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.

Structural characterization of POM6 Fab and mouse prion protein complex identifies key regions for prions conformational conversion

“…Judging by the additional interactions, the b2-a2 loop in moPrP:POM6 Fab appears more stable than the one in moPrP:POM1 Fab. It should also be noted, that similar orientations for this loop to that of the POM1 Fab bound moPrP have been observed in the PDB structure of the ICSM18 Fab bound with the human prion protein [35] which seems to cause dose dependent neurotoxicity [36]. Furthermore, the regions of the C-terminal part of helix a3 near to the b2-a2 loop in the moPrP:POM1 Fab has an angular shift of 9.6 degrees compared to the Cterrminus of the moPrP in the moPrP:POM6 Fab complex without any significant changes through the crystal contacts (Fig.…”

Interaction between Prion Protein's Copper-Bound Octarepeat Domain and a Charged C-Terminal Pocket Suggests a Mechanism for N-Terminal Regulation

“…The surface of the PrP globular domain involved in the Cu 2+ -promoted cis interaction observed here overlaps the binding epitopes of several PrP C -specific antibodies that cause acute neurotoxicity (Reimann et al, 2016; Sonati et al, 2013). Sonati et al reported rapid neurotoxicity in mice and cultured cerebellar brain slices with antibody-based ligands that target specific regions of the PrP C globular domain (Sonati et al, 2013).…”

Protective anti-prion antibodies in human immunoglobulin repertoires

“…Antibodies that bind to the FT have been demonstrated to be neuroprotective, whereas those directed against certain epitopes of the GD are invariably toxic 11,21 . We therefore asked whether Fabs against CC123-50 (Fab3 and Fab83), the OR51-91 (Fab8, Fab44, Fab71 and Fab100) and the GD (Fab25, Fab1 and Fab29) may counteract neurotoxicity in prion-infected cerebellar slices (COCS) 11,22 .…”