title: Penetration of a topically administered anti-tumor necrosis factor alpha antibody fragment into the anterior chamber of the human eye.
abstract: OBJECTIVE
  To determine whether topically applied ESBA105, a single-chain antibody fragment against tumor necrosis factor (TNF)-α, could efficiently penetrate into the anterior chamber of the human eye.
  
  
  METHODS
  Multicenter, interventional cohort study.
  
  
  METHODS
  Otherwise healthy patients undergoing cataract surgery (cohorts I-III) or combined cataract surgery and vitrectomy (cohort IV).
  
  
  METHODS
  ESBA105 (n = 57) or placebo (n = 22) was preoperatively applied as eye drops to 1 eye in patients scheduled for cataract surgery (n = 73) or combined cataract surgery and vitrectomy (n = 6). ESBA105 was administered on the day of surgery at 1-hour intervals (last dose 1 hour preoperatively) as 1.6 mg in 4 drops for cohort I (n = 15) and as 3.2 mg in 8 drops for cohorts II (n = 15) and IV (n = 6). Cohort III (n = 43) was randomized 1:1 in double-masked fashion to receive either ESBA105 6.4 mg or placebo over 4 days using 4 drops per day at 4-hour intervals (last dose 12 hours preoperatively). Aqueous humor (all cohorts), vitreous humor (cohort IV only), and blood samples (all cohorts) were collected for measurement of ESBA105.
  
  
  METHODS
  ESBA105 intraocular concentration.
  
  
  RESULTS
  Both 4 times daily over 4 days dosing (cohort III) and 8 times daily dosing (cohorts II and IV) resulted in reliably high ESBA105 concentrations in aqueous humor. Mean molar excess of intraocular ESBA105 over its target (intraocular TNF-α) was calculated as 96-fold (cohort III) to 359-fold (cohorts II and IV). Results from the cohorts receiving 4 and 8 hourly drops per 1 day (cohorts I, II, and IV) indicated that dose-dependent intraocular concentrations of ESBA105 were achieved within hours of dosing. After 8 times daily dosing, 5 of 6 vitreous samples (cohort IV) had undetectable ESBA105 levels. ESBA105 was detected in 17 of 55 preoperative serum samples but no longer detectable in serum 1 day after surgery (0 of 19 samples). In cohort III, treatment-emergent adverse events were identical between ESBA105 and placebo groups (2 cases each of eye irritation).
  
  
  CONCLUSIONS
  These results demonstrate that the topically applied single-chain antibody fragment ESBA105 penetrated into the anterior chamber of the human eye at therapeutic levels.
authors.affiliation: Luzerner Kantonsspital, Augenklinik, Luzern, Switzerland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thiel
authors.forename: Andreas
authors.initials: A
authors.lastname: Wild
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schmid
authors.forename: Oliver
authors.initials: O
authors.lastname: Job
authors.forename: Frank
authors.initials: F
authors.lastname: Bochmann
authors.forename: Vlasios
authors.initials: V
authors.lastname: Loukopoulos
authors.forename: Wolfan
authors.initials: W
authors.lastname: Alcantara
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtlen
authors.forename: Dominik
authors.initials: D
authors.lastname: Escher
mesh_terms: D000287:Administration, Topical; D000368:Aged; D000867:Anterior Chamber / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism*; D001682:Biological Availability; D002387:Cataract Extraction; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014821:Vitrectomy; D014822:Vitreous Body / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C547155:ESBA105; D009883:Ophthalmic Solutions; D014409:Tumor Necrosis Factor-alpha