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Yin Shan Eric Ng, Norihiro Nagai, Meihua Ju, Kanako Izumi-Nagai, Scott Robbie, James W B Bainbridge, Achim H Krauss, David C Gale, Peter S Adamson, David Shima; Novel CCR3 antagonists are effective mono- and combination inhibitors of CNV growth and vascular permeability. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2290. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We explored the functional role of CCR3 in laser-induced- and spontaneous choroidal neovascularisation (CNV) in mouse and non-human primate laser-CNV models.
Models of spontaneous CNV (JR5558 mice) and laser-induced CNV (mice and primates) were used to assess the therapeutic efficacy of novel C-C chemokine receptor 3 (CCR3) antagonists GW766994 and GW782415. CCR3 and ligands expression was analyzed by immunohistochemistry (IHC), real-time PCR and ELISA. GW766994 and GW782415 were administered by systemic, intraocular and topical routes. Neutralizing antibodies to vascular endothelial growth factor receptor 2 (VEGFR2), CCR3 and ligands were administered by intravitreal injection (IVT), and also systemic injection for anti-VEGFR2. CNV number, area and permeability were evaluated by fundus fluorescein angiography (FFA) and IHC in the mouse, and by FFA in the primate.
Oral dosing with GW766994 reduced development of laser-induced CNV in the mouse model in a dose-dependent fashion. In the JR5558 mice, both number and size of spontaneous CNV lesions were significantly reduced in a dose-dependent manner following systemic exposure to GW766994, and CCR3 expression was associated with CNV. Increased expression of CCR3 ligands was localized to CNV-associated macrophages and from isolated retinal pigment epithelium/choroid complex. IVT antibodies against VEGFR2, CCR3, eotaxin-1 and eotaxin-2 all significantly reduced CNV area and lesion number. Combination treatment with anti-VEGFR2 and GW766994 inhibited CNV leakiness and resulted in an additive reduction in CNV area. Topical CCR3 antagonist was effective in inhibiting spontaneous CNV. Importantly, strong systemic effects on CNV inhibition from topical dosing of CCR3 antagonist and IVT anti-CCR3 antibody were detected. In the primate, oral dosing of GW782415 resulted in a significant suppression of grade IV CNV lesions at 16, 24 and 30 days following laser photocoagulation, whereas neither topical nor intravitreal dosing yielded an efficacy response.
We have demonstrated a direct functional role for CCR3 in the development of CNV, and oral systemic administration of CCR3 antagonists can reduce development of CNV in both mice and primates. Our data suggest that CCR3 signaling may be an attractive therapeutic target for neovascular AMD, and that it is at least partly distinct from the VEGF signaling pathway.
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