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Research ArticleArticle

Antigen-Dependent Internalization Is Related to Rapid Elimination from Plasma of Humanized Anti-HM1.24 Monoclonal Antibody

Jun Amano, Naoko Masuyama, Yuko Hirota, Yoshitaka Tanaka, Yuriko Igawa, Rie Shiokawa, Taichi Okutani, Takashi Miyayama, Masahiko Nanami and Masaki Ishigai
Drug Metabolism and Disposition December 2010, 38 (12) 2339-2346; DOI: https://doi.org/10.1124/dmd.110.035709
Jun Amano
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Naoko Masuyama
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Yuko Hirota
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Yoshitaka Tanaka
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Yuriko Igawa
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Rie Shiokawa
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Taichi Okutani
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Takashi Miyayama
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Masahiko Nanami
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Masaki Ishigai
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Abstract

Anti-HM1.24 monoclonal antibody (AHM) is a humanized anti-HM1.24 monoclonal antibody that binds to the HM1.24 antigen, a protein that is highly expressed in multiple myeloma cells. The pharmacokinetics of AHM was determined in experiments in which AHM was administered intravenously to cynomolgus monkeys. The area under the plasma concentration-time curve increased by more than the dose ratio between 2 and 20 mg/kg, and nonlinear pharmacokinetics was observed. The elimination half-life of AHM from the plasma was 7.56 h at 2 mg/kg and 28.6 h at 20 mg/kg, which was shorter than that observed for other therapeutic humanized monoclonal antibodies, such as trastuzumab and bevacizumab. Although antibodies to AHM were detected in all monkeys on or after 10 days of administration, there was a temporal disassociation between the rapid elimination of AHM and the appearance of anti-AHM antibodies. HM1.24 antigen-dependent internalization and intracellular metabolism of AHM were investigated in peripheral blood mononuclear, KPMM2, and U937 cells. In all cases, AHM was rapidly internalized from the cell surface; this internalization was significantly prevented by phenylarsine oxide in KPMM2 cells, an inhibitor of receptor-mediated endocytosis, and the internalized AHM was subsequently degraded within the cells. Furthermore, immunofluorescence microscopy revealed that the internalized AHM is delivered to and degraded in late endosomes/lysosomes. Taken together, our results suggest that the rapid elimination of AHM from plasma in monkey is due to HM1.24 antigen-dependent internalization followed by delivery to the lysosomes.

Footnotes

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

    doi:10.1124/dmd.110.035709.

  • ABBREVIATIONS:

    MM
    multiple myeloma
    PBMC
    peripheral blood mononuclear cell
    TGN
    trans-Golgi network
    AHM
    humanized anti-HM1.24 monoclonal antibody
    CHO
    Chinese hamster ovary
    FBS
    fetal bovine serum
    PAO
    phenylarsine oxide (arsorosobenzene)
    EEA1
    early endosome antigen 1
    LAMP-1
    lysosomal-associated membrane protein 1
    TfnR
    transferrin receptor
    ELISA
    enzyme-linked immunosorbent assay
    TCA
    trichloroacetic acid
    AUC
    area under the plasma concentration-time curve
    MRT
    mean retention time
    PBS
    phosphate-buffered saline
    FcRN
    neonatal Fc receptor.

  • Received July 28, 2010.
  • Accepted September 7, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Antigen-Dependent Internalization Is Related to Rapid Elimination from Plasma of Humanized Anti-HM1.24 Monoclonal Antibody

Jun Amano, Naoko Masuyama, Yuko Hirota, Yoshitaka Tanaka, Yuriko Igawa, Rie Shiokawa, Taichi Okutani, Takashi Miyayama, Masahiko Nanami and Masaki Ishigai
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2339-2346; DOI: https://doi.org/10.1124/dmd.110.035709

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Research ArticleArticle

Antigen-Dependent Internalization Is Related to Rapid Elimination from Plasma of Humanized Anti-HM1.24 Monoclonal Antibody

Jun Amano, Naoko Masuyama, Yuko Hirota, Yoshitaka Tanaka, Yuriko Igawa, Rie Shiokawa, Taichi Okutani, Takashi Miyayama, Masahiko Nanami and Masaki Ishigai
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2339-2346; DOI: https://doi.org/10.1124/dmd.110.035709
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