NR AWCT
AU Campana,V.; Legname,G.T.; Prusiner,S.; Zurzolo,C.
TI Mono and bi-functional antibodies as therapeutics for prion diseases
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions THE-03
PT Konferenz-Poster
AB Prions are the infectious proteinaceous agents of Transmissible Spongiform Encephalopathies (TSEs) or prion diseases. According to the protein-only theory, prions propagate by recruiting and converting the cellular prion protein (PrPc) to the disease causing isoform (PrPscor scrapie). No effective therapies exist at present for these fatal diseases. Although several reports have shown that both antibodies and Fab fragments against PrPc are able to cure scrapie-infected cells, their effectiveness in prion disease therapy in vivo has not yet been evaluated because passage of antibodies to the brain through the blood brain barrier (BBB) is prevented. In order to overcome this problem, monoclonal antibodies against transcytotic receptors present at the BBB have been used to deliver different therapeutic molecules into the brain by exploiting their transcytotic pathway. Therefore, in order to test the potential of the anti-prion antibody D18 in passive immunotherapy as a therapeutic intervention in TSEs, we have produced both monofunctional (scFv) and bifunctional (diabody) versions of the anti-PrP D18 Fab. Our studies suggest that D18 scFv might be directly used in TSE therapy in vivo because its dimensions could allow a faster and more efficient spreading of the molecule in the brain after i.c. injection and even a passage into the brain after nasal administration. Addionally, we have also produced a small chimeric antibody (or diabody) containing both anti-PrP and anti-transferrin receptor specificities that should be able to cross the BBB via this transcytotic pathway. We have shown that some of these molecules are able to bind recombinant PrP and PrPc from mouse brain homogenate and reduce PrPsc levels in scrapie-infected GT1 cells. We are currently evaluating their potential therapeutic effect after intracerebral and peripheral administration in prioninfected mice.
AD V. Campana, C. Zurzolo: Unité postulante de Trafic Membranaire et Pathogenese, Institut Pasteur, Paris France, and Dipartimento di Biologia e Patologia Cellulare e Molecolare Univesità Federico II, Napoli, Italy; G. Legname, S.B. Prusiner: Institute for Neurodegenerative Diseases UCSF, San Francisco, CA, USA
SP englisch
PO Italien