Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor.
OBJECTIVE
This study compared the effects of intraocular injections of ranibizumab (RBZ) and bevacizumab (BVZ) in transgenic mouse models in which human vascular endothelial growth factor (VEGF) causes subretinal neovascularization (NV) or exudative retinal detachment.


METHODS
Randomized trials in animal models.


METHODS
Transgenic mice in which the rhodopsin promoter drives expression of human VEGF in photoreceptors (rho/VEGF mice) and double transgenic mice with doxycycline-inducible expression of human VEGF in photoreceptors (Tet/opsin/VEGF mice).


METHODS
Rho/VEGF mice received intraocular injections of RBZ, BVZ, or vehicle, and after various time periods the area of subretinal NV was measured. Tet/opsin/VEGF mice were given an intraocular injection of RBZ, BVZ, or vehicle, and after 5 days of doxycycline treatment the presence or absence of retinal detachment was determined.


METHODS
Area of subretinal NV per retina in rho/VEGF mice and the occurrence of retinal detachment in Tet/opsin/VEGF mice.


RESULTS
In rho/VEGF mice, intraocular injections of RBZ or BVZ strongly suppressed subretinal NV, but the duration of effect was greater for BVZ. Three injections of 10 microg of BVZ over the course of 2 weeks not only suppressed subretinal NV in the injected eye but also caused significant suppression in the fellow eye, indicating a systemic effect. In doxycycline-treated Tet/opsin/VEGF mice, intraocular injection of 10 microg of BVZ significantly reduced the incidence of exudative retinal detachment compared with injection of 10 microg of RBZ. Injection of 25 microg of BVZ reduced the incidence of retinal detachment in both eyes.


CONCLUSIONS
Intraocular injections of RBZ and BVZ had similar efficacy in rho/VEGF mice, but the duration of effect was greater for BVZ. In Tet/opsin/VEGF mice, in which expression levels of human VEGF are very high and the phenotype is severe, BVZ showed greater efficacy than RBZ. In both models, higher doses or repeated injections of BVZ, but not RBZ, resulted in a systemic effect. These data suggest that BVZ is not inferior to RBZ for treatment of subretinal NV in mice and is superior in a severe model. The systemic effects of BVZ after intraocular injection deserve further study and consideration of their potential consequences.


BACKGROUND
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Miki
Katsuaki
K
Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277, USA.
Miki
Akiko
A
Matsuoka
Masato
M
Muramatsu
Daisuke
D
Hackett
Sean F
SF
Campochiaro
Peter A
PA
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007267:Injections; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D000069579:Ranibizumab; D012163:Retinal Detachment / Q000188:drug therapy* / Q000235:genetics; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000235:genetics; D012243:Rhodopsin / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D014822:Vitreous Body
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D012243:Rhodopsin; D004318:Doxycycline; D000069579:Ranibizumab