Immunotherapy to ameliorate neurodegeneration by targeting brain protein aggregates with antibodies is an area of intense investigation. A study published on January 28th in PLOS Pathogens examines seemingly contradictory earlier results of targeting the prion protein and proposes a cautionary way forward to further test related therapeutic approaches.
Damaging aggregation of proteins in the brain is a hallmark of several neurodegenerative diseases, including Alzheimer and Parkinson diseases. In prion diseases such as Creutzfeld-Jakob disease, aggregates of abnormally folded versions of the PrP protein cause the death of brain cells. The use of anti-PrP antibodies to target such aggregates and mediate their destruction by the immune system has been proposed as a therapy, with the caveat that such antibodies could themselves be toxic.
Prompted by the publication of seemingly contradictory reports on the potential neurotoxicity of antibodies against the prion protein in mice, Adriano Aguzzi from the University of Zurich, Switzerland, and colleagues set out to rigorously test several antibodies side-by-side. The researchers examined whether toxicity was influenced by where and how the antibodies were delivered into the brain, the antibody dose, which area on the PrP protein the antibodies bind to, and the genetic background of the mice.
For several of the antibodies, they found, toxicity depended strictly on the administered dose, results that could explain some of the seemingly different earlier results. Other factors tested, including which target regions (or epitopes) on the PrP protein the antibodies bound to, also seemed to affect the toxicity of at least some antibodies.
Because the researchers observed toxicity for most of the antibodies that bind to the so-called globular region of PrP, they conclude that such antibodies might not be suitable for immunotherapy. In contrast, since no toxicity was found in tests of antibodies against the flexible tail region of PrP, they suggest that those might be more promising candidates.
“In summary”, they say, “these data illustrate that the efficacy profile (i.e. the curative effectiveness versus the potential toxicity) of anti-prion antibodies is complex and depends both on intrinsic factors such as, crucially, the nature of the engaged epitope, and extrinsic factors such as the route of administration. Detailed analyses and mapping of the involved epitopes and–most importantly–appropriate dose-escalation studies in vivo are prerequisite not only for preparing clinical trials in humans, but also to avoid the reporting of contradictory, confusing, and potentially misleading results.”
Funding: 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.
Competing Interests: The authors have declared that no competing interests exist. The authors pledge to distribute all reagents described in this article, and particularly POM antibodies and derivatives therefrom, with all interested parties at fair market value.
Source: Adriano Aguzzi – PLOS
Image Source: The image is credited to Reimann et al./PLOS Pathogens
Original Research: Full open access research for “Differential Toxicity of Antibodies to the Prion Protein” by Regina R. Reimann, Tiziana Sonati, Simone Hornemann, Uli S. Herrmann, Michael Arand, Simon Hawke, and Adriano Aguzzi in PLOS Pathogens. Published online January 28 2016 doi:10.1371/journal.ppat.1005401
Abstract
Differential Toxicity of Antibodies to the Prion Protein
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.
“Differential Toxicity of Antibodies to the Prion Protein” by Regina R. Reimann, Tiziana Sonati, Simone Hornemann, Uli S. Herrmann, Michael Arand, Simon Hawke, and Adriano Aguzzi in PLOS Pathogens. Published online January 28 2016 doi:10.1371/journal.ppat.1005401
