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A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity


Bardelli, Marco; Frontzek, Karl; Simonelli, Luca; Hornemann, Simone; Pedotti, Mattia; Mazzola, Federica; Carta, Manfredi; Eckhardt, Valeria; D’Antuono, Rocco; Virgilio, Tommaso; González, Santiago F; Aguzzi, Adriano; Varani, Luca (2018). A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity. PLoS Pathogens, 14(10):e1007335.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Immunology, Genetics, Molecular Biology, Microbiology, Parasitology, Virology
Language:English
Date:1 October 2018
Deposited On:25 Oct 2018 12:34
Last Modified:01 Nov 2018 01:15
Publisher:Public Library of Science (PLoS)
ISSN:1553-7366
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.ppat.1007335
PubMed ID:30273408
Project Information:
  • : FunderSNSF
  • : Grant ID310030_166445
  • : Project TitleCharacterization of antibody-antigen interactions in human pathogens
  • : FunderSNSF
  • : Grant ID316030_157699
  • : Project TitleAcquisition of a 600MHz solution NMR spectrometer
  • : FunderTheodor and Ida Herzog- Egli Stiftung
  • : Grant ID
  • : Project Title
  • : FunderSynapsis Foundation
  • : Grant ID
  • : Project Title

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