Antibody-drug conjugates (ADCs) are a unique class of biotherapeutics of inherent heterogeneity and correspondingly complex absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we consider the contribution of various components of ADCs such as various classes of warheads, linkers, and conjugation strategies on ADME of ADCs. Understanding the metabolism and disposition of ADCs and interpreting exposure-efficacy and exposure-safety relationships of ADCs in the context of their various catabolites is critical for design and subsequent development of a clinically successful ADCs. Sophisticated bioanalytical assays are required for the assessments of intact ADC, total antibody, released warhead and relevant metabolites. Both ligand-binding assays (LBA) and hybrid LBA-liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) methods have been employed to assess pharmacokinetics (PK) of ADCs. Future advances in bioanalytical techniques will need to address the rising complexity of this biotherapeutic modality as more innovative conjugation strategies, antibody scaffolds and novel classes of warheads are employed for the next generation of ADCs. This review reflects our considerations on ADME of ADCs and provides a perspective on the current bioanalytical strategies for pharmacokinetic assessments of ADCs.
Keywords: ADC; ADME; LBA; PK; antibody-drug conjugates; bioanalysis; hybrid LBA-LC-MS/MS.