Targeting interleukin 18 with interleukin 18 binding protein
- University of Colorado Health Sciences Center, Division Infectious Diseases, B168, 4200 East Ninth Avenue, Denver, CO 80262, USA
- Dr Dinarello ( )
A novel, constitutively expressed and secreted interleukin 18 (IL18) binding protein (IL18BP) neutralises IL18. IL18BP shares many characteristics with soluble cytokine receptors of the IL1 family in that the protein exhibits specificity for IL18, belongs to the immunoglobulin-like class of receptors and has limited amino acid sequences with those of the IL1 receptor type II. However, unlike soluble cytokine receptors, IL18BP does not have a transmembrane domain and hence is not anchored to the cell membrane. IL18BP is a secreted protein and not cleaved from the cell surface. IL18BP is naturally occurring and was isolated from the urine of healthy subjects. Because IL18 is an important inducer of interferon γ (IFNγ), IL18BP suppresses the production of IFNγ resulting in reduced T-helper type 1 immune responses. There are four human and two mouse isoforms—resulting from mRNA splicing and found in various cDNA libraries. Each of these IL18BP isoforms have been expressed, purified and assessed for binding and neutralisation of IL18 biological activities. Two human IL18BP isoforms exhibited the greatest affinity for IL18 with a rapid on-rate, a slow off-rate and a dissociation constant (kDa) of 399 pM. The two other isoforms with an incomplete immunoglobulin domain were unable to neutralise IL18. The two human isoforms that possess a complete immunoglobulin domain, neutralise >95% IL18 at a molar excess of two. Molecular modelling identified a large mixed electrostatic and hydrophobic binding site in the immunoglobulin domain of IL18BP, which could account for its high affinity binding to the ligand. These high affinity forms may be ideally suited for blocking IL18 in human disease. It is likely that preferential secretion of high affinity functional and non-functional isoforms of IL18BP affect the immune response and the outcome of disease.
Funding: these studies are supported by NIH Grant A-15614, AI-2532359, Colorado Cancer Center CA 46934 (to CAD).