The advent of anti-vascular endothelial growth factor (anti-VEGF) therapies has revolutionized the treatment of neovascular age-related macular degeneration (AMD) as well as other retinopathies driven by VEGF. In recent years, a multitude of studies has provided evidence that therapy with intravitreal monoclonal antibodies directed against VEGF improves visual outcome in patients with exudative macular degeneration (1,2,3).

The family of VEGF proteins includes multiple subtypes including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF (placental growth factor). The VEGF family members predominantly involved in ocular neovascularization are VEGF-A and PIGF. VEGF-A and PIGF increase permeability of choroidal neovascular tissues through the action of the VEGF receptors, which are tyrosine kinase receptors with an extracellular binding domain and an intracellular tyrosine kinase domain. Upon ligand (VEGF) binding to the receptor, the receptors dimerize, and the tyrosine kinase domain initiates phosphorylation at the C-terminus of the molecule. This initiates an intracellular signaling cascade that ultimately leads to changes in gene transcription. Many forms of ocular neovascularization are currently treated with intravitreal monoclonal antibodies (ranibizumab and bevacizumab), which target all isoforms of VEGF-A but do not target PIGF. The VEGF Trap-Eye (aflibercept) offers an alternate to the standard anti-VEGF therapies used in ocular neovascular disease and may have several advantages over the monoclonal antibodies.

The VEGF Trap-Eye (aflibercept) is a 110 kDa fusion protein that was engineered to have several potential advantageous properties over monoclonal antibodies, including increased intravitreal half-life compared to ranibizumab, high binding affinity for VEGF-A, and broader activity including binding of PIGF (4). VEGF Trap-Eye consists of the extracellular portions of the normally membrane-bound VEGF receptors 1 and 2, fused to the Fc portion of human immunoglobulin G. The rationale is that this drug has a low likelihood of inciting an immune response against itself and will be more effective at decreasing the pathologic activity of choroidal neovascular membranes.

Stewart et al. (5,6) have used mathematical modeling to predict the biologic activity of VEGF Trap-Eye. This model shows that due to the increased binding affinity of VEGF Trap-Eye (140× that of ranibizumab) and the increased intravitreal half-life compared to ranibizumab (estimated at 4-5 days for aflibercept), the biologic activity of VEGF
Trap-Eye 10 weeks after injection is roughly equivalent to the biologic activity of ranibizumab 30 days after injection (5).

Stewart et al. (6

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