Effects of Intraocular Ranibizumab and Bevacizumab in Transgenic Mice Expressing Human Vascular Endothelial Growth Factor
Received 10 February 2009; received in revised form 11 May 2009; accepted 12 May 2009. published online 29 July 2009.
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.
Design
Randomized trials in animal models.
Participants
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.
Main Outcome Measures
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 μg 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 μg of BVZ significantly reduced the incidence of exudative retinal detachment compared with injection of 10 μg of RBZ. Injection of 25 μg 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.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
Available online: July 29, 2009.
Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Correspondence: Peter A. Campochiaro, MD, Maumenee 719, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287-9277
Manuscript no. 2009-179.
Financial Disclosure(s): The author(s) have made the following disclosure(s): PAC has an institutional consulting agreement with Genentech, Inc. (South San Francisco, CA), for which payment is made to Johns Hopkins University, has research funding for clinical trials sponsored by Genentech Inc., but not for this study, and is on the Data and Safety Monitoring Committee for the View 1 Trial sponsored by Regeneron, Inc. (Tarrytown, NY). No other authors have any potential conflict of interest.
Supported by EY12609 and core grant P30EY1765 from the National Eye Institute. PAC is the George S. and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience.
ABSTRACT