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Vol. 227, Suppl. 1, 2012
Issue release date: April 2012

Biological, Preclinical and Clinical Characteristics of Inhibitors of Vascular Endothelial Growth Factors

Chong V.
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Abstract

Vascular endothelial growth factor (VEGF) plays an important role in the pathophysiology of several sight-threatening retinal disorders such as age-related macular degeneration, diabetic macular edema and proliferative diabetic retinopathy. The discovery of anti-VEGF agents has revolutionized our treatment of these conditions. There are 4 anti-VEGF agents that are either approved or in common use in ophthalmology, namely pegaptanib (Macugen, Pfizer), ranibizumab (Lucentis, Novartis), aflibercept or VEGF Trap-Eye (EYLEA, Bayer) and bevacizumab (Avastin, Roche). There are differences between them. In this review, the differences are discussed in detail. Furthermore, an attempt is made to explain some of the clinical trial data based on their differences in ocular efficacy, duration of action, and local and systemic safety concerns.



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References

  1. Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003;9:669–676.
  2. Ribatti D: From the discovery of vascular endothelial growth factor to the introduction of Avastin in clinical trials – an interview with Napoleone Ferrara by Domenico Ribatti. Int J Dev Biol 2011;55:383–388.

    External Resources

  3. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306–1309.
  4. Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611.
  5. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB: Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 1991;6:1677–1683.
  6. Takahashi H, Shibuya M: The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions (review). Clin Sci (Lond) 2005;109:227–241.
  7. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992;255:989–991.
  8. Gerber HP, Condorelli F, Park J, Ferrara N: Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 1997;272:23659–23667.
  9. Park JE, Chen HH, Winer J, Houck KA, Ferrara N: Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994;269:25646–25654.
  10. Zhang F, Tang Z, Hou X, Lennartsson J, Li Y, Koch AW, et al: VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci USA 2009;106:6152–6157.
  11. Li Y, Zhang F, Nagai N, Tang Z, Zhang S, Scotney P, et al: VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats. J Clin Invest 2008;118:913–923.
  12. Lohela M, Saaristo A, Veikkola T, Alitalo K: Lymphangiogenic growth factors, receptors and therapies. Thromb Haemost 2003;90:167–184.
  13. Tolentino M: Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol 2011;56:95–113.

    External Resources

  14. Ferrara N, Mass RD, Campa C, Kim R: Targeting VEGF-A to treat cancer and age-related macular degeneration (review). Annu Rev Med 2007;58:491–504.
  15. Adamis AP, Shima DT: The role of vascular endothelial growth factor in ocular health and disease. Retina 2005;25:111–118.
  16. Miller JW, Adamis AP, Shima DT, D’Amore PA, Moulton RS, O’Reilly MS, Folkman J, Dvorak HF, Brown LF, Berse B, et al: Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 1994;145:574–584.
  17. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, et al: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487.
  18. Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J, D’Amore PA, Miller JW: Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 1996;114:66–71.
  19. Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP: Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 1996;114:964–970.
  20. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR: Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816.
  21. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al: Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431.
  22. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al: Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444.
  23. Regeneron Pharmaceuticals. VEGF Trap-Eye – Ophthalmologic Drugs Advisory Committee, June 17, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM259143.pdf (accessed Jan 2012).
  24. Ng EW, Shima DT, Calias P, Cunningham ET Jr, Guyer DR, Adamis AP: Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 2006;5:123–132.
  25. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, et al: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593–4599.
  26. Ferrara N, Damico L, Shams N, Lowman H, Kim R: Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006;26:859–870.
  27. Chen Y, Wiesmann C, Fuh G, Li B, Christinger HW, McKay P, et al: Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. J Mol Biol 1999;293:865–881.
  28. Baca M, Presta LG, O’Connor SJ, Wells JA: Antibody humanization using monovalent phage display. J Biol Chem 1997;272:10678–10684.
  29. Yu L, Liang XH, Ferrara N: Comparing protein VEGF inhibitors: in vitro biological studies. Biochem Biophys Res Commun 2011;408:276–281.
  30. Meyer CH, Holz FG: Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab (review). Eye (Lond) 2011;25:661–672.
  31. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ: Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179–2182.
  32. Kim H, Robinson SB, Csaky KG: FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye. Mol Vis 2009;15:2803–2812.
  33. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ: Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179–2182.
  34. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ: Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855–859.
  35. Byeon SH, Kang SY: Pharmacokinetics. Ophthalmology 2009;116:168–169, author reply 169–170.

    External Resources

  36. Ferrara N, Hillan KJ, Gerber HP, Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391–400.
  37. Lu JF, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J: Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol 2008;62:779–786.
  38. Stewart MW: Predicted biologic activity of intravitreal bevacizumab. Retina 2007;27:1196–1200.

    External Resources

  39. Stewart MW, Rosenfeld PJ: Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 2008;92:667–668.
  40. Meyer CH, Krohne TU, Holz FG: Intraocular pharmacokinetics after a single intravitreal injection of 1.5 mg versus 3.0 mg of bevacizumab in humans. Retina 2011;31:1877–1884.
  41. Meyer CH, Krohne TU, Holz FG: Concentrations of unbound bevacizumab in the aqueous of untreated fellow eyes after a single intravitreal injection in humans. Acta Ophthalmol 2012;90:68–70.

    External Resources

  42. Sawada O, Kawamura H, Kakinoki M, Ohji M: Vascular endothelial growth factor in fellow eyes of eyes injected with intravitreal bevacizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:1379–1381.
  43. Miyake T, Sawada O, Kakinoki M, Sawada T, Kawamura H, Ogasawara K, et al: Pharmacokinetics of bevacizumab and its effect on vascular endothelial growth factor after intravitreal injection of bevacizumab in macaque eyes. Invest Ophthalmol Vis Sci 2010;51:1606–1608.

    External Resources

  44. Matsuyama K, Ogata N, Matsuoka M, Wada M, Takahashi K, Nishimura T: Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010;94:1215–1218.
  45. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al: VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129–1136.
  46. Novartis. Lucentis prescribing information. 2006.
  47. Gamulescu MA, Helbig H: Lack of therapeutic effect of ranibizumab in fellow eyes after intravitreal administration. J Ocul Pharmacol Ther 2010;26:213–216.
  48. Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, Freund KB: Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials. Am J Ophthalmol 2010;149:939–946.e1.

    External Resources

  49. Schmidt-Erfurth U: Clinical safety of ranibizumab in age-related macular degeneration. Expert Opin Drug Saf 2010;9:149–165.
  50. Funk M, Karl D, Georgopoulos M, Benesch T, Sacu S, Polak K, et al: Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab. Ophthalmology 2009;116:2393–2399.
  51. CATT Research Group, Martin DF, Maguire MG, et al: Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–908.
  52. Curtis LF, Hammill BG, Schulman KA, et al: Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol 2010;128:1273–1279, erratum 1623.
  53. Gower EW, Chu L, Varma R, Klein R: Adverse event rates following intravitreal injection of Avastin or Lucentis for treating age-related macular degeneration, poster 6644, ARVO 2011.


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