Development of CB1 Monoclonal Antibodies for Treating NASH

治疗 NASH 的 CB1 单克隆抗体的开发

• 批准号: 9918931
• 负责人: Benjamin Jacob Doranz
• 金额: $ 33.95万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918931
• 关键词: Abbreviations; Address; Affect; Affinity; Animal Model; Bacteriophages; Binding; Biological Products; Biosensor; Blood - brain barrier anatomy; Brain; CNR1 gene; Cannabis; Cell Line; Chronic; Clinical; Clinical Trials; Complex; Data; Desire for food; Development; Disease; Drug Kinetics; Engineering; Environment; Epitopes; Fatty Liver; Formulation; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Goals; Human; Hydrophobicity; Hyperlipidemia; Industry; Inflammatory; Kinetics; Lead; Ligands; Lipids; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Maps; Marijuana; Mediating; Mediator of activation protein; Medical; Membrane; Membrane Proteins; Metabolic; Metabolic Pathway; Metabolism; Monoclonal Antibodies; Moods; Mutagenesis; Neuraxis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peripheral; Pharmaceutical Preparations; Phase; Probability; Production; Proteome; Protocols documentation; Public Health; Research; Risk; Safety; Shotguns; Small Business Innovation Research Grant; Specificity; Structure; Technology; Testing; Therapeutic Monoclonal Antibodies; TimeLine; Tissues; candidate selection; cell type; clinical development; efficacy testing; endogenous cannabinoid system; human disease; immunogenicity; improved; in vivo; inhibitor/antagonist; intrahepatic; lead candidate; liver transplantation; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; phase 1 study; phase 2 study; preclinical study; rimonabant; side effect; small molecule; small molecule inhibitor; success; therapeutic development; therapeutic target; western diet

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the accumulation of intra-hepatic lipids within hepatocellular lipid droplets, or “hepatic steatosis”. Hepatic steatosis can progress to nonalcoholic steatohepatitis (NASH), a chronic inflammatory condition that can lead to liver fibrosis and cirrhosis. Underlying factors associated with the development of NAFLD/NASH include obesity and hyperlipidemia. NASH currently affects over 10 million people in the U.S. and is becoming the primary cause of liver failure and transplant, with no approved medical therapies. The cannabinoid receptor CB1 is a validated target for treating NASH and obesity. As a G protein-coupled receptor (GPCR), CB1 regulates metabolic pathways and appetite through the natural endocannabinoid system, and is also the primary mediator for the effects of THC in marijuana. CB1 is highly expressed in the liver and other peripheral tissues, where it regulates metabolism independent of its effects on the brain. Small-molecule inhibitors of CB1 have been well studied and even clinically approved (rimonabant). However, nearly all have been withdrawn from the market and clinical development due to their central nervous system- mediated adverse psychoactive effects. Drugs that can de-couple the peripheral (metabolic) effects of CB1 from its central (psychoactive) effects, such as MAbs that naturally do not cross the blood-brain barrier, are predicted to be highly effective in treating NASH, obesity, and their associated complications. However, inhibitory MAbs against GPCRs such as CB1 are extremely challenging to isolate because GPCRs are hydrophobic, form complex transmembrane structures, and are difficult to purify away from their native lipid environment. Here we propose to develop MAbs targeting the GPCR CB1 for the treatment of NASH.

摘要 非酒精性脂肪性肝病（NAFLD）是指肝内脂质的积累， 肝细胞脂滴或“肝脂肪变性”。肝脂肪变性可进展为 非酒精性脂肪性肝炎（NASH），一种慢性炎症性疾病，可导致肝脏 纤维化和肝硬化。与NAFLD/NASH发展相关的潜在因素 包括肥胖症和高脂血症。NASH目前影响美国超过1000万人。 并且正在成为肝功能衰竭和移植的主要原因， 治疗大麻素受体CB 1是治疗NASH和肥胖症的有效靶点。作为 作为一种G蛋白偶联受体（GPCR），CB 1通过以下途径调节代谢途径和食欲： 天然内源性大麻素系统，也是THC在体内作用的主要介质。 大麻CB 1在肝脏和其他外周组织中高度表达，在那里它调节 代谢独立于其对大脑的影响。CB 1的小分子抑制剂已经被 研究充分，甚至临床批准（利莫那班）。然而，几乎所有人都被 由于其中枢神经系统问题而退出市场和临床开发- 介导的不良精神作用。可以使外周（代谢） CB 1的中枢（精神活性）效应，如天然不交叉的MAb 血脑屏障，被预测在治疗NASH、肥胖及其相关疾病中是高度有效的。 相关并发症。然而，针对GPCR如CB 1的抑制性MAb是极其不稳定的。 分离具有挑战性，因为GPCR是疏水性的， 这些脂质分子是天然的脂质结构，并且难以从它们的天然脂质环境中纯化出来。在这里我们建议 开发靶向GPCR CB 1的单克隆抗体用于治疗NASH。