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

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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To review the barriers, uptake and clearance mechanisms affecting monoclonal antibody exposure in the CNS and assess methods to enhance their delivery to the brain.

Cargo name and characteristics Monoclonal antibodies (mAbs) — protein biologics with high affinity and specificity for CNS targets; large molecular weight therapeutic antibodies with inherently low brain exposure, discussed in context of strategies to enhance CNS delivery (e.g., receptor-mediated transcytosis, osmotic BBB opening, focused ultrasound, BBB-modulating peptides).

Outcomes and Safety

Summary of Outcomes Monoclonal antibodies exhibit poor CNS exposure due to the blood–brain and blood–CSF barriers and clearance (including glymphatic pathways), and approaches such as receptor-mediated transcytosis, osmotic BBB opening, focused ultrasound, BBB‑modulating peptides, and enhancing mAb brain retention can increase brain delivery though clinical translation has been limited.

Safety-related matter The paper notes potential safety concerns with increasing permeation across CNS barriers when enhancing mAb brain exposure, while also stating that many delivery methods have shown promise in safely facilitating this delivery. However, limited clinical success and few FDA approvals indicate ongoing safety and translational challenges in applying these methods to patients.

Brain Region

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Ultrasound Parameters

Focal Characteristics focal depth: None; focal length: None; aperture size: None

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