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 内源性蛋白抑制物(NV)和血管渗漏具有很大的潜力 治疗视网膜和脉络膜血管疾病的药物，但到目前为止，这种潜力还没有实现 部分原因是大的蛋白质对制造、维持适当的折叠和 穿透到组织中。我们开发了一种IV型胶原衍生的20肽模拟物AXT107，它可以 强烈抑制眼部新生血管和血管渗漏。玻璃体腔内注射1微克AXT107 在小鼠体内的活性与40微克的阿普利赛特相当，当两者合用时，活性比单独使用更强 独自一人。在兔眼中，50微克AXT107抑制血管渗漏的时间比500微克阿普利康更长，因为它 自组装成玻璃体腔内的凝胶库，为视网膜提供持续的输送。的目标是 这项建议旨在阐明AXT107的作用机制及其自组装机制 进入一个凝胶库，提供长时间的活动。初步数据显示，AXT107与αvβ3结合 中断通过VEGFR2的信号。AXT107还通过血小板衍生生长因子干扰信号转导 受体β(PDGFRβ)、c-蛋氨酸和胰岛素样生长因子-1受体；我们将检验这些受体的假设 影响也是αvβ3结合的结果。AXT107结合α5β1并激活Tie2 血管生成素2(Angpt2)。我们将测试AXT107结合将α5β1解离为单体的假设， 从而消除了α5β1诱导的Tie2的限制，使其能够移位到细胞连接并形成 由Angpt2激活的多聚体增加了连接的完整性。氧诱导的小鼠脑缺血 视网膜病变(OIR)，我们将检验这一假设，即高水平的Angpt2降低了血管内皮生长因子的作用 拮抗剂afLibercept，增强AXT107的抗血管生成和抗通透性作用，因为在其 存在Angpt2从Tie2拮抗剂转变为Tie2激动剂。我们还将检验这一假设 AXT107优于afLibercept+抗Angpt2，因为它不完全依赖内源性Angpt1 Tie2激活。AXT107的组装和拆解机制及其对药代动力学的影响 被调查。这些研究将推动AXT107的开发，AXT107是一种结合了两种药物的新型疗法 重要的活性，血管内皮生长因子抑制和Tie2激活，作用持续时间延长，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。