Complex Pharmacokinetics of a Humanized Antibody Against Human Amyloid Beta Peptide, Anti-Abeta Ab2, in Nonclinical Species
- 518 Downloads
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.
In vivo PK profile of Ab2 in preclinical species and in vitro mechanistic studies in preclinical and human systems were used for pharmacokinetic predictions.
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 t1/2 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.
These data predict that elimination of Ab2 in healthy or AD humans is expected to be slow, with t1/2 similar to that observed for other humanized antibodies.
KEY WORDSAlzheimer’s disease anti-Abeta antibody fibrinogen human PK prediction pharmacokinetics
All authors are current or former employees of Pfizer, Inc. We thank JANSSEN Alzheimer Immunotherapy (South San Francisco, CA) for their contribution to this study. We also thank Mike Agostino and Michelle Mader for help with sequence alignment, Chris Shea and Nicole Duriga for help with bionalytical assays, and Andrew Hill and Ioannis Moutsatsos for help with protein bioinformatics.
- 5.Wilcockand DM, Colton CA. Anti-amyloid-beta immunotherapy in Alzheimer’s disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers Dis. 2008;15:555–69.Google Scholar
- 16.Vugmeyster Y, DeFranco D, Szklut P, Wang Q, Xu X. Biodistribution of [125I]-labeled therapeutic proteins: application in protein drug development beyond oncology. J Pharm Sci. 99:1028–45.Google Scholar
- 20.Davis CB, Garver EM, Kwok DC, Urbanski JJ. Disposition of metabolically radiolabeled CE9.1–a macaque-human chimeric anti-human CD4 monoclonal antibody–in transgenic mice bearing human CD4. Drug metabolism and disposition: the biological fate of chemicals. 1996;24:1032–7.Google Scholar
- 28.Bonfanti U, Lamparelli D, Colombo P, Bernardi C. Hematology and serum chemistry parameters in juvenile cynomolgus monkeys (Macaca fascicularis) of Mauritius origin: comparison between purpose-bred and captured animals. J Med Primatol. 2009.Google Scholar
- 31.Cortes-Canteli M, Paul J, Norris EH, Bronstein R, Ahn HJ, Zamolodchikov D et al. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer’s disease. Neuron. 66:695–709.Google Scholar