Purchase this article with an account.
Michael Schmidt, Yuri Matsumoto, Alison Tisdale, Patricia Lowden, Joe Kovalchin, Paul Wu, Kathryn Golden, Chris Dombrowski, Blanca Lain, Eric S Furfine; Optimized intravitreal IL-6 antagonist for the treatment of diabetic macular edema. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3488.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
IL-6 is a pleiotropic cytokine with established roles in inflammation and angiogenesis. Vitreal IL-6 levels are significantly elevated in patients with diabetic macular edema and are positively correlated with disease severity. In animal models including laser CNV, IL-6 blockade reduces retinal leukostasis and angiogenesis. In humans, systemic IL-6 blockade can lower VEGF levels in rheumatoid arthritis patients and separately reduce cystoid macular edema in patients with uveitis. EBI-031 is an anti-IL-6 antibody optimized for intravitreal (IVT) treatment of diabetic macular edema (DME) and other ocular inflammatory diseases with high potency, long intravitreal retention, and rapid systemic clearance.
EBI-031 binding to IL-6 was assessed by ELISA and SPR. IL-6 antagonism was assessed using a HEK-BlueTM IL-6 reporter cell line with either IL-6 (cis- signaling) or “hyper-IL-6” which is a covalent complex with soluble IL-6 receptor (trans-signaling). Intravitreal pharmacokinetics were determined in New Zealand White rabbits and drug levels measured by ELISA.
EBI-031 binds human IL-6 at site II, or the site that contacts gp130, with pM affinity and blocks signaling of IL-6 and the IL-6/sIL-6Rα complex in cellular assays >900 fold more potently than the commercial IL-6 inhibitor tocilizumab. The antibody is thermally stable (Tm = 76oC for its Fab fragment) and can be concentrated to >100 mg/mL with little measurable aggregation. In rabbit PK studies, IVT administered EBI-031 had a vitreal clearance half-time of ~10 days, longer than aflibercept (~6 days) or tocilizumab (~5 days). EBI-031 also accumulated at higher levels in the retina. A single mutation in the IgG2 Fc domain of EBI-031 reduced FcRn-mediated recycling such that systemic levels after IVT exposure were lower than the wild-type antibody or tocilizumab. Finally, a computational model of IL-6 signaling suppression suggests that sufficient concentrations of EBI-031 should be present in the vitreous to inhibit 95% of IL-6 signaling for over 100 days in humans.
A novel anti-human IL-6 antibody, EBI-031, potently inhibits IL-6 cis- and trans- signaling and has excellent biophysical properties for IVT administration. In addition, the long intravitreal half-life and retinal residence time suggest IL-6 signaling could be substantially blocked for 3 or more months in patients with DME.
This PDF is available to Subscribers Only