Current status of antibody-drug conjugate bioanalysis

Abstract

ADC bioanalytical strategies With the US FDA approval of Adcetris® (brentuximab vedotin) in 2011 and Kadcyla® (ado-transtuzumab emtansine) in 2013, antibody-drug conjugate (ADC) has been a hot topic in industry. Because of the complexity of an ADC, combining monoclonal antibody and small molecule toxin, its bioanalysis has seen unprecedented amount of discussion compared to other drug modalities. Two review articles, Stephan et al. [1] and Kaur et al. [2], and an AAPS Drug Conjugate Working Group position paper [3] best describe the challenges and strategies of ADC bioanalysis. There are three key points from these milestone publications on ADC bioanalysis: 1. These articles outline the bioanalytical strategies to measure three PK analytes for non-clinical and clinical studies: total antibody, conjugated-antibody or antibody conjugated-drug, and free drug and its metabolites using ligand-binding, LC-MS or hybrid ligand-binding LC-MS assays [1,2]. They also point out that the analytes measured for a particular ADC could vary and the number of analytes could possibly be reduced late in clinical development. 2. Drug-to-antibody ratio (DAR) in vivo may change due to deconjugation and/or different clearance rates. The total-antibody and conjugated-antibody assay should measure different DAR species equally without DAR bias. DAR bias or DAR sensitivity has been the most challenging and debated topic in ADC bioanalytical assays. 3. Affinity capture LC-MS measurement of intact ADCs to characterize DAR distribution change in vitro and in vivo is important to understanding ADC biotransformation in developing ADCs. JOURNAL OF APPLIED BIOANALYSIS, April 2017, p. 26-30. http://dx.doi.org/10.17145/jab.17.004 (ISSN 2405-710X) Vol. 3, No. 2