Development of anti-murine IL-18 binding protein antibodies to stimulate IL-18 bioactivity
Graphical Abstract ©ArnaudHUARD/UNIGE
SUMMARY
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 signalling can lead to systemic inflammation. Indeed, the severity of CpG-induced macrophage activation syndrome is exacerbated in IL-18BP knockout (KO) mice. On the contrary, targeting IL-18BP can have promising effects to enhance immune responses against pathogens and cancer. The authors of this article, led by GCIr Professor Cem Gabay, generated monoclonal rabbit anti-mouse IL-18BP antibodies labelled from 441 to 450. All antibodies, except from antibody 443, captured mouse (m)IL-18BP when used in a sandwich enzyme-linked immunosorbent assay. Using an IL-18 bioassay, they 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 macrophage activation syndrome as compared with antibody 441. Additional experiments using naïve wild-type, IL-18BP KO, and IL-18 KO mice confirmed the specificity of the neutralizing effect of antibody 445 toward IL-18BP. These studies led to the development of a monoclonal anti-IL-18BP antibody with neutralizing activity that results in the promotion of IL-18 activities.
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Why is it important?
IL-18 is a key molecule that helps immune cells fight infections and cancer, but it is tightly controlled by IL-18BP, which limits its activity. GCIR researchers led by Prof. Cem Gabay developed new antibodies that block IL-18BP, allowing IL-18 to work more effectively. One antibody, 445, significantly increased IL-18 activity but also intensified inflammation in an experimental disease model. While this approach could enhance immune responses in cancer therapy, it may also pose risks. This study highlights the importance of balancing immune activation and regulation in future treatments. These findings could have implications for diseases such as cancer, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and macrophage activation syndrome, conditions where IL-18 plays a crucial role in disease progression.
25 Mar 2025