September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Galectin-1 is an Angiogenic Factor Associated with Proliferative Diabetic Retinopathy: Novel Target for Aflibeccept
Author Affiliations & Notes
  • Atsuhiro Kanda
    Ophthalmology, Hokkaido University, Sapporo, Hokkaido, Japan
  • Kousuke Noda
    Ophthalmology, Hokkaido University, Sapporo, Hokkaido, Japan
  • Wataru Saito
    Ophthalmology, Hokkaido University, Sapporo, Hokkaido, Japan
  • Susumu Ishida
    Ophthalmology, Hokkaido University, Sapporo, Hokkaido, Japan
  • Footnotes
    Commercial Relationships   Atsuhiro Kanda, None; Kousuke Noda, None; Wataru Saito, None; Susumu Ishida, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Atsuhiro Kanda, Kousuke Noda, Wataru Saito, Susumu Ishida; Galectin-1 is an Angiogenic Factor Associated with Proliferative Diabetic Retinopathy: Novel Target for Aflibeccept. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Aflibercept is an anti-vascular endothelial growth factor (VEGF) agent pharmacologically engineered as a chimeric receptor-based decoy protein fused to the immunoglobulin Fc fragment (i.e., VEGFR1/VEGFR2-Fc). We revealed a novel anti-angiogenic function for aflibercept beyond its antagonism against VEGF family members, and characterized the newly identified aflibercept-binding protein in vitro and in vivo using patient samples as well.

Methods : Immunoprecipitation and mass spectrometry analyses were carried out to identify aflibercept-interacting proteins. Protein binding affinities were quantified by biolayer interferometry. Peptide:N-glycosidase F was used to cleave N-linked glycans of aflibercept. Real-time polymerase chain reaction was performed to measure mRNA expression levels in hypoxic cell culture and disease mouse models including streptozotocin-induced diabetes and laser-induced choroidal neovascularization. Human surgical samples were examined by immunofluorescence and enzyme-linked immunosorbent assay.

Results : Aflibercept exhibited firm binding to galectin-1 with higher affinity than VEGFR1-Fc and VEGFR2-Fc, which was abolished by deglycosylation of aflibercept. Retinal LGALS1/Galectin-1 mRNA expression was enhanced in vitro by hypoxic stimulation and in vivo by induction of various retinal diseases. Galectin-1 immunoreactivity co-localized with VEGFR2 in neovascular tissues surgically excised from human eyes with PDR (proliferative diabetic retinopathy). Compared with non-diabetic controls, intravitreal galectin-1 protein levels were elevated in PDR eyes, showing no correlation with increased VEGF-A levels. Preoperative injection of bevacizumab, a monoclonal antibody to VEGF-A, reduced the VEGF-A, but not galectin-1, levels. Galectin-1 as well as VEGF-A application to human retinal microvascular endothelial cells up-regulated VEGFR2 phosphorylation, both of which were eliminated by aflibercept.

Conclusions : Our present findings demonstrated the neutralizing efficacy of aflibercept against galectin-1, an angiogenic factor associated with PDR independently of VEGF-A.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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