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J. Biol. Chem., Vol. 279, Issue 38, 39671-39676, September 17, 2004

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PrP^Sc Binding Antibodies Are Potent Inhibitors of Prion Replication in Cell Lines^*

Vincent Beringue, Didier Vilette, Gary Mallinson||, Fabienne Archer¶, Maria Kaisar||, Mourad Tayebi||, Graham S. Jackson||, Anthony R. Clarke||, Hubert Laude, John Collinge||, and Simon Hawke||**

From the Department of Neurogenetics, CNS Infection and Immunity Group, Faculty of Medicine, Imperial College, London W2 1PG, United Kingdom, Unité de Virologie et Immunologie Moléculaires, Institut National de la Recherche Agronomique, 78 352 Jouy en Josas, France, and ^||Medical Research Council, Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom

Conversion of the cellular -helical prion protein (PrP^C) into a disease-associated isoform (PrP^Sc) is central to the pathogenesis of prion diseases. Molecules targeting either normal or disease-associated isoforms may be of therapeutic interest, and the antibodies binding PrP^C have been shown to inhibit prion accumulation in vitro. Here we investigate whether antibodies that additionally target disease-associated isoforms such as PrP^Sc inhibit prion replication in ovine PrP-inducible scrapie-infected Rov cells. We conclude from these experiments that antibodies exclusively binding PrP^C were relatively inefficient inhibitors of ScRov cell PrP^Sc accumulation compared with antibodies that additionally targeted disease-associated PrP isoforms. Although the mechanism by which these monoclonal antibodies inhibit prion replication is unclear, some of the data suggest that antibodies might actively increase PrP^Sc turnover. Thus antibodies that bind to both normal and disease-associated isoforms represent very promising anti-prion agents.

Received for publication, March 1, 2004 , and in revised form, May 6, 2004.

^* This work was supported by grants from the Medical Research Council (London, United Kingdom) and by a Marie Curie Fellowship grant from the European Union. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: UMR754 Rétrovirus et Pathologie Comparée, Institut National de la Recherche Agronomique, 69 366 Lyon, France.

^** Present address. To whom correspondence should be addressed: Brain and Mind Research Institute, University of Sydney, New South Wales 2006, Australia. Tel.: 61263620711; Fax: 61263620129; E-mail: s.hawke{at}imperial.ac.uk.

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