A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy
1 Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
2 The Molecular Biology Institute, University of California, Los Angeles, CA, USA
3 Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
4 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA
5 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
6 Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA
7 Advanced Immune Therapeutics, Inc, Charlestown, MA, USA
8 Current Affiliation: Momenta Pharmaceuticals, Inc, Cambridge, MA, USA
9 Current Affiliation: School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
10 Current Affiliation: Unit of Biomedical Research in Cancer, Basic Research Division, National Institute of Cancerology, Mexico City, Mexico
11 Current Affiliation: AIT Strategies, Franconia, NH, USA
BMC Cancer 2013, 13:195 doi:10.1186/1471-2407-13-195Published: 17 April 2013
Prostate 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.
Binding 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.
The 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.
The 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.