title: Targeting tissue factor for immunotherapy of choroidal neovascularization by intravitreal delivery of factor VII-Fc chimeric antibody.
abstract: OBJECTIVE
  ICON is a fusion protein composed of factor VII, the natural ligand for tissue factor, conjugated to the Fc domain of a human IgG1 immunoglobulin. It binds to the tissue factor expressed on neovascular endothelia and initiates a cytolytic immune attack that destroys the neovascular tissue. We previously showed that mouse factor VII-Fc chimeric antibody (mICON) dramatically decreases the frequency of choroidal neovascularization in a laser-induced choroidal neovascularization model in mice. Herein, we determined the safety and efficacy of mICON in destroying subretinal choroidal neovascularization in pig eyes.
  
  
  METHODS
  mICON (150-1200 microg) was administered into the midvitreous cavity of the pig eye either before (on Day 0) or after (on Day 10) induction of choroidal neovascularization with laser photocoagulation. On Day 14, the incidence of choroidal neovascularization was determined using confocal microscopy. We also determined the binding specificity (% binding to choroidal neovascularization/% binding to non-choroidal neovascularization areas) of mICON to tissue factor expressed on endothelial cells of laser-induced choroidal neovascularization.
  
  
  RESULTS
  We observed that mICON selectively destroyed choroidal neovascularization in a dose-dependent manner (r = -0.93; EDB50B = 571.3 microg). Obliteration of the choroidal neovascular complex was more prominent at doses > 300 microg (p < 0.05). No systemic or local complications (including retinal tear/detachment, inflammation, infection, cataract, or glaucoma) were observed. Binding specificities of hICON (2.2 +/- 0.2) and mICON (3.4 +/- 0.4) were significantly higher than that of anti-von Willebrand antibody (0.1 +/- 0.01, p < 0.001).
  
  
  CONCLUSIONS
  Both hICON and mICON bound to the neovascular endothelia of choroidal neovascularization with greater specificity than anti-von Willebrand antibody. Furthermore, mICON can selectively obliterate already established choroidal neovascularization, which suggests that it may be useful for immunotherapy in patients with exudative (wet) macular degeneration.
authors: Department of Ophthalmology & Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. Tongalp.Tezel@louisville.edu
authors: Tongalp H
authors: TH
authors: Tezel
authors: Ewa
authors: E
authors: Bodek
authors: Kenan
authors: K
authors: Sönmez
authors: Sankar
authors: S
authors: Kaliappan
authors: Henry J
authors: HJ
authors: Kaplan
authors: Zhiwei
authors: Z
authors: Hu
authors: Alan
authors: A
authors: Garen
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000627:therapeutic use*; D007267:Injections; D017075:Laser Coagulation; D018613:Microscopy, Confocal; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D016896:Treatment Outcome; D014822:Vitreous Body
chemical_list: D007141:Immunoglobulin Fc Fragments; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D005167:Factor VII