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：
10547688
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/10547688
关键词：
Acids Address Adoption Adverse reactions Agonist Animal Model Antibodies Apoptosis Architecture Attenuated Biological Assay Biopsy Bioreactors Blood - brain barrier anatomy Blood Pressure Blood flow CNR1 gene CNR2 gene Cause of Death Cell Communication Cells Certification Cessation of life Characteristics Chronic Chronic Disease Cicatrix Cirrhosis Clinical Clinical Research Clinical Trials Cyclic AMP Data Development Diagnosis Disease Progression Disease model Dose Drug Targeting Engineering Failure Fibrosis Freezing Funding GMP lots Goals 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 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 chronic liver disease clinical candidate clinical material cross reactivity design dimer efficacy study efficacy testing immunogenicity improved in vitro Assay in vitro testing in vivo in vivo Model liver injury manufacturability 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.

抽象的肝硬化是美国十大死亡原因之一，每项死亡人数均超过 35,000 人肝硬化的一个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。血液流经肝脏，导致血压升高并扰乱正常功能，目前尚未获得批准。治疗纤维化非酒精性脂肪性肝炎 (NASH) 的药物，这种疾病经常进展为肝硬化，因此患者经常留下难以维持的“生活方式改变”，最多只能让患者与疾病赛跑 CB2 激动进展是治疗肝纤维化/NASH 的一种有前景的作用方式。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激动剂有缺点，包括与免疫细胞中促炎/促纤维化 CB1 受体和精神药物 CB1 的交叉反应 CB2 激动剂抗体 (Ab) 是高度的。与 CB1 相比，CB2 具有特异性，无法通过血脑屏障进入中枢神经系统，且寿命较长与经常表现出肝脏毒性的小分子药物不同，抗体药物具有治疗肝纤维化的理想药物。 Abalone Bio 使用其专有的抗体发现来治疗慢性疾病，具有良好的安全记录。分离选择性 CB2 激活纳米抗体 (VHH) ABt101 的平台在第一阶段，ABt101 获得成功。修饰并重新格式化为 VHH-Fc 融合抗体 (ABt140)，以增加其稳定性和体内半衰期。使用两个互补的体内模型证明了 CB2 Ab 激动剂治疗肝纤维化的可行性。在这个二期SBIR项目中，Abalone Bio将通过合理的方法提高ABt140的免疫原性和可制造性工程，并通过从数百万计算设计的中选择更强的激动剂来提高其效力使用 Abalone Bio 专有的功能性抗体选择平台进行变体，然后，选定的候选抗体将被选中。根据良好生产规范 (GMP) 标准进行生产。推进 CB2 激动剂抗体另一个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 的毒物研究）。拟议的 GMP 生产运行将进行临床试验。 500L生物反应器规模的原料药（DS）供应，为肝脏I期临床研究产生足够的DS 与此同时，候选抗体将在两种最相关的疾病模型中进行功效测试。 NASH 和纤维化将应用于肝脏切片以了解 CB2 的作用机制。 FAT-NASH 动物模型将验证内源性细胞间相互作用的激动剂。优化抗体和 TAA 较低剂量水平下 CB2 激动剂的功能性抗纤维化活性模型将测试 CB2 激动剂在严重纤维化模型中的活性。这些研究将产生材料。用于临床研究并帮助选择最适合接受 CB2 激动剂抗体治疗的患者群体。