IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates.
OBJECTIVE
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.
Department of Clinical Medicine School of Medicine, Trinity College Dublin, Dublin, Ireland.
Sarah L
SL
Doyle
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States.
Francisco J
FJ
López
Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Lucia
L
Celkova
Department of Clinical Medicine School of Medicine, Trinity College Dublin, Dublin, Ireland.
Kiva
K
Brennan
Department of Clinical Medicine School of Medicine, Trinity College Dublin, Dublin, Ireland.
Kelly
K
Mulfaul
Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Ema
E
Ozaki
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.
Paul F
PF
Kenna
Statistics Consulting Group, Quantitative Science, PTS, GlaxoSmithKline, King of Prussia, Pennsylvania, United States.
Edit
E
Kurali
Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Natalie
N
Hudson
Department of Ophthalmology and Visual Science, Washington University School of Medicine, St. Louis, Missouri, United States.
Teresa
T
Doggett
Department of Ophthalmology and Visual Science, Washington University School of Medicine, St. Louis, Missouri, United States.
Thomas A
TA
Ferguson
Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Peter
P
Humphries
Ophthalmology Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom 8Ocular Biology and Therapeutics, Institute of Ophthalmology, University College London, London, United Kingdom.
Peter
P
Adamson
Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
Matthew
M
Campbell
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004596:Electroretinography; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020382:Interleukin-18 / Q000008:administration & dosage*; D058449:Intravitreal Injections; D008252:Macaca fascicularis; D008268:Macular Degeneration / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D011323:Primates; D012313:RNA / Q000235:genetics; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015861:Retinal Neovascularization / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D020382:Interleukin-18; D042461:Vascular Endothelial Growth Factor A; D012313:RNA