Thomas D. Kempe

An integrated multiplatform bioanalytical strategy for antibody–drug conjugates: a novel case study

BACKGROUND The bioanalytical strategy for antibody-drug conjugates (ADC) includes numerous measurements integrally designed to provide comprehensive characterization of PK, PD and immunogenicity. This manuscript describes the utilization of reagents specifically tailored to an ADC with a microtubule polymerization inhibitor payload and cathepsin B cleavable linker. METHODS The PK strategy includes the evaluation of physiological levels of total antibody, active ADC, total ADC, antibody-conjugated payload and unconjugated payload. These data are evaluated in the context of target and antidrug antibody levels to elucidate bioactive ADC. RESULTS & CONCLUSION Herein, we discuss how this strategy has been applied and present our preliminary observations. Continuously evolving to meet pipeline demands, the integrated bioanalytical data will provide critical insights into the exposure-response relationship.

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 (αCD70_MED‐A) is an antibody‐drug conjugate composed of a fully human anti‐CD70 monoclonal antibody (αCD70) 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 αCD70_MED‐A followed a rank order of mouse > rat > > monkey > dog ~ human. Pharmacokinetics of αCD70_MED‐A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, αCD70_MED‐A was cleared rapidly, with no detectable exposures after 15 min following dosing. In contrast, αCD70_MED‐A was much more stable in monkeys and dogs. The clearance of αCD70_MED‐A in monkeys was 58 mL/d/kg, ~2‐fold faster than that in dogs (31 mL/d/kg). The human PK profiles of the total αCD70 and αCD70_MED‐A were predicted using allometrically scaled monkeys PK parameters of αCD70 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 αCD70_MED‐A and the total αCD70 were largely within the 5th‐95th percentile of the predicted profiles. Copyright