Prion Protein-Specific Antibodies-Development, Modes of Action and Therapeutics Application

Abstract

Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are lethal neurodegenerative disorders involving the misfolding of the host encoded cellular prion protein, PrPC. This physiological form of the protein is expressed throughout the body, and it reaches the highest levels in the central nervous system where the pathology occurs. The conversion into the pathogenic isoform denoted as prion or PrPSc is the key event in prion disorders. Prominent candidates for the treatment of prion diseases are antibodies and their derivatives. Anti-PrPC antibodies are able to clear PrPSc from cell culture of infected cells. Furthermore, application of anti-PrPC antibodies suppresses prion replication in experimental animal models. Major drawbacks of immunotherapy are immune tolerance, the risks of neurotoxic side effects, limited ability of compounds to cross the blood-brain barrier and their unfavorable pharmacokinetic. The focus of this review is to recapitulate the current understanding of the molecular mechanisms for antibody mediated anti-prion activity. Although relevant for designing immunotherapeutic tools, the characterization of key antibody parameters shaping the molecular mechanism of the PrPC to PrPSc conversion remains elusive. Moreover, this review illustrates the various attempts towards the development of anti-PrP antibody compounds and discusses therapeutic candidates that modulate PrP expression.

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

“…[15] Among these neurodegenerative diseases, the prion disease has long been recognized to have a protein only self-propagation infectious mechanism. Anti-prion antibodies and new vaccines have been tested over more than decade, aiming to break the immune tolerance to the prion protein, [16] including an antibody that can specifically neutralize PrP Sc . [17] It now appears that similar prion-like mechanisms of self-propagation may underlie other neurodegenerative diseases as well.…”

Characterization of four new monoclonal antibodies against the distal N-terminal region of PrPc

“…Antibodies are one of the most promising tools in developing effective cures for prion diseases ( Rovis & Legname, 2014 ). Indeed, they have been shown to clear prion infectivity in cellular models of prion replication ( Peretz et al, 2001 ) and to significantly delay the disease development in mice if mAbs are administered shortly after infection ( White et al, 2003 ).…”

Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

“…There is a body of evidence substantiating prion immunotherapy as effective in curing an infected cell as outlined in the review by Rovis and Legname [122]. Anti-PrP , which is thought to serve as a reservoir for prion transformation.…”

“…Alternative antibody formats such as recombinant Fab fragments, camelid antibody fragments and scFvs have also been successful at clearing pathogenic prion from infected cells [122] (and references within). The advantage of VHs and scFvs is the single polypeptide sequence used for the gene transfer-based passive immunisation.…”