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Research ArticleNeuropharmacology

Exposure Levels of Anti-LINGO-1 Li81 Antibody in the Central Nervous System and Dose-Efficacy Relationships in Rat Spinal Cord Remyelination Models after Systemic Administration

R. Blake Pepinsky, Zhaohui Shao, Benxiu Ji, Qin Wang, Gym Meng, Lee Walus, Xinhua Lee, Yinghui Hu, Christilyn Graff, Ellen Garber, Werner Meier and Sha Mi
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 519-529; DOI: https://doi.org/10.1124/jpet.111.183483
R. Blake Pepinsky
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Zhaohui Shao
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Benxiu Ji
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Qin Wang
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Gym Meng
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Lee Walus
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Xinhua Lee
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Yinghui Hu
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Christilyn Graff
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Ellen Garber
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Werner Meier
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Sha Mi
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Abstract

LINGO-1 (leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1) is a negative regulator of myelination and repair of damaged axons in the central nervous system (CNS). Blocking LINGO-1 function leads to robust remyelination. The anti-LINGO-1 Li81 antibody is currently being evaluated in clinical trials for multiple sclerosis (MS) and is the first MS therapy that directly targets myelin repair. LINGO-1 is selectively expressed in brain and spinal cord but not in peripheral tissues. Perhaps the greatest concern for Li81 therapy is the limited access of the drug to the CNS. Here, we measured Li81 concentrations in brain, spinal cord, and cerebral spinal fluid in rats after systemic administration and correlated them with dose-efficacy responses in rat lysolecithin and experimental autoimmune encephalomyelitis spinal cord models of remyelination. Remyelination was dose-dependent, and levels of Li81 in spinal cord that promoted myelination correlated well with affinity measurements for the binding of Li81 to LINGO-1. Observed Li81 concentrations in the CNS of 0.1 to 0.4% of blood levels are consistent with values reported for other antibodies. To understand the features of the antibody that affect CNS penetration, we also evaluated the pharmacokinetics of Li81 Fab2, Fab, and poly(ethylene glycol)-modified Fab. The reagents all showed similar CNS exposure despite large differences in their sizes, serum half-lives, and volumes of distribution, and area under the curve (AUC) measurements in the CNS directly correlated with AUC measurements in serum. These studies demonstrate that exposure levels achieved by passive diffusion of the Li81 monoclonal antibody into the CNS are sufficient and lead to robust remyelination.

Footnotes

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

    doi:10.1124/jpet.111.183483.

  • ABBREVIATIONS:

    MS
    multiple sclerosis
    CNS
    central nervous system
    CSF
    cerebrospinal fluid
    CV
    column volumes
    PEG
    poly(ethylene glycol)
    PAGE
    polyacrylamide gel electrophoresis
    SEC
    size exclusion chromatography
    ELISA
    enzyme-linked immunosorbent assay
    EAE
    experimental autoimmune encephalomyelitis
    MBP
    myelin basic protein
    MOG
    myelin oligodendrocyte glycoprotein
    LPC
    lysolecithin
    AUC
    area under the curve
    BBB
    blood-brain barrier
    mAb
    monoclonal antibody
    LINGO-1
    leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1
    CHO
    Chinese hamster ovary
    PBS
    phosphate-buffered saline
    OPC
    oligodendrocyte progenitor cell.

  • Received May 5, 2011.
  • Accepted July 29, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleNeuropharmacology

Dose-Efficacy Relationship of Anti-LINGO-1 mAb

R. Blake Pepinsky, Zhaohui Shao, Benxiu Ji, Qin Wang, Gym Meng, Lee Walus, Xinhua Lee, Yinghui Hu, Christilyn Graff, Ellen Garber, Werner Meier and Sha Mi
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 519-529; DOI: https://doi.org/10.1124/jpet.111.183483

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Research ArticleNeuropharmacology

Dose-Efficacy Relationship of Anti-LINGO-1 mAb

R. Blake Pepinsky, Zhaohui Shao, Benxiu Ji, Qin Wang, Gym Meng, Lee Walus, Xinhua Lee, Yinghui Hu, Christilyn Graff, Ellen Garber, Werner Meier and Sha Mi
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 519-529; DOI: https://doi.org/10.1124/jpet.111.183483
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