Immunotherapy Targeting Tau Aggregate Polymorphs

Project Summary Pathological aggregation of the microtubule-associated protein tau and its subsequent accumulation into neurofibrillary tangles (NFTs) or other hyperphosphorylated tau-containing inclusions are defining histopathological features of frontotemporal lobar degeneration (FTLD) and many other neurodegenerative conditions, collectively known as tauopathies, including Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and even traumatic brain injury (TBI). Recent studies suggest that the most pathogenic tau species are soluble oligomers. We created several novel tau oligomer-specific monoclonal antibodies (TOMA clones) that specifically recognize tau oligomers but do not recognize functional tau monomer in vitro, these antibodies recognize non-continues epitopes in the middle and c-terminal part of tau protein. TOMA clones are potent neutralizing mAbs that effectively and specifically remove toxic tau oligomers and have potential therapeutic and diagnostic applications. Moreover, we recently established the specificity and efficacy of one of our novel TOMA clones in three different mouse models. We hypothesize that tau forms conformationally distinct toxic oligomeric strains/polymorphs. Herein we will determine the efficacy of four TOMA clones on the propagation of disease relevant tau oligomeric strains/polymorphs, and their efficacy to specifically targeting specific disease relevant tau strains/polymorphs through passive immunotherapy. Moreover, we will generate humanized TOMA clones with the ultimate goal of developing antibodies that can target aberrant tau species in clinical settings. The successful completion of this research project will deliver very compelling data that will move the tau field forward and facilitate the clinical development of safe, effective, personalized therapeutic strategies for neurodegenerative tauopathies.