Structural convergence of antibody binding of carbohydrate determinants in Lewis Y tumor antigens

Journal of Molecular Biology
P A RamslandAndrew M Scott

Abstract

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.

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Citations

Jul 22, 2005·Immunology and Cell Biology·Paula Ramsland
Aug 15, 2014·PloS One·Somdutta SahaThomas Kieber-Emmons
Dec 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Jennifer A WestwoodMichael H Kershaw
Jul 14, 2009·Expert Opinion on Biological Therapy·Elizabeth YurievPaul A Ramsland
Aug 9, 2005·Developmental and Comparative Immunology·John J MarchalonisPaul A Ramsland
Jun 3, 2015·Glycobiology·Omid Haji-GhassemiStephen V Evans
Nov 9, 2016·Current Opinion in Structural Biology·Caroline SolimanPaul A Ramsland
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Aug 23, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Paul A RamslandP Mark Hogarth
Aug 14, 2020·The Biochemical Journal·Caroline SolimanPaul A Ramsland
Mar 14, 2017·The Journal of Clinical Investigation·Zinaida PolonskayaLuc Teyton
Dec 3, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mi LiAlexander Wlodawer
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Dec 10, 2009·Journal of Chemical Information and Modeling·Mark AgostinoElizabeth Yuriev
Jun 24, 2021·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Magdalena Thurin

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