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Research ArticleDrug Discovery and Translational Medicine

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

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 and Marc W. Retter
Journal of Pharmacology and Experimental Therapeutics April 2015, 353 (1) 119-131; DOI: https://doi.org/10.1124/jpet.114.221242
Kirk R. Henne
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
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Brandon Ason
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
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Monique Howard
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
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Wei Wang
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
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Jeonghoon Sun
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
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Jared Higbee
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
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Jie Tang
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
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Katherine C. Matsuda
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
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Ren Xu
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
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Lei Zhou
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
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Joyce C. Y. Chan
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
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Chadwick King
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
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Derek E. Piper
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
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Randal R. Ketchem
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
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Mark Leo Michaels
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
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Simon M. Jackson
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
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Marc W. Retter
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
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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.

Footnotes

    • Received November 3, 2014.
    • Accepted February 3, 2015.
  • dx.doi.org/10.1124/jpet.114.221242.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 1
1 Apr 2015
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Research ArticleDrug Discovery and Translational Medicine

PCSK9- and FcRn-Binding Affinities Affect Antibody PK and PD

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 and Marc W. Retter
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 119-131; DOI: https://doi.org/10.1124/jpet.114.221242

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Research ArticleDrug Discovery and Translational Medicine

PCSK9- and FcRn-Binding Affinities Affect Antibody PK and PD

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 and Marc W. Retter
Journal of Pharmacology and Experimental Therapeutics April 1, 2015, 353 (1) 119-131; DOI: https://doi.org/10.1124/jpet.114.221242
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