| Title : Pharmacokinetic characterization of BMS-936561, an anti-CD70 antibody-drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans - Wang_2016_Biopharm.Drug.Dispos_37_93 |
| Author(s) : Wang H , Rangan VS , Sung MC , Passmore D , Kempe T , Wang X , Thevanayagam L , Pan C , Rao C , Srinivasan M , Zhang Q , Gangwar S , Deshpande S , Cardarelli P , Marathe P , Yang Z |
| Ref : Biopharmaceutics & Drug Disposition , 37 :93 , 2016 |
| Abstract : 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 (alphaCD70_MED-A) is an antibody-drug conjugate composed of a fully human anti-CD70 monoclonal antibody (alphaCD70) 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 alphaCD70_MED-A followed a rank order of mouse > rat > > monkey > dog ~ human. Pharmacokinetics of alphaCD70_MED-A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, alphaCD70_MED-A was cleared rapidly, with no detectable exposures after 15 min following dosing. In contrast, alphaCD70_MED-A was much more stable in monkeys and dogs. The clearance of alphaCD70_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 alphaCD70 and alphaCD70_MED-A were predicted using allometrically scaled monkeys PK parameters of alphaCD70 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 alphaCD70_MED-A and the total alphaCD70 were largely within the 5(th) -95(th) percentile of the predicted profiles. Copyright (c) 2015 John Wiley & Sons, Ltd. |
| ESTHER : Wang_2016_Biopharm.Drug.Dispos_37_93 |
| PubMedSearch : Wang_2016_Biopharm.Drug.Dispos_37_93 |
| PubMedID: 25869904 |
Wang H, Rangan VS, Sung MC, Passmore D, Kempe T, Wang X, Thevanayagam L, Pan C, Rao C, Srinivasan M, Zhang Q, Gangwar S, Deshpande S, Cardarelli P, Marathe P, Yang Z (2016)
Pharmacokinetic characterization of BMS-936561, an anti-CD70 antibody-drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans
Biopharmaceutics & Drug Disposition
37 :93
Wang H, Rangan VS, Sung MC, Passmore D, Kempe T, Wang X, Thevanayagam L, Pan C, Rao C, Srinivasan M, Zhang Q, Gangwar S, Deshpande S, Cardarelli P, Marathe P, Yang Z (2016)
Biopharmaceutics & Drug Disposition
37 :93