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

Paul A. Ramsland, William Farrugia, Tessa M. Bradford, P. Mark Hogarth, Andrew M. Scott

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

Abstract

Antibodies targeting human epithelial carcinomas bearing Lewis Y (Le y) carbohydrate antigens provide a striking illustration of convergent immune recognition. We report a 1.9Å resolution crystal structure of the Fab of a humanized antibody (hu3S193) in complex with the Ley tetrasaccharide, Fuc(α1→2)Gal(β1→4) [Fuc(α1→3)]GlcNAc. Comparisons of the hu3S193 and BR96 antibodies bound to Ley tumor antigens revealed extremely similar mechanisms for recognition of the carbohydrate epitopes. Solvent plays a critical role in hu3S193 antibody binding to the Ley carbohydrate epitope. Specificity for Ley is maintained because a conserved pocket accepts an N-acetyl group of the core Gal(β1→4)GlcNAc disaccharide. Closely related blood-group determinants (Lea and Leb) cannot enter the specificity pocket, making the Ley antibodies promising candidates for immunotherapy of epithelial cancer.

Original languageEnglish
Pages (from-to)809-818
Number of pages10
JournalJournal of Molecular Biology
Volume340
Issue number4
DOIs
Publication statusPublished - 16 Jul 2004
Externally publishedYes

Keywords

  • ADCC, antibody-dependent cellular cytotoxicity
  • antibody crystallography
  • cancer treatments
  • carbohydrate antigens
  • CDC, complement-dependent cytotoxicity
  • CDR, complementarity-determining regions
  • D, diversity minigene
  • humanized antibody
  • tumor targeting

Cite this

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title = "Structural convergence of antibody binding of carbohydrate determinants in Lewis Y tumor antigens",
abstract = "Antibodies targeting human epithelial carcinomas bearing Lewis Y (Le y) carbohydrate antigens provide a striking illustration of convergent immune recognition. We report a 1.9{\AA} resolution crystal structure of the Fab of a humanized antibody (hu3S193) in complex with the Ley tetrasaccharide, Fuc(α1→2)Gal(β1→4) [Fuc(α1→3)]GlcNAc. Comparisons of the hu3S193 and BR96 antibodies bound to Ley tumor antigens revealed extremely similar mechanisms for recognition of the carbohydrate epitopes. Solvent plays a critical role in hu3S193 antibody binding to the Ley carbohydrate epitope. Specificity for Ley is maintained because a conserved pocket accepts an N-acetyl group of the core Gal(β1→4)GlcNAc disaccharide. Closely related blood-group determinants (Lea and Leb) cannot enter the specificity pocket, making the Ley antibodies promising candidates for immunotherapy of epithelial cancer.",
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Structural convergence of antibody binding of carbohydrate determinants in Lewis Y tumor antigens. / Ramsland, Paul A.; Farrugia, William; Bradford, Tessa M.; Hogarth, P. Mark; Scott, Andrew M.

In: Journal of Molecular Biology, Vol. 340, No. 4, 16.07.2004, p. 809-818.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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AU - Bradford, Tessa M.

AU - Hogarth, P. Mark

AU - Scott, Andrew M.

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AB - Antibodies targeting human epithelial carcinomas bearing Lewis Y (Le y) carbohydrate antigens provide a striking illustration of convergent immune recognition. We report a 1.9Å resolution crystal structure of the Fab of a humanized antibody (hu3S193) in complex with the Ley tetrasaccharide, Fuc(α1→2)Gal(β1→4) [Fuc(α1→3)]GlcNAc. Comparisons of the hu3S193 and BR96 antibodies bound to Ley tumor antigens revealed extremely similar mechanisms for recognition of the carbohydrate epitopes. Solvent plays a critical role in hu3S193 antibody binding to the Ley carbohydrate epitope. Specificity for Ley is maintained because a conserved pocket accepts an N-acetyl group of the core Gal(β1→4)GlcNAc disaccharide. Closely related blood-group determinants (Lea and Leb) cannot enter the specificity pocket, making the Ley antibodies promising candidates for immunotherapy of epithelial cancer.

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