Antibody–Drug Conjugates Nonclinical Support: from Early to Late Nonclinical Bioanalysis Using Ligand-Binding Assays

Abstract

The objective of antibody-drug conjugate (ADC) bioanalysis at different stages of drug development may vary and so are the associated bioanalytical challenges. While at early drug discovery stage involving candidate selection, optimization and preliminary nonclinical assessments, the goal of ADC bioanalysis is to provide PK, toxicity and efficacy data that assists in the design and selection of potential drug candidates, the late nonclinical and clinical drug development stage typically involves regulated ADC bioanalysis that delivers TK data to define and understand pharmacological and toxicological properties of the lead ADC candidate. Bioanalytical strategies and considerations involved in developing successful ligand binding assays for ADC characterization from early discovery to late nonclinical stages of drug development are presented here.

Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

“…These methods rely on techniques used for biologics and small molecule drugs, but there are also novel methods developed specifically for ADCs such as DAR determination Hengel et al, 2014). A comprehensive description of the most important ADC analytes and details on the toolbox of bioanalytical techniques was recently published in special issues of Bioanalysis (Gorovits et al, 2013;Kaur et al, 2013;Gorovits 2015;Kumar et al, 2015;Myler et al, 2015;Saad et al, 2015); thus, it is not the intent of this article to discuss them. ADCs could be considered as "prodrugs" because the small molecule drug has to be released from the ADC to exert its effect.…”

Current status of antibody-drug conjugate bioanalysis

“…Ideally, a DAR insensitive ADC conjugated-antibody assay is preferred [1][2][3]20]. Three recent articles brought a different perspective for the preference on DAR sensitivity of conjugated-antibody assays [21][22][23]. Kumar et al [21] proposed to develop DAR sensitive conjugated-antibody assays during early Discovery and DAR insensitive conjugated-antibody assays from IND (Investigational New Drug) enabling toxicology studies and into clinical development stage.…”

“…Three recent articles brought a different perspective for the preference on DAR sensitivity of conjugated-antibody assays [21][22][23]. Kumar et al [21] proposed to develop DAR sensitive conjugated-antibody assays during early Discovery and DAR insensitive conjugated-antibody assays from IND (Investigational New Drug) enabling toxicology studies and into clinical development stage. Myler et al [22,23] proposed DAR sensitive conjugated-antibody assay be used throughout the entire ADC discovery and development stages when safety and efficacy are antibody mediated and DAR dependent.…”

“…These topics and different perspectives were discussed extensively in the overviews provided by Kaur et al [2] and Gorovits et al [3] and the research reports from Kumar et al [21] and Wang et al [8] as well as in special reports [24][25][26]. Different bioanalytical strategies, e.g., stage specific [21,27] or discovery and development integrated [8] for ADC PK were proposed.…”

“…Different bioanalytical strategies, e.g., stage specific [21,27] or discovery and development integrated [8] for ADC PK were proposed. We are looking forward to seeing these questions be thoroughly discussed in conferences and literature in the years to come and believe an industry-wide harmonization will be achieved in the near future.…”