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.

抽象的 非酒精性脂肪肝疾病（NAFLD）是在羊角内脂质的积累 肝细胞脂质液滴或“肝脂肪变性”。肝脂肪变性可以发展到 非酒精性脂肪性肝炎（NASH），这是一种慢性炎症疾病，可导致肝脏 纤维化和肝硬化。与NAFLD/NASH的发展相关的基本因素 包括肥胖和高脂血症。纳什目前在美国影响超过1000万人 并且正在成为肝衰竭和移植的主要原因，没有批准的医疗 疗法。大麻素受体CB1是治疗NASH和肥胖症的验证靶标。作为 G蛋白偶联受体（GPCR），CB1调节代谢途径和食欲通过 天然内源性大麻素系统，也是THC在 大麻。 CB1在肝脏和其他周围组织中高度表达 代谢独立于其对大脑的影响。 CB1的小分子抑制剂已经 良好的研究，甚至临床批准（Rimonabant）。但是，几乎所有人都是 由于中枢神经系统而退出市场和临床发展 - 介导的不良心理活性。可以解散外围（代谢）的药物 CB1从其中心（精神活性）效应的影响，例如自然不会跨越的mAb 血脑屏障预测在治疗纳什，肥胖症及其方面非常有效 相关并发症。但是，对CB1等GPCR的抑制作用mAB极为 由于GPCR是疏水，形成复杂的跨膜 结构，很难净化其本地脂质环境。我们在这里提出 开发针对GPCR CB1治疗NASH的mAB。