Abstract: 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 antiprien potential of recombinant single-chain antibody (scFv) fragments. scFv fragments derived from monoclonal anti-PrP antibody 6114, flagged with c-myc and His(6) 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.

Paracrine inhibition of prion propagation by anti-PrP single-chain Fv miniantibodies / Donofrio, Gaetano; Heppner, Fl; Polymenidou, M; Musahl, C; Aguzzi, A.. - In: JOURNAL OF VIROLOGY. - ISSN 0022-538X. - 79:(2005), pp. 8330-8338. [10.1128/JVI.79.13.8330-8338.2005]

Paracrine inhibition of prion propagation by anti-PrP single-chain Fv miniantibodies

DONOFRIO, Gaetano;
2005-01-01

Abstract

Abstract: 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 antiprien potential of recombinant single-chain antibody (scFv) fragments. scFv fragments derived from monoclonal anti-PrP antibody 6114, flagged with c-myc and His(6) 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.
2005
Paracrine inhibition of prion propagation by anti-PrP single-chain Fv miniantibodies / Donofrio, Gaetano; Heppner, Fl; Polymenidou, M; Musahl, C; Aguzzi, A.. - In: JOURNAL OF VIROLOGY. - ISSN 0022-538X. - 79:(2005), pp. 8330-8338. [10.1128/JVI.79.13.8330-8338.2005]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/1444892
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