Differential Toxicity of Antibodies to the Prion Protein

PLoS Pathog. 2016 Jan 28;12(1):e1005401. doi: 10.1371/journal.ppat.1005401. eCollection 2016 Jan.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / toxicity*
  • Brain / drug effects
  • Brain / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epitopes, B-Lymphocyte / immunology
  • Immunohistochemistry
  • Immunotherapy / methods*
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PrPC Proteins / immunology*
  • Prion Diseases / immunology*
  • Prion Diseases / pathology

Substances

  • Antibodies, Monoclonal
  • Epitopes, B-Lymphocyte
  • PrPC Proteins

Grant support

AA is a recipient of an Advanced Grant of the European Research Council (ERC: 670958 http://erc.europa.eu/advanced-grants) and is supported by a grant from the European Union (E-rare program: 160672 http://www.erare.eu/) and the Swiss National Foundation (SNF: 160329), the Clinical Research Priority Programs “Small RNAs” and “Human Hemato-Lymphatic Diseases”, SystemsX.ch, the Novartis Research Foundation, and the National Organization for Rare Disorders. RRR is supported by a Career Development Award from the Stavros Niarchos Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.