A new drug entity for combination therapy of diabetic retinopathy

项目摘要 糖尿病视网膜病变(DR)是导致在职成年人视力丧失的主要原因。DR治疗的重大突破 是血管内皮生长因子(VEGF)抑制剂的问世和批准。然而，抗血管内皮生长因子治疗 疗效有限。关键障碍是如何提高对血管内皮生长因子耐药患者的治疗效果 抑制剂。其中一种策略是同时抑制两种不同的血管生成因子的相加或 抗血管内皮生长因子耐药DR的协同联合治疗我们发现了一种新的疾病选择性 血管生成因子通过血管内皮生长因子非依赖的受体途径参与DR的发病。 因此，是联合治疗的潜在靶点。我们进一步研制出中和单抗。 并在动物模型中证明了它们在缓解DR方面的高效性，副作用最小。这样做的目的是 项目是开发一种新的药理学试剂，能够同时抑制血管内皮生长因子和这一新的 在目标1中，我们将设计这样的双重药物抑制物 同时靶向血管内皮生长因子和我们的新血管生成因子并鉴定它们的配体结合亲和力 和中和活性。在目标2中，我们将表征这些双重抑制剂的治疗效果并分析 他们的安全状况。这些双重抑制剂的有效性和安全性将与单一疗法进行比较。 将选择效果最好、副作用最小的最佳双重抑制剂之一用于 下一阶段临床试验的进一步发展。因此，这个项目有可能开发出一种 抗血管生成联合治疗糖尿病视网膜病变疗效提高的新药物实体。

Project Summary Diabetic retinopathy (DR) is a leading cause of vision loss in working adults. A major breakthrough in DR therapy is the advent and approval of vascular endothelial growth factor (VEGF) inhibitors. However, anti-VEGF therapy has limited efficacy. The critical barrier is how to improve treatment efficacy in patients resistant to VEGF inhibitors. One of the strategies is to simultaneously inhibit two different angiogenic factors for additive or synergistic combination therapy of anti-VEGF-resistant DR. We have discovered a novel disease-selective angiogenic factor that contributes to DR pathogenesis through a VEGF-independent receptor pathway and, therefore, is a potential target for combination therapy. We further developed neutralizing monoclonal antibodies and demonstrated their high efficacy to alleviate DR in animal models with minimal side effects. The goal of this project is to develop a new pharmacological agent that enables concurrent inhibition of VEGF and this novel angiogenic factor for combination therapy of DR. In Aim 1, we will engineer such dual pharmacological inhibitors to simultaneously targets VEGF and our novel angiogenic factor and characterize their ligand-binding affinity and neutralizing activity. In Aim 2, we will characterize therapeutic efficacy of these dual inhibitors and analyze their safety profiles. The efficacy and safety profiles of these dual inhibitors will be compared to monotherapies. One of the optimal dual inhibitors with maximal improved efficacy and minimal side effects will be selected for further development toward clinical trials in the next phase. Therefore, this project has a potential to develop a new drug entity for combination anti-angiogenic therapy of DR with improved efficacy.