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SUMMARY Abalone Bio will develop antibody (Ab) drugs that inhibit intestinal inflammation to treat inflammatory bowel disease (IBD). IBD comprises chronic, debilitating, idiopathic inflammatory diseases that result in severe dam- age to the gut wall, including Crohnandapos;s disease (CD) and ulcerative colitis (UC). The primary etiology is chronic inflammation, which causes pain, diarrhea, weight loss, fever, bleeding ulcers, fistulas, and abscesses in the abdomen and perianal region, and CD patients develop obstructive intestinal fibrosis that must be surgically removed. There is an unmet need for long-acting, broadly applicable disease-modifying, and pain-reliev- ing IBD therapies. There are currently immunomodulators effective as disease-modifying therapies; however, some patients do not respond to them, they have adverse side effects, and their efficacies wane over time. To address this need, we used our proprietary Ab discovery platform to identify first-of-their-kind Ab agonists for a G protein-coupled receptor (GPCR), the cannabinoid receptor CB2. CB2 has immunomodulatory functions in many diseases that affect several body systems. In humans, CB2 is constitutively expressed in immune cells, and its expression is broadly induced in IBD, including in the colon. Consistently, CB2 function has been firmly linked to IBD: (1) CB2-KO mice are more susceptible to IBD in disease models, and (2) a common partial loss- of-function CB2 allele has been associated with increased risk of IBD in humans. CB2 agonism has limited adverse effects, and it can suppress inflammation in the gut and elsewhere, and, in contrast to CB1 agonism, it is not psychoactive. Abalone’s CB2-specific agonist Abs have many advantages over small-mole- cule CB2 agonist drug candidates, including CNS exclusion and high specificity, which minimize CB1 activation. Furthermore, Abs are natural proteins; thus, they are unlikely to have unexpected adverse effects due to chem- ical by-products. We will test the hypothesis that Abalone’s CB2 agonist Abs are feasible pre-clinical IBD thera- peutic candidates with anti-inflammatory effects. Our three major aims are (1) to engineer, produce, and char- acterize CB2 agonist Ab variants based on previously isolated and characterized agonist hits; (2) to eval- uate the anti-inflammatory activity of these CB2 agonist Abs on human immune cells; and (3) to assess the effects of the top CB2 agonist Abs in two complementary IBD mouse models. Successful completion of this Phase I project will validate this strategy for the treatment of IBD and will pave the way for further devel- opment of these Ab drugs. Although this SBIR application focuses on IBD, Abalone’s CB2 agonist Ab drugs are applicable to other inflammatory, chronic pain, and fibrotic diseases. Compared with small-molecule drugs, bio- logics have an excellent safety record, which supports development and approval for clinical trials and increased odds of marketing.NARRATIVE Inflammatory bowel diseases (IBD) are idiopathic, debilitating disorders caused by chronic intestinal inflamma- tion, and life-disrupting symptoms include pain, diarrhea, weight loss, fever, bleeding ulcers, fistulas, abscesses in the abdomen, and release of blood and mucus. While there are IBD therapeutics, some patients do not re- spond to them, most have adverse side effects, and their efficacies wane over time. In this Phase I project, Abalone Bio will develop innovative and highly specific CB2 antibody agonists that do not cross the blood-brain barrier, making them safer and more effective IBD therapeutics with fewer side effects than small-molecule CB2 agonists currently in clinical trials.