Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability

Norihiro Nagai, Meihua Ju, Kanako Izumi-Nagai, Scott J. Robbie, James W. Bainbridge, David C. Gale, Esaie Pierre, Achim H P Krauss, Peter Adamson, David T. Shima, Yin Shan Ng

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2534-2549
Number of pages16
JournalAmerican Journal of Pathology
Volume185
Issue number9
DOIs
Publication statusPublished - 2015 Sep 1
Externally publishedYes

Fingerprint

Choroidal Neovascularization
Capillary Permeability
Growth
Primates
CC Chemokines
Vascular Endothelial Growth Factor Receptor
Ligands
Chemokine CCL24
Chemokine CCL11
Ophthalmic Administration
Vascular Endothelial Growth Factor Receptor-2
Intravitreal Injections
Choroid
Retinal Pigment Epithelium
Macular Degeneration
Neutralizing Antibodies
Anti-Idiotypic Antibodies
Lasers

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability. / Nagai, Norihiro; Ju, Meihua; Izumi-Nagai, Kanako; Robbie, Scott J.; Bainbridge, James W.; Gale, David C.; Pierre, Esaie; Krauss, Achim H P; Adamson, Peter; Shima, David T.; Ng, Yin Shan.

In: American Journal of Pathology, Vol. 185, No. 9, 01.09.2015, p. 2534-2549.

Research output: Contribution to journalArticle

Nagai, N, Ju, M, Izumi-Nagai, K, Robbie, SJ, Bainbridge, JW, Gale, DC, Pierre, E, Krauss, AHP, Adamson, P, Shima, DT & Ng, YS 2015, 'Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability', American Journal of Pathology, vol. 185, no. 9, pp. 2534-2549. https://doi.org/10.1016/j.ajpath.2015.04.029
Nagai, Norihiro ; Ju, Meihua ; Izumi-Nagai, Kanako ; Robbie, Scott J. ; Bainbridge, James W. ; Gale, David C. ; Pierre, Esaie ; Krauss, Achim H P ; Adamson, Peter ; Shima, David T. ; Ng, Yin Shan. / Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability. In: American Journal of Pathology. 2015 ; Vol. 185, No. 9. pp. 2534-2549.
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