Aflibercept
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Original Author: Christian Swinney B.A. and Peter A Karth, M.D., M.B.A.
Aflibercept is a soluble decoy receptor that binds vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF) with a greater affinity than the body’s native receptors. VEGF-A is a biochemical signal protein that promotes angiogenesis throughout the body and in the eye. By decreasing VEGF-A’s activation of its native receptors, aflibercept reduces subsequent growth of new blood vessels.1,2
Overview of VEGF and its Role in Retinal Disease
VEGF is a member of the platelet-derived growth factor (PDGF) family. The VEGF gene family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF), located on chromosome 6p12.3 The binding of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel growth and therefore plays a key role in angiogenesis. New blood vessel growth and development are extremely complex and coordinated processes that require a cascade of receptor activations. In this cascade, VEGF represents an initial and critical rate-limiting step in physiological angiogenesis. 4,5,6 The critical role of VEGF in angiogenesis can be seen in the fact that a loss of a single VEGF allele can result in defective vascularization.7
There are nine VEGF-A isoforms: VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF165b, VEGF183, VEGF189 and VEGF206. 8 The most abundant isoform found in the eye is VEGF165. 9,10 VEGF165 is a secreted heparin-binding homodimeric 45-kDa glycoprotein with a significant fraction bound to the cell surface. 11 VEGF activates endothelial cells by binding VEGFR-1 (Flt-1) and VEGFR-2 (KDR) endothelial cell receptors, which in turn activate intracellular signal transduction cascades. 11 VEGFR-2 is thought to be principally responsible for VEGF signaling in angiogenesis.11
VEGF-A levels have been found to be elevated in the vitreous of patients with neovascular (wet) age-related macular degeneration (AMD),12 diabetic macular edema, and retinal vein occlusion. Choroidal neovascularization (CNV) in AMD may be instigated by several events, such as accumulation of lipid metabolic byproducts, oxidative stress, reduction in choriocapillaris blood flow, and alterations in Bruch’s membrane. 13-15 Hypoxia has been shown to induce VEGF gene transcription. As a response to metabolic distress, the retinal pigment epithelium (RPE) and retinal tissue produce various factors, particularly VEGF, which induce CNV proliferation. VEGF has been shown to be a chemo-attractant for endothelial cell precursors, causing CNV in mouse models. 16 VEGF also prevents endothelial cell apoptosis. 17 Additionally, VEGF promotes metalloproteinase production by endothelial cells, causing tissue degradation that facilitates invasion by new vessels. 18,19
VEGF is a powerful agonist of vascular permeability, which causes vascular leakage and macular edema. 20 Placental Growth Factor (PIGF) may work synergistically with VEGF, contributing to vascular inflammation and leukocyte infiltration.1,2 VEGF is thought to cause increased vascular permeability by formation of fenestrations in microvascular endothelium. 21,22 Furthermore, VEGF was shown to up-regulate leukocyte adhesion to ICAM-1 in mice, thereby promoting vascular permeability and capillary non-perfusion. 23 On this basis, inhibition of VEGF activity is central to the treatment of macular edema and prevention of progressive capillary non-perfusion, especially in diabetic retinopathy and retinal vein occlusion.
Mechanism of Action
Aflibercept is a 115 kDa fusion protein. It consists of an IgG backbone fused to extracellular VEGF receptor sequences of the human VEGFR1 and VEGFR2. 1,2 As a soluble decoy receptor, it binds VEGF-A with a greater affinity than its natural receptors. In an experimental model, aflibercept’s equiibrium disassociation constant (Kd, inversely related to binding affinity) for VEGF-A165 was 0.49 pM, compared with 9.33 pM and 88.8 pM for experimental native VEGFR1 and VEGFR2, respectively.1 Aflibercept’s high affinity for VEGF prevents the subsequent binding and activation of native VEGF receptors. Reduced VEGF activity leads to decreased angiogenesis and vascular permeability. 1,2 Inhibition of PIGF and VEGF-B may also aid the treatment of angiogenic conditions.1 PIGF has been associated with angiogenesis and can be elevated in multiple conditions, such as wet AMD.1,24,25,26,27 VEGF-B overexpression has recently been connected with breakdown of the blood-retinal battier retinal angiogenesis.28 Thus, inhibition of VEGF-A, VEGF-B, and PIGF may all contribute to the efficacy of aflibercept.
Aflibercept has a unique binding action and binds to both sides of the VEGF dimer, forming an inert 1:1 complex, also termed a VEGF trap. Additionally, aflibercept is the only drug in its class to bind to PIGF-2.1,2
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