Interleukin-18 Binding Protein (IL-18BP): A Long Journey From Discovery to Clinical Application

IL -18 binding protein (IL-18BP) was originally discovered in 1999 while attempting to identify an IL -18 receptor ligand binding chain (also known as IL-18R alpha) by subjecting concentrated human urine to an IL -18 ligand affinity column. The IL -18 ligand chromatography purified molecule was analyzed by protein microsequencing. The result revealed a novel 40 amino acid polypeptide. To isolate the complete open reading frame (ORF), various human and mouse cDNA libraries were screened using cDNA probe derived from the novel IL -18 affinity column bound molecule. The identified entire ORF gene was thought to be an IL-18R alpha gene. However, IL-18BP has been proven to be a unique soluble antagonist that shares homology with a variety of viral proteins that are distinct from the IL-18R alpha and IL-18R beta chains. The IL-18BP cDNA was used to generate recombinant IL-18BP (rIL-18BP), which was indispensable for characterizing the role of IL-18BP in vitro and in vivo. Mammalian cell lines were used to produce rIL-18BP due to its glycosylation-dependent activity of IL-18BP (approximately 20 kDa). Various forms of rIL-18BP, intact, C -terminal his -tag, and Fc fusion proteins were produced for in vitro and in vivo experiments. Data showed potent neutralization of IL -18 activity, which seems promising for clinical application in immune diseases involving IL -18. However, it was a long journey from discovery to clinical use although there have been various clinical trials since IL-18BP was discovered in 1999. This review primarily covers the discovery of IL-18BP along with how basic research influences the clinical development of IL-18BP.