Therapeutic antibodies for treating liver fibrosis

用于治疗肝纤维化的治疗性抗体

• 批准号: 10666671
• 负责人: SCOTT L. FRIEDMAN
• 金额: $ 100万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10666671
• 关键词: Acids; Adoption; Adverse reactions; Agonist; Animal Model; Antibodies; Apoptosis; Architecture; Biological Assay; Biopsy; Bioreactors; Blood - brain barrier anatomy; Blood Pressure; Blood flow; CNR1 gene; CNR2 gene; Cause of Death; Cell Communication; Cells; Cessation of life; Characteristics; Chronic; Chronic Disease; Cicatrix; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Cross Reactions; Cyclic AMP; Data; Development; Diagnosis; Disease Progression; Disease model; Dose; Drug Targeting; Engineering; Failure; Fibrosis; Freezing; Funding; GMP lots; Goals; Good Manufacturing Process; Growth; Half-Life; Hepatic; Hepatic Stellate Cell; Hepatotoxicity; Human; Immune; In Vitro; Inflammatory; Kupffer Cells; Lead; Left; Life Style Modification; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Modeling; Mus; Myocardial Infarction; Patients; Peripheral; Pharmaceutical Preparations; Phase; Preclinical Testing; Production; Proliferating; Quality of life; Race; Rattus; Records; Running; Safety; Slice; Small Business Innovation Research Grant; Specificity; Summary Reports; Systemic Scleroderma; Technology; Testing; Therapeutic antibodies; Tissues; Variant; abalone; candidate selection; chronic liver disease; clinical candidate; clinical material; commercialization; cross reactivity; design; dimer; efficacy study; efficacy testing; immunogenicity; improved; in vitro Assay; in vitro testing; in vivo; in vivo Model; liver injury; manufacturability; manufacture; manufacturing run; meter; nanobodies; nonalcoholic steatohepatitis; painful neuropathy; paralogous gene; patient population; preclinical development; prevent; rational design; receptor; research clinical testing; scaffold; small molecule; treatment group

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, i.e., scar tissue that blocks the flow of blood through the liver, raising blood pressure and disturbing normal function. There are no approved drugs for fibrotic non-alcoholic steatohepatitis (NASH), which often progresses to cirrhosis, so patients are often left with “lifestyle modifications” that are difficult to sustain, and, at best, put patients in a race against disease progression. CB2 agonism is a promising mode of action for treating liver fibrosis/NASH. Small molecule agonists of the cannabinoid receptor CB2 have reduced liver fibrosis in several established animal models by inhibiting hepatic immune cells and hepatic stellate cells. However, small molecule CB2 agonists have drawbacks, including cross-reactivity with pro-inflammatory/pro-fibrotic CB1 receptors in immune cells and psychotropic CB1 receptors in the CNS, and rapid elimination from the body. Therefore, a CB2 agonist antibody (Ab) that is highly specific for CB2 over CB1, restricted from passing the blood-brain barrier into the CNS, and is long-lived would be an ideal drug for liver fibrosis. Unlike small molecules, which often show liver toxicities, Ab drugs have excellent safety track records in treating chronic diseases. Abalone Bio used its proprietary antibody discovery platform to isolate a selective CB2-activating nanobody (VHH), ABt101. In Phase I, ABt101 was successfully modified and reformatted into a VHH-Fc fusion antibody (ABt140) to increase its stability and in vivo half-life. Feasibility of the CB2 Ab agonist for liver fibrosis was demonstrated using two complementary in vivo models. In this Phase II SBIR project, Abalone Bio will improve ABt140’s immunogenicity an manufacturability by rational engineering, and increase its potency by selecting stronger agonists from millions of computationally designed variants using Abalone Bio’s proprietary functional Ab selection platform. Then, the selected candidate Ab will be manufactured according to Good Manufacturing Practices (GMP) standards. Progress made in parallel to this project in advancing the CB2 agonist Ab for another indication will cover remaining manufacturing development and preclinical testing (i.e., IND-enabling tox studies). The proposed GMP production run will produce clinical drug substance (DS) supply at 500L bioreactor scale, generating sufficient DS for phase I clinical studies in liver fibrosis. In parallel, the candidate Ab will be tested for efficacy in two of the most relevant disease models of NASH and fibrosis. The Ab will be applied to liver slices to understand the mechanism of action of the CB2 agonist in the context of endogenous cell-cell interactions. The FAT-NASH animal model will validate the functional anti-fibrotic activity of the CB2 agonist at a lower dose level of the optimized antibody, and the TAA model will test the activity of the CB2 agonist in a model of severe fibrosis. These studies will generate material for clinical studies and help select the most suitable patient groups for treatment with the CB2 agonist antibody.

摘要 在美国，肝硬变是十大主要死因之一，每个死因都有超过3.5万人死亡 年。肝硬变的一个主要潜在原因是与肝纤维化相关的肝损伤，即阻塞 血液流经肝脏，升高血压，扰乱正常功能。没有审批通过的 治疗纤维性非酒精性脂肪性肝炎(NASH)的药物，这种肝炎通常会进展为肝硬变，因此患者通常 留下的是难以维持的“生活方式改变”，充其量只能让患者与疾病赛跑。 进步。CB2激动剂是治疗肝纤维化/NASH的一种有前景的作用模式。小分子激动剂 在几个已建立的动物模型中，大麻素受体CB2通过抑制 肝免疫细胞和肝星状细胞。然而，小分子CB2激动剂也有缺点， 包括与免疫细胞中促炎症/促纤维化CB1受体和精神药物CB1的交叉反应 中枢神经系统中的受体，并迅速从体内消除。因此，一种CB2激动剂抗体(Ab)高度 CB2比CB1特异，限制血脑屏障进入中枢神经系统，并且是长寿的 是治疗肝纤维化的理想药物。与通常表现出肝脏毒性的小分子药物不同，抗体药物有 在治疗慢性病方面有出色的安全记录。鲍鱼生物利用其专利抗体发现 分离选择性激活CB2的纳米体(VHH)ABt101的平台。在第一阶段，ABt101成功 修饰和重塑成VHH-Fc融合抗体(ABt140)，以增加其稳定性和体内半衰期。 用两个互补的体内模型验证了CB2Ab激动剂治疗肝纤维化的可行性。 在此二期SBIR项目中，鲍鱼生物将通过Rational公司提高ABT140的S免疫原性和可制造性 工程学，并通过从数以百万计的计算设计的更强的激动剂中选择增强其效力 变种使用鲍鱼生物的专有功能抗体选择平台。然后，选定的候选AB将 按照良好制造规范(GMP)标准生产。与此同时取得的进展 推进CB2激动剂单抗用于另一适应症的项目将涵盖剩余的制造开发 和临床前测试(即，支持IND的毒性研究)。拟议的GMP生产运行将产生临床 500升生物反应器规模的药物物质(DS)供应，为肝脏I期临床研究产生足够的DS 纤维化症。同时，候选抗体将在两个最相关的疾病模型中进行疗效测试 纳什和纤维化。抗体将应用于肝脏切片，以了解CB2的作用机制 内源性细胞-细胞相互作用背景下的激动剂。胖子-纳什动物模型将验证 CB2激动剂在优化抗体的较低剂量水平下的功能性抗纤维化活性，以及TAA 模型将在严重纤维化模型中测试CB2激动剂的活性。这些研究将产生材料 用于临床研究，并帮助选择最适合使用CB2激动剂抗体进行治疗的患者组。