Therapeutic antibodies for treating liver fibrosis

用于治疗肝纤维化的治疗性抗体

基本信息

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
项目类别：
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

项目摘要

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.

抽象的肝脏的肝硬化是美国十大主要死亡原因之一，每个死亡人数超过35,000 年。肝硬化的主要根本原因是与肝纤维化相关的肝损伤，即阻塞的疤痕组织血液通过肝脏的流动，升高血压和干扰正常功能。没有批准纤维化非酒精性脂肪性肝炎（NASH）的药物通常会发展为肝硬化，因此患者通常是剩下难以维持的“生活方式修改”，充其量是将患者置于反疾病的比赛中进展。 CB2激动剂是治疗肝纤维化/NASH的有希望的作用方式。小分子激动剂在几种已建立的动物模型中，大麻素受体CB2的CB2降低了肝纤维化肝免疫细胞和肝星状细胞。但是，小分子CB2激动剂有缺点，包括与免疫细胞和精神CB1中促炎/纤维化CB1受体的交叉反应性中枢神经系统中的受体，并从体内快速消除。因此，高度的CB2激动剂抗体（AB）特定于CB2超过CB1，仅限于将血脑屏障传递到CNS中，并且长期存在成为肝纤维化的理想药物。与经常显示肝毒性的小分子不同，AB药物具有出色的安全往绩记录治疗慢性疾病。鲍鱼生物使用其专有抗体发现隔离选择性CB2激活纳米机构（VHH）的平台，ABT101。在第一阶段，ABT101成功修改并重新格式化为VHH-FC融合抗体（ABT140），以提高其稳定性和体内半衰期。使用两种完整性在体内模型中证明了CB2 AB激动剂对肝纤维化的可行性。在此II阶段SBIR项目中，鲍鱼生物将改善ABT140的免疫原性工程学，并通过从数百万计算设计中选择更强大的激动剂来提高其效力使用鲍鱼生物专有功能AB选择平台的变体。然后，选定的候选人AB将根据良好的制造实践（GMP）标准制造。与此并行取得的进度推进CB2激动剂AB以供其他迹象的项目将涵盖其余的制造开发和临床前测试（即，托克斯研究）。拟议的GMP生产运行将产生临床在500升生物反应器量表的药物药物（DS）供应，为肝脏I期临床研究产生足够的DS 纤维化。同时，将在两个最相关的疾病模型中测试候选AB的效率纳什和纤维化。 AB将应用于肝切片以了解CB2的作用机理在内源性细胞相互作用的背景下激动剂。脂肪纳什动物模型将验证 CB2激动剂的功能性抗纤维化活性在优化抗体的较低剂量水平和TAA下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合适的患者组，用于用CB2激动剂抗体治疗。