Pharmacokinetic characterization of BMS-936561, an anti-CD70 antibody-drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans

CD70 is a tumor necrosis factor (TNF)-like type II integral membrane protein that is transiently expressed on activated T- and B-lymphocytes. Aberrant expression of CD70 was identified in both solid tumors and haematologic malignancies. BMS-936561 (CD70_MED-A) is an antibody-drug conjugate composed of a fully human anti-CD70 monoclonal antibody (CD70) conjugated with a duocarmycin derivative, MED-A, through a maleimide-containing citrulline-valine dipeptide linker. MED-A is a carbamate prodrug that is activated by carboxylesterase to its active form, MED-B, to exert its DNA alkylation activity. In vitro serum stability studies suggested the efficiencies of hydrolyzing the carbamate-protecting group in CD70_MED-A followed a rank order of mouse>rat >>monkey>dog similar to human. Pharmacokinetics of CD70_MED-A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, CD70_MED-A was cleared rapidly, with no detectable exposures after 15min following dosing. In contrast, CD70_MED-A was much more stable in monkeys and dogs. The clearance of CD70_MED-A in monkeys was 58mL/d/kg, similar to 2-fold faster than that in dogs (31mL/d/kg). The human PK profiles of the total CD70 and CD70_MED-A were predicted using allometrically scaled monkeys PK parameters of CD70 and the carbamate hydrolysis rate constant estimated in dogs. Comparing the predicted and observed human PK from the phase I study, the dose-normalized concentration-time profiles of CD70_MED-A and the total CD70 were largely within the 5(th)-95(th) percentile of the predicted profiles. Copyright (c) 2015 John Wiley & Sons, Ltd.