April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Optimized IL-6 Blockade for the Treatment of Diabetic Macular Edema
Author Affiliations & Notes
  • Michael Schmidt
    Eleven Biotherapeutics, Cambridge, MA
  • Alison Tisdale
    Eleven Biotherapeutics, Cambridge, MA
  • Patricia Lowden
    Eleven Biotherapeutics, Cambridge, MA
  • Joseph Kovalchin
    Eleven Biotherapeutics, Cambridge, MA
  • Eric S Furfine
    Eleven Biotherapeutics, Cambridge, MA
  • Footnotes
    Commercial Relationships Michael Schmidt, Eleven Biotherapeutics (E), Eleven Biotherapeutics (P); Alison Tisdale, Eleven Biotherapeutics (E), Eleven Biotherapeutics (P); Patricia Lowden, Eleven Biotherapeutics (E); Joseph Kovalchin, Eleven Biotherapeutics (E); Eric Furfine, Eleven Biotherapeutics (E), Eleven Biotherapeutics (P)
  • Footnotes
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Investigative Ophthalmology & Visual Science April 2014, Vol.55, 1062. doi:
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      Michael Schmidt, Alison Tisdale, Patricia Lowden, Joseph Kovalchin, Eric S Furfine; Optimized IL-6 Blockade for the Treatment of Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1062.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: 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 and resistance to therapeutic VEGF blockade. Here we test the hypothesis that intravitreal administration of a rodent specific IL-6 antagonist can reduce choroidal neovascularization in a rat model and report development of EBI-029, a novel antagonistic anti-human IL-6 antibody optimized for ocular administration.

Methods: In a rat choroidal neovascularization (CNV) model, six animals per group received bilaterial laser treatment on Day 0 producing three lesions per eye. On Days 3 and 10, animals received either 3 µg of a polyclonal anti-rat-IL-6 antibody, PBS, or an anti-VEGF polyclonal antibody intravitreally (ITV). Lesion areas were measured on Day 15 and 22 by retinal angiography. EBI-029 was created by immunizing mice with recombinant human IL-6 and humanizing the resulting monoclonal through CDR grafting and affinity maturation by yeast display. IL-6 antagonism was assessed using a HEK-BlueTM IL-6 reporter cell line with either IL-6 alone (cis-signaling) or IL-6 in complex with soluble IL-6 receptor (trans-signaling).

Results: In the rat CNV model, ITV administered anti-IL6 antibody significantly reduced lesion size compared to the vehicle control (p = 0.0054 on Day 15 and p = 0.0005 on Day 22), and was indistinguishable from the anti-VEGF positive control. EBI-029 binds human IL-6 with 200 pM affinity and blocks signaling of IL-6 and the IL-6/sIL-6Rα complex in cellular assays. A Fab fragment of EBI-029 was thermally stable (Tm ~ 80oC), concentrated to 20 mg/mL with no aggregation, and had a vitreal clearance half-time of 80 hours in rabbits. Full-length IgG2 variants of EBI-029 with mutations in the Fc domain to ablate FcRn binding have been generated to further extend vitreal residence and reduce systemic exposure.

Conclusions: Local (ITV) IL-6 antagonism reduced choroidal neovascularization in a rat model, supporting the role of IL-6 in pathologic ocular angiogenesis. A novel anti-human IL-6 antibody, EBI-029, potently inhibits IL-6 cis- and trans-signaling and has excellent biophysical properties for ITV administration. Together, this work supports the further development of EBI-029 as a therapy for diabetic macular edema either as monotherapy or in combination with VEGF blockade.

Keywords: 490 cytokines/chemokines • 453 choroid: neovascularization • 498 diabetes  

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