Development of a brain penetrating single-chain antibody selectively targeting three repeat tau protein as a new treatment for frontotemporal dementia

PROJECT SUMMARY Frontotemporal dementia (FTD) is the most common form of dementia in people less than 60 years of age, and the lifetime risk of developing FTD is 1 in 742. The overall disruption and accompanying economic and social costs of this disease are catastrophic, with estimated direct and indirect annual costs per patient totaling $119,654—nearly two times higher than costs reported for Alzheimer’s Disease patients. Symptoms of FTD include severe and unusual behavioral disturbances, neuropsychiatric issues including apathy, lack of empathy, hallucinations and psychosis, changes in personality, and decreases in executive control. Given the extensive public health burden, the lack of any approved, effective disease modifying treatment for FTD represents a critical unmet need. Abnormal accumulation of tau proteins in the brain is a defining characteristic of primary tauopathies such as FTD, and alternative splicing of tau proteins can generate six tau isoforms that are differentially expressed in frontolobar degeneration (FTLD) subtypes. For example, behavioral variant FTD (bvFTD) primarily expresses the three-repeat tau (3R tau) isoform. The removal of tau pathology to treat primary tauopathies has gained increased attention in recent years; however, the majority of anti-tau therapies have focused on non- specific tau targets, which to date have not proven successful. To address this gap in the market, the antibody to be developed through this SBIR Phase I application, 3RT-085653, is a brain and neuronal penetrating single chain antibody that selectively targets and binds to the 3R tau protein predominantly expressed in bvFTD. Preclinical studies have demonstrated that 3RT-085653 crosses the blood brain barrier, selectively binds to 3R tau, reduces levels of 3R tau in the neocortex and hippocampus without significantly affecting levels of total tau, and transports 3R tau to the endosomal compartment for lysosomal degradation. Treatment with the antibody also showed reduced loss of neuronal cells including NeuN positive neurons and MAP2 immunoreactive dendrites, as well as amelioration of behavioral deficits in both pre-pulse inhibition and novel habituation. This Phase I SBIR proposal will build upon these encouraging preliminary findings by pursuing two Specific Aims to de-risk and develop 3RT-085653 to inform and plan for an IND application. In Aim 1, we will perform detailed pharmacokinetic and efficacy studies to determine the relevant biologic characterization of 3RT-085653. In Aim 2, we will assess immunogenicity and the potential for the formation of anti-drug antibodies (ADAs). Successful achievement of these Aims will determine if further investment in this technology is warranted, and enable continued development during Phase II, in which detailed IND-enabling non-rodent animal studies will be performed. Following Phase II, we will seek partnerships with pharmaceutical and/or biotechnology companies to allow the antibody to progress into human trials and then the eventual full commercialization of the product. Overall, we hope to improve the quality of life for patients with FTD and other neurodegenerative disorders by developing a new therapeutic that targets this currently untreatable condition.