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

Metabolic engineering of monoclonal antibody carbohydrates for antibody-drug conjugation.

Author information

1
Seattle Genetics, Inc. , Bothell, Washington 98021, United States.

Abstract

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.

PMID:
24050213
DOI:
10.1021/bc4002695
[Indexed for MEDLINE]

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