Considerable advances in treating autoimmune diseases have been made with agents that block the action of cytokines. New work published in the January issue of Nature Medicine describes the design and production of a novel class of cytokine antagonists, termed cytokine traps, which overcome some of the problems with existing antagonists.

The best results to date with cytokine antagonists have been achieved using soluble decoy receptors that bind and block the cytokine of interest. The tumour necrosis factor-α (TNF-α) blocker etanercept (Enbrel), which is made up of the extracellular ligand-binding portion of the TNF-α receptor fused to the constant region (Fc) of a human immunoglobulin (Ig) chain, has been approved for the treatment of rheumatoid arthritis (RA), and has good clinical activity. However, for most cytokines, two distinct receptor components cooperate to bind the cytokine very tightly, and so a single-component receptor antagonist does not work very well. Perhaps because of these limitations, single-component soluble receptor antagonists for IL-1 and IL-4 have not been successful.

In an effort to overcome problems of low binding affinity, and short half-life (which necessitates frequent injections), Stahl and colleagues developed soluble cytokine receptors, termed traps, that incorporate both of the receptor components normally required to achieve high-affinity binding. The traps were constructed by engineering linear fusions of both receptor extracellular domains followed by the human IgG1 Fc domain. The Fc portion directed the formation of disulphide-linked dimers. The affinity of cytokines for the traps is significantly greater than for their individual cellular receptor components. IL-1, IL-4 and IL-6 traps were able to bind the specific cytokine in vitro with high affinity and potently block cytokine action. In vivo, mouse versions of the IL-1 and IL-4 traps were able to block the development of arthritic joints in a mouse arthritis model and to prevent the high numbers of eosinophils that accumulate in mouse models of asthma, respectively. The human IL-4 trap was also able to block IL-4 action in primates.

Phase II human clinical trials of the IL-1 trap to assess safety and efficacy in RA patients are underway. Pharmacokinetic data suggest that dosing is compatible with a once-weekly shot, which would be a great improvement over existing treatments, which are injected daily.