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
| Autor: | Marc W. Retter, Mark Leo Michaels, Derek E. Piper, Katherine C Matsuda, Lei Zhou, Chadwick T. King, Wei Wang, Higbee Jared Martin, Jeonghoon Sun, Howard Monique L, Simon Jackson, Ren Xu, Randal R. Ketchem, Brandon Ason, Jie Tang, Kirk Henne, Joyce Chi Yee Chan |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Receptor complex medicine.drug_class Plasma protein binding Receptors Fc Pharmacology Monoclonal antibody Neonatal Fc receptor Antigen medicine Animals Humans Receptor Mice Knockout biology Chemistry PCSK9 Serine Endopeptidases Antibodies Monoclonal Cholesterol LDL Hydrogen-Ion Concentration Macaca mulatta Immunoglobulin Fc Fragments Mice Inbred C57BL biology.protein Molecular Medicine Proprotein Convertases Antibody Proprotein Convertase 9 Protein Binding |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 353(1) |
| ISSN: | 1521-0103 |
| Popis: | 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 ( |
| Databáze: | OpenAIRE |
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