RT Journal Article
SR Electronic
T1 Glycemic Control and Chronic Dosing of Rhesus Monkeys with a Fusion Protein of Iduronidase and a Monoclonal Antibody Against the Human Insulin Receptor
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2021
OP 2025
DO 10.1124/dmd.112.046375
VO 40
IS 10
A1 Ruben J. Boado
A1 Eric Ka-Wai Hui
A1 Jeff Zhiqiang Lu
A1 William M. Pardridge
YR 2012
UL http://dmd.aspetjournals.org/content/40/10/2021.abstract
AB Hurler's syndrome, or mucopolysaccharidosis type I, is a lysosomal storage disorder caused by mutations in the gene encoding the lysosomal enzyme iduronidase (IDUA). The disease affects both peripheral tissues and the central nervous system (CNS). Recombinant IDUA treatment does not affect the CNS, because IDUA does not cross the blood-brain barrier (BBB). To enable BBB penetration, human IDUA was re-engineered as an IgG-IDUA fusion protein, where the IgG domain is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb penetrates the brain from the blood via transport on the endogenous BBB insulin receptor and acts as a molecular Trojan horse to deliver the fused IDUA to the brain. Before human testing, the HIRMAb-IDUA fusion protein was evaluated in a 6-month weekly dosing toxicology study at doses of 0, 3, 9, and 30 mg/kg/week of the fusion protein administered to 40 rhesus monkeys. The focus of the present study is the effect of chronic high dose administration of this fusion protein on plasma glucose and long-term glycemic control. The results show that the HIRMAb has weak insulin agonist activity and causes hypoglycemia at the high dose, 30 mg/kg, after intravenous infusion in normal saline. When dextrose is added to the saline infusion solution, no hypoglycemia is observed at any dose. An intravenous glucose tolerance test performed at the end of the 6 months of chronic treatment showed no change in glucose tolerance at any dose of the HIRMAb-IDUA fusion protein.