Abstract
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.
Highlights
Introduction to AntibodyDrug Conjugates (ADC)Antibody-drug conjugates (ADC) comprise a complex biotherapeutic modality composed of a warhead conjugated to a monoclonal antibody via a chemical linker
ADCs have relatively narrow therapeutic margin, careful immunogenicity assessment is required for understanding of the potential impact of anti-drug antibodies on their PK/PD, safety and efficacy [55,56]
Since it is not possible to know a priori what epitopes would be susceptible to anti-drug antibodies (ADA) or what the affinity and concentrations of ADA would be, it is not possible to evaluate the potential impact of ADA on bioanalytical method performance during early stages of ADC assay development
Summary
Several different classes of warheads conjugated to antibodies are currently being developed for the treatment of cancer. One of the most clinically relevant classes of cytotoxic/cytostatic warheads consists of microtubule-disrupting agents. Auristatins, such as monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF), are synthetic analogs of cytostatic dolastatins 10 and 15 [2]. MMAE and MMAF auristatins emerged amongst various analogues due to combination of physicochemical properties, cytotoxic/cytostatic activity and in vivo stability. The second most commonly used ADC warhead class are DNA-damaging agents, such as pyrrolobenzodiazepines (PBD) [10,11,12,13,14], calicheamicins [15,16,17,18,19], duocarmycins [20] and novel topoisomerase inhibitors [21]. An ADC carrying a pyranoindolizinoquinoline topoisomerase I inhibitor, exatecan mesylate (DX-8951f), has shown promising clinical activity that appears to be distinct from trastuzumab emtansine [25,26]
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