Antibodies that bind to pathological tau species and uses thereof

Abstract

The present disclosure relates to antibodies that bind selectively to pathological Tau, including compositions and methods relating to such antibodies, such as for treating tauopathies, neurodegenerative diseases associated with pathological aggregation of Tau.

What is claimed is: 
     
         1 . A method of treating or preventing a Tau-associated neurodegenerative disease in a subject, comprising administering to the subject an anti-Tau antibody or antigen-binding moiety thereof comprising a heavy chain variable region and a light chain variable region;
 wherein: (I) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 3 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 15, or (II) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 107.   
     
     
         2 . The method of  claim 1 , wherein the heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 50, a CDR2 comprising the amino acid sequence of SEQ ID NO: 61, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 72; and wherein the light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 83, a CDR2 comprising the amino acid sequence of SEQ ID NO: 91, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 97. 
     
     
         3 . The method of  claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 3. 
     
     
         4 . The method of  claim 2 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 15. 
     
     
         5 . The method of  claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 3, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 15. 
     
     
         6 . The method of  claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 3, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 15. 
     
     
         7 . The method of  claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 2, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 14. 
     
     
         8 . The method of  claim 2 , wherein the anti-Tau antibody or antigen-binding moiety binds to amino acid residues 5131, K132, T135, 5137 and R155 of a human 2N4R Tau isoform. 
     
     
         9 . The method of  claim 1 , wherein the heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 59, a CDR2 comprising the amino acid sequence of SEQ ID NO: 70, a CDR3 comprising the amino acid sequence of SEQ ID NO: 81; and wherein the light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 87, a CDR2 comprising the amino acid sequence of SEQ ID NO: 93, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 105. 
     
     
         10 . The method of  claim 9 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 106. 
     
     
         11 . The method of  claim 9 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 107. 
     
     
         12 . The method of  claim 9 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 106, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 107. 
     
     
         13 . The method of  claim 9 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 106, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 107. 
     
     
         14 . The method of  claim 9 , wherein the anti-Tau antibody or antigen-binding moiety binds to amino acid residues R230, T231, 5237, T245, K281 and 5289 of a human 2N4R Tau isoform. 
     
     
         15 . The method of  claim 9 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 12, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 24 or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 24. 
     
     
         16 . The method of  claim 1 , wherein the anti-Tau antibody or antigen-binding moiety is a monoclonal antibody. 
     
     
         17 . The method of  claim 1 , wherein the anti-Tau antibody or antigen-binding moiety preferentially binds to pathological human Tau species relative to normal human Tau species. 
     
     
         18 . The method of  claim 17 , wherein the pathological human Tau species is a Tau aggregate or an abnormally phosphorylated Tau, a Tau aggregate or an abnormally phosphorylated Tau accumulated at synapses of brain, or a Tau aggregate or an abnormally phosphorylated Tau accumulated at synapses of tauopathy brain. 
     
     
         19 . The method of  claim 1 , wherein the Tau-associated neurodegenerative disease is a tauopathy. 
     
     
         20 . The method of  claim 19 , wherein the tauopathy is selected from the group consisting of Alzheimer's Disease (AD), primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), dementia pugilistica, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia, frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17), Lytico-Bodig disease, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing pan encephalitis, Pick's Disease (PiD), corticobasal degeneration, traumatic brain injury (TBI), argyrophilic grains disease, postencephalic parkinsonism (PEP), parkinsonism dementia complex of Guam (PDCG), tangle-dominant dementia, and globular glial tauopathies (GGTs). 
     
     
         21 . The method of  claim 19 , wherein the tauopathy is Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or Pick's disease (PiD). 
     
     
         22 . A method for retaining or increasing cognitive memory capacity or slowing memory loss in a subject having or at risk of developing a Tau-associated neurodegenerative disease, comprising administering to the subject an anti-Tau antibody or antigen-binding moiety thereof comprising a heavy chain variable region and a light chain variable region;
 wherein: (I) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 3 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 15, or (II) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 107.   
     
     
         23 . A method for reducing the level of Tau aggregates in a subject having or at risk of developing a Tau-associated neurodegenerative disease, comprising administering to the subject an anti-Tau antibody or antigen-binding moiety thereof comprising a heavy chain variable region and a light chain variable region;
 wherein: (I) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 3 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 15, or (II) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 107;   wherein: the level of Tau aggregates or abnormally phosphorylated Tau is reduced in the subject as compared to its level in the subject prior to administration of the anti-Tau antibody or antigen-binding moiety, or the level of Tau aggregates or abnormally phosphorylated Tau accumulated at synapses of brain is reduced in the subject as compared to its level in the subject prior to administration of the anti-Tau antibody or antigen-binding moiety.   
     
     
         24 . A method for inhibiting Tau seeding or the propagation of Tau aggregation in a subject having or at risk of developing a Tau-associated neurodegenerative disease, comprising administering to the subject an anti-Tau antibody or antigen-binding moiety thereof comprising a heavy chain variable region and a light chain variable region;
 wherein: (I) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 3 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 15, or (II) the heavy chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 106 and the light chain variable region comprising CDR1, CDR2, and CDR3 comprised in the amino acid sequence of SEQ ID NO: 107.