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Research ArticleArticle

Pharmacokinetics of Humanized Monoclonal Anti-Tumor Necrosis Factor-α Antibody and Its Neonatal Fc Receptor Variants in Mice and Cynomolgus Monkeys

Rong Deng, Kelly M. Loyet, Samantha Lien, Suhasini Iyer, Laura E. DeForge, Frank-Peter Theil, Henry B. Lowman, Paul J. Fielder and Saileta Prabhu
Drug Metabolism and Disposition April 2010, 38 (4) 600-605; DOI: https://doi.org/10.1124/dmd.109.031310
Rong Deng
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Kelly M. Loyet
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Samantha Lien
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Suhasini Iyer
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Laura E. DeForge
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Frank-Peter Theil
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Henry B. Lowman
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Paul J. Fielder
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Saileta Prabhu
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Abstract

The neonatal Fc receptor (FcRn) plays a critical role in maintaining homeostasis of IgG antibodies. Recent studies have shown that the FcRn-IgG interaction can be modulated to alter the pharmacokinetics of the antibody. This has been achieved by altering amino acid residues in the FcRn-binding domain of the antibody, resulting in a change in the pH-dependent binding affinity of the antibody to FcRn. The purpose of this study was to examine the impact of the pH-dependent FcRn binding affinity on the pharmacokinetics of the antibody with changes in the Asn434 residue. Two anti-tumor necrosis factor-α monoclonal antibody (mAb) FcRn variants (N434A and N434H) were engineered, and pharmacokinetic studies of the two FcRn variants together with the wild type (WT) were conducted in mice and cynomolgus monkeys. N434A, which had binding properties to murine FcRn similar to those of the WT, had the same pharmacokinetic profile as the WT in mice. N434H, with the highest binding affinity to murine FcRn at pH 7.4, had a faster clearance (16.1 ml/day/kg) and a lower bioavailability (61.3%) compared with the WT (5.07 ml/day/kg, 73.2%) and N434A (5.90 ml/day/kg, 72.4%) in mice. N434A and N434H, which had higher binding affinity at pH 6.0 to monkey FcRn with comparable affinity at pH 7.4, had significantly higher areas under the serum concentration-time curve from time 0 to day 7 than the WT (749 ± 71.9 and 819 ± 81.5 versus 592 ± 56.8 μg/ml · day) in monkeys. Thus, increasing the binding affinity of mAbs to FcRn at pH 6.0 while keeping a low binding affinity at pH 7.4 improves the pharmacokinetics of these molecules.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.031310.

  • ABBREVIATIONS:

    FcRn
    neonatal Fc receptor
    β2m
    β2-macroglobulin
    WT
    wild type
    mAb
    monoclonal antibody
    TNF
    tumor necrosis factor
    SCID
    severe combined immunodeficiency
    PK
    pharmacokinetic(s)
    ATA
    anti-therapeutic antibody
    AUC
    area under the serum concentration-time curve
    CL
    clearance
    mFcRn
    murine FcRn
    cFcRn
    cynomolgus monkey FcRn
    hFcRn
    human FcRn.

    • Received November 23, 2009.
    • Accepted January 13, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (4)
Drug Metabolism and Disposition
Vol. 38, Issue 4
1 Apr 2010
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Research ArticleArticle

Pharmacokinetics of Humanized Monoclonal Anti-Tumor Necrosis Factor-α Antibody and Its Neonatal Fc Receptor Variants in Mice and Cynomolgus Monkeys

Rong Deng, Kelly M. Loyet, Samantha Lien, Suhasini Iyer, Laura E. DeForge, Frank-Peter Theil, Henry B. Lowman, Paul J. Fielder and Saileta Prabhu
Drug Metabolism and Disposition April 1, 2010, 38 (4) 600-605; DOI: https://doi.org/10.1124/dmd.109.031310

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Research ArticleArticle

Pharmacokinetics of Humanized Monoclonal Anti-Tumor Necrosis Factor-α Antibody and Its Neonatal Fc Receptor Variants in Mice and Cynomolgus Monkeys

Rong Deng, Kelly M. Loyet, Samantha Lien, Suhasini Iyer, Laura E. DeForge, Frank-Peter Theil, Henry B. Lowman, Paul J. Fielder and Saileta Prabhu
Drug Metabolism and Disposition April 1, 2010, 38 (4) 600-605; DOI: https://doi.org/10.1124/dmd.109.031310
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