title: Investigation of the mechanism of clearance of AMG 386, a selective angiopoietin-1/2 neutralizing peptibody, in splenectomized, nephrectomized, and FcRn knockout rodent models.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., One Amgen Center Drive, Mailstop 28-3-B, Thousand Oaks, California, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Marcus
authors.initials: M
authors.lastname: Soto
authors.forename: Manuel
authors.initials: M
authors.lastname: Ponce
authors.forename: Dominador
authors.initials: D
authors.lastname: Calamba
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
mesh_terms: D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D042787:Receptor, TIE-2; C100688:Fc receptor, neonatal; C551398:trebananib