SOLOT-Eye TM (Anti-VEGF mAb, ophthalmic injection) 苏洛晍眼用注射液


Overview

SOLOT-Eye苏洛晍眼用注射液(hPV19单抗眼用注射液)是公司在其已进入临床研究的广谱治疗恶性肿瘤的抗VEGF单抗静脉注射液基础上,通过成品处方及剂型优化,新成功开发出的眼用注射剂药物。

该药物的拟用眼科适应症包括老年性黄斑变性(age-related macular degeneration,AMD)、糖尿病性黄斑水肿(diabetic macular edema, DME)等与新生血管相关的眼底疾病。

 

苏洛晍眼用注射液(hPV19单抗眼用注射液)结合VEGF抗原的表位不同于目前国内外市场上唯一在售的抗VEGF单抗药物贝伐单抗Beavacizumab(商品名Avastin, Roche/Genentech公司产品)及其孪生姐妹Avastin-Fab片段药物Ranibizumab雷珠单抗(商品名Lucentis诺适得,Novartis /Genentech公司产品)。 体外系列研究结果显示hPV19单抗的生物活性及与VEGF抗原的结合能力是 Avastin或Ranibizumab的6-8倍。在激光诱导的食蟹猴脉络膜新生血管形成(CNV)疾病测试模型中:苏洛晍眼用注射液(hPV19单抗眼用注射液)疗效优于Ranibizumab雷珠单抗(眼内给予仅1/10至1/3 剂量的hPV19单抗注射液(0.05mg/眼或0.15mg/眼)即可达到剂量为0.5mg/眼的Ranibizumab对照药相近疗效)。

 

1.1 VEGF介导的眼底血管新生与老年黄斑变性(AMD)及糖尿病性黄斑水肿(DME)关系

年龄相关性黄斑变性(age-related macular degeneration,AMD)又称为老年黄斑变性,为眼底视网膜黄斑区结构的衰老性改变,是65岁以上老年人最常见致盲眼病[1]

糖尿病性黄斑水肿(diabetic macular edema,DME)则是导致糖尿病患者视力下降最主要的病因,危害数以千万计的患有糖尿病的工薪阶层者视力[2]

AMD/DME 的主要病理特征为眼底如脉络膜血管异常新生(choroidal neovascularization, CNV)及新生血管的出血或渗出,导致黄斑区域水肿及变性(如下图B)。

A:正常眼底            B:黄斑变性(渗出性)眼底

血管内皮生长因子(vascular endothelial growth factor, VEGF),又称为血管渗透因子(vascular permeability factor),是诱导血管新生及渗出的最重要因子 [3-6] 。VEGF在眼内过量表达造成的血管新生和渗漏可导致AMD及DME等疾病。 近年来的临床研究表明,通过玻璃体内注射VEGF拮抗剂药物如Lucentis (Ranibizumab)抑制眼底新生血管形成,可明显改善AMD和DME患者的视力[7-11]。 Lucentis为抗体Fab 片段,实际上与Roche/Genentech公司的抗肿瘤VEGF单抗药物Avastin(贝伐单抗)同源。


1.2 In-vitro data: hPV19单抗眼用注射液生物活性显著强于Avastin,Ranibizumab及Conbercept (Fig.1,Fig.2)

(Fig.1 in-vitro binding of hPV19, Avastin and Conbercept to VEGF )


 

(Fig2. hPV19, Ranibizumab, Avastin and Conbercept block the binding of VEGF to VEGF-receptor)

 

1.3  In-vivo preclinical data: 在激光诱导的食蟹猴脉络膜新生血管形成(CNV)疾病测试模型中,hPV19单抗眼用注射液疗效优于Ranibizumab

食蟹猴中测试结果表明:眼内给予仅1/10至1/3 剂量的hPV19单抗注射液(0.05mg/眼或0.15mg/眼)即可达到剂量为0.5mg/眼的Ranibizumab雷珠单抗对照药相近疗效(Fig.3)

(Fig.3 Effect of hPV19 and Ranibizumab treatment: laser-induced CNV in monkeys)


References

1      Lurence SL, Paul M, Johanna MS, et al. Age-related macular degeneration. Lancet. 2012; 379: 1728-1738.

2      Gupta N , Mansoor S , Sharma A , et al. Diabetic retinopathy and VEGF. Open Ophthalmol J. 2013;7:4-10.

3      Leung DW, Cachianes G, Kuang WJ, Goeddel DV, and Ferrara N: Vascular endothelial growth actor is a secreted angiogenic mitogen.  Science. 1989;8;246:1306-1309.

4      Keck PJ,Hauser SD,Krivi G, Sanzo K, Warren T, Feder J, Connolly DT:Vascular permeability factor, an endothelial cell mitogen related to PDGF.  Science. 1989; 246:1309-1312.

5      Carmeliet P, Ferreira V, Breier G,  et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.  Nature. 1996;380:435-439.

6      Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.  Nature. 1996;380:439-442.

7      Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration.  N Engl J Med. 2006;355: 1432-1444.

8      Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355: 1419-1431.

9      Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011; 364: 1897-1908.

10    Stepien KE, Rosenfeld PJ, Puliafito CA, et al. Comparison of intravitreal bevacizumab followed by ranibizumab for the treatment of neovascular age-related macular degeneration. Retina 2009; 29: 1067-1073.

11    Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016; 123:1351-1359.