June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Angiopoietin-like 3 (ANGPTL3) Does not Induce Protein-Specific Corneal Neovascularization (CoNV) after Intrastromal Implantation of ANGPTL3 Pellet in Rat
Author Affiliations & Notes
  • Duo Sun
    Ophthalmology, Regeneron Pharmaceuticals Inc, Ossining, New York, United States
  • Yang Liu
    Ophthalmology, Regeneron Pharmaceuticals Inc, Ossining, New York, United States
  • Hong Li
    Ophthalmology, Regeneron Pharmaceuticals Inc, Ossining, New York, United States
  • Ashwin Chandrashekar Parenky
    Formulation Department, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Hunter Chen
    Formulation Department, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Andria Skinner
    Formulation Department, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Xiaolin Charlie Tang
    Formulation Department, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Jingtai Cao
    Ophthalmology, Regeneron Pharmaceuticals Inc, Ossining, New York, United States
  • Carl Romano
    Ophthalmology, Regeneron Pharmaceuticals Inc, Ossining, New York, United States
  • Footnotes
    Commercial Relationships   Duo Sun, None; Yang Liu, None; Hong Li, None; Ashwin Parenky, None; Hunter Chen, None; Andria Skinner, None; Xiaolin Tang, None; Jingtai Cao, None; Carl Romano, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 999. doi:
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      Duo Sun, Yang Liu, Hong Li, Ashwin Chandrashekar Parenky, Hunter Chen, Andria Skinner, Xiaolin Charlie Tang, Jingtai Cao, Carl Romano; Angiopoietin-like 3 (ANGPTL3) Does not Induce Protein-Specific Corneal Neovascularization (CoNV) after Intrastromal Implantation of ANGPTL3 Pellet in Rat. Invest. Ophthalmol. Vis. Sci. 2017;58(8):999.

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

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Abstract

Purpose : ANGPTL3, a member of the angiopoietin-like family, is produced and secreted by liver and a determinant factor for LDL-cholesterol (C), HDL-C and triglycerides (Jin et al. 2007, Jusarova V et al. 2015). It might also bind αvβ3 integrins, inducing endothelial cell adhesion and migration, and play a role in regulation of angiogenesis (Camenisch et al. 2002). REGN1500, a fully human monoclonal antibody, binds ANGPTL3 and thereby lowers plasma lipids. Using a rat corneal angiogenesis assay with pellet intrastromal implantation, we evaluated the angiogenic potential of human ANGPTL3 and compared its angiogenic effect with human Fc (hFc, negative control) and human vascular endothelial growth factor A (VEGF-A, positive control), and the ability of specific blockers to inhibit the CoNV.

Methods : Corneal intrastromal implantation of pellets was performed in SD rats, with or without systemic inhibitor treatment (at Day 0, 6 eyes/3 rats/formulation, 1 pellet/eye). Treatment groups included sucralfate-blank pellet, sucralfate-hFc (500ng/pellet), sucralfate-hANGPTL3 (500ng/pellet), sucralfate-hANGPTL3 (500ng/pellet+REGN1500, 25mg/kg, s.c.), sucralfate-hVEGF165 (100ng/pellet), and sucralfate-hVEGF165 (100ng/pellet+Aflibercept 12.5mg/kg, s.c.), respectively. An additional group of 3 rats (6 eyes) was used as intact baseline control. At Day 6, animals were euthanized and perfused with fluorescein-Concanavalin A for vessel staining followed by dissection for corneal flat-mounts and fluorescence microscopy for corneal blood vessel area measurement.

Results : Compared with baseline, blank pellet induced minimal CoNV. hVEGF pellet demonstrated significant induction of CoNV, which was dramatically inhibited by systemic aflibercept treatment. hFc and hANGPTL3 pellets both also resulted in similar level of CoNV which was a bit less than that from hVEGF pellet. REGN1500 (25 mg/kg, 5-fold above the effective dose for triglyceride reduction) did not inhibit the non-specific CoNV induced by pellets containing ANGPTL3.

Conclusions : Our study reproduces the results of the literature that pellet containing hANGPTL3 induces CoNV with comparable magnitude as observed for pellet containing hVEGF. However, corneal angiogenesis induced by ANGPTL3 pellets appears to be a non-specific protein effect and is not blocked by REGN1500.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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