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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.

摘要