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Research ArticleArticle

Brain-Penetrating IgG-Iduronate 2-Sulfatase Fusion Protein for the Mouse

Qing-Hui Zhou, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui and William M. Pardridge
Drug Metabolism and Disposition February 2012, 40 (2) 329-335; DOI: https://doi.org/10.1124/dmd.111.042903
Qing-Hui Zhou
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Ruben J. Boado
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Jeff Zhiqiang Lu
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Eric Ka-Wai Hui
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William M. Pardridge
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Abstract

Mucopolysaccharidosis (MPS) type II (Hunter's syndrome) is caused by mutations in the iduronate 2-sulfatase (IDS) fusion protein. MPS-II affects the brain, and enzyme replacement therapy is not effective in the brain, because the enzyme does not cross the blood-brain barrier. To treat mouse models of MPS-II with brain-penetrating IDS, the lysosomal enzyme was reengineered as an IgG-IDS fusion protein. The mature human IDS was fused to the carboxyl terminus of both heavy chains of the chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and the fusion protein is designated cTfRMAb-IDS. The purity and identity of the fusion protein was confirmed by electrophoresis and Western blotting with antibodies to mouse IgG and human IDS. The EC50 of binding of the cTfRMAb-IDS fusion protein to the mouse TfR (0.85 ± 0.15 nM) was comparable to the EC50 of binding of the cTfRMAb (0.78 ± 0.05 nM). The IDS enzyme activity of the cTfRMAb-IDS fusion protein was 126 ± 1 nmol · h−1 · μg−1 protein. After intravenous injection in the mouse, the cTfRMAb-IDS fusion protein was rapidly removed from plasma and distributed to tissues, including brain and spinal cord. The uptake of the fusion protein by brain or spinal cord was 1.3 ± 0.1 and 2.2 ± 0.2% injected dose/g, respectively, which is 100-fold greater than the brain uptake of IDS alone. This work shows that a lysosomal sulfatase can be reengineered as an IgG-enzyme fusion protein that rapidly penetrates the brain after intravenous administration.

Footnotes

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

    doi:http://dx.doi.org/10.1124/dmd.111.042903.

  • ABBREVIATIONS:

    MPS
    mucopolysaccharidosis
    IDS
    iduronate 2-sulfatase
    BBB
    blood-brain barrier
    MAb
    monoclonal antibody
    HIR
    human insulin receptor
    HIRMAb
    engineered MAb against the HIR
    TfR
    transferrin receptor
    cTfRMAb
    chimeric MAb against the mouse TfR
    IDUA
    iduronidase
    SUMF1
    sulfatase modifying factor 1
    RT
    reverse transcription
    ODN
    oligodeoxynucleotide
    TV
    tandem vector
    LC
    light chain
    orf
    open reading frame
    PCR
    polymerase chain reaction
    CM
    conditioned medium
    ELISA
    enzyme-linked immunosorbent assay
    PAGE
    polyacrylamide gel electrophoresis
    CHO
    Chinese hamster ovary
    ECD
    extracellular domain
    DMEM
    Dulbecco's modified Eagle's medium
    TCA
    trichloroacetic acid
    VD
    volume of distribution
    ID
    injected dose
    AUC
    area under the curve
    PS
    permeability-surface area
    AA
    amino acid
    HC
    heavy chain.

  • Received September 19, 2011.
  • Accepted November 7, 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

BRAIN-PENETRATING IgG-IDS FUSION PROTEIN

Qing-Hui Zhou, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui and William M. Pardridge
Drug Metabolism and Disposition February 1, 2012, 40 (2) 329-335; DOI: https://doi.org/10.1124/dmd.111.042903

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Research ArticleArticle

BRAIN-PENETRATING IgG-IDS FUSION PROTEIN

Qing-Hui Zhou, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui and William M. Pardridge
Drug Metabolism and Disposition February 1, 2012, 40 (2) 329-335; DOI: https://doi.org/10.1124/dmd.111.042903
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