Treatment of Alzheimer's disease by clearing both tau and amyloid beta pathologies

PROJECT SUMMARY Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. Nearly six million Americans suffer from AD, at an annual cost of almost $300 billion for their health care. At present, no effective treatment of this disease is available. If no treatment is found that can inhibit, prevent, or cure this disease, the number of cases will triple by 2050. Thus, there is an urgent need to develop an effective treatment for AD. AD is histopathologically characterized by the occurrence of numerous Aβ plaques and neurofibrillary tangles of abnormally hyperphosphorylated tau in the brain. Tau pathology of hyperphosphorylated tau is also a hallmark lesion of several related neurodegenerative diseases, called tauopathies. The density of tau pathology, and not of Aβ plaques, correlates with the degree of dementia in AD patients. There is increasing belief in the field that the clearance of both Aβ or tau pathologies could be required to successfully treat AD. So far, none of the antibodies used in human clinical trials have had such activity. We have generated several high-affinity tau mouse monoclonal antibodies, and one of these, tau antibody 43D to human tau 6-18, can clear not only tau pathology but also Aβ pathology and rescued cognitive impairment in the 3xTg-AD transgenic mouse model of AD and tauopathy. We propose to further develop this unique tau antibody for immunotherapy of AD and related conditions. The PI has patented 43D for the treatment of AD and related neurodegenerative disorders. The specific aims of this SBIR Phase I application are (1) to study the humanization of the tau mouse monoclonal antibodies 43D and 77E9 and (2) to study the immunotherapy activities of the humanized antibodies from Aim 1 in comparison with the corresponding mouse monoclonals in 3xTg-AD transgenic mice treated with AD ptau. Hyperphosphorylated tau (ptau), free from any Aβ and TDP43, will be isolated from AD frozen autopsied AD brain and used to induce tau seeding and spread in 3xTg-AD mice, which will be immunized with humanized 43D in comparison with a Aβ-negative effective tau antibody 77E9 to tau 184-195 and the corresponding mouse monoclonals. The effect of immunization of tau and Aβ pathologies will be evaluated immunohistochemically and biochemically. These Phase I studies will be followed by a Phase II application on generation of a cell line of the lead humanized antibody with similar or higher activity as the corresponding mouse monoclonal and then leading to large-scale GMP manufacture, IND, and test of cross-reactions and non-target tissue binding, along with the safety studies and human clinical trials. The successful completion of the proposed studies will lead to Phase I human clinical trials in healthy volunteers and Phase II and then Phase III human clinical trials on AD and related neurodegenerative conditions and will potentially lead to the treatment and prevention of these diseases. At Phanes Biotech, we believe that given its multifactorial nature and heterogeneity, AD could require a combination therapy. While on one side we are developing the neurotrophic compound P021 to stimulate regeneration of the brain, combining it with tau immunotherapy, which can inhibit neurodegeneration, could further increase our success and is the long-term goal of our company.