Antibodies as Therapeutic Agents for Prion Disease

Abstract

Prions are infectious proteins that cause fatal neurodegenerative disorders in humans and animals. The emergence of variant Creutzfeldt-Jakob disease (vCJD) in humans, which seems to be caused by the consumption of prion-infected beef, has heightened the urgency for developing effective therapeutic agents. Prions reproduce by recruiting normal prion protein (PrPc) and stimulating its conversion to the disease-causing isoform (PrPSc): PrPSc + PrPC → PrPScPrPG → PrPSc + PrPSc. This mechanism suggests that compounds specifically binding either PrP isoform may interrupt prion production by inhibiting this misfolding process. We and other researchers have demonstrated that antibodies specific to PrP inhibit prion propagation in cultured, prion-infected mouse neuroblastoma (ScN2a) cells (Peretz et al. 2001; Enari et al. 2001). In experiments by other researchers, transgenic mice expressing the heavy chain of an anti-PrP antibody were protected against prions inoculated intraperitoneally (Heppner et al. 2001). When we consider the mechanism of prion production in neuronal cell cultures and the binding properties of efficient antibodies, the inhibitory effect is most readily explained by antibodies binding specifically to PrPC molecules on the cell surface and thereby hampering their transition to PrPSc. Significantly, in cells treated with the most potent antibody, D18, prion replication is completely abolished and preexisting PrPSc is rapidly cleared, suggesting that antibodies may cure established infection. These data support the use of antibodies in the prevention and treatment of prion diseases.