The Focus Point With Anti-VEGF Treatment

VEGF is a protein called vascular endothelial growth factor. Generally, this is a protein that encourages the growth of new blood vessels as part of a healing response to injury.

However, when it is produced in the eye, it promotes the growth of abnormal blood vessels beneath the retina in the choroid. This can be dangerous.

VEGF also increases the permeability of existing blood vessels, which means they have an increased likelihood of leaking. When the abnormal blood vessels leak, it causes swelling.

This can damage retinal cells and may even lead to retinal detachment, leading to impaired vision.

Anti-VEGF drugs work by blocking VEGF and minimizing its effects. Although VEGF can be beneficial in other parts of the body to promote healing and blood vessel formation, it is problematic when overproduced in the eye due to the delicate nature of the retina and surrounding tissue layers.

When trying to minimize VEGF in the eye, it is important to concentrate the effects of any anti-VEGF drug in the eye and minimize the effects in the rest of the body. This means that a direct injection into the eye is the most effective.

Anti-VEGF drugs inhibit VEGF by binding or trapping it, thereby preventing it from promoting the growth of new abnormal blood vessels. Synthetic nucleic acid or protein molecules called aptamers have been designed to bind VEGF and prevent it from exerting downstream effects.

It is well established that, in diabetic eye disease, excessive activation of VEGF receptors 1 and 2 (VEGFR-1/ VEGFR-2) contributes to the development of inflammation, retinal vascular leakage and edema, and formation of new capillaries leading to neovascularization.

Recent research demonstrates the involvement of VEGFR-1 and its family of ligands in angiogenesis, vascular permeability and microinflammatory cascades within the retina.

VEGFR-1 is one of three known human VEGF receptors; its ligands are VEGF-A, VEGF-B, and placental growth factor (PlGF).

It is astonishing that VEGFR-1 is expressed in multiple different cell types in the retina and choroid. Intraocular VEGF and PlGF are significantly elevated in patients with diabetic eye disease and concentrations are significantly increased in the course of disease progression.

Following aflibercept treatment in patients with DME, intraocular VEGF and PlGF concentrations are significantly decreased. Several different characteristics and molecular factors determine how a drug interacts with the body, including charge, half-life, binding affinity, potency and concentration.

Binding affinity is the strength of binding of a drug to its ligand and is a key determinant of its biological activity.

Aflibercept incorporates domains from both VEGFR-1 and VEGFR-2 fused to the Fc portion of human IgG1 for tight binding of both VEGF and PlGF, preventing them from interacting with their natural receptors.

Aflibercept binds to VEGF165 with a binding affinity (0.45 pM) that is ~100-fold greater than ranibizumab and bevacizumab, in a tenacious attachment creating a ‘nearly irreversible two-fisted grasp’.

VEGF-A binds VEGFR-1 and VEGFR-2, whereas VEGF-B and PlGF only bind VEGFR-1. With this blockade, aflibercept inhibits the downstream effects of VEGFR-1 and VEGFR-2 signaling in retinal and choroidal tissues.

If VEGF-A alone is targeted,  PlGF remains available to bind VEGFR-1, as would be the case for anti-VEGF agents ranibizumab and bevacizumab that specifically target VEGF-A only.