Antibody-drug conjugates (ADCs) represent a form of targeted biopharmaceuticals where an antibody binds a tumor antigen to facilitate the endocytosis of a chemotherapeutic or diagnostic agent. Most current conjugation technologies non-selectively ligate the chemotherapeutic to cysteine or lysine, leading to a heterogeneous population of ADCs with unpredictable pharmacological properties. To overcome these drawbacks, we are combining genetic engineering with metabolic glycoengineering to site-specifically incorporate bioorthogonal functional groups into an antibody’s glycans. The presence of such groups, for example azides or alkynes, enables controlled and predictable conjugation of chemotherapeutics through “click chemistry” ligation reactions resulting in the production of homogeneous ADCs. Our strategy involves CRISPR/Cas9-mediated gene editing of Chinese hamster ovary cells used to produce the antibodies to bolster metabolic flux from an exogenous sialic acid precursors, such as the azido-analog 1,3,4-<i>O</i>-Bu<sub>3</sub>ManNAz, into the sialic acid biosynthetic pathway to increase incorporation of azide-modified sialic acid in the antibody’s glycans. This combined genetic and metabolic engineering approach both facilitates the production of ADCs with greater homogeneity and improves the antibody to drug ratio.

Genetic and metabolic glycoengineering for production of antibody-drug conjugates

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.