Purpose: To investigate the mechanisms of clearance of AMG 386, an investigational recombinant peptide-Fc fusion protein (peptibody) that blocks tumor angiogenesis by neutralizing the interaction between angiopoietin-1 and -2 and the Tie2 receptor.
Methods: The role of the neonatal Fc receptor (FcRn) in AMG 386 clearance was assessed in wild-type and FcRn-knockout mice; the roles of the spleen and kidneys were assessed in splenectomized and 5/6th nephrectomized rats, respectively, compared with sham-operated rats. Animals were administered AMG 386 as a single intravenous dose of 3 or 10 mg/kg. Blood samples for pharmacokinetic analysis were collected periodically throughout a 504-hour postdose period.
Results: Compared with wild-type mice, AMG 386 clearance in FcRn-knockout mice was 18-fold faster at the 3-mg/kg dose (FcRn knockout, 13.2 mL/h/kg; wild-type, 0.728 mL/h/kg) and 14-fold faster at the 10-mg/kg dose (FcRn knockout, 10.7 mL/h/kg; wild-type, 0.777 mL/h/kg). Clearance in nephrectomized rats was slower than in sham-operated rats at both the 3-mg/kg dose (nephrectomized, 1.23 mL/h/kg; sham-operated, 1.75 mL/h/kg) and the 10-mg/kg dose (nephrectomized, 1.14 mL/h/kg; sham-operated, 1.65 mL/h/kg). Splenectomy had no apparent effect on the pharmacokinetics of AMG 386.
Conclusions: The FcRn is integral to maintaining circulating levels of AMG 386 in mice. Renal clearance contributed approximately 30% to total AMG 386 clearance in rats.