title: Antibodies inhibit prion propagation and clear cell cultures of prion infectivity.
abstract: Prions are the transmissible pathogenic agents responsible for diseases such as scrapie and bovine spongiform encephalopathy. In the favoured model of prion replication, direct interaction between the pathogenic prion protein (PrPSc) template and endogenous cellular prion protein (PrPC) is proposed to drive the formation of nascent infectious prions. Reagents specifically binding either prion-protein conformer may interrupt prion production by inhibiting this interaction. We examined the ability of several recombinant antibody antigen-binding fragments (Fabs) to inhibit prion propagation in cultured mouse neuroblastoma cells (ScN2a) infected with PrPSc. Here we show that antibodies binding cell-surface PrPC inhibit PrPSc formation in a dose-dependent manner. In cells treated with the most potent antibody, Fab D18, prion replication is abolished and pre-existing PrPSc is rapidly cleared, suggesting that this antibody may cure established infection. The potent activity of Fab D18 is associated with its ability to better recognize the total population of PrPC molecules on the cell surface, and with the location of its epitope on PrPC. Our observations support the use of antibodies in the prevention and treatment of prion diseases and identify a region of PrPC for drug targeting.
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143-0518, USA.
authors.forename: D
authors.initials: D
authors.lastname: Peretz
authors.forename: R A
authors.initials: RA
authors.lastname: Williamson
authors.forename: K
authors.initials: K
authors.lastname: Kaneko
authors.forename: J
authors.initials: J
authors.lastname: Vergara
authors.forename: E
authors.initials: E
authors.lastname: Leclerc
authors.forename: G
authors.initials: G
authors.lastname: Schmitt-Ulms
authors.forename: I R
authors.initials: IR
authors.lastname: Mehlhorn
authors.forename: G
authors.initials: G
authors.lastname: Legname
authors.forename: M R
authors.initials: MR
authors.lastname: Wormald
authors.forename: P M
authors.initials: PM
authors.lastname: Rudd
authors.forename: R A
authors.initials: RA
authors.lastname: Dwek
authors.forename: D R
authors.initials: DR
authors.lastname: Burton
authors.forename: S B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001681:Biological Assay; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D004926:Escherichia coli; D007128:Immunoglobulin Fragments / Q000276:immunology*; D051379:Mice; D018621:PrPC Proteins / Q000276:immunology; D011328:Prions / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
chemical_list: D018985:Epitopes, B-Lymphocyte; D007128:Immunoglobulin Fragments; D018621:PrPC Proteins; D011328:Prions; D011994:Recombinant Proteins