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

一种肝细胞特异性 R-spondin 模拟双特异性融合蛋白，可刺激急性酒精性肝炎患者的肝细胞再生

• 批准号: 10488068
• 负责人: Jay Tibbitts
• 金额: $ 50.5万
• 依托单位: SURROZEN OPERATING, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488068
• 关键词: Abdominal Cavity; Acetaminophen; Acute Alcoholic Hepatitis; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Antibodies; Ascites; Benefits and Risks; Biological Assay; Biological Markers; Cell Line; Child; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Clone Cells; Development; Disease model; Dose; Drug Kinetics; Fatigue; Fibrosis; Formulation; Gene Activation; Grant; Hepatic Encephalopathy; Hepatocyte; Homeostasis; Human; Icterus; Impairment; Infection; Inflammatory; Informed Consent; Ligands; Liver; Liver Cirrhosis; Liver Regeneration; Liver diseases; Manufactured Materials; Measures; Metabolic; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Mutate; Natural regeneration; Nature; Partial Hepatectomy; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Pharmacology and Toxicology; Phase; Play; Process; Proteins; Regimen; Regulation; Rodent; Rodent Diseases; Role; Running; Safety; Serum; Signal Transduction; Signs and Symptoms; Steroids; Testing; Tissues; Toxicology; WNT Signaling Pathway; beta catenin; cross reactivity; effective therapy; human tissue; improved; injured; interest; liver development; liver function; liver injury; liver repair; liver transplantation; manufacturing process; mimetics; mortality; mouse model; nonhuman primate; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical study; predicting response; receptor; regeneration following injury; sobriety; tissue regeneration; tissue repair; treatment response

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.

抽象的 酒精性肝炎（AH）的特点是炎症性肝损伤伴肝细胞再生受损， 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 有使用类固醇的禁忌症（例如活动性感染）且无法治疗 存在明显的未满足需求。 Wnt 信号传导在肝脏发育、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 此外，Wnt/β-连环蛋白信号传导对于肝细胞再生至关重要。 β-连环蛋白的缺失或过度激活已被证明具有关键作用。 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 动物模型损伤中，R-spondins (RSPO) 在肝脏稳态和肝细胞中发挥着重要作用。 部分肝切除等损伤后的再生增强了 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 配体倾向于上调并且 重要的是，在人类 AH 患者中，肝细胞再生和成熟缺乏。 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 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。 对小鼠和非人灵长类动物的临床前研究表明，SZN-043 诱导 Wnt 靶基因 我们感兴趣的是肝脏中的激活并选择性地刺激肝细胞的增殖和成熟。 探索 SZN-043 是否能够改善 AH 的肝功能和/或纤维化。 首先推进SZN-043的细胞系和材料制造工艺的开发。 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 SZN-043 能够安全有效地进行人体测试。 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。