Publication in detail

J Pharmacol Exp Ther. 2015 Apr;353(1):119-31. doi: 10.1124/jpet.114.221242. Epub 2015 Feb 4.

Anti-PCSK9 Antibody Pharmacokinetics and Low-Density Lipoprotein-Cholesterol Pharmacodynamics in Nonhuman Primates Are Antigen Affinity-Dependent and Exhibit Limited Sensitivity to Neonatal Fc Receptor-Binding Enhancement.

Henne, KR; Ason, B; Howard, M; Wang, W; Sun, J; Higbee, J; Tang, J; Matsuda, KC; Xu, R; Zhou, L; Chan, JC; King, C; Piper, DE; Ketchem, RR; Michaels, ML; Jackson, SM; Retter, MW

Amgen, South San Francisco, California, USA.

Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive therapeutic target for cardiovascular disease. Monoclonal antibodies (mAbs) that bind PCSK9 and prevent PCSK9:low-density lipoprotein receptor complex formation reduce serum low-density lipoprotein-cholesterol (LDL-C) in vivo. PCSK9-mediated lysosomal degradation of bound mAb, however, dramatically reduces mAb exposure and limits duration of effect. Administration of high-affinity mAb1:PCSK9 complex (1:2) to mice resulted in significantly lower mAb1 exposure compared with mAb1 dosed alone in normal mice or in PCSK9 knockout mice lacking antigen. To identify mAb-binding characteristics that minimize lysosomal disposition, the pharmacokinetic behavior of four mAbs representing a diverse range of PCSK9-binding affinities at neutral (serum) and acidic (endosomal) pH was evaluated in cynomolgus monkeys. Results revealed an inverse correlation between affinity and both mAb exposure and duration of LDL-C lowering. High-affinity mAb1 exhibited the lowest exposure and shortest duration of action (6 days), whereas mAb2 displayed prolonged exposure and LDL-C reduction (51 days) as a consequence of lower affinity and pH-sensitive PCSK9 binding. mAbs with shorter endosomal PCSK9:mAb complex dissociation half-lives (

ยป Online Version

Proven Track Record

The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 350 scientific publications are based on research using Ozgene mice.

Go to Publications

Global Client Base

Ozgene generates genetically customised mice for researchers around the world. Ozgene mice can be found in 31 different countries on 5 continents from small academic institutions to multinational pharmaceutical companies.

See Map

Lean Management

Ozgene is applying Lean Management principles to deliver the highest quality services and shortest lead times to our customers. The implementation of Lean Culture has already seen an improvement in our processes and timelines.

Read More