title: Selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species-specific receptor-targeted antibodies.
abstract: Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood-brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb-IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb-IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb-IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein.
authors: Department of Medicine, University of California-Los Angeles, CA 90024, USA.
authors: Qing-Hui
authors: QH
authors: Zhou
authors: Ruben J
authors: RJ
authors: Boado
authors: William M
authors: WM
authors: Pardridge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D016503:Drug Delivery Systems; D007066:Iduronate Sulfatase / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017527:Receptor, IGF Type 2 / Q000276:immunology / Q000378:metabolism; D011972:Receptor, Insulin / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins; D011972:Receptor, Insulin; D007066:Iduronate Sulfatase