title: Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor.
abstract: 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.
authors: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA.
authors: Ruben J
authors: RJ
authors: Boado
authors: Eric Ka-Wai
authors: EK
authors: Hui
authors: Jeff Zhiqiang
authors: JZ
authors: Lu
authors: William M
authors: WM
authors: Pardridge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000633:toxicity; D001786:Blood Glucose / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D056947:Enzyme Replacement Therapy; D005260:Female; D005947:Glucose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D007068:Iduronidase / Q000008:administration & dosage* / Q000633:toxicity; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D008059:Mucopolysaccharidosis I / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000633:toxicity; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D011993:Recombinant Fusion Proteins; D011972:Receptor, Insulin; D007068:Iduronidase; D005947:Glucose; C546866:valanafusp alpha