Novel Long-Acting Inhibitors of Vascular Endothelial Growth Factor (VEGF) for Treatment of Intraocular Vascular Disorders

摘要 新生血管是缺血性视网膜疾病的一个重要特征，也是与年龄相关的湿性视网膜病变 黄斑变性(AMD)，所有导致严重视力丧失的主要原因。血管内皮细胞 生长因子(VEGF)抑制剂改变了这些疾病的治疗方法。目前， 三种抗血管内皮生长因子药物在美国被广泛用于眼科适应症，贝伐单抗， Ranibizumab和afLibercept。全世界已有数百万患者接受了这些药物的治疗。 在用这些药物治疗五年后，大约一半的新生血管性AMD患者效果良好。 视力，即视力20/40或更高，这是以前遥不可及的结果 目前已有抗血管内皮生长因子的药物。然而，在现实生活中的临床环境中，许多患者并不 体验在临床试验中观察到的相同程度的益处，部分原因是他们获得了 较少注射抗血管内皮生长因子。因此，迫切需要发现和识别长效小说 血管内皮生长因子抑制剂。我们假设，在细胞内结合硫酸乙酰肝素蛋白多糖的能力 玻璃体可能是一种促进眼内滞留的策略，最终会减轻负担。 玻璃体内注射。我们设计了一系列的血管内皮生长因子受体1变异体，并鉴定了一些 具有很强的肝素结合特性和与玻璃体结合的能力。初步数据 表明我们的一些变种在动物模型中具有更长的持续时间和更好的疗效 眼内新生血管高于目前的护理标准。我们的提案是第一个 系统性尝试开发与肝素亲和力相关的血管内皮生长因子的功能多样性 受体。我们预计，这将导致发现和开发更有效和 用于玻璃体内给药的持久的血管内皮生长因子抑制剂。

ABSTRACT Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Currently, three anti-VEGF drugs are widely used in the USA for ophthalmological indications, bevacizumab, ranibizumab and aflibercept. Millions of patients have been treated with these drugs worldwide. After five-year treatment with these drugs, about half of neovascular AMD patients had good vision, i.e. visual acuity 20/40 or better, an outcome that would have been out of reach before anti-VEGF agents were available. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injection. So, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that the ability to bind heparan sulfate proteoglycans in the vitreous may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to the vitreous. Preliminary data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our proposal represents the first systematic attempt to exploit the functional diversity associated with heparin-affinity of a VEGF receptor. We anticipate that it will result in the discovery and development of more effective and durable VEGF inhibitors for intravitreal administration.