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CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice.

Abstract
A murine monoclonal anti-idiotype (Id) antibody, 3H1 has been developed and characterized previously. Anti-Id 3H1 mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate antigen for CEA. 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colon cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. In this study, we have evaluated the efficacy of 3H1 as a tumor vaccine when admixed with a select CpG ODN 1826 in transgenic mice that express human CEA. The vaccine potential of 3H1 was also assessed in the presence of another widely used adjuvant, QS-21. 3H1 coupled to keyhole limpet hemocyanin (KLH) and mixed with Freund's adjuvant (FA) was used as a gold standard in this system. 3H1 vaccination with different adjuvants induced both humoral and cellular anti-3H1, as well as anti-CEA immunity in CEA transgenic mice. The immune sera could lyse CEA-transfected murine colon carcinoma cells, C15 effectively in an antibody-dependent cellular cytotoxicity assay. The anti-CEA antibody responses were somewhat comparable in each adjuvant-treated group of mice, whereas cellular immune responses were significantly greater when CpG was used as an adjuvant. Splenocytes obtained from 3H1-CpG-immunized mice showed an increased proliferative CD4(+) Th1-type T-cell response when stimulated in vitro with 3H1 or CEA and secreted elevated levels of Th1 cytokines (IL-2, IFN-gamma). This vaccine also induced MHC class I antigen-restricted CD8(+) T-cell responses. In a solid tumor model, C15 tumor growth was significantly inhibited by 3H1 vaccinations. In 3H1-CpG-vaccinated mice, the duration of survival was, however, longer compared to the 3H1-QS21-vaccinated mice. These findings suggest that 3H1-CpG vaccinations can break peripheral tolerance to CEA and induce protective antitumor immunity in this murine model transgenic for human CEA.
AuthorsAsim Saha, Rathindra Nath Baral, Sunil K Chatterjee, Kartik Mohanty, Smarajit Pal, Kenneth A Foon, F James Primus, Arthur M Krieg, George J Weiner, Malaya Bhattacharya-Chatterjee
JournalCancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 55 Issue 5 Pg. 515-27 (May 2006) ISSN: 0340-7004 [Print] Germany
PMID16044253 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Adjuvants, Immunologic
  • Antibodies, Anti-Idiotypic
  • Antigens, Neoplasm
  • CPG-oligonucleotide
  • Cancer Vaccines
  • Carcinoembryonic Antigen
  • Cell Cycle Proteins
  • Cep290 protein, human
  • Cytoskeletal Proteins
  • Neoplasm Proteins
  • Oligodeoxyribonucleotides
  • Saponins
  • saponin QA-21V1
  • Hemocyanins
  • keyhole-limpet hemocyanin
Topics
  • Adjuvants, Immunologic (therapeutic use)
  • Animals
  • Antibodies, Anti-Idiotypic (immunology, therapeutic use)
  • Antigens, Neoplasm (immunology)
  • Cancer Vaccines
  • Carcinoembryonic Antigen (immunology)
  • Cell Cycle Proteins
  • Colonic Neoplasms (drug therapy, immunology)
  • Cytoskeletal Proteins
  • Female
  • Hemocyanins (immunology)
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasm Proteins (immunology)
  • Oligodeoxyribonucleotides (immunology, therapeutic use)
  • Saponins (immunology, therapeutic use)

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