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Toll-like receptor 4
(TLR4); fibrinogen

In vitro and mouse studies suggest blocking the interaction between fibrinogen cleavage products and TLR4 could help treat allergic asthma. In mice, Tlr4 knockout or treatment with a proteinase inhibitor decreased allergic airway disease induced by a fungal proteinase or ovalbumin compared with no knockout or with vehicle treatment. In human and mouse macrophages, fibrinogen cleavage products, generated from serum fibrinogen by fungal or airway proteinases, induced an antifungal immune response that was prevented by Tlr4 knockout. Next steps include identifying the specific fibrinogen cleavage products involved in antifungal immunity and airway hyperresponsiveness.
Eisai Co. Ltd.'s Eritoran (E5564), a synthetic lipid A analog that blocks TLR4 activation, failed to meet the primary endpoint of reduced mortality in Phase III testing for sepsis, and development has been put on hold.
At least two other companies have TLR4 inhibitors in Phase II or earlier testing to treat inflammatory or autoimmune diseases (see TLR4 signaling in

allergic asthma, page 1).

SciBX 6(35); doi:10.1038/scibx.2013.964
Published online Sept. 12, 2013

Findings unpatented; unavailable for licensing

Millien, V.O. et al. Science; published online Aug. 16, 2013;
Contact: Farrah Kheradmand, Baylor College of Medicine, Houston, Texas

Contact: David B. Corry, same affiliation as above