title: AGT-181: expression in CHO cells and pharmacokinetics, safety, and plasma iduronidase enzyme activity in Rhesus monkeys.
abstract: Enzyme replacement therapy is not effective for the brain, owing to the lack of transport of the enzyme across the blood-brain barrier (BBB). Recombinant proteins such as the lysosomal enzyme, iduronidase, can penetrate the human BBB, following the re-engineering of the protein as an IgG fusion protein, where the IgG moiety targets an endogenous BBB transport system. The IgG acts as a molecular Trojan horse to ferry the fused protein into brain. AGT-181 is a genetically engineered fusion protein of human iduronidase and a chimeric monoclonal antibody against the human insulin receptor. Adult Rhesus monkeys were administered repeat intravenous doses of AGT-181 ranging from 0.2 to 20 mg/kg. Chronic AGT-181 dosing resulted in no toxicity at any dose, no changes in organ histology, no change in plasma or cerebrospinal fluid glucose, and no significant immune response. AGT-181 was rapidly removed from plasma, based on measurements of either plasma immunoreactive AGT-181 or plasma iduronidase enzyme activity. Plasma pharmacokinetics analysis showed a high systemic volume of distribution, and a clearance rate comparable to a small molecule. The safety pharmacology studies provide the basis for future drug development of AGT-181 as a new therapeutic approach to treatment of the brain in Hurler's syndrome.
authors.affiliation: ArmaGen Technologies Inc, Santa Monica, CA 90401, USA.
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Boado
authors.forename: Eric K-W
authors.initials: EK
authors.lastname: Hui
authors.forename: Jeff Zhiqiang
authors.initials: JZ
authors.lastname: Lu
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000134:cerebrospinal fluid; D006801:Humans; D007068:Iduronidase / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta / Q000097:blood* / Q000378:metabolism*; D011972:Receptor, Insulin / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; 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