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Aflibercept Traps Galectin-1, an Angiogenic Factor Associated with Diabetic Retinopathy
Atsuhiro Kanda1,2, Kousuke Noda1,2, Wataru Saito2
1Laboratory of Ocular Cell Biology and Visual Science, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
Abstract:
Vascular endothelial growth factor (VEGF)-A-driven angiogenesis contributes to various disorders including cancer and proliferative diabetic retinopathy (PDR). Among several VEGF-A blockers clinically used is aflibercept, a chimeric VEGFR1/VEGFR2-based decoy receptor fused to the Fc fragment of IgG1 (i.e., VEGFR1/VEGFR2-Fc). Here, we revealed a novel anti-angiogenic function for aflibercept beyond its antagonism against VEGF family members. Immunoprecipitation and mass spectrometry analyses identified galectin-1 as an aflibercept-interacting protein. Biolayer interferometry revealed aflibercept binding to galectin-1 with higher affinity than VEGFR1-Fc and VEGFR2-Fc, which was abolished by deglycosylation of aflibercept with peptide:N-glycosidase F. Retinal LGALS1/Galectin-1 mRNA expression was enhanced in vitro by hypoxic stimulation and in vivo by induction of diseases including diabetes. Galectin-1 immunoreactivity co-localized with VEGFR2 in neovascular tissues surgically excised from human eyes with PDR. 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 application to human retinal microvascular endothelial cells up-regulated VEGFR2 phosphorylation, which was eliminated by aflibercept. Our present findings demonstrated the neutralizing efficacy of aflibercept against galectin-1, an angiogenic factor associated with PDR independently of VEGF-A.
Insights
Aflibercept neutralizes galectin-1, a novel anti-angiogenic target in proliferative diabetic retinopathy (PDR). This finding reveals a new mechanism of action for aflibercept beyond blocking vascular endothelial growth factor (VEGF)-A.
Area of Science:
- Ophthalmology
- Molecular Biology
- Angiogenesis Research
Background:
- Vascular endothelial growth factor (VEGF)-A drives angiogenesis in diseases like proliferative diabetic retinopathy (PDR).
- Aflibercept is a VEGF-A inhibitor used clinically, acting as a decoy receptor.
- The precise mechanisms of aflibercept's action and potential additional targets remain areas of investigation.
Purpose of the Study:
- To identify novel functions and interacting proteins of aflibercept.
- To investigate the role of galectin-1 in PDR pathogenesis.
- To determine if aflibercept neutralizes galectin-1's angiogenic effects.
Main Methods:
- Immunoprecipitation and mass spectrometry to identify aflibercept-binding proteins.
- Biolayer interferometry to quantify binding affinities.
- In vitro and in vivo models of angiogenesis and PDR.
- Analysis of retinal tissue and fluid from PDR patients.
Main Results:
- Galectin-1 was identified as a novel aflibercept-interacting protein with high binding affinity.
- Galectin-1 expression and protein levels were elevated in PDR models and patient samples, independent of VEGF-A.
- Aflibercept treatment inhibited galectin-1-induced VEGFR2 phosphorylation in retinal cells.
- Bevacizumab, a VEGF-A inhibitor, did not affect galectin-1 levels in PDR.
Conclusions:
- Aflibercept exhibits anti-angiogenic efficacy against galectin-1, a factor implicated in PDR independently of VEGF-A.
- This study uncovers a new therapeutic mechanism for aflibercept in PDR.
- Galectin-1 represents a potential therapeutic target for PDR and other angiogenesis-driven disorders.
