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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.

Project description:ObjectiveTo evaluate the recent practice of design and statistical analysis of ophthalmic randomized clinical trials (RCTs).DesignReview of 96 ophthalmic RCTs.MethodsTwo authors (R.D., G.S.Y.) reviewed primary result papers published from January 2020 through December 2021 in Ophthalmology, JAMA Ophthalmology, American Journal of Ophthalmology, and British Journal of Ophthalmology. Data were extracted and analyzed for the characteristics of design (1-eye design, 2-eye design, paired-eye design, and subject design), sample size and power, and statistical analysis for intereye correlation adjustment, missing data, and correction for multiplicity.Main outcome measuresCharacteristics of trial design and statistical analysis.ResultsAmong 96 RCTs, 50 (52%) used 1-eye design, 21 (22%) 2-eye design, 10 (10%) paired-eye design, and 15 (16%) subject design. In 31 trials of 2-eye design or paired-eye design, 18 (58%) trials had suboptimal analysis of data from both eyes by analyzing data from 1 eye (n = 10), taking the average of 2 eyes (n = 2), analyzing 2 eyes separately (n = 1), ignoring intereye correlation (n = 3), or not specifying how 2-eye data were analyzed (n = 2), and 13 trials (42%) properly adjusted the intereye correlation by using the mixed-effects model (n = 6), paired t test (n = 5), generalized estimating equations (n = 1), or marginal Cox regression model (n = 1). Among 96 trials, 75 (78%) provided both sample size and statistical power estimation, and 16 (17%) trials described statistical test for sample size or power estimation. Missing data in primary outcome occurred in 86 (90%) trials with a median missing data rate of 8%, 32 (37%) trials applied statistical methods for missing data, including last value carried forward (n = 10), multiple imputation (n = 14), or other approaches (n = 8). Among 25 trials with > 2 arms, 16 (64%) corrected for multiplicity using the Bonferroni procedure (n = 8), Hochberg procedure (n = 2), Gatekeeping procedure (n = 2), or hierarchical procedure (n = 4). Among 16 trials with multiple primary outcomes, 4 (25%) corrected for multiplicity by the Bonferroni procedure.ConclusionsThere are opportunities for improvement in the design and statistical analyses of ophthalmic trials, particularly in the aspects of adjustment for intereye correlation, missing data, and multiplicity. Continuing education in ophthalmology and vision research community may improve the quality of ophthalmic trials.Financial disclosuresProprietary or commercial disclosure may be found after the references.

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Design of a superior cytokine antagonist for topical ophthalmic use.

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Design of a superior cytokine antagonist for topical ophthalmic use.

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