July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
In Vitro and In Vivo Characterization of Abicipar Pegol, an anti-VEGF DARPin® Therapeutic
Author Affiliations & Notes
  • Gerry A Rodrigues
    Research, Allergan plc, Irvine, California, United States
  • Matthew Mason
    Allergan plc, Irvine, California, United States
  • Lori-Ann Christie
    Allergan plc, Irvine, California, United States
  • Candice Hansen
    Allergan plc, Irvine, California, United States
  • James A Burke
    Allergan plc, Irvine, California, United States
  • Keith Luhrs
    Allergan plc, Irvine, California, United States
  • Thomas C Hohman
    Envision Consulting, LLC, Ocean City, New Jersey, United States
  • Footnotes
    Commercial Relationships   Gerry Rodrigues, Allergan plc (E); Matthew Mason, Allergan plc (E); Lori-Ann Christie, Allergan plc (E); Candice Hansen, Allergan plc (E); James Burke, Allergan plc (E); Keith Luhrs, Allergan plc (E); Thomas Hohman, Allergan plc (C)
  • Footnotes
    Support  Allergan plc
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 233. doi:
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      Gerry A Rodrigues, Matthew Mason, Lori-Ann Christie, Candice Hansen, James A Burke, Keith Luhrs, Thomas C Hohman; In Vitro and In Vivo Characterization of Abicipar Pegol, an anti-VEGF DARPin® Therapeutic. Invest. Ophthalmol. Vis. Sci. 2018;59(9):233.

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

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Abstract

Purpose : To characterize the properties and biological activity of abicipar pegol (abicipar) in vitro and in animal models. Abicipar, a pegylated 34 kDa recombinant ankyrin repeat protein that binds vascular endothelial growth factor (VEGF)-A, is currently in phase 3 evaluation for treatment of neovascular age-related macular degeneration.

Methods : Abicipar was assessed alone or in comparison with ranibizumab, an antibody-based anti-VEGF therapeutic. Binding affinity to VEGF in solution was determined using a kinetic exclusion assay. Calcium mobilization in human umbilical vein endothelial cells was measured using calcium-sensitive Fluo-4 AM and FLIPR. Inhibition of angiogenesis in vitro was evaluated using a three-dimensional model of vessel sprouting. Anti-VEGF activity in vivo was evaluated in a mouse corneal neovascularization model, a rabbit model of chronic retinal neovascularization, and a rabbit model of retinal vasculopathy induced by intravitreal VEGF-A165 injection.

Results : Abicipar demonstrated sub-picomolar affinity for human VEGF-A165 and its splice variants as well as rat VEGF-A164, and picomolar affinity for rabbit VEGF-A165. Kd values for binding to human VEGF-A165 were 486 fM for abicipar vs 42.5 pM for ranibizumab. IC50 values for inhibition of VEGF-induced calcium mobilization were 24.8 pM for abicipar vs 102 pM for ranibizumab (p<0.0001). Abicipar exhibited concentration-dependent inhibition of VEGF-induced angiogenesis in vitro. In vivo abicipar administration reduced the area of neovascularization by 84% in the mouse model of corneal neovascularization and blocked vascular leakage in the rabbit model of chronic neovascularization. The duration of inhibition of vascular leakage by abicipar was longer than that of an equimolar dose of ranibizumab in a rabbit model of VEGF-A–induced retinal vasculopathy.

Conclusions : Abicipar binds all soluble VEGF-A isoforms with high affinity, potently neutralizes VEGF-A165 effects in vitro, and effectively blocks neovascularization and vascular leakage in animal models. In comparison with ranibizumab, abicipar has ~100-fold greater affinity for VEGF-A and provides a longer duration of inhibition of vascular leakage in a rabbit model of VEGF-A–induced vasculopathy. These data suggest that abicipar has the potential to be clinically effective with a longer duration of effect than ranibizumab in patients with retinal neovascularization and vascular leakage.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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