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

中枢神经系统（CNS）疾病，包括神经、肿瘤和精神疾病 是全世界最大的医疗费用。生物技术药物，如抗体，是一个前沿， 在身体的其他地方的治疗进展，但中枢神经系统疾病很少受益于他们主要是由于血液 脑屏障（BBB）限制了它们对脑的渗透，因为它们具有相对大的尺寸。的利益 大分子方法主要来自于比传统小分子方法更高的特异性和安全性。 将治疗剂递送至脑的动脉内途径是一种直观的方法，并且其已经被广泛应用。 多年来一直在尝试，但到目前为止，它一直受到可变性的困扰。我们最近发现， MRI引导能够克服这些限制。此外，大分子如抗体可以是 在大多数情况下，它比小分子更容易标记和成像，这提供了一种独特的 有机会更加精确。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，即使是生物学家也可以完成， 因此不需要现场回旋加速器。我们是第一个展示 合并抗体放射性标记和动脉内递送技术的可行性，并观察到 这条运输路线的巨大优势。虽然我们的早期结果很有说服力， 为了更好地理解动脉内途径的优点， 这对于患者动脉内注射的正确设计至关重要，不仅要消除变异性，而且要了解 什么是最佳的条件采取最大的程序。 首先，在这里，我们将了解脑血管系统中的抗体浓度如何有助于其 以及我们将探讨血浆-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。这些知识将提供明确的准则， 在患者动脉内输注期间定位导管，就好像高浓度且无暴露 血液抗体是促成因素，则导管应放置在脑内相当远的位置 血管，以最大限度地发挥动脉内途径的益处。然后，我们将学习什么是最佳浓度， 安全地进行手术，同时最大限度地增加大脑对抗体的摄取。直接号码将适用于 对于小鼠，它也将为临床翻译的考虑提供背景。然后，我们将详细研究 通过深入了解抗体递送至CNS对基本脑过程的潜在影响， 转录组学和蛋白质组学来检测潜在的负面影响，然后作为基础， 寻找对策。最终，我们将研究抗体从大脑中的清除以及 抗体在大脑中滞留的目标。这部分还将允许评估抗体的差异 此外，还将提供关于其治疗活性的初步数据。

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.