Inhibitory effects of IBI302 on experimental choroidal neovascularization_Chinese Journal of Ocular Fundus Diseases

Authors：

FengYuliang ,  ZhangMing , LiJia , WangChunming , DanQiaorong

Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China (Feng Yuliang, Zhang Ming); Innovent Biologics, Suzhou 215123, China (Li Jia, Wang Chunming, Dan Qiaorong);

Corresponding author：

ZhangMing, Email: zhangmingscu@126.com

Keywords：

Choroidal neovascularization/prevention & control; Recombinant fusion proteins/antagonists & inhibitors; Animal experimentation

DOI：

10.3760/cma.j.issn.1005-1015.2016.02.015

Video：

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Objective To investigate the inhibitory effects of IBI302 on experimental choroidal neovascularization (CNV). Methods Affinity of IBI302 to vascular endothelial growth factor (VEGF) family cytokines (including VEGF-A₁₆₅, VEGF-A₁₂₁ and placental growth factor PlGF) and complements (C3b, C4b) was determined by enzyme-linked immunosorbent assay (ELISA). The antagonist effect of IBI302 on VEGF was measured by proliferation, migration and tube formation tests of human umbilical vein endothelial cells (HUVEC). The anti-complement activity of IBI302 was measured by hemolysis test mediated by complement classical pathway and alternative pathway. Rhesus laser-induced CNV model was divided into 5 groups including model control group, bevacizumab group, IBI302 0.25 mg group, IBI302 0.50 mg group and IBI302 1.25 mg group. Fluorescein angiography and optical coherence tomography were performed on these monkeys at 14 and 28 days after drug delivery to observe the fluorescein leakage area and retinal thickness. The aqueous VEGF concentration was measured at 29 days after drug delivery. Results IBI302 showed good affinity to VEGF-A₁₆₅, VEGF-A₁₂₁ and PlGF, as well as C3b and C4b. IBI302 significantly inhibited the proliferation, migration and tube formation of HUVEC induced by VEGF-A₁₆₅. IBI302 inhibited the hemolysis induced by complements obviously. At 14 and 28 days after drug delivery, the area of fluorescein leakage and retinal thickness in IBI302 0.25 mg group, IBI302 0.50 mg group, IBI302 1.25 mg group were reduced. The differences of the area of fluorescein leakage and retinal thickness in three IBI302 groups were not significant (P > 0.05). At 29 days after drug delivery, the VEGF concentration in the aqueous of rhesus monkey in bevacizumab group [(38.644±6.521) pg/ml] was decreased than that in model control group [(94.203±17.360) pg/ml], the difference was significant (P < 0.05). The VEGF concentration in the aqueous of rhesus monkey in three IBI302 groups were less than 31.300 pg/ml. Conclusion IBI302 inhibited experimental CNV through blocking the activity of VEGF and complement.

Citation： FengYuliang, ZhangMing, LiJia, WangChunming, DanQiaorong. Inhibitory effects of IBI302 on experimental choroidal neovascularization. Chinese Journal of Ocular Fundus Diseases, 2016, 32(2): 177-183. doi: 10.3760/cma.j.issn.1005-1015.2016.02.015 Copy

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10.	Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization[J]. Proc Natl Acad Sci USA, 2006, 103(7):2328-2333.
11.	Rohrer B, Couqhlin B, Bandyopadhyay M, et al. Systemic human CR2-targeted complement alternative pathway inhibitor ameliorates mouse laser-induced choroidal neovascularization[J]. J Ocul Pharmacol Ther, 2012, 28(4):402-409.DOI:10.1089/jop.2011.02.0212.
12.	Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration[J]. New Engl J Med, 2006,355(14):1419-1431.
13.	Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study[J]. Ophthalmology, 2009,116(1):57-65.
14.	Singer MA, Awh CC, Sadda S, et al. HORIZON: An open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular dengeration[J]. Ophthalmology, 2012,119(6):1175-1183.DOI:10.1016/j.ophtha.2011.12.016.

1. Silva R, Axer-Siegel R, Eldem B, et al. The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration[J]. Ophthalmology, 2013,120(1):130-139. DOI: 10.1016/j.ophtha.2012.07.026.
2. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP)[J]. Ophthalmology, 2013, 120(11):2292-2299. DOI: 10.1016/j.ophtha.2013.03.046.
3. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study[J]. BMJ, 2010, 340:2459. DOI: 10.1136/bmj.c2459.
4. IVAN Study Investigators, Chakravarthy U, Harding SP, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial[J]. Ophthalmology, 2012, 119(7):1399-1411. DOI: 10.1016/j.ophtha.2012.04.015.
5. Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. The neovascular age-related macular degeneration database: multicenter study of 92976 Ranibizumab injections[J]. Ophthalmology, 2014, 121(5):1092-1101. DOI: 10.1016/j.ophtha.2013.11.031.
6. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration[J]. Science, 2005, 308(5720):385-389.
7. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration[J]. Science, 2005, 308(5720):421-424.
8. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and risk of age-related macular degeneration[J]. N Engl J Med, 2007, 357(6):553-561.
9. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration[J]. Nature Genetics, 2006, 38(4):458-462.
10. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization[J]. Proc Natl Acad Sci USA, 2006, 103(7):2328-2333.
11. Rohrer B, Couqhlin B, Bandyopadhyay M, et al. Systemic human CR2-targeted complement alternative pathway inhibitor ameliorates mouse laser-induced choroidal neovascularization[J]. J Ocul Pharmacol Ther, 2012, 28(4):402-409.DOI:10.1089/jop.2011.02.0212.
12. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration[J]. New Engl J Med, 2006,355(14):1419-1431.
13. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study[J]. Ophthalmology, 2009,116(1):57-65.
14. Singer MA, Awh CC, Sadda S, et al. HORIZON: An open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular dengeration[J]. Ophthalmology, 2012,119(6):1175-1183.DOI:10.1016/j.ophtha.2011.12.016.

Chinese Journal of Ocular Fundus Diseases

Inhibitory effects of IBI302 on experimental choroidal neovascularization

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