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Eric S. Furfine, Jay Hou, Kathy Collins, Sharon Townson, Kathryn Golden, Emily Schirmer, Joe Kovalchin, Greg Papastoitstis, Tom Barnes; EBI-005: an Interleukin-1 Receptor Inhibitor Designed for the Treatment of Dry Eye Syndrome. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2340.
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Interleukin-1α (IL-1α) and IL-1β are upregulated in dry eye syndrome (DES) in humans and mouse models of the disease. Blockade of IL-1 signaling by topical application of anakinra (recombinant IL-1 receptor antagonist, IL-1Ra), pharmacy compounded as eye drops for experimental purposes, reduced disease signs (corneal fluorescence staining) in mouse models of DES and reduced signs and symptoms (ocular surface disease index) in an investigator-sponsored Phase 2 study. Because anakinra is a drug approved for systemic anti-inflammatory treatment, a protein with superior pharmaceutical properties for topical use, such as potency and thermal stability was created to make an improved DES treatment.
A chimera of IL-1β and IL-1Ra, EBI-005, was constructed and expressed in E. coli. In vitro potency was measured by surface plasmon resonance, blockade of IL-1β-induced intracellular signaling in HEK-blue cells, and reduction of IL-1β-induced IL-6 production in MG63 cells. In vivo potency was measured in a mouse model of DES where a chamber maintains relative humidity at approximately 20%, which induces corneal fluorescence staining. Thermal stability was measured by fluorescence dye interaction.
A single-domain protein, EBI-005, was created by fusing the most potent IL-1 receptor binding sub-domains of IL-1β and IL-1Ra. EBI-005 bound IL-1R1 ~30-fold more potently than anakinra, 10-fold more potently blocked IL-1β-induced intracellular signaling and ~3-fold more potently reduced IL-1β-induced IL-6 production in cellular assays. EBI-005 was more active than topical cyclopsporin (the active ingredient of Restasis™) in a mouse model of DES. Topical delivery resulted in distribution to multiple eye compartments but very low systemic exposure in rabbits (F < 0.2%). EBI-005 was 9°C more thermally stable than anakinra and had a Tm of ~65°C. Finally, a high yield scalable E. coli production process was developed.
EBI-005 is an IL-1 receptor blocker that is optimized for topical ocular delivery. EBI-005’s potency should result in an optimal frequency of administration as a result of long receptor occupancy time. The thermal stability of EBI-005 creates the potential for an ambient temperature stable product. The low systemic exposure reduces risk of immune suppression related adverse events associated with systemic IL-1 antagonism. EBI-005 is Eleven Biotherapeutics’ lead program and is targeted to enter the clinic in 2012
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