Premium
Preparation of Well‐Defined Antibody–Drug Conjugates through Glycan Remodeling and Strain‐Promoted Azide–Alkyne Cycloadditions
Author(s) -
Li Xiuru,
Fang Tao,
Boons GeertJan
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201402606
Subject(s) - chemistry , azide , combinatorial chemistry , glycan , alkyne , cycloaddition , bioorthogonal chemistry , click chemistry , conjugate , glycosyltransferase , antibody , biochemistry , enzyme , organic chemistry , biology , catalysis , glycoprotein , immunology , mathematical analysis , mathematics
Antibody–drug conjugates hold considerable promise as anticancer agents, however, producing them remains a challenge and there is a need for mild, broadly applicable, site‐specific conjugation methods that yield homogenous products. It was envisaged that enzymatic remodeling of the oligosaccharides of an antibody would enable the introduction of reactive groups that can be exploited for the site‐specific attachment of cytotoxic drugs. This is based on the observation that glycosyltransferases often tolerate chemical modifications in their sugar nucleotide substrates, thus allowing the installation of reactive functionalities. An azide was incorporated because this functional group is virtually absent in biological systems and can be reacted by strain‐promoted alkyne–azide cycloaddition. This method, which does not require genetic engineering, was used to produce an anti‐CD22 antibody modified with doxorubicin to selectively target and kill lymphoma cells.