Development of CB1 Monoclonal Antibodies for Treating NASH

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 However, nearly all have been withdrawn from the market and clinical development due to their central nervous system- mediated adverse psychoactive effects.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