Protective anti-prion antibodies in human immunoglobulin repertoires

Abstract

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here we identified >6000 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 protective anti-prion antibodies in unbiased human immunological repertoires, combined with the reported lack of such antibodies in carriers of disease-associated PRNP mutations, suggests a link to the low incidence of spontaneous prion diseases in human populations.We thank Rita Moos and Cinzia Tiberi for support in recombinant antigens and Fab purification, Irina Abakumova for TR-FRET antibody-fluorophore conjugation, and Stefan Schauer for the SPR experiments. We also thank the hospital patients supporting research, especially the individuals who generously agreed to grant us a second blood donation. We acknowledge the help provided by the Clinical

Immunotherapy against Prion Disease

“…The similarities between the neurotoxicity caused by the globular domain-binding antibodies and prion infection [113] suggest that the octarepeat-binding antibodies have a great therapeutic potential. This view is consistent with a recent report showing that the octarepeat-binding human Fabs prevent neurotoxicity caused by prion infection [114]. In the same study, Senatore et al also identified a small number of human carriers of high-titer anti-PrP antibody and found no specific pathologies associated with the presence of these antibodies.…”

Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

“…Immunoprecipitation (IP) of FT2Fc from cell culture supernatant was performed as previously described with minor modifications (Senatore et al, 2020). Briefly, sheep-anti mouse IgG paramagnetic beads (Dynal, 11201D) were coupled with anti-His mAb (Invitrogen, 37-2900) in coating buffer (PBS plus 0.1% immunoglobulin-free BSA) for 2 h at RT on a rotating wheel.…”

“…Finally, we immunoprecipitated FT2Fc from cell culture supernatant using beads coupled with Fab83. Peptides derived from the linear sequence of mouse PrP were previously used to map the epitope of Fab83 (Senatore et al, 2020). FT2Fc could be eluted from the beads with a peptide competing for the Fab83 binding site (amino acids 23-34 of mouse PrP), but not with a non-competing peptide (amino acids 53-64) (Fig.…”

Recent developments in antibody therapeutics against prion disease

“…Stimulators of autophagy Lithium [43], tacrolimus [44], rapamycin [45] Promotion of PrP Sc degradation significant association between the presence of plasma anti-PrP C autoantibodies and specific pathologies [30].…”

“…Comparative sequence analyses of variable immunoglobulin fragments, however, showed an overlap between therapeutic monoclonal anti-PrP C antibodies and naturally occurring autoantibodies in publicly available immunological repertoires [30]. One might wonder whether the presence of protective naturally occurring autoantibodies is responsible for delayed clinical manifestations in individuals harboring germline mutations of the human prion protein gene PRNP.…”