Structural convergence of antibody binding of carbohydrate determinants in Lewis Y tumor antigens.
Antibodies targeting human epithelial carcinomas bearing Lewis Y (Le(y)) carbohydrate antigens provide a striking illustration of convergent immune recognition. We report a 1.9A resolution crystal structure of the Fab of a humanized antibody (hu3S193) in complex with the Le(y) tetrasaccharide, Fuc(alpha 1-->2)Gal(beta 1-->4)[Fuc(alpha 1-->3)]GlcNAc. Comparisons of the hu3S193 and BR96 antibodies bound to Le(y) tumor antigens revealed extremely similar mechanisms for recognition of the carbohydrate epitopes. Solvent plays a critical role in hu3S193 antibody binding to the Le(y) carbohydrate epitope. Specificity for Le(y) is maintained because a conserved pocket accepts an N-acetyl group of the core Gal(beta 1-->4)GlcNAc disaccharide. Closely related blood-group determinants (Le(a) and Le(b)) cannot enter the specificity pocket, making the Le(y) antibodies promising candidates for immunotherapy of epithelial cancer.
Ramsland
Paul A
PA
Structural Immunology Laboratory, Austin Research Institute, Heidelberg, Vic. 3084, Australia. p.ramsland@ari.unimelb.edu.au
Farrugia
William
W
Bradford
Tessa M
TM
Mark Hogarth
P
P
Scott
Andrew M
AM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000918:Antibody Specificity; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry* / Q000276:immunology; D001666:Binding Sites, Antibody; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology; D022801:Complementarity Determining Regions; D018360:Crystallography, X-Ray; D000939:Epitopes; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007983:Lewis Blood Group Antigens / Q000737:chemistry* / Q000276:immunology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology; D009844:Oligosaccharides / Q000737:chemistry / Q000276:immunology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015295:Antigens, Tumor-Associated, Carbohydrate; D002241:Carbohydrates; D022801:Complementarity Determining Regions; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007983:Lewis Blood Group Antigens; D008024:Ligands; D009844:Oligosaccharides