Our proprietary drug discovery and development engine has identified several immune drivers that have the ability to be “tuned up” or “tuned down” to modulate the immune system, either to initiate an immune response against a tumor in cancer or to suppress an overactive immune response in allergic inflammatory diseases.
Our lead drug candidates, FLX475 and RPT193, target the important cell surface receptor CCR4 (C-C Motif Chemokine Receptor 4). Receptors such as CCR4 bind to chemoattractant molecules called chemokines that orchestrate migration and homing of cells to specific tissues throughout the body. Chemokines specific to CCR4 are secreted from tumors and from allergically inflamed tissues, but not from healthy tissues. Our proprietary approach is designed to prevent the recruitment of disease-promoting immune cells into tumors and inflamed tissues in order to treat cancer and allergic inflammatory diseases.

The potential to unlock antitumor immunity

In cancer, the secretion of certain chemokines from tumor cells and tumor-resident immune cells is responsible for recruitment of immunosuppressive Treg cells to tumor sites. Treg represent a dominant pathway for downregulating the immune response, and thus may limit the effectiveness of currently available therapies such as checkpoint inhibitors. Blocking the migration of Treg has the potential to restore naturally occurring antitumor immunity as well as to synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators and adoptive T cell therapy.
Our proprietary approach is designed to enable selective restoration of the immune response within tumors without systemically depleting T cells or broadly suppressing the immune system, a side effect experienced with existing CCR4 therapies. We believe that the inhibition of CCR4 has the potential to bring therapeutic benefit to patients across a wide spectrum of tumors in a manner similar to other immuno-oncology therapies that have been shown to be effective against multiple tumor types, while also potentially deepening and/or broadening clinical responses to these therapies.

The capacity to “down regulate” the inflammatory response

In allergic inflammatory diseases, chemokines recruit helper T type 2 (Th2) cells to inflamed tissues. Once Th2 cells enter tissues such as the skin or the airways in the lung, they secrete proteins known to drive the inflammatory response. In atopic dermatitis, there are higher levels of these inflammatory ligands compared with healthy humans and these ligands also correlate with the severity of disease.
We believe that by inhibiting CCR4, RPT193 (our novel drug candidate) has the potential to bring therapeutic benefit to patients across a broad spectrum of allergic diseases, including asthma, chronic urticaria, chronic rhinosinusitis, allergic conjunctivitis and eosinophilic esophagitis.

The key to converting the dysregulated tumor metabolism and inducing potent antitumor responses

GCN2, or general control nonderepressible 2, is a stress response kinase that regulates the immune system and survival of tumor cells in the tumor microenvironment. Due to the aberrant vasculature of tumors, the blood supply is limited and results in a lack of oxygen and deprivation of nutrients, including amino acids. In human tumors, the GCN2 pathway is activated and, importantly, we have demonstrated that pharmacologic inhibition of GCN2 limits tumor growth in preclinical mouse tumor models. Activation of the normal immune response cells is highly dependent on the availability of amino acids and other nutrients. GCN2 is a key cellular sensor and integrating node in T and other cells for amino acid and glucose limitation.

Low levels of amino acids such as tryptophan, arginine and other amino acids lead to activation of GCN2. This triggers a cascade of cell-signaling events in T cells, leading to the inhibition of effector cell function and growth. GCN2, through this regulatory pathway, prevents immune cells from mounting an effective response when amino acid levels are in limited supply. Inactivation of GCN2 removes this regulatory block and allows effector cell proliferation and activation even under conditions of amino acid starvation similar to what may exist in tumors.