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.

项目摘要 新生血管形成（NV）和血管渗漏的内源性蛋白抑制剂具有很大的潜力， 用于视网膜和脉络膜血管疾病的治疗剂，但迄今为止尚未实现该潜力 部分原因是大蛋白质对制造、维持适当的折叠以及 渗入组织。我们已经开发了胶原IV衍生的20-mer肽模拟物AXT 107，其 强烈抑制眼部新生血管形成和血管渗漏。玻璃体内注射1µg AXT 107 在小鼠中的活性与40μg阿柏西普相当，当联合使用时，活性大于 一个人在兔眼中，50µg AXT 107抑制血管渗漏的时间长于500µg阿柏西普，因为 自组装成玻璃体腔中的凝胶贮库，其提供持续递送至视网膜。的目标 该建议旨在阐明AXT 107的作用机制及其自组装机制 形成一个凝胶储存库，提供延长的活性。初步数据显示，AXT 107结合αvβ3， 通过VEGFR 2破坏信号传导。AXT 107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。AXT 107结合α5β1并在存在下激活Tie 2。 血管生成素2（Angpt 2）。我们将检验AXT 107结合将α5β1解离成单体的假设， 从而消除α5β1诱导的Tie 2限制，使其易位到细胞连接处并形成 这些多聚体被Angpt 2激活，增加连接完整性。在氧诱导的缺血性小鼠中， 在视网膜病变（OIR）中，我们将检验高水平的Angpt 2降低VEGF的作用的假设， 拮抗剂阿柏西普增强AXT 107的抗血管生成和抗渗透性作用，因为其 存在Angpt 2从Tie 2拮抗剂转化为Tie 2激动剂。我们还将检验以下假设： AXT 107上级阿柏西普+抗Angpt 2，因为它不完全依赖于内源性Angpt 1， Tie 2激活。AXT 107的组装和拆卸机制及其对药代动力学的影响将 追究这些研究将推进AXT 107的开发，AXT 107是一种结合两种药物的新型治疗药物。 重要的活性，VEGF抑制和Tie 2激活，具有延长的作用持续时间，因此 解决了视网膜和脉络膜血管疾病的未满足的医疗需求。