权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

开发针对 CNV 的新型疾病靶向抗血管生成疗法

基本信息

批准号：
10726508
负责人：
Wei Li
金额：
$ 44万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726508
关键词：
Acceleration Address Adverse effects Affinity Age related macular degeneration Alternative Therapies American Angiogenesis Inhibitors Angiogenic Factor Animal Model Binding Blindness Blood Vessels Cells Choroidal Neovascularization Clinical Clinical assessments Combined Modality Therapy Data Developed Countries Development Diabetic Retinopathy Disease Drug Targeting Elderly Extravasation Eye diseases Family Immunize Investigation Ligands Maps Monoclonal Antibodies Mus Neurons Outcome Pathogenesis Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Physiologic Neovascularization Proteins Recombinants Reporting Research Resistance Retinopathy of Prematurity Safety Technology Therapeutic Therapeutic Monoclonal Antibodies Treatment Efficacy Tumor Angiogenesis Vascular Endothelial Growth Factor B Vascular Endothelial Growth Factors Visual Acuity alternative treatment angiogenesis clinical translation comparative comparative efficacy efficacy evaluation humanized antibody improved inhibitor innovation innovative technologies neutralizing monoclonal antibodies novel novel therapeutics polyclonal antibody pre-clinical retina blood vessel structure retinal neuron secretogranin III side effect success targeted treatment thrombospondin 4

项目摘要

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.

项目摘要湿性年龄相关性黄斑变性（AMD）是发达国家中老年人视力丧失的主要原因。在一些国家，以脉络膜新生血管（CNV）为特征。目前治疗该病的方法是抗血管血管内皮生长因子（VEGF）药物，如阿柏西普，但疗效有限，并有潜在的副作用。湿性AMD治疗的一个未满足的临床需求是鉴定疾病限制性血管生成因子并开发新的治疗方法。 VEGF非依赖性疾病靶向抗血管生成治疗，替代或联合治疗具有最佳安全性治疗，以提高抗VEGF耐药患者的疗效。我们将创新技术应用于比较CNV和健康小鼠的配体组学，发现了一种新的CNV选择性血管生成因子，选择性结合CNV，但不结合健康的脉络膜血管。相比之下，VEGF不分青红皂白地驱动血管生成初步数据显示，针对CNV选择性血管生成因子的多克隆抗体（pAbs）因子减轻小鼠CNV的疗效与aflibercept相当。然而，缺乏中和性单克隆抗体，针对这种新靶点的单克隆抗体（mAb）是发展疾病靶向抗血管生成治疗的主要障碍用于临床转化并评估疗效和安全性。这个探索性项目的目标是产生并表征针对新靶标的中和mAb。我们的核心假设是，抗血管生成因子的药物有效缓解CNV，疗效高，但副作用小，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的mAb，表征其中和活性。在目标2中，我们将描述药物的治疗效果和安全性中和mAb。据我们所知，所有已批准或正在开发的抗血管生成药物都是针对常规的血管生成。血管生成因子不加区别地调节患病和健康的血管。该项目具有有可能开发一种新的疾病靶向VEGF非依赖性抗血管生成治疗湿性AMD，对健康视网膜血管和神经元的副作用极小。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体组学技术，疾病的病理机制研究和药物靶点发现。