Tau pathology, which is made up of the hyperphosphorylated state of the protein, is a hallmark of Alzheimer’s disease (AD) and a family of related neurodegenerative diseases, called tauopathies. These diseases include frontotemporal dementias, progressive supranuclear palsy (PSP), cortico-basal degeneration, Pick disease, chronic traumatic encephalopathy, Guam Parkinsonism dementia, and adults with Down syndrome. Tau pathology, without fail is associated with clinical phenotype in human tauopathies and in experimental transgenic animal models. The density of tau pathology seen as neurofibrillary tangles in AD brain correlates with the degree of dementia. Tau, although a neuronal cytoplasmic protein, is released in the extracellular space by an unconventional protein secretion mechanism. Thus, tau pathology, which spreads transcellularly, can be targeted with antibodies.
Clinical trials with Aβ therapies, including immunotherapy, have thus far failed to show any reduction in tau pathology or improvement in cognitive performance of patients with AD. Multivariate analyses indicate that the density of tau pathology, neuron number loss, and synapse loss, but not amyloid load, strongly correlate with cognitive impairment in patients with AD. Thus, targeting both tau and Aβ pathologies could be clinically more efficacious than only Aβ-directed clearance therapy for patients with AD.
Our lead tau antibody, PB43D, is unique and extremely potent. Only six weekly doses of 15 µg tau antibody (PB43D/animal) administered through the tail vein resulted in the clearance of not only tau but also Aβ pathology and rescue of cognitive impairment in 3xTg-AD transgenic mouse model of AD and tauopathy; this intravenous (i.v.) dose in mouse corresponds to ~3 mg (i.v.) tau antibody/70 Kg adult human. Antibody PB43D is an IgG1 isotype and is ideally suited for passive immunotherapy. No other company is known to have such a potent tau antibody that can clear both tau and Aβ pathologies by immunization. Plasma and cerebrospinal fluid (CSF) levels of tau, hyperphosphorylated tau, and Aβ can serve as markers of target engagement and efficacy and as biomarkers of reduction of the pathology by tau immunization. Our approach is to employ PB43D as our lead compound/antibody, humanize it, and develop it further for immunotherapy of AD and related tauopathies.
