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IDRA - Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616729/

Inappropriate or uncontrolled TLR signaling has been implicated in certain autoimmune and inflammatory conditions, including SLE, psoriasis, rheumatoid arthritis and multiple sclerosis (3–8). Endogenous immune complexes containing self-nucleic acids act as ligands for TLR7 and TLR9 and induce pro-inflammatory cytokines, including expression of IL-12, TNF-a, IL-1ß, IL-6, IFN-a and IFN-inducible genes, contributing to the pathogenesis of SLE and other autoimmune diseases (9,10). The current treatment options for autoimmune and inflammatory diseases include cytotoxic and immune-modulatory agents. The antimalarial drug HCQ, commonly used for the treatment of autoimmune diseases, inhibits TLR activation through neutralization of endosomal acidification and/or by direct interaction with nucleic acids present within immune complexes (19,20). Monoclonal antibodies directed against cytokines such as TNF-a, IFN-a, IL-6, IL-12/IL-23, IL-17 and IP-10, and factors such as B-cell activating factor (BAFF) that activate B cells are also commonly used as treatments for autoimmune diseases (54–56). These agents act on a single component of the inflammatory response or one type of cell population. The antagonist compounds described herein selectively inhibited multiple cytokines produced after TLR7, 8 and 9 activation in human PBMCs, DCs and B cell proliferation, suggesting that the antagonists can inhibit all sources of inflammation mediated through these receptors implicated in autoimmune diseases. An antagonist compound, referred to as IMO-3100, has shown good safety profile and proof of concept of target engagement of TLR7 and TLR9 in healthy human subjects in phase 1 clinical trials (57) and is currently being evaluated in psoriasis patients in a phase 2 clinical trial. Another antagonist compound IMO-8400, which inhibits TLR7-, 8- and 9-mediated immune responses, is being developed for lupus treatment and is in phase 1 safety studies.