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关键特征，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 生长因子（VEGF）抑制剂已经改变了这些疾病的治疗。目前， 三种抗VEGF药物在美国广泛用于眼科适应症，贝伐单抗， 雷珠单抗和阿柏西普。全世界已有数百万患者接受了这些药物的治疗。 经过5年的药物治疗，大约一半的新生血管性AMD患者有良好的治疗效果。 视力，即视力20/40或更好，这是以前无法达到的结果 抗VEGF剂可用。然而，在现实生活中的临床环境中，许多患者并不 在临床试验中观察到相同程度的益处，部分原因是他们接受了 更少的抗VEGF注射。因此，迫切需要发现和鉴定新的长效 VEGF抑制剂。我们假设，结合硫酸乙酰肝素蛋白聚糖的能力， 玻璃体可能是促进眼内滞留的策略，最终导致负担减轻 玻璃体内注射我们设计了一系列VEGF受体1变体，并鉴定了一些 具有强的肝素结合特性和结合玻璃体的能力。初步数据 表明我们的一些变体在动物模型中具有更长的持续时间和更大的功效， 眼内新生血管形成的可能性。我们的建议代表了第一个 系统性尝试利用与VEGF的肝素亲和力相关的功能多样性 受体的我们预计，这将导致发现和发展更有效的， 用于玻璃体内给药的持久VEGF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.