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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
- Source :
- The Journal of pharmacology and experimental therapeutics. 353(1)
- Publication Year :
- 2015
-
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 (
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15210103
- Volume :
- 353
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....a6f51d0f83b17b3574d22d7dc84b3f51