title: Pharmacokinetic characterization of BMS-936561, an anti-CD70 antibody-drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans.
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 (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 5(th)-95(th) percentile of the predicted profiles.
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ, United States.
authors: Haiqing
authors: H
authors: Wang
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Vangipuram S
authors: VS
authors: Rangan
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Mei-Chen
authors: MC
authors: Sung
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: David
authors: D
authors: Passmore
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Thomas
authors: T
authors: Kempe
authors: Clinical Pharmacology, Bristol-Myers Squibb, Princeton, NJ, United States.
authors: Xiaoli
authors: X
authors: Wang
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Lourdes
authors: L
authors: Thevanayagam
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Chin
authors: C
authors: Pan
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Chetana
authors: C
authors: Rao
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Mohan
authors: M
authors: Srinivasan
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Qian
authors: Q
authors: Zhang
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Sanjeev
authors: S
authors: Gangwar
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Shrikant
authors: S
authors: Deshpande
authors: Biologics Discovery California, Bristol-Myers Squibb, Redwood City, CA, United States.
authors: Pina
authors: P
authors: Cardarelli
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ, United States.
authors: Punit
authors: P
authors: Marathe
authors: Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ, United States.
authors: Zheng
authors: Z
authors: Yang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics*; D053282:CD27 Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology; D004285:Dogs; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000493:pharmacokinetics*; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D011355:Prodrugs / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D053282:CD27 Ligand; D018796:Immunoconjugates; D007211:Indoles; C585822:MDX-1203; D011355:Prodrugs
keywords: BMS-936561; antibody-drug conjugate; carboxylesterase; pharmacokinetics; αCD70_MED-A