A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling

Abstract

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyper-inflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 Receptor 5 (IL-1R5, also known as IL-18 Receptor alpha chain), leading to the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7, also known as IL-18 Receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs), and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6 and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans -induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling, and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

“…It acts by reducing IL-18 induced NFkB and IFN-γ activation and IL-6 production in human cell lines. It is important to note that IL-1R7 is a potential virgin therapeutic strategy for the investigation of its clinical potential in treating IL-18 mediated diseases as this area remains to be explored ( 232 ).…”

Identification of Robust Protein Associations With COVID-19 Disease Based on Five Clinical Studies

“…Twelve proteins were assigned to the IL18 pathway, a host defense pathway following bacterial or viral infection that is activated via an interplay between the inflammasome and IL1-beta and IL18 ( 23 ). Recently, an in vitro study used humanized anti-IL1R7 antibody to suppress IL18-mediated inflammatory pathways, including NFκB activation and IFNγ, IL6, and TNFα production ( 24 ). In comparison to other pathways or groups, three interaction proteins, KITLG, GRN, and PTX3, are rather unique that play significant role in several physiological processes.…”

“…Satış et al ( 39 ) reported high serum concentrations of IL18 that correlated with other inflammatory markers, which is also consistent with our findings. A candidate COVID-19 therapy is an anti-human IL1R7 antibody that suppresses IL18-mediated inflammatory signaling ( 24 ). For these reasons, it is necessary to perform comparative multi-disease studies with e.g., bacterial sepsis, allergy, and diabetes patients to filter out specific protein release patterns.…”

Tumor-Associated Macrophages: Key Players in Triple-Negative Breast Cancer

“…It is produced by a variety of cell types including macrophages. Tumor-derived IL-18 levels are significantly related to the low survival rate of TNBC patients (81)(82)(83). TGF-b is a multifunctional cytokine, which participates in the production of Treg in the mouse tumor microenvironment and supports its suppression of effector T cells (18).…”