A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity
| Autor: | Federica Mazzola, Valeria Eckhardt, Rocco D'Antuono, Manfredi Carta, Marco Bardelli, Simone Hornemann, Mattia Pedotti, Luca Simonelli, Adriano Aguzzi, Tommaso Virgilio, Luca Varani, Karl Frontzek, Santiago F. Gonzalez |
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| Přispěvatelé: | University of Zurich, Supattapone, Surachai, Varani, Luca |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Physiology
medicine.medical_treatment animal diseases 2405 Parasitology Toxicology Pathology and Laboratory Medicine Molecular Dynamics Biochemistry Prion Diseases Animal Diseases Mice 0302 clinical medicine Computational Chemistry Zoonoses Immune Physiology Cerebellum Antibodies Bispecific Medicine and Health Sciences Biology (General) Enzyme-Linked Immunoassays Materials Cells Cultured 0303 health sciences Immune System Proteins biology Chemistry 2404 Microbiology Proteases 3. Good health Cell biology Enzymes Animal Prion Diseases Infectious Diseases Toxicity Physical Sciences Immunotherapy Antibody Research Article QH301-705.5 Prions Materials Science Immunology 10208 Institute of Neuropathology 610 Medicine & health Mice Transgenic Research and Analysis Methods Neuroprotection Microbiology Antibodies Prion Proteins Pom1 03 medical and health sciences 1311 Genetics Virology medicine 1312 Molecular Biology Genetics Animals Prion protein Immunoassays Molecular Biology 030304 developmental biology 2403 Immunology Neurotoxicity Biology and Life Sciences Proteins RC581-607 medicine.disease Complementarity Determining Regions nervous system diseases Oligomers biology.protein 2406 Virology Enzymology Immunologic Techniques 570 Life sciences Parasitology Immunologic diseases. Allergy Zoology 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 14, Iss 10, p e1007335 (2018) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | 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. Author summary Antibody immunotherapy is considered a viable strategy against prion disease. We previously showed that antibodies against the so-called globular domain of Prion Protein (PrP) can cause PrP dependent neurotoxicity; this does not happen for antibodies against the flexible tail of PrP, which therefore ought to be preferred for therapy. Here we show that simultaneous targeting of both globular domain and flexible tail by a bispecific, combination of a toxic and a non-toxic antibody, results in stronger protection against prion toxicity, even if the bispecific is administered when prion pathology is already conspicuous. We hypothesize that neurotoxicity arises from binding to specific “toxicity triggering sites” in the globular domain. We designed our bispecific with two aims: i) occupying one such site and preventing prion or other factors from docking to it and ii) binding to the flexible tail to engage the region of PrP necessary for neurotoxicity. We also show that neurotoxic antibodies cause the formation of soluble PrP oligomers that cause toxicity on PrP expressing cell lines; these are not formed in the presence of prion protective antibodies. We suggest that these soluble species might play a role in prion toxicity, similarly to what is generally agreed to happen in other neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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