Glycan engineering for tumor T antigen immunotargeting

SENDRA VG; IRAZOQUI FJ

Monte Hermoso, Cba, Argentina

Congreso; Tango Lesson for Brain Cancer Research; 2007

James McDonnell Foundation

Mucin-type O-glycans are upregulated and aberrantly glycosylated in many carcinomas. O-glycan Core 1 (Galb1-3GalNAca-O-Ser/Thr), called Thomsen-Friedenreich antigen (T antigen), is an example of a cryptic structure that is over-expressed in cancer cells by changing its glycosyltransferase profile. Glycan residue of T antigen (Galb1-3GalNAca-), Thomsen-Friedenreich disaccharide (TFD), is an attractive model to study carbohydrate immunogenicity and a potential candidate for active specific immunotherapy of patients with cancer. The aim of present work is study a topological redesign of disaccharide in the attempt to improve the glycan immunogenicity. Theory studies focused to reduce the flexibility of disaccharide were developed by minimization with MM2 energy function. The synthetic glycoconjugate was used as immunogen in Balb-C mice. Antibody titers were measured by using ELISA against several antigens. They recognize benzyl alpha TFD (BzlaTFD) and tumor T-MUC1 antigen by direct binding assays. Carbohydrate binding was demonstrated by inhibitory assays. Direct immunofluorescense and Cell ELISA evidenced that yielded IgG and IgM antibodies bind epithelial tumor cell lines (T47D, HT29 and MCF7), and interaction is partially mediated by related TFD structures. Yielded antibodies have inhibitory capacity on adhesion of epithelial tumor cells. Glycan engineering shows beneficial properties in immunogen design of TFD when the purpose is direct the immune response to related T antigen molecules expressed on epithelial tumor cells.