Galactose Oxidase Enables Modular Assembly of Conjugates from Native Antibodies with High Drug-to-Antibody Ratios**

Antonio Angelastro, Alexey Barkhanskiy, Ashley P. Mattey, Edward G. Pallister, Reynard Spiess, William Goundry, Perdita Barran, Sabine L. Flitsch

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere202102592
JournalChemsuschem
Volume15
Issue number9
DOIs
Publication statusPublished - 6 May 2022

Keywords

  • antibodies
  • antibody–drug conjugates
  • biocatalysis
  • glycoengineering
  • medicinal chemistry

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