biostudies-literatureHuard ASwiss National Science Foundation180-191https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617445biostudies-literatureUnknown214(1)Interleukin (IL)-18 is an immunoregulatory cytokine that acts as a potent inducer of T helper 1 and cytotoxic responses. IL-18 activity is regulated by its decoy receptor IL-18 binding protein (IL-18BP) which forms a high affinity complex with IL-18 to block binding of the cognate receptors. A disbalance between IL-18 and IL-18BP associated with excessive IL-18 signaling can lead to systemic inflammation. Indeed, the severity of CpG-induced macrophage activation syndrome (MAS) is exacerbated in IL-18BP KO mice. On the contrary, targeting IL-18BP can have promising effects to enhance immune responses against pathogens and cancer. We generated monoclonal rabbit anti-mouse IL-18BP antibodies labeled from 441 to 450. All antibodies, except from antibody 443, captured mIL-18BP when used in a sandwich ELISA. Using an IL-18 bioassay, we showed that antibody 441 did not interfere with the regulatory effect of mIL-18BP, whereas all other antibodies displayed different levels of antagonism. Further experiments were performed using antibody 445 endowed with potent neutralizing activity and antibody 441. Despite binding to IL-18BP with the same affinity, antibody 445, but not antibody 441, was able to release IL-18 from preformed IL-18-IL-18BP complexes. Administration of antibody 445 significantly aggravated the severity of CpG-induced MAS as compared to antibody 441. Additional experiments using naïve WT, IL-18BP KO, and IL-18 KO mice confirmed the specificity of the neutralizing effect of antibody 445 towards IL-18BP. Our studies led to the development of a monoclonal anti-IL-18BP antibody with neutralizing activity that results in the promotion of IL-18 activities.Journal of immunology (Baltimore, Md. : 1950)Development of anti-murine IL-18 binding protein antibodies to stimulate IL-18 bioactivity.PMC7617445201269Gabay CDiaz-Barreiro ASavvides SNHuard ACaruso AAndries JMartin PVaillant LFauteux-Daniel SGoldstein JRodriguez EJarlborg MfalseDevelopment of anti-murine IL-18 binding protein antibodies to stimulate IL-18 bioactivity.Interleukin (IL)-18 is an immunoregulatory cytokine that acts as a potent inducer of T helper 1 and cytotoxic responses. IL-18 activity is regulated by its decoy receptor IL-18 binding protein (IL-18BP) which forms a high affinity complex with IL-18 to block binding of the cognate receptors. A disbalance between IL-18 and IL-18BP associated with excessive IL-18 signaling can lead to systemic inflammation. Indeed, the severity of CpG-induced macrophage activation syndrome (MAS) is exacerbated in IL-18BP KO mice. On the contrary, targeting IL-18BP can have promising effects to enhance immune responses against pathogens and cancer. We generated monoclonal rabbit anti-mouse IL-18BP antibodies labeled from 441 to 450. All antibodies, except from antibody 443, captured mIL-18BP when used in a sandwich ELISA. Using an IL-18 bioassay, we showed that antibody 441 did not interfere with the regulatory effect of mIL-18BP, whereas all other antibodies displayed different levels of antagonism. Further experiments were performed using antibody 445 endowed with potent neutralizing activity and antibody 441. Despite binding to IL-18BP with the same affinity, antibody 445, but not antibody 441, was able to release IL-18 from preformed IL-18-IL-18BP complexes. Administration of antibody 445 significantly aggravated the severity of CpG-induced MAS as compared to antibody 441. Additional experiments using naïve WT, IL-18BP KO, and IL-18 KO mice confirmed the specificity of the neutralizing effect of antibody 445 towards IL-18BP. Our studies led to the development of a monoclonal anti-IL-18BP antibody with neutralizing activity that results in the promotion of IL-18 activities.2025-01-01T00:00:00Z2025 Jan2026-06-03T01:23:54.765Z2025-04-04T02:05:06.773ZS-EPMC76174454001867810.1093/jimmun/vkae022