IL-18 and IL-18BP: A Unique Dyad in Health and Disease

Abstract

Interleukin-18 (IL-18) serves a dual function in the immune system, acting as a “double-edged sword” cytokine. Depending on the microenvironment and timing, IL-18 can either drive harmful inflammation or restore immune homeostasis. Pathologies characterized by elevated IL-18, recently proposed to be termed IL-18opathies, highlight the therapeutic potential for IL-18 blockade. IL-18 Binding Protein (IL-18BP) is one of only four natural cytokine antagonists encoded by a separate gene, distinguishing it from canonical soluble receptors. IL-18BP’s exceptionally high affinity and slow dissociation rate make it an effective regulator of IL-18, essential for maintaining immune balance and influencing disease outcomes, and positions IL-18BP as a promising alternative to more aggressive treatments that carry risks of severe infections and other complications. Tadekinig alfa, the drug form of IL-18BP, represents a targeted therapy that modulates the IL-18/IL-18BP axis, offering a safe adverse-effect-free option. With orphan drug designation, Phase III clinical trial completion, and seven years of compassionate use, Tadekinig alfa holds promise in treating autoimmune and inflammatory diseases, cancer, and genetically linked disorders. Levels of IL-18, free IL-18 and IL-18BP, may serve as biomarkers for disease severity and therapeutic response. Given its pivotal role in immune balance, the IL-18/IL-18BP dyad has attracted interest from over ten pharmaceutical companies and startups, which are currently developing innovative strategies to either inhibit or enhance IL-18 activity depending on the therapeutic need. The review focuses on the features of the dyad members and screens the therapeutic approaches.