title: Complex pharmacokinetics of a humanized antibody against human amyloid beta peptide, anti-abeta Ab2, in nonclinical species.
abstract: OBJECTIVE
  Anti-Aβ Ab2 (Ab2) is a humanized monoclonal antibody against amino acids 3-6 of primate (but not rodent) amyloid β (Aβ) and is being evaluated for the treatment of Alzheimer's disease (AD). This study was conducted to predict the human pharmacokinetics of Ab2.
  
  
  METHODS
  In vivo PK profile of Ab2 in preclinical species and in vitro mechanistic studies in preclinical and human systems were used for pharmacokinetic predictions.
  
  
  RESULTS
  In Tg2576 and PSAPP mice that have ~100-fold higher circulating levels of human Aβ compared to humans, elimination of Ab2 was target-mediated, such that exposure was 5-10 fold lower compared to wild-type rodents or to PDAPP mice that have human Aβ concentrations in plasma similar to humans. In cynomolgus monkeys, the t(1/2) of Ab2 was faster (<2.5 days) compared to that of the control antibody (~13 days). The fast elimination of Ab2 in cynomolgus monkeys was linked to off-target binding to cynomolgus monkey fibrinogen that was also causing incomplete recovery of Ab2 in cynomolgus monkey serum in blood partitioning experiments. Ab2 had significantly weaker to undetectable binding to human (and mouse) fibrinogen and had good recovery in human serum in blood partitioning experiments.
  
  
  CONCLUSIONS
  These data predict that elimination of Ab2 in healthy or AD humans is expected to be slow, with t(1/2) similar to that observed for other humanized antibodies.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Andover, Massachusetts 01810, USA. yulia.vugmeyster@pfizer.com
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Pam
authors.initials: P
authors.lastname: Szklut
authors.forename: David
authors.initials: D
authors.lastname: Wensel
authors.forename: John
authors.initials: J
authors.lastname: Ross
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Michel
authors.initials: M
authors.lastname: Awwad
authors.forename: Davinder
authors.initials: D
authors.lastname: Gill
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Tchistiakov
authors.forename: Garvin
authors.initials: G
authors.lastname: Warner
mesh_terms: D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D010446:Peptide Fragments