IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates

• Published in: Investigative ophthalmology & visual science Vol. 56; no. 9; pp. 5424 - 5430
• Main Authors: Doyle, Sarah L, López, Francisco J, Celkova, Lucia, Brennan, Kiva, Mulfaul, Kelly, Ozaki, Ema, Kenna, Paul F, Kurali, Edit, Hudson, Natalie, Doggett, Teresa, Ferguson, Thomas A, Humphries, Peter, Adamson, Peter, Campbell, Matthew
• Format: Journal Article
• Language: English
• Published: United States 01.08.2015
• Subjects: Animals; Blotting, Western; Disease Models, Animal; Electroretinography; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Fluorescein Angiography; Fundus Oculi; Gene Expression Regulation - drug effects; Humans; Immunotherapy - methods; Interleukin-18 - administration & dosage; Intravitreal Injections; Macaca fascicularis; Macular Degeneration - diagnosis; Macular Degeneration - drug therapy; Macular Degeneration - etiology; Mice; Mice, Mutant Strains; Polymerase Chain Reaction; Primates; Retina - metabolism; Retina - pathology; Retina - physiopathology; Retinal Neovascularization - complications; Retinal Neovascularization - diagnosis; Retinal Neovascularization - drug therapy; RNA - genetics; Treatment Outcome; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.15-17264

Age-related macular degeneration is the most common form of central retinal blindness in the elderly. Of the two end stages of disease, neovascular AMD-although the minority form-is the most severe. Current therapies are highly successful at controlling progression of neovascular lesions; however, a significant number of patients remain refractory to treatment and the development of alternative and additive therapies to anti-VEGFs is essential. In order to address the translational potential of interleukin (IL)-18 for use in neovascular AMD, we initiated a nonhuman primate tolerability and efficacy study for the use of intravitreally (IVT) administered clinical grade human IL-18 (SB-485232). Cynomolgus monkeys were injected IVT with increasing doses of human IL-18 (two each at 1000, 3000, and 10,000 ng per eye). In tandem, 21 monkeys were administered nine laser burns in each eye prior to receiving IL-18 as an IVT injection at a range of doses. Fundus fluorescein angiography (FFA) was performed on days 8, 15, and 22 post injection and the development of neovascular lesions was assessed. We show intravitreal, mature, recombinant human IL-18 is safe and can reduce choroidal neovascular lesion development in cynomolgus monkeys. Based on our data comparing human IL-18 to current anti-VEGF-based therapy, clinical deployment of IL-18 for neovascular AMD has the potential to lead to a new adjuvant immunotherapy-based treatment for this severe form of central blindness.