Treatment of IL-18-binding protein biologics suppresses fibrotic progression in metabolic dysfunction-associated steatohepatitis

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Authors: Kim, Dong-Hyun ; Choi, Gona ; Song, Eun-Bi ; Lee, Hanna ; Kim, Jaehui ; Jang, Young-Saeng ; Park, JinJoo ; Chi, Susan ; Han, Jaekyu ; Kim, Sun-Mi ; Kim, Dongyoon ; Bae, Soo Han ; Lee, Hye Won ; Park, Jun Yong ; Kang, Seung Goo ; Cha, Sang-Hoon ; Han, Yong-Hyun

MeSH: Animals ; Biological Products* / pharmacology ; Biological Products* / therapeutic use ; Disease Progression ; Fatty Liver* / drug therapy ; Fatty Liver* / metabolism ; Fatty Liver* / pathology ; Female ; Hepatic Stellate Cells / drug effects ; Hepatic Stellate Cells / metabolism ; Humans ; Intercellular Signaling Peptides and Proteins* / metabolism ; Intercellular Signaling Peptides and Proteins* / therapeutic use ; Interleukin-18 / metabolism ; Liver / metabolism ; Liver / pathology ; Liver Cirrhosis* / drug therapy ; Liver Cirrhosis* / metabolism ; Liver Cirrhosis* / pathology ; Male ; Mice ; Mice, Inbred C57BL ; Signal Transduction / drug effects

Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by inflammation and fibrosis, with enhanced interleukin-18 (IL-18) signaling. IL-18-binding protein (IL-18BP) neutralizes IL-18, but its therapeutic potential in MASH is unclear. We find elevated IL-18BP and IL-18 levels in patients with MASH and mice, with free IL-18 correlating with disease severity. IL-18 stimulates interferon-gamma (IFNg) production in CD4 T cells, increasing hepatic IL-18BP. IL-18BP-deficient mice show worsened liver inflammation and fibrosis. We develop a human IL-18BP biologics (APB-R3) and inject it to mice to evaluate its pharmacologic efficacy. APB-R3 significantly improves MASH in reducing fibrosis and inflammation and inhibits hepatic stellate cell activation via the cGMP pathway. This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis, and our engineered IL-18BP biologics can become a promising therapeutic candidate for curing MASH.