CCR4, a Novel Target for Cancer and Inflammation

Chemokines are signaling proteins that influence many key biological processes in tumor biology. Chemokines play an important role in mediating inflammation, recruiting cells to specific environments, tumor metastasis, tumor cell proliferation and tumor cell survival. Because of their extensive role in biology, chemokines and their receptors have become an exciting target for therapeutic intervention. Humans have 44 chemokines, all of which bind and act through G-protein coupled receptors (GPCRs) that can be classified into four groups: CXC, CC, C and CX3C.

Two of these chemokines, CCL17, also named thymus- and activation-regulated chemokine (TARC) and CCL22, also termed macrophage-derived chemokine, function as a distress signal to recruit cells to a specific environment. Both CCL17 and CCL22 bind exclusively to the C-Chemokine Receptor 4 (CCR4) receptor. Several immune cells express the CCR4 receptor, though CCR4 is predominantly found on Treg cells and Th2 cells.

When an active tumor is present, cells within the tumor microenvironment produce an abundance of CCL17 and CCL22, recruiting regulatory T cells en masse into the tumor microenvironment to suppress the immune response against the tumor. Our oral small molecule compound FLX475 blocks binding of CCL17 and CCL22 to the regulatory T cells, and encourages an immune response. FLX475 binds preferentially to regulatory T cells over Th2 cells, allowing routine immune surveillance in normal tissues to continue.

In allergic asthma and atopic dermatitis, these same chemokines recruit T helper type 2 (Th2) cells to overstimulate an immune response, resulting in severe inflammation in the lungs (allergic asthma) or skin (atopic dermatitis).

Due to the complementary biology, we are pursuing two different small molecule therapeutics that target CCR4: FLX475 targets overactive Treg cells for the treatment of cancer and FLX193 targets overactive Th2 cells for the treatment of allergic disorders.