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Matthew Campbell, Peter S Adamson, Francisco J Lopez, Edit Kurali, Peter Humphries, Sarah Doyle; IL-18 immunotherapy for neovascular AMD; Tolerability and efficacy in non-human primates. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4803.
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Age-related macular degeneration (AMD) is the most common form of central retinal blindness in the developed world. Inflammation is known to play a key role in the pathogenesis of AMD. The activation of the NLRP3-inflammasome, has come to the fore in recent years as being involved, in some capacity, in the development of both “dry” and neovascular (“wet”) forms of the disease. We have shown that IL-18 can regulate choroidal neovascularization (CNV) formation in mice. We observed that exogenous administration of mature recombinant IL-18 has no effect on retinal pigment epithelial (RPE) cell viability in vitro.
In order to address the translational potential of IL-18 for use in neovascular AMD, we initiated a non-human primate tolerability and efficacy study for the use of intravitreally (IVT) and/or systemically administered clinical grade human IL-18 (SB-485232). Cynomolgus monkeys were injected IVT with increasing doses of human IL-18 (2 each at 100 ng, 1000 ng, 3000 ng and 10,000 ng per eye). In tandem, 26 monkeys were administered 9 laser burns in each eye prior to receiving IL-18 as an IVT or systemic injection at a range of doses. Fundus fluorescein angiography (FFA) was performed on days 15, 22 and 29 post injection and the development of neovascular lesions was assessed. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.
No IL-18-related ophthalmoscopic findings were apparent even at a dose of 10,000 ng per eye. In addition, we show that IL-18 has efficacy in preventing laser induced CNV development in the non-human primate eye, paving the way for its potential use in human subjects. Recombinant human IL-18 has already entered clinical trial as a systemic agent in a range of cancer indications.
We now show that IL-18 is safe and has efficacy in preventing laser induced CNV in the non-human primate eye. Human IL-18 is bioactive in monkeys yet does not cause RPE or retinal cell death and could now represent a novel immuno-therapeutic based adjunctive strategy for the treatment of neovascular AMD in human subjects.
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