Nanobodies for topical delivery to inhibit abnormal choroidal angiogenesis

描述(申请人提供)：老年性黄斑变性(AMD)以视网膜下脉络膜新生血管的形成为特征，是老年人失明的主要原因。血管内皮生长因子(VEGF)调节血管生成，增强血管通透性，导致视力下降。阻断血管内皮生长因子的作用是目前预防脉络膜血管生成和降低血管通透性最有效的策略。玻璃体内注射抗血管内皮生长因子药物已被广泛用于减缓疾病进展和改善受影响患者的视力结果。遗憾的是，玻璃体内注射需要在医院给药，存在严重感染、视网膜脱离、白内障、眼内炎、眼内炎症、眼压升高和玻璃体出血的风险，患者依从性低。Abzyme Treateutics LLC建议开发一种新的治疗方法，用于自我管理的非侵入性局部给药，以抑制视网膜和脉络膜中异常的血管生成。AMD治疗的抗新生血管治疗将被设计为克服视网膜和脉络膜障碍，以便治疗可以以滴眼液的形式提供。主动的抗血管生成治疗将通过转铁蛋白受体(TFR)介导的跨细胞和经角膜转运，达到玻璃体液中的血管内皮生长因子靶点。在第一阶段，将产生人单结构域高亲和力抗血管内皮生长因子中和纳米体和双功能的与转铁蛋白受体低亲和力和高亲和力的血管内皮生长因子/转铁蛋白受体纳米体。纳米小体在玻璃体和视网膜中的积聚将在接受局部滴眼液的小鼠模型中确定。在第二阶段，转铁蛋白受体介导的抗血管内皮生长因子疗法的抗新生血管活性将在追踪IND应用的AMD动物模型中进行表征和验证。

DESCRIPTION (provided by applicant): The age-related macular degeneration (AMD) characterized by the formation of subretinal choroidal neovascularization is the main cause of blindness in the elderly. Vascular endothelial growth factor (VEGF) regulates angiogenesis and enhances vascular permeability that results in visual acuity deterioration. Blockade of VEGF action is currently the most effective strategy in preventing choroidal angiogenesis and reducing vascular permeability. The intravitreal injection of anti-VEGF drugs has been widely employed to reduce the disease progression and improve the visual outcomes of the affected patients. Unfortunately, intravitreal injection requires the administration in hospital, poses a risk of sevee infection, retinal detachment, cataract, endophthalmitis, intraocular inflammation, increase of intraocular pressure and vitreous hemorrhage as well as has low patient compliance. Abzyme Therapeutics LLC proposes to develop a new therapeutic for self-administrable noninvasive topical delivery to inhibit abnormal angiogenesis in the retina and choroid. The anti-neovascularization therapeutic for AMD treatment will be designed to overcome the retinal and choroidal barriers such that the therapeutic can be delivered in the form of eye drop. Active anti-angiogenesis therapeutics will reach the VEGF target in the vitreous humor via transferrin receptor (TfR) mediated transcytosis and transcorneal transport. In Phase I, human single domain high affinity anti-VEGF neutralizing nanobodies and bispecific VEGF/TfR nanobodies with low affinity to TfR and high affinity to VEGF will be produced. The accumulation of nanobodies in the vitreous humor and retina will be determined in a mouse model that receives topical eye drops. In Phase II, the anti-neovascularization activity of transferrin receptor- mediated anti-VEGF therapeutics will be characterized and validated in animal AMD models pursuing the IND application.