Antibodies inhibit prion propagation and clear cell cultures of prion infectivity

Abstract

Prions are the transmissible pathogenic agents responsible for diseases such as scrapie and bovine spongiform encephalopathy. In the favoured model of prion replication, direct interaction between the pathogenic prion protein (PrPSc) template and endogenous cellular prion protein (PrPC) is proposed to drive the formation of nascent infectious prions. Reagents specifically binding either prion-protein conformer may interrupt prion production by inhibiting this interaction. We examined the ability of several recombinant antibody antigen-binding fragments (Fabs) to inhibit prion propagation in cultured mouse neuroblastoma cells (ScN2a) infected with PrPSc. Here we show that antibodies binding cell-surface PrPC inhibit PrPSc formation in a dose-dependent manner. In cells treated with the most potent antibody, Fab D18, prion replication is abolished and pre-existing PrPSc is rapidly cleared, suggesting that this antibody may cure established infection. The potent activity of Fab D18 is associated with its ability to better recognize the total population of PrPC molecules on the cell surface, and with the location of its epitope on PrPC. Our observations support the use of antibodies in the prevention and treatment of prion diseases and identify a region of PrPC for drug targeting.

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

“…It also indicates that no significant conformational rearrangements occur in this region of the protein during the association process. Monoclonal antibody fragments reacting with different epitopes of PrP C have been reported to inhibit efficiently prion propagation in scrapie prion-infected neuroblasma cells [76]. The inhibitory effect was explained by the antibody binding to PrP C thereby preventing the docking of the PrP Sc template or a cofactor critical for the conversion of the PrP C into PrP Sc [76].…”

“…Monoclonal antibody fragments reacting with different epitopes of PrP C have been reported to inhibit efficiently prion propagation in scrapie prion-infected neuroblasma cells [76]. The inhibitory effect was explained by the antibody binding to PrP C thereby preventing the docking of the PrP Sc template or a cofactor critical for the conversion of the PrP C into PrP Sc [76]. Identification of the epitope of these antibody fragments indicated that the 96-104 and 132-156 regions of the prion protein (PrP) are likely to be critical components of the PrP C -PrP Sc interface.…”

“…Recent studies report the success of both active and passive vaccination approaches to slowing and/or reversing the aggregation process, and its pathological consequences, in mouse models of light chain amyloidosis [71], Alzheimer's disease [77,79,80,[86][87][88][89][90] and mammalian prion diseases [76,[91][92][93]. The molecular mechanisms by which antibodies act in a therapeutic manner are just beginning to be understood (for recent reviews see [94][95][96][97][98][99]) (Textbox 3).…”

Misfolding of the prion protein: linking biophysical and biological approaches

“…Other experimental data support the evidence that the H1 helix is a possible site of association of PrP Sc with PrP C during formation of the PrP Sc -PrP C complex. For instance, an antibody directed against H1 cured prion infections in two separate cell lines chronically infected with PrP Sc [34,45,92]. It is noteworthy that antibodies obtained against other regions of PrP have also been reported to inhibit the replication of the infectivity [35,85], suggesting that PrP Sc replication may involve different regions of the prion protein.…”

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

“…Recently, immunotherapeutic approaches have been developed in experimental model of neurodegenerative diseases with some success (Peretz et al, 2001;White et al, 2003;Polymenidou et al, 2004;Schenk et al, 1999;Rosset et al, 2009). PrP antibodies inhibit the conversion of PrP c to PrP Sc in vitro (Beringue et al, 2004;Pankiewick et al, 2006) and confer some degree of protection against murine scrapie in vivo (Peretz et al, 2001;White et al, 2003;Polymenidou et al, 2004). Yet, they have been effective only during the peripheral lymphoreticular phase of the disease, presumably as a result of their poor blood-brain barrier penetration.…”