Glycan bioengineering in immunogen design for tumor T antigen immunotargeting.
Bioengineering of Galbeta3GalNAcalpha, known as Thomsen-Friedenreich disaccharide (TFD), is studied to promote glycan immunogenicity and immunotargeting to tumor T antigen (Galbeta3GalNAcalpha-O-Ser/Thr). Theoretical studies on disaccharide conformations by energy minimization of structures using MM2 energy function showed that pentalysine (Lys5) linker and benzyl (Bzl) residue enhance TFD rigidity of the glycosidic bond. Antibodies raised against BzlalphaTFD-Lys5 immunogen recognize tumor T antigen. Competitive assays confirm that TFD-related structures are the main glycan epitope. Antibodies produced by glycan bioengineering recognize HT29, T47D, MCF7, and CT26 epithelial tumor cells. Epithelial tumor cell adhesion to T antigen-binding lectins and endothelial cells was lower in the presence of antibodies raised against the engineered immunogen. The immune response directed to the bioengineered glycoconjugate inhibited CT26 tumor cell proliferation and reduced tumor growth in an in vivo mouse model. These results show that TFD bioengineering is a useful immunogenic strategy with potential application in cancer therapy. The same approach can be extended to other glycan immunogens for immunotargeting purposes.
Sendra
Victor G
VG
Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, UNC-CONICET), Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Argentina.
Zlocowski
Natacha
N
Ditamo
Yanina
Y
Copioli
Silvina
S
Tarp
Mads P
MP
Bennett
Eric P
EP
Clausen
Henrik
H
Roth
German A
GA
Nores
Gustavo A
GA
Irazoqui
Fernando J
FJ
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D002236:Carbohydrate Conformation; D045744:Cell Line, Tumor; D004187:Disaccharides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology / Q000628:therapy*; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D004187:Disaccharides; D018984:Epitopes, T-Lymphocyte; D014614:Vaccines, Synthetic