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Replies to post #171891 on Biotech Values
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.
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