March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Inhibition Of Vascular Leakage And Choroidal Neovascularization Using Vegf-inhibiting Darpins In Rodents
Author Affiliations & Notes
  • Andreas Stahl
    University Eye Hospital Freiburg, Freiburg, Germany
  • Michael T. Stumpp
    Molecular Partners AG, Zurich, Switzerland
  • Anja Schlegel
    Molecular Partners AG, Zurich, Switzerland
  • Savira Ekawardhani
    Molecular Partners AG, Zurich, Switzerland
  • Gottfried Martin
    University Eye Hospital Freiburg, Freiburg, Germany
  • Maya Gulotti-Georgieva
    Molecular Partners AG, Zurich, Switzerland
  • Denis Villemagne
    Molecular Partners AG, Zurich, Switzerland
  • Patrik Forrer
    Molecular Partners AG, Zurich, Switzerland
  • Hansjürgen T. Agostini
    University Eye Hospital Freiburg, Freiburg, Germany
  • Kaspar H. Binz
    University Eye Hospital Freiburg, Freiburg, Germany
  • Footnotes
    Commercial Relationships  Andreas Stahl, None; Michael T. Stumpp, Inventor at Molecular Partners AG (P), Shareholder of Molecular Partners AG (I); Anja Schlegel, Employee of Molecular Partners (E); Savira Ekawardhani, Employee at Molecular Partners (E); Gottfried Martin, None; Maya Gulotti-Georgieva, Employee at Molecular Partners (E); Denis Villemagne, Employee at Molecular Partners (E); Patrik Forrer, Inventor at Molecular Partners AG (P), Shareholder of Molecular Partners AG (I); Hansjürgen T. Agostini, None; Kaspar H. Binz, Inventor at Molecular Partners AG (P), shareholder of Molecular Partners AG (I)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 3009. doi:
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      Andreas Stahl, Michael T. Stumpp, Anja Schlegel, Savira Ekawardhani, Gottfried Martin, Maya Gulotti-Georgieva, Denis Villemagne, Patrik Forrer, Hansjürgen T. Agostini, Kaspar H. Binz; Inhibition Of Vascular Leakage And Choroidal Neovascularization Using Vegf-inhibiting Darpins In Rodents. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3009.

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

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Abstract

Purpose: : Vascular endothelial growth factor (VEGF) is a key controller of pathological angiogenesis and leakage in various retinal diseases. Clinically, anti-VEGF agents have revolutionized treatment of exudative age related macular degeneration (AMD), diabetic retinopathy and retinal vein occlusion. However, one of the main limitations of current VEGF inhibitors remains the need for repeated intravitreal injections. Second-generation VEGF inhibitors should thus aim at providing more efficient VEGF-inhibition to reduce injection frequency.

Methods: : In the current study, we use highly potent anti-VEGF DARPins (designed ankyrin repeat proteins) to inhibit VEGF receptor phosphorylation and endothelial cell sprouting in vitro, retinal vascular leakage in rabbits and choroidal angiogenesis in the Laser CNV model in rats.

Results: : Our results demonstrate the successful isolation and purification of several DARPins with picomolar affinity to VEGF. In vitro, VEGF receptor phosphorylation was strongly inhibited compared to controls. Functional experiments using endothelial spheroid sprouting demonstrated potent inhibition of VEGF-induced angiogenic tube formation. Upon intravitreal injection, DARPins were found to penetrate into the retina and inhibit VEGF-induced retinal vascular leakage (p=0.025 vs. controls). In addition, topical DARPin application was found to suppress Laser-induced choroidal neovascularization in rats (p=0.025 vs. controls). No ocular or systemic side effects were observed in both in vivo models.

Conclusions: : DARPins are a new class of antibody mimetic molecules with increased anti-VEGF potency and prolonged intraocular activity that are derived from the abundant protein family of naturally occurring ankyrin repeat proteins. Anti-VEGF DARPins are promising candidates for the treatment of neovascular eye diseases in humans and currently under investigation in phase I/II clinical trials.

Keywords: retina • age-related macular degeneration • choroid: neovascularization 
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