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）的特征是炎性肝损伤伴肝细胞再生受损， 发病率和死亡率高。目前，类固醇是严重糖尿病患者的唯一治疗选择。 然而，它们的疗效有限（超过28天未显示治疗获益），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。有一个明显的未满足的需求 新的治疗方法。Wnt信号转导在肝脏发育、代谢和免疫调节中起着重要作用。 肝细胞的分区、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-catenin信号传导对肝细胞再生至关重要 各种形式的肝损伤。β-连环蛋白的缺失或过度激活已被证明具有关键的 对乙酰氨基酚、四氯化碳或酒精诱导肝部分切除术后对肝细胞再生影响 动物模型中的损伤。R-spondins（RSPOs）在维持肝脏内环境稳定和肝细胞功能中起重要作用 损伤后的再生，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配体倾向于被上调， 局限于受伤的组织重要的是，在人类AH患者中，缺乏肝细胞再生和成熟是一个重要的因素。 一个主要问题。Surrozen开发了SZN-043，一种双特异性融合蛋白，是R-spondin模拟物 靶向肝细胞受体ASGR 1，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RSPO 2相比，SZN-043的作用高度 在啮齿类动物疾病模型中，其对肝细胞具有特异性，并且可以改善肝功能并减少纤维化。我们 在小鼠和非人灵长类动物中的临床前研究表明，SZN-043诱导Wnt靶基因 在肝脏中激活并选择性地刺激肝细胞的增殖和成熟。我们有兴趣 探索SZN-043是否能够改善AH的肝功能和/或纤维化。在这份补助金中，我们建议 首先是开发SZN-043的细胞系和材料生产工艺。随后将 通过IND使能研究，包括药理学、毒理学、药代动力学和生物标志物信息， 告知并使SZN-043能够安全有效地用于人体试验。然后我们将进行 在人类患者中进行的I期单次和多次给药剂量递增研究，以评估药代动力学， SZN-043用于治疗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.