A hepatocyte-specific R-spondin mimetic bispecific fusion protein to stimulate hepatocyte regeneration in patients with acute alcoholic hepatitis

摘要 酒精性肝炎（AH）的特点是炎症性肝损伤伴肝细胞再生受损， 发病率和死亡率高。目前，类固醇是重症患者唯一的治疗选择 然而，它们的疗效有限（超过 28 天没有显示治疗益处），并且许多患者 有类固醇使用禁忌症（例如活动性感染）且无法治疗。有明显未满足的需求 寻找 AH 的新治疗方法。 Wnt信号在肝脏发育、代谢中发挥着重要作用 分区、肝细胞稳态周转、肝细胞分化和成熟以及正常功能 和肝细胞的调节。此外，Wnt/β-连环蛋白信号传导对于肝细胞再生至关重要 各种形式的肝损伤后。 β-连环蛋白的缺失或过度激活已被证明是一个关键 部分肝切除、对乙酰氨基酚、CCl4 或酒精诱导后对肝细胞再生的影响 动物模型中的损伤。 R-spondins (RSPO) 在肝脏稳态和肝细胞中发挥重要作用 损伤后的再生，例如部分肝切除术。 RSPO 增强 Wnt 信号传导和 RSPO 功能 取决于内源性 Wnt 配体的存在；内源性 Wnt 配体往往被上调 位于受伤组织中。重要的是，在人类 AH 患者中，肝细胞再生和成熟的缺乏是 一个重大问题。 Surrozen 开发了 SZN-043，一种双特异性融合蛋白，是一种 R-spondin 模拟物 靶向肝细胞受体 ASGR1，用于肝脏特异性增强 Wnt 信号传导和组织 再生和修复。我们的研究表明，与 RSPO2 相比，SZN-043 的效果非常显着 对肝细胞具有特异性，可以改善啮齿动物疾病模型的肝功能并减少纤维化。我们的 在小鼠和非人灵长类动物中的临床前研究表明，SZN-043 可诱导 Wnt 靶基因 激活肝脏并选择性刺激肝细胞的增殖和成熟。我们感兴趣的是 探索 SZN-043 是否能够改善 AH 的肝功能和/或纤维化。在这笔赠款中，我们建议 首先推进SZN-043的细胞系和材料制造工艺的开发。这将被遵循 通过支持 IND 的研究，包括药理学、毒理学、药代动力学和生物标志物信息 告知并确保安全有效地管理 SZN-043 进行人体测试。然后我们将进行 在人类患者中进行单次和多次递增剂量的 1 期研究，以评估药代动力学， SZN-043治疗AH的药效学和安全性。

Abstract Alcoholic hepatitis (AH) is characterized by inflammatory liver injury with impaired hepatocyte regeneration, with high rates of morbidity and mortality. Currently, steroids are the only treatment option for patients with severe AH, however, they have limited efficacy (no treatment benefit demonstrated beyond 28 days) and many patients have contra-indications to steroid use (e.g. active infections) and cannot be treated. There is a clear unmet need for new therapeutic approaches in AH. Wnt signaling plays an important role in liver development, metabolic zonation, homeostatic turnover of hepatocytes, hepatocyte differentiation and maturation, and normal function and regulation of hepatocytes. Furthermore, Wnt/β-catenin signaling is critical to hepatocyte regeneration following various forms of liver injury. Deletion or overactivation of β-catenin has been shown to have a key impact on hepatocyte regeneration following partial hepatectomy, acetaminophen, CCl4, or alcohol-induced injuries in animal models. R-spondins (RSPOs) play an important role in liver homeostasis and hepatocyte regeneration following injury such as partial hepatectomy. RSPOs enhance Wnt signaling, and RSPO function depends on the presence of endogenous Wnt ligands; endogenous Wnt ligands tend to be upregulated and localized in injured tissues. Importantly in human AH patients, lack of hepatocyte regeneration and maturation is a major issue. Surrozen has developed SZN-043, a bi-specific fusion protein which is an R-spondin mimetic targeted to the hepatocyte receptor ASGR1 for liver-specific enhancement of Wnt signaling and tissue regeneration and repair. Our studies suggest that the effects of SZN-043, in contrast to RSPO2, are highly specific to hepatocytes, and can improve liver function and reduce fibrosis in rodent disease models. Our preclinical studies in mice and non-human primates have demonstrated that SZN-043 induces Wnt-target gene activation in the liver and selectively stimulates proliferation and maturation of hepatocytes. We are interested in exploring whether SZN-043 is capable of improving liver function and/or fibrosis in AH. In this grant, we propose first moving forward to develop cell line and material manufacturing process for SZN-043. This will be followed by IND-enabling studies, including, pharmacology, toxicology, pharmacokinetics, and biomarker information to inform and enable safe and effective administration of SZN-043 for testing in humans. We will then conduct Phase 1 single- and multiple-ascending dose studies in human patients to assess pharmacokinetics, pharmacodynamics, and safety of SZN-043 for the treatment of AH.