Blood-brain barrier delivery for lysosomal storage disorders with IgG-lysosomal enzyme fusion proteins
- PMID: 35307484
- DOI: 10.1016/j.addr.2022.114234
Blood-brain barrier delivery for lysosomal storage disorders with IgG-lysosomal enzyme fusion proteins
Abstract
The majority of lysosomal storage diseases affect the brain. Treatment of the brain with intravenous enzyme replacement therapy is not successful, because the recombinant lysosomal enzymes do not cross the blood-brain barrier (BBB). Biologic drugs, including lysosomal enzymes, can be re-engineered for BBB delivery as IgG-enzyme fusion proteins. The IgG domain of the fusion protein is a monoclonal antibody directed against an endogenous receptor-mediated transporter at the BBB, such as the insulin receptor or the transferrin receptor. This receptor transports the IgG across the BBB, in parallel with the endogenous receptor ligand, and the IgG acts as a molecular Trojan horse to ferry into brain the lysosomal enzyme genetically fused to the IgG. The IgG-enzyme fusion protein is bi-functional and retains both high affinity binding for the BBB receptor, and high lysosomal enzyme activity. IgG-lysosomal enzymes are presently in clinical trials for treatment of the brain in Mucopolysaccharidosis.
Keywords: Cerebrospinal fluid; Drug targeting; Endothelium; Fusion proteins; Mathematical model; Receptor-mediated transport.
Copyright © 2022 The Author. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Similar articles
-
Blood-brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody.Expert Opin Drug Deliv. 2015 Feb;12(2):207-22. doi: 10.1517/17425247.2014.952627. Epub 2014 Aug 20. Expert Opin Drug Deliv. 2015. PMID: 25138991 Review.
-
Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery.Sci Rep. 2019 Dec 9;9(1):18632. doi: 10.1038/s41598-019-55136-4. Sci Rep. 2019. PMID: 31819150 Free PMC article.
-
Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells.Mol Pharm. 2014 Aug 4;11(8):2928-34. doi: 10.1021/mp500258p. Epub 2014 Jun 26. Mol Pharm. 2014. PMID: 24949884 Free PMC article.
-
Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier.Methods Enzymol. 2012;503:269-92. doi: 10.1016/B978-0-12-396962-0.00011-2. Methods Enzymol. 2012. PMID: 22230573 Review.
-
Insulin Receptor Antibody-α-N-Acetylglucosaminidase Fusion Protein Penetrates the Primate Blood-Brain Barrier and Reduces Glycosoaminoglycans in Sanfilippo Type B Fibroblasts.Mol Pharm. 2016 Apr 4;13(4):1385-92. doi: 10.1021/acs.molpharmaceut.6b00037. Epub 2016 Mar 2. Mol Pharm. 2016. PMID: 26910785
Cited by
-
A Historical Review of Brain Drug Delivery.Pharmaceutics. 2022 Jun 16;14(6):1283. doi: 10.3390/pharmaceutics14061283. Pharmaceutics. 2022. PMID: 35745855 Free PMC article. Review.
-
Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier.Front Drug Deliv. 2023;3:1227816. doi: 10.3389/fddev.2023.1227816. Epub 2023 Jul 10. Front Drug Deliv. 2023. PMID: 37583474 Free PMC article.
-
Polymer-based drug delivery systems under investigation for enzyme replacement and other therapies of lysosomal storage disorders.Adv Drug Deliv Rev. 2023 Jun;197:114683. doi: 10.1016/j.addr.2022.114683. Epub 2023 Jan 16. Adv Drug Deliv Rev. 2023. PMID: 36657645 Free PMC article. Review.
-
Therapeutic potential of lysosomal cathepsins for neurodegenerative diseases.Neural Regen Res. 2023 Aug;18(8):1713-1714. doi: 10.4103/1673-5374.363181. Neural Regen Res. 2023. PMID: 36751788 Free PMC article. No abstract available.
-
Neurological glycogen storage diseases and emerging therapeutics.Neurotherapeutics. 2024 Sep;21(5):e00446. doi: 10.1016/j.neurot.2024.e00446. Epub 2024 Sep 14. Neurotherapeutics. 2024. PMID: 39277505 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
