Metabolic Engineering of Monoclonal Antibody Carbohydrates for Antibody–Drug Conjugation
| Autor: | Xinqun Zhang, Nicole M. Okeley, Scott C. Jeffrey, Patrick J. Burke, Stephen C. Alley, Peter D. Senter, Brian E. Toki |
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| Rok vydání: | 2013 |
| Předmět: |
Glycan
Immunoconjugates Fucosyltransferase medicine.drug_class Carbohydrates Biomedical Engineering Pharmaceutical Science Bioengineering Monoclonal antibody Fucose Cell Line Metabolic engineering chemistry.chemical_compound medicine Humans Disulfides Pharmacology biology Chemistry Organic Chemistry Antibody-Dependent Cell Cytotoxicity Antibodies Monoclonal Metabolic Engineering Biochemistry biology.protein Antibody Function (biology) Biotechnology Conjugate |
| Zdroj: | Bioconjugate Chemistry. 24:1650-1655 |
| ISSN: | 1520-4812 1043-1802 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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