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

Overview

Journal J Nanotheranostics

Publisher MDPI

Date 2025 Feb 3

PMID 39897432

Authors

Kelly Schwinghamer

Teruna J Siahaan

Affiliations

Soon will be listed here.

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.

References

Ineichen B, Plattner P, Good N, Martin R, Linnebank M, Schwab M . Nogo-A Antibodies for Progressive Multiple Sclerosis. CNS Drugs. 2017; 31(3):187-198. DOI: 10.1007/s40263-017-0407-2. View

On N, Kiptoo P, Siahaan T, Miller D . Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide. Mol Pharm. 2014; 11(3):974-81. PMC: 3993937. DOI: 10.1021/mp400624v. View

Kemshead J, Hopkins K, Pizer B, Papanastassiou V, Coakham H, Bullimore J . Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies. Br J Cancer. 1998; 77(12):2324-30. PMC: 2150406. DOI: 10.1038/bjc.1998.386. View

Friden P, Walus L, Musso G, Taylor M, Malfroy B, Starzyk R . Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci U S A. 1991; 88(11):4771-5. PMC: 51748. DOI: 10.1073/pnas.88.11.4771. View

Busatto S, Morad G, Guo P, Moses M . The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier. FASEB Bioadv. 2021; 3(9):665-675. PMC: 8409556. DOI: 10.1096/fba.2021-00045. View

Pizzo M, Wolak D, Kumar N, Brunette E, Brunnquell C, Hannocks M . Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery. J Physiol. 2017; 596(3):445-475. PMC: 5792566. DOI: 10.1113/JP275105. View

Niewoehner J, Bohrmann B, Collin L, Urich E, Sade H, Maier P . Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014; 81(1):49-60. DOI: 10.1016/j.neuron.2013.10.061. View

Spector R, Keep R, Snodgrass S, Smith Q, Johanson C . A balanced view of choroid plexus structure and function: Focus on adult humans. Exp Neurol. 2015; 267:78-86. DOI: 10.1016/j.expneurol.2015.02.032. View

Ulapane K, Kopec B, Siahaan T . Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides. Pharmaceutics. 2019; 11(11). PMC: 6920923. DOI: 10.3390/pharmaceutics11110568. View

10.

Sinaga E, Jois S, Avery M, Makagiansar I, Tambunan U, Audus K . Increasing paracellular porosity by E-cadherin peptides: discovery of bulge and groove regions in the EC1-domain of E-cadherin. Pharm Res. 2002; 19(8):1170-9. DOI: 10.1023/a:1019850226631. View

11.

Agbandje-Mckenna M, Kleinschmidt J . AAV capsid structure and cell interactions. Methods Mol Biol. 2011; 807:47-92. DOI: 10.1007/978-1-61779-370-7_3. View

12.

Rapoport S . Effect of concentrated solutions on blood-brain barrier. Am J Physiol. 1970; 219(1):270-4. DOI: 10.1152/ajplegacy.1970.219.1.270. View

13.

Friden P, Walus L, Watson P, Doctrow S, Kozarich J, Backman C . Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science. 1993; 259(5093):373-7. DOI: 10.1126/science.8420006. View

14.

Pardridge W . Blood-brain barrier delivery. Drug Discov Today. 2007; 12(1-2):54-61. DOI: 10.1016/j.drudis.2006.10.013. View

15.

Chang H, Morrow K, Bonacquisti E, Zhang W, Shah D . Antibody pharmacokinetics in rat brain determined using microdialysis. MAbs. 2018; 10(6):843-853. PMC: 6260134. DOI: 10.1080/19420862.2018.1473910. View

16.

Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T . Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008; 28(27):6787-93. PMC: 6670967. DOI: 10.1523/JNEUROSCI.2377-07.2008. View

17.

Lossinsky A, Vorbrodt A, Wisniewski H . Scanning and transmission electron microscopic studies of microvascular pathology in the osmotically impaired blood-brain barrier. J Neurocytol. 1995; 24(10):795-806. DOI: 10.1007/BF01191215. View

18.

Ruggieri S, Tortorella C, Gasperini C . Anti lingo 1 (opicinumab) a new monoclonal antibody tested in relapsing remitting multiple sclerosis. Expert Rev Neurother. 2017; 17(11):1081-1089. DOI: 10.1080/14737175.2017.1378098. View

19.

Mayhan W, Heistad D . Permeability of blood-brain barrier to various sized molecules. Am J Physiol. 1985; 248(5 Pt 2):H712-8. DOI: 10.1152/ajpheart.1985.248.5.H712. View

20.

Yang L, Kress B, Weber H, Thiyagarajan M, Wang B, Deane R . Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J Transl Med. 2013; 11:107. PMC: 3665671. DOI: 10.1186/1479-5876-11-107. View