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Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery.

Abstract：

: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.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Boado RJ,Lu JZ,Hui EK,Lin H,Pardridge WM

doi

10.1038/s41598-019-55136-4

subject

Has Abstract

pub_date

2019-12-09 00:00:00

pages

18632

issue

1

issn

2045-2322

pii

10.1038/s41598-019-55136-4

journal_volume

9

pub_type

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