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Design of a superior cytokine antagonist for topical ophthalmic use.

ABSTRACT: IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1? and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an ?100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other ?-trefoil family proteins in the IL-1 and FGF families.

SUBMITTER: Hou J

PROVIDER: S-EPMC3593924 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Design of a superior cytokine antagonist for topical ophthalmic use.

Hou Jinzhao J Townson Sharon A SA Kovalchin Joseph T JT Masci Allyson A Kiner Olga O Shu Yanqun Y King Bracken M BM Schirmer Emily E Golden Kathryn K Thomas Christoph C Garcia K Christopher KC Zarbis-Papastoitsis Gregory G Furfine Eric S ES Barnes Thomas M TM

Proceedings of the National Academy of Sciences of the United States of America 20130219 10

IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1β and IL-1Ra, to create an optimized receptor an ...[more]

PMID: 23431173

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Project description:PURPOSE:To evaluate the presence and concentration of citicoline and its metabolites (choline, cytidine and uridine) in the vitreous body in human eyes after topical application of an ophthalmic solution of citicoline 2%, in vivo. METHODS:Twenty-one subjects affected by epiretinal membrane with surgical indication for pars-plana vitrectomy underwent treatment with 1 drop 3 times/day of a solution of citicoline 2%, 0.2% high molecular weight hyaluronic acid and 0.01% benzalkonium chloride (OMK1, Omikron Italia s.r.l., Rome, Italy) 14 days before surgery and 2 hours prior to surgery. Five additional patients served as controls and received an OMK1 vehicle solution without citicoline. The vitreous samples were taken at the beginning of the pars-plana vitrectomy and analyzed for qualitative/quantitative determination of vitreous concentration of citicoline and its metabolites by means of high performance liquid chromatography. RESULTS:The overall mean concentration of citicoline in patients treated with citicoline 2% solution was 406.72 ± 52.99 ?g/mL, while the mean concentration of choline, cytidine and uridine was 180.88 ± 41.49 ?g/mL, 44.45 ± 10.19 ?g/mL and 330.41 ± 75.8 ?g/mL, respectively. The concentration of citicoline in phakic eyes (n = 13, 366.61 ± 129.61 ?g/mL) was lower compared to that found in pseudophakic eyes (n = 8, 435.89 ± 131.42 ?g/mL) and the difference was not statistically significant. The concentration of citicoline in the control eyes was 45.66 ± 26.36 ?g/mL, while the concentration of choline, cytidine and uridine were 17.21 ± 9.93 ?g/mL, 6.24 ± 3.6 ?g/mL and 172.80 ± 99.76 ?g/mL, respectively. CONCLUSION:Citicoline can reach the human vitreous in high concentration when administered in ophthalmic solution. This evidence contributes to the build-up of the pyramid of the evidences required for determining the role of citicoline administered in ophthalmic formulation in retinal and optic nerve neurodegenerative diseases.

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Design of a superior cytokine antagonist for topical ophthalmic use.

Publications

Design of a superior cytokine antagonist for topical ophthalmic use.

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