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.

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 (<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.

• Authors: Kirk R Henne, Brandon Ason, Monique Howard, Wei Wang, Jeonghoon Sun, Jared Higbee, Jie Tang, Katherine C Matsuda, Ren Xu, Lei Zhou, Joyce C Y Chan, Chadwick King, Derek E Piper, Randal R Ketchem, Mark Leo Michaels, Simon M Jackson, Marc W Retter
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 353 Issue 1 Pg. 119-31 (Apr 2015) ISSN: 1521-0103 [Electronic] United States
• PMID: 25653417 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antibodies, Monoclonal
• Cholesterol, LDL
• Immunoglobulin Fc Fragments
• Receptors, Fc
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases

Topics

• Animals
• Antibodies, Monoclonal (genetics, metabolism, pharmacokinetics, pharmacology)
• Cholesterol, LDL (blood)
• Humans
• Hydrogen-Ion Concentration
• Immunoglobulin Fc Fragments (genetics)
• Macaca mulatta
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Proprotein Convertase 9
• Proprotein Convertases (genetics, immunology, metabolism)
• Protein Binding
• Receptors, Fc (metabolism)
• Serine Endopeptidases (genetics, immunology, metabolism)