title: Targeting human Ep-CAM in transgenic mice by anti-idiotype and antigen based vaccines.
abstract: Anti-idiotypic antibodies (anti-Id) as surrogate TAAs have been shown to induce immunity against tumours in animals and humans. SM262 is a human monoclonal anti-Id raised against MAb 17-1A recognising Ep-CAM. Plasmids encoding the variable regions of SM262 with either murine or human Fc regions, both with and without fusion to GM-CSF were constructed. DNA was delivered by gene gun to C57BL/6 (wt) mice and mice expressing the transgene for human Ep-CAM (tg). The immunogenicity of anti-Id DNA constructs, anti-Id protein and Ep-CAM DNA vaccines was compared. SM262 plasmids induced antibodies (Abs) inhibiting MAb 17-1A binding to SM262 as well as recognising Ep-CAM in wt and tg mice. Fusion to GM-CSF evoked significantly higher Ab titres, whereas a xenogeneic Fc region had no significant effect. The highest Ab titres were elicited by protein immunisation. The original Ag was superior as compared to the anti-Id vaccines in wt but not tg mice in terms of Ab induction. A weak Ep-CAM-specific cytotoxic response was induced in wt but not tg mice. The data suggest that B cell tolerance to Ep-CAM can be circumvented by anti-Id DNA, anti-Id protein as well as Ep-CAM DNA immunisation. Fusion of GM-CSF to anti-Id increased the magnitude of the immune response with no requirement of a foreign Fc domain. Furthermore, no superiority of Ep-CAM as compared to anti-Id DNA vaccine was noted in tg mice and protein immunisation induced a more potent humoral response than DNA. The results might have implications for the design of future vaccine trials using Ep-CAM as a target structure.
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology, (Radiumhemmet), Karolinska Institute, Stockholm, Sweden.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Mosolits
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Litvinov
authors.forename: Jan
authors.initials: J
authors.lastname: Fagerberg
authors.forename: J Scott
authors.initials: JS
authors.lastname: Crowe
authors.forename: Håkan
authors.initials: H
authors.lastname: Mellstedt
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Ellis
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology*; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D019496:Cancer Vaccines / Q000276:immunology*; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010957:Plasmids
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor