Coley Pharmaceutical Group Diversifies Pipeline with First-in-Class TLR Antagonist for the Treatment of Systemic Lupus Ery...(is where TLRs 7 8 and 9 areinappropriate...),Health

CPG 52364's Mechanism of Action in SLE

The defining characteristic of SLE is the production of autoantibodies, abnormal antibodies produced against the body's own tissues or organs. In SLE, these autoantibodies bind to DNA and/or RNA, and their associated cellular proteins, forming "immune complexes". Immune complexes containing anti-DNA antibodies activate TLR9, while immune complexes that contain RNA activate TLR7 and TLR8.

Recent studies show that the development and progression of SLE are driven by the inappropriate activation of TLR7, TLR8 and TLR9. TLRs7 and 9 are present within B cells, which secrete high levels of interferon-alpha and contribute to disease severity. TLR8 is expressed in monocytes and other dendritic cells, which are thought to produce proinflammatory cytokines, which further contribute to disease process. Other studies have indicated that autoimmunity in rheumatoid arthritis (RA) and psoriasis also is mediated through one or more of these TLRs.

Coley evaluated and selected TLR7, 8 and 9 as important targets by elucidating the therapeutic mechanism of action for a commonly used treatment for SLE and RA. For many years, SLE and RA patients have been treated with certain antimalarial drugs as a treatment for SLE, such as hydroxychloroquine (HCQ), which was serendipitously discovered to be a moderately effective therapy for the disease. The therapeutic mechanism for HCQ in these autoimmune diseases had been unknown, until research from Coley and other scientists revealed that the compound is an antagonist of TLR9, and to a lesser extent TLRs7 and 8.

Based on the new recognition by Coley that the efficacy of HCQ appears to result from blocking TLRs 7, 8 and 9, Coley designed and
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