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Journal of Virology, July 2005, p. 8330-8338, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8330-8338.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Paracrine Inhibition of Prion Propagation by Anti-PrP Single-Chain Fv Miniantibodies

Gaetano Donofrio ,{dagger},{ddagger} Frank L. Heppner,{ddagger} Magdalini Polymenidou, Christine Musahl,§ and Adriano Aguzzi*

Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland

Received 5 February 2005/ Accepted 3 March 2005

Prion diseases are characterized by the deposition of PrPSc, an abnormal form of the cellular prion protein PrPC. A growing body of evidence suggests that antibodies to PrPC can antagonize deposition of PrPSc. However, host tolerance hampers the induction of immune responses to PrPC, and cross-linking of PrPC by bivalent anti-PrP antibodies is neurotoxic. In order to obviate these problems, we explored the antiprion potential of recombinant single-chain antibody (scFv) fragments. scFv fragments derived from monoclonal anti-PrP antibody 6H4, flagged with c-myc and His6 tags, were correctly processed and secreted by mammalian RD-4 rhabdomyosarcoma cells. When cocultured with cells secreting anti-PrP scFv, chronically prion-infected neuroblastoma cells ceased to produce PrPSc, even if antibody-producing cells were physically separated from target cells in transwell cultures. Expression of scFv with irrelevant specificity, or of similarly tagged molecules, was not curative. Therefore, eukaryotically expressed scFv exerts a paracrine antiprion activity. The effector functions encoded by immunoglobulin constant domains are unnecessary for this effect. Because of their small size and their monovalent binding, scFv fragments may represent candidates for gene transfer-based immunotherapy of prion diseases.

* Corresponding author. Mailing address: University Hospital Zurich, Institute of Neuropathology, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland. Phone: 41-1-255 2107. Fax: 41-1-255 4402. E-mail: adriano{at}pathol.unizh.ch.

{dagger} Present address: Dipartimento di Salute Animale, Sezione di Malattie Infettive degli Animali, Via del Taglio 8, I-43100 Parma, Italy.

{ddagger} G.D. and F.L.H. contributed equally.

§ Present address: Prionics AG, Wagistr. 27a, CH-8952 Schlieren, Switzerland.

Journal of Virology, July 2005, p. 8330-8338, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8330-8338.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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