Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment
Department of Medicine, Division of Preventive and Behavioral Medicine
Animals; Antibodies, Monoclonal; Choroidal Neovascularization; Disease Models, Animal; Endothelial Growth Factors; Fluorescein Angiography; Immunoglobulin Fragments; Injections; Laser Coagulation; Lymphokines; Macaca fascicularis; Recombinant Fusion Proteins; Safety; Uveitis, Anterior; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vitreous Body
OBJECTIVE: To evaluate the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward vascular endothelial growth factor (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV).
METHODS: In phase 1 of the study, each animal received intravitreal injections, 500 microg per eye, of rhuFab VEGF in one eye (prevention eye), while the contralateral eye received rhuFab VEGF vehicle (control eye) at 2-week intervals. On day 21, laser photocoagulation was performed to induce CNV. In phase 2, the vehicle-treated eye was crossed over and both eyes received 500 microg of rhuFab VEGF beginning 21 days following laser-induced injury at days 42 and 56. The eyes were monitored by ophthalmic examinations, color photographs, and fluorescein angiography.
RESULTS: rhuFab VEGF did not cause any ocular hemorrhages. All eyes treated with rhuFab VEGF developed acute anterior chamber inflammation within 24 hours of the first injection that resolved within 1 week, and this inflammation was less severe with subsequent injections. The incidence of CNV, defined angiographically, was significantly lower in the prevention eyes than the control eyes (P<.001). Subsequent treatments were associated with less leakage in eyes with established CNV that were crossed over from the control eyes to the treatment eyes (P =.001).
CONCLUSIONS: Intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already formed CNV with no significant toxic effects.
CLINICAL RELEVANCE: This study provides the nonclinical proof of principle for ongoing clinical studies of intravitreally injected rhuFab VEGF in patients with neovascular age-related macular degeneration.
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Citation: Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NA, Li W, Connolly E, O'Neill CA, Miller JW. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002 Mar;120(3):338-46. doi:10.1001/archopht.120.3.338.
Krzystolik, Magdalena G.; Afshari, Mehran A.; Adamis, Anthony P.; Gaudreault, Jacques; Gragoudas, Evangelos S.; Michaud, Norman A.; Li, Wenjun; Connolly, Edward; O'Neill, Charles A.; and Miller, Joan W., "Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment" (2002). Preventive and Behavioral Medicine Publications and Presentations. Paper 311.