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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Binding and Functional Comparisons of Two Types of Tumor Necrosis Factor Antagonists

Bernie Scallon, Ann Cai, Nancy Solowski, Amy Rosenberg, Xiao-Yu Song, David Shealy and Carrie Wagner
Journal of Pharmacology and Experimental Therapeutics May 2002, 301 (2) 418-426; DOI: https://doi.org/10.1124/jpet.301.2.418
Bernie Scallon
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Ann Cai
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Nancy Solowski
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Amy Rosenberg
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Xiao-Yu Song
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David Shealy
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Carrie Wagner
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Abstract

Two tumor necrosis factor (TNF) antagonists infliximab (a chimeric monoclonal antibody) and etanercept (a p75 TNF receptor/Fc fusion protein) have been approved for treatment of rheumatoid arthritis. However, these agents have shown different degrees of clinical benefit in controlled clinical trials in other TNF-mediated diseases such as Crohn's disease (CD) and psoriasis. We investigated whether structural differences between these two antagonists translate into different binding and functional characteristics. To study the binding of infliximab and etanercept to both the soluble and cell-surface transmembrane forms of TNF, a variety of in vitro binding and cell-based assays were performed. Binding assays using125I-labeled TNF showed that infliximab binds to both monomer and trimer forms of soluble TNF (sTNF), whereas etanercept binding is restricted to the trimer form. Infliximab formed stable complexes with sTNF, whereas etanercept formed relatively unstable complexes, resulting in release of dissociated TNF. KYM-1D4 cell killing assays and human umbilical vein endothelial cell activation assays demonstrated that TNF that had dissociated from etanercept was bioactive. Infliximab also formed more stable complexes with the transmembrane form of TNF expressed on transfected cells relative to analogous complexes formed with etanercept. Additionally, more infliximab molecules bound to the transmembrane TNF with higher avidity than etanercept. Although both infliximab and etanercept inhibited transmembrane TNF-mediated activation of human endothelial cells, infliximab was significantly more effective. The differences between infliximab and etanercept in their TNF binding characteristics may help explain their differential efficacy in CD and psoriasis clinical trials.

Footnotes

  • Abbreviations:
    TNF
    tumor necrosis factor
    CD
    Crohn's disease
    RA
    rheumatoid arthritis
    mAb
    monoclonal antibody
    LTα
    lymphotoxin α
    HBSS
    Hanks' balanced salt solution
    PBS
    phosphate-buffered saline
    FBS
    fetal bovine serum
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium-bromide
    HUVE
    human umbilical vein endothelial
    IMDM
    Iscove's modified Dulbecco's medium
    DMSO
    dimethyl sulfoxide
    PBS-T
    phosphate-buffered saline-0.05% Tween 20
    tmTNF
    transmembrane tumor necrosis factor
    sTNF
    soluble tumor necrosis factor
    • Received September 19, 2001.
    • Accepted January 9, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 2
1 May 2002
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Binding and Functional Comparisons of Two Types of Tumor Necrosis Factor Antagonists

Bernie Scallon, Ann Cai, Nancy Solowski, Amy Rosenberg, Xiao-Yu Song, David Shealy and Carrie Wagner
Journal of Pharmacology and Experimental Therapeutics May 1, 2002, 301 (2) 418-426; DOI: https://doi.org/10.1124/jpet.301.2.418

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Binding and Functional Comparisons of Two Types of Tumor Necrosis Factor Antagonists

Bernie Scallon, Ann Cai, Nancy Solowski, Amy Rosenberg, Xiao-Yu Song, David Shealy and Carrie Wagner
Journal of Pharmacology and Experimental Therapeutics May 1, 2002, 301 (2) 418-426; DOI: https://doi.org/10.1124/jpet.301.2.418
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