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Research ArticleArticle

Effects of PEGylation and Immune Complex Formation on the Pharmacokinetics and Biodistribution of Recombinant Interleukin 10 in Mice

Hamsell M. Alvarez, On-Yee So, SuChun Hsieh, Natasha Shinsky-Bjorde, Huiping Ma, Yaoli Song, Yinuo Pang, Melinda Marian and Enrique Escandón
Drug Metabolism and Disposition February 2012, 40 (2) 360-373; DOI: https://doi.org/10.1124/dmd.111.042531
Hamsell M. Alvarez
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On-Yee So
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SuChun Hsieh
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Natasha Shinsky-Bjorde
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Huiping Ma
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Yaoli Song
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Yinuo Pang
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Melinda Marian
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Enrique Escandón
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Abstract

Interleukin 10 (IL-10) is a potent cytokine homodimer with multiple immunoregulatory functions. Here, we have characterized the effects of PEGylation and formation of human IL-10 (hIL-10)/humanized anti-human IL-10 (hαhIL-10) immune complexes in the pharmacokinetics, biodistribution, and biotransformation of IL-10 in mice. To assess the fate of native, PEGylated, and antibody-bound IL-10; we implemented an analytical set of fluorescence emission-linked assays. Plasma size exclusion chromatography analysis indicated that fluoro-labeled native and PEGylated murine IL-10 (PEG-mIL-10) are stable in the circulation. PEGylation of IL-10 resulted in a 21-fold increased exposure, 2.7-fold increase in half-life, and 20-fold reduction in clearance. Kidney is the major organ of disposition for both native and PEGylated mIL-10 with renal uptake directly related to systemic clearance. The fluorescence signal in the kidneys reached tissue/blood ratios up to 150 and 20 for native and PEG-mIL-10, respectively. hIL-10/hαhIL-10 immune complexes are detectable in the circulation without evidence of unbound or degraded hIL-10. The exposure of hIL-10 present in immune complexes versus that of hIL-10 alone increased from 0.53 to 11.28 μg · day/ml, with a half-life of 1.16 days and a 23-fold reduction in clearance. Unlike hIL-10 alone, antibody-bound hIL-10 was targeted mainly to the liver with minimal renal distribution. In addition, we found an 11-fold reduction (from 9.9 to 113 nM) in binding to the neonatal Fc receptor (FcRn) when the hαhIL10 antibody is conjugated to hIL-10. The potential changes in FcRn binding in vivo and increased liver uptake may explain the unique pharmacokinetic properties of hIL-10/hαhIL-10 immune complexes.

Footnotes

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

    doi:http://dx.doi.org/10.1124/dmd.111.042531.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    IL-10
    interleukin 10
    IL-10R
    IL-10 receptor
    mIL-10
    native murine IL-10
    PEG-mIL-10
    PEGylated murine IL-10
    hIL-10
    humanized IL-10
    hαhIL-10
    humanized anti-human IL-10 12G8 monoclonal antibody
    DOL
    degree of labeling
    SEC
    size exclusion chromatography
    HPLC
    high-performance liquid chromatography
    ELISA
    enzyme-linked immunosorbent assay
    PBS
    phosphate-buffered saline buffer
    FcRn
    neonatal Fc receptor
    mFcRn
    murine FcRn
    GST
    glutathione transferase
    mαmIL-10
    mouse anti-mouse IL-10 11D8 monoclonal antibody
    PK
    pharmacokinetic
    FELA
    fluorescence-emission-linked assay
    CT
    computer tomography
    PAGE
    polyacrylamide gel electrophoresis
    bis-Tris
    2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol
    HMW
    high molecular weight
    VEGF
    vascular endothelial growth factor
    TNF-α
    tumor necrosis factor-α.

  • Received August 26, 2011.
  • Accepted November 14, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (2)
Drug Metabolism and Disposition
Vol. 40, Issue 2
1 Feb 2012
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Research ArticleArticle

EFFECTS OF PEG VERSUS ANTIBODY BINDING ON IL-10 DISPOSITION

Hamsell M. Alvarez, On-Yee So, SuChun Hsieh, Natasha Shinsky-Bjorde, Huiping Ma, Yaoli Song, Yinuo Pang, Melinda Marian and Enrique Escandón
Drug Metabolism and Disposition February 1, 2012, 40 (2) 360-373; DOI: https://doi.org/10.1124/dmd.111.042531

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Research ArticleArticle

EFFECTS OF PEG VERSUS ANTIBODY BINDING ON IL-10 DISPOSITION

Hamsell M. Alvarez, On-Yee So, SuChun Hsieh, Natasha Shinsky-Bjorde, Huiping Ma, Yaoli Song, Yinuo Pang, Melinda Marian and Enrique Escandón
Drug Metabolism and Disposition February 1, 2012, 40 (2) 360-373; DOI: https://doi.org/10.1124/dmd.111.042531
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