Use of molecular imaging to quantify response to IKK-2 inhibitor treatment in murine arthritis

Authors

  • Elena S. Izmailova,

    Corresponding author
    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
    • Millennium Pharmaceuticals, Inc., 35 Lansdowne Street, Cambridge, MA 02139
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Nancy Paz,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
    Current affiliation:
    1. Merrimack Pharmaceuticals, Cambridge, Massachusetts
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  • Herlen Alencar,

    1. Massachusetts General Hospital, Charlestown
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  • Miyoung Chun,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
    Current affiliation:
    1. University of California, Santa Barbara
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  • Lisa Schopf,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Michael Hepperle,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
    Current affiliation:
    1. Phenomix Corporation, San Diego, California
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  • Joan H. Lane,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Geraldine Harriman,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Yajun Xu,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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  • Timothy Ocain,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Ralph Weissleder,

    1. Massachusetts General Hospital, Charlestown
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Umar Mahmood,

    1. Massachusetts General Hospital, Charlestown
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.

  • Aileen M. Healy,

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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  • Bruce Jaffee

    1. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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    • Drs. Izmailova, Schopf, Lane, Harriman, Ocain, and Jaffee have or have had stock or stock options in Millennium Pharmaceuticals, Inc. Drs. Weissleder and Mahmood have stock or stock options in Visen Medical. Dr. Mahmood holds patents on activatable optical agents.


Abstract

Objective

The NF-κB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-κB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis.

Methods

ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-κB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase–polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.

Results

Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-κB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-κB pathway, i.e., KC, epithelial neutrophil–activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.

Conclusion

Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.

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