Targeting tissue factor for immunotherapy of choroidal neovascularization by intravitreal delivery of factor VII-Fc chimeric antibody.
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.
Tezel
Tongalp H
TH
Department of Ophthalmology & Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. Tongalp.Tezel@louisville.edu
Bodek
Ewa
E
Sönmez
Kenan
K
Kaliappan
Sankar
S
Kaplan
Henry J
HJ
Hu
Zhiwei
Z
Garen
Alan
A
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
D007141:Immunoglobulin Fc Fragments; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D005167:Factor VII