Developing a novel disease-targeted anti-angiogenic therapy for CNV

项目摘要 湿性老年性黄斑变性(AMD)是发达国家老年人视力丧失的主要原因 以脉络膜新生血管(CNV)为特征的国家。目前这种疾病的治疗方法是抗血管 血管内皮细胞生长因子(VEGF)药物，如阿普利赛特，但疗效有限，潜在副作用。 湿性AMD治疗的一个尚未得到满足的临床需求是识别疾病限制性血管生成因素并开发新的 具有最佳安全性的血管内皮生长因子非依赖性疾病靶向抗血管生成治疗方案或组合 治疗以提高抗血管内皮生长因子耐药患者的疗效。我们应用了我们的创新技术 与CNV和健康小鼠的比较配基组学并发现了一种新的CNV选择性血管生成因子 选择性地与CNV结合，但不与健康的脉络膜血管结合。相比之下，血管内皮生长因子不分青红皂白地 血管生成。初步数据显示，抗CNV选择性血管生成的多克隆抗体(PAb) 该因子可减轻小鼠的CNV，疗效与阿普利赛特相当。然而，缺乏中和性的单抗 针对该新靶点的抗体(MAb)是发展疾病靶向抗血管生成治疗的主要障碍。 用于临床翻译，并评估其疗效和安全性。这个探索性项目的目标是产生 并对针对新靶点的中和单抗进行表征。我们的中心假设是中和单抗 抗血管生成因子能有效缓解CNV，疗效高，副作用小。 健康的视网膜血管和神经元。在目标1中，我们将产生针对血管生成因子和 表征它们的中和活性。在目标2中，我们将描述该药的疗效和安全性。 中和单抗。据我们所知，所有已获批准或正在研制中的抗血管生成药物都以常规药物为靶点。 不分青红皂白地调节患病血管和健康血管的血管生成因子。这个项目有 联合应用血管内皮生长因子非依赖性抗血管生成药物治疗湿性AMD的研究 对健康的视网膜血管和神经元的副作用最小。这种新疗法的成功开发将 还支持广泛适用于血管和非血管的创新配基组学技术 疾病的病理机制研究和药物靶点的发现。

Project Summary Wet age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly in developed countries, characterized by choroidal neovascularization (CNV). The disease is currently treated by anti-vascular endothelial growth factor (VEGF) drugs, such as aflibercept, but with limited efficacy and potential side effects. An unmet clinical need for wet AMD therapy is to identify disease-restricted angiogenic factors and develop novel VEGF-independent disease-targeted anti-angiogenic therapies with optimal safety for alternative or combination treatment to improve the efficacy for anti-VEGF-resistant patients. We applied our innovative technology of comparative ligandomics to CNV and healthy mice and discovered a novel CNV-selective angiogenic factor that selectively binds to CNV but not healthy choroidal vessels. In contrast, VEGF indiscriminately drives angiogenesis. Preliminary data showed that polyclonal antibodies (pAbs) against the CNV-selective angiogenic factor alleviate CNV in mice with comparable efficacy to aflibercept. However, lack of a neutralizing monoclonal antibody (mAb) against this novel target is a major obstacle to develop disease-targeted anti-angiogenic therapy for clinical translation and assess the efficacy and safety. The objective of this exploratory project is to generate and characterize neutralizing mAbs against the new target. Our central hypothesis is that the neutralizing mAbs against the angiogenic factor efficiently alleviate CNV with high efficacy but minimal adverse side effects to healthy retinal vessels and neurons. In Aim 1, we will generate mAbs against the angiogenic factor and characterize their neutralizing activity. In aim 2, we will characterize the therapeutic efficacy and safety of the neutralizing mAbs. To our knowledge, all anti-angiogenic drugs, approved or in the pipeline, target conventional angiogenic factors that indiscriminately regulate both diseased and healthy vasculatures. This project has the potential to develop a novel disease-targeted VEGF-independent anti-angiogenic therapy for wet AMD with minimal side effects on healthy retinal vessels and neurons. Successful development of this novel therapy will also support the innovative ligandomics technology that is broadly applicable to vascular and non-vascular diseases for pathological mechanism research and drug target discovery.