Abstract
Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous. The existence of anti‐prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease‐associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations.
Highlights
Many neurodegenerative syndromes, including prion diseases, Alzheimer’s disease, and Parkinson’s disease, go along with the accumulation of misfolded and aggregated proteins in the central nervous system
The first and second biopanning rounds were performed against full-length recombinant mouse prion protein (PrP) to enrich for Fabs covering a large variety of PrP epitopes
To optimize our chances to identify CC123–50 binders, and to avoid misfolding artifacts caused by nonspecific plate adsorption, the selection against the biotinylated CC123–50 peptide was conducted in solid phase and by liquid-phase panning followed by neutravidin (Neu)-mediated capture
Summary
Many neurodegenerative syndromes, including prion diseases, Alzheimer’s disease, and Parkinson’s disease, go along with the accumulation of misfolded and aggregated proteins in the central nervous system. Antibodies against such proteins may be beneficial (Schenk et al, 1999), e.g., by opsonizing pathological aggregates and mediating their degradation by phagocytic cells (Heppner et al, 2001; Kranich et al, 2010). While the clinical effectiveness of antibody-based therapies against neurodegenerative diseases is still being debated (Schilling et al, 2018), there is ample evidence that both active immunization and passive antibody transfer can effectively clear pathological aggregates in preclinical animal models and, to some extent, in affected humans. Suppression of PrPC by means of antiPrPC antibodies represents a rational strategy against prion diseases
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