IL-18 is not therapeutic for neovascular age-related macular degeneration

Hirano, Yoshio; Yasuma, Tetsuhiro; Mizutani, Takeshi; Fowler, Benjamin J.; Tarallo, Valeria; Yasuma, Reo; Kim, Young‐Hee; Bastos-Carvalho, Ana; Kerur, Nagaraj; Gelfand, Bradley D.; Bogdanovich, Sasha; He, Shikun; Zhang, Xiaohui; Nozaki, Miho; Ijima, Ryo; Kaneko, Hiroki; Ogura, Yuichiro; Terasaki, Hiroko; Nagai, Hiroshi; Haro, Isao; Núñez, Gabriel; Ambati, Balamurali K.; Hinton, David R.; Ambati, Jayakrishna

doi:10.1038/nm.3671

Cited by 41 publications

(42 citation statements)

References 29 publications

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“…Our data pertaining to a role for IL-18 in regulating neovascularization was supported by independent reports in the literature, 10,11 and strongly indicated that IL-18 could have some therapeutic benefit in neovascular AMD, in contrast to a report by Ambati et al 12 Human IL-18 (SB-485232, GSK) is a clinically enabled investigational drug that has been injected systemically in >170 cancer patients with an excellent safety profile, with numerous on-going studies. 13,14 We sought to examine the tolerability and efficacy of SB-485232 in a nonhuman primate model of neovascular AMD.…”

Section: Mature Il-18 Is Safe and Reduces Development Of Laser-inducesupporting

confidence: 83%

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

Doyle

López

Celkova

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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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 formis 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.

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Section: Mature Il-18 Is Safe and Reduces Development Of Laser-inducesupporting

confidence: 83%

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

Doyle

López

Celkova

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…However, a conglomeration of five laboratories determined that this finding was in fact due to glycerol, a proangiogenic excipient in the IL-18 neutralizing antibody preparation (27). Subsequently, it was reported that recombinant murine IL-18 reduced choroidal neovascularization in a laser injury model (28).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, it was reported that recombinant murine IL-18 reduced choroidal neovascularization in a laser injury model (28). However, a multicentered study failed to reproduce those data, finding instead that IL-18 had no effect on CNV over 5-log dose range, and instead that IL-18 induced RPE degeneration (27), which has been independently corroborated (29). Given the findings of this study, Fas, FasL, and Caspase-8 emerge as potential therapeutic targets for atrophic AMD.…”

Section: Discussionmentioning

confidence: 99%

DICER1/ Alu RNA dysmetabolism induces Caspase-8–mediated cell death in age-related macular degeneration

Kim

Tarallo

Kerur

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the disease. In this study, we implicate the involvement of Caspase-8 as a critical mediator of RPE degeneration. Here we show that DICER1 deficiency, Alu RNA accumulation, and IL-18 up-regulation lead to RPE cell death via activation of Caspase-8 through a Fas ligand-dependent mechanism. Coupled with our observation of increased Caspase-8 expression in the RPE of human eyes with geographic atrophy, our findings provide a rationale for targeting this apoptotic pathway in this disease. macular degeneration | inflammasome | caspase

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“…This suggests that overactivated purinergic signaling may contribute to the development of geographic atrophy, a hallmark of dry AMD. Alu RNA, coded by retrotransposons, induces a degeneration of the RPE in dry AMD via activation of P2X 7 , the NLRP3 inflammasome, caspase-1, and interleukin (IL)-18 (Tarallo et al, 2012;Kerur et al, 2013;Fowler et al, 2014;Hirano et al, 2014). P2X 7 activation in RPE cells may also contribute to another hallmark of AMD, the impaired digestion of peroxidized photoreceptor lipids, resulting in accumulation of lipofuscin within the cells and lipoprotein-containing drusen beneath the cells.…”

Section: Purinergic Regulation Of Retinal Cell Deathmentioning

confidence: 99%