title: Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability.
abstract: Choroidal neovascularization (CNV) is a defining feature of wet age-related macular degeneration. We examined the functional role of CCR3 in the development of CNV in mice and primates. CCR3 was associated with spontaneous CNV lesions in the newly described JR5558 mice, whereas CCR3 ligands localized to CNV-associated macrophages and the retinal pigment epithelium/choroid complex. Intravitreal injection of neutralizing antibodies against vascular endothelial growth factor receptor 2, CCR3, CC chemokine ligand 11/eotaxin-1, and CC chemokine ligand 24/eotaxin-2 all reduced CNV area and lesion number in these mice. Systemic administration of the CCR3 antagonists GW766994X and GW782415X reduced spontaneous CNV in JR5558 mice and laser-induced CNV in mouse and primate models in a dose-dependent fashion. Combination treatment with antivascular endothelial growth factor receptor 2 antibody and GW766994X yielded additive reductions in CNV area and hyperpermeability in mice. Interestingly, topical GW766994X and intravitreal anti-CCR3 antibody yielded strong systemic effects, reducing CNV in the untreated, contralateral eye. Contrarily, ocular administration of GW782415X in primates failed to substantially elevate plasma drug levels or to reduce the development of grade IV CNV lesions. These findings suggest that CCR3 signaling may be an attractive therapeutic target for CNV, utilizing a pathway that is at least partly distinct from that of vascular endothelial growth factor receptor. The findings also demonstrate that systemic exposure to CCR3 antagonists may be crucial for CNV-targeted activity.
authors.affiliation: Department of Ocular Biology & Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Nori
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Department of Ocular Biology & Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Meihua
authors.initials: M
authors.lastname: Ju
authors.affiliation: Department of Ocular Biology & Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Kanako
authors.initials: K
authors.lastname: Izumi-Nagai
authors.affiliation: Department of Genetics, University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Robbie
authors.affiliation: Department of Genetics, University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.affiliation: Ophthiris Discovery Performance Unit, GlaxoSmithKline, Stevenage Herts, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Gale
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Esaie
authors.initials: E
authors.lastname: Pierre
authors.affiliation: Ophthiris Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Achim H P
authors.initials: AH
authors.lastname: Krauss
authors.affiliation: Department of Ocular Biology & Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom; Ophthiris Discovery Performance Unit, GlaxoSmithKline, Stevenage Herts, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Adamson
authors.affiliation: Department of Ocular Biology & Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Shima
authors.affiliation: Department of Ocular Biology & Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom. Electronic address: eric_ng@meei.harvard.edu.
authors.forename: Yin-Shan
authors.initials: YS
authors.lastname: Ng
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000276:immunology; D002829:Choroid / Q000473:pathology; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D054397:Receptors, CCR3; D042461:Vascular Endothelial Growth Factor A