Therapeutic antibodies for treating liver fibrosis

用于治疗肝纤维化的治疗性抗体

• 批准号: 10011650
• 负责人: SCOTT L. FRIEDMAN
• 金额: $ 34.9万
• 依托单位: ABALONE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011650
• 关键词: Acids; Affinity; Agonist; Alcohol abuse; Animal Model; Antibodies; Apoptosis; Architecture; Benchmarking; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood flow; CNR1 gene; CNR2 gene; Cannabinoids; Cause of Death; Cell Line; Cell division; Cells; Cellular Assay; Cessation of life; Chemistry; Chronic Disease; Cicatrix; Cirrhosis; Clinical; Clinical Trials; Cognitive; Collagen; Data; Development; Disease; Disease Progression; Effectiveness; Engineering; Evaluation; Fatty acid glycerol esters; Fibrosis; Future; G-Protein-Coupled Receptors; Gene Expression; Government; Hand; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Histopathology; Human; Immune; In Vitro; Inflammation; Inflammatory; Kupffer Cells; Lead; Left; Life Style Modification; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Lung; Lung diseases; Measures; Messenger RNA; Modeling; Monitor; Mus; Pathologic; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Race; Rattus; Research; Rodent Model; Runaway; Safety; Sampling; Scleroderma; Site; Technology; Testing; Text; Therapeutic; Therapeutic antibodies; Thioacetamide; Tissues; abalone; base; blood-brain barrier crossing; cannabinoid receptor; cell type; chronic liver disease; common treatment; cross reactivity; cytokine; design; idiopathic pulmonary fibrosis; in vivo; in vivo Model; innovation; liver function; liver injury; macrophage; nonalcoholic steatohepatitis; oxidation; receptor; response; side effect; skin disorder; small molecule; success

Abstract Cirrhosis of the liver is among the top ten leading causes of death in the US, with more than 35,000 deaths each year. A major underlying cause of cirrhosis is liver injury associated with liver fibrosis; the pathological indication of cirrhosis is the development of scar tissue that replaces normal parenchyma. The scar tissue blocks the flow of blood through the liver, raising blood pressure and disturbing normal function. Current drugs that treat fibrosis are not always effective. Patients are often left with “lifestyle modifications” that are difficult to sustain, and, at best, put patients in a race against disease progression. Small molecule agonists of the cannabinoid receptor CB2 have reduced liver fibrosis in several established animal models. CB2 agonists achieve this by inhibiting hepatic immune cells and hepatic stellate cells. CB2 agonism is a promising mode of action for treating liver fibrosis. However, small molecule CB2 agonists have drawbacks that undercut their effectiveness and safety, including cross-reactivity with CB1, crossing the blood- brain barrier and cross-activating CB1, causing the adverse cognitive effects of cannabinoids and rapid elimination from the body. A highly specific CB2 agonist antibody that is long-lived and restricted to peripheral tissues would be an ideal drug to test the CB2 agonism mode of action. Abalone Bio proposes 3 aims to test the feasibility of using CB2 agonist antibody drugs to treat liver fibrosis. (1) Engineer, produce, characterize CB2 agonist antibodies. VHH-Fc versions of identified hits will be made and characterized using multiple non-liver in vitro cell-based assays. (2) Assess effects of CB2 agonist antibodies on liver cells. In this aim, the antibodies from Aim 1 will be used to characterize anti-fibrotic effects in primary liver cells and stable liver cell lines in vitro. The data will bridge receptor pharmacology in standard cell lines with in vivo data from Aim 3 and can validate and expand biomarkers for fibrosis. (3) Assess anti-fibrotic effects of a CB2 agonist antibody in an in vivo model of liver fibrosis (with leading liver fibrosis expert and Consortium PI, Dr. Scott Friedman). This aim will test the feasibility of using CB2 agonism to treat liver fibrosis in thioacetamide rat models by measuring the effects of the antibody on blood markers, collagen levels, histopathology metrics, and gene expression. Success in the Phase I project will lead to a safe and effective drug for liver fibrosis, increase scientific understanding of liver disease, and define non-invasive biomarkers to monitor disease progression. Phase II (including IND-enabling studies) will involve selecting and optimizing a lead antibody, with a focus on good clinical and manufacturing attributes. This research will enable Abalone Bio to expand the impact of its CB2 antibody agonist drugs to other diseases involving fibrosis and inflammation, e.g., skin and lung diseases such as scleroderma and idiopathic pulmonary fibrosis.

摘要 在美国，肝硬变是十大主要死亡原因之一，死亡人数超过3.5万人 每年。肝硬变的主要潜在原因是与肝纤维化相关的肝损伤；病理 肝硬变的指征是疤痕组织取代正常实质的发展。疤痕组织 阻断通过肝脏的血液流动，升高血压，扰乱正常功能。 目前治疗纤维化的药物并不总是有效的。患者经常会被留给“生活方式的改变”， 很难维持，充其量也就是让患者与疾病进展赛跑。小分子激动剂 在几个已建立的动物模型中，大麻素受体CB2的作用可以减少肝纤维化。CB2 激动剂通过抑制肝脏免疫细胞和肝星状细胞来实现这一点。CB2激动剂是一种 治疗肝纤维化的有前景的作用模式。然而，小分子CB2激动剂已经 削弱其有效性和安全性的缺点，包括与CB1的交叉反应，跨越血液- 脑屏障和交叉激活CB1，引起大麻类物质的不良认知效应并迅速 从身体里排出。一种高度特异的CB2激动剂抗体，寿命长，仅限于 外周组织可能是测试CB2激动剂作用方式的理想药物。 鲍鱼生物提出3项旨在测试使用CB2激动剂抗体药物治疗肝纤维化的可行性。 (1)设计、生产和鉴定CB2激动剂抗体。将制作识别命中的VHH-FC版本，并 采用多种非肝脏体外细胞检测方法进行表征。(2)评估CB2激动剂抗体的效果 在肝细胞上。在这个目标中，来自目标1的抗体将被用来表征初级患者的抗纤维化效果。 体外培养肝细胞和稳定的肝细胞系。这些数据将在标准细胞系中连接受体药理学 利用AIM 3的体内数据，可以验证和扩展纤维化的生物标记物。(3)评价抗肝纤维化作用 CB2激动剂抗体在体内肝纤维化模型中的作用(与领先的肝纤维化专家和财团合作 Pi，Scott Friedman博士)。这一目的将检验使用CB2激动剂治疗肝纤维化的可行性。 通过测定抗体对硫代乙酰胺大鼠血液标记物、胶原蛋白水平、 组织病理学指标和基因表达。 一期项目的成功将带来安全有效的治疗肝纤维化的药物，增加科学 了解肝脏疾病，并定义非侵入性生物标志物以监测疾病进展。第二阶段 (包括支持IND的研究)将涉及选择和优化铅抗体，重点是好的 临床和制造属性。这项研究将使鲍鱼生物扩大其CB2的影响 其他涉及纤维化和炎症的疾病的抗体激动剂药物，如皮肤和肺部疾病 如硬皮病和特发性肺纤维化。