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Thomas Clayton MacPherson, Bibiana Iglesias, Yang Liu, Stanley J Wiegand, George Yancopoulos, Jingtai Cao, Carl Romano; Co-administration of an Antibody to Angiopoietin2 Extends the Duration of the Anti-Vascular Leak Activity of Aflibercept in a Model of Sustained Retinal Neovascularization (RNV). Invest. Ophthalmol. Vis. Sci. 2017;58(8):4069.
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Purpose: Ligands and receptors of both the VEGF and angiopoietin families are critical for normal vascular development and both have been implicated in pathological angiogenesis. In adults, Ang2 is expressed at low levels in endothelial cells of healthy blood vessels, but at high levels in pathological vessels. In the presence of VEGF, Ang2 has been shown to promote neovascularization. This study investigated if suppression of VEGF-A and Ang2 may lead to a more pronounced effect on pathological neovascularization than anti-VEGF treatment alone in a model of sustained RNV.
Methods: Male New Zealand White rabbits weighing 2.0-2.5 kg received AAA intravitreally (IVT), with follow-up examinations by fluorescein angiography (FA) and optical coherence tomography (OCT). After 10 weeks, rabbits were divided into treatment or control groups with an equal distribution of RNV. Animals were administered a single 50 μl IVT dose of buffer (n=6), anti-Ang2 (REGN910, a fully human, monoclonal, Ang2 neutralizing antibody; 500 μg/eye, n=13), aflibercept (125 ug/eye, n=5; or 500μg/eye, n=6), or a co-formulation of anti-Ang2 and aflibercept (500μg anti-Ang2 and 500μg aflibercept/eye, n=6; or 500μg anti-Ang2 and 125μg aflibercept/eye, n=8). Animals recieved the same treament in both OD and OS. FA and OCT were performed at baseline and weekly (weeks 1 to 20) post IVT treatment. Retinal NV leak was quantified using Photoshop CS6. At different time-points, the eyes were collected for histology analysis.
Results: Treatment with aflibercept completely suppressed vascular leak after treatment, and leak reappeared between 2 and 3 weeks in the low dose and 7 and 8 weeks post administration in the high dose groups. REGN910 alone did not alter pathological leak. Delivery of the co-formulation completely suppressed vascular leak and resulted in an extension in the period of disease remission compared to aflibercept monotherapy, with very minor leak reappearing between 8 and 9 weeks post-administration in both dosing groups.
Conclusion: These findings indicate that, in this pre-clinical model, co-formulation of IVT anti-Ang2 and aflibercept substantially enhances the duration of anti-leak effects compared to a single IVT injection of aflibercept or anti-Ang2 alone.
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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