Development of CB1 Monoclonal Antibodies for Treating NASH

摘要 非酒精性脂肪性肝病(NAFLD)是指肝内脂肪在 肝细胞脂滴，或“肝脏脂肪变性”。肝脏脂肪变性可进展为 非酒精性脂肪性肝炎(NASH)，一种可导致肝脏的慢性炎症性疾病 纤维化和肝硬变。与NAFLD/NASH发展相关的潜在因素 包括肥胖和高脂血症。NASH目前在美国影响着1000多万人。 它正在成为肝功能衰竭和移植的主要原因，目前还没有批准的医疗方法 治疗。大麻素受体CB1是治疗NASH和肥胖症的有效靶点。AS CB1是G蛋白偶联受体，通过调节代谢途径和食欲 天然内源性大麻素系统，也是THC作用的主要媒介。 大麻。CB1在肝脏和其他外周组织中高度表达，在这些组织中它调节 与其对大脑的影响无关的新陈代谢。CB1的小分子抑制剂已经被 经过充分研究，甚至临床批准(利莫那班)。然而，几乎所有的人都是 由于他们的中枢神经系统而退出市场和临床开发- 调节了不良的精神活动效应。能使外周(代谢)解偶联的药物 CB1的中枢(精神活性)效应，如天然不交叉的单抗 血脑屏障，被预测在治疗NASH、肥胖症和他们的 相关并发症。然而，针对GPCR的抑制单抗，如CB1，是非常 由于GPCRs是疏水性的，形成复杂的跨膜，因此分离具有挑战性 结构，很难从天然的脂类环境中提纯出来。在这里，我们建议 目的：研制针对GPCRCB1的单抗，用于NASH的治疗。

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 However, nearly all have been withdrawn from the market and clinical development due to their central nervous system- mediated adverse psychoactive effects.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.