T Helper Type 2 (Th2) Cells and Allergic Disease

Th2 cells express high levels of CCR4 and are clinically validated drivers of allergic diseases along the “atopic march”, which includes atopic dermatitis (AD), asthma, chronic urticaria (skin rash), allergic conjunctivitis, rhinosinusitis and eosinophilic esophagitis (inflammation of the esophagus). When a pathogen comes into contact with the skin or mucosal lining of the nose or lungs, an immune response is triggered. It is believed that innate immune cells and antibodies that recognize the pathogen initiate a release of inflammatory cytokines, leading to the recruitment of other immune system components, including Th2 cells. Th2 cells secrete inflammatory cytokines, such as interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13). While this Th2 response may be highly effective against foreign pathogens, particularly parasites, sometimes the body overreacts to benign substances in this way, resulting in a significant and presumably unnecessary influx of Th2 cells, leading to conditions along the atopic march.

At a cellular and molecular level, the Th2 response is initiated and sustained when Th2 cells are recruited to the site of inflammation by the binding of CCL17 and CCL22 to CCR4. Patients suffering from AD and other allergic disorders have significantly elevated levels of both CCL17 and CCL22, suggesting that inhibiting the ability of these chemokines to bind to CCR4 may prevent migration of Th2 cells into these inflamed sites, thus reducing inflammation.

CCL17 and CCL22 levels have been found to strongly correlate with many allergic disorders including atopic dermatitis. Dupilumab works by blocking the receptor for IL-4 and IL-13, two of the cytokines produced by Th2 cells, leading to a reduction in the level of inflammation. Dupilumab also indirectly leads to reductions in the level of CCL17, thus breaking the Th2-driven inflammatory cycle. We believe that inhibition of the CCR4 receptor will block the migration of Th2 into these inflammatory sites, leading to reductions in inflammation thereby blocking the secretion of IL-4, IL-5 and IL-13 before they can induce tissue damage.

RPT193 is an oral CCR4 antagonist that we believe will provide a competitive advantage to injectable antibodies, systemic corticosteroids and topical agents. RPT193 blocks CCL17 and CCL22 from binding to CCR4 on Th2 cells. This prevents these Th2 cells from migrating to the site of inflammation and releasing IL-4, IL-5 and IL-13, inflammatory cytokines that lead to increased inflammation and tissue damage.