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: 10707988
• 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/10707988
• 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; 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 Fibrosis; 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; Phase; Play; Prediction of Response to Therapy; Process; Proliferating; 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; manufacture; manufacturing process; mimetics; mortality; mouse model; nonhuman primate; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical; preclinical study; receptor; regeneration following injury; safety assessment; sobriety; tissue regeneration; tissue repair

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.

摘要 酒精性肝炎(AH)以炎性肝损伤和肝细胞再生受损为特征， 高发病率和高死亡率。目前，类固醇是重症患者的唯一治疗选择 啊，然而，它们的疗效有限(超过28天没有治疗益处)，许多患者 有使用类固醇的禁忌症(如活动性感染)，不能治疗。有一个明显的未得到满足的需求 寻找治疗急性胰腺炎的新方法。WNT信号在肝脏发育、代谢中发挥重要作用 分区、肝细胞内稳态周转、肝细胞分化成熟和正常功能 和肝细胞的调节。此外，Wnt/β-catenin信号对肝细胞再生至关重要。 在各种形式的肝脏损伤之后。β-连环蛋白的缺失或过度激活已被证明有一个关键 肝部分切除、对乙酰氨基酚、CCl4或酒精诱导对肝细胞再生的影响 动物模型中的损伤。R-海绵蛋白(RSPO)在肝脏内稳态和肝细胞中起重要作用 损伤后的再生，如肝部分切除。RSPO增强WNT信号转导和RSPO功能 取决于内源性Wnt配体的存在；内源性Wnt配体倾向于上调和 定位于受损组织。重要的是，在人类AH患者中，肝细胞再生和成熟不足 这是个大问题。苏罗岑开发了SZN-043，这是一种双特异性融合蛋白，是一种R-响应素模拟物 靶向肝细胞受体ASGR1的肝脏特异性增强Wnt信号和组织 再生和修复。我们的研究表明，与RSPO2相比，SZN-043的效果非常好 对肝细胞具有特异性，并能改善肝功能，减少啮齿类疾病模型的纤维化。我们的 在小鼠和非人灵长类动物上的临床前研究表明，SZN-043诱导Wnt-靶基因 在肝脏中激活，选择性地刺激肝细胞的增殖和成熟。我们感兴趣的是 探讨SZN-043是否能改善急性肝炎患者的肝功能和/或纤维化。在这笔赠款中，我们建议 率先为SZN-043开发电池线和材料制造工艺。这将是遵循的 通过IND-Enabling研究，包括药理学、毒理学、药代动力学和生物标志物信息 告知并启用安全有效的SZN-043人体试验给药。然后我们将进行 在人类患者中进行第一阶段单次和多次递增剂量研究以评估药物动力学， SZN-043治疗急性肝炎的药效学和安全性。