Sarah L Doyle1, Francisco J López2, Lucia Celkova3, Kiva Brennan1, Kelly Mulfaul1, Ema Ozaki3, Paul F Kenna4, Edit Kurali5, Natalie Hudson3, Teresa Doggett6, Thomas A Ferguson6, Peter Humphries3, Peter Adamson7, Matthew Campbell3. 1. Department of Clinical Medicine School of Medicine, Trinity College Dublin, Dublin, Ireland. 2. Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States. 3. Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. 4. Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland 4The Research Foundation, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin, Ireland. 5. Statistics Consulting Group, Quantitative Science, PTS, GlaxoSmithKline, King of Prussia, Pennsylvania, United States. 6. Department of Ophthalmology and Visual Science, Washington University School of Medicine, St. Louis, Missouri, United States. 7. Ophthalmology Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom 8Ocular Biology and Therapeutics, Institute of Ophthalmology, University College London, London, United Kingdom.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: We show intravitreal, mature, recombinant human IL-18 is safe and can reduce choroidal neovascular lesion development in cynomolgus monkeys. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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 humanIL-18 (SB-485232). Cynomolgus monkeys were injected IVT with increasing doses of humanIL-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. RESULTS: We show intravitreal, mature, recombinant humanIL-18 is safe and can reduce choroidal neovascular lesion development in cynomolgus monkeys. CONCLUSIONS: Based on our data comparing humanIL-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.
Authors: Pavlina Tsoka; Paulo R Barbisan; Keiko Kataoka; Xiaohong Nancy Chen; Bo Tian; Peggy Bouzika; Joan W Miller; Eleftherios I Paschalis; Demetrios G Vavvas Journal: Exp Eye Res Date: 2019-01-29 Impact factor: 3.467
Authors: Sofia Theodoropoulou; David A Copland; Jian Liu; Jiahui Wu; Peter J Gardner; Ema Ozaki; Sarah L Doyle; Matthew Campbell; Andrew D Dick Journal: J Pathol Date: 2016-11-16 Impact factor: 7.996