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Drug Insight: different mechanisms of action of tumor necrosis factor antagonists—passive-aggressive behavior?

Nature Clinical Practice Rheumatology volume 3, pages 227–233 (2007)Cite this article

Abstract

Antagonists of tumor necrosis factor (TNF) have revolutionized the treatment of selected inflammatory diseases. In rheumatology, this has been most notable for ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis. Despite their specificity for TNF, these agents, which include the soluble p75 receptor etanercept and the anti-TNF antibodies adalimumab and infliximab, have demonstrated differential clinical efficacy in studies of rheumatoid arthritis; patients who do not respond to one antagonist often respond to another. Therapeutic disparity of these agents is also seen in specific diseases, most notably Crohn's disease. Differences in pharmacodynamics, pharmacokinetics and mechanisms of action, as well as disease heterogeneity, have been proposed to account for these effects. Reverse signaling by transmembrane TNF in response to anti-TNF antibodies, but not soluble receptor, might also influence the therapeutic response.

Key Points

  • Tumor necrosis factor (TNF) exerts its pleiotropic effects through soluble and transmembrane forms, which interact with two different forms of the receptor—p55 and p75, respectively

  • The remarkable efficacy of TNF antagonists on inflammation is induced through apoptosis-dependent and apoptosis-independent effects that might vary in an organ-specific and disease-specific manner

  • TNF antagonist efficacy is influenced by differences in pharmacodynamics, ligand specificity, and qualitative and quantitative interactions with soluble and transmembrane TNF

  • Clarification of the mechanism of action of TNF antagonists in humans will require agents that selectively antagonize specific forms of TNF or block its actions through monomeric interactions

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Figure 1: Neutralization of transmembrane and soluble tumor necrosis factor by soluble receptor or anti-TNF antibodies, including Fabs

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Acknowledgements

I thank the careful reading of the manuscript and suggestions by P-P Tak and J Yost.

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  1. Borwell Research Building – HB 7510, 1 Medical Center Drive, Dartmouth Medical School, Lebanon, NH 03756, USA wfcr@dartmouth.edu

Authors and Affiliations

  1. WFC Rigby is a Professor of Medicine, Microbiology and Immunology at Dartmouth Medical School, Lebanon, NH, USA.,

    William FC Rigby

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Rigby, W. Drug Insight: different mechanisms of action of tumor necrosis factor antagonists—passive-aggressive behavior?. Nat Rev Rheumatol 3, 227–233 (2007). https://doi.org/10.1038/ncprheum0438

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