COMPOUNDS AND METHODS TARGETED AT HUMAN TAU

Abstract

The present invention provides compounds and methods targeting human tau, particularly human tau phosphorylated at threonine 217 and tau isoforms expressed only in the CNS, including therapeutic antibodies, pharmaceutical compositions, and diagnostic applications useful in the field of neurodegenerative diseases such as AD, PSP, and FTD.

Description

The present invention pertains to the field of medicine. More particularly, the present invention relates to compounds, pharmaceutical compositions, diagnostics, and methods that include an antibody or fragment thereof directed against human tau. It is expected that the compounds and methods of the present invention will be useful in the field of neurodegenerative diseases, particularly tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD), and similar conditions, including the treatment of these diseases and related diagnostics. Tau is an axonal microtubule-binding protein expressed both in the central nervous system (CNS) and peripherally, promoting microtubule assembly and stability. Known isoforms of human tau are expressed in the CNS and participate in the aberrant formation and aggregation of intraneuronal neurofibrillary tangles (NFTs). In neurodegenerative diseases such as Alzheimer's disease (AD), the density and neuroanatomical location of CNS NFTs correlate with dementia severity, degree of neuronal loss, and overall disease progression. In progressive neurosyndrome (PSP), CNS NFT formation is also observed, and their density likewise correlates with the severity of neuronal loss. Alzheimer's disease (AD) is a neurodegenerative disease characterized by dementia, which causes problems with memory, thinking, and behavior. According to the Alzheimer's Association, an estimated 5.6 million Americans aged 65 and older (approximately 1 in 10) have AD, and another 200,000 Americans under 65 have AD. The Alzheimer's Association also anticipates a more than 26% increase by 2025 in the number of Americans aged 65 and older with AD. This represents a significant healthcare burden; in 2019 alone, direct healthcare costs related to AD were estimated to reach $290 billion in the United States, and this figure does not include unpaid care costs for caregivers. Despite the significant personal and healthcare impact of AD, there are currently no approved disease-modifying therapies for the treatment of AD, and such treatment remains an unmet medical need.Additionally, to aid in the discovery and / or development of disease-modifying therapies, reliable and sensitive diagnostics for AD are needed. One approved diagnostic application for AD is Amyvid™. Flourtaucipir is a diagnostic application for AD currently under FDA review. Both Amyvid™ and flortaucipir are radioisotopic neuroimaging agents useful in the detection and staging of AD and other neurodegenerative diseases. Furthermore, a diagnostic assay targeting phosphorylated threonine at human tau residue 181 (hTau-pT181) (residue number based on SEQ ID No. 1) in patient samples was recently disclosed.However, the hTau-pT181 diagnostic application lacks the necessary sensitivity for diagnostic tests, such as identifying different stages of Alzheimer's disease (AD) in patients or determining patient prognosis, using blood, plasma, and cerebrospinal fluid (CSF) analyses. Therefore, a diagnostic tool applicable to blood, plasma, and / or CSF tests is needed that offers a less expensive and less invasive diagnostic option while also being sensitive and reliable. Preferably, such a diagnostic tool will be able to identify and / or differentiate between patients with AD (e.g., based on AD stage or prognosis). Preferably, such a diagnostic tool will also be able to identify and / or differentiate between effective therapeutic responses.In these modalities, such diagnosis will also be able to identify and / or differentiate between patients who need further diagnostic evaluation, for example, patients for whom neurological imaging is appropriate, such as with flurotaucipir and / or amyvid. Accordingly, in one embodiment, the present description provides antibodies, and pharmaceutical compositions thereof, directed against human tau phosphorylated at threonine at residue 217 (residue number based on SEQ ID NO. 1) (hTau-pT217), as well as diagnostic methods and applications using such antibodies and pharmaceutical compositions. Additionally, according to one embodiment of the present description, antibodies and pharmaceutical compositions thereof are provided that are directed against human tau isoforms expressed in the CNS (i.e., they recognize isoforms expressed in the CNS and do not recognize human tau isoforms expressed exclusively outside the CNS).According to some modalities, antibodies are provided that bind specifically to hTau-pT217. In more specific modalities, antibodies are provided that bind to a human tau epitope region comprising phosphorylated threonine at residue 217 of SEQ ID NO. 1, wherein such antibodies do not bind to human tau if the threonine at residue 217 of SEQ ID NO. 1 is not phosphorylated.In even more specific embodiments of the present description, such antibodies comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO: 13, LCDR2 has the amino acid sequence of SEQ ID NO: 14, LCDR3 has the amino acid sequence of SEQ ID NO: 15, HCDR1 has the amino acid sequence of SEQ ID NO: 10, HCDR2 has the amino acid sequence of SEQ ID NO: 11, and HCDR3 has the amino acid sequence of SEQ ID NO: 12.In some modalities, LCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 13, LCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 14, LCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 15, HCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 10, HCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 11, and HCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 12. According to some antibody modalities provided by the present description, LCVR has the amino acid sequence of SEQ ID NO: 5 and HCVR has the amino acid sequence of SEQ ID NO: 3.In some antibody modalities provided by this description, LCVR has the amino acid sequence of SEQ ID NO: 8 and HCVR has the amino acid sequence of SEQ ID NO: 6. In some additional modalities, LCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 5 and HCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 3. Still in other modalities, LCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 8 and HCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 6. According to embodiments of the present description, antibodies are provided that bind specifically to human tau isoforms expressed in the CNS (e.g., known human tau isoforms expressed in the CNS), and such antibodies do not bind to human tau isoforms expressed exclusively in regions outside the CNS, including the peripheral nervous system. According to particular embodiments, such antibodies that bind specifically to human tau isoforms expressed in the CNS bind to a human tau epitope region comprising residues 124 (glutamine) and 125 (alanine) of SEQ ID NO.1.In specific modalities, such antibodies comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO: 23, LCDR2 has the amino acid sequence of SEQ ID NO: 24, LCDR3 has the amino acid sequence of SEQ ID NO: 25, HCDR1 has the amino acid sequence of SEQ ID NO: 20, HCDR2 has the amino acid sequence of SEQ ID NO: 21, and HCDR3 has the amino acid sequence of SEQ ID NO: 22.In some modalities, LCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 23, LCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 24, LCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 25, HCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 20, HCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 21, and HCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 22. According to some antibody modalities provided by this description, LCVR has the amino acid sequence of SEQ ID NO: 17 and HCVR has the amino acid sequence of SEQ ID NO: 19.In some additional modalities, LCVR_ has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 17 and HCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 19. According to some embodiments, the antibodies described herein can be humanized. In some embodiments, the antibodies described herein comprise an IgG4 heavy chain. In some embodiments, the antibodies described herein comprise a kappa light chain. According to still other embodiments, this description provides pharmaceutical compositions comprising an antibody described herein and one or more pharmaceutically acceptable vehicles, diluents, or excipients. According to other modalities, the present description provides a method for treating a neurodegenerative disease comprising administering to a patient in need an effective quantity of an antibody, or pharmaceutical composition thereof, of the present description. In some of these modalities, the neurodegenerative disease is a tauopathy. In even more specific modalities, the tauopathy is one of AD, PSP, and FTD. According to some modalities, this description provides an antibody, or a pharmaceutical composition thereof, for use in therapy. Additionally, an antibody, or a pharmaceutical composition thereof, is provided for use in the treatment of a neurodegenerative disease. In some of these modalities, the neurodegenerative disease is a tauopathy. In some more specific modalities, the tauopathy is selected from the group consisting of AD, PSP, and FTD. According to some embodiments of this description, an antibody, or a pharmaceutical composition thereof, is provided for use in the manufacture of a medicament for the treatment of a neurodegenerative disease. In some of these embodiments, the neurodegenerative disease is a tauopathy. In even more specific embodiments, the tauopathy is selected from the group consisting of AD, PSP, and FTD. According to additional embodiments of the present description, a method is provided for detecting hTau-pT217 in a patient sample. Such methods comprise the steps of contacting the patient sample with an antibody of the present description that binds specifically to hTau-pT217, and detecting a signal provided by said contact step. According to the modalities, a method is provided for detecting only human tau isoforms expressed in the CNS. Such methods comprise the steps of contacting the patient sample with an antibody of the present description that binds specifically to human tau isoforms expressed in the CNS (i.e., and that does not bind to human tau isoforms expressed exclusively outside the CNS), and detecting a signal provided by said contact step. According to some embodiments, a method for quantifying hTau-pT217 in a patient sample is provided. Such methods comprise the steps of contacting the patient sample with an antibody of the herein description that binds specifically to hTau-pT217 and detecting a signal provided by said contact step. In some embodiments, such methods further comprise the steps of contacting a control standard with the antibody and detecting a signal provided by said contact step of the control standard. In some embodiments, this description provides a method for quantifying hTau-pT217 in a patient sample. Such methods comprise the steps of contacting the patient sample with an antibody of this description that binds specifically to hTau-pT217 and contacting the patient sample with an antibody of this description that binds specifically to human tau isoforms expressed in the CNS, wherein the antibodies do not bind to overlapping epitope regions of the antibody and one of the antibodies comprises a detectable marker; detecting a signal provided by the detectable marker upon formation of a complex comprising the antibodies and hTau-pT217; contacting a control standard with the antibodies; and detecting a signal provided by the detectable marker upon formation of a complex comprising the antibodies and the control standard. According to some modalities of the present description, a method is provided for diagnosing a patient as one or more of the following: (i) having a neurodegenerative disease; (ii) being at risk of having a neurodegenerative disease; (iii) needing treatment for a neurodegenerative disease; (iv) being in Braak stage I, II, III, IV, V, or VI of Alzheimer's disease; or (v) needing neurological imaging. According to such modalities, these methods comprise the steps of contacting the patient sample with an antibody of the present description that binds specifically to hTau-pT217 and detecting the binding between the antibody and hTau-pT217 in the patient sample.In some of these modalities, the method also includes the step of diagnosing the patient as one of: (i) having a neurodegenerative disease; (ii) at risk of having a neurodegenerative disease; (iii) needing treatment for a neurodegenerative disease; (iv) in Braak stage I, II, III, IV, V or VI of AD; or (v) needing neurological imaging if the hTau-pT217 level detected in the patient sample exceeds a reference level. In some embodiments of the present description, a method is provided for diagnosing and treating a neurodegenerative disease in a patient. According to such embodiments, the methods comprise the steps of: contacting a patient sample with an antibody of the present description that binds specifically to hTau-pT217; detecting the binding between the antibody and hTau-pT217 in the patient sample; diagnosing the patient with a neurodegenerative disease; and administering a therapeutically effective amount of a human anti-Tau antibody to the diagnosed patient. In some embodiments, the diagnostic step comprises diagnosing the patient with a neurodegenerative disease when the presence of hTau-pT217 in the patient sample exceeds a reference level. According to some variations of the methods described herein, these methods also include the step of quantifying hTau-pT217 in the patient sample. In these variations, the step of quantifying hTau-pT217 comprises quantifying hTau-pT217 in the patient sample relative to a reference standard. According to some modalities of the methods described herein, the patient sample is one of blood, plasma, serum or CSF. According to some embodiments of the methods described herein, the methods further comprise the step of contacting the patient sample with an antibody that binds specifically to hTau-pT217 and a second antibody, said second antibody binding specifically to human tau isoforms expressed in the CNS. In some of these methods, one of the antibodies or the second antibody comprises a detectable marker, and the detection step comprises detecting a signal provided by the detectable marker after the formation of a complex comprising the antibody, the second antibody, and hTau-pT217. According to some of these embodiments, one of the antibodies and the second antibody are immobilized on a substrate.In some embodiments of the methods described herein, the steps of contacting the patient sample with the antibody and contacting the patient sample with the second antibody occur simultaneously. According to some more specific embodiments, the second antibody comprises an antibody of the description herein that binds specifically to human tau isoforms expressed in the CNS as described herein. As used in this description, an antibody is an immunoglobulin molecule comprising two hydrocarbons (HC) and two carbonyl groups (LC) interconnected by disulfide bonds. The amino-terminal portion of each LC and HC includes a variable region of approximately 100–120 amino acids, primarily responsible for antigen recognition via the complex receptor domains (CRDs) contained within it. The CRDs are interspersed with more conserved regions called framework regions (FRs). Each high-concentrated antibody receptor (HCVR) and low-concentrated antibody receptor (LCVR) is composed of three CRDs and four FRs, arranged from the amino-terminal to the carboxy-terminal end in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CRDs of the LC are designated LCDR1, LCDR2, and LCDR3, and the three CRDs of the HC are designated HCDR1, HCDR2, and HCDR3. The CRDs contain most of the residues that form specific interactions with the antigen. The functional ability of an antibody to bind to a particular antigen is greatly influenced by the six CDRs.The assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies of the present invention is based on the well-known Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, fifth edition, US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)), and the North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)). According to some embodiments of the present description, LCs are classified as kappa or lambda, each characterized by a particular constant region as known in the art. HCs, according to some embodiments of the present description, are classified as gamma, mu, alpha, delta, or epsilon, defining an antibody's isotype as IgG, IgM, IgA, IgD, or IgE, respectively. According to some embodiments, antibodies include IgG HCs, which may be further divided into subclasses, for example, IgG1, IgG2, IgG3, and IgG4. The carboxy-terminal portion of each HC defines a constant region primarily responsible for the effector function. In one particular embodiment, the antibodies of the present invention have one or more modifications in the constant region of each HC that reduce the effector function. The antibodies of the present invention are monoclonal antibodies. Monoclonal antibodies are antibodies derived from a single copy or clone, which may include, for example, any eukaryotic, prokaryotic, or phage clone, and are not defined by the method by which they are produced. Monoclonal antibodies may be produced, for example, by hybridoma technologies, recombinant technologies, phage presentation technologies, synthetic technologies, such as CDR grafting, or combinations of such or other technologies known in the art. Methods for producing and purifying antibodies are well known in the art and can be found, for example, in Harlow and Lañe (1988), Antibodies, A Laboratory Manual, Coid Spring Harbor Laboratory Press, Coid Spring Harbor, NY, chapters 5-8 and 15, ISBN 0-87969-314-2. For example, mice or rabbits can be immunized with hTau-pT217, and the resulting antibodies can be recovered, purified, and their amino acid sequences determined using conventional methods well known in the art. Similarly, a phage library can be screened, whereby thousands of Fab fragments are screened for interaction with hTau-pT217, and the resulting interactions can be recovered, purified, and their amino acid sequences determined using conventional methods well known in the art, by which the original initial antibodies can be constructed.The antibody variants described herein include genetically engineered antibodies that contain one or more human frame regions surrounding non-human antibody-derived CDRs. Human frame germline sequences can be obtained, for example, from ImMunoGeneTics (INGT) via their website, http: / / imgt.cines.fr, or from The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic Press, 2001, ISBN 012441351. In particular embodiments of the present invention, the antibody, or the nucleic acids encoding it, is provided in isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is free or substantially free of any other macromolecular species found in a cellular environment. The antibodies provided herein may be used in the treatment of patients. More particularly, the antibody formulations herein may be useful in the treatment of neurodegenerative diseases or disorders, including tauopathies such as AD, PSP, and FTD. Although the antibodies of the present invention may be useful in the treatment of AD, PSP, and FTD, such antibodies may also be useful in the treatment of other neurodegenerative diseases, particularly those involving tau pathology such as NFT formation. As used interchangeably herein, "treatment" and / or "treat" are intended to refer to any process in which there may be a slowing, interruption, arrest, control, or reversal of the progression of the disorders herein, but do not necessarily imply a complete elimination of all symptoms of the disorder.The treatment includes administering an antibody of the present invention for the treatment of a disease or condition in a human being who would benefit from a reduction in the spread of at least one of the following: tau aggregate formation, NFT formation, and neuronal loss, and includes: (a) inhibiting further disease progression, i.e., halting its development; and (b) alleviating the disease, i.e., causing regression of the disease or disorder or relieving the symptoms or complications thereof. As used interchangeably in this description, the terms patient, subject, and individual refer to a human being. In certain modalities, the patient is further characterized by a disease, disorder, or condition (e.g., a neurodegenerative disorder) that would benefit from a reduction in the spread of at least one of the following: tau aggregate formation, neurofibrillary tangle formation, and neuronal loss. In another modality, the patient is further characterized by being at risk of developing a neurodegenerative disorder, disease, or condition that would benefit from a reduction in the spread of at least one of the following: tau aggregate formation, NFT formation, and neuronal loss. As used in this description, the term "binding specifically to hTau-pT217" refers to an interaction of an antibody with a human tau epitope region comprising a phosphorylated threonine at residue 217 of SEQ ID NO. 1. Such binding is dependent on the phosphorylation of the threonine at residue 217 of SEQ ID NO. 1. It should be understood that known variations or isoforms of human tau exist, for example, resulting from splicing variants. It is also understood that such known variants may result in altered residue numbering for some amino acid residues of SEQ ID NO. 1 that include the phosphorylated threonine as provided herein, with reference to the human tau sequence as indicated in SEQ ID NO. 1. As used herein, the term "binds specifically to human tau isoforms expressed in the CNS" refers to an interaction of an antibody of this description with an epitope region common to, or present in, human tau isoforms expressed in the CNS and whose epitope region is not present in human tau isoforms expressed exclusively outside the CNS. Antibodies that bind specifically to human tau isoforms expressed in the CNS do not bind to human tau isoforms expressed exclusively outside the CNS (e.g., isoforms expressed only in other body regions such as the peripheral nervous system).According to some modalities, antibodies that bind specifically to human tau isoforms expressed in the CNS bind to, or recognize, an epitope region of human tau isoforms expressed in the CNS comprising glutamine at residue 124 (Q124) and alanine at residue 125 (A125), residue number in reference to SEQ ID NO. 1. It should be understood that there are known variations or isoforms of human tau, for example, resulting from splicing variants and that such variants may result in altered residue numbering for some amino acid residues in reference to SEQ ID NO. 1, including glutamine and alanine as provided herein in reference to the human tau sequence set out in SEQ ID NO. 1. The term epitope region, as used herein, refers to discrete three-dimensional sites on an antigen that are recognized, in whole or in part, by the antibodies of the present invention. The amino acids of an epitope region provide chemically active surface clusters of human tau and form a human tau-specific three-dimensional structure, and may provide specific charge characteristics. Conformational and non-conformational / linear epitopes can be distinguished in that binding to conformational epitope regions is lost in the presence of denaturing solvents, whereas linear epitope regions are not. An antibody of the present invention can be incorporated into a pharmaceutical composition that can be prepared by methods well known in the art and that comprises an antibody of the present invention and one or more pharmaceutically acceptable vehicles and / or diluents (e.g., Remington, The Science and Practice of Pharmacy, 22nd edition, Lloyd V., Ed., Pharmaceutical Press, 2012, ML / a / ZUZ 1 / U144 ZJ, which provides a compendium of formulation techniques generally known to practitioners. Suitable vehicles for pharmaceutical compositions include any material that, when combined with the antibody of the present invention, retains the activity of the molecule and is non-reactive with the patient's immune system. A pharmaceutical composition comprising an antibody of the present invention may be administered to a patient at risk of, or exhibiting, diseases or disorders as described herein by parenteral routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal). A pharmaceutical composition of the present invention contains an effective or therapeutically effective amount, as used interchangeably herein, of an antibody of the present invention.An effective amount refers to the quantity required (in terms of dosage, time period, and means of administration) to achieve the desired therapeutic result. An effective amount of an antibody may vary according to several factors, such as the individual's pathological condition, age, sex, and weight, and the antibody's ability to induce a desired response in the individual. An effective amount is also one in which any toxic or harmful effects of the antibody of the present invention are outweighed by the therapeutically beneficial effects. The percent homology, as defined herein, in the context of two or more amino acid sequences, refers to two or more sequences that have a specific percentage of identical amino acid residues when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm (e.g., BLASTP and BLASTN or other algorithms available to trained personnel) or by visual inspection. Depending on the application, the percent homology may exist in a region of the sequence being compared, for example, in a functional domain, or alternatively, it may exist along the entire length of the two sequences being compared. For example, the percent homology of a sequence may be compared to a reference sequence.For example, when using a sequence comparison algorithm, the test and reference sequences can be entered into a computer (and subsequence coordinates can also be specified, if desired, along with the algorithm's program parameters). The sequence comparison algorithm then calculates the percentage of sequence identity, or homology, for the test sequence(s) relative to the reference sequence(s), based on the specified program parameters. Exemplary sequence alignment and / or homology algorithms are available from Smith and Waterman, Adv. Api. Math. 2:482 (1981), Needleman and Wunsch, J. Mol. Biol. 48:443 (1970), and Pearson and Lipman, Proc. Nati. Acad. Sci. USA 85:2444 (1988), GAP, BESTFIT, FASTA, and TFASTA (in Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).An example of an algorithm suitable for determining sequence identity and sequence similarity percentages is the BLAST algorithm, described in Altschul et al., J. Mol. Biol. 215: 403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ). ML / a / ZUZl / U144 ZJ A patient sample as used herein refers to a human sample. Non-limiting sources of a sample for use in the present invention include blood, plasma, serum, and CSF. Additionally, the sample may also refer to lymphatic fluid, biopsy aspirates, ascites, fluid extracts, solid tissue, external sections of skin, respiratory, nasal, intestinal, and genitourinary tracts, tears, saliva, milk, tumors, organs, cell cultures, and / or cell culture constituents. This description also refers to clinical diagnostic, prognostic, or theranostic methods performed on a subject by a medical professional using the methods described herein. These methods, as described herein, may be performed by an individual, a healthcare professional, or a third party, such as a service provider who interprets the subject's information. As explained herein, a medical professional may initiate or modify treatment after receiving information about a diagnostic method described herein. For example, a medical professional may recommend a therapy, a change in therapy, or further diagnostic evaluation (e.g., neurological imaging). The anti-tau antibodies described herein, which bind specifically to hTau-pT217, can be used to isolate, detect, and / or quantify hTau-pT217 using techniques such as affinity chromatography, immunoprecipitation, immunohistochemistry, or ELISA-based assays. Such an assay can be used to detect and / or evaluate the abundance and / or expression patterns of hTau-pT217 for diagnostic, prognostic, or theranostic purposes, to monitor polypeptide levels (e.g., in serum, plasma, blood, or CSF), or as part of a clinical analysis procedure (e.g., to determine the efficacy of a given treatment regimen). The anti-tau antibodies described herein, which bind specifically to human tau isoforms expressed in the CNS, can be used to isolate and / or detect human tau isoforms expressed in the CNS (excluding human tau isoforms expressed exclusively outside the CNS) using techniques such as affinity chromatography, immunoprecipitation, immunohistochemistry, or ELISA-based assays. Such an assay can be used to detect and / or evaluate the abundance and / or patterns of human tau expression isoforms expressed in the CNS for diagnostic, prognostic, or theranostic purposes, or to monitor polypeptide levels, for example, in serum, plasma, blood, or CSF, as part of a clinical analysis procedure, for example, to determine the efficacy of a given treatment regimen. As understood in the art, an antibody of the present invention can be coupled to a detectable substance or marker to facilitate its detection.Examples of detectable substances or markers include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, diluminescent materials, chemiluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotzinilamine, fluorescein, dansyl chloride, or phycoerythrin; an example of a luminescent material. ML / a / ZUZ 1 / U144 includes luminol; examples of bioluminescent materials include luciferase, luciferin, ruthenium, and aequorin, and examples of suitable radioactive material include 125I, 1311, 35S, or 3H. The antibodies of the present invention may also be useful in pharmacogenomic analysis. Such modalities may be used to identify individuals who may benefit from specific or modified treatment modalities and / or to monitor the efficacy of current treatment regimens. The levels or measurements of hTau-pT217, as provided by the assays of the present invention, can be absolute values ​​(e.g., concentration within a biological sample) or relative values ​​(e.g., concentration compared to a reference). As used herein, hTau-pT217 is referred to as elevated in a patient sample if the method for detecting hTau-pT217 indicates that the level or concentration of hTau-pT217 in the patient sample is higher than a reference value. Conversely, hTau-pT217 is referred to as decreased in a patient sample if the level or concentration of hTau-pT217 in a patient sample is lower than a reference value, or, for example, the measured value of hTau-pT217 in a sample from a previous patient. A reference value, as used herein, refers to a known or approximate concentration of hTau-pT217 associated with a specific condition. The concentration levels in a reference value may be an absolute or relative amount, an amount range, or a minimum, average, and / or mean amount of hTau-pT217. A reference value may also serve as an hTau-pT217 baseline against which the patient sample is compared. A control standard, as used herein, refers to a sample that can be used to compare the results obtained from a patient sample using the methods of the invention. Control standards may be cells, blood, plasma, CSF, tissue, or known protein concentrations added to a medium. The concentration levels in a control standard may be an absolute or relative amount, an amount range, or a minimum, average, and / or mean amount of hTau-pT217. A control standard may also serve as an hTau-pT217 baseline against which the patient sample is compared. The control standard may include a concentration value from the same patient or a known normal reference value of hTau-pT217. In addition, in some embodiments, a control standard may express hTau-pT217 concentrations in the form of a standard curve. As used in this description, the term capture antibody refers to an antibody that will bind to hTau-pT217. In such modalities, the capture antibody is capable of binding to and capturing hTau-pT217—for example, specifically binding to hTau-pT217 (for example, not binding to human Tau if the threonine at residue 217 of SEQ ID NO. 1 is not phosphorylated)—in a patient sample under suitable conditions, such that the capture antibody-hTau-pT217 complex can be separated from the rest of the sample. In some modalities, the capture antibody may be an antibody that binds specifically to isoforms of human tau expressed in the CNS (for example, which may include hTau phosphorylated at the threonine residue 217), and an antibody that binds specifically to hTau-pT217 is used as the second (or detection) antibody. In some modalities, the capture antibody is immobilized. In some modalities, the detection antibody is labeled with a detectable marker. In some modalities, the capture antibody is immobilized in a sandwich immunoassay, and the first antibody or capture antibody is specifically bound to a human tau epitope region comprising phosphorylated threonine at residue 217 of SEQ ID NO. 1. In such sandwich immunoassays, a detection antibody (or second antibody) is also used. According to some modalities, a second antibody or detection antibody may be specifically bound to the capture antibody and may be labeled with a detectable marker. In some modalities, the second antibody or detection antibody is specifically bound to hTau-pT217 already bound, or captured, by the first antibody or capture antibody.In such embodiments, the detection antibody binds to hTau-pT217 at a second epitope region that does not overlap with the first antibody or capture antibody and can be labeled with a detectable marker. In some of such embodiments, the second antibody is an antibody of the present invention that binds specifically to human tau isoforms expressed in the CNS. As used herein, a detectable marker is a residue, composition, or technique that can be used to detect the formation of a complex between an antibody of the present invention that specifically binds to hTau-pT217 and hTau-pT217. According to some embodiments, the detectable marker can be conjugated to the antibody (whether capture or detection, as the case may be) directly or indirectly. Exemplary embodiments of detectable markers include biotin; radioisotopes; fluorophores or other fluorescent residues; and enzyme residues. The term diagnosis or diagnose, as used interchangeably herein, refers to methods by which a person skilled in the art can estimate and / or determine the probability of whether or not a patient has a particular disease or condition. In the case of the present invention, diagnosing a patient includes using the results of an assay of the present invention to identify or diagnose a neurological disorder such as AD, PSP, or FTD, as well as identifying in a patient, for example, the presence or onset of a neurological disease or disorder, the need for treatment, or the effectiveness of a treatment against the neurological disease in the patient. A diagnosis may, according to the present invention, be based on a combination of other clinical indications, as understood by a healthcare professional, to arrive at a diagnosis.According to some embodiments of the present invention, the diagnostic applications of the present invention can be used to diagnose a patient in a Braak stage I, II, III, IV, V, or VI of AD. The Braak stages of AD are known in the field and as described in Braak, et al., (2006) Acta Neuropathol 112(4): 389-404. Examples Anti-hTau-pT217 antibodies The anti-hTau-pT217 antibodies, or antibodies that bind specifically to hTau-pT217, described herein are generated using hybridoma methodology (e.g., as first described by Kohler et al., Nature, 256:495 (1975)). Briefly, by way of example, a rabbit is immunized with a peptide that includes phosphorylated threonine and four or more N-terminal and C-terminal amino acids of such threonine, as represented by SEQ ID NO. 1 (an example of a peptide that may be used in immunization is provided by SEQ ID NO. 26). Lymphocytes capable of producing antibodies that bind to hTau-pT217 are isolated and fused with a myeloma cell line using a suitable fusion agent to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).Hybridomas are seeded and grown in a suitable culture medium (preferably containing one or more substances that inhibit the survival of unfused myeloma cells). The binding specificity of the monoclonal antibodies produced by the hybridomas is then determined by an in vitro binding assay (e.g., immunoprecipitation, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA)) using both hTau-pT217 and recombinant tau unphosphorylated at residue 217 (number based on reference to SEQ ID NO. 1). Antibodies that bind specifically to hTau-pT217 (e.g., and do not bind to human tau unphosphorylated at residue 217, numbering based on SEQ ID NO. 1) are identified.Preferred hybridomas can be subcloned by limited dilution procedures and cultured using standard methods, including in vivo as ascitic tumors in an animal (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59–103 (Academic Press, 1986)). Monoclonal antibodies secreted by hybridomas (and / or subclones) are purified according to conventional procedures such as, for example, affinity chromatography (e.g., protein A or protein G-Sepharose) or ion-exchange chromatography, hydroxylapatite chromatography, gel electrophoresis, dialysis, or similar methods. The cDNA encoding the antibodies of the present invention is sequenced using conventional procedures. An exemplified rabbit anti-hTau-pT217 antibody (mAb A), generated by following procedures substantially as described herein, comprises a heavy chain of SEQ ID NO. 2 and a light chain of SEQ ID NO. 4. The complementarity-determining regions (CDRs) or variable regions of the sequenced antibodies can be used in conversion into chimeric or humanized antibodies, and / or converted into other forms of mammalian IgG. For example, a clone can be converted into a murine chimeric IgG antibody such as the exemplified rabbit variable region, murine chimeric constant-region IgG anti-hTau-pT217 antibody (mAb B) having a variable heavy chain region of SEQ ID NO. 6 and a heavy chain of SEQ ID NO. 7 and a variable light chain region of SEQ ID NO. 8.8 and a light chain of SEQ ID NO. 9. The binding specificity can then be reassessed. The cDNA sequences encoding the heavy and light chains can be cloned and genetically engineered into an expression vector containing GS (glutamine synthetase). The genetically engineered immunoglobulin expression vector can then be stably transfected into CHO cells. As someone skilled in the technique will appreciate, mammalian antibody expression will result in glycosylation, typically at highly conserved N-glycosylation sites in the Fe region. Stable clones can be verified for the expression of an antibody that binds specifically to hTaupT217. Positive clones can be expanded in serum-free culture medium for antibody production in bioreactors. The medium, into which an antibody was secreted, can be purified using conventional techniques.For example, the medium can be conveniently applied to a G sepharose or Protein A FF column equilibrated with a compatible buffer, such as phosphate-buffered saline. The column is washed to remove nonspecific binding components. The bound antibody is eluted, for example, by pH gradient, and the antibody fractions are detected, such as by SDS-PAGE, and then pooled. The antibody can be concentrated and / or sterilized by filtration using common techniques. Soluble aggregates and multimers can be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The product can be immediately frozen, for example, at -70 °C, or lyophilized. Specific antibodies against hTau isoforms expressed only in the CNS The antibodies described herein that bind specifically to human tau isoforms expressed in the CNS can be generated using hybridoma methodology (e.g., as first described by Kohler et al., Nature, 256:495 (1975)). Briefly, by way of example, a non-human mammal (e.g., a murine or a rabbit) can be immunized with a human tau protein (e.g., hTau given by SEQ ID NO. 1), or a peptide thereof that includes glutamine at residue 124 and alanine at residue 125, with the numbering as represented by SEQ ID NO. 1. Lymphocytes capable of producing antibodies that bind specifically to human tau isoforms expressed in the CNS can be isolated and fused with a myeloma cell line by using a suitable fusion agent to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).Hybridomas can be seeded and cultured in a suitable culture medium (preferably containing one or more substances that inhibit the survival of unfused myeloma cells). The binding specificity of the monoclonal antibodies produced by the hybridomas is then determined by an in vitro binding assay (e.g., immunoprecipitation, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA)) against both human tau isoforms expressed in the CNS (e.g., a peptide having the sequence of SEQ ID NO. 1) and / or peripherally expressed human tau isoforms (e.g., a peptide having the sequence given by SEQ ID NO. 27 that does not include glutamine at residue 124 adjacent to alanine at residue 125 represented by SEQ ID NO. 1).Antibodies that bind specifically to human tau isoforms expressed in the CNS (e.g., and do not bind to peripherally expressed human tau) can be identified. Preferred hybridomas can be subcloned using limited dilution procedures and cultured by standard methods, including in vivo ascitic tumors in an animal (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59–103 (Academic Press, 1986)). Monoclonal antibodies secreted by hybridomas (and / or subclones) can be purified according to conventional procedures such as, for example, affinity chromatography (e.g., Protein A or Protein G-Sepharose) or ion-exchange chromatography, hydroxyapatite chromatography, gel electrophoresis, dialysis, or similar methods. The cDNA encoding the antibodies of the present invention can be sequenced using conventional procedures. An exemplified murine antibody of the present description that binds specifically to human tau isoforms expressed in the CNS (mAb C), generated by following procedures substantially as described herein, comprises a heavy chain of SEQ ID NO. 16 and a light chain of SEQ ID NO. 18. The complementarity-determining regions (CDRs) or variable regions of the sequenced antibodies can be used in conversion into chimeric or humanized antibodies and / or converted into other forms of mammalian IgG and expressed in component host cells such as CHO cells. Kinetics and binding affinity A biolayer interferometry (BLI) assay, measured with a ForteBio-available Octet Red96® instrument (using HBS-EP+ running buffer (GE Healthcare, Hepes 10 mM pH7.4 + NaCl 150 mM + EDTA 3 mM + P20 surfactant 0.05%) at 25 °C), is used to measure the binding of an antibody of the present invention that specifically binds to hTau-pT217 to the recombinant hTau-pT217 protein having the amino acid sequence SEQ ID NO: 1. Unless otherwise noted, all reagents and materials are from ForteBio (Freemont, GA). A protein A biosensor is used to immobilize the antibody of interest for analysis. Samples of the present invention's exemplary antibodies (mAb A) are prepared at 5 pg / mL by dilution in running buffer. Recombinant hTau-pT217 protein is prepared at concentrations of 300, 100, 33.3, 11.1, 3.7, 1.24, 0.4115, and 0 (blank) nM by dilution in running buffer.Each assay consists of: (1) capturing antibody samples in biosensors for 240 seconds; (2) establishing a baseline by incubating the antibody-loaded biosensors with run buffer for 60 seconds; (3) incubating the antibody-loaded biosensors with serially diluted recombinant hTau-pT217 protein for 300 seconds to monitor the association phase; (4) returning the biosensor to the run buffer to monitor the dissociation phase. The bonding data are processed using a double standard reference and fitted to a 1:1 bonding model using Data Analysis v9.0 evaluation software to determine the association rate (kon, units MΎ) and the dissociation rate (ko«, units s1). The equilibrium dissociation constant (Kd) is calculated from the relationship Kd = k0ff / k0n and is in molar units. The results are provided in Table 1. Table 1: BLI binding data to recombinant hTau-pT217. IVIA / a / ¿U¿ 1 / Ul 44 ZJ Antibody exemplified kon (units M'1s'1) k0« (units M-1s'1) KD* (nM) mAb A 3.39E+05 2.36E-04 6.95E- 10 'The Kd results are considered relative since the results are not normalized by the influence of avidity. Binding specificity to hTau-pT217 The specificity of the antibodies exemplified by the present invention that bind specifically to hTau-pT217 (mAb A and mAb B) is determined using synthetic peptides by means of a BLI assay, measured with an available Octet Red96® instrument from ForteBio (using HBS-EP+ running buffer (GE Healthcare, Hepes 10 mM pH 7.4 + NaCl 150 mM + EDTA 3 mM + P20 surfactant 0.05%) at 25°C). The N-terminal biotin-labeled peptides of SEQ ID NO. 26, with and without phosphorylated threonine at residue 7, are immobilized on streptavidin biosensors (ForteBio). The peptides were incubated with IgG from mAb A and mAb B diluted to 5 pg / mL in run buffer for 300 seconds, followed by dissociation for 300 seconds. Binding data were determined using Data Analysis v9.0 evaluation software. The binding signal (nm) for each peptide at the end of dissociation is provided in Table 2. Table 2: Binding data of BLI pf mAb A and mAb B to recombinant hTau with and without pT217. Example antibody phosphorylated threonine (nm units) non-phosphorylated threonine (nm units) mAb A 4.4178 -0.0024 mAb B 4.7715 0.3389 hTau-pT217 immunoassay Immunoassays for measuring hTau-pT217 in plasma were designed to measure disease-related differences in patients with Alzheimer's disease. As an example, an immunoassay of the present description is performed on a streptavidin small dot plate using the Meso Scale Discovery (MSD) platform. mAb A or mAb B is used as a capture antibody and is biotinylated. A second SULFO-TAG antibody, such as mAb C (an antibody of the present description that binds specifically to human tau isoforms expressed in the CNS), is used as a detection antibody. The antibodies are conjugated with Sulfo-NHS-Biotin (Thermo Scientific, catalog number: 21329) or MSD GOLD SULFO-TAG NHS-Ester (MSD, catalog number: R91AO-1) according to the manufacturer's protocol.The assay is calibrated using recombinant tau protein (4R2N, NCBI tau v2) that is phosphorylated in vitro using a reaction with glycogen synthase kinase-3 and characterized by mass spectrometry. The sample is thawed on wet ice, briefly shaken on a shaker, and the plasma is diluted 1:4 in sample buffer: for mAb A (phosphate-buffered saline (PBS), 0.5% bovine serum albumin (BSA), 0.5% Tween20, 5 mM EDTA, 5 mM EGTA); For mAb 2 HEPES 50 mM, NaCl 300 mM, EDTA 5 mM, EGTA 5 mM, Triton X-100 1%, MSD Blocker A 1%, PEG 2%), with the addition of Heterophilic Blocking Reagent 1 at a concentration of 200 µg / mL (Scantibodies Inc, catalog number: 3KC533). The calibrator diluent is prepared by mixing the sample buffer 50 / 50 with Knock-Out serum replacement (Gibco, 10828-010). Streptavidin-coated plates in small spots of MSD (MSD, L45SA) were blocked for 1 hour at room temperature with 200 µL of 3% BSA in PBS with shaking at 650 rpm on a plate shaker. The plates were washed three times with 200 µL of wash buffer (PBS + 0.05% Tween 20) and 25 µL of biotinylated capture antibody (mAb A) at 0.464 µg / mL (diluted in DPBS + 0.1% BSA + 0.05% Tween 20, plus 2% PEG for mAb 2) were added to the hTau-pT217 plates and incubated for 1 hour at room temperature with shaking at 650 rpm on a plate shaker. The plates are washed again three times with 200 µL of wash buffer, and 50 µL of diluted calibrator or sample is added to the plate. They are then incubated for 2 hours at room temperature with shaking at 650 rpm on a plate shaker. Afterward, the plates are washed three times with 200 µL of wash buffer, and 25 µL of SULFO-labeled detection antibody (mAb C) is added.25 µg / mL (diluted in MSD 35 diluent, plus 2% PEG for mAb 2) for hTau-pT217 and incubated for 1 hour at room temperature with shaking at 650 rpm on a plate shaker. The plates were washed one last time with 200 µL of wash buffer and 150 µL of MSD 2X surfactant T reading buffer (MSD, R92TC) was added to each plate and read on the MSD SQ120 within 10 minutes of adding the reading buffer. The results were calculated by MSD software using a 1 / y², 4PL weighting of the standard curve for interpolation using the equation: Y = bi + ((b² - bi) / (1 + (x / 0³)b⁴)). hTau-pT217 immunoassay as a prognostic assay for neurological imaging hTau-pT217 and hTau-pT181 levels were assessed in the blood of subjects enrolled in Alzheimer's disease (AD) clinical trials. An hTau-pT217 immunoassay, as described herein, was used to assess hTau-pT217 in the plasma of AD subjects from two studies (Study 1: N = 42; Study 2: N = 185). The hTau-pT181 immunoassay, previously described in this field, was also used to measure hTau-pT181 in the same patients. All patients underwent positron emission tomography (PET) of tau measured by neuroimaging with flortaucipir. Samples were acquired during two separate clinical trials, including the baseline, and stored at -80 °C for future biomarker research. Flortaucipir SUVRs are determined in a neocortical region of interest with respect to a reference signal in the white matter.The correlations between the SUVR of flortaucipir and plasma pTau (pT181 and pT217, respectively) were assessed using Spearman's rank correlation coefficients. Receiver operating characteristic (ROC) curve analyses used logistic regression models incorporating age and sex as covariates and a flortaucipir SUVR positivity threshold >1.1. Baseline pTau predicting future cognitive decline was assessed using mixed-effects models evaluating pTau by quartile. The hTau-pT217 immunoassay showed a statistically significant higher correlation with flortaucipir PET in both studies (p <0.05), as shown in Table 3. IVIA / a / ZUZ I / U I44 ZJ Table 3. Correlation of hTau-pT217 and hTau-pT181 immunoassays with Flortaucipir PET hTau-pT217 Immunoassay hTau-pT181 Immunoassay Study 1 0.783 0.332 Study 2 0.463 0.308 IVIA / a / ¿U¿ I / U 144 ZJ The area under the ROC curve for flortaucipir positivity shows higher values ​​for hTau-pT217 compared to hTau-pT181 in both studies (Study 1: 0.88 vs. 0.79; Study 2: 0.83 vs. 0.81, respectively). Additionally, mixed-effects models of hTau-pT271 by quartile show significant increases in cognitive impairment. As demonstrated by the results of this example, the hTau-pT217 immunoassays described here are able to identify subjects suitable for neuroimaging and at risk of cognitive impairment due to neurodegenerative disease, and show a significant improvement over the hTau-pT181 immunoassay. hTau-pT217 immunoassay as a diagnostic indicator of AD and disease progression hTau-pT217 levels in CSF were assessed using an immunoassay as described and compared with hTau-pT181 immunoassay assessments. Briefly, CSF samples from intact elderly patients (CU, n=65); patients with mild cognitive impairment due to AD (MCI-AD, n=29); AD dementia (n=43); and other neurodegenerative disorders (n=57) from the Swedish BioFINDER study were assessed using hTau-pT217 and hTau-pT181 immunoassays. One hundred and eighty-four participants underwent 18F-flortaucipir positron emission tomography (PET). 18F-flortaucipir uptake was quantified in predefined regions linked to tau pathology in AD, including Braak stages I-II, III-IV, and V-VI of tau and temp. lower. In patients with UC, both the hTau-pT217 and hTau-pT181 immunoassays correlate with 18F-Flortaucipir in Braak stages I-II; in patients with AD, both the hTau-pT217 and hTau-pT181 immunoassays correlate in regions in Braak stages III-IV and V-VI; in patients with MCI, hTau-pT217 correlates with 18F-Flortaucipir in regions I-II, in Braak stages III-IV and V-VI, while hTau-pT181 correlates only in the region of Braak stage I-II. It is important to highlight that the correlations between regional 18F-Flortaucipir and hTau-pT2 immunoassay17 show a statistically significant improvement (p<0.001-0.016) over the correlation between hTau-pT181 immunoassay and 18F-Flortaucipir in all three diagnostic groups (UC, MCI and AD) and in all regions (Braak stages I-II, III-IV and V-VI). The correlation coefficients of the hTau-pT217 immunoassay consistently showed statistically significant higher values ​​(all p<0.001) compared to the hTau-pT181 immunoassay for 18F-Flortaucipir in all regions: hTau-pT217 (0.698–0.752) vs. hTau-pT181 (0.572–0.706). Furthermore, the hTau-pT217 immunoassay proved to be a statistically significant (p<0.001) more accurate predictor of pathological 18F-Flortaucipir states in all regions (hTau-pT217: AUC 0.890–0.929; hTau-pT181 immunoassay: AUC 0.859–0.904). Additionally, the hTau-pT217 immunoassay demonstrates statistically significant improved performance (p=0.026) over the hTau-pT181 immunoassay in distinguishing AD from non-AD neurodegenerative disease (hTau-pT217: AUC 0.943; hTau-pT181: AUC 0.914).These results indicate that the hTau-pT217 immunoassay correlates with the neurological imaging of 18F-Flortaucipir and is able to differentiate AD from other neurological disorders and stages, and shows a significant improvement over the hTau-pT181 immunoassay. hTau-pT217 immunoassay is associated with Tau SUVr PET Tau SUVr PET has been shown in the literature to be associated with Tau pathology. The hTau-pT217 immunoassay, as described herein, correlates with Tau SUVr PET in a study measuring hTau-pT217 in plasma, serum, and CSF from patients with mild AD. Briefly, 190 subjects underwent hTau-pT217 immunoassay in plasma at baseline. Of these 190 subjects, 185 underwent Tau SUVr PET assays. Data were analyzed using Spearman's rank correlation coefficient, and a significant correlation was observed with a Spearman's p-value of 0.49 and an uncorrected p-value of <0.001. Additionally, hTau-pT217 was measured in serum at baseline in 187 subjects. Of these 187 subjects, 182 underwent Tau SUVr PET assays. The data are analyzed using a Spearman test and a significant correlation is observed with a Spearman p = 0.41, uncorrected p value of < 0.001.In addition, 86 subjects had hTau-pT217 measured in CSF at baseline. Of these 86 subjects, 29 underwent a Tau SUVr PET scan. Data were analyzed using Spearman's rank correlation coefficient, and a significant correlation was observed with a Spearman's rank correlation coefficient of 0.70 and an uncorrected p-value <0.001. These results support the use of pTau217 levels measured in CSF, plasma, or serum to identify Tau pathology. hTau-pT217 immunoassay is associated with mild cognitive impairment in AD Mean hTau-pT217 values ​​in plasma, serum, and CSF from subjects with mild AD were calculated according to an immunoassay as described above. The results for each matrix are provided in Table 4. Table 4. Mean hTau-pT217 values ​​in plasma, serum, and CSF of subjects with mild AD Liquid Mean Standard Deviation N Plasma 14.2 6.2 190 Serum 13.4 6.2 187 CSF 684.9 531.1 86 The hTau-pT217 immunoassay, as described herein, is associated with the cognitive status of patients with mild Alzheimer's disease (based on the Mini-Mental State Examination, MMSE) and the change from baseline versus placebo for the MMSE. hTau-pT217 is assessed by immunoassay in plasma, serum, and cerebrospinal fluid (CSF) from patients with mild Alzheimer's disease. Briefly, for each matrix (plasma, serum, and CSF), subjects with hTau-pT217 measurements (as described herein) and baseline MMSE scores, and the change from baseline scores, are evaluated for significance using Spearman's rank correlation coefficient.The hTaupT217 immunoassay shows a statistically significant association with both cognitive status and change from baseline in plasma and serum (the number of CSF samples is too small for statistical significance, but the data showed an association such that with a larger number of samples, such as those evaluated for serum and plasma, CSF is expected to have statistically significant associations with both MMSE change and MMSE from baseline). The results are provided in Table 5. Table 5· Evaluations of the hTau-pT217 immunoassay in plasma, serum, and CSF with change in MMSE and MMSE at baseline in subjects diagnosed with mild AD Variable (X) Variable (Y) Spearman p Prob> | p| N Baseline MMSE score Log10 pTau217 Log10 OCSF* pTau217 -0.16 1.71E-01 78 Change in MMSE from baseline (placebo only) Log10 pTau217 Log10 OCSF* pTau217 -0.25 1.48E-01 35 Baseline MMSE score Log10 pTau217 Plasma -0.19 9.41 E-03 187 Change in MMSE from baseline (placebo only) Log10 pTau217 Plasma -0.43 3.27E-05 89 Baseline MMSE score Log10 pTau217 Serum -0.17 2.17E-02 184 Change in MMSE from baseline (placebo only) Log10 pTau217 Serum -0.32 3.11 E-03 86 *Not considered statistically significant due to the small sample size of patients assessed for MMSE change from baseline. These results demonstrate a cross-sectional association of hTau-pT217 with a measure of cognition, MMSE, and demonstrate the usefulness of hTau-pT217 to determine the future risk of cognitive decline. hTau-pT217 immunoassay associated with amyloid status The hTau-pT217 immunoassay, as described herein, is associated with amyloid status. Briefly, plasma samples from four distinct groups of patients with known Alzheimer's disease (AD) and amyloid status (based on neurological PET imaging) were evaluated to determine the association of hTau-pT217: (i) elderly, amyloid-positive (CU-A+); (ii) elderly, amyloid-negative (CU-A-); (iii) elderly, amyloid-positive AD (AD-A+); and (iv) clinically unaffected young adults (CUY-A-). Samples from each group were analyzed using the hTau-pT217 immunoassay as described herein. The results are presented in Table 6. Table 6. Amyloid and hTau-pT217 status associated with AD Group Mean Standard Deviation N Alzheimer's Disease - Amyloid positive 11.4 6.9 14 Clinically unaffected elderly - Amyloid positive 6.7 1.9 14 Clinically unaffected elderly - Amyloid negative 3.6 1.4 16 Clinically unaffected young adults - Amyloid negative 3.6 1.3 10 The evaluation of the hTau-pT217 immunoassay for the identification of amyloid-positive subjects was determined by evaluating the results provided in Table 6 for separate groups using a Student's t-test. The results are provided in Table 7. Table 7· Student's t-test of the difference of means of amyloid status and plasma hTau-pT217 associated with AD Level 1 Level 2 Difference Standard Error Difference p-value Alzheimer's Disease Amyloid positive Clinically unaffected elderly - Amyloid negative 7.8 1.4 4.60E-06 Alzheimer's Disease Amyloid positive Clinically unaffected young - Amyloid negative 7.8 1.6 4.67E-05 Alzheimer's Disease - Amyloid positive Clinically unaffected elderly - Amyloid positive 4.7 1.4 1.05E-02 Clinically unaffected elderly - Amyloid positive Clinically unaffected elderly - Amyloid negative 3.2 1.4 1.17E-01 As shown in Tables 6 and 7, the mean for the AD-A+ group is 11.4 pg / mL, three times higher than that of the age-matched CU-A- group at 3.6, resulting in an uncorrected p-value of 4.60E06. A receiver operating characteristic (ROC) curve analysis was also used to assess the sensitivity and specificity of hTau-pT217 in identifying amyloid-positive subjects. The area under the ROC curve was 0.94, as shown in Figure 1. The data provided in this description demonstrate that the hTau-pT217 assays described herein are capable of identifying amyloid-positive subjects; serving as a diagnostic tool for Alzheimer's disease (AD) and determining the cognitive status of subjects in relation to AD; identifying subjects at risk for AD and / or in the early stages of AD; and serving as a diagnostic tool for AD progression. The data also demonstrate that the hTau-pT217 assay described herein correlates with neuroimaging, is functional in serum, plasma, and cerebrospinal fluid (CSF) matrices, and is superior to the known hTau-pT181 assay. Examples of the following modalities are provided in this description: 1. An antibody that specifically binds to phosphorylated human tau at threonine residue 217 of SEQ ID NO. 1 (hTau-pT217). 2. An antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO: 13, LCDR2 has the amino acid sequence of SEQ ID NO: 14, LCDR3 has the amino acid sequence of SEQ ID NO: 15, HCDR1 has the amino acid sequence of SEQ ID NO: 10, HCDR2 has the amino acid sequence of SEQ ID NO: 11, and HCDR3 has the amino acid sequence of SEQ ID NO: 12. 3. An antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 13;LCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 14, LCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 15, HCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 10, HCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 11, and HCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 12. 4. The modality 2 or 3 antibody, comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR) selected from: ML / a / ZUZ 1 / U144 ZJ a. the LCVR having the amino acid sequence of SEQ ID NO: 5 and the HCVR having the amino acid sequence of SEQ ID NO: 3; and b. the LCVR that has the amino acid sequence of SEQ ID NO: 8 the HCVR that has the amino acid sequence of SEQ ID NO: 6. 5. The modality 2 or 3 antibody, comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR) selected from: a. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 5 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 3; and b. the LCVR that has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 8 and the HCVR that has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 6. 6. The antibody of any of the modalities 1-5, wherein said antibody was humanized. 7. The antibody of any of the modalities 1-6, wherein said antibody comprises an lgG4 heavy chain. 8. The antibody of any of the modalities 1-7, wherein said antibody comprises a kappa light chain. 9. A pharmaceutical composition comprising an antibody of any one of modality 1-8 and one or more pharmaceutically acceptable vehicles, diluents or excipients. 10. Antibody that binds specifically to human tau isoforms expressed in the CNS. 11. The modality 10 antibody, wherein the antibody binds to a human tau epitope region comprising glutamine at residue 124 and alanine at residue 125 of SEQ ID NO. 1. 12. An antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO: 23, LCDR2 has the amino acid sequence of SEQ ID NO: 24, LCDR3 has the amino acid sequence of SEQ ID NO: 25, HCDR1 has the amino acid sequence of SEQ ID NO: 20, HCDR2 has the amino acid sequence of SEQ ID NO: 21, and HCDR3 has the amino acid sequence of SEQ ID NO: 22. 13. An antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 23; LCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 24; LCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 25; and HCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 25. ML / a / ZUZ 1 / Ul 44 ZJ % homology with the amino acid sequence of SEQ ID NO: 20, HCDR2 has an amino acid sequence with at least 95% homology with the amino acid sequence of SEQ ID NO: 21, and HCDR3 has an amino acid sequence with at least 95% homology with the amino acid sequence of SEQ ID NO: 22. 14. The antibody of modality 12 or 13, comprising a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 17 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 19. 15. The antibody of modality 12 or 13, comprising a light chain variable region (LCVR) having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 17 and a heavy chain variable region (HCVR) having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 19. 16. The antibody of any of the modalities 10-15, wherein said antibody was humanized. 17. The antibody of any of the modalities 10-16, wherein said antibody comprises an lgG4 heavy chain. 18. The antibody of any of the modalities 10-17, wherein said antibody comprises a kappa light chain. 19. A pharmaceutical composition comprising an antibody of any one of the forms 10-18 and one or more pharmaceutically acceptable vehicles, diluents or excipients. 20. A method for treating a neurodegenerative disease comprising administering to a patient in need an effective amount of an antibody, or pharmaceutical composition thereof, in any one of modalities 1-19. 21. The modality 20 method, where the neurodegenerative disease is a tauopathy. 22. The modality 21 method, where tauopathy is one of AD, PSP and FTD. 23. An antibody, or a pharmaceutical composition thereof, of any one of modalities 1-19 for use in therapy. 24. An antibody, or a pharmaceutical composition thereof, of any one of modalities 1-19 for use in the treatment of a neurodegenerative disease. 25. The antibody, or pharmaceutical composition thereof, of modality 24, wherein said neurodegenerative disease is a tauopathy. 26. The antibody, or pharmaceutical composition thereof, of modality 25, wherein said tauopathy is selected from the group consisting of AD, PSP and FTD. 27. An antibody, or a pharmaceutical composition thereof, of any one of modalities 1-19 for use in the manufacture of a medicament for the treatment of a neurodegenerative disease. 28. The antibody, or pharmaceutical composition thereof, of modality 27, wherein said neurodegenerative disease is a tauopathy. 29. The antibody, or pharmaceutical composition thereof, of modality 28, wherein said tauopathy is selected from the group consisting of AD, PSP, and FTD. 30. A method for detecting hTau-pT217 in a patient sample comprising the steps of: contacting the patient sample with an antibody of any one of modalities 1-8; and detecting a signal provided by said contact step. 31. A method for quantifying hTau-pT217 in a patient sample comprising the steps of: contacting the patient sample with an antibody of any one of modalities 1-8; and detecting a signal provided by said contact step. 32. The method of modality 31 further comprises the steps of: contacting a control standard with the antibody; and detecting a signal provided by said contacting the control standard step. 33. A method for quantifying hTau-pT217 in a patient sample comprising the steps of: contacting the patient sample with an antibody of modalities 1-8; contacting the patient sample with a second antibody, wherein the second antibody is an antibody of modalities 10-18 and one of the antibody or the second antibody comprises a detectable marker; detecting a signal provided by the detectable marker after the formation of a complex comprising the antibody, the second antibody, and hTau-pT217; contacting a control standard with the antibody; contacting the control standard with the second antibody, wherein one of the antibody or the second antibody comprises a detectable marker; and detecting a signal provided by the detectable marker after the formation of a complex comprising the antibody, the second antibody, and the control standard. 34. A method for diagnosing a patient as one or more of: (i) having a neurodegenerative disease; (ii) being at risk of having a neurodegenerative disease; (iii) needing treatment for a neurodegenerative disease; or (iv) needing neurological imaging comprising the steps of: contacting the patient sample with an antibody of any one of modalities 1-8; and detecting the binding between the antibody and hTau-pT217 in the patient sample. 35. The modality 34 method further comprises the step of diagnosing the patient as one of: (i) having a neurodegenerative disease; (ii) at risk of having a neurodegenerative disease; (iii) needing treatment for a neurodegenerative disease; or (iv) needing neurological imaging if the hTau-pT217 level detected in the patient sample exceeds a reference level. 36. A method for diagnosing and treating a neurodegenerative disease in a patient, said method comprising the steps of: contacting a patient sample with an antibody of any one of modalities 1-8; detecting the binding between the antibody and hTau-pT217 in the patient sample; diagnosing the patient with a neurodegenerative disease; and administering a therapeutically effective amount of a human anti-Tau antibody to the diagnosed patient. 37. The modality 36 method, in which the diagnostic stage involves diagnosing that the patient has a neurodegenerative disease when the presence of hTau-pT217 in the patient sample exceeds a reference level. 38. The method of any of the modalities 31-37 which also includes the step of quantifying hTau-pT217 in the patient sample. 39. The modality 38 method, wherein said stage of quantifying hTau-pT217 comprises quantifying hTau-pT217 in the patient sample with respect to a reference standard. 40. The method of any of the modalities 30-39, where the patient sample is one of blood, plasma, serum or CSF. 41. The method of any of the modalities 30-32 and 34-40 which further comprises the step of contacting the patient sample with a second antibody, said second antibody being bound to an epitope region of hTau-pT217 that does not overlap with the antibody. 42. The method of modality 41, wherein one of the antibody or the second antibody comprises a detectable marker and said detection step comprises detecting a signal provided by the detectable marker after the formation of a complex comprising the antibody, the second antibody and hTau-pT217. 43. The method of any of the modalities 41-42, wherein one of the antibody and the second antibody are immobilized on a substrate. 44. The method of any of the modalities 30-43, wherein said steps of contacting the patient sample with the antibody and contacting the patient sample with the second antibody occur simultaneously. 45. The method of any of modalities 32 and 41-44, wherein the second antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has the amino acid sequence of SEQ ID NO: 23, LCDR2 has the amino acid sequence of SEQ ID NO: 24, LCDR3 has the amino acid sequence of SEQ ID NO: 25, and wherein HCDR1 has the amino acid sequence of SEQ ID NO: 20, HCDR2 has the amino acid sequence of SEQ ID NO: 21, and HCDR3 has the amino acid sequence of SEQ ID NO: 22. 46. ​​The method of any of modalities 33 and 41-44, wherein the second antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein LCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 23, LCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 24, LCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 25, and HCDR1 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 20, HCDR2 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 21,and HCDR3 has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 22., 47. The method of any of the modalities 46-47, wherein the second antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR having the amino acid sequence of SEQ ID NO: 19 and the HCVR having the amino acid sequence of SEQ ID NO: 17. 48. The method of any of the modalities 46-47, wherein the second antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 19 and the HCVR has an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 17. 49. A method for forming a complex between a first antibody, a second antibody and human tau expressed in the CNS and phosphorylated at the threonine residue 217 of SEQ ID NO. 1, said method comprising: contacting a patient sample with a first antibody, wherein the first antibody is an antibody of one of modalities 1-8; and contacting the patient sample with a second antibody, wherein the second antibody is an antibody of one of modalities 10-18. 50. An assay for detecting human tau expressed in the CNS and phosphorylated at the threonine residue 217 of SEQ ID NO. 1, said assay comprising: an antibody of one of the modalities 1-8; and an antibody of one of the modalities 10-18. 51. The modality 50 assay, wherein one of the antibodies comprises a detectable marker. LIST OF SEQUENCES SEQ ID NO: 1 (hTau-pT217) MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAK STPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKDGTGS DDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPACTTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDDLKNVKSKIGSTENLKHQPGGGKV QIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDF KDRVQSKIGSLDNITHVPGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSI DMVDVDEVSQLQSLQTLG SEQ ID NO: 2 (Exemplary rabbit anti-hTau-pT217 antibody HC) QSVEESGGRLVTPGTPLTLTCTVSGLSPSWYGVHWVRQAPGKGLEWIGVLRAGSHTYYAGWAKGRFAI SCTSTTVALKITSPTTEDTAIYFCGSVGRGIWGPGTLVTVSLGQPKAPSVFPLAPCCGDTPSSTVTLGCLV KGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCCNVAHPATNTKVDKTVAPST IVIA / a / ZUZ I / U144 ZJ CSKPTCPPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLRE QQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNCALPAPIEKTISKGQPLEPKVYTMGPPREELSSRSVS LTCMINGFYPSDISVWEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALH NHYTQKSISRSPGK SEQ ID NO: 3 (HCVR of the exemplary rabbit anti-hTau-pT217 antibody) QSVEESGGRLVTPGTPLTLTCTVSGLSPSWYGVHWVRQAPGKGLEWIGVLRAGSHTYYAGWAKGRFAI SCTSTTVALKITSPTTEDTAIYFCGSVGRGIWGPGTLVTVSL SEQ ID NO: 4 (Exemplary rabbit anti-hTau-pT217 antibody LC) AQVLTQTASPVSATVGGTVTINCQASLAVYNNLAWYQQKPGQPPKRLIYLASSLSSGVSSSHFKGSGSG TQFTLTISDVQADDAATYFCQGSYDCTIADCVAFGGGTEVVVKGDPVAPTVLIFPPAADQVATGTVTIVCV ANKYFPDVTWEVDGTTQTTGIENSKTPQNSADNTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQS FNRGDC SEQ ID NO: 5 (LCVR of exemplified rabbit anti-hTau-pT217 antibody) AQVLTQTASPVSATVGGTVTINCQASLAVYNNLAWYQQKPGQPPKRLIYLASSLSSGVSSHFKGSGSG TQFTLTISDVQADDAATYFCQGSYDCTIADCVAFGGGTEVVVK SEQ ID NO: 6 (HCVR of the exemplified chimeric anti-hTau-pT217 antibody) QSVEESGGRLVTPGTPLTLTCTVSGLSPSWYGVHWVRQAPGKGLEWIGVLRAGSHTYYAGWAKGRFAI SCTSTTVALKITSPTTEDTAIYFCGSVGRGIWGPGTLVTVSL SEQ ID NO: 7 (HC of the exemplified chimeric anti-hTau-pT217 antibody) QSVEESGGRLVTPGTPLTLTCTVSGLSPSWYGVHWVRQAPGKGLEWIGVLRAGSHTYYAGWAKGRFAI SCTSTTVALKITSPTTEDTAIYFCGSVGRGIWGPGTLVTVSLAKTTPPSVYPLAPGSAAQTNSMVTLGCLVK GYFPEPPVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETTVTCNVAHPASSTKVDKKIVPR DCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVVHTAQTQPREE QFNSTFRSSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKMAKDKVSL TCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHN HHTEKSLSHSHKSPGSPGC SEQ ID NO: 8 (LCVR of the exemplified chimeric anti-hTau-pT217 antibody) AQVLTQTASPVSATVGGTVTINCQASLAVYNNLAWYQQKPGQPPKRLIYLASSLSSGVSSHFKGSGSG TQFTLTISDVQADDAATYFCQGSYDCTIADCVAFGGGTEVVVK SEQ ID NO: 9 (LC of the chimeric anti-hTau-pT217 antibody exemplified) AQVLTQTASPVSATVGGTVTINCQASLAVYNNNYLAWYQQKPGQPPKRLIYLASSLSSGVSSHFKGSGSG TQFTLTISDVQADDAATYFCQGSYDCTIADCVAFGGGTEVVVKRADAAPTVSIFPPSSEQLTSGGASVVCF LNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPI VKSFNRNEC SEQ ID NO: 10 (HCDR1 exemplified) GLSPSWYGVH SEQ ID NO: 11 (HCDR2 exemplified) VLRAGSHTYYAGWAKG SEQ ID NO: 12 (HCDR3 exemplified) VGRGI SEQ ID NO: 13 (LCDR1 exemplified) QASLAVYNNNYLA SEQ ID NO: 14 (LCDR2 example) LASSLSS SEQ ID NO: 15 (LCDR3 example) LASSLSS SEQ ID NO: 16 (HC of the human tau-binding antibody expressed only in the CNS exemplified) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSPYYWSWIRQPPDKGLEWIGEINWSGDTNYNPSLKSRVTI SLDTSKNQFSLNLSSVTAADTAVYYCARSFDRWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVH TAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPE EEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYS CSVVHEGLHNHHTTKSFSRTPGK SEQ ID NO: 17 (HCVR of the human tau-binding antibody expressed only in the CNS exemplified) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSPYYWSWIRQPPDKGLEWIGEINWSGDTNYNPSLKSRVTI SLDTSKNQFSLNLSSVTAADTAVYYCARSFDRWGQGTLVTVSS SEQ ID NO: 18 (LC of human tau-binding antibody expressed only in the exemplified CNS) EIVLTQSPGTLSLSPGERATLSCRASQSVRSNYFAWYQQKPGQAPRLLIYGVSRRAFGIPDRFSGSGSGT DFTLTISRLEPEDFAVYYCQQYGASLITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 19 (LCVR of human tau-binding antibody expressed only in the CNS exemplified) EIVLTQSPGTLSLSPGERATLSCRASQSVRSNYFAWYQQKPGQAPRLLIYGVSRRAFGIPDRFSGSGSGT DFTLTISRLEPEDFAVYYCQQYGASLITFGQGTRLEIK SEQ ID NO: 20 (HCDR1 of the exemplified binding antibody) AVYGGSFSPYYWS SEQ ID NO: 21 (HCDR2 of the exemplified binding antibody) EINWSGDTN SEQ ID NO: 22 (HCDR3 of the exemplified binding antibody) ARSFDR SEQ ID NO: 23 (LCDR1 of the exemplified binding antibody) RASQSVRSNYFA SEQ ID NO: 24 (LCDR2 of the exemplified binding antibody) YGVSRRAF SEQ ID NO: 25 (LCDR3 of the exemplified binding antibody) QQYGASLIT a human tau expressed only in the CNS a human tau expressed only in the CNS a human tau expressed only in the CNS a human tau expressed only in the CNS a human tau expressed only in the CNS a human tau expressed only in the CNS a human tau expressed only in the CNS SEQ ID NO: 26 (exemplified peptide for immunization) RTPSLPTPPTR where T at residue 7 was phosphorylated SEQ ID NO: 27 (exemplified peptide for immunization) AEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQT PTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPE GTTAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREPGPP GLSHQLMSGMPGAPLLPEGPREATRQP SGTGPEDTEGGRHAPELLKHQ LLGDLHQEGPPLKGAGGKE RPGSKEEVDEDRDVDESSPQ DSPPSKASPA QDGRPPQTAAREATSIPGFPAEGAILPPVDFLSKVSTEIPASEPDGPSVG RAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGP SLGEDTKEAD LPEPSEKQPAAAPRGKPVSRVPQLKARMVS KSKDGTGSDD KKAKTSTRSSAKTLKNRPCLSPKHPTPGSSDPLIQPSSPAVCPEPPSSPKYVSSVT SRTG SSGAKEMKLKGADGKTKIAT PRGAAPPGQKGQANATRIPAKTPP APKTPPSSGEPPKSGDRSGYSSPGTPGSRSRTP SLPTPPTREP KKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGG KVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKC GSLGNIHHKPG GGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGG NKKIETHKLTFR ENAKAKTDHGAEIVYKSPVVSGDT SPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

Claims

1. A method for detecting hTau-pT217 in a patient sample comprising the steps of: contacting the patient sample with an antibody that specifically binds to phosphorylated human tau at threonine residue 217 of SEQ ID NO. 1 (“hTau-pT217”); contacting the patient sample with a second antibody, said second antibody binding to an epitope region of hTau-pT217 that does not overlap with the antibody; and detecting the binding of the antibody to hTau-pT217, wherein the second antibody specifically binds to CNS-expressed human tau isoforms and wherein the second antibody binds to a human tau epitope region comprising glutamine at residue 124 and alanine at residue 125 of SEQ ID NO.

1.

2. The method of claim 1, further comprising the step of quantifying hTau-pT217 in a patient sample.

3. A method for diagnosing a patient as one or more of: (i) having a neurodegenerative disease; (ii) being at risk of having a neurodegenerative disease; (iii) needing treatment for a neurodegenerative disease; or (iv) needing neurological imaging, comprising the steps of: contacting a patient sample with an antibody that binds specifically to hTau-pT217; contacting the patient sample with a second antibody, said second antibody binding to an epitope region of hTau-pT217 that does not overlap with the antibody; and detecting the binding between the antibody and hTau-pT217 in the patient sample, wherein the second antibody binds specifically to human tau isoforms expressed in the CNS and wherein the second antibody binds to a human tau epitope region comprising glutamine at residue 124 and alanine at residue 125 of SEQ ID NO.

1.

4. The method of claim 3 further comprising the step of diagnosing the patient as one of: (i) having a neurodegenerative disease; (ii) at risk of having a neurodegenerative disease; (iii) needing treatment for a neurodegenerative disease; or (iv) needing neurological imaging, if the hTau-pT217 level detected in the patient sample exceeds a reference level.

5. The method of claim 3 further comprising the step of diagnosing the patient as having a neurodegenerative disease, wherein the neurodegenerative disease is a tauopathy. MA / a / ZUZ 1 / U144 ZJ 6. The method of claim 5, wherein the tauopathy is selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD).

7. The method of any of claims 1-6, wherein the patient sample is one of blood, plasma, serum or CSF.

8. The method of any of claims 1-7, wherein one of the antibody or the second antibody comprises a detectable marker and said detection step comprises detecting a signal provided by the detectable marker after the formation of a complex comprising the antibody, the second antibody and hTau-pT217.

9. The method of any of claims 1-8, wherein the antibody specifically binding to hTau-pT217 comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3 and the HCVR comprises the CDRs HCDR1, HCDR2, and HCDR3, wherein the amino acid sequences of the CDRs are selected from: (a) LCDR1 having the amino acid sequence of SEQ ID NO: 13; LCDR2 having the amino acid sequence of SEQ ID NO: 14, LCDR3 having the amino acid sequence of SEQ ID NO: 15, HCDR1 having the amino acid sequence of SEQ ID NO: 10, HCDR2 having the amino acid sequence of SEQ ID NO: 11 and HCDR3 having the amino acid sequence of SEQ ID NO: 12; or (b) LCDR1 having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 13;LCDR2 having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 14, LCDR3 having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 15, HCDR1 having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 10, HCDR2 having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 11 and HCDR3 having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 12.; 10. The method of claim 9, wherein the LCVR and HCVR of the antibody are selected from: a. the LCVR having the amino acid sequence of SEQ ID NO: 5 and the HCVR having the amino acid sequence of SEQ ID NO: 3; b. the LCVR having the amino acid sequence of SEQ ID NO: 8 and the HCVR having the amino acid sequence of SEQ ID NO: 6; c. the LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 5 and the HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 3; and d. LCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO: 8 and HCVR having an amino acid sequence with at least 95% homology to the amino acid sequence of SEQ ID NO:

6.

11. The method of claim 6, wherein tauopathy is Alzheimer's disease (AD).

12. The method of claim 7, wherein the patient sample is CSF.

13. The method of claim 7, wherein the patient sample is plasma.

14. The method of any of claims 1-13, wherein one of the antibody or the second antibody is immobilized on a substrate.

15. The method of claim 14, wherein the substrate is selected from one of a microwell plate or a bead.

16. The method of any of claims 1-13, wherein said steps of contacting the patient sample with the antibody and contacting the patient sample with the second antibody occur simultaneously.

17. The method of claim 8, wherein the detectable marker is a chemiluminescent or enzymatic marker.

18. The method of claim 3 further comprising the step of diagnosing the patient as needing neurological imaging, wherein the neurological imaging is Amyvid™ or flortaucipir.