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标题：Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery
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作者：Ruben J. Boado ; Jeff Zhiqiang Lu ; Eric Ka-Wai Hui 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2019
卷号：9
期号：1
页码：1-9
DOI：10.1038/s41598-019-55136-4
出版社：Springer Nature
摘要：Most lysosomal storage disorders affect the central nervous system. However, lysosomal enzymes do not cross the blood-brain barrier (BBB), and intravenous enzyme infusion is not effective for the brain. Lysosomal enzymes can be re-engineered for BBB transport as IgG-enzyme fusion proteins, where the IgG domain is a monoclonal antibody (MAb) against an endogenous BBB receptor/transporter, and which acts as a molecular Trojan horse to deliver the enzyme to brain. However, the problem is retention of high enzyme activity following enzyme fusion to the IgG. The present investigation shows this is possible with a versatile approach that employs fusion of the enzyme to either the IgG heavy chain or light chain using a long flexible linker. The model IgG is a chimeric monoclonal antibody (MAb) against the human insulin receptor (HIR). The enzyme activity of the HIRMAb-enzyme fusion protein is preserved for hexosaminidase A, which is mutated in Tay Sachs disease, for protein palmitoylthioesterase-1, which is mutated in Batten disease type 1, acid sphingomyelinase, which is mutated in Niemann Pick disease type A, and beta galactosidase-1, which is mutated in GM1 gangliosidosis.