What is the mechanism of Aflibercept?

Aflibercept, also known by its brand name Eylea, is a fusion protein used in the treatment of various eye diseases, including age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO). Its mechanism of action hinges on its ability to inhibit vascular endothelial growth factor (VEGF), a primary factor in the pathogenesis of these conditions.

VEGF is a signal protein that promotes the growth of new blood vessels, a process known as angiogenesis. Under normal circumstances, VEGF plays a crucial role in wound healing and embryonic development. However, in certain pathological conditions such as AMD and DME, VEGF levels are abnormally elevated. This leads to the formation of fragile and leaky blood vessels in the retina, causing fluid accumulation, hemorrhage, and ultimately, vision loss.

Aflibercept works by acting as a decoy receptor for VEGF. It is engineered through recombinant DNA technology and consists of portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. When administered via intravitreal injection, aflibercept binds to VEGF-A with higher affinity than the natural receptors on the endothelial cells. This binding prevents VEGF from interacting with its native receptors, thereby inhibiting the downstream signaling pathways that lead to angiogenesis and increased vascular permeability.

The high binding affinity of aflibercept to VEGF-A is a critical aspect of its mechanism. This high affinity ensures that even low concentrations of VEGF are effectively neutralized, which is particularly important in conditions where VEGF levels can fluctuate. Additionally, aflibercept also binds to placental growth factor (PlGF), another molecule involved in pathological angiogenesis. By blocking both VEGF and PlGF, aflibercept provides a more comprehensive inhibition of the angiogenic process.

The efficacy of aflibercept is evident in its clinical outcomes. Patients receiving aflibercept injections show significant improvements in visual acuity and reductions in retinal thickness. The treatment regimen typically involves an initial phase of monthly injections followed by less frequent maintenance doses, depending on the patient’s response and the specific condition being treated.

In summary, aflibercept is a potent anti-VEGF agent that exerts its therapeutic effects by sequestering VEGF and PlGF, thereby inhibiting abnormal blood vessel growth and reducing vascular permeability. Its role as a decoy receptor with high binding affinity makes it an effective treatment option for various retinal diseases characterized by excessive angiogenesis and fluid leakage.