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Attenuation of Oxygen-Induced Neovascularization and Inflammation by Neutralizing VEGFA and/or ANG-2 With an Antibody
Hirokazu Oohashi1,2, Toshiro Iwagawa1, Hiroto Abe3
1Department of Retinal Biology and Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
Neovascularization is a major cause of blindness in various retinal diseases, and inflammation aggravates the pathological and clinical conditions of these diseases. VEGFA or ANG-2 neutralizing antibodies have been used to block pathological neovascularization. In this work, the effects of intraocular administration of neutralizing antibodies against VEGFA, ANG-2, or bispecific to these two factors on pathological findings were examined in the oxygen-induced retinopathy (OIR) mouse model. At both postnatal day (P)17 and P19, anti-VEGFA and -ANG-2 administration suppressed neovascularization, and the bispecific antibody attenuated neovascularization more efficiently. However, oxygen-induced vaso-obliteration was not modified by these antibodies. Numbers of photoreceptor, amacrine, and bipolar cells were reduced in the OIR retina, and the antibodies reversed these changes. Microglia-specific gene expression increased in the OIR retina, and administration of the antibodies reduced the IBA1-positive area in the OIR retina, although these antibodies did not affect Iba1 gene expression. Labeled VEGFA and ANG-2 were found to be co-localized with microglia, suggesting that VEGFA and ANG-2 affect microglia activation directly. Taken together, neutralizing antibody to VEGFA or ANG-2 attenuated oxygen-induced neovascularization and inflammation, and the bispecific antibody more efficiently suppressed some features than the single antibody to VEGFA or ANG-2.
Insights
Neutralizing antibodies targeting VEGFA or ANG-2 reduced neovascularization and inflammation in a mouse model of retinopathy. A bispecific antibody showed greater efficacy in suppressing these pathological features.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Neovascularization and inflammation are key drivers of vision loss in retinal diseases.
- Vascular Endothelial Growth Factor A (VEGFA) and Angiopoietin-2 (ANG-2) are implicated in pathological neovascularization.
- Current treatments include neutralizing antibodies against VEGFA or ANG-2.
Purpose of the Study:
- To investigate the efficacy of intraocular neutralizing antibodies against VEGFA, ANG-2, or a bispecific antibody targeting both factors.
- To evaluate the impact of these antibodies on pathological neovascularization, cell survival, and inflammation in the oxygen-induced retinopathy (OIR) mouse model.
Main Methods:
- Oxygen-induced retinopathy (OIR) mouse model was established.
- Intraocular administration of neutralizing antibodies against VEGFA, ANG-2, or a bispecific antibody.
- Assessment of neovascularization, vaso-obliteration, cell counts (photoreceptor, amacrine, bipolar), and microglia activation (IBA1 expression) at postnatal days 17 and 19.
Main Results:
- Both anti-VEGFA and anti-ANG-2 antibodies suppressed neovascularization; the bispecific antibody demonstrated superior efficacy.
- Antibodies did not alter oxygen-induced vaso-obliteration.
- Retinal cell loss was reversed by antibody treatment.
- Microglia activation markers increased in OIR retinas, and antibody treatment reduced the IBA1-positive area, suggesting direct effects on microglia.
Conclusions:
- Neutralizing antibodies against VEGFA and ANG-2 effectively attenuate oxygen-induced neovascularization and inflammation.
- The bispecific antibody targeting both VEGFA and ANG-2 offers enhanced suppression of certain pathological features.
- VEGFA and ANG-2 may directly influence microglia activation in the context of retinal disease.
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