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  • Review Article
  • Published:

Anti-TNF-α therapies: the next generation

Key Points

  • The development of protein-based therapies that inhibit the activities of tumour-necrosis factor-α (TNF-α), including etanercept (Enbrel; Amgen/Wyeth), infliximab (Remicade; Centocor), and adalimumab (Humira; Abbott), has been an important advancement in the treatment of autoimmune diseases such as rheumatoid arthritis. The recent US FDA approval of Kineret — an interleukin-1 (IL-1) receptor antagonist — further indicates the clinical activity of protein-based therapies that regulate cytokine activities. However, current injectable therapies have associated limitations and risks, including the potential for increased malignancies and infections and increased congestive heart failure.

  • Studies in rodent models have provided evidence that targeting specific pathways involved in TNF-α activities are effective approaches to interrupting the pro-inflammatory process. Oral small molecules that regulate these pathways should be the next significant advancement in the treatment of chronic inflammatory diseases when used either as a monotherapy or in combination with the current injectables.

  • There are potentially significant advantages of small-molecule therapies: their non-injectable format could lead to greater patient compliance; small molecules could facilitate tissue penetration; pharmacology should suggest once a day dosing; small molecules have shorter half-lives with reduced immunosuppression; small molecules are non-immunogenic; small molecules are easier to manufacture and are cheaper; and there is the potential to use them in combination with other agents.

  • Clinical trials are ongoing with small-molecule TNF-α-converting enzyme, p38 mitogen-activated protein kinase and phosphodiesterase inhibitors that specifically interrupt the synthesis and signalling pathways for TNF-α and downstream pro-inflammatory molecules such as IL-1, IL-6, nitric oxide synthase and cyclooxygenase-2. These studies will provide the basis for the development of the next-generation therapies.

  • Natural products are also being further evaluated due to their ability to regulate various anti-inflammatory functions including the signalling pathways required for the activation of the transcription factor NF-κB.

  • The signalling pathways that regulate cytokine activities are complex and there are many approaches that can effectively regulate TNF-α expression. New small-molecule approaches that selectively inhibit both TNF-α and IL-1 activities could provide greater clinical activity.

Abstract

The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Unregulated activities of these mediators can lead to the development of serious inflammatory diseases. In particular, enhanced tumour-necrosis factor-α (TNF-α) synthesis is associated with the development of rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Inhibiting TNF-α activities in these diseases has been remarkably successful. However, the current injectable protein therapies have associated risks and limitations. An oral, small molecule that regulates TNF-α biology could either replace the injectables or provide better disease control when used alone or in conjunction with existing therapies. In this review, we discuss briefly the present understanding of TNF-α-mediated biology and the current injectable therapies in clinical use, and focus on some of the new therapeutic approaches with oral, small-molecule inhibitors.

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Figure 1: Potential targets for the inhibition of TNF-α signalling pathways or protein expression.
Figure 2
Figure 3
Figure 4: Proposed effects of IκB-α/NF-κB inhibitors on TNF-α-induced sensitization of resistant macrophages to LeTx.

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Acknowledgements

We thank the University of California Discovery Program for financial support.

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Correspondence to Michael A. Palladino.

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bFGF

FADD

IL-1

IL-1β

IL-6

IL-10

TACE

TNF-α

TNFR1

TNFR2

TRADD

TRAF2

VEGF

Online Mendelian Inheritance in Man

Crohn's disease

rheumatoid arthritis

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Encyclopedia of Life Sciences

tumour-necrosis factors

Glossary

ENDOTOXIN

Toxin derived from the disruption of the outer membrane of Gram-negative bacteria.

JUXTACRINE SIGNALLING

The interaction of membrane-bound proteins that are normally secreted with receptors on adjacent cells.

ACR20

American College of Rheumatology 20% improvement criteria.

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Palladino, M., Bahjat, F., Theodorakis, E. et al. Anti-TNF-α therapies: the next generation. Nat Rev Drug Discov 2, 736–746 (2003). https://doi.org/10.1038/nrd1175

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