Integrin-binding Peptide for Ocular Neovascularization and Macular Edema: Molecular Mechanism of Action

整合素结合肽治疗眼部新生血管和黄斑水肿：分子作用机制

• 批准号: 10361561
• 负责人: Peter A Campochiaro
• 金额: $ 39.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361561
• 关键词: Address; Advanced Development; Agonist; Angiogenesis Inhibitors; Angiogenic Peptides; Angiopoietin-2; Angiostatins; Binding; Biomimetics; Blindness; Blood Vessels; Cell Proliferation; Characteristics; Cicatrix; Collagen Type IV; Complex; Data; Disease; Disease Progression; Dissociation; Dose; Doxycycline; Drug Kinetics; Endostatins; Endothelial Cells; Extravasation; Exudative age-related macular degeneration; Eye; Family; Gel; Goals; Human; Injections; Insulin-Like-Growth Factor I Receptor; Integrin Binding; Intercellular Junctions; KDR gene; Maintenance; Malignant neoplasm of brain; Malignant neoplasm of lung; Medical; Methods; Migration Assay; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Opsin; Oryctolagus cuniculus; Oxygen; Patients; Penetration; Peptides; Permeability; Phosphorylation; Photoreceptors; Physiological; Platelet-Derived Growth Factor beta Receptor; Process; Production; Property; Proteins; Receptor Signaling; Retina; Retinal Diseases; Retinal Vein Occlusion; Sampling; Series; Signal Transduction; Structure; Systems Biology; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Agents; Time; Tissues; Transgenic Mice; Transgenic Organisms; Translating; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Visual; Wild Type Mouse; antagonist; aqueous; diabetic; dimer; disability; experimental study; in vivo; inducible gene expression; macular edema; malignant breast neoplasm; monomer; mouse model; multicatalytic endopeptidase complex; neovascularization; novel therapeutics; ocular neovascularization; peptidomimetics; prevent; receptor; response; retina blood vessel structure; rho; wound healing

Project Summary Endogenous protein inhibitors of neovascularization (NV) and vascular leakage have great potential as therapeutic agents for retinal and choroidal vascular diseases, but thus far that potential has not been realized partly because large proteins present challenges for manufacturing, maintenance of appropriate folding, and penetration into tissues. We have developed a collagen IV-derived 20-mer peptide mimetic, AXT107 that strongly suppresses ocular neovascularization and vascular leakage. Intravitreous injection of 1µg of AXT107 in mice has comparable activity to 40µg of aflibercept and when combined, activity is greater than with either alone. In rabbit eyes, 50µg AXT107 suppresses vascular leakage longer than 500µg aflibercept because it self-assembles into a gel depot in the vitreous cavity that provides sustained delivery to the retina. The goal of this proposal is to elucidate the mechanism of action of AXT107 and the mechanism by which it self-assembles into a gel depot which provides prolonged activity. Preliminary data show that AXT107 binds αvβ3 which disrupts signaling through VEGFR2. AXT107 also disrupts signaling through platelet-derived growth factor receptor β (PDGFRβ), c-Met, and insulin-like growth factor-1 receptor; we will test the hypothesis that these effects are also a consequence of αvβ3 binding. AXT107 binds α5β1 and activates Tie2 in the presence of Angiopoietin 2 (Angpt2). We will test the hypothesis that AXT107 binding dissociates α5β1 into monomers, thereby eliminating α5β1-induced constraint of Tie2 allowing it to translocate to cell junctions and form multimers that are activated by Angpt2 increasing junctional integrity. In mice with oxygen-induced ischemic retinopathy (OIR), we will test the hypothesis that high levels of Angpt2 which reduce the effects of the VEGF antagonist aflibercept, enhance the antiangiogenic and anti-permeability effects of AXT107 because in its presence Angpt2 is converted from a Tie2 antagonist to a Tie2 agonist. We will also test the hypothesis that AXT107 is superior to aflibercept + anti-Angpt2 because it does not depend solely on endogenous Angpt1 for Tie2 activation. The mechanism of AXT107 assembly and disassembly, and its effect on pharmacokinetics will be investigated. These studies will advance the development of AXT107 a novel therapeutic that combines two important activities, VEGF suppression and Tie2 activation, with prolonged duration of action, and thus addresses unmet medical needs for retinal and choroidal vascular diseases.

项目概要 新血管形成（NV）和血管渗漏的内源性蛋白质抑制剂具有巨大的潜力 视网膜和脉络膜血管疾病的治疗剂，但迄今为止其潜力尚未实现 部分原因是大蛋白质对制造、适当折叠的维护和维护提出了挑战 渗透到组织中。我们开发了一种 IV 型胶原蛋白衍生的 20 聚肽模拟物 AXT107， 强烈抑制眼部新生血管形成和血管渗漏。玻璃体内注射 1μg AXT107 在小鼠中的活性与 40μg 阿柏西普相当，联合使用时的活性比任一药物都强 独自的。在兔眼中，50μg AXT107 抑制血管渗漏的时间比 500μg 阿柏西普更长，因为它 自组装成玻璃体腔中的凝胶库，持续输送至视网膜。目标是 该提案旨在阐明 AXT107 的作用机制及其自组装机制 进入凝胶储存库，提供持久的活性。初步数据显示 AXT107 结合 αvβ3， 破坏 VEGFR2 的信号传导。 AXT107 还通过血小板衍生生长因子破坏信号传导 受体 β (PDGFRβ)、c-Met 和胰岛素样生长因子-1 受体；我们将检验这些假设 效应也是 αvβ3 结合的结果。 AXT107 结合 α5β1 并在存在以下物质的情况下激活 Tie2 血管生成素 2 (Angpt2)。我们将测试 AXT107 结合将 α5β1 解离成单体的假设， 从而消除 α5β1 诱导的 Tie2 限制，使其易位至细胞连接处并形成 Angpt2 激活的多聚体增加了连接的完整性。在氧诱导缺血的小鼠中 视网膜病变 (OIR)，我们将检验以下假设：高水平的 Angpt2 会降低 VEGF 的作用 拮抗剂阿柏西普，增强 AXT107 的抗血管生成和抗渗透作用，因为 Angpt2 的存在从 Tie2 拮抗剂转化为 Tie2 激动剂。我们还将检验以下假设： AXT107 优于阿柏西普 + 抗 Angpt2，因为它不仅仅依赖于内源性 Angpt1 Tie2 激活。 AXT107组装和分解的机制及其对药代动力学的影响将 被调查。这些研究将推动 AXT107 的开发，这是一种结合了两种药物的新型疗法 VEGF 抑制和 Tie2 激活等重要活性，且作用持续时间较长，因此 解决视网膜和脉络膜血管疾病未得到满足的医疗需求。