Fusion proteins for treatment of retinal diseases: aflibercept, ziv-aflibercept, and conbercept

Abstract

In the last few years, monoclonal antibodies have revolutionized the treatment of retinal neovascular diseases. More recently, a different class of drugs, fusion proteins, has provided an alternative treatment strategy with pharmacological differences. In addition to commercially available aflibercept, two other drugs, ziv-aflibercept and conbercept, have been studied in antiangiogenic treatment of ocular diseases. In this scenario, a critical review of the currently available data regarding fusion proteins in ophthalmic diseases may be a timely and important contribution. Aflibercept, previously known as VEGF Trap Eye, is a fusion protein of VEGF receptors 1 and 2 and a treatment for several retinal diseases related to angiogenesis. It has firmly joined ranibizumab and bevacizumab as an important therapeutic option in the management of neovascular AMD-, DME- and RVO-associated macular edema. Ziv-aflibercept, a systemic chemotherapeutic agent approved for the treatment of metastatic colorectal cancer, has recently drawn attention because of its potential for intravitreal administration, since it was not associated with ERG-related signs of toxicity in an experimental study and in human case reports. Conbercept is a soluble receptor decoy that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and PlGF, which has a high binding affinity for VEGF and a long half-life in vitreous. It has been studied in a phase three clinical trial and has shown efficacy and safety. This review discusses three fusion proteins that have been studied in ophthalmology, aflibercept, ziv-aflibercept and conbercept, with emphasis on their clinical application for the treatment of retinal diseases.

Keywords: Aflibercept; Conbercept; Fusion proteins; VEGF Trap Eye; Vascular endothelial growth factor (VEGF); Ziv-aflibercept.

Fig. 1

Spectral-domain OCT 7 days after intravitreal injection of 0.05 mL of ziv-aflibercept (25 mg/mL) (a) or aflibercept (40 mg/mL) (b) in two rabbits’ right eye

Fig. 2

Baseline color fundus image (a), fluorescein angiography (b) and SD-OCT (c) of the right eye of a patient presenting DME. a At baseline, hard exudates and diffuse intraretinal fluid are seen in the perifoveal area. b At baseline, diffuse hyperfluorescence due to leakage (especially supero-temporally) and hypofluorescence due to non-perfusion (infero-temporally) are seen in the perifoveal area. c Cystoid spaces and subretinal and intraretinal fluid are seen in the foveal and perifoveal area

Fig. 3

Color fundus image (a) fluorescein angiography (b) and SD-OCT (c) of the right eye of the same patient shown in Fig. 2. 4 weeks after the 3rd monthly injection of ziv-aflibercept. a 4 weeks after the third ziv-aflibercept injection, a decrease of intraretinal fluid and hard exudates is noticed in the perifoveal area of the right eye. b 4 weeks after the third ziv-aflibercept injection, a decrease of leakage is seen in the perifoveal area of the right eye. c 4 weeks after the third ziv-aflibercept injection, a decrease in the subretinal and intraretinal fluid is noticed