A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity

PLoS Pathog. 2018 Oct 1;14(10):e1007335. doi: 10.1371/journal.ppat.1007335. eCollection 2018 Oct.

Abstract

Antibodies to the prion protein, PrP, represent a promising therapeutic approach against prion diseases but the neurotoxicity of certain anti-PrP antibodies has caused concern. Here we describe scPOM-bi, a bispecific antibody designed to function as a molecular prion tweezer. scPOM-bi combines the complementarity-determining regions of the neurotoxic antibody POM1 and the neuroprotective POM2, which bind the globular domain (GD) and flexible tail (FT) respectively. We found that scPOM-bi confers protection to prion-infected organotypic cerebellar slices even when prion pathology is already conspicuous. Moreover, scPOM-bi prevents the formation of soluble oligomers that correlate with neurotoxic PrP species. Simultaneous targeting of both GD and FT was more effective than concomitant treatment with the individual molecules or targeting the tail alone, possibly by preventing the GD from entering a toxic-prone state. We conclude that simultaneous binding of the GD and flexible tail of PrP results in strong protection from prion neurotoxicity and may represent a promising strategy for anti-prion immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacology*
  • Cells, Cultured
  • Cerebellum / immunology*
  • Complementarity Determining Regions / immunology
  • Immunotherapy*
  • Mice
  • Mice, Transgenic
  • Prion Diseases / immunology
  • Prion Diseases / therapy*
  • Prion Proteins / immunology*
  • Prions / immunology
  • Prions / toxicity*

Substances

  • Antibodies, Bispecific
  • Complementarity Determining Regions
  • Prion Proteins
  • Prions

Grant support

LV is grateful for support by Swiss National Science Foundation (grant 310030_166445 and grant 157699), Synapsis Foundation -Alzheimer Research Switzerland ARS- and Lions Club Monteceneri. KF is funded by a research grant from the Theodor and Ida Herzog-Egli foundation and a "Rising Star“ grant by Ono Pharmaceuticals. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.