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，包括神经系统、肿瘤和精神疾病 是全球最大的医疗保健费用。抗体等生物技术药物是研究的前沿 身体其他部位的治疗进展，但中枢神经系统疾病很少从中受益，主要是由于血液 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。的好处是 大分子主要来自于比传统小分子方法更高的特异性和安全性。 动脉内途径将治疗剂递送至大脑是一种直观的方法，并且已被广泛应用。 多年来一直在尝试，但迄今为止一直受到可变性的困扰。我们最近展示了实时 MRI 引导能够克服这些限制。此外，抗体等大分子可以 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。抗体的放射性标记可以通过放射性金属的螯合来进行， 这是一个相对简单的过程，即使是生物学家也能完成，并且放射性核素可以轻松运输 来自全国各地，因此不需要现场回旋加速器。我们已经率先展示了 抗体放射性标记和动脉内递送技术合并的可行性并观察到 这种运输方式的好处令人印象深刻。虽然我们的早期结果非常引人注目，但仍然存在 将许多难题放在一起，以更好地了解动脉内途径的优势 对于患者动脉内注射的正确设计至关重要，不仅可以消除变异性，还可以学习 充分利用该程序的最佳条件是什么？ 首先，在这里我们将了解脑血管系统中的抗体浓度如何影响其 外渗以及我们将研究血浆-抗体相互作用作为限制因素的潜在作用 静脉内施用的抗体外渗。这些知识将为 患者动脉内输注时定位导管，犹如高浓度且无暴露 血液抗体是贡献因素，因此导管应放置在大脑的远端 血管，以最大限度地发挥动脉内路线的优势。然后，我们将了解什么是最佳浓度 安全地执行手术，同时最大限度地提高大脑对抗体的吸收。同时，直接数字将适用 仅针对小鼠，它也将为临床转化的考虑因素提供背景。那么接下来我们就来详细研究一下 通过深入了解抗体输送到中枢神经系统对基本大脑过程的潜在影响 转录组学和蛋白质组学来检测潜在的负面后果，然后作为基础 以便寻找对策。最终，我们将研究抗体从大脑中的清除以及抗体的作用 大脑保留抗体的目标。这部分还可以评估抗体的差异 外渗至脑癌，并将提供其治疗活性的初步数据。