NR AXME
AU Feraudet,C.; Andreoletti,O.; Morel,N.; Chouaf-Lakhdar,L.; Mathey,J.; Simon,S.; Lacroux,C.; Vollad,H.; Lamourette,P.; Betemps,D.; Frobert,Y.; Torres,J.M.; Creminon,C.; Baron,T.G.M.; Grassi,J.
TI Immunotherapeutic Effect of Anti-PrP Monoclonal Antibodies on TSE Mouse Models: Pharmacodynamic and Pharmacokinetic Analysis
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Oral Abstracts FC3.8
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Vortrag
AB Prion diseases are transmissible neurodegenerative disorders for which no curative or palliative therapeutic exist. Passive immunization with antibodies directed against the cellular form of the prion protein (PrPc) has been shown to delay the onset of disease after peripheral contamination. However, mechanisms and parameters determining their in vivo efficacy remain unknown. Here, we have characterized the main lines of the pharmacokinetic properties of anti-PrP antibodies in different prion mouse models expressing various levels of PrPc (Prnp0/0, C57BL/6, Tga20 and Tg338 mice) in relation with therapeutic effect, as assessed by incubation duration and delay in PrPsc accumulation process. We have shown that treatment efficacy after peripheral inoculation is correlated to the ability of antibodies to form stable and long-lasting complexes with endogenous plasmatic PrPc, reminiscent of a PrP-Fc2 like molecule. Pharmacokinetic investigations of these circulating PrPc/anti-PrP antibody complexes allowed us to substantially optimize passive immunization efficacy in various mouse models of prion diseases. We also identified that in vivo treatment with anti-PrP antibodies specifically induced a dramatic increase in total plasmatic PrPc (up to 100 fold), proportional to therapeutic efficacy. This increase was demonstrated to be linked to a mobilisation of PrPc from peripheral tissues: this phenomenon was accompanied by a modification of PrP metabolism and PrP expression level in key cellular target of the prion peripheral replication. This event could partly explain the therapeutic action of anti-PrP antibodies. Finally, our work allowed us to define better the main characteristics of anti-PrP mAbs associated with therapeutic efficacy and factors determining the issue of the treatment. This study will be a useful guide in designing optimized therapy for prion diseases.
AD C. Feraudet, J. Mathey, C. Lacroux, INRA (UMR INRA/ENVT 1225), Service de Pathologie du Bétail, France; O. Andreoletti, N. Morel, S. Simon, H. Vollad, P. Lamourette, Y. Frobert, C. Creminon, J. Grassi, CEA Saclay, DSV/iBiTec-S/SPI, France; L. Chouaf-Lakhdar, D. Betemps, T. Baron, AFSSA Lyon, Unité ATNC, France; J.M. Torres, INIA, Spain
SP englisch
PO Schottland