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

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.