Monoclonal antibody therapy targeting the shared pathological conformer of both beta-amyloid and hyperphosphorylated tau

Abstract

Currently there is no effective therapy for Alzheimer's Disease (AD). Active and passive immunomodulation still holds promise but current attempts only address one side of the pathology: either amyloid β (Aβ) or the hyperphosphorylated tau (ptau) protein. Furthermore current approaches are not specific for the pathological conformers of either protein. From our novel immunization method targeting pathological β-sheet conformation (PLoS ONE 5(10): e13391, 2010) we have developed monoclonal antibodies, some of them with promising binding capacities; and we propose to characterize a monoclonal specific for pathological conformers of Aβ and tau (TAB1) to be used for immunotherapy in AD mouse models. Monoclonal antibodies were obtained from our conformational inoculation of BALBc mice. Positive hybridomas were selected by their shared reactivity against Aβ, PHF and PrP Res. The best conformational candidate (TAB1) was selected after characterization by blots, ELISA and histology against pathological conformers in AD tissue. TAB1 is being used of treatment by intraperitoneal injection in 3xTg mice with both tau and Aβ related pathology. TAB1 on tissue sections specifically immunolabels AD tissue with no labeling in young, health normal control brains. On Western blots TAB1 detects purified paired helical filament preparations, aggregated/oligomeric Aβ and PrP Res, extracted from CJD brain tissue. Use of TAB1 therapeutically in 3xTg mice is on-going. We have developed a novel immunization procedure which we have used to produce monoclonal antibodies (mAbs) that recognize multiple pathological proteins, including PrP Res, oligomer A b and ptau. We have characterized one of these mAbs, TAB1, which gives specific immunolabeling in AD tissue and on Western blots to pathological conformers. We believe that immunotherapy that specifically targets the most toxic, oligomeric forms of Aβ and ptau, has the greatest chance of success with little risk of toxicity.