PT  - JOURNAL ARTICLE
AU  - Henne, Kirk R.
AU  - Ason, Brandon
AU  - Howard, Monique
AU  - Wang, Wei
AU  - Sun, Jeonghoon
AU  - Higbee, Jared
AU  - Tang, Jie
AU  - Matsuda, Katherine C.
AU  - Xu, Ren
AU  - Zhou, Lei
AU  - Chan, Joyce C. Y.
AU  - King, Chadwick
AU  - Piper, Derek E.
AU  - Ketchem, Randal R.
AU  - Michaels, Mark Leo
AU  - Jackson, Simon M.
AU  - Retter, Marc W.
TI  - 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
AID  - 10.1124/jpet.114.221242
DP  - 2015 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 119--131
VI  - 353
IP  - 1
4099  - http://jpet.aspetjournals.org/content/353/1/119.short
4100  - http://jpet.aspetjournals.org/content/353/1/119.full
SO  - J Pharmacol Exp Ther2015 Apr 01; 353
AB  - 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 (<20 seconds) produced optimal exposure-response profiles. Interestingly, incorporation of previously reported Fc-region amino acid substitutions or novel loop-insertion peptides that enhance in vitro neonatal Fc receptor binding, led to only modest pharmacokinetic improvements for mAbs with pH-dependent PCSK9 binding, with only limited augmentation of pharmacodynamic activity relative to native mAbs. A pivotal role for PCSK9 in mAb clearance was demonstrated, more broadly suggesting that therapeutic mAb-binding characteristics require optimization based on target pharmacology.