Abstract
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 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, DM1 payload and catabolites) needed to be monitored with different technologies (LSC, LC-MS, ELISA, SEC), the pharmacokinetic data were nearly superimposable with the various techniques. [3H]DM1-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 [3H]DM1-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. Maysine and a cysteine conjugate of DM1 could be identified in serum and excreta besides previously published LYS-MCC-DM1 and MCC-DM1.
- The American Society for Pharmacology and Experimental Therapeutics