Differential Toxicity of Antibodies to the Prion Protein

Regina R. Reimann ,
Contributed equally to this work with: Regina R. Reimann, Tiziana Sonati

Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland


Tiziana Sonati ,
Contributed equally to this work with: Regina R. Reimann, Tiziana Sonati

Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland


Simone Hornemann,
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland


Uli S. Herrmann,
Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland


Michael Arand,
Affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland


Simon Hawke,
Affiliation: Vascular Immunology Laboratory, Department of Pathology, University of Sydney, Camperdown, Australia


Adriano Aguzzi
* E-mail: adriano.aguzzi@usz.ch

Affiliation: Institute of Neuropathology, University of Zurich, Zurich, Switzerland


Differential Toxicity of Antibodies to the Prion Protein
Regina R. Reimann,
Tiziana Sonati,
Simone Hornemann,
Uli S. Herrmann,
Michael Arand,
Simon Hawke,
Adriano Aguzzi
PLOS
x
Published: January 28, 2016
DOI: 10.1371/journal.ppat.1005401


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.


Author Summary

The human prion disease, Creutzfeldt-Jakob disease (CJD), is a progressive neurodegenerative syndrome. Although far less prevalent, CJD shows many molecular and clinical similarities to Alzheimer's disease, such as the buildup of protein aggregates in the brain and the absence of effective treatments. Many attempts at immunotherapy for Alzheimer’s disease are being reported in specialized journals and in the lay press, and have been linked to strong hopes for a cure. The same therapeutic strategy appears plausible for Creutzfeldt-Jakob disease, and indeed, there are some encouraging preclinical studies. However, there have also been reports that antibodies against the prion protein (PrPC) can also wreak damage on the brain. We have gathered evidence that various antiprion antibodies vary not only in their efficacy but also in their potential to induce serious untoward effects. In a dose-escalation study, we report that all antibodies against a set of epitopes in the globular domain of the prion protein display acute neurotoxicity. These issues need to be carefully assessed before considering any clinical studies involving human subjects.





http://journals.plos.org/plospathoge...l.ppat.1005401