Development, characterization, and immunotherapeutic use of peptide mimics of the Thomsen-Friedenreich carbohydrate antigen.
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.
Heimburg-Molinaro
Jamie
J
Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA.
Almogren
Adel
A
Morey
Susan
S
Glinskii
Olga V
OV
Roy
Rene
R
Wilding
Gregory E
GE
Cheng
Richard P
RP
Glinsky
Vladislav V
VV
Rittenhouse-Olson
Kate
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry / Q000276:immunology*; D019151:Peptide Library; D010455:Peptides / Q000276:immunology*; D020349:Surface Plasmon Resonance
D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines; D019151:Peptide Library; D010455:Peptides; C016467:Thomsen-Friedenreich antigen