Aflibercept

Aflibercept is a recombinant protein composed of the binding domains of two human vascular endothelial growth factor (VEGF) receptors, VEGFR1 and VEGFR2, fused with the Fc region of human immunoglobulin gamma 1 (IgG1). Structurally, Aflibercept is a dimeric glycoprotein with a protein molecular weight of 96.9 kilo Daltons (kDa). It contains approximately 15% glycosylation to give a total molecular weight of 115 kDa. All five putative N-glycosylation sites on each polypeptide chain predicted by the primary sequence can be occupied with carbohydrates and exhibit some degree of chain heterogeneity, including heterogeneity in terminal sialic acid residues, except at the single unsialylated site associated with the Fc domain. Due to the 2 fused VEGFR, aflibercept has a higher affinity to the cognate ligands than the endogenous individual receptor. However, it lacks the intracellular structure to propagate subsequent signal transduction, thus essentially sequestering the ligands to prevent activation of VEGFR.

Ziv-aflibercept, under the brand name Zaltrap, was developed as an intravenous injection for the treatment of metastatic colorectal cancer, and it was approved by the FDA and EMA in August 2012 and February 2013, respectively. The intravitreal formulation, under the brand name EYELEA, was approved by the FDA for the treatment of retinopathy of prematurity in preterm infants in February 2023 and for the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy in August 2023.

The opthalmic agent is used for the treatment of neovascular (Wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), and retinopathy of prematurity (ROP).

The systemic injection, known as ziv-aflibercept, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is for the treatment of metastatic colorectal cancer that is resistant to or progressed following treatment with oxaliplatin.