Anti-PrP Mab 6D11 suppresses PrP(Sc) replication in prion infected myeloid precursor line FDC-P1/22L and in the lymphoreticular system in vivo.
The pathogenesis of prion diseases is related to conformational transformation of cellular prion protein (PrP(C)) into a toxic, infectious, and self-replicating conformer termed PrP(Sc). Following extracerebral inoculation, the replication of PrP(Sc) is confined for months to years to the lymporeticular system (LRS) before the secondary CNS involvement results in occurrence of neurological symptoms. Therefore, replication of PrP(Sc), in the early stage of infection can be targeted by therapeutic approaches, which like passive immunization have limited blood-brain-barrier penetration. In this study, we show that 6D11 anti-PrP monoclonal antibody (Mab) prevents infection on a FDC-P1 myeloid precursor cell line stably infected with 22L mouse adapted scrapie strain. Passive immunization of extracerebrally infected CD-1 mice with Mab 6D11 resulted in effective suppression of PrP(Sc) replication in the LRS. Although, a rebound of PrP(Sc) presence occurred when the Mab 6D11 treatment was stopped, passively immunized mice showed a prolongation of the incubation period by 36.9% (pb0.0001) and a significant decrease in CNS pathology compared to control groups receiving vehicle or murine IgG. Our results indicate that antibody-based therapeutic strategies can be used, even on a short-term basis, to delay or prevent disease in subjects accidentally exposed to prions.
Sadowski
Martin J
MJ
Department of Neurology, New York University School of Medicine, NY 10016, USA. sadowm01@med.nyu.edu
Pankiewicz
Joanna
J
Prelli
Frances
F
Scholtzova
Henrieta
H
Spinner
Daryl S
DS
Kascsak
Regina B
RB
Kascsak
Richard J
RJ
Wisniewski
Thomas
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D008208:Lymphatic System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017096:Prion Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D012608:Scrapie / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D018620:PrPSc Proteins