Monoclonal Antibodies: A Therapeutic Option for the Treatment of Ophthalmic Diseases of the Eye Posterior Segment (original) (raw)
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Investigative Ophthalmology & Visual Science, 2007
To evaluate the preclinical safety of intravitreal bevacizumab, which is a full-length humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), in rabbit eyes over a short-term period. METHODS. Twenty-four rabbits were divided into two groups, each with two subgroups. The first group (groups 1 and 2) received 1.25 mg (0.05 mL) intravitreal bevacizumab, and the second group (groups 3 and 4) received 3.00 mg (0.12 mL) intravitreal bevacizumab. The right eyes were designated as the study eyes, and the left eyes served as a control and received the same volume of saline intravitreally. Groups 1 and 3 were labeled as early groups and scheduled to be terminated at 14 days. Groups 2 and 4, labeled as late groups, were scheduled to be terminated at 28 days. Besides electroretinography (ERG) and visually evoked potentials (VEP), central corneal thickness, intraocular pressure, fundus photography, and anterior segment imaging were performed at baseline and scheduled time points. Enucleated eyes were preserved for light and electron microscopic investigation. RESULTS. No anterior segment inflammation was observed, except in one eye in group 1 which showed a uveitic reaction. No evidence of retinal toxicity was seen with intravitreal bevacizumab at doses of 1.25 and 3.00 mg, by either ERG or light microscopy. Electron microscopic assessment revealed mitochondrial damage in the inner segments of photoreceptors. Immunohistochemical staining with bax and caspase-3 and -9 showed intensive apoptotic protein expression in all study sections and minimal expression in the control eyes. CONCLUSIONS. Although electrophysiologic investigation and light microscopy showed normal retinal function and structure, mitochondrial disruption in the inner segments of photoreceptors was detected by electron microscopy, and apoptotic expression was detected after the injection of intravitreal bevacizumab. (Invest Ophthalmol Vis Sci.
Life Sciences, 1999
Vascular endothelial growth factor (VEGF), the strongest known angiogenic cytokine and also a potent enhancer of vascular permeability, is closely associated with diabetic ocular complications and other intraocular neovascular diseases. The therapeutic effect of VEGF-neutralizing antibody on oxygen-induced retinopathy in an experimental murine model of proliferative retinopathy was investigated. Intraocular and systemic injection of the antibody resulted in 46% and 18% reductions in the number of nuclei of newly formed vessels of this model, respectively. The results demonstrated that a neutralizing antibody against VEGF was highly effective in the treatment of intraocular neovascularization and suggested possible modes of therapy in human intraocular neovascular diseases, including diabetic proliferative retinopathy.
Investigative Ophthalmology & Visual Science, 2013
Purpose: The study investigated the effect of intravitreally administered tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, in a rat model of laser-induced choroidal neovascularization (CNV). Methods: CNV was induced by laser photocoagulation on day 0 in the eyes of Brown Norway rats. Intravitreal injection of tanibirumab or phosphate-buffered saline (PBS) was done on day 0 (prevention arm) or day 7 (treatment arm). Seven days after injection, the eyes were enucleated and retinal pigment epithelium-choroid-sclera flat mounts were prepared. Areas of CNV were determined in the flat mounts using tetramethylrhodamine isothiocyanate Bandeiraea simplicifolia (BS) isolectin labeling and intravenously administered fluorescein isothiocyanate-dextran and quantified using an image analysis program. Results: In the prevention arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.2% and 53.9% in tanibirumab-treated eyes (20 and 60 mg, respectively) compared with PBS-treated control eyes on day 7 (P = 0.038 and P < 0.001, respectively). In the treatment arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.7% and 46.0% in tanibirumab-treated eyes (20 and 60 mg, respectively) compared with PBS-treated control eyes on day 14 (P = 0.048 and P < 0.001, respectively). Conclusions: Intravitreally administered tanibirumab partially suppressed the formation of new CNV and partially regressed preformed laser-induced CNV in the rat model. Tanibirumab may be a feasible treatment for CNV associated with age-related macular degeneration or other causes.
Brazilian Journal of Pharmaceutical Sciences, 2014
Age-related macular degeneration (AMD) is an ocular inflammatory diseases treated mainly by means of a bevacizumab (Avastin ® ) or ranibizumab (Lucentis ® ) intravitreal injection. Among these drugs, only ranibizumab has a specific therapeutic indication for AMD. Considering that, the off-label use on ophthalmic therapy seems to become a rule when it should be an exception. Furthermore, bevacizumab presentation consists of multi-dose vials although it does not contain preservatives in its formula. The current literature review aimed at assessing the risks for the patient related to the use of off-label indication and multi-dose vials on AMD treatment. Considering this, the proposal related to the Brazilian Public Consultation no.10, dated September 12, 2012, which proposes the Clinical Protocol and Therapeutic Guidelines for AMD treatment, was evaluated. This systematic review allowed to conclude that the bevacizumab off-label indication results in increased risks for the patient when compared to the product with specific therapeutic indication for AMD treatment (ranibizumab), especially referring to the significant raise in the adverse events. The risks for the patient related to the multi-dose vial use, referring to the microbiological stability and dose precision, were also made clear.
Monoclonal antibody-mediated drug targeting to laser-induced choroidal neovascularization in the rat
2000
PURPOSE. Active drug targeting mediated by monoclonal antibodies (mAbs) of vascular endothelial cells in tumors is a new concept in cancer therapy. Integrin ␣v3 has been reported to be strongly expressed in vascular endothelial cells of surgically excised choroidal neovascular membranes and is thought to be a potential antigen for mAb-mediated drug targeting of choroidal neovascularization (CNV). The objective of this study was to evaluate the efficacy of drug targeting mediated by antiintegrin ␣v3 mAbs in a laser-induced CNV rat model. METHODS. The mitomycin C (MMC)-dextran (MMCD) conjugate was synthesized with a carbodiimide-catalyzed reaction. The mAb was conjugated with MMCD (MMCD-mAb). To evaluate the feasibility of mAb-mediated drug targeting in vitro, we investigated the effect of the immunoconjugates involving dextran-binding MMC on the proliferation of human umbilical vein endothelial cells (HUVECs). CNV was induced by laser photocoagulation in male Brown Norway rats. Immunolocalization of integrin ␣v3 in CNV lesions was assessed immunohistochemically with the anti-von Willebrand factor antibody as an endothelial cell marker. Intravenous administration of saline (n ϭ 7), 1 mg/day mAb (n ϭ 7), 100 g/kg per day free MMC (n ϭ 7), MMCD with irrelevant Ab (n ϭ 7), unconjugated MMCD with unconjugated mAb (MMCDϩmAb; n ϭ 7), or MMCD with mAb (MMCD-mAb; n ϭ 8) containing an equal amount of free MMC, was performed daily for 3 days from day 14 after CNV induction. CNV was assessed by fluorescein angiography 2 weeks after treatment. Fluorescein leakage was scored on a four-grade scale. The animals were killed 2 weeks after treatment, and the lesions were evaluated histologically. RESULTS. The inhibition of immunoconjugates on the proliferation of HUVECs was enhanced specifically by the mediatory effect of the mAb. Endothelial cells demonstrated strong immunoreactivity of integrin ␣v3 in the CNV. In the vehicletreated group, fluorescein leakage equal to that before treatment was observed 2 weeks after treatment, with an average score of 2.00 Ϯ 0.17 (mean Ϯ SEM). MMCD-mAb significantly inhibited the development of CNV in rats (P Ͻ 0.01). More-over, the thickness of the lesions was significantly reduced in the MMCD-mAb-treated group (P Ͻ 0.01). CONCLUSIONS. Immunoconjugates effectively inhibited progression of CNV in this model. The results suggest that mAbmediated drug targeting may be beneficial in the treatment of
Biologic agents in the management of inflammatory eye diseases
2008
Biologics are a new class of drugs that comprise recombinant cytokines and monoclonal antibodies directed against selected cell-surface markers. They include the tumor necrosis factor-α inhibitors infl iximab, etanercept, and adalimumab; the antilymphocyte drugs rituximab and alemtuzumab; the interleukin-2 receptor blocker daclizumab; and recombinant interferon-α . This article reviews the rationale and current evidence for their use in uveitis, scleritis, and orbital infl ammation.