Metabolic Engineering of Monoclonal Antibody Carbohydrates
for Antibody–Drug Conjugation
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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