Metabolism of bioconjugate therapeutics: why, when, and how?

Abstract

Bioconjugation of therapeutic agents has been used as a selective drug delivery platform for many therapeutic areas. Bioconjugates are prepared by the covalent linkage of active compounds (small or large molecule) to a carrier molecule (lipids, proteins, peptides, carbohydrates, and polymers) through a chemical linker. The linkage of the active component to a carrier molecule enhances the therapeutic window through a targeted delivery and by reducing toxicity. Bioconjugates also possess improved pharmacokinetic properties such as a long half-life, increased stability, and cleavage by intracellular enzymes/environment. However, premature cleavage of the bioconjugates and the resulting metabolites/catabolites may produce undesirable toxic effects and, hence, it is critical to understand cleavage mechanisms, metabolism of bioconjugates, and translatability to human in the discovery stages. This article provides a comprehensive overview of linker cleavage pathways and catabolism/metabolism of antibody–drug conjugates, glycoconjugates, polymer–drug conjugates, lipid–drug conjugates, folate-targeted small molecule–drug conjugates, and drug–drug conjugates.

Keywords:

• Bioconjugate
• metabolism
• pharmacokinetics
• linkers
• antibody–drug conjugates
• glycoconjugates
• polymer–drug conjugates
• lipid–drug conjugates
• folate-targeted small molecule-drug conjugates
• drug–drug conjugates

Acknowledgments

Medical writing support was provided by PRA Health Sciences.

Disclosure statement

No potential conflict of interest was reported by the author(s).