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 2018-10-01 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. application/pdf https://susi.usi.ch/global/documents/318891 https://localhost:5000/ark:/12658/srd1318891 https://susi.usi.ch/documents/318891/files/Bardelli_PP_2018.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1007335 info:eu-repo/semantics/altIdentifier/ark/12658/srd1318891 info:eu-repo/semantics/openAccess CC BY Plos pathogens. - 2018, vol. 14, no. 10, p. e1007335 info:eu-repo/classification/udc/61 A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity http://purl.org/coar/resource_type/c_6501