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Research ArticleArticle

Use of Cryopreserved Hepatocytes as Part of an Integrated Strategy to Characterize In Vivo Clearance for Peptide-Antibody Conjugate Inhibitors of Nav1.7 in Preclinical Species

Robert S. Foti, Kaustav Biswas, Jennifer Aral, Xuhai Be, Loren Berry, Yuan Cheng, Kip Conner, James R. Falsey, Charles Glaus, Brad Herberich, Dean Hickman, Tayo Ikotun, Hongyan Li, Jason Long, Liyue Huang, Les P. Miranda, Justin Murray, Bryan Moyer, Chawita Netirojjanakul, Thomas E. Nixey, Kelvin Sham, Marcus Soto, Christopher M. Tegley, Linh Tran, Bin Wu, Lin Yin and Dan A. Rock
Drug Metabolism and Disposition October 2019, 47 (10) 1111-1121; DOI: https://doi.org/10.1124/dmd.119.087742
Robert S. Foti
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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  • For correspondence: rfoti@amgen.com
Kaustav Biswas
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Jennifer Aral
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Xuhai Be
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Loren Berry
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Yuan Cheng
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Kip Conner
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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James R. Falsey
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Charles Glaus
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Brad Herberich
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Dean Hickman
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Tayo Ikotun
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Hongyan Li
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Jason Long
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Liyue Huang
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Les P. Miranda
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Justin Murray
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Bryan Moyer
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Chawita Netirojjanakul
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Thomas E. Nixey
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Kelvin Sham
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Marcus Soto
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Christopher M. Tegley
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Linh Tran
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Bin Wu
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Lin Yin
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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Dan A. Rock
Pharmacokinetics and Drug Metabolism, Amgen Research, Cambridge, Massachusetts (R.S.F., X.B., L.B., D.H., L.H.); Therapeutic Discovery (K.B., J.A., Y.C., J.R.F., C.G., B.H., T.I., J.L., L.P.M., J.M., C.N., T.E.N., K.S., C.M.T., B.W., L.Y.), Neuroscience (B.M.), and Pharmacokinetics and Drug Metabolism (H.L., M.S., L.T.), Amgen Research, Thousand Oaks, California; and Pharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, California (K.C., D.A.R.)
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  • For correspondence: drock@amgen.com
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  • Fig. 1.
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    Fig. 1.

    Effect of charge (A) and hydrophobicity (B) on Nav1.7 peptide-antibody conjugate pharmacokinetics. A reduction in clearance was observed for peptide-antibody conjugates with a peptide charge of +1 or +2 as compared with a peptide charge of +6, whereas a Pearson correlation (r = 0.8005) was observed between the HIC retention time and in vivo clearance. Mouse data are denoted with closed circles, whereas cynomolgus monkey data are denoted by open circles.

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    Fig. 2.

    64Cu-NOTA–labeled imaging studies of the unconjugated antibody (aDNP) and three peptide-antibody conjugates. At 3 hours postdose, aDNP and a representative symmetrical divalent conjugate (P2S-aDNP) were confined primarily to the central compartment, while the asymmetric divalent conjugate (P2A-aDNP) and a tetravalent peptide-antibody conjugate (P4S-aDNP) distributed rapidly to the liver. B, bladder; H, heart; %ID/g, percent injected dose per gram; L, liver.

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    Fig. 3.

    Percentage of peptide-antibody conjugates remaining in the medium after 2.5 hours in plated mouse hepatocyte assays versus in vivo clearance from intravenous pharmacokinetic studies (A) or HIC retention time (B). Peptide conjugates exhibiting extensive association with hepatocytes (lower percentage remaining in media) demonstrated higher in vivo clearance values than those with decreased association (higher percentage remaining in media; Pearson r = −0.5525). A correlation was also observed between HIC retention time and percentage remaining in the hepatocyte media (Pearson r = −0.7185). Mouse data are denoted with closed circles, whereas cynomolgus monkey data are denoted by open circles.

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    Fig. 4.

    Observed correlation between FcRn binding affinity of peptide conjugates at pH 7.4 or 5.5 (RUs) and in vivo clearance (A and B), HIC retention time (C and D), or percentage remaining in hepatocyte media (E and F). Peptide conjugates with high affinity for FcRn tended to exhibit higher in vivo clearances, HIC retention times, and depletion rates from hepatocyte media (Pearson r values noted in Table 3). Mouse data are denoted with closed circles, whereas cynomolgus monkey data are denoted by open circles.

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    Fig. 5.

    Depletion of unconjugated antibody (aDNP) or conjugate 4 from media of plated mouse hepatocyte assays. aDNP demonstrated limited uptake into mouse hepatocytes, whereas greater than 60% of conjugate 4 was removed from the media over 2.5 hours. Uptake of conjugate 4 into mouse hepatocytes was attenuated in FcRn knockout hepatocytes or by the addition of acetylated LDL (acLDL; Stab/Scarb1) or ovalbumin (mannose/galactose receptors) to wild-type hepatocytes.

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    Fig. 6.

    IC50 determination for the inhibition of conjugate 4 association with mouse hepatocytes by acetylated LDL (acLDL; Stab/Scarb1 receptor) or ovalbumin (mannose/galactose receptors). Addition of acetylated LDL to wild-type mouse hepatocytes resulted in complete inhibition of conjugate 4 uptake (IC50 = 0.024 mg/ml), whereas addition of ovalbumin reached a maximum inhibition of 64% of control uptake (IC50 = 1.91 mg/ml).

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    Fig. 7.

    In vivo pharmacokinetics of aDNP and conjugate 4 in wild-type (WT), FcRn knockout , LDL receptor (LDLr) knockout, mannose receptor knockout, or ASGR1 knockout mouse models following 2-mg/kg intravenous administration. Both aDNP and conjugate 4 exhibited higher in vivo clearance values in FcRn knockout mice as opposed to wild-type controls. Conjugate 4 also exhibited higher in vivo clearance values in mannose receptor knockout mice. No difference was observed between wild-type and LDL receptor or ASGR1 knockout mice.

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    TABLE 1

    List of peptide conjugates

    ConjugateAb CoreLinkeraPeptidePeptide ChargeIn Vivo ClearanceAUCintact/AUCtotalPercentage Remaining in Hep MediaFcRn at pH 7.4FcRn at pH 5.5HIC Retention Time
    l/h/kgmin
    aDNPaDNP D88CN/AN/AN/A0.0006N/A9321.50.83.90
    1aDNP D88CPEG11AM-042260.02050.157.7
    2aDNP E384CbisPEG23AM-042260.079ND38
    3aDNP D88CCPEG11AM-612220.001750.337492.525.1
    4aDNP D88CGGSAM-275220.00440.4247.814730.95.18
    5aDNP E384CGGSAM-275220.00320.768847.7239.25.69
    6aDNP D88CGGSAM-545410.00620.51765.43
    7aDNP D88CGGSAM-575910.00240.2774.95.45
    8aDNP D88CGGSAM-545810.00450.6174.85.42
    9aDNP-3A4-F D88CGGSAM-691810.00370.3672.65.61
    10aDNP-3A4-F D88CGGSAM-626210.00830.2639228.13376.46
    113B1HC-3A4LC D88CGGSAM-275220.00330.4463.879.793.75.71
    123B1HC-3A4LC D88CGGSAM-275220.00130.473.473.134.64.92
    13aDNP-3A4-F D88CGGSAM-896010.00130.2475.65.43
    14aDNP-3A4-F D88CPEG11AM-824810.01180.2837.66.65
    • Ab, antibody; bisPEG23, bis-23-unit polyethylene glycol; GGS, glycine-glycine-serine; Hep, %ID/g, percent injected dose per gram; N/A, not applicable; ND, data not collected; PEG11, 11-unit polyethylene glycol.

    • View popup
    TABLE 2

    In vivo pharmacokinetic parameters following 2-mg/kg intravenous administration of aDNP or conjugate 4 to wild-type mice and receptor knockout mouse models

    Mouse StrainT1/2AUC0–168ClVssAUCKO/AUCWTClKO/ClWT
    hμM *hl/h/kgl/kg
    aDNP
     WT19111.40.00060.150——
     FcRn KO4.981.360.00920.0630.1215.3
     LDL KO1838.450.00070.1990.741.16
     MR KO24012.30.00050.1501.080.83
     ASGR1 KO33314.20.00090.1421.241.50
    Conjugate 4 (total)
     WT1642.790.00270.544——
     FcRn KO1.190.0960.1330.2370.0349.3
     LDL KO1184.670.00280.3761.671.04
     MR KO1041.550.00590.7590.562.18
     ASGR1 KO1973.570.00360.4561.281.33
    Conjugate 4 (intact)
     WT26.30.9430.01310.277——
     FcRn KO1.270.1490.08920.1640.166.81
     LDL KO38.41.300.01030.2861.380.79
     MR KO24.71.120.01170.4181.190.89
     ASGR1 KO19.91.320.00920.1741.390.70
    • Cl, clearance; KO, knockout; MR, mannose receptor; WT, wild-type.

    • View popup
    TABLE 3

    Summary of Pearson correlation results for in vivo clearance (Cl), percentage remaining in hepatocyte media, HIC retention time, and FcRn binding at pH 7.4 or 5.5

    x-Axis Datay-Axis DataPearson rNP ValueSignificant
    HIC RTIn vivo Cl0.8005120.0018Yes
    Percentage remaining in mediaIn vivo Cl−0.5525150.0327Yes
    HIC RTPercent remaining in media−0.7185150.0085Yes
    FcRn (pH 7.4)In vivo Cl0.910770.0044Yes
    FcRn (pH 5.5)In vivo Cl0.808870.0276Yes
    FcRn (pH 7.4)HIC RT0.714460.1129No
    FcRn (pH 5.5)HIC RT0.844960.0342Yes
    FcRn (pH 7.4)Percent remaining in media−0.945570.0013Yes
    FcRn (pH 5.5)Percent remaining in media−0.390270.3868No
    • RT, retention time.

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Table -

      Surrogate Peptide Sequences and MRM Ion Transitions

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Drug Metabolism and Disposition: 47 (10)
Drug Metabolism and Disposition
Vol. 47, Issue 10
1 Oct 2019
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Use of Cryopreserved Hepatocytes as Part of an Integrated Strategy to Characterize In Vivo Clearance for Peptide-Antibody Conjugate Inhibitors of Nav1.7 in Preclinical Species
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Research ArticleArticle

PK Characterization of Nav1.7 Peptide-Antibody Conjugates

Robert S. Foti, Kaustav Biswas, Jennifer Aral, Xuhai Be, Loren Berry, Yuan Cheng, Kip Conner, James R. Falsey, Charles Glaus, Brad Herberich, Dean Hickman, Tayo Ikotun, Hongyan Li, Jason Long, Liyue Huang, Les P. Miranda, Justin Murray, Bryan Moyer, Chawita Netirojjanakul, Thomas E. Nixey, Kelvin Sham, Marcus Soto, Christopher M. Tegley, Linh Tran, Bin Wu, Lin Yin and Dan A. Rock
Drug Metabolism and Disposition October 1, 2019, 47 (10) 1111-1121; DOI: https://doi.org/10.1124/dmd.119.087742

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Research ArticleArticle

PK Characterization of Nav1.7 Peptide-Antibody Conjugates

Robert S. Foti, Kaustav Biswas, Jennifer Aral, Xuhai Be, Loren Berry, Yuan Cheng, Kip Conner, James R. Falsey, Charles Glaus, Brad Herberich, Dean Hickman, Tayo Ikotun, Hongyan Li, Jason Long, Liyue Huang, Les P. Miranda, Justin Murray, Bryan Moyer, Chawita Netirojjanakul, Thomas E. Nixey, Kelvin Sham, Marcus Soto, Christopher M. Tegley, Linh Tran, Bin Wu, Lin Yin and Dan A. Rock
Drug Metabolism and Disposition October 1, 2019, 47 (10) 1111-1121; DOI: https://doi.org/10.1124/dmd.119.087742
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