Soluble cytokine receptors: novel immunotherapeutic agents

Being mediators of immune and inflammatory reactions, abnormal or excessive production of cytokines is often the main cause of the pathology in many types of disease. Targeting cytokines by means of inhibitory drugs may thus offer a valid therapeutic approach in particular diseases. Soluble forms of cytokine receptors (sCR) normally participate in the control of cytokine activity in vivo by inhibiting the ability of cytokines to bind their membrane receptors and from generating a biological response. The ability of sCR to act as cytokine inhibitors, coupled to their specificity, high affinities and low immunogenicities have prompted considerable interest in their use as immunotherapeutic agents. In fact, many types of sCR have been shown to inhibit the biological activity of their cytokines in vitro and in different experimental models. Several sCR, particularly the soluble TNF receptors sTNFR-I (p55) and sTNFR-II (p75), have been modified by linking them to the Fc portion of human immunoglobulin (e.g., 'immunoadhesins') or by the addition of polyethylene-glycol (PEG) (e.g., 'PEGylation'), in order to enhance their affinity and/or biological half-life. These agents have shown significant therapeutic value in clinical trials of patients with rheumatoid arthritis (RA). Indeed, a sTNFR-II:Fc hybrid molecule (etanercept), the first sCR-derived therapeutic agent to receive approval for human use, is already utilised for the treatment of some forms of RA. Additional applications of this drug in other inflammatory conditions are currently being evaluated, while another sCR-derived agent, a human sIL-4R, is undergoing trials for the treatment of asthma. Many other sCR, such as sIL-1R, sIL-5R, sIFNgammaR, may also have significant potential for the treatment of a wide variety of human diseases.