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Development, characterization, and immunotherapeutic use of peptide mimics of the Thomsen-Friedenreich carbohydrate antigen.

Abstract
The tumor-associated carbohydrate Thomsen-Friedenreich antigen (TF-Ag; Galbeta1-3GalNAcalpha-O-Ser/Thr) is overexpressed on the cell surface of several types of tumor cells, contributing to cancer cell adhesion and metastasis to sites containing TF-Ag-binding lectins. A highly specific immunoglobulin G(3) monoclonal antibody (Ab) developed to TF-Ag (JAA-F11) impedes TF-Ag binding to vascular endothelium, blocking a primary metastatic step and providing a survival advantage. In addition, in patients, even low levels of antibodies to TF-Ag seem to improve prognosis; thus, it is expected that vaccines generating antibodies toward TF-Ag would be clinically valuable. Unfortunately, vaccinations with protein conjugates of carbohydrate tumor-associated Ags have induced clinically inadequate immune responses. However, immunization using peptides that mimic carbohydrate Ags such as Lewis has resulted in both Ab and T-cell responses. Here, we tested the hypothesis that vaccinations with unique TF-Ag peptide mimics may generate immune responses to TF-Ag epitopes on tumor cells, useful for active immunotherapy against relevant cancers. Peptide mimics of TF-Ag were selected by phage display biopanning using JAA-F11 and rabbit anti-TF-Ag Ab and were analyzed in vitro to confirm TF-Ag peptide mimicry. In vitro, TF-Ag peptide mimics bound to TF-Ag-specific peanut agglutinin and blocked TF-Ag-mediated rolling and stable adhesion of cancer cells to vascular endothelium. In vivo, the immunization with TF-Ag-mimicking multiple antigenic peptides induced TF-Ag-reactive Ab production. We propose that this novel active immunotherapy approach could decrease tumor burden in cancer patients by specifically targeting TF-Ag-positive cancer cells and blocking metastasis.
AuthorsJamie Heimburg-Molinaro, Adel Almogren, Susan Morey, Olga V Glinskii, Rene Roy, Gregory E Wilding, Richard P Cheng, Vladislav V Glinsky, Kate Rittenhouse-Olson
JournalNeoplasia (New York, N.Y.) (Neoplasia) Vol. 11 Issue 8 Pg. 780-92 (Aug 2009) ISSN: 1476-5586 [Electronic] United States
PMID19649208 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antibodies, Monoclonal
  • Antigens, Tumor-Associated, Carbohydrate
  • Cancer Vaccines
  • Peptide Library
  • Peptides
  • Thomsen-Friedenreich antigen
Topics
  • Animals
  • Antibodies, Monoclonal (immunology)
  • Antibody Specificity
  • Antigens, Tumor-Associated, Carbohydrate (immunology)
  • Cancer Vaccines (immunology)
  • Cell Adhesion (immunology)
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoblotting
  • Immunotherapy (methods)
  • Mice
  • Mice, Inbred BALB C
  • Molecular Mimicry (immunology)
  • Peptide Library
  • Peptides (immunology)
  • Surface Plasmon Resonance

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