title: Differential Toxicity of Antibodies to the Prion Protein.
abstract: Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.
authors.affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
authors.forename: Regina R
authors.initials: RR
authors.lastname: Reimann
authors.affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sonati
authors.affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
authors.forename: Uli S
authors.initials: US
authors.lastname: Herrmann
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Arand
authors.affiliation: Vascular Immunology Laboratory, Department of Pathology, University of Sydney, Camperdown, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Hawke
authors.affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018621:PrPC Proteins / Q000276:immunology*; D017096:Prion Diseases / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D018985:Epitopes, B-Lymphocyte; D018621:PrPC Proteins
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