Xanthus Pharmaceuticals, Inc (CAMBRIDGE, Massachusetts), a clinical-stage biopharmaceutical company that focuses on the discovery, development, acquisition, and commercialization of small-molecule therapeutics for the treatment of autoimmune diseases and cancer, announced that it has acquired an exclusive worldwide license to a patent estate from The Johns Hopkins University (JHU) for treating immune-related disorders by inhibiting the FLT3 receptor tyrosine kinase. FLT3 is highly expressed on dendritic cells (DCs), which are responsible for the stimulation of T-cells.

A large portion of DCs are derived from hematopoietic progenitors that express the FLT3 receptor (CD135), and stimulation of the receptor drives expansion and differentiation of these progenitors toward an antigen-presenting cell phenotype. FLT3 expression is maintained on mature DCs and plays a role in protecting mature DCs from apoptosis. Thus, inhibition of DC-induced stimulation of T-cells may downregulate inappropriate immune responses to ameliorate autoimmune disease.

In preclinical studies conducted by JHU researchers, inhibition of FLT3 signaling induced apoptosis in murine and human cell cultures of mature DCs, decreased T-cell stimulation, and significantly improved the course of chronic disease in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE) without the induction of gross immunosuppression or marked changes in the B- and T-cell populations. These findings suggest the FLT3 pathway as a potential target for immune modulation.

Xanthus and JHU are collaborating to assess novel compounds for FLT3 inhibitory activity and the downstream pathways relevant to a range of autoimmune diseases. The new compounds are, imidazoacridinones, and Symadexâ„¢ (formerly C-1311), the lead compound in this series. Symadex is a potent and selective orally available antiproliferative agent that targets FLT3 in the platelet-derived growth factor (PDGF) family. Symadex lacks efficacy in the treatment of the acute, T-cell mediated portion of the disease, but the compound can reverse the clinical and pathological changes of chronic EAE and permit spinal cord remyelination. Symadex is currently in phase II clinical trials in oncology and Xanthus is exploring its use for the treatment of a number of autoimmune diseases including rheumatoid arthritis and inflammatory bowel disease, where early preclinical studies have shown encouraging signs of activity.

—A. Techman

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