title: Imaging amyloid plaque in Alzheimer's disease brain with a biotinylated Aβ peptide radiopharmaceutical conjugated to an IgG-avidin fusion protein.
abstract: The Aβ amyloid peptide of Alzheimer's disease (AD) is a potentially large molecule radiopharmaceutical for imaging the brain amyloid burden, should the peptide be made transportable across the blood-brain barrier (BBB). Peptides can be made BBB-penetrating with the combined use of Trojan horse and avidin-biotin technologies. The peptide is monobiotinylated and attached to a fusion protein of avidin (AV) and a genetically engineered monoclonal antibody (mAb) against the human insulin receptor (HIR). The fusion protein is designated HIRMAb-AV, and is produced by stably transfected mammalian host cells grown in biotin free medium. The HIRMAb domain of the fusion protein acts as a molecular Trojan horse, which crosses the BBB via transport on the endogenous insulin receptor. The avidin domain of the fusion protein creates a high-affinity linker between the HIRMAb and the biotinylated peptide radiopharmaceutical. The 4 kDa Aβ(1-40) amyloid peptide of AD was N-biotinylated and radiolabeled with (125)I. The amyloid plaque binding of the [(125)I]-N-biotinyl-Aβ(1-40) peptide, either without or with conjugation to the HIRMAb-AV fusion protein, was tested with film autoradiography and tissue sections of autopsy AD brain. The study shows the biotinyl-Aβ(1-40) peptide still binds to amyloid plaque in AD brain to the same extent when the peptide radiopharmaceutical is either free or conjugated to the HIRMAb-AV fusion protein. The study supports further evaluation of antibody-targeted peptide radiopharmaceuticals as large molecule neuro-imaging agents that penetrate the BBB.
authors.affiliation: Department of Medicine, University of Califonia Los Angeles , Los Angeles, California 90024, United States.
authors.forename: Rachita K
authors.initials: RK
authors.lastname: Sumbria
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Boado
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry; D001345:Autoradiography; D001360:Avidin / Q000737:chemistry; D019921:Biotinylation; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000737:chemistry; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000473:pathology; D011859:Radiography; D019275:Radiopharmaceuticals / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; C078592:amyloid beta-protein (1-40); D001360:Avidin