Image-guided, intra-arterial delivery of antibodies to the central nervous system

图像引导、动脉内将抗体输送至中枢神经系统

• 批准号: 10383753
• 负责人: Miroslaw Janowski
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383753
• 关键词: Address; Adoption; Animal Model; Antibodies; Binding; Biodistribution; Biotechnology; Blood; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Catheters; Central Nervous System Diseases; Cerebrovascular system; Cerebrum; Chronic; Clinical; Country; Cyclotrons; Data; Dependence; Deposition; Disease; Distal; Dose; Drug Kinetics; Extravasation; Goals; Guidelines; Half-Life; Healthcare; Image; Infusion procedures; Injections; Intra-Arterial Infusions; Intra-Arterial Injections; Intravenous; Intuition; Knowledge; Learning; Magnetic Resonance Imaging; Malignant neoplasm of brain; Methodology; Modeling; Molecular Target; Mus; Neuraxis; Neurologic; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Plasma; Play; Positioning Attribute; Positron-Emission Tomography; Procedures; Process; Production; Proteomics; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Reporting; Role; Route; Safety; Ships; Site; Specificity; Suspensions; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Therapeutic procedure; Thrombosis; Time; Validation; base; chelation; clinical translation; design; image guided; improved; insight; macromolecule; prevent; procedure safety; protective effect; response; safety study; small molecule; stem cells; targeted delivery; therapy outcome; transcriptomics; treatment choice; uptake

Central nervous system (CNS) diseases including neurological, oncological and psychiatric conditions are the biggest healthcare expense worldwide. Biotechnological drugs such as antibodies are a frontline of therapeutic progress elsewhere in the body, but the CNS diseases rarely benefit from them mostly due blood brain barrier (BBB) limiting their penetration to the brain, as they have relatively large size. The benefit of macromolecules mostly comes from higher specificity and safety over traditional small molecule approaches. Intra-arterial route of delivery of therapeutic agents to the brain is an intuitive approach and it has been attempted for years but so far it has been plagued by the variability. We have recently shown that real-time MRI guidance is capable to overcome these limitations. Moreover, macromolecules such as antibodies can be far easier tagged and imaged than small molecules in majority of circumstances, which provides a unique opportunity to be even more precise. Radiolabeling of antibodies can be performed by chelation of radiometals, which is relatively simple process to be completed even by a biologist, and radionuclides can be easily shipped from all over the country so no need for on-site cyclotron is needed. We have been first to show the feasibility of merging technologies of antibody radiolabeling and intra-arterial delivery and observed impressive benefits of this route of delivery. While, our early results are quite compelling there are still many puzzles to be put together to better understand the advantages of intra-arterial route as they might be crucial for a proper design of intra-arterial injections in patients, not only to eradicate variability but also to learn what are the optimal conditions to take the most of the procedure. First, here we will learn how the antibody concentration in cerebral vasculature contributes to their extravasation as well as we will look into the potential role of plasma-antibody interaction as a factor limiting extravasation of intravenously administered antibody. This knowledge will provide clear guidelines on a positioning catheter during intra-arterial infusions in patients, as if high concentration and no exposure of antibody to blood are contribution factors, then the catheter should be placed quite distally in the cerebral vessels to maximize the benefit of intra-arterial route. Then, we will learn what is the optimal concentration to perform procedure safely while to maximize the brain uptake of antibodies. While, the direct numbers will apply to mice only, it will also give a context to considerations to clinical translation. Then, we will study in detail the potential impact of antibody delivery to the CNS on essential brain processes through getting insight into transcriptomics and proteomics to detect potential negative consequences, which would then serve as a basis for finding countermeasures. Ultimately, we will look into antibody clearance from the brain and the role of targets for brain retention of antibodies. This part will also allow to assess the difference in antibody extravasation to the brain cancer as well as will provide preliminary data on their therapeutic activity.

中枢神经系统（CNS）疾病，包括神经，肿瘤和精神病病 是全球最大的医疗费用。生物技术药物（例如抗体）是 治疗性在体内其他地方的进展，但中枢神经系统疾病很少受益于它们 大脑屏障（BBB）限制了它们对大脑的渗透，因为它们的尺寸相对较大。好处 大分子主要来自传统小分子方法的更高特异性和安全性。 动脉内治疗剂向大脑传递的途径是一种直观的方法，它已经是 尝试了多年，但到目前为止，它一直受到变异性的困扰。我们最近显示了实时 MRI指南能够克服这些局限性。而且，诸如抗体之类的大分子可以是 在大多数情况下，比小分子更容易标记和成像，这提供了独特的 有机会变得更加精确。可以通过放射线静脉螯合进行抗体的放射性标记， 即使是由生物学家也可以完成的相对简单的过程，并且放射性核素很容易运输 来自全国各地，因此不需要现场回旋。我们是第一个向 合并抗体放射性标记和动脉内输送技术的可行性并观察到 这种交付途径的令人印象深刻的好处。虽然我们的早期结果令人信服，但仍有 许多难题要组合在一起，以更好地理解动物内路线的优势，因为它们可能是 对于患者的动脉内注射的适当设计至关重要，不仅可以消除可变性 采取最佳过程的最佳条件是什么。 首先，在这里我们将了解脑脉管系统中的抗体浓度如何有助于其 渗出以及我们将研究等离子体抗体相互作用的潜在作用作为因素限制 静脉内施用的抗体的渗出。这些知识将提供明确的指导方针 在患者动脉内输注过程中定位导管，好像高浓度和没有暴露 血液的抗体是贡献因素，然后应将导管放在大脑中 容器以最大化动脉内途径的益处。然后，我们将了解什么是最佳集中 安全执行程序，同时最大程度地吸收抗体的大脑。而直接数字将适用 仅对于小鼠，它也将为临床翻译的考虑。然后，我们将详细研究 通过深入了解，抗体向中枢神经系统递送对中枢神经系统的潜在影响 转录组学和蛋白质组学检测潜在的负面后果，然后将作为基础 寻找对策。最终，我们将研究大脑的抗体清除和 抗体脑部保留的靶标。该部分还将允许评估抗体的差异 对脑癌的外渗以及将提供有关其治疗活性的初步数据。