TY - JOUR T1 - New Insights in Tissue Distribution, Metabolism, and Excretion of [<sup>3</sup>H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 897 LP - 910 DO - 10.1124/dmd.115.069021 VL - 44 IS - 7 AU - Markus Walles AU - Bettina Rudolph AU - Thierry Wolf AU - Julien Bourgailh AU - Martina Suetterlin AU - Thomas Moenius AU - Gisela Peraus AU - Olivier Heudi AU - Walid Elbast AU - Christian Lanshoeft AU - Sanela Bilic Y1 - 2016/07/01 UR - http://dmd.aspetjournals.org/content/44/7/897.abstract N2 - For antibody drug conjugates (ADCs), the fate of the cytotoxic payload in vivo needs to be well understood to mitigate toxicity risks and properly design the first in-patient studies. Therefore, a distribution, metabolism, and excretion (DME) study with a radiolabeled rat cross-reactive ADC ([3H]DM1-LNL897) targeting the P-cadherin receptor was conducted in female tumor-bearing nude rats. Although multiple components [total radioactivity, conjugated ADC, total ADC, emtansine (DM1) payload, and catabolites] needed to be monitored with different technologies (liquid scintillation counting, liquid chromatography/mass spectrometry, enzyme-linked immunosorbent assay, and size exclusion chromatography), the pharmacokinetic data were nearly superimposable with the various techniques. [3H]DM1-LNL897 was cleared with half-lives of 51–62 hours and LNL897-related radioactivity showed a minor extent of tissue distribution. The highest tissue concentrations of [3H]DM1-LNL897–related radioactivity were measured in tumor. Complimentary liquid extraction surface analysis coupled to micro-liquid chromatography–tandem mass spectrometry data proved that the lysine (LYS)–4(maleimidylmethyl) cyclohexane-1-carboxylate–DM1 (LYS-MCC-DM1) catabolite was the only detectable component distributed evenly in the tumor and liver tissue. The mass balance was complete with up to 13.8% ± 0.482% of the administered radioactivity remaining in carcass 168 hours postdose. LNL897-derived radioactivity was mainly excreted via feces (84.5% ± 3.12%) and through urine only to a minor extent (4.15% ± 0.462%). In serum, the major part of radioactivity could be attributed to ADC, while small molecule disposition products were the predominant species in excreta. We show that there is a difference in metabolite profiles depending on which derivatization methods for DM1 were applied. Besides previously published results on LYS-MCC-DM1 and MCC-DM1, maysine and a cysteine conjugate of DM1 could be identified in serum and excreta. ER -