The interleukin-1 receptor antagonist and its delivery by gene transfer

The interleukin-1 receptor antagonist (IL-1ra or IRAP) is a small, acidic glycoprotein that competitively inhibits the biological activities of interleukin-1 (IL-1). Alternative splicing gives rise to secreted and intracellular forms of IL-1ra. Both forms block cellular responses to IL-1 by occupying IL-1 receptors without triggering an agonist response. The affinity of IL-1ra for the type I IL-1 receptor is approximately that of IL-1. However, because of IL-1's pronounced "spare receptor" effect, IL-1ra is a weak inhibitor of biological responses to IL-1. The value for the affinity constant of IL-1ra's binding to the type II IL-1 receptor has been the subject of disagreement. However, recent data suggest that human IL-1ra has only weak affinity for the human type II receptor. This is consistent with the likelihood that the type II receptor plays no role in signal transduction, instead being a "decoy" that can be shed as a soluble receptor with the ability bind, and thus inhibit, IL-1. Under the name Antril, IL-1ra is being tested in clinical trials of a number of human diseases where IL-1 plays a major pathophysiologic role. These diseases include sepsis, rheumatoid arthritis, chronic myelogenous leukemia, and asthma, among others. Although IL-1ra has clear pharmacologic potential in such conditions, its application in chronic diseases is limited by difficulties associated with delivering proteins as drugs. As an alternative, we have suggested transfer of the gene coding for IL-1ra; strategies for both local and systemic gene delivery are being developed.(ABSTRACT TRUNCATED AT 250 WORDS)