Soluble cytokine receptors: novel immunotherapeutic agents

Being mediators of immune and inflammatory reactions, abnormal or excessive production of cytokinesis often the main cause of the pathology in many ty pes of disease. Targeting cytokines by means of inhibitory drugs may thus o ffer a valid therapeutic approach in particular diseases. Soluble forms of cytokine receptors (sCR) normally participate in the control of cytokine ac tivity in vivo by inhibiting the ability of cytokines to bind their membran e receptors and from generating a biological response. The ability of sCR t o 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 differe nt experimental models. Several sCR, particularly the soluble TNF receptors sTNFR-I (p55) and sTNFR-II (p75), have been modified by linking them to th e Fe portion of human immunoglobulin (e.g., 'immunoadhesins') or by the add ition of polyethylene-glycol (PEG) (e.g., 'PEGylation'), in order to enhanc e their affinity and/or biological half-life. These agents have shown signi ficant therapeutic value in clinical trials of patients with rheumatoid art hritis (RA). Indeed, a sTNFR-II:Fe hybrid molecule (etaner-cept), the first sCR-derived therapeutic agent to receive approval for human use, is alread y utilised for the treatment of some forms of RA. Additional applications o f 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, sIFN gamma R, may also have significant potential for the treatment of a wide variety of human diseases.