Immunotherapeutic effect of anti-PrP monoclonal antibodies in transmissible spongiform encephalopathy mouse models: pharmacokinetic and pharmacodynamic analysis.
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.
Féraudet-Tarisse
Cécile
C
UMR INRA/ENVT 1225, Interactions Hôte-Agent Pathogène, Ecole Nationale Vétérinaire, 23 chemin des Capelles, 31076 Toulouse, France. cecile.feraudet-tarisse@cea.fr
Andréoletti
Olivier
O
Morel
Nathalie
N
Simon
Stéphanie
S
Lacroux
Caroline
C
Mathey
Jacinthe
J
Lamourette
Patricia
P
Relaño
Aroa
A
Torres
Juan Maria
JM
Créminon
Christophe
C
Grassi
Jacques
J
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
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D018621:PrPC Proteins