Cannabinoid Receptor 2 Activating Antibodies: A Promising Therapeutic Strategy for Macrophage-Driven...

Fibrotic diseases, often fueled by chronic inflammation, represent a major unmet medical need. A critical driver of this process is the activation of macrophages, which secrete pro-inflammatory cytokines and chemokines, leading to immune cell recruitment and collagen deposition by myofibroblasts. Agonizing the cannabinoid receptor 2 (CB2), expressed on macrophages, offers a potential therapeutic avenue to suppress this activation. Despite widespread interest in CB2 modulation, challenges remain in the development of small molecule agonists, including insufficient specificity and poor drug-like properties. Antibodies are highly specific with favorable pharmacokinetics and bioavailability, but GPCR agonist antibodies have been difficult to discover. Here we present first-in-class CB2 agonist antibodies, AB120 and AB150. These antibodies are CB2 specific, G-alpha biased, and effectively decrease the expression of macrophage activation markers and key pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α. Furthermore, using an ex vivo human precision-cut liver slice (hPCLS) model of liver fibrosis, we observe that treatment with these CB2 agonist antibodies not only reduces inflammatory markers but also significantly decreases collagen expression, indicating a potential to halt or reverse fibrosis. These novel CB2-specific agonist antibodies hold promise as therapeutics for a range of fibrotic and inflammatory conditions driven by chronic macrophage activation and demonstrate the potential of GPCR antibody agonists to drug this challenging class of targets.