PrP Antibodies Do Not Trigger Mouse Hippocampal Neuron Apoptosis

Abstract

Intraperitoneal administration of ICSM18 and 35, monoclonal antibodies against prion protein (PrP), has been shown to significantly delay the onset of prion disease in mice, and humanized versions are candidate therapeutics for prion and Alzheimer's diseases. However, a previous report of severe and widespread apoptosis after intracerebral injection of anti-PrP monoclonal antibodies raised concerns about such therapy and led to an influential model of prion neurotoxicity via cross-linking of cell surface PrP by disease-related PrP aggregates. In extensive studies including ICSM18 and 35, fully humanized ICSM18, and the previously reported proapoptotic antibodies, we found no evidence of apoptosis, thereby questioning this model of prion neurotoxicity.

Prion Protein—Antibody Complexes Characterized by Chromatography-Coupled Small-Angle X-Ray Scattering

“…Although no treatments exist for PrP prion diseases, studies have shown that antibodies directed against certain regions (including residues 95-110 and 221-230) are effective in clearing PrP Sc from chronically infected cultured cells, whereas antibodies against more N-terminal residues were largely ineffective (19,20). In one study, treatment of mice with these antibodies triggered neuronal apoptosis.…”

Homodimerization as a molecular switch between low and high efficiency PrPCcell surface delivery and neuroprotective activity

“…[12][13][14] Results from two different studies led to the conclusion that dimerization of PrP C is actually a positive mechanism in physiological conditions. First, in experimental settings where PrP C displays a stress-protective signaling activity, dimerization correlates with neuroprotection.…”

Advances in the development of antibody-based immunotherapy against prion disease

“…96 But Klöhn et al found no evidence to show that the brain delivery of PrP antibody triggered mouse hippocampal neuron apoptosis. 118 They stereotaxically injected ICSM18, recognizing PrP epitope 143 to 153; ICSM35, binding 93 to 105; and fully humanized ICSM18 (both IgG1 and G4 isotypes), into the hippocampus of C57BL/10 mice, using IgG P and IgG D13 as positive controls. Apoptotic cell death throughout the hippocampal region was not observed.…”

“…Apoptotic cell death throughout the hippocampal region was not observed. 118 To minimize neurotoxicity, anti-PrP C scFv antibodies have been investigated. ScFvs have been considered an option for passive immunotherapy in recent years.…”