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 是全球最大的医疗保健支出。生物技术药物，如抗体，是最前沿的 身体其他部位的治疗进展，但中枢神经系统疾病很少受益，主要是血液 脑屏障(BBB)限制了它们对大脑的渗透，因为它们的体积相对较大。的好处 与传统的小分子方法相比，大分子药物大多具有更高的特异性和安全性。 通过动脉途径将治疗剂输送到大脑是一种直观的方法，它已经 多年来一直在尝试，但到目前为止，它一直受到变异性的困扰。我们最近展示了实时的 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，标记和成像比小分子容易得多，这提供了一个独特的 更准确地说，这是一个机会。抗体的放射性标记可以通过放射性金属的螯合来执行， 这是一个相对简单的过程，即使是生物学家也可以完成，而且放射性核素可以很容易地运输 来自全国各地，因此不需要现场回旋加速器。我们第一个向大家展示了 抗体放射性标记与动脉内给药融合技术的可行性及观察 这条运输路线带来了令人印象深刻的好处。虽然我们的初步结果相当令人信服，但仍有 为了更好地理解动脉内途径的优势，需要将许多谜题放在一起 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，而且要学习 最大限度地利用这一过程的最佳条件是什么？ 首先，我们将在这里了解脑血管中的抗体浓度是如何影响他们的 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 静脉注射的抗体渗出。这一知识将为 在患者动脉内输液过程中定位导管，就好像高浓度且没有暴露 抗血液抗体是促成因素，那么导管应该放置在脑部相当远的位置。 血管，最大限度地发挥动脉内路线的效益。然后，我们将了解到什么是最佳的浓度 安全地进行手术，同时最大限度地提高大脑对抗体的摄取。而直接号码将适用于 仅对小鼠来说，它还将为临床翻译的考虑提供一个背景。然后，我们将详细研究 通过深入了解抗体向中枢神经系统传递对基本脑过程的潜在影响 转录组学和蛋白质组学，以检测潜在的负面后果，然后作为基础 用来寻找对策。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靶标。这一部分还将允许评估抗体的差异 此外，还将提供有关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.