A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity
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Bardelli, Marco
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Frontzek, Karl
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
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Simonelli, Luca
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Hornemann, Simone
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
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Pedotti, Mattia
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Mazzola, Federica
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Carta, Manfredi
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
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Eckhardt, Valeria
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
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D’Antuono, Rocco
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Virgilio, Tommaso
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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González, Santiago F.
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Aguzzi, Adriano
Institute of Neuropathology, University of Zurich, Zurich, Switzerland
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Varani, Luca
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Published in:
- Plos pathogens. - 2018, vol. 14, no. 10, p. e1007335
English
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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Medicine
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https://n2t.net/ark:/12658/srd1318891
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