Complex Pharmacokinetics of a Humanized Antibody Against Human Amyloid Beta Peptide, Anti-Abeta Ab2, in Nonclinical Species

ABSTRACT Purpose 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 (