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J. Biol. Chem., Vol. 280, Issue 12, 11247-11258, March 25, 2005

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Screening of 145 Anti-PrP Monoclonal Antibodies for Their Capacity to Inhibit PrPSc Replication in Infected Cells^*

Cécile Féraudet, Nathalie Morel, Stéphanie Simon, Hervé Volland, Yveline Frobert, Christophe Créminon, Didier Vilette, Sylvain Lehmann¶, and Jacques Grassi||

From the Commissariat à l'Energie Atomique (CEA), Service de Pharmacologie et d'Immunologie, CEA/Saclay, 91191 Gif sur Yvette, France, Institut National de la Recherche Agronomique, Virologie Immunologie Moléculaire, 78350 Jouy en Josas, France, and ^¶CNRS, Biologie des Encéphalopathies Spongiformes Transmissibles, 34396 Montpellier cedex 5, France

Prion diseases are transmissible neurodegenerative disorders affecting humans and animals for which no therapeutic or prophylactic regimens exist. During the last three years several studies have shown that anti-PrP monoclonal antibodies (mAbs) can antagonize prion propagation in vitro and in vivo, but the mechanisms of inhibition are not known so far. To identify the most powerful mAbs and characterize more precisely the therapeutic effect of anti-PrP antibodies, we have screened 145 different mAbs produced in our laboratory for their capacity to cure cells constitutively expressing PrPSc. Our results confirm for a very large series of antibodies that mAbs recognizing cell-surface native PrPc can efficiently clean and definitively cure infected cells. Antibodies having a cleaning effect are directed against linear epitopes located in at least four different regions of PrP, suggesting an epitope-independent inhibition mechanism. The consequence of antibody binding is the sequestration of PrPc at the cell surface, an increase of PrPc levels recovered in cell culture medium, and an internalization of antibodies. Taken together these data suggest that the cleaning process is more likely due to a global effect on the PrP trafficking and/or transconformation process. Two antibodies, Sha31 and BAR236, show an IC₅₀ of 0.6 nM, thus appearing 10-fold more efficient than previous antibodies described in the literature. Finally, five co-treatments were also tested, and only one of them, described previously (SAF34 + SAF61), lowered PrPSc levels in the cells synergistically.

Received for publication, June 23, 2004 , and in revised form, November 22, 2004.

^* 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.

^|| To whom correspondence should be addressed. Tel.: 33-1-69-08-28-71; Fax: 33-1-69-08-59-07; E-mail: jacques.grassi{at}cea.fr.

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