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Jian Liu, David A. Copland, Shintaro Horie, B. Paul Morgan, Lindsay B. Nicholson, Andrew D. Dick; Local Anti-C5 Therapy Suppresses Experimental Choroidal Neovascularization Through Reduction Of Macrophage Infiltrate. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1236.
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© ARVO (1962-2015); The Authors (2016-present)
Increasing evidence demonstrates that abnormal complement activation plays a critical role in the development of choroidal neovascularization (CNV), a complex pathological process underlying the wet form of age-related macular degeneration (AMD). The present study aimed to determine the efficacy of local administration of the murine anti-C5 mAb (BB5.1) to prevent cleavage of C5 and suppress laser-induced CNV.
CNV was induced in C57BL/6 mice by laser photocoagulation (4 laser spots/eye). The BB5.1 mAb or an isotype control antibody (25μg/eye) were administered by intravitreal injection immediately following laser burn either as a single dose treatment, or a repeated regimen with an additional injection performed on day 7. The CNV formation was assessed by isolectin B4 staining on retinal pigment epithelium (RPE)/choroid whole-mounts. Deposition of the end product of complement activation, membrane attack complex (MAC), was detected by immunostaining. Flow cytometric analysis and confocal microscopy were used to examine cell infiltrate in RPE/choroid and retina tissues. Expression of VEGF and Arginase-1 (Arg-1) mRNA in the tissues were measured by real-time PCR.
Laser photocoagulation led to disruption of Bruch’s membrane and RPE. No significant new blood vessel growth was found at the laser-induced lesion sites before day 4, and fully-developed CNV was observed after day 7. During the early stage of CNV, there were elevated Arg-1 mRNA level and significant leukocyte infiltrate in the RPE/choroid, including accumulation of amoeboid macrophages (CD11b+VEGF+) surrounding and within the lesions prior to formation of the new blood vessels. Inhibition of C5 cleavage by local BB5.1 injection markedly suppressed MAC at the peak of MAC deposition (day 4). Furthermore, reduced macrophage and neutrophil infiltration in the RPE/choroid were seen as early as 48 hours following BB5.1 injection with diminished VEGF and Arg-1 mRNA expression in the RPE/choroid on day 4. Single dose administration showed a 52% reduction in CNV volume by day 7 compared to control treatment, but suppression of CNV was not maintained with blood vessel growth evident by day 14. However, the repeated dose regimen of BB5.1 with treatments on days 0 and 7 significantly reduced CNV volume by 56% at day 14.
This data demonstrates that blocking of C5 cleavage has clinical potential to reduce CNV development via inhibiting complement activation, cell infiltrate and VEGF/Arg-1 expression. Repeated administration of anti-C5 mAb may be required for effective suppression of the pathological disease, and would provide an alternative to or combined with current VEGF-targeting therapy for wet AMD.
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