Metabolic engineering of monoclonal antibody carbohydrates for antibody-drug conjugation

Bioconjug Chem. 2013 Oct 16;24(10):1650-5. doi: 10.1021/bc4002695. Epub 2013 Sep 19.


The role that carbohydrates play in antibody function and pharmacokinetics has made them important targets for modification. The terminal fucose of the N-linked glycan structure, which has been shown to be involved in modulation of antibody-directed cellular cytotoxicity, is a particularly interesting location for potential modification through incorporation of alternative sugar structures. A library of fucose analogues was evaluated for their ability to incorporate into antibody carbohydrates in place of the native fucose. A number of efficiently incorporated molecules were identified, demonstrating the ability of fucosyltransferase VIII to utilize a variety of non-natural sugars as substrates. Among these structures was a thiolated analogue, 6-thiofucose, which was incorporated into the antibody carbohydrate with good efficiency. This unnatural thio-sugar could then be used for conjugation using maleimide chemistry to produce antibody-drug conjugates with pronounced cytotoxic activities and improved homogeneity compared to drug attachment through hinge disulfides.

MeSH terms

  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / immunology
  • Antibody-Dependent Cell Cytotoxicity
  • Carbohydrates / chemistry*
  • Carbohydrates / immunology
  • Cell Line
  • Disulfides / chemistry
  • Fucose / analogs & derivatives*
  • Fucose / immunology
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / immunology
  • Metabolic Engineering


  • Antibodies, Monoclonal
  • Carbohydrates
  • Disulfides
  • Immunoconjugates
  • Fucose