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 Table of Contents  
Year : 2013  |  Volume : 3  |  Issue : 4  |  Page : 128-133

Vascular endothelial growth factor and its inhibitor in age-related macular degeneration

1 Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan; Key Laboratory of Harbin Medical University Eye Center, Eye Hospital, First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China
2 Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan

Date of Web Publication20-Nov-2013

Correspondence Address:
Masahito Ohji
Department of Ophthalmology, Shiga University of Medical Science, Seta Tukinowacho, Otsu, Shiga 520-2192
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.tjo.2013.09.002

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Intraocular angiogenesis is considered the leading cause for severe loss of vision, and contributes to many ocular diseases such as neovascular age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, the main causes of blindness in developed countries.[1] An enormous body of work has demonstrated that vascular endothelial growth factor (VEGF) plays a prominent role as mediator in the procedure of pathological angiogenesis. This makes VEGF a potential target for the medical therapies of retinal angiogenesis and some clinical trials have proved the efficacy of anti-VEGF strategies. This review evaluates the role of VEGF in the pathogenesis of age-related macular degeneration and provides an overview of recent developments in therapeutic modalities.

Keywords: age-related macular degeneration, intravitreal injection, vascular endothelial growth factor

How to cite this article:
Wang X, Ohji M. Vascular endothelial growth factor and its inhibitor in age-related macular degeneration. Taiwan J Ophthalmol 2013;3:128-33

How to cite this URL:
Wang X, Ohji M. Vascular endothelial growth factor and its inhibitor in age-related macular degeneration. Taiwan J Ophthalmol [serial online] 2013 [cited 2023 Mar 28];3:128-33. Available from: https://www.e-tjo.org/text.asp?2013/3/4/128/203908

  1. Introduction Top

Angiogenesis is defined as the growth of new blood vessels from existing blood vessels. In normal circumstances, new blood vessels develop and this is considered a positive response of normal biologic functions such as hair growth, wound healing, menstruation, and regulation of blood pressure in adults.[1],[2],[3],[4] The execution of this complex angiogenesis cascade needs a precise physiological balance between proangiogenic and antiangiogenic factors. Once proangiogenic factors prevail, endothelial cells begin to proliferate, migrate, differentiate, and may induce capillary formation and several pathological processes happen, such as tumor growth, rheumatoid arthritis, and age-related macular degeneration (AMD). To date, several proangiogenic factors have been identified including vascular endothelial growth factor (VEGF), fibroblast growth factor families, and transforming growth factor.[3],[5],[6] One of the most potent proangiogenic factors is VEGF.

  2. VEGF and its receptors Top

VEGF is a 40 kDa, homodimeric glycoprotein, specific for vascular endothelial cells and able to induce vasculogenesis and angiogenesis.[7] VEGF is an endothelial cell mitogen, promoting endothelial cell growth and survival and increases vascular permeability in vivo.[6],[8] It is essential for angiogenesis during early embryogenesis and the loss of one single allele of the VEGF gene may lead to embryonic lethality.[9] In the VEGF family, there are seven members: VEGF-A (hereafter referred to as VEGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and placental growth factor.

Among these factors, VEGF has been studied most widely. In humans, the VEGF gene is located on the short arm of chromosome 6 (6p21.1) and organized into eight exons, separated by seven in-trons.[10],[11] Alternative splicing of the pre-mRNA leads to the generation of several different isoforms named as VEGFxxx (xxx denotes the number of amino acids) with same exons 1–5 and various combinations of exons 6–8. The principal ones include VEGF121, VEGF165, VEGF189, and VEGF206.[11] All extracellular VEGF isoforms are cleaved by plasmin to VEGF110.[12],[13]

Recently, it was discovered that VEGF alternative splicing in exon 8 generated sister isoforms, producing proteins with the same length, but with a different C-terminal amino acid sequence. This family has been termed VEGFxxxb.[14] Because VEGFxxxb has been shown to be able to inhibit VEGFxxx-dependent angiogenesis, it has been tested in patients with diabetic retinopathy and retinal vein occlusion, and a mouse model of oxygen-induced retinopathy.[15],[16],[17] A VEGF splicing switch was observed, from an antiangiogenic VEGFxxxb to a proangiogenic VEGFxxx environment, which may indicate that changing the ratio of VEGFxxxb/VEGFxxx could be a potential therapy for treating ocular angiogenesis diseases.

To date, three VEGF receptors belonging to the receptor tyrosine kinase type have been identified: VEGFR-1 (Flt-1 or fms-like tyro-sine kinase) and VEGFR-2 (kinase insert domain-containing receptor or KDR) are mainly involved with angiogenesis[18],[19],[20]; and VEGFR-3 (fms-like tyrosine kinase-4 or Flt-4) is a receptor for VEGF-C and VEGF-D, which are involved in lymphangiogenesis.[20],[21]

  3. VEGF in AMD Top

AMD is one of the leading causes of irreversible blindness in people aged 55 years and older in developed countries.[22],[23],[24],[25] It can be classified into two types: atrophic (dry) and neovascular (wet). The more severe neovascular form (nAMD) accounts for approximately 90% to legal blindness and is characterized by choroidal neovascularization (CNV) which can intrude into the subretinal space, leading to hemorrhage and exudation.[26] Neovascular AMD often has a poor prognosis, leading to a rapid vision loss. It can deeply affect the quality of life of patients. So far the precise mechanism of AMD is still unclear, but VEGF is thought to be a potent mediator contributing to CNV.[27] As a possible path for pathogenesis of CNV in AMD, it is suggested that VEGF plays a major part at the initial stage of CNV by promoting angiogenesis and is a mitogen specific for endothelial cells as part of the angio-genesis pathway, inducing their differentiation.[28] In addition, VEGF also increases vascular permeability by breaking the vascular endothelial cells’ junction, which results in over-secretion of fluid, proteins, and circulating cells and destroys the retinal anatomy, making the retina detach from the basement,[29] leading to the loss of vision.

In 1996, the relationship of VEGF and neovascular AMD was reported by two groups, who identified VEGF localized in fibro-blastic cells and choroidal neovascular membranes and suggested a crucial role of VEGF in the development of the choroidal neo-vascularization in nAMD patients.[30],[31] As well as in rodent models, VEGF was found to be expressed in laser-induced CNV.[32] In addition, many investigators have tested that the VEGF concentration of ocular fluid in human eyes with AMD elevates significantly compared with normal eyes.[33],[34],[35],[36],[37] Some experiments have shown that suppression of VEGF can restrain the progress of CNV. Inhibition of VEGF has been associated with an inhibition of iris neo-vascularisation and suppression of the formation of new retinal vessels in primates.[38] There is strong evidence that, in AMD patients, both VEGF121 and VEGF165 are expressed in excised CNV membranes.[39]

  4. VEGF inhibitors and VEGF concentration in patients with nAMD Top

Because there is considerable evidence to suggest that VEGF plays a major role in pathological angiogenesis, it has become a suitable target to treat neovascular AMD. So far, three anti-VEGF agents (pegaptanib sodium, ranibizumab, aflibercept) have been approved for AMD by the Food and Drug Administration (FDA). These drugs were developed for inhibiting VEGF-A by different approaches.

  5. Pegaptanib sodium Top

Pegaptanib sodium (Macugen; EyeTech, New York, NY, USA) was the first approved anti-VEGF drug for treating nAMD by intravitreal injection; its molecular weight is approximately 50 kDa. It is an pegylated, 28-base RNA aptamer specific to inhibit VEGF165 isoform [Table 1].[40],[41],[42],[43],[44],[45],[46],[47] In two pivotal clinical trials, the efficacy of pegap-tanib sodium for the treatment of CNV secondary to AMD were evaluated (VEGF Inhibition Study In Ocular Neovascularisation: VISION). Although patients in the pegaptanib sodium injection group lost less letters compared with a sham injection group at 1 year (p < 0.002), they did not maintain the visual acuity (VA) by pegaptanib sodium treatment.[48] However, in the LEVEL study and the LEVEL-J study, pegaptanib sodium showed its effect on improving VA after induction treatments of nonselective VEGF-inhibitor or photodynamic therapy for a 1-year maintenance period.[49],[50]
Table 1: Differences among anti-vascular endothelial growth factor (VEGF) drugs.

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In animal models, pegaptanib sodium is cleared from the eye with an estimated vitreous half-life of 3.9 days after intravitreal administration and accumulation of pegaptanib sodium in the plasma was not found.[42] In our previous study, we reported that intravitreal injection of pegaptanib sodium increased VEGF level in aqueous humor at 6 weeks after injection.[35] This result was unexpected because pegaptanib sodium is designed to suppress VEGF165, but could be explained by an increase in VEGF121 isoform as we explained in the study. Based on the recent new finding of VEGF antiangiogenic VEGFxxxb isoforms, another potential reason has emerged. In the 6-week follow-up after injection, pegaptanib sodium may have the effect of increasing VEGFxxxb, returning VEGFxxxb/VEGFxxx balance to level, which maycontribute to normal ocular circumstance. This hypothesis needs to be verified in future studies, but there is no significant change of plasma VEGF levels observed in patients receiving pegaptanib sodium injection during 1 month follow-up.[51] That may account for the small molecular weight and fast clearance of pegaptanib sodium in systemic circulation, also confirmed by the pegaptanib sodium pharmacoki-netics result in the animal experiment.[42]

  6. Ranibizumab Top

Ranibizumab (Lucentis; Genentech Inc., South San Francisco, CA, USA) is a humanized, recombinant, monoclonal antibody Fab fragment binding to all isoforms of VEGF. Molecular weight is 48 kDa. It was approved by the FDA for treating nAMD in 2006 [Table 1]. Monthly intravitreal injections of ranibizumab not only prevent visual loss but also increase mean VA after 2 years in patients with all types of CNV secondary to AMD. The efficacy and safety of ranibizumab in all types of AMD related CNV have been verified in view of two phase III clinical trials.[52],[53],[54] On average, patients after intravitreal ranibizumab administration gained 1–2 lines VA in the first year of treatment [Figure 1]A. Ranibizumab was considered as the first VEGF antagonist able to improve VA in nAMD patients. In addition, VEGF concentrations in the aqueous humor of eyes with AMD can be suppressed 1 month after intra-vitreal administration of ranibizumab.[33],[34],[35] Although VEGF concentration in plasma of patients with nAMD presented different phenomenon,[51],[55],[56] no significant suppression of plasma VEGF levels were observed in patients receiving ranibizumab for 1 month.
Figure 1: Mean change of best-corrected visual acuity (BCVA) from several clinical trials. (A) ANCHOR study, (B) PIER study, (C) EXCITE study, (D) PrONTO study, (E) SUSTAIN study, and (F) CATT study. Note. Fig. 1A is from “Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study”, by DM Brown, M Michel, PK Kaiser, JS Heier, JP Sy, T Ianchulev, et al, 2009, Ophthalmology, 116, p. 61. Copyright 2009, Elsevier. Reprinted with permission. Fig. 1B is from “Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1”, by CD Regill, DM Brow, P Abraham, H Yue, T Ianchulev, S Schneider, et al, 2008, Am J Ophthalmol 145, p. 243. Copyright 2008, Elsevier. Reprinted with permission. Fig. 1C is from “Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study”, by U Schmidt-Erfurt, B Eldem, R Guymer, JF Korobelnik, RO Schlingemann, R Axer-Siegel, et al, 2011, Ophthalmology, 118, p. 835. Copyright 2011, Elsevier. Reprinted with permission. Fig. 1D is from “A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study”, by GA Lalwan, PJ Rosenfel, AE Fung, SR Dubovy, S Michels,WFeuer, et al, 2009, Am J Ophthalmol, 148, p. 46, Copyright 2009, Elsevier. Reprinted with permission. Fig. 1E is from “Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study”, by FG Holz, WAmoaku, J Donate, RH Guymer, U Kellner, RO Schlingemann, 2011, Ophthalmology 118, p. 668. Copyright 2011, Elsevier. Reprinted with permission. Fig. 1F is from “Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results”, by Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, DF Martin, MG Maguire, SL Fine, GS Ying, GJ Jaffe, et al, 2012, Ophthalmology, 119, p. 1391. Copyright 2012, Elsevier. Reprinted with permission.

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However, a monthly injection may bring the risk of intraocular infection and heavy economic burden to patients. Therefore, some researchers administrated a less frequent regimen to treat AMD. In the Phase IIIb, multicenter, randomized, double-masked, sham injection- controlled study of the efficacy and safety of ranibizumab in subjects with subfoveal CNV with or without classic CNV secondary to AMD (PIER) study, quarterly injections following three consecutive monthly injections were given. Although clinically meaningful VA benefit was gained by the ranibizumab group compared with the sham group, mean VA improved from baseline only lasted 3 months with monthly ranibizumab injection and it declined during the 21-month maintenance phase [Figure 1]B.[57],[58] The EXCITE study also used the quarterly injection regimen in the maintenance stage and compared with monthly injection directly. However, at the end of this study, quarterly injection showed inferiority to monthly injection in spite of increased VA, which demonstrates that more frequent monitoring is needed [Figure 1]C.[59]

The Prospective OCT Imaging of Patients with Neovascular AMD Treated with intra Ocular Ranibizumab (PrONTO) study adopted an optical coherence tomography-guided, variable dosing regimen after three monthly loading doses for the treatment of nAMD, which resulted in similar VA benefit as the Anti-vascular endo-thelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-related Macular Degeneration (ANCHOR) and the Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular Age-related macular degeneration studies and with fewer injections [Figure 1]D.[60],[61] In SUSTAIN, another phase III, multicenter, open-label, single-arm study, monthly monitoring and individualized retreatment based on VA and OCT findings after three monthly injections showed VA improvement of 3.6 letters with fewer injections [Figure 1]E.[62] The Safety Assessment of Intra-vitreous Lucentis for AMD (SAILOR) study also brought VA improvement of 2.3 letters with quarterly monitoring but was inferior to the result of monthly injection.[63] Head-to-head ranibi-zumab and bevacizumab trials (Comparison of Age-Related Macu-lar Degeneration Treatments Trials: CATT) reported that monthly injection of ranibizumab gained 8.8 letters at 24 months, which is significantly higher than the prorenata regimen of ranibizumab’s 6.7 letters [Figure 1]F.[64] The Presented within are the 12-month results of the phase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed basis (PRN) in patients with subfoveal neovascular age-related macular degeneration (HARBOR) study also demonstrated that monthly injection of 0.5 mg ranibizumab provides optimum results in patients with nAMD.[65] According to the studies above, monthly intravitreal injection of ranibizumab seems to be the best regimen for the treatment of nAMD. Recently we conducted a 6-month pilot study of bimonthly intravitreal injection of ranibizu-mab for AMD patients. In the preliminary result, the mean BCVA in logMAR kept improving from baseline until 6 months. (0.50 at baseline, 0.46 at 1 month, 0.44 at 2 months, 0.39 at 3 months, 0.36 at 4 months, 0.37 at 5 months, and 0.33 at months) and a significant difference was seen at 4 months, 5 months, and 6 months (p < 0.05). The mean central retinal subfield thickness was 316 μm at baseline, 239 μm at 1 month, 262 μm at 2 months, 242 μm at3 months, 255 μm at 4 months, 256 μm at 5 months, and 275 μm at 6 months. It decreased significantly at 1 month, 3 months, and 5 months compared with baseline (p < 0.05).[66] Our results demonstrate that bimonthly injection also benefits both anatomy and function, and is evidence that bimonthly intravitreal injection could be a choice for the treatment of nAMD.

  7. Aflibercept Top

Aflibercept (Eylea; Regeneron Pharmaceuticals, New York, NY, USA) is a fusion protein with high-affinity, combining the second domain of human VEGFR-1 and the third domain of human VEGFR-2 fused to the Fc portion of human immunoglobulin (Ig)G [Table 1]. Unlike pegaptanib, ranibizumab, and bevacizumab, aflibercept blocks all VEGF isoforms, VEGF-B and placental growth factor.[67] Up to now, there are no studies in human eyes demonstrating the half-life of aflibercept; however, the high affinity and the similar molecular weight (115 kDa) suggest that aflibercept’s ocular half-life would be similar to bevacizumab (approximately 9 days in human vitreous).[47] One intravitreal injection of 2 mg aflibercept would last between 48 days and 83 days, whereas ranibizumab lasts 30 days, estimated by mathematical modeling.[68] This was also confirmed by the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2] trials. In these two parallel, phase III, double-masked, randomized, multicenter studies, the efficacy of bimonthly injection of aflibercept following three loading doses of 2 mg aflibercept showed to be noninferior over a 1-year period when compared with the gold standard monthly injection of ranibizumab. There are no differences in systemic or ocular safety among groups. This not only reduces the risk from monthly intravitreal injections but also the economic and psychological burden.

  8. Bevacizumab Top

Bevacizumab (Avastin; Genentech) is a recombinant humanized monoclonal IgG antibody against VEGF with molecular weight of 149 kDa that binds and neutralizes all human VEGF-A isoforms [Table 1]. It is approved by the FDA for intravenous administration for the treatment of metastatic colorectal cancer.[69] Although bev-acizumab was used as an off-label drug for nAMD patients, probably because it is less expensive than ranibizumab, it has shown to be effective and well tolerated in short term,[70],[71],[72],[73] despite the absence of data from randomized clinical trials supporting its use.[74]

Recently, the randomized clinical CATT assessed the efficacy and safety of ranibizumab and bevacizumab in both monthly and as needed (PRN) regimens for nAMD.[64] At the end of the second year, patients who received monthly intravitreal injection of ranibizumab gained a mean of 8.8 letters which showed no significant difference compared to 7.8 letters of monthly injection of bevacizumab (p = 0.21). PRN injection of either drug gained less visual acuity compared with monthly regimen (ranibizumab, 6.7 letters; bevacizumab, 5.0 letters, p = 0.046). However, bevacizumab had higher rates of serious systemic adverse events than ranibizumab. It has been reported that plasma VEGF level was 89.7 pg/mL in nAMD patients and it significantly decreased to 25.1 pg/mLafter1 week(p = 0.01), and to 22.8 pg/ mL after 1 month (p = 0.008).[51] In Carneiro’s study,[75] bevacizumab could suppress plasma VEGF for up to 1 month in nAMD patients (p < 0.001). Whether the lack of specificity to conditions is associated with inhibition of VEGF requires further study.[64]

  9. Summary Top

The development of therapeutic approaches that aim to inhibit VEGF and suppress angiogenesis has heralded a new era and become a landmark in the history of treatment for nAMD. This new therapy has significantly not only improved the VA but also the quality of life of patients with nAMD. However, it must be considered that VEGF also has its physiological function in human development, such as wound healing, regulation of angiogenesis and blood viscosity, promoting neuronal survival, and anti-inflammatory effects.[2],[6],[76],[77],[78],[79] Suppression of VEGF may result in thrombosis, hemorrhage, inflammation, and vasoconstriction. The long-term effect of systemic VEGF inhibition is always an interest topic and debate in both scientific and clinical domains. Future studies and surveillance of long-term safety is required. More new agents to treat nAMD will be invented in the future and patients will also benefit from greater and longer efficacy of the combination of different therapies.

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1. Introduction
2. VEGF and its ...
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5. Pegaptanib sodium
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