Research progress of anti-vascular endothelial growth factor receptor 2 drugs in the treatment of retinal neovascularization disease_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Mingliang , Yang Songyang , Hu Lanlan ,  Li Xiaorong

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Li Xiaorong, Email: lixiaorong@tmu.edu.cn

Keywords：

Receptors, vascular endothelial growth factor; Retinal neovascularization; Review

DOI：

10.3760/cma.j.cn511434-20201028-00516

Video：

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Neovascularization is a characteristic manifestation of a variety of retinal diseases. Vascular endothelial growth factor (VEGF) mainly regulates the proliferation and migration of endothelial cells. VEGF receptor 2 (VEGFR2) is the main receptor to mediate this effect. The activation of downstream signals requires the binding of VEGF and VEGFR2, followed by receptor dimerization and autophosphorylation. Blocking this process and inhibiting neovascularization is very attractive treatment ideas. Monoclonal antibodies and fusion protein drugs currently used in ophthalmology can bind free VEGF. In addition, there are also macromolecular antibodies binding VEGFR2 and small molecule tyrosine kinase inhibitors, which is expected to further expand into the field of ophthalmology. Although anti-VEGFR2 therapy is a revolutionary method to inhibit neovascularization, there are no sufficient clinical evidences at present. In-depth understanding of the application status and progress of anti-VEGFR2 in the treatment of retinal neovascular diseases has important clinical significance.

Citation： Zhang Mingliang, Yang Songyang, Hu Lanlan, Li Xiaorong. Research progress of anti-vascular endothelial growth factor receptor 2 drugs in the treatment of retinal neovascularization disease. Chinese Journal of Ocular Fundus Diseases, 2021, 37(7): 562-566. doi: 10.3760/cma.j.cn511434-20201028-00516 Copy

1.	Seah I, Zhao X, Lin Q, et al. Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases[J]. Eye, 2020, 34(8): 1341-1356. DOI: 10.1038/s41433-020-0770-y.
2.	杨茜, 黄欣. 抗血管内皮生长因子药物治疗早产儿视网膜病变的复发研究现状及进展[J]. 中华眼底病杂志, 2019, 35(6): 617-620. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.024.Yang Q, Huang X. Current status and progress of recurrence of retinopathy in prematurity after intravitreal injection with anti-vascular endothelial growth factor drugs[J]. Chin J Ocul Fundus Dis, 2019, 35(6): 617-620. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.024.
3.	徐惠娟, 杨正林. 抗血管内皮生长因子药物治疗渗出型老年性黄斑变性的局限性研究现状[J]. 中华眼底病杂志, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.Xu HJ, Yang ZL. The limitation of anti-vascular endothelial growth factor treatment for wet age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.
4.	Campbell M, Doyle SL. Current perspectives on established and novel therapies for pathological neovascularization in retinal disease[J]. Biochem Pharmacol, 2019, 164: 321-325. DOI: 10.1016/j.bcp.2019.04.029.
5.	Folkman J, Klagsbrun M. Angiogenic factors[J]. Science, 1987, 235(4787): 442-447. DOI: 10.1126/science.2432664.
6.	Plouët J, Moro F, Bertagnolli S, et al. Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect[J]. J Biol Chem, 1997, 272(20): 13390-13396. DOI: 10.1074/jbc.272.20.13390.
7.	Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling[J]. Nat Rev Mol Cell Biol, 2016, 17(10): 611-625. DOI: 10.1038/nrm.2016.87.
8.	Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice[J]. Nature, 1995, 376(6535): 62-66. DOI: 10.1038/376062a0.
9.	Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells[J]. EMBO J, 2001, 20(11): 2768-2778. DOI: 10.1093/emboj/20.11.2768.
10.	Dougher M, Terman BI. Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization[J]. Oncogene, 1999, 18(8): 1619-1627. DOI: 10.1038/sj.onc.1202478.
11.	Zeng H, Sanyal S, Mukhopadhyay D. Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively[J]. J Biol Chem, 2001, 276(35): 32714-32719. DOI: 10.1074/jbc.M103130200.
12.	Mac Gabhann F, Popel AS. Dimerization of VEGF receptors and implications for signal transduction: acomputational study[J]. Biophys Chem, 2007, 128(2-3): 125-139. DOI: 10.1016/j.bpc.2007.03.010.
13.	Lu D, Shen J, Vil MD, et al. Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity[J]. J Biol Chem, 2003, 278(44): 43496-43507. DOI: 10.1074/jbc.M307742200.
14.	Fontanella C, Ongaro E, Bolzonello S, et al. Clinical advances in the development of novel VEGFR2 inhibitors[J/OL]. Ann Transl Med, 2014, 2(12): 123[2014-12-02]. https://pubmed.ncbi.nlm.nih.gov/25568876/. DOI: 10.3978/j.issn.2305-5839.2014.08.14.
15.	Spratlin JL, Cohen RB, Eadens M, et al. Phase Ⅰ pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2[J]. J Clin Oncol, 2010, 28(5): 780-787. DOI: 10.1200/JCO.2009.23.7537.
16.	Falcon BL, Chintharlapalli S, Uhlik MT, et al. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents[J]. Pharmacol Ther, 2016, 164: 204-225. DOI: 10.1016/j.pharmthera.2016.06.001.
17.	Fuchs CS, Tomasek J, Cho JY, et al. REGARD: a phase Ⅲ, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum-and/or fluoropyrimidine-containing combination therapy[J/OL]. Gastric Cancer, 2014, 73(8): LB67[2013-03-15]. https://ascopubs.org/doi/abs/10.1200/jco.2013.31.4_suppl.lba5. DOI: 10.1158/1538-7445.AM2013-LB-67.
18.	de Moraes Neto JE, Pereira F, Neves RL, et al. Preclinical assessment of intravitreal ramucirumab: In vitro and in vivo safety profile[J/OL]. Int J Retin Vitr, 2020, 6(1): 40[2020-09-04]. https://journalretinavitreous.biomedcentral.com/articles/10.1186/s40942-020-00243-y. DOI: 10.1186/s40942-020-00243-y.
19.	Modi SJ, Kulkarni VM. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: medicinal chemistry perspective[J/OL]. Medicine in Drug Discovery, 2019, 2: 100009[2019-06-01]. https://www.sciencedirect.com/science/article/pii/S2590098619300090. DOI: 10.1016/j.medidd.2019.100009.
20.	Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration[J]. Br J Ophthalmol, 2015, 99(2): 220-226. DOI: 10.1136/bjophthalmol-2014-305327.
21.	Ciulla TA, Huang F, Westby K, et al. Real-world outcomes of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States[J]. Ophthalmol Retina, 2018, 2(7): 645-653. DOI: 10.1016/j.oret.2018.01.006.
22.	Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration[J]. Ophthalmology, 2013, 120(5): 1046-1056. DOI: 10.1016/j.ophtha.2012.10.014.
23.	Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2016, 123(8): 1751-1761. DOI: 10.1016/j.ophtha.2016.03.045.
24.	陈霞, 许迅. 抗血管内皮生长因子药物治疗无应答的原因与应对措施[J]. 中华眼底病杂志, 2016, 32(4): 444-448. DOI: 10.3760/cma.j.issn.1005-1015.2016.04.027.Chen X, Xu X. The causes and countermeasures of non-response to anti-vascular endothelial growth factor therapy[J]. Chin J Ocul Fundus Dis, 2016, 32(4): 444-448. DOI: 10.3760/cma.j.issn.1005-1015.2016.04.027.
25.	Dedania VS, Grob S, Zhang K, et al. Pharmacogenomics of response to anti-VEGF therapy in exudative age-related macular degeneration[J]. Retina, 2015, 35(3): 381-391. DOI: 10.1097/IAE.0000000000000466.
26.	Abdullah SE, Perez-Soler R. Mechanisms of resistance to vascular endothelial growth factor blockade[J]. Cancer, 2012, 118(14): 3455-3467. DOI: 10.1002/cncr.26540.
27.	Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy[J]. Clin Cancer Res, 2008, 14(20): 6371-6375. DOI: 10.1158/1078-0432.CCR-07-5287.
28.	Augustin HG, Koh GY, Thurston G, et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system[J]. Nat Rev Mol Cell Biol, 2009, 10(3): 165-177. DOI: 10.1038/nrm2639.
29.	Ebos JML, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis[J]. Cancer Cell, 2009, 15(3): 232-239. DOI: 10.1016/j.ccr.2009.01.021.
30.	Marmor MF, Martin LJ, Tharpe S. Osmotically induced retinal detachment in the rabbit and primate. Electron miscoscopy of the pigment epithelium[J]. Invest Ophth Vis Sci, 1980, 19(9): 1016-1029.
31.	Bhojani N, Jeldres C, Patard JJ, et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma[J]. Eur Urol, 2008, 53(5): 917-930. DOI: 10.1016/j.eururo.2007.11.037.
32.	Gressett SM, Shah SR. Intricacies of bevacizumab-induced toxicities and their management[J]. Ann Pharmacother, 2009, 43(3): 490-501. DOI: 10.1345/aph.1L426.
33.	Jackson TL, Boyer D, Brown DM, et al. Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: a phase 1 dose-escalation study[J]. JAMA Ophthalmol, 2017, 135(7): 761-767. DOI: 10.1001/jamaophthalmol.2017.1571.

1. Seah I, Zhao X, Lin Q, et al. Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases[J]. Eye, 2020, 34(8): 1341-1356. DOI: 10.1038/s41433-020-0770-y.
2. 杨茜, 黄欣. 抗血管内皮生长因子药物治疗早产儿视网膜病变的复发研究现状及进展[J]. 中华眼底病杂志, 2019, 35(6): 617-620. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.024.Yang Q, Huang X. Current status and progress of recurrence of retinopathy in prematurity after intravitreal injection with anti-vascular endothelial growth factor drugs[J]. Chin J Ocul Fundus Dis, 2019, 35(6): 617-620. DOI: 10.3760/cma.j.issn.1005-1015.2019.06.024.
3. 徐惠娟, 杨正林. 抗血管内皮生长因子药物治疗渗出型老年性黄斑变性的局限性研究现状[J]. 中华眼底病杂志, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.Xu HJ, Yang ZL. The limitation of anti-vascular endothelial growth factor treatment for wet age-related macular degeneration[J]. Chin J Ocul Fundus Dis, 2020, 36(2): 156-161. DOI: 10.3760/cma.j.issn.1005-1015.2020.02.017.
4. Campbell M, Doyle SL. Current perspectives on established and novel therapies for pathological neovascularization in retinal disease[J]. Biochem Pharmacol, 2019, 164: 321-325. DOI: 10.1016/j.bcp.2019.04.029.
5. Folkman J, Klagsbrun M. Angiogenic factors[J]. Science, 1987, 235(4787): 442-447. DOI: 10.1126/science.2432664.
6. Plouët J, Moro F, Bertagnolli S, et al. Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect[J]. J Biol Chem, 1997, 272(20): 13390-13396. DOI: 10.1074/jbc.272.20.13390.
7. Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling[J]. Nat Rev Mol Cell Biol, 2016, 17(10): 611-625. DOI: 10.1038/nrm.2016.87.
8. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice[J]. Nature, 1995, 376(6535): 62-66. DOI: 10.1038/376062a0.
9. Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells[J]. EMBO J, 2001, 20(11): 2768-2778. DOI: 10.1093/emboj/20.11.2768.
10. Dougher M, Terman BI. Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization[J]. Oncogene, 1999, 18(8): 1619-1627. DOI: 10.1038/sj.onc.1202478.
11. Zeng H, Sanyal S, Mukhopadhyay D. Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively[J]. J Biol Chem, 2001, 276(35): 32714-32719. DOI: 10.1074/jbc.M103130200.
12. Mac Gabhann F, Popel AS. Dimerization of VEGF receptors and implications for signal transduction: acomputational study[J]. Biophys Chem, 2007, 128(2-3): 125-139. DOI: 10.1016/j.bpc.2007.03.010.
13. Lu D, Shen J, Vil MD, et al. Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity[J]. J Biol Chem, 2003, 278(44): 43496-43507. DOI: 10.1074/jbc.M307742200.
14. Fontanella C, Ongaro E, Bolzonello S, et al. Clinical advances in the development of novel VEGFR2 inhibitors[J/OL]. Ann Transl Med, 2014, 2(12): 123[2014-12-02]. https://pubmed.ncbi.nlm.nih.gov/25568876/. DOI: 10.3978/j.issn.2305-5839.2014.08.14.
15. Spratlin JL, Cohen RB, Eadens M, et al. Phase Ⅰ pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2[J]. J Clin Oncol, 2010, 28(5): 780-787. DOI: 10.1200/JCO.2009.23.7537.
16. Falcon BL, Chintharlapalli S, Uhlik MT, et al. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents[J]. Pharmacol Ther, 2016, 164: 204-225. DOI: 10.1016/j.pharmthera.2016.06.001.
17. Fuchs CS, Tomasek J, Cho JY, et al. REGARD: a phase Ⅲ, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum-and/or fluoropyrimidine-containing combination therapy[J/OL]. Gastric Cancer, 2014, 73(8): LB67[2013-03-15]. https://ascopubs.org/doi/abs/10.1200/jco.2013.31.4_suppl.lba5. DOI: 10.1158/1538-7445.AM2013-LB-67.
18. de Moraes Neto JE, Pereira F, Neves RL, et al. Preclinical assessment of intravitreal ramucirumab: In vitro and in vivo safety profile[J/OL]. Int J Retin Vitr, 2020, 6(1): 40[2020-09-04]. https://journalretinavitreous.biomedcentral.com/articles/10.1186/s40942-020-00243-y. DOI: 10.1186/s40942-020-00243-y.
19. Modi SJ, Kulkarni VM. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: medicinal chemistry perspective[J/OL]. Medicine in Drug Discovery, 2019, 2: 100009[2019-06-01]. https://www.sciencedirect.com/science/article/pii/S2590098619300090. DOI: 10.1016/j.medidd.2019.100009.
20. Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration[J]. Br J Ophthalmol, 2015, 99(2): 220-226. DOI: 10.1136/bjophthalmol-2014-305327.
21. Ciulla TA, Huang F, Westby K, et al. Real-world outcomes of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration in the United States[J]. Ophthalmol Retina, 2018, 2(7): 645-653. DOI: 10.1016/j.oret.2018.01.006.
22. Busbee BG, Ho AC, Brown DM, et al. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration[J]. Ophthalmology, 2013, 120(5): 1046-1056. DOI: 10.1016/j.ophtha.2012.10.014.
23. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2016, 123(8): 1751-1761. DOI: 10.1016/j.ophtha.2016.03.045.
24. 陈霞, 许迅. 抗血管内皮生长因子药物治疗无应答的原因与应对措施[J]. 中华眼底病杂志, 2016, 32(4): 444-448. DOI: 10.3760/cma.j.issn.1005-1015.2016.04.027.Chen X, Xu X. The causes and countermeasures of non-response to anti-vascular endothelial growth factor therapy[J]. Chin J Ocul Fundus Dis, 2016, 32(4): 444-448. DOI: 10.3760/cma.j.issn.1005-1015.2016.04.027.
25. Dedania VS, Grob S, Zhang K, et al. Pharmacogenomics of response to anti-VEGF therapy in exudative age-related macular degeneration[J]. Retina, 2015, 35(3): 381-391. DOI: 10.1097/IAE.0000000000000466.
26. Abdullah SE, Perez-Soler R. Mechanisms of resistance to vascular endothelial growth factor blockade[J]. Cancer, 2012, 118(14): 3455-3467. DOI: 10.1002/cncr.26540.
27. Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy[J]. Clin Cancer Res, 2008, 14(20): 6371-6375. DOI: 10.1158/1078-0432.CCR-07-5287.
28. Augustin HG, Koh GY, Thurston G, et al. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system[J]. Nat Rev Mol Cell Biol, 2009, 10(3): 165-177. DOI: 10.1038/nrm2639.
29. Ebos JML, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis[J]. Cancer Cell, 2009, 15(3): 232-239. DOI: 10.1016/j.ccr.2009.01.021.
30. Marmor MF, Martin LJ, Tharpe S. Osmotically induced retinal detachment in the rabbit and primate. Electron miscoscopy of the pigment epithelium[J]. Invest Ophth Vis Sci, 1980, 19(9): 1016-1029.
31. Bhojani N, Jeldres C, Patard JJ, et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma[J]. Eur Urol, 2008, 53(5): 917-930. DOI: 10.1016/j.eururo.2007.11.037.
32. Gressett SM, Shah SR. Intricacies of bevacizumab-induced toxicities and their management[J]. Ann Pharmacother, 2009, 43(3): 490-501. DOI: 10.1345/aph.1L426.
33. Jackson TL, Boyer D, Brown DM, et al. Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: a phase 1 dose-escalation study[J]. JAMA Ophthalmol, 2017, 135(7): 761-767. DOI: 10.1001/jamaophthalmol.2017.1571.

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Research progress of anti-vascular endothelial growth factor receptor 2 drugs in the treatment of retinal neovascularization disease

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