title: Immunotherapeutic effect of anti-PrP monoclonal antibodies in transmissible spongiform encephalopathy mouse models: pharmacokinetic and pharmacodynamic analysis.
abstract: Prion diseases are transmissible neurodegenerative disorders for which no therapeutic or prophylactic regimens exist. Passive immunization with appropriate antibodies directed against the cellular form of the prion protein (PrPC) can delay the onset of prion disease after peripheral infection, but mechanisms and parameters determining their in vivo efficacy remain unknown. In the present study, we characterized the main pharmacokinetic properties of anti-PrP antibodies in different mouse models expressing various levels of PrPC (Prnp(0/0), C57BL/6 and tga20 mice) in correlation with therapeutic effect. Plasma levels of free antibodies, total endogenous PrPC and PrPC-antibody complexes were monitored after a single intraperitoneal monoclonal antibody (mAb) injection. Efficacy in delaying PrPSc peripheral accumulation seemed to be associated with mAb capacity to form long-lasting complexes with endogenous PrPC in the plasma. In agreement with previous observations on cellular models of transmissible spongiform encephalopathy infection, we observed that injection of anti-PrP antibodies induced a large (up to 100-fold) increase in circulating PrPC. Finally, the most efficient antibody extended the lifespan of infected animals greatly. These results allowed us to define critical characteristics of anti-PrP mAbs associated with therapeutic efficacy and could constitute a useful reference for designing optimized passive immunotherapies for prion diseases.
authors.affiliation: UMR INRA/ENVT 1225, Interactions Hôte-Agent Pathogène, Ecole Nationale Vétérinaire, 23 chemin des Capelles, 31076 Toulouse, France. cecile.feraudet-tarisse@cea.fr
authors.forename: Cécile
authors.initials: C
authors.lastname: Féraudet-Tarisse
authors.forename: Olivier
authors.initials: O
authors.lastname: Andréoletti
authors.forename: Nathalie
authors.initials: N
authors.lastname: Morel
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Simon
authors.forename: Caroline
authors.initials: C
authors.lastname: Lacroux
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Mathey
authors.forename: Patricia
authors.initials: P
authors.lastname: Lamourette
authors.forename: Aroa
authors.initials: A
authors.lastname: Relaño
authors.forename: Juan Maria
authors.initials: JM
authors.lastname: Torres
authors.forename: Christophe
authors.initials: C
authors.lastname: Créminon
authors.forename: Jacques
authors.initials: J
authors.lastname: Grassi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D000936:Antigen-Antibody Complex / Q000097:blood; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018621:PrPC Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D017096:Prion Diseases / Q000628:therapy*; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D018621:PrPC Proteins