Developing a novel therapy for diabetic retinopathy

开发糖尿病视网膜病变的新疗法

基本信息

批准号：
9347615
负责人：
Wei Li
金额：
$ 22.5万
依托单位：
EVERGLADES BIOPHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2019-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347615
关键词：
Adult Adverse effects Affect Affinity Alleles Alternative Therapies Angiogenesis Inhibitors Angiogenic Factor Antibodies Binding Blindness Blood Vessels Businesses Cells Clinical Clinical Trials Combined Modality Therapy Complementarity Determining Regions Data Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Dose Embryo Endothelial Cells Extravasation Exudative age-related macular degeneration Fab Immunoglobulins Human Investigational New Drug Application Knockout Mice Ligand Binding Ligands Lucentis Molecular Monoclonal Antibodies Mus Mutation Oxygen Pathogenesis Pathogenicity Pathologic Pathway interactions Performance Pharmacotherapy Phase Phenotype Play Prevention Receptor Signaling Resistance Retinal Retinal Diseases Retinal Neovascularization Role Route Safety Signal Pathway Small Business Technology Transfer Research Technology Therapeutic Therapeutic antibodies Toxic effect Translations Treatment Efficacy Treatment-related toxicity Vascular Diseases Vascular Endothelial Growth Factors Vascular Permeabilities Vision angiogenesis base bench to bedside comparative efficacy diabetic flexibility human monoclonal antibodies humanized antibody improved inhibitor/antagonist innovation macular edema novel novel therapeutics polyclonal antibody prevent proliferative diabetic retinopathy ranibizumab receptor secretogranin III

项目摘要

Project Summary Diabetic retinopathy (DR) is a leading cause of vision loss, affecting about 93 million people worldwide. A major breakthrough in DR therapy is the recent approval of vascular endothelial growth factor (VEGF) inhibitors. However, anti-VEGF therapy has limited efficacy with a number of side effects. The critical barrier is how to identify other angiogenic targets for alternative or combination therapy of anti-VEGF-resistant DR. We have discovered a novel DR-associated angiogenic factor that selectively binds to and stimulates angiogenesis of diseased but not normal vessels. In contrast, VEGF binds to and induces the angiogenesis of both diseased and normal vasculature. This new ligand has a different receptor pathway than VEGF, and therefore their inhibitors will have different spectra of anti-angiogenic activity for alternative or combination therapy of DR. We developed a monoclonal antibody against this new target and demonstrated its capacity to alleviate DR in mice with high efficacy. Based on the normal phenotype of the knockout mice, we predicted and confirmed that the therapeutic antibody at an excessively high dose has minimal side effects. Therefore, anti-angiogenic therapy against this new ligand has the advantages of high efficacy, minimal side effects and a different mechanism of action than anti-VEGF. Antibody humanization is an essential step for the translation of this novel therapy. This project will humanize the monoclonal antibody (Aim 1). Humanized antibodies will be selected based on their ligand-binding affinity, neutralizing activity, therapeutic efficacy and side effects (Aim 2). Humanized antibody with optimal therapeutic activity and minimal side effects will be used for clinical trials in the next phase. Therefore, this project will lead to the development of a new drug for anti-angiogenic therapy of DR with high efficacy and safety.

项目概要糖尿病视网膜病变 (DR) 是视力丧失的主要原因，影响着全球约 9300 万人。一个专业 DR治疗的突破是最近批准的血管内皮生长因子（VEGF）抑制剂。然而，抗 VEGF 疗法的疗效有限，并有许多副作用。关键的障碍是如何确定抗 VEGF 耐药 DR 的替代或联合治疗的其他血管生成靶点。我们有发现了一种新的 DR 相关血管生成因子，它选择性地结合并刺激患病血管而非正常血管。相反，VEGF 结合并诱导患病和血管的血管生成。正常的脉管系统。这种新配体具有与 VEGF 不同的受体途径，因此它们的抑制剂对于 DR 的替代或联合治疗，将具有不同的抗血管生成活性谱。我们开发了针对这一新靶标的单克隆抗体，并证明其能够缓解高血糖小鼠的 DR 功效。根据基因敲除小鼠的正常表型，我们预测并证实了治疗方法过高剂量的抗体副作用极小。因此，针对这种情况的抗血管生成治疗新型配体具有功效高、副作用小、作用机制不同等优点比抗VEGF。抗体人源化是转化这种新疗法的重要一步。该项目将使单克隆抗体人源化（目标 1）。人源化抗体将根据其配体结合亲和力、中和活性、治疗功效和副作用（目标 2）。人性化具有最佳治疗活性和最小副作用的抗体将用于下一阶段的临床试验。因此，该项目将导致开发一种用于 DR 抗血管生成治疗的新药，具有高功效和安全性。