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Daiju Iwata, Peter Lundh von Leithner, Yin Shan Eric Ng, Guido Hartmann, David T Shima; Anti -VEGF/Ang2 bi-specific antibody ameliorates endotoxin-induced uveitis in mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2354.
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Two vascular growth factors, VEGF-A (VEGF) and angiopoietin-2 (Ang2), play critical and coordinate roles in pathological angiogenesis and vascular leakage. VEGF is recognized as a pro-inflammatory cytokine and involved in chemotaxis of macrophages and granulocytes. Ang2 is classically considered as a Tie2 antagonist, counteracting the stabilizing action of Ang1, which promotes the structural integrity of blood vessels and exhibits anti-inflammatory properties. Ang2 acts at the leukocyte adhesion step by upregulating the response of endothelial cells to TNF-α. Endotoxin induced uveitis (EIU) serves as a model of acute inflammatory response in the anterior and posterior segment of the eye with a breakdown of the blood-aqueous barrier and the blood-retinal barrier. The therapeutic effect of anti-VEGF/Ang2 bispecific antibody (Ab) was examined in EIU mice.
EIU was induced in C57BL/6 mice by a single intraperitoneal injection of 7.5mg/kg lipopolysaccharide (LPS). Antibodies to VEGF, Ang2 or a bispecific Ab were administered one day prior to EIU induction. Twenty-four hours after LPS administration, retinal leukocyte infiltration was evaluated. Protein concentration and inflammatory cells in the aqueous humor were also measured. Eye sections were stained with anti-NF-κB p65 Ab and western blot analysis for IκB-α was performed.
The retinal leukocyte infiltration and the number of inflammatory cells in aqueous humor were significantly decreased only after treatment with the anti-VEGF/Ang2 bispecific Ab. No effect was observed with monotherapy or IgG control antibodies. (P < 0.05). The protein concentration of aqueous humor in anti-VEGF/Ang2 bispecific Ab-treated EIU mice was also significantly lower (P < 0.01). Furthermore, this treatment suppressed the translocation of NF-κB p65 subunit into nuclei and prevented the EIU-induced degradation of IκB-α protein in both the retina and RPE/choroid.
Systemic administration of anti-VEGF/Ang2 bispecific Ab decreased retinal leukocyte invasion and suppressed NF-κB translocation in EIU mice. These results suggest anti-VEGF/Ang2 bi-specific Ab as a potential therapeutic strategy in the treatment of ocular inflammatory diseases.
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