgE complexed to PSA significantly prolonged the survival of human FcεRIα transgenic mice challenged with PSA-expressing tumors, under conditions in which its chimeric mouse/human anti-PSA IgG1 counterpart failed to confer protection. Our results provide initial proof-of principle that the anti-PSA IgE can stimulate immune activation against tumor cells expressing PSA, and further studies on the anti-tumor activity of this antibody are warranted. These studies belong to the new field of AllergoOncology that aims to reveal the function of IgE-mediated immune responses against cancer and develop novel IgE-based cancer therapies. Citation Format: Tracy R. Daniels-Wells, Gustavo Helguera, Richard K. Leuchter, Rafaela Quintero, Maggie Kozman, Jose A. Rodríguez, Elizabeth Ortiz-Sánchez, Otoniel Martínez-Maza, Birgit C. Schultes, Christopher F. Nicodemus, Manuel L. Penichet. IgE-mediated immune activation targeting the prostate specific antigen: a potential prostate cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2848. doi:10.1158/1538-7445.AM2013-2848