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  • Review Article
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Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention

Nature Reviews Drug Discovery volume 3, pages 330–340 (2004)Cite this article

Key Points

  • Interleukin-1 (IL-1) is a pro-inflammatory cytokine that plays a role in many acute and chronic human diseases.

  • Elevated levels of IL-1, or the naturally occurring receptor antagonist IL-1Ra, can be measured in human samples of tissue or body fluids from patients with rheumatoid arthritis (RA), osteoarthritis, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease and atherosclerosis.

  • Blockade of IL-1 binding to the IL-1 receptor has been achieved with biological agents that neutralize IL-1. Anakinra, a recombinant form of IL-1Ra, shows clinical efficacy in RA. Other agents show promise in preclinical models and are safe and well tolerated in Phase I volunteer studies.

  • Small-molecule drugs are being developed that interfere with IL-1 signalling production or processing. The most advanced of these is an inhibitor of IL-1-converting enzyme, which has has shown clinical efficacy in RA. Other approaches include targeting the post-translational processing or release of IL-1 and have yielded encouraging results in preclinical studies.

Abstract

The cytokine interleukin-1 (IL-1) is important in many human diseases, and drives a wide range of inflammatory responses in a number of cell types. Biological agents that target IL-1 neutralization have shown efficacy in patients with rheumatoid arthritis. Recently, new classes of compounds that target IL-1 production or processing, or regulatory steps on the IL-1 pathway, are being investigated as new drugs for the management of inflammatory disease. Such compounds will have wide utility in numerous inflammatory conditions.

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Figure 1: IL-1 processing.
Figure 2: IL-1β signalling.
Figure 3: Effects of 24 weeks therapy with anakinra on Larsen score and erosive joint count.
Figure 4: Comparison of proportions achieving ACR20, -50 and -70 responses at weeks 24 with MTX/infliximab, MTX/anakinra and anakinra monotherapy.
Figure 5: Comparison of proportions achieving ACR20, 50 and 70 responses at weeks 24 in rheumatoid arthritis patients treated with the interleukin-1 trap.
Figure 6: Chemical structures of some compounds described.

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Acknowledgements

We thank our colleagues in the Respiratory and Inflammation Research Area and in clinical development within AstraZeneca for their support and stimulating discussion.

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  1. Discovery Bioscience Department, Disease Sciences Section, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK

    Martin Braddock

  2. Department of Experimental Medicine, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK

    Anthony Quinn

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DATABASES

LocusLink

ICE

IL-1

IL-1Ra

IL-1RacP

IL-1RI

IL-1RII

TNF-α

Online Mendelian Inheritance in Man

Alzheimer's disease

chronic obstructive pulmonary disease

multiple sclerosis

osteoarthritis

rheumatoid arthritis

ulcerative colitis

Glossary

AUTOCRINE

The secretion of a substance, such as a cytokine, that stimulates the secretory cell itself.

PROXIMAL

Nearest the point of origin of a biochemical pathway or molecular process, as opposed to distal, which represents a point towards or at the end of a pathway or process.

ACUTE-PHASE PROTEINS

Antibody-proteins or glycoproteins usually found in the plasma whose concentration increases in response to infection or injury.

PHARMACOKINETICS

The rate by which a drug is absorbed, distributed, metabolized and eliminated by the body.

PEGYLATED

Attachment of non-toxic polyethylene (PEG) polymers to drug and protein molecules to alter their properties to improve safety and efficacy.

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Braddock, M., Quinn, A. Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention. Nat Rev Drug Discov 3, 330–340 (2004). https://doi.org/10.1038/nrd1342

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