title: 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: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California khenne@amgen.com.
authors: Kirk R
authors: KR
authors: Henne
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Brandon
authors: B
authors: Ason
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Monique
authors: M
authors: Howard
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Wei
authors: W
authors: Wang
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Jeonghoon
authors: J
authors: Sun
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Jared
authors: J
authors: Higbee
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Jie
authors: J
authors: Tang
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Katherine C
authors: KC
authors: Matsuda
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Ren
authors: R
authors: Xu
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Lei
authors: L
authors: Zhou
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Joyce C Y
authors: JC
authors: Chan
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Chadwick
authors: C
authors: King
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Derek E
authors: DE
authors: Piper
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Randal R
authors: RR
authors: Ketchem
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Mark Leo
authors: ML
authors: Michaels
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Simon M
authors: SM
authors: Jackson
authors: Departments of Pharmacokinetics and Drug Metabolism (K.R.H., K.C.M., M.W.R.), Metabolic Disorders (B.A., J.C.Y.C., S.M.J.), Therapeutic Discovery (M.H., W.W., J.S., J.H., J.T., C.K., D.E.P., R.R.K., M.L.M.), Molecular Sciences (R.X.), and Biostatistics (L.Z.), Amgen, South San Francisco, California.
authors: Marc W
authors: MW
authors: Retter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000097:blood*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D011961:Receptors, Fc / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D008078:Cholesterol, LDL; D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases