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Research ArticleArticle

Brain-Penetrating Tumor Necrosis Factor Decoy Receptor in the Mouse

Qing-Hui Zhou, Ruben J. Boado, Eric Ka-Wai Hui, Jeff Zhiqiang Lu and William M. Pardridge
Drug Metabolism and Disposition January 2011, 39 (1) 71-76; DOI: https://doi.org/10.1124/dmd.110.036012
Qing-Hui Zhou
Department of Medicine, University of California Los Angeles, Los Angeles, California (Q.-H.Z., R.J.B., W.M.P.); and ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Ruben J. Boado
Department of Medicine, University of California Los Angeles, Los Angeles, California (Q.-H.Z., R.J.B., W.M.P.); and ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Eric Ka-Wai Hui
Department of Medicine, University of California Los Angeles, Los Angeles, California (Q.-H.Z., R.J.B., W.M.P.); and ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Jeff Zhiqiang Lu
Department of Medicine, University of California Los Angeles, Los Angeles, California (Q.-H.Z., R.J.B., W.M.P.); and ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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William M. Pardridge
Department of Medicine, University of California Los Angeles, Los Angeles, California (Q.-H.Z., R.J.B., W.M.P.); and ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Abstract

Biologic tumor necrosis factor inhibitors (TNFIs) include TNF decoy receptors (TNFRs). TNFα plays a pathologic role in both acute and chronic brain disease. However, biologic TNFIs cannot be developed as brain therapeutics because these large molecule drugs do not cross the blood-brain barrier (BBB). To enable penetration of the brain via receptor-mediated transport, the human TNFR type II was re-engineered as an IgG fusion protein, where the IgG part is a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb part of the fusion protein acts as a molecular Trojan horse to ferry the TNFR across the BBB via transport on the endogenous BBB TfR. cTfRMAb-TNFR was expressed by stably transfected Chinese hamster ovary cells and purified by affinity chromatography to homogeneity on electrophoretic gels. The fusion protein reacted with antibodies to both mouse IgG and the human TNFR and bound TNFα with high affinity (Kd = 96 ± 34 pM). cTfRMAb-TNFR was rapidly transported into mouse brain in vivo after intravenous administration, and the brain uptake of the fusion protein was 2.8 ± 0.5% of injected dose per gram of brain, which is >45-fold higher than the brain uptake of an IgG that does not recognize the mouse TfR. This new IgG-TNFR fusion protein can be tested in mouse models of brain diseases in which TNFα plays a pathologic role.

Footnotes

    • Received August 19, 2010.
    • Accepted September 30, 2010.
  • This work was supported by the National Institutes of Health National Institute on Aging [Grant R01-AG032244].

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

    doi:10.1124/dmd.110.036012.

  • ABBREVIATIONS:

    TNFα
    tumor necrosis factor alpha
    PD
    Parkinson's disease
    AD
    Alzheimer's disease
    TNFI
    TNF inhibitor
    TNFR-II ECD
    extracellular domain of the type II TNF receptor
    CNS
    central nervous system
    BBB
    blood-brain barrier
    MTH
    molecular Trojan horse
    MAb
    monoclonal antibody
    HIR
    human insulin receptor
    IV
    intravenous
    TfR
    transferrin receptor
    CHO
    Chinese hamster ovary
    TV
    tandem vector
    LC
    light chain
    AA
    amino acid
    HC
    heavy chain
    ELISA
    enzyme-linked immunosorbent assay
    PAGE
    polyacrylamide gel electrophoresis
    TBS
    Tris-buffered saline
    PBS
    phosphate-buffered saline
    TCA
    trichloroacetic acid
    IP
    intraperitoneal
    ID
    injection dose
    VD
    volume of distribution
    DPM
    disintegrations per minute
    AUC
    area under the plasma concentration curve
    PS
    permeability-surface area
    C
    constant
    BAA06141
    mouse immunoglobulin gamma-1 light chain
    BAC44885
    mouse immunoglobulin gamma-1 heavy chain.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

Brain-Penetrating Tumor Necrosis Factor Decoy Receptor in the Mouse

Qing-Hui Zhou, Ruben J. Boado, Eric Ka-Wai Hui, Jeff Zhiqiang Lu and William M. Pardridge
Drug Metabolism and Disposition January 1, 2011, 39 (1) 71-76; DOI: https://doi.org/10.1124/dmd.110.036012

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Research ArticleArticle

Brain-Penetrating Tumor Necrosis Factor Decoy Receptor in the Mouse

Qing-Hui Zhou, Ruben J. Boado, Eric Ka-Wai Hui, Jeff Zhiqiang Lu and William M. Pardridge
Drug Metabolism and Disposition January 1, 2011, 39 (1) 71-76; DOI: https://doi.org/10.1124/dmd.110.036012
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