New Insights in Tissue Distribution, Metabolism and Excretion of [3H]-labeled Antibody Maytansoid Conjugates in Female Tumor Bearing Nude Rats

For antibody drug conjugates (ADCs), the fate of the cytotoxic payload in vivo needs to be well understood in order to mitigate toxicity risks and properly design the first in patient studies. Therefore, a DME study with a rat cross reactive ADC (LNL897) targeting the p-cadherin receptor was conducted in female tumor bearing nude rats. Although multiple components needed to be monitored in the DME study (total radioactivity, conjugated ADC, total ADC, payload DM1 and catabolites) with different technologies (LSC, LC-MS, ELISA, SEC), the pharmacokinetic data were nearly superimposable. LNL897 was cleared in the rat with half-lives of 51-62 h and LNL897 related radioactivity showed a minor extent of tissue distribution. The highest tissue concentrations of LNL897 related radioactivity were measured in tumor tissue. Complimentary LESA-µLC-MS/MS data proved that the 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 h post dose. 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 showed that there is a difference in metabolite profiles depending if derivatization methods for DM1 were applied and got more insights into metabolic disposition as a cysteine conjugate of DM1 and maysine could be identified in serum and excreta besides previously published LYS-MCC-DM1 and MCC-DM1