Progress of anti-integrin drug risuteganib in the treatment of ocular fundus diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Hu Yanan ,  Zheng Zhi

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China;

Corresponding author：

Zheng Zhi, Email: zzheng88@sjtu.edu.cn

Keywords：

Integrins; Vitreous detachment; Macular degeneration/drug therapy; Macular edema/drug therapy; Review

DOI：

10.3760/cma.j.cn511434-20190821-00262

Video：

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Integrins is a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix to actin cytoskeleton in the cell cortex, thus regulating various physiological and pathological processes. Risuteganib (Luminate^®) is a novel broad-spectrum integrin inhibitor. Based on multiple biological functions of anti-angiogenesis, vitreolysis, and neuroprotection, risuteganib is hopeful in treating several fundus diseases such as diabetic macular edema, vitreomacular traction, and non-exudative age-related macular degeneration. By far, risuteganib has successfully met the endpoints for three phase 2 studies and is preparing to enter the phase 3 of diabetic macular edema clinical trials. Overall the risuteganib is safe with no serious ocular or systemic adverse events. Given the unique mechanism of action and longer duration of efficacy, intravitreal injection of risuteganib has the potential to serve as a primary therapy, or adjunctive therapy to anti-VEGF agents.

Citation： Hu Yanan, Zheng Zhi. Progress of anti-integrin drug risuteganib in the treatment of ocular fundus diseases. Chinese Journal of Ocular Fundus Diseases, 2020, 36(10): 813-816. doi: 10.3760/cma.j.cn511434-20190821-00262 Copy

1.	Hynes RO. Integrins: bidirectional, allosteric signaling machines[J]. Cell, 2002, 110(6): 673-687. DOI: 10.1016/S0092-8674(02)00971-6.
2.	Elner SG, Elner VM. The integrin superfamily and the eye[J]. Invest Ophthalmol Vis Sci, 1996, 37(5): 696-701.
3.	Brooks PC. Role of integrins in angiogenesis[J]. Eur J Cancer, 1996, 32(14): 2423-2429. DOI: 10.1016/s0959-8049(96)00381-4.
4.	Kenney CM, Chwa M, Caceres-del-Carpio J, et al. Effects of anti-VEGF and ALG-1001 on human retinal cells in vitro[J]. Invest Ophthalmol Vis Sci, 2018, 59(9): 771.
5.	Beltran MA, Zamora-Alvarado R, Gonzalez-Salinas R, et al. Cytoprotective effect of ALG-1001 peptide (Luminate) on human retinal pigment epithelial cells exposed to oxidative injury. a novel functional-outcome for an anti-VEGF agent[J]. Invest Ophthalmol Vis Sci, 2018, 59(9): 1465.
6.	Friedlander M, Theesfeld CL, Sugita M, et al. Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases[J]. Proc Natl Acad Sci USA, 1996, 93(18): 9764-9769. DOI: 10.1073/pnas.93.18.9764.
7.	Umeda N, Kachi S, Akiyama H, et al. Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist[J]. Mol Pharmacol, 2006, 69(6): 1820-1828. DOI: 10.1124/mol.105.020941.
8.	Guenther SR, Schumann RG, Hagenau F, et al. Comparison of surgically excised premacular membranes in eyes with macular pucker and proliferative vitreoretinopathy[J]. Curr Eye Res, 2019, 44(3): 341-349. DOI: 10.1080/02713683.2018.1542006.
9.	Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells[J]. J Cell Biochem, 1999, 74(1): 135-143. DOI: 10.1002/(SICI)1097-4644(19990701)74:1<135::AID-JCB15>3.0.CO;2-#.
10.	Santulli RJ, Kinney WA, Ghosh S, et al. Studies with an orally bioavailable alpha V integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats[J]. J Pharmacol Exp Ther, 2008, 324(3): 894-901. DOI: 10.1124/jpet.107.131656.
11.	Chen Z, Chen CZ, Gong WR, et al. Integrin-alpha5 mediates epidermal growth factor-induced retinal pigment epithelial cell proliferation and migration[J]. Pathobiology, 2010, 77(2): 88-95. DOI: 10.1159/000278290.
12.	Han J, Yan XL, Han QH, et al. Integrin beta1 subunit signaling is involved in the directed migration of human retinal pigment epithelial cells following electric field stimulation[J]. Ophthalmic Res, 2011, 45(1): 15-22. DOI: 10.1159/000313552.
13.	Yang P, Shao Z, Besley NA, et al. Risuteganib protects against hydroquinone-induced injury in human RPE cells[J]. Invest Ophthalmol Vis Sci, 2020, 61(10): 35. DOI: 10.1167/iovs.61.10.35.
14.	Park SW, Yun JH, Kim JH, et al. Angiopoietin 2 induces pericyte apoptosis via alpha3beta1 integrin signaling in diabetic retinopathy[J]. Diabetes, 2014, 63(9): 3057-3068. DOI: 10.2337/db13-1942.
15.	Silva RLE, Kanan Y, Mirando AC, et al. Tyrosine kinase blocking collagen IV-derived peptide suppresses ocular neovascularization and vascular leakage[J/OL]. Sci Transl Med, 2017, 9(373): 8030[2017-01-18]. https://pubmed.ncbi.nlm.nih.gov/28100839/. DOI: 10.1126/scitranslmed.aai8030.
16.	Mirando AC, Shen J, Silva RLE, et al. A collagen Ⅳ-derived peptide disrupts alpha5beta1 integrin and potentiates Ang2/Tie2 signaling[J/OL]. JCI Insight, 2019, 4(4): 87[2019-02-21].https://pubmed.ncbi.nlm.nih.gov/30668550/. DOI: 10.1172/jci.insight.122043.
17.	Bhatwadekar AD, Kansara V, Luo Q, et al. Anti-integrin therapy for retinovascular diseases[J/OL]. Expert Opin Investig Drugs, 2020 :1-11[2020-09-09]. https://www.tandfonline.com/doi/full/10.1080/13543784.2020.1795639. DOI: 10.1080/13543784.2020.1795639.
18.	Milloud R, Destaing O, de Mets R, et al. αvβ3 integrins negatively regulate cellular forces by phosphorylation of its distal NPXY site[J]. Biol Cell, 2017, 109(3): 127-137. DOI: 10.1111/boc.201600041.
19.	Sepulveda-Vazquez HE, Guerrero-Naranjo JL, Schoonewolff F, et al. Intravitreal injection of integrin peptide ALG-1001 for the induction of posterior vitreous detachment in rabbit eyes[J]. Invest Ophthalmol Vis Sci, 2012, 53(14): 5360.
20.	Wan R, Hong T, Tariq Y, et al. Pharmacotherapy of vitreomacular traction[J]. Curr Pharm Des, 2018, 24(41): 4874-4881. DOI: 10.2174/1381612825666190124102148.
21.	Sebag J. VI.A. Pharmacologic vitreolysis[M]//Sebag J. Vitreous: in health and disease. New York: Springer, 2014: 799-815.
22.	Stupack DG. Integrins as a distinct subtype of dependence receptors[J]. Cell Death Differ, 2005, 12(8): 1021-1030. DOI: 10.1038/sj.cdd.4401658.
23.	Bonfoco E, Chen W, Paul R, et al. Beta1 integrin antagonism on adherent, differentiated human neuroblastoma cells triggers an apoptotic signaling pathway[J]. Neuroscience, 2000, 101(4): 1145-1152. DOI: 10.1016/s0306-4522(00)00429-2.
24.	Han S, Zhang F, Hu Z, et al. Dose-dependent anti-inflammatory and neuroprotective effects of an alphanubeta3 integrin-binding peptide[J/OL]. Mediators Inflamm, 2013, 2013(6): 268486[2013-11-17]. https://pubmed.ncbi.nlm.nih.gov/24347822/. DOI: 10.1155/2013/268486.
25.	Santos AR, Corredor RG, Obeso BA, et al. Beta1 integrin-focal adhesion kinase (FAK) signaling modulates retinal ganglion cell (RGC) survival[J/OL]. PLoS One, 2012, 7(10): 48332[2012-08-31]. https://pubmed.ncbi.nlm.nih.gov/23118988/. DOI: 10.1371/journal.pone.0048332.
26.	D'Onofrio PM, Shabanzadeh AP, Choi BK, et al. MMP inhibition preserves integrin ligation and FAK activation to induce survival and regeneration in RGCs following optic nerve damage[J]. Invest Ophthalmol Vis Sci, 2019, 60(2): 634-649. DOI: 10.1167/iovs.18-25257.
27.	Karageozian V. Allegro ophthalmics announces positive topline results from DEL MAR phase 2b trial evaluating Luminate® in patients with diabetic macular edema[EB/OL][2017-08-09]. https://www.allegroeye.com/allegro-ophthalmics-announces-positive-topline-results-from-del-mar-phase-2b-stage-2-trial-evaluating-luminate-in-patients-with-diabetic-macular-edema-2/.
28.	Quiroz-Mercado H, Boyer DS, Campochiaro PA, et al. Randomized, prospective, double-masked, controlled phase 2b trial to evaluate the safety & efficacy of ALG-1001 (Luminate (R)) in diabetic macular edema[J]. Invest Ophthalmol Vis Sci, 2018, 59(9): 1960.
29.	Kaiser P, Boyer D, Campochiaro P, et al. Integrin peptide therapy: the first wet AMD experience[J]. Invest Ophthalmol Vis Sci, 2013, 54(15): 2177.
30.	Kuppermann BD. A dual-mechanism drug for vitreoretinal diseases[EB/OL][2015-07-01]. https://retinatoday.com/articles/2015-july-aug/a-dual-mechanism-drug-for-vitreoretinal-diseases.
31.	Kuppermann BD, Boyer DS, Kaiser PK, et al. Topline results from prospective, double-masked, placebo controlled phase 2 clinical study evaluating Luminate (R) (ALG-1001) in patients with symptomatic focal vitreomacular adhesion[J/OL]. Invest Ophthalmol Vis Sci, 2016, 57(12):1809.
32.	Evans DW, Yu MCM, Davey PG. Luminance and visual acuity: 20/30 could be 20/40![J]. Invest Ophthalmol Vis Sci, 2019, 60(9): 5909.
33.	Cammalleri M, Dal Monte M, Locri F, et al. The urokinase-type plasminogen activator system as drug target in retinitis pigmentosa: new pre-clinical evidence in the rd10 mouse model[J]. J Cell Mol Med, 2019, 23(8): 5176-5192. DOI: 10.1111/jcmm.14391.

1. Hynes RO. Integrins: bidirectional, allosteric signaling machines[J]. Cell, 2002, 110(6): 673-687. DOI: 10.1016/S0092-8674(02)00971-6.
2. Elner SG, Elner VM. The integrin superfamily and the eye[J]. Invest Ophthalmol Vis Sci, 1996, 37(5): 696-701.
3. Brooks PC. Role of integrins in angiogenesis[J]. Eur J Cancer, 1996, 32(14): 2423-2429. DOI: 10.1016/s0959-8049(96)00381-4.
4. Kenney CM, Chwa M, Caceres-del-Carpio J, et al. Effects of anti-VEGF and ALG-1001 on human retinal cells in vitro[J]. Invest Ophthalmol Vis Sci, 2018, 59(9): 771.
5. Beltran MA, Zamora-Alvarado R, Gonzalez-Salinas R, et al. Cytoprotective effect of ALG-1001 peptide (Luminate) on human retinal pigment epithelial cells exposed to oxidative injury. a novel functional-outcome for an anti-VEGF agent[J]. Invest Ophthalmol Vis Sci, 2018, 59(9): 1465.
6. Friedlander M, Theesfeld CL, Sugita M, et al. Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases[J]. Proc Natl Acad Sci USA, 1996, 93(18): 9764-9769. DOI: 10.1073/pnas.93.18.9764.
7. Umeda N, Kachi S, Akiyama H, et al. Suppression and regression of choroidal neovascularization by systemic administration of an alpha5beta1 integrin antagonist[J]. Mol Pharmacol, 2006, 69(6): 1820-1828. DOI: 10.1124/mol.105.020941.
8. Guenther SR, Schumann RG, Hagenau F, et al. Comparison of surgically excised premacular membranes in eyes with macular pucker and proliferative vitreoretinopathy[J]. Curr Eye Res, 2019, 44(3): 341-349. DOI: 10.1080/02713683.2018.1542006.
9. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells[J]. J Cell Biochem, 1999, 74(1): 135-143. DOI: 10.1002/(SICI)1097-4644(19990701)74:1<135::AID-JCB15>3.0.CO;2-#.
10. Santulli RJ, Kinney WA, Ghosh S, et al. Studies with an orally bioavailable alpha V integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats[J]. J Pharmacol Exp Ther, 2008, 324(3): 894-901. DOI: 10.1124/jpet.107.131656.
11. Chen Z, Chen CZ, Gong WR, et al. Integrin-alpha5 mediates epidermal growth factor-induced retinal pigment epithelial cell proliferation and migration[J]. Pathobiology, 2010, 77(2): 88-95. DOI: 10.1159/000278290.
12. Han J, Yan XL, Han QH, et al. Integrin beta1 subunit signaling is involved in the directed migration of human retinal pigment epithelial cells following electric field stimulation[J]. Ophthalmic Res, 2011, 45(1): 15-22. DOI: 10.1159/000313552.
13. Yang P, Shao Z, Besley NA, et al. Risuteganib protects against hydroquinone-induced injury in human RPE cells[J]. Invest Ophthalmol Vis Sci, 2020, 61(10): 35. DOI: 10.1167/iovs.61.10.35.
14. Park SW, Yun JH, Kim JH, et al. Angiopoietin 2 induces pericyte apoptosis via alpha3beta1 integrin signaling in diabetic retinopathy[J]. Diabetes, 2014, 63(9): 3057-3068. DOI: 10.2337/db13-1942.
15. Silva RLE, Kanan Y, Mirando AC, et al. Tyrosine kinase blocking collagen IV-derived peptide suppresses ocular neovascularization and vascular leakage[J/OL]. Sci Transl Med, 2017, 9(373): 8030[2017-01-18]. https://pubmed.ncbi.nlm.nih.gov/28100839/. DOI: 10.1126/scitranslmed.aai8030.
16. Mirando AC, Shen J, Silva RLE, et al. A collagen Ⅳ-derived peptide disrupts alpha5beta1 integrin and potentiates Ang2/Tie2 signaling[J/OL]. JCI Insight, 2019, 4(4): 87[2019-02-21].https://pubmed.ncbi.nlm.nih.gov/30668550/. DOI: 10.1172/jci.insight.122043.
17. Bhatwadekar AD, Kansara V, Luo Q, et al. Anti-integrin therapy for retinovascular diseases[J/OL]. Expert Opin Investig Drugs, 2020 :1-11[2020-09-09]. 10.1080/13543784.2020.1795639">https://www.tandfonline.com/doi/full/10.1080/13543784.2020.1795639. DOI: 10.1080/13543784.2020.1795639.
18. Milloud R, Destaing O, de Mets R, et al. αvβ3 integrins negatively regulate cellular forces by phosphorylation of its distal NPXY site[J]. Biol Cell, 2017, 109(3): 127-137. DOI: 10.1111/boc.201600041.
19. Sepulveda-Vazquez HE, Guerrero-Naranjo JL, Schoonewolff F, et al. Intravitreal injection of integrin peptide ALG-1001 for the induction of posterior vitreous detachment in rabbit eyes[J]. Invest Ophthalmol Vis Sci, 2012, 53(14): 5360.
20. Wan R, Hong T, Tariq Y, et al. Pharmacotherapy of vitreomacular traction[J]. Curr Pharm Des, 2018, 24(41): 4874-4881. DOI: 10.2174/1381612825666190124102148.
21. Sebag J. VI.A. Pharmacologic vitreolysis[M]//Sebag J. Vitreous: in health and disease. New York: Springer, 2014: 799-815.
22. Stupack DG. Integrins as a distinct subtype of dependence receptors[J]. Cell Death Differ, 2005, 12(8): 1021-1030. DOI: 10.1038/sj.cdd.4401658.
23. Bonfoco E, Chen W, Paul R, et al. Beta1 integrin antagonism on adherent, differentiated human neuroblastoma cells triggers an apoptotic signaling pathway[J]. Neuroscience, 2000, 101(4): 1145-1152. DOI: 10.1016/s0306-4522(00)00429-2.
24. Han S, Zhang F, Hu Z, et al. Dose-dependent anti-inflammatory and neuroprotective effects of an alphanubeta3 integrin-binding peptide[J/OL]. Mediators Inflamm, 2013, 2013(6): 268486[2013-11-17]. https://pubmed.ncbi.nlm.nih.gov/24347822/. DOI: 10.1155/2013/268486.
25. Santos AR, Corredor RG, Obeso BA, et al. Beta1 integrin-focal adhesion kinase (FAK) signaling modulates retinal ganglion cell (RGC) survival[J/OL]. PLoS One, 2012, 7(10): 48332[2012-08-31]. https://pubmed.ncbi.nlm.nih.gov/23118988/. DOI: 10.1371/journal.pone.0048332.
26. D'Onofrio PM, Shabanzadeh AP, Choi BK, et al. MMP inhibition preserves integrin ligation and FAK activation to induce survival and regeneration in RGCs following optic nerve damage[J]. Invest Ophthalmol Vis Sci, 2019, 60(2): 634-649. DOI: 10.1167/iovs.18-25257.
27. Karageozian V. Allegro ophthalmics announces positive topline results from DEL MAR phase 2b trial evaluating Luminate® in patients with diabetic macular edema[EB/OL][2017-08-09]. https://www.allegroeye.com/allegro-ophthalmics-announces-positive-topline-results-from-del-mar-phase-2b-stage-2-trial-evaluating-luminate-in-patients-with-diabetic-macular-edema-2/.
28. Quiroz-Mercado H, Boyer DS, Campochiaro PA, et al. Randomized, prospective, double-masked, controlled phase 2b trial to evaluate the safety & efficacy of ALG-1001 (Luminate (R)) in diabetic macular edema[J]. Invest Ophthalmol Vis Sci, 2018, 59(9): 1960.
29. Kaiser P, Boyer D, Campochiaro P, et al. Integrin peptide therapy: the first wet AMD experience[J]. Invest Ophthalmol Vis Sci, 2013, 54(15): 2177.
30. Kuppermann BD. A dual-mechanism drug for vitreoretinal diseases[EB/OL][2015-07-01]. https://retinatoday.com/articles/2015-july-aug/a-dual-mechanism-drug-for-vitreoretinal-diseases.
31. Kuppermann BD, Boyer DS, Kaiser PK, et al. Topline results from prospective, double-masked, placebo controlled phase 2 clinical study evaluating Luminate (R) (ALG-1001) in patients with symptomatic focal vitreomacular adhesion[J/OL]. Invest Ophthalmol Vis Sci, 2016, 57(12):1809.
32. Evans DW, Yu MCM, Davey PG. Luminance and visual acuity: 20/30 could be 20/40![J]. Invest Ophthalmol Vis Sci, 2019, 60(9): 5909.
33. Cammalleri M, Dal Monte M, Locri F, et al. The urokinase-type plasminogen activator system as drug target in retinitis pigmentosa: new pre-clinical evidence in the rd10 mouse model[J]. J Cell Mol Med, 2019, 23(8): 5176-5192. DOI: 10.1111/jcmm.14391.

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Progress of anti-integrin drug risuteganib in the treatment of ocular fundus diseases

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