Targeting host response to DAMP for therapy of Rheumatoid Arthritis
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AbstractDESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is among the most common autoimmune diseases. The current treatment for RA is mainly by targeting tumor-necrosis factor (TNF). Despite the remarkable efficacy, significant portion of RA patients are not responsive to this class of drugs. Therefore, there is an urgent need to develop therapeutic that can complement existing therapeutic biologics. Recently, it has been suggested that danger (or damage)-associated molecular patterns (DAMPs), a group of intracellular component released from necrotic cells, such as HMGB1 and HSP70, may be involved in the pathogenesis of RA. In consistency with this notion, partial inhibition of collagen-induced arthritis was achieved by administration of anti-HMGB1 mAb. These data support the notion that tissue destruction by autoreactive cells can form a vicious cycle of chronic inflammation, as is the case of RA. However, it appears that the impact of anti-HMGB1 antibodies remains modest. The relatively minor effectsare to be expected as multiple DAMPs are expected to be released during autoimmune tissue damage. On the other hand, we have recently identified that CD24-Siglec 10 mediate a negatively regulatory pathway that selective regulates host response to DAMP 1.Since the CD24 binds to multiple DAMPs, including HMGB1, HSP70, HSP90 and nucleolin, it is conceivable that CD24 fusion proteins can be explored for therapy of RA. As the proof of concept, we have shown that CD24Fc, a fusion protein consisting extracellular domain of human CD24 and the Fc of human IgG1, protected mice against RA induced by a cocktail of anti-collagen antibodies. Based on this exciting observation, we will use collagen-induced arthritis (CIA) model, the gold standard for clinical developmentof RA drug, to confirm the therapeutic effect of CD24Fc and compare CD24Fc with Enbrel, the clinically used soluble receptor for TNFa. In addition, we will establish an in vitro model to demonstrate the mode of action of the CD24Fc, as detailed in two specific aims. Specifically, we will establish the therapeutic effect of CD24Fc using CIA model and determine whether the therapeutic efficacy of CD24Fc can be used in combination with TNFa antagonist to increase therapeutic efficacy. Then we will determine the CD24 expression in DC and macrophages among the inflammatory cells and identify the population that produces inflammatory cytokine. We will also test whether CD24Fc inhibit the production of inflammatory cytokines on these cells. The completion of thisproposal will not only substantiate the therapeutic potential of CD24Fc, but also provide a mechanism of action for CD24Fc and facilitate the down-stream drug development. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is among the most common autoimmune diseases and it affects 0.5-1% of humans. Despite the remarkable efficacy of the current therapies that mostly target on TNF-alpha, significant portion of RA patients are not responsive to these treatments. The ultimate goal of this application is to develop a novel biological therapeutics, namely CD24Ig Fc fusion protein, by targeting danger (or damage)-associated molecular patterns (DAMPs), which was recently been demonstrated to be involved in the pathogenesis of Rheumatoid arthritis.
* information listed above is at the time of submission.