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Targeting human Ep‐CAM in transgenic mice by anti‐idiotype and antigen based vaccines
Author(s) -
Mosolits Szilvia,
Campbell Fiona,
Litvinov Sergey V.,
Fagerberg Jan,
Crowe J. Scott,
Mellstedt Håkan,
Ellis Jonathan H.
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20453
Subject(s) - immunogenicity , dna vaccination , microbiology and biotechnology , antibody , idiotype , transgene , immune system , monoclonal antibody , antigen , fusion protein , biology , genetically modified mouse , fusion gene , gene gun , virology , immunology , gene , recombinant dna , immunization , biochemistry
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 F c 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 F c 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 F c 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. © 2004 Wiley‐Liss, Inc.