title: Bioanalytical approaches for characterizing catabolism of antibody-drug conjugates.
abstract: The in vivo stability and catabolism of antibody-drug conjugates (ADCs) directly impact their PK, efficacy and safety, and metabolites of the cytotoxic or small molecule drug component of an ADC can further complicate these factors. This perspective highlights the importance of understanding ADC catabolism and the associated bioanalytical challenges. We evaluated different bioanalytical approaches to qualitatively and quantitatively characterize ADC catabolites. Here we review and discuss the rationale and experimental strategies used to design bioanalytical assays for characterization of ADC catabolism and supporting ADME studies during ADC clinical development. This review covers both large and small molecule approaches, and uses examples from Kadcyla® (T-DM1) and a THIOMAB™ antibody-drug conjugate to illustrate the process.
authors.affiliation: Department of Bioanalytical Sciences, Assay Development and Technology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ola M
authors.initials: OM
authors.lastname: Saad
authors.affiliation: Department of Preclinical & Translational Pharmacokinetics & Pharmacodynamics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
authors.affiliation: Department of Bioanalytical Sciences, Assay Development and Technology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.affiliation: Department of Clinical Pharmacology, Genentech, Inc., Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
authors.affiliation: Department of Bioanalytical Sciences, Assay Development and Technology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D001681:Biological Assay; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology*; D008660:Metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates