Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery
Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery
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DOI：
10.1038/s41598-019-55136-4
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发表时间：
2019-12-09
影响因子：
4.6
通讯作者：
Pardridge, William M.
中科院分区：
文献类型：
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作者：
Boado, Ruben J.;Lu, Jeff Zhiqiang;Pardridge, William M.
大多数溶酶体贮积紊乱影响中枢神经系统。然而，溶酶体酶不能穿过血脑屏障（BBB），静脉输注酶对大脑无效。溶酶体酶可以作为IgG-酶融合蛋白重新设计用于血脑屏障运输，其中IgG结构域是针对内源性血脑屏障受体/转运体的单克隆抗体（MAb），并作为分子特洛伊木马将酶运送到大脑。然而，问题是在酶与IgG融合后保留高酶活性。目前的研究表明，这是可能的与一个通用的方法，采用融合酶的IgG重链或轻链使用一个长柔性连接。模型IgG是一种针对人胰岛素受体（HIR）的嵌合单克隆抗体（MAb）。hirmab -酶融合蛋白的酶活性在Tay Sachs病中突变的己糖氨酸酶A、在Batten病1型中突变的棕榈酰硫酯酶1、在Niemann Pick病A型中突变的酸性鞘磷脂酶和在GM1神经节脂质病中突变的β -半乳糖苷酶1中保持不变。
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.