title: Induction of autoantibodies to syngeneic prostate-specific membrane antigen by xenogeneic vaccination.
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.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. gregorp@mskcc.org
authors.forename: Polly D
authors.initials: PD
authors.lastname: Gregor
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Vandana
authors.initials: V
authors.lastname: Turaga
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Latouche
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Dean
authors.initials: D
authors.lastname: Bacich
authors.forename: Warren D W
authors.initials: WD
authors.lastname: Heston
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology*; D000917:Antibody Formation; D000954:Antigens, Surface / Q000096:biosynthesis* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D042783:Endothelial Cells; D020869:Gene Expression Profiling; D043425:Glutamate Carboxypeptidase II / Q000096:biosynthesis* / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000662:veterinary; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000662:veterinary; D019444:Vaccines, DNA
chemical_list: D000910:Antibodies, Heterophile; D000954:Antigens, Surface; D001323:Autoantibodies; D019444:Vaccines, DNA; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II