Characterization of a Monoclonal Antibody Targeting Alzheimer's Disease-Specific Tau Species in models of transmission of tau pathology
Yuan Tian1, Jonathan Sugam1, Angela Jablonski1, Yi Wang1, Jacky Wong1, Steven Grauer2, Geoffrey Varty2, Thomas Rosahl2, Xiaoyan Du3, Toya Baral3, Sripriya Dhandapani3, Jeanne Baker3, Sophie Parmentier-Batteur1
1Neurodegenerative Disease Discovery, 2Pharmacology, West Point, PA; 3Biology-Discovery, Palo Alto, CA, Merck & Co Inc.
In Alzheimer's disease (AD), abnormal phosphorylation, misfolding and aggregation of microtubule-associated protein tau leads to neurofibrillary tangles and ultimately to neuronal death. In addition, the progression of tau pathology has suggested the concept that tau can spread in a prion-like manner between interconnected neurons implying that toxic tau species are exposed in the extracellular space. Despite uncertainty about the exact composition of the tau spreading species, many groups have reported that tau immunotherapy leads to reduced pathology in preclinical models of tau pathology. Our strategy is to develop an antibody that specifically targets a pathological relevant pool of tau present in AD patient brains which could block tau transmission and the progression of tau pathology. We showed that MAFT-0617, a mouse anti-tau monoclonal antibody specifically and potently binds to tau species that are found in post-mortem AD brains but not in healthy control brains. A robust and quantitative in vitro tau seeding assay was validated using the addition of preparations of brain homogenates from either Tau P301L transgenic mice or AD patients. We showed that MAFT-0617 was able to efficiently reduce tau pathology induced by seeding in these two in vitro assays. In addition, we developed a relevant in vivo model consisting in the injection of brain homogenates from rTg(tauP301L)4510 mice (Car:Car) into the hippocampi of Tg4510 mice (WT:Car) to trigger pathology. This model reproduced the transmission of tau pathology around the injection site and spreading of tau pathology in the entorhinal cortex and contralateral hippocampus. We also demonstrated that the weekly administration of MAFT-0617 (40 mg/kg, i.p.) significantly reduced both the transmission and spreading of the tau pathology after four weeks. Taken together, these in vitro and in vivo data provide evidence for the efficacy of MAFT-0617 in preventing the spread of tau pathology by disrupting transcellular propagation of toxic tau species.