Genetic engineering of IgG-glucuronidase fusion proteins

Abstract

β-Glucuronidase (GUSB) is a lysosomal enzyme that could be developed as a brain therapy for Type VII Mucopolysaccharidosis. However, GUSB does not cross the blood–brain barrier (BBB). To enable BBB transport of the enzyme, human GUSB was re-engineered as a fusion protein with the chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb crosses the BBB on the endogenous insulin receptor, and acts as a molecular Trojan horse to ferry into brain the GUSB. The 611 amino acid GUSB was fused to either the carboxyl or amino terminus of the heavy chain of the HIRMAb. This study illustrates the differential retention of functionality of IgG-enzyme fusion proteins depending on how the fusion protein is engineered.

Keywords::

• Blood–brain barrier
• drug targeting
• monoclonal antibody
• lysosomal enzyme

Acknowledgements

This work was supported by NIH grant R44-HD052303. Drs. Yun Zhang and Yufeng Zhang, and Winnie Tai provided technical support.

Declaration of interest

Dr. Boado is an employee/shareholder and Dr. Pardridge is a consultant/shareholder of ArmaGen Technologies, Inc.