Lewis Y肿瘤抗原中碳水化合物决定簇的抗体结合的结构趋同
Structural convergence of antibody binding of carbohydrate determinants in Lewis Y tumor antigens.
作者信息
Ramsland Paul A, Farrugia William, Bradford Tessa M, Mark Hogarth P, Scott Andrew M
机构信息
Structural Immunology Laboratory, Austin Research Institute, Heidelberg, Vic. 3084, Australia.
出版信息
J Mol Biol. 2004 Jul 16;340(4):809-18. doi: 10.1016/j.jmb.2004.05.037.
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.
靶向带有Lewis Y（Le(y)）碳水化合物抗原的人类上皮癌的抗体为趋同免疫识别提供了一个显著例证。我们报道了一种人源化抗体（hu3S193）的Fab片段与Le(y)四糖Fuc(α1→2)Gal(β1→4)[Fuc(α1→3)]GlcNAc复合物的1.9埃分辨率晶体结构。对与Le(y)肿瘤抗原结合的hu3S193和BR96抗体的比较揭示了识别碳水化合物表位的极其相似的机制。溶剂在hu3S193抗体与Le(y)碳水化合物表位的结合中起关键作用。对Le(y)的特异性得以维持，因为一个保守口袋容纳核心Gal(β1→4)GlcNAc二糖的N-乙酰基。密切相关的血型决定簇（Le(a)和Le(b)）不能进入特异性口袋，这使得Le(y)抗体成为上皮癌免疫治疗的有前景的候选物。
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