Date Published: October 1, 2018
Publisher: Public Library of Science
Author(s): Marco Bardelli, Karl Frontzek, Luca Simonelli, Simone Hornemann, Mattia Pedotti, Federica Mazzola, Manfredi Carta, Valeria Eckhardt, Rocco D’Antuono, Tommaso Virgilio, Santiago F. González, Adriano Aguzzi, Luca Varani, Surachai Supattapone.
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.
Prions are the causative agent of sporadic, hereditary and iatrogenic forms of transmissible spongiform encephalopathies, which afflict humans and broad spectrum of mammals and are invariably fatal[1–3]. Whereas Bovine Spongiform Encephalopathy (the most prevalent prion disease in the 1990s, also known as “Mad Cow” disease) has been largely defeated, Chronic Wasting Disease, which affects deer, elk and moose, remains prominent in parts of the US, Canada, South Korea and has recently reached Norway. These findings are raising renewed concerns about the contamination of the food chain. Transmission of infectious animal material to humans causes variant Creutzfeldt-Jakob disease (vCJD). A common Met/Val polymorphism at codon 129 of the PRNP gene is assumed to be important in susceptibility of humans to prion infections, with homozygous individuals (Met/Met and Val/Val) being overrepresented in collectives of CJD patients. The recent discovery of a case of vCJD in a 36-year-old man producing both M129 and V129 variants of PrP, which is much more frequent in the population and is thought to conduce to a disease developing more slowly, has led to suggestion that we might be facing a new wave of vCJD cases .
The discovery that anti-PrP antibodies can block prion pathogenesis in vivo  has suggested that such antibodies might be exploited as therapeutics against human prion diseases. However, caution must be exercised as some antibodies directed against the GD of PrP can trigger PrP-mediated cellular neurotoxicity in the absence of prions [12,31]. This finding has far-reaching implications, including the possibility that autoimmunity to PrP may lead to neurodegenerative diseases. At the molecular level, it suggests that binding to specific sites in the GD can trigger changes in PrP leading to toxicity.