Metabolic Engineering of Monoclonal Antibody Carbohydrates for Antibody鈥揇rug Conjugation

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• 作者：Nicole M. Okeley ; Brian E. Toki ; Xinqun Zhang ; Scott C. Jeffrey ; Patrick J. Burke ; Stephen C. Alley ; Peter D. Senter
• 刊名：Bioconjugate Chemistry
• 出版年：2013
• 出版时间：October 16, 2013
• 年：2013
• 卷：24
• 期：10
• 页码：1650-1655
• 全文大小：341K
• 年卷期：v.24,no.10(October 16, 2013)
• ISSN：1520-4812

文摘

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鈥揹rug conjugates with pronounced cytotoxic activities and improved homogeneity compared to drug attachment through hinge disulfides.