Anti-VEGF Strategies in Ocular Angiogenesis-mediated Disorders, with Special Emphasis on Age-related Macular Degeneration

  • Shaker A. Mousa


Pathological angiogenesis in the eye including exudative age-related macular degeneration (AMD), proliferative diabetic retinopathy, diabetic macular edema, neovascular glaucoma, and corneal neovascularization (trachoma) underlies the major causes of blindness in both developed and developing nations. Additionally, increased rates of angiogenesis are associated with several other disease states including cancer, psoriasis, rheumatoid arthritis and other vascular-associated disorders. Vascular endothelial growth factor (VEGF) and its receptors play an important role in the modulation of angiogenesis and have been implicated in the pathology of a number of conditions, including AMD, diabetic retinopathy, and cancer. AMD is a progressive disease of the macula and the third major cause of blindness worldwide. If not treated appropriately, AMD might progress to the second eye. Until recently, the treatment options for AMD were limited, with photodynamic therapy the mainstay treatment, which is effective at slowing disease progression but rarely results in improved vision. There are currently three approved anti-angiogenesis biologic therapies for ophthalmic diseases: an anti-VEGF aptamer (pegaptanib, Macugen®), a Fab fragment of a monoclonal antibody directed against VEGF-A (ranibizumab, Lucentis®), and VEGF trap (aflibercept, Eylea®). Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances. In AMD patients these therapies slow the rate of vision loss and in some cases increase visual acuity. Although these therapies are a milestone in the treatment of these disease states, several concerns need to be addressed before their impact can be fully understood.


Vascular Endothelial Growth Factor Vascular Endothelial Growth Factor Receptor Diabetic Macular Edema Intravitreal Bevacizumab Vascular Endothelial Growth Factor Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Mousa SA (2000) Mechanisms of angiogenesis in vascular disorders: potential therapeutic targets. In: Mousa SA (ed) Angiogenesis inhibitors & stimulators: potential therapeutic implications. Landes Bioscience (Autsin, TX), pp 1–12, Chapter 1Google Scholar
  2. 2.
    Relf M, LeJeune S, Scott P et al (1997) Expression of the angiogenic factors vascular endothelial growth factor, acidic and basic fibroblast growth factor, tumor growth factor-β-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57:963–969PubMedGoogle Scholar
  3. 3.
    Ferrara N, Alitalo K (1999) Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5:1359–1364PubMedCrossRefGoogle Scholar
  4. 4.
    Mousa SA, Mousa AS (2004) Angiogenesis inhibitors: current & future directions. Curr Pharm Des 10(1):1–9PubMedCrossRefGoogle Scholar
  5. 5.
    De Jong PT (2006) Age-related macular degeneration. N Engl J Med 355(14):1474–1485PubMedCrossRefGoogle Scholar
  6. 6.
    Spilsbury K, Garrett KL, Shen WY, Constable IJ, Rakoczy PE (2000) Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am J Pathol 157(1):135–144PubMedCrossRefGoogle Scholar
  7. 7.
    Fink AM, Cauza E, Hassfeld W, Dunky A, Bayer PM, Jurecka W, Steiner A (2007) Vascular endothelial growth factor in patients with psoriatic arthritis. Clin Exp Rheumatol 25(2):305–308PubMedGoogle Scholar
  8. 8.
    Murakami M, Iwai S, Hiratsuka S, Yamauchi M, Nakamura K, Iwakura Y, Shibuya M (2006) Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Blood 108(6):1849–1856PubMedCrossRefGoogle Scholar
  9. 9.
    Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739PubMedCrossRefGoogle Scholar
  10. 10.
    Marx J (2002) Cancer research: obstacle for promising cancer therapy. Science 295:1444PubMedCrossRefGoogle Scholar
  11. 11.
    Casanovas O, Hicklin D, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 4(8):299–309CrossRefGoogle Scholar
  12. 12.
    Nemunaitis J, Dillman RO, Schwarzenberger PO et al (2006) Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non–small-cell lung cancer. J Clin Oncol 24(29):4721–4730PubMedCrossRefGoogle Scholar
  13. 13.
    Kelly RJ, Giaccone G (2011) Lung cancer vaccines. Cancer J 17(5):302–308PubMedCrossRefGoogle Scholar
  14. 14.
    Suzuki E, Kapoor V, Cheung H, Ling LE, DeLong PA, Kaiser LR, Albelda SM (2004) Soluble type II transforming growth factor-ß receptor inhibits established murine malignant mesothelioma tumor growth by augmenting host antitumor immunity. Clin Cancer Res 10(17):5907–5918PubMedCrossRefGoogle Scholar
  15. 15.
    Brown LF, Detmar M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF (1997) Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. EXS 79:233–269PubMedGoogle Scholar
  16. 16.
    Joukov V, Kaipainen A, Jeltsch M et al (1997) Vascular endothelial growth factors VEGF-B and VEGF-C. J Cell Physiol 173(2):211–215PubMedCrossRefGoogle Scholar
  17. 17.
    Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA (1991) The human gene for vascular endothelial growth factor: multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266(18):11947–11954PubMedGoogle Scholar
  18. 18.
    Ferrara N (1999) Molecular and biological properties of vascular endothelial growth factor. J Mol Med 77(7):527–543PubMedCrossRefGoogle Scholar
  19. 19.
    Dvorak HF, Nagy JA, Feng D et al (1999) Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237:97–132PubMedCrossRefGoogle Scholar
  20. 20.
    Senger DR, Van De Water L, Brown LF et al (1993) Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 12(3–4):303–324PubMedCrossRefGoogle Scholar
  21. 21.
    Pettersson A, Nagy JA, Brown LF et al (2000) Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 80(1):99–115PubMedCrossRefGoogle Scholar
  22. 22.
    Ford KM, D’Amore PA (2012) Molecular regulation of vascular endothelial growth factor expression in the retinal pigment epithelium. Mol Vis 18:519–527PubMedGoogle Scholar
  23. 23.
    Landa G, Amde W, Doshi V, Ali A, McGevna L, Gentile RC, Muldoon TO, Walsh JB, Rosen RB (2009) Comparative study of intravitreal bevacizumab (avastin) versus ranibizumab (lucentis) in the treatment of neovascular age-related macular degeneration. Ophthalmologica 223(6):370–375PubMedCrossRefGoogle Scholar
  24. 24.
    Schouten JS, La Heij EC, Webers CA, Lundqvist IJ, Hendrikse F (2009) A systematic review on the effect of bevacizumab in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 247(1):1–11PubMedCrossRefGoogle Scholar
  25. 25.
    Hirawat S, Elfring GL, Northcutt VJ, Paquette N (2007) Phase 1 studies assessing the safety, PK, and VEGF-modulating effects of PTC299, a novel VEGF. J Clin Oncol 25(18S):3562Google Scholar
  26. 26.
    Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR (2004) VEGF inhibition study in ocular neovascularization clinical trial group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351(27):2805–2816PubMedCrossRefGoogle Scholar
  27. 27.
    Chakravarthy U, Adamis AP, VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group et al (2006) Year 2 efficacy results of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 113(9):1508–1525PubMedGoogle Scholar
  28. 28.
    Wolowacz SE, Roskell N, Kelly S, Maciver FM, Brand CS (2007) Cost effectiveness of pegaptanib for the treatment of age-related macular degeneration in the UK. Pharmaco­economics 25(10):863–879PubMedCrossRefGoogle Scholar
  29. 29.
    Earnshaw SR, Moride Y, Rochon S (2007) Cost-effectiveness of pegaptanib compared to photodynamic therapy with verteporfin and to standard care in the treatment of subfoveal wet age-related macular degeneration in Canada. Clin Ther 29(9):2096–2106PubMedCrossRefGoogle Scholar
  30. 30.
    Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355(14):1419–1431PubMedCrossRefGoogle Scholar
  31. 31.
    Heier JS, Antoszyk AN, Pavan P et al (2006) Ranibizumab for treatment of neovascular age-related macular degeneration – a phase I/II multicenter, controlled, multidose study. Ophthalmology 113(N4):633–642PubMedCrossRefGoogle Scholar
  32. 32.
    Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355(14):1432–1444PubMedCrossRefGoogle Scholar
  33. 33.
    Nguyen QD, Shah SM, Hafiz G, Quinlan E, Sung J, Chu K, Cedarbaum JM, Campochiaro PA, CLEAR-AMD 1 Study Group (2006) A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 113(9):1522.e1–1522.e14CrossRefGoogle Scholar
  34. 34.
    Singerman L (2009) Combination therapy using the small interfering RNA bevasiranib. Retina 29(6 Suppl):S49–S50PubMedCrossRefGoogle Scholar
  35. 35.
    Lommatzsch A, Heimes B, Gutfleisch M, Spital G, Zeimer M, Pauleikhoff D (2009) Serious pigment epithelial detachment in age-related macular degeneration: comparison of different treatments. Eye 23(12):2163–2168PubMedCrossRefGoogle Scholar
  36. 36.
    Maier MM, Feucht N, Fiore B, Winkler von Mohrenfels C, Kook P, Fegert C, Lohmann C (2009) Photodynamic therapy with verteporfin combined with intravitreal injection of ranibizumab for occult and classic CNV in AMD. Klin Monatsbl Augenheilkd 226(6):496–502PubMedCrossRefGoogle Scholar
  37. 37.
    Vascular Endothelial Growth Factor (VEGF) (2012) Trap-eye: investigation of efficacy and safety in wet Age-Related Macular Degeneration (AMD) (VIEW 2). Accessed 13 Mar 2013
  38. 38.
    Vascular Endothelial Growth Factor (2012) VEGF trap-eye: investigation of efficacy and safety in wet Age-Related Macular Degeneration (AMD) (VIEW1). Accessed 13 Mar 2013
  39. 39.
    Nguyen QD et al (2012) Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration. J Ocul Pharmacol Ther 28:581–588PubMedGoogle Scholar
  40. 40.
    Frampton JE (2012) Aflibercept for intravitreal injection: in neovascular age-related macular degeneration. Drugs Aging 29(10):839–846PubMedCrossRefGoogle Scholar
  41. 41.
    Xu D, Kaiser PK (2013) Intravitreal aflibercept for neovascular age-related macular degeneration. Immunotherapy 5(2):121–130Google Scholar
  42. 42.
    Potter MJ, Claudio CC, Szabo SM (2010) A randomised trial of bevacizumab and reduced light dose photodynamic therapy in age-related macular degeneration: the VIA study. Br J Ophthalmol 94:174–179PubMedCrossRefGoogle Scholar
  43. 43.
    Busch T (2009) Approaches toward combining photodynamic therapy with pharmaceuticals that alter vascular microenvironment. Retina 29(6 Suppl):S36–S38PubMedCrossRefGoogle Scholar
  44. 44.
    Kaiser PK, Registry of Visudyne AMD Therapy Writing Committee, Boyer DS, Garcia R, Hao Y, Hughes MS, Jabbour NM, Kaiser PK, Mieler W, Slakter JS, Samuel M, Tolentino MJ, Roth D, Sheidow T, Strong HA (2009) Verteporfin photodynamic therapy combined with ­intravitreal bevacizumab for neovascular age-related macular degeneration. Ophthalmology 116(4):747–755PubMedCrossRefGoogle Scholar
  45. 45.
    Yip PP, Woo CF, Tang HH, Ho CK (2009) Triple therapy for neovascular age-related macular degeneration using single-session photodynamic therapy combined with intravitreal bevacizumab and triamcinolone. Br J Ophthalmol 93(6):754–758PubMedCrossRefGoogle Scholar
  46. 46.
    Takahashi H, Obata R, Tamaki Y (2006) A novel vascular endothelial growth factor receptor 2 inhibitor, SU11248, suppresses choroidal neovascularization in vivo. J Ocul Pharmacol Ther 22(4):213–218PubMedCrossRefGoogle Scholar
  47. 47.
    Faivre S, Delbaldo C, Vera K et al (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24(1):25–35PubMedCrossRefGoogle Scholar
  48. 48.
    Demetri GD, VanOosterom AT, Garrett CR et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338PubMedCrossRefGoogle Scholar
  49. 49.
    Strumberg D, Richly H, Hilger RA et al (2005) Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43–9006 in patients with advanced refractory solid tumors. J Clin Oncol 23(5):965–972PubMedCrossRefGoogle Scholar
  50. 50.
    Awada A, Hendlisz A, Gil T et al (2005) Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumors. Br J Cancer 92(10):1855–1861PubMedCrossRefGoogle Scholar
  51. 51.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134PubMedCrossRefGoogle Scholar
  52. 52.
    Ratain MJ, Eisen T, Stadler WM et al (2005) Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma (RCC) (4544). J Clin Oncol 23(16 suppl):388sGoogle Scholar
  53. 53.
    Traxler P, Allegrini PR, Brandt R et al (2004) AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 64:4931–4941PubMedCrossRefGoogle Scholar
  54. 54.
    Rixe O, Bukowski RM, Michaelson MD et al (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8(11):975–984PubMedCrossRefGoogle Scholar
  55. 55.
    Wedge SR, Kendrew J, Hennequin LF, Valentine PJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4395PubMedCrossRefGoogle Scholar
  56. 56.
    Drevs J, Siegert P, Medinger M et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(21):3045–3054PubMedCrossRefGoogle Scholar
  57. 57.
    Ciardiello F, Caputo R, Damiano V et al (2003) Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 9:1546–1556PubMedGoogle Scholar
  58. 58.
    Miller KD, Trigo J, Wheeler C et al (2005) A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 11(9):3369–3376PubMedCrossRefGoogle Scholar
  59. 59.
    Thomas AL, Trarbach T, Bartel C et al (2007) A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer. Ann Oncol 18(4):782–788PubMedCrossRefGoogle Scholar
  60. 60.
    Hutson TE, Davis ID, Machiels JP et al (2007) Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): interim results of a phase II randomized discontinuation trial (RDT). J Clin Oncol 25(18S):5031Google Scholar
  61. 61.
    Suttle AB, Hurwitz H, Dowlati A et al (2004) Pharmacokinetics (PK) and tolerability of GW786034, a VEGFR tyrosine kinase inhibitor, after daily oral administration to patients with solid tumors. J Clin Oncol 22:3054Google Scholar
  62. 62.
    Nakamura K, Taguchi E, Miura T et al (2006) KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res 66(18):9134–9142PubMedCrossRefGoogle Scholar
  63. 63.
    Eskens FA, Planting A, Van Doorn L et al (2006) An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors. J Clin Oncol [supplement ASCO Annual Meeting] 24(18S):2034Google Scholar
  64. 64.
    Nosov DA, Esteves B, Lipatov ON, Lyulko AA, Anischenko AA, Chacko RT, Doval DC, Strahs A, Slichenmyer WJ, Bhargava P (2012) Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J Clin Oncol 30(14):1678–1685PubMedCrossRefGoogle Scholar
  65. 65.
    Rosen LS, Kurzrock R, Mulay M et al (2007) Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(17):2369–2376PubMedCrossRefGoogle Scholar
  66. 66.
    Polverino A, Coxon A, Starnes C et al (2006) AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 66(17):8715–8721PubMedCrossRefGoogle Scholar
  67. 67.
    Rosen R, Kurzrock E, Jackson L et al (2005) Safety and pharmacokinetics of AMG 706 in patients with advanced solid tumors. J Clin Oncol 23(16S):3013Google Scholar
  68. 68.
    Carter P (2001) Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1:118–129PubMedCrossRefGoogle Scholar
  69. 69.
    Vedula SS, Krzystolik MG (2008) Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev Apr 16(2):CD005139Google Scholar
  70. 70.
    Costagliola C, Agnifili L, Arcidiacono B, Duse S, Fasanella V, Mastropasqua R, Verolino M, Semeraro F (2012) Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration. Expert Opin Biol Ther 12(10):1299–1313PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.The Pharmaceutical Research Institute at Albany College of Pharmacy and Health SciencesRensselaerUSA

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