Enhancing Antibody Exposure in the Central Nervous System: Mechanisms of Uptake, Clearance, and Strategies for Improved Brain Delivery

Abstract

Antibodies (mAbs) are attractive molecules for their application as a diagnostic and therapeutic agent for diseases of the central nervous system (CNS). mAbs can be generated to have high affinity and specificity to target molecules in the CNS. Unfortunately, only a very small number of mAbs have been specifically developed and approved for neurological indications. This is primarily attributed to their low exposure within the CNS, hindering their ability to reach and effectively engage their potential targets in the brain. This review discusses aspects of various barriers such as the blood–brain barrier (BBB) and blood–cerebrospinal fluid (CSF) barrier (BCSFB) that regulate the entry and clearance of mAbs into and from the brain. The roles of the glymphatic system on brain exposure and clearance are being described. We also discuss the proposed mechanisms of the uptake of mAbs into the brain and for clearance. Finally, several methods of enhancing the exposure of mAbs in the CNS were discussed, including receptor-mediated transcytosis, osmotic BBB opening, focused ultrasound (FUS), BBB-modulating peptides, and enhancement of mAb brain retention.

Exploring How Antibody Format Drives Clearance from the Brain

“…11 Moreover, mAbs have been found to clear quickly from the CNS, posing a significant challenge in developing diagnostic and therapeutic agents for neurological disorders. 11 Most research efforts focus on improving antibody penetration across the BBB to enhance CNS exposure. 33 However, there has been limited exploration of the potential benefits of enhancing retention as a strategy to increase exposure.…”

“…Developing effective treatments for neurological disorders requires a comprehensive understanding of the complex mechanisms behind antibody elimination from the brain . Moreover, mAbs have been found to clear quickly from the CNS, posing a significant challenge in developing diagnostic and therapeutic agents for neurological disorders . Most research efforts focus on improving antibody penetration across the BBB to enhance CNS exposure .…”

“…A key challenge in developing monoclonal antibodies (mAbs) for CNS disorders is their limited exposure within the CNS. When administered peripherally, the CNS-to-plasma or serum AUC ratios have been reported at a range of 0.075–0.35%. − Additionally, mAbs experience rapid clearance through the glymphatic drain following direct delivery to the CNS, with half-lives on the order of minutes to hours. − These limitations present significant hurdles to developing effective antibody-based treatments for CNS disorders.…”