Targeting human Ep-CAM in transgenic mice by anti-idiotype and antigen based vaccines

Int J Cancer. 2004 Nov 20;112(4):669-77. doi: 10.1002/ijc.20453.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / immunology*
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • CD3 Complex
  • Cancer Vaccines / immunology*
  • Cell Adhesion Molecules
  • Epithelial Cell Adhesion Molecule
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plasmids

Substances

  • Antibodies, Anti-Idiotypic
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • CD3 Complex
  • Cancer Vaccines
  • Cell Adhesion Molecules
  • Epithelial Cell Adhesion Molecule
  • Granulocyte-Macrophage Colony-Stimulating Factor