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Galactose Oxidase Enables Modular Assembly of Conjugates from Native Antibodies with High Drug‐to‐Antibody Ratios **
Author(s) -
Angelastro Antonio,
Barkhanskiy Alexey,
Mattey Ashley P.,
Pallister Edward G.,
Spiess Reynard,
Goundry William,
Barran Perdita,
Flitsch Sabine L.
Publication year - 2022
Publication title -
chemsuschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.412
H-Index - 157
eISSN - 1864-564X
pISSN - 1864-5631
DOI - 10.1002/cssc.202102592
Subject(s) - bioconjugation , conjugate , chemistry , combinatorial chemistry , biocatalysis , antibody , drug , antibody drug conjugate , galactose oxidase , iminosugar , biochemistry , enzyme , monoclonal antibody , pharmacology , biology , catalysis , mathematical analysis , ionic liquid , mathematics , immunology
The potential of antibody conjugates with high drug loading in anticancer therapy has recently been highlighted by the approval of Trastuzumab deruxtecan and Sacituzumab govitecan. These biopharmaceutical approaches have spurred interest in bioconjugation strategies with high and defined degrees of drug‐to‐antibody ratio (DAR), in particular on native antibodies. Here, a glycoengineering methodology was developed to generate antibody drug conjugates with DAR of up to eight, by combining highly selective enzymatic galactosylation and oxidation with biorthogonal tandem Knoevenagel–Michael addition chemistry. This four‐step approach offers a selective route to conjugates from native antibodies with high drug loading, and thus illustrates how biocatalysis can be used for the generation of biopharmaceuticals using mild reaction conditions.