代谢功能障碍相关脂肪性肝炎 (MASH) 是全世界肝病最常见的原因，只有一种经批准的治疗方法。先前的研究表明，白细胞介素-22 (IL-22) 可以抑制 β 细胞应激，减少局部胰岛炎症，恢复适当的胰岛素产生，逆转高血糖，并改善临床前糖尿病模型中的胰岛素抵抗。在临床试验中，长效形式的 IL-22 导致皮肤和肠道增殖增加，而 IL-22RA1 受体在这些部位高度表达。为了最大限度地发挥有益作用，同时降低上皮增殖和癌症的风险，我们设计了短效 IL-22 双特异性生物药物，成功靶向肝脏和胰腺。在这里，我们展示了这些双特异性生物制剂在多个 MASH 临床前模型中的剂量比天然 IL-22 的有益效果低 10 倍，且没有脱靶效应。治疗可恢复血糖控制，显着减少肝脏脂肪变性、炎症和纤维形成。这些短效 IL-22 双特异性靶向生物制剂是一种有前景的 MASH 新治疗方法。© 2024。作者。

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress β-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.© 2024. The Author(s).