US20230265175A1 - High affinity antibodies targeting tau phosphorylated at serine 413 - Google Patents

High affinity antibodies targeting tau phosphorylated at serine 413 Download PDF

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US20230265175A1
US20230265175A1 US18/011,856 US202118011856A US2023265175A1 US 20230265175 A1 US20230265175 A1 US 20230265175A1 US 202118011856 A US202118011856 A US 202118011856A US 2023265175 A1 US2023265175 A1 US 2023265175A1
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amino acid
seq
acid sequence
antibody
tau
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Jeanne E. Baker
Sophie Parmentier Batteur
Ming-Tang Chen
Alan C. Cheng
Chung-Ming Hsieh
Carl Mieczkowski
Sokreine Suon
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Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/522—CH1 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to high affinity antibodies or antigen binding fragments thereof that specifically bind to tau-pS413 (e.g., a human tau having the amino acid sequence of SEQ ID NO:1 that is phosphorylated at serine 413).
  • tau-pS413 e.g., a human tau having the amino acid sequence of SEQ ID NO:1 that is phosphorylated at serine 413
  • the invention also relates to compositions, kits, methods, and uses involving the high affinity antibodies or antigen binding fragments disclosed herein.
  • Tau is a protein encoded by the MAPT gene, which is located on chromosome 17 (17q21) in the human genome.
  • the tau protein is one of the microtubule-binding proteins abundantly expressed in the central nervous system. Tau has been found to be a major constituent protein in the paired helical filaments and straight filaments forming neurofibrillary tangles (NFT) in Alzheimer's disease (AD), one of the most prominent neurodegenerative diseases, and its intracellular accumulation has been demonstrated in a variety of neuropathological conditions.
  • NFT neurofibrillary tangles
  • AD Alzheimer's disease
  • the diseases caused by such intracellular accumulation of tau are collectively referred to as “tauopathies” (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol.
  • Tauopathies include neurodegenerative diseases such as AD, corticobasal degeneration (CBD) or corticobasal syndrome (CBS), progressive supranuclear palsy, Pick's disease, argyrophilic grain dementia (argyrophilic grain disease), multiple system tauopathy with dementia (MSTD), chromosome 17-linked frontotemporal dementia with Parkinsonism (FTDP-17), neurofibrillary tangle dementia, diffuse neurofibrillary tangles with calcification (DNTC), white matter tauopathy with globular glial inclusions (WMT-GGI), frontotemporal lobar degeneration with tau-positive inclusions (FTLD-tau).
  • AD corticobasal degeneration
  • CBS corticobasal syndrome
  • MSTD multiple system tauopathy with dementia
  • FTDP-17 chromosome 17-linked frontotemporal dementia with Parkinsonism
  • DNTC diffuse neurofibrillary tangles with calcification
  • WMT-GGI white matter tauopathy with glob
  • Tauopathies also include non-neurodegenerative diseases including: infectious diseases such as Economo's encephalitis sequela and subacute sclerosing panencephalitis; and trauma-induced conditions such as boxer's encephalopathy (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • infectious diseases such as Economo's encephalitis sequela and subacute sclerosing panencephalitis
  • trauma-induced conditions such as boxer's encephalopathy (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • Tau can be phosphorylated on a large number of amino acid residues, and phosphorylated tau has been believed to be the pathological tau species in tauopathies. While there are many known phosphorylation sites on tau and anti-tau antibodies with different specificities (e.g., targeting total tau, nonphosphorylated tau, or tau that is phosphorylated at various amino acid residues) in the art, it is still uncertain which phosphorylated tau species is the best target for treating tauopathies.
  • pathological tau species e.g., tau in the brain of AD patients
  • normal tau e.g., tau in the brain of healthy human beings
  • others do not have a sufficiently high affinity and thus have to be administered at very high doses to reach an effective amount in the brain.
  • pathological tau species e.g., tau-pS413
  • the present disclosure provides high affinity antibodies or antigen binding fragments thereof that bind to human tau-pS413 (e.g., tau having the amino acid sequence of SEQ ID NO:1 that is phosphorylated at serine 413).
  • isolated nucleic acids and vectors comprising polynucleotide sequences encoding such high affinity antibodies or antigen binding fragments thereof, cells (e.g., host cells) comprising such isolated nucleic acids or vectors, compositions or kits comprising such high affinity antibodies or antigen binding fragments thereof, and methods or uses involving such high affinity antibodies or antigen binding fragments thereof.
  • an antibody or antigen binding fragment thereof that binds to tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a heavy chain variable region complementarity determining region 1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:41; a heavy chain variable region complementarity determining region 2 (VH-CDR2) comprising the amino acid sequence of SEQ ID NO:42; and a heavy chain variable region complementarity determining region 3 (VH-CDR3) comprising the amino acid sequence of SEQ ID NO:43; and a light chain variable region complementarity determining region 1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO:29; a light chain variable region complementarity determining region 2 (VL-CDR2) comprising the amino acid sequence of SEQ ID NO:30; and a light chain variable region complementarity determining region 3 (VL-CDR3) comprising the amino acid sequence of SEQ ID NO:31.
  • VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:87; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:88; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:83; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:84; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:85.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:94; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:89; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:90; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:91.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:98; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:99; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:100; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:97.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:104; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:105; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:106; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:101; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:102; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:103.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, 60, 61, 62, 63, 64, 65, 66, 67, or 68. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:60. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:61.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:62. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:63. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:64. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:65. In still another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:66.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:67. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:68.
  • the antibody or antigen-binding fragment thereof further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:57 or 58. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:57. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, 60, 61, 62, 63, 64, 65, 66, 67, or 68, and a light chain constant region having the amino acid sequence of SEQ ID NO:57 or 58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:60, and a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:63, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:68, and a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:71 and a heavy chain comprising the amino acid sequence of SEQ ID NO:72.
  • the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74.
  • the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:75 and a heavy chain comprising the amino acid sequence of SEQ ID NO:76.
  • the antibody or antigen-binding fragment thereof consists of two light chains comprising the amino acid sequence of SEQ ID NO:71 and two heavy chains comprising the amino acid sequence of SEQ ID NO:72.
  • the antibody or antigen-binding fragment thereof consists of two light chains comprising the amino acid sequence of SEQ ID NO:73 and two heavy chains comprising the amino acid sequence of SEQ ID NO:74.
  • the antibody or antigen-binding fragment thereof consists of two light chains comprising the amino acid sequence of SEQ ID NO:75 and two heavy chains comprising the amino acid sequence of SEQ ID NO:76.
  • the antibody or antigen-binding fragment thereof consists of two light chains consisting of the amino acid sequence of SEQ ID NO:71 and two heavy chains consisting of the amino acid sequence of SEQ ID NO:72.
  • the antibody or antigen-binding fragment thereof consists of two light chains consisting of the amino acid sequence of SEQ ID NO:73 and two heavy chains consisting of the amino acid sequence of SEQ ID NO:74.
  • the antibody or antigen-binding fragment thereof consists of two light chains consisting of the amino acid sequence of SEQ ID NO:75 and two heavy chains consisting of the amino acid sequence of SEQ ID NO:76.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 1 ⁇ 10 ⁇ 8 M or less for tau-pS413. In some embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 9 ⁇ 10 ⁇ 9 M or less for tau-pS413. In other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 8 ⁇ 10 ⁇ 9 M or less for tau-pS413. In yet other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 7 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 6 ⁇ 10 ⁇ 9 M or less for tau-pS413. In other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 5 ⁇ 10 ⁇ 9 M or less for tau-pS413. In yet other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 4 ⁇ 10 ⁇ 9 M or less for tau-pS413. In still other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 3 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 2 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • KD equilibrium dissociation constant
  • the KD is measured by Surface Plasmon Resonance (SPR) assay with the antibody or antigen binding fragment thereof being immobilized.
  • the KD is measured by Biacore.
  • the KD is measured by KinExA.
  • nucleic acid encoding various polypeptides disclosed herein.
  • the isolated nucleic acid encodes the VH of various antibodies or antigen binding fragments thereof disclosed herein. In some embodiments, the isolated nucleic acid encodes the VL of various antibodies or antigen binding fragments thereof disclosed herein. In other embodiments, the isolated nucleic acid encodes the VH and the VL of various antibodies or antigen binding fragments thereof disclosed herein.
  • the isolated nucleic acid encodes the heavy chain of various antibodies or antigen binding fragments thereof disclosed herein. In some embodiments, the isolated nucleic acid encodes the light chain of various antibodies or antigen binding fragments thereof disclosed herein. In other embodiments, the isolated nucleic acid encodes the heavy chain and the light chain of various antibodies or antigen binding fragments thereof disclosed herein.
  • an expression vector comprising the various isolated nucleic acids disclosed herein.
  • a host cell comprising one or more of the various isolated nucleic acids or one of more of the various expression vectors disclosed herein.
  • the host cell comprises one of more of the various isolated nucleic acids disclosed herein.
  • the host cell comprises one of more of the various expression vectors disclosed herein.
  • the method of producing the antibody or antigen binding fragment thereof disclosed herein comprises expressing an isolated nucleic acid described herein under conditions wherein the antibody or antigen binding fragment thereof is expressed. In some embodiments, the method of producing the antibody or antigen binding fragment thereof disclosed herein comprises expressing an expression vector described herein under conditions wherein the antibody or antigen binding fragment thereof is expressed. In other embodiments, the method of producing the antibody or antigen binding fragment thereof disclosed herein comprises culturing the host cell comprising an isolated nucleic acid or an expression vector described herein under conditions wherein the antibody or antigen binding fragment thereof is expressed.
  • composition comprising the antibodies or antigen binding fragments thereof described herein and a pharmaceutically acceptable carrier.
  • the composition further comprises an additional agent.
  • the additional agent is an agent effective to treat the same or different disorder as the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein are being used to treat.
  • the additional agent is an agent effective to mitigate one or more side effects of the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein.
  • Exemplary additional agents include, but are not limited to: cholinesterase inhibitors (such as donepezil, galantamine, rovastigmine, and tacrine), NMDA receptor antagonists (such as memantine), amyloid beta peptide aggregation inhibitors, antioxidants, gamma-secretase modulators, nerve growth factor (NGF) mimics or NGF gene therapy, PPAR ⁇ agonists, HMS-CoA reductase inhibitors (statins), ampakines, calcium channel blockers, GABA receptor antagonists, glycogen synthase kinase inhibitors, intravenous immunoglobulin, muscarinic receptor agonists, nicotinic receptor modulators, active or passive amyloid beta peptide for immunization, phosphodiesterase inhibitors, serotonin receptor antagonists, anti-amyloid beta peptide antibodies, growth hormone, neurotrophic factor, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-4
  • kits comprising the antibodies or antigen binding fragments thereof described herein.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of the antibodies or antigen binding fragments thereof described herein.
  • the method further comprises administering to the subject an additional agent.
  • the additional agent is an agent effective to treat the same or different disorder as the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein are being used to treat.
  • the additional agent is an agent effective to mitigate one or more side effects of the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein.
  • Exemplary additional agents include, but are not limited to: cholinesterase inhibitors (such as donepezil, galantamine, rovastigmine, and tacrine), NMDA receptor antagonists (such as memantine), amyloid beta peptide aggregation inhibitors, antioxidants, gamma-secretase modulators, nerve growth factor (NGF) mimics or NGF gene therapy, PPAR ⁇ agonists, HMS-CoA reductase inhibitors (statins), ampakines, calcium channel blockers, GABA receptor antagonists, glycogen synthase kinase inhibitors, intravenous immunoglobulin, muscarinic receptor agonists, nicotinic receptor modulators, active or passive amyloid beta peptide for immunization, phosphodiesterase inhibitors, serotonin receptor antagonists, anti-amyloid beta peptide antibodies, growth hormone, neurotrophic factor, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-4
  • the tauopathy is a neurodegenerative disease, including but not limited to Alzheimer's disease (AD), corticobasal degeneration (CBD) or corticobasal syndrome (CBS), progressive supranuclear palsy, Pick's disease, argyrophilic grain dementia (argyrophilic grain disease), multiple system tauopathy with presenile dementia (MSTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), dementia with neurofibrillary tangles, diffuse neurofibrillary tangle with calcification (DNTC), white matter tauopathy with globular glial inclusions (WMT-GGI), or frontotemporal lobar degeneration with tau pathology (FTLD-tau).
  • AD Alzheimer's disease
  • CBD corticobasal degeneration
  • CBS corticobasal syndrome
  • Pick's disease argyrophilic grain dementia
  • MSTD multiple system tauopathy with presenile dementia
  • FTDP-17 frontotemporal dementia and parkinsonism
  • the tauopathy is AD. In another embodiment, the tauopathy is CBD. In yet another embodiment, the tauopathy is progressive supranuclear palsy. In still another embodiment, the tauopathy is Pick's disease. In one embodiment, the tauopathy is argyrophilic grain dementia. In another embodiment, the tauopathy is MSTD. In yet another embodiment, the tauopathy is FTDP-17. In still another embodiment, the tauopathy is dementia with neurofibrillary tangles. In one embodiment, the tauopathy is DNTC. In another embodiment, the tauopathy is WMT-GGI. In yet another embodiment, the tauopathy is FTLD-tau.
  • the tauopathy is a non-neurodegenerative disease, including but not limited to infectious diseases, such as Economo's encephalitis sequela and subacute sclerosing panencephalitis, and trauma-induced conditions, such as boxer's encephalopathy.
  • infectious diseases such as Economo's encephalitis sequela and subacute sclerosing panencephalitis
  • trauma-induced conditions such as boxer's encephalopathy.
  • the tauopathy is Economo's encephalitis sequela.
  • the tauopathy is subacute sclerosing panencephalitis.
  • the tauopathy is boxer's encephalopathy.
  • a method of decreasing the amount of tau-pS413 in the brain of a subject comprising administering to the subject in need thereof an effective amount of the antibodies or antigen binding fragments thereof of described herein.
  • the method further comprises administering to the subject an additional agent.
  • the additional agent is an agent effective to treat the same or different disorder as the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein are being used to treat.
  • the additional agent is an agent effective to mitigate one or more side effects of the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein.
  • Exemplary additional agents include, but are not limited to: cholinesterase inhibitors (such as donepezil, galantamine, rovastigmine, and tacrine), NMDA receptor antagonists (such as memantine), amyloid beta peptide aggregation inhibitors, antioxidants, gamma-secretase modulators, nerve growth factor (NGF) mimics or NGF gene therapy, PPAR ⁇ agonists, HMS-CoA reductase inhibitors (statins), ampakines, calcium channel blockers, GABA receptor antagonists, glycogen synthase kinase inhibitors, intravenous immunoglobulin, muscarinic receptor agonists, nicotinic receptor modulators, active or passive amyloid beta peptide for immunization, phosphodiesterase inhibitors, serotonin receptor antagonists, anti-amyloid beta peptide antibodies, growth hormone, neurotrophic factor, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-4
  • an antibody or antigen binding fragment thereof as disclosed herein to treat tauopathy in a subject.
  • an antibody or antigen binding fragment thereof as disclosed herein for the treatment of tauopathy in a subject.
  • an antibody or antigen binding fragment thereof as disclosed herein for the preparation of a medicament to treat tauopathy in a subject.
  • the tauopathy is Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, Pick's disease, argyrophilic grain dementia (argyrophilic grain disease), multiple system tauopathy with presenile dementia (MSTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), dementia with neurofibrillary tangles, diffuse neurofibrillary tangle with calcification (DNTC), white matter tauopathy with globular glial inclusions (WMT-GGI), frontotemporal lobar degeneration with tau pathology (FTLD-tau), Economo's encephalitis sequela, subacute sclerosing panencephalitis, or boxer's encephalopathy.
  • argyrophilic grain dementia argyrophilic grain disease
  • MSTD multiple system tauopathy with presenile dementia
  • FTDP-17 frontotemporal dementia and parkinsonism linked to chromosome 17
  • DNTC diffuse neurofibrill
  • the tauopathy is AD. In another embodiment, the tauopathy is CBD. In yet another embodiment, the tauopathy is progressive supranuclear palsy. In still another embodiment, the tauopathy is Pick's disease. In one embodiment, the tauopathy is argyrophilic grain dementia. In another embodiment, the tauopathy is MSTD. In yet another embodiment, the tauopathy is FTDP-17. In still another embodiment, the tauopathy is dementia with neurofibrillary tangles. In one embodiment, the tauopathy is DNTC. In another embodiment, the tauopathy is WMT-GGI. In yet another embodiment, the tauopathy is FTLD-tau. In one embodiment, the tauopathy is Economo's encephalitis sequela. In another embodiment, the tauopathy is subacute sclerosing panencephalitis. In yet another embodiment, the tauopathy is boxer's encephalopathy.
  • an antibody or antigen binding fragment thereof as disclosed herein for use in a method for treating tauopathy in a subject.
  • an antibody or antigen binding fragment thereof as disclosed herein for use in a method for diagnosing tauopathy in a subject.
  • FIGS. 1 A and 1 B show amino acid sequence alignment of VH ( FIG. 1 A ) and VL ( FIG. 1 B ) of representative antibodies described herein. CDRs shown in these figures are defined by the Kabat numbering system.
  • FIGS. 2 A- 2 F demonstrate that exemplary high affinity anti-tau-pS413 antibodies V8-AFM and V5-AFM bind specifically to tau-pS413 peptide.
  • V8-AFM e.g., V8-AFM-hIgG1-LALA-YTE, V8-AFM-hIgG1-LALA, V8-AFM-hIgG4-S228P
  • V5-AFM e.g., V5-AFM-hIgG4-S228P
  • bind to a peptide that has phosphorylated serine 413 FIG. 2 A
  • do not bind to the same peptide without serine 413 phosphorylated FIG. 2 B
  • peptides that are phosphorylated at other positions in the tau protein FIGS. 2 C- 2 F ).
  • FIGS. 3 A and 3 B show competitive tau-pS413 immunoassay demonstrating binding of various exemplary anti-tau-pS413 antibodies to AD patient brain homogenates.
  • FIG. 3 A shows representative graph of curve fits with OD 450 nm as readouts and hIgGs as isotype control.
  • FIG. 3 B shows representative graph of curve fits with % of occupancy as readouts.
  • FIGS. 4 A- 4 E demonstrate that immuno-depletion of P2 extract of AD brain homogenates with various exemplary anti-tau-pS413 antibodies prevents the induction of tau pathology in hiPSC neurons.
  • FIG. 4 A illustrates schematic representation of the neutralization protocol.
  • FIGS. 4 B and 4 C represent AlphaLISA® data used to confirm successful depletion of tau-pS413 and total tau, respectively.
  • FIG. 4 D shows representative images demonstrating pathological MC1 tau (red spots) in neurons treated with P2 fraction (right panel) compared to no-treatment control (left panel).
  • FIG. 4 E represents the high-content image analysis of MC1 tau pathology in hiPSC neurons 5 days after seeding with immuno-depleted AD brain-derived P2 fractions with various concentration of exemplary anti-tau-pS413 antibodies or IgG control.
  • FIG. 5 demonstrates dose response upon administration of an exemplary high affinity anti-tau-pS413 antibody V8-AFM-mIgG1 versus the mouse parental anti-tau-pS413 antibody pTa1505-mIgG1 on the reduction of tau pathology.
  • FIG. 6 shows that V6-AFM-hIgG1-LALA-YTE, which includes a K54E mutation in the VH, had improved production of the antibody molecule compared to V1-AFM-hIgG1-LALA-YTE, which does not include the K54E mutation in its VH.
  • FIGS. 7 A and 7 B demonstrate ex vivo target engagement by V8-AFM-hIgG1-LALA-YTE in CSF samples from AD patients or non-AD humans.
  • FIG. 7 A shows A.U. readings in a tau-pS413 MSD assay for CSF samples from AD patients or non-AD humans in the presence of increased concentration of V8-AFM-hIgG1-LALA-YTE.
  • FIG. 7 B shows the percentage of reduction of free tau-pS413 (unbound by V8-AFM-hIgG1-LALA-YTE) in CSF samples from AD patients or non-AD humans.
  • tau protein when used in the context of human species, refers to six isoforms of human tau protein having the amino acid sequences defined in SEQ ID NOs:1 to 6, i.e., 4R2N (defined in SEQ ID NO:1), 4R1N (defined in SEQ ID NO:2), 4R0N (defined in SEQ ID NO:3), 3R2N (defined in SEQ ID NO:4), 3R1N (defined in SEQ ID NO:5), and 3R0N (defined in SEQ ID NO:6), as well as gene variants thereof.
  • 4R2N defined in SEQ ID NO:1
  • 4R0N defined in SEQ ID NO:3
  • 3R2N defined in SEQ ID NO:4
  • 3R1N defined in SEQ ID NO:5
  • 3R0N defined in SEQ ID NO:6
  • the tau protein according to the present invention also encompasses proteins having similarities or identities of 80% or more to the amino acid sequence of the human tau protein defined in SEQ ID NO:1 in accordance with the BLAST method (with default conditions of PBLAST provided by NCBI) and their isoforms.
  • Such tau proteins also include tau derived from non-human species, such as chimpanzees, macaques, horses, pigs, dogs, mice, rabbits, and rats. It is possible to produce a therapeutic or prophylactic agent targeted to tau derived from such a non-human animal for the purpose of improving the cognitive function of the target animal.
  • tau peptide used herein means a peptide including a part of the amino acid sequence of a tau protein.
  • the position of the tau peptide derived from a tau protein should not be limited.
  • the length of the tau peptide should also not be limited, but should preferably have an amino acid length of four or more, particularly six or more, more particularly eight or more.
  • tau used herein means a tau protein or a tau peptide collectively.
  • the position of an amino acid residue in a tau protein or a tau peptide is indicated by an amino acid number, which is identified based on the amino acid sequence defined in SEQ ID NO:1 for clarification.
  • “serine 413,” “Ser413,” or “S413” refers to the amino acid residue corresponding to Ser413 of SEQ ID NO:1, including the serine residue at amino acid position 413 of SEQ ID NO:1 (4R2N), amino acid position 384 of SEQ ID NO:2 (4R1N), amino acid position 355 of SEQ ID NO:3 (4R0N), amino acid position 382 of SEQ ID NO:4 (3R2N), amino acid position 353 of SEQ ID NO:5 (3R1N), or amino acid position 324 of SEQ ID NO:6 (3R0N). Correspondence of the positions of amino acid residues between tau isoforms is shown in TABLE 1 below.
  • FIGS. 1 A and 1 B of WO 2018/254390 show an alignment of the amino acid sequences of the six human isoforms (indicated with one letter codes) based on ClustalW. These figures indicate that the structure surrounding the amino acid residue corresponding to Ser413 of the amino acid sequence defined in SEQ ID NO:1 is conserved among the six isoforms, and also help to identify the amino acids corresponding to one another.
  • an amino acid residue is “phosphorylated” as used herein means that a phosphate group is ester-linked to the side chain of the amino acid residue.
  • Typical amino acid residues that may be phosphorylated include serine (Ser), threonine (Thr), and tyrosine (Tyr).
  • tau-pS413 refers to a tau protein or peptide that is phosphorylated at the amino acid residue corresponding to Ser413 of SEQ ID NO:1, including the serine residue at amino acid position 413 of SEQ ID NO:1 (4R2N), amino acid position 384 of SEQ ID NO:2 (4R1N), amino acid position 355 of SEQ ID NO:3 (4R0N), amino acid position 382 of SEQ ID NO:4 (3R2N), amino acid position 353 of SEQ ID NO:5 (3R1N), or amino acid position 324 of SEQ ID NO:6 (3R0N).
  • tau-pS413 is phosphorylated only at 5413.
  • tau-pS413 is phosphorylated at 5413 and one or more additional amino acid residues
  • Anti-tau-pS413 antibody refers to an antibody that specifically binds to a tau-pS413 protein or a tau-pS413 peptide.
  • V1-AFM refers to an affinity matured variant of HmzTa1505-hIgG4-S228P as described herein, comprising the defined VH and VL as described in TABLE 4, with SEQ ID NOs disclosed in TABLES 5 and 6.
  • Each term encompasses antibodies with any one of known heavy chain constant region (e.g., IgG1, IgG1-LALA, IgG1-LALA-YTE, IgG2, IgG3, IgG4, IgG4-S228P, etc.) or variant thereof and any one of known light chain constant region (e.g., lambda or kappa) or variant thereof.
  • heavy chain constant region e.g., IgG1, IgG1-LALA, IgG1-LALA-YTE, IgG2, IgG3, IgG4, IgG4-S228P, etc.
  • light chain constant region e.g., lambda or kappa
  • binding refers to an interaction between molecules including, for example, to form a complex. Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and/or van der Waals interactions. A complex can also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as tau, is the “affinity” of the antibody or functional fragment for that epitope or target.
  • binding affinity refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the ratio of dissociation rate (k off ) to association rate (k on ) of an antibody to a monovalent antigen (k off /k on ) is the “dissociation constant” (or “equilibrium dissociation constant” as used interchangeably) KD, which is inversely related to affinity.
  • KD the dissociation constant
  • the dissociation constant KD for an antibody provided herein can be determined using any method provided herein or any other method well known to those skilled in the art, such as surface plasmon resonance (SPR) assay, including but not limited to Biacore and KinExA.
  • SPR surface plasmon resonance
  • the affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen.
  • complex antigens containing multiple, repeating antigenic determinants such as a polyvalent antigen
  • the strength of such multiple interactions between a multivalent antibody and antigen is called the “avidity.”
  • the avidity of an antibody can be a better measure of its binding capacity than is the affinity of its individual binding sites. For example, high avidity can compensate for low affinity as is sometimes found for pentameric IgM antibodies, which can have a lower affinity than IgG, but the high avidity of IgM, resulting from its multivalence, enables it to bind antigen effectively.
  • the term “affinity” or “binding affinity” as used herein refers to monovalent (1:1) interaction between an anti-tau-pS413 antibody and a tau-pS413 protein or peptide.
  • the KD can be measured using SPR with either the anti-tau-pS413 antibody or tau-pS413 immobilized. The KD values disclosed in this specification are measured with the anti-tau-pS413 antibody immobilized.
  • antibodies that specifically bind to tau-pS413 refer to antibodies that specifically bind to a tau-pS413 polypeptide, such as a tau-pS413 protein or peptide (e.g., human tau-pS413 such as a human tau-pS413 protein or peptide).
  • An antibody that specifically binds to tau-pS413 may be cross-reactive with tau-pS413 derived from another species (e.g., cynomolgus tau-pS413).
  • an antibody that specifically binds to tau-pS413 does not cross-react with other [tau] proteins or peptides, such as a tau protein or peptide that is not phosphorylated at 5413 or a tau protein or peptide that is phosphorylated at another amino acid residue other than 5413.
  • An antibody that specifically binds to tau-pS413 can be identified, for example, by immunoassays, Biacore, or other techniques known to those of skill in the art.
  • an antibody binds specifically to tau-pS413 when it binds to tau-pS413 with higher affinity than to any cross-reactive protein or peptide as determined using experimental techniques, such as radioimmunoassays (MA) and enzyme linked immunosorbent assays (ELISAs).
  • MA radioimmunoassays
  • ELISAs enzyme linked immunosorbent assays
  • a specific reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding antibody specificity.
  • the term “specific binding,” “specifically binds to,” or “is specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction.
  • Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity.
  • specific binding to a target can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • subject includes any organism, preferably an animal, more preferably a mammal (e.g., human, rat, mouse, dog, cat, or rabbit). In a preferred embodiment, the term “subjects” refers to a human.
  • antibody immunoglobulin
  • Ig immunoglobulin
  • monoclonal antibodies including neutralizing antibodies, full length or intact monoclonal antibodies
  • antibody compositions with polyepitopic or monoepitopic specificity polyclonal or monovalent antibodies
  • multivalent antibodies multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity)
  • An antibody can be human, humanized, chimeric and/or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc.
  • Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments thereof) of any of the above, which refers to a portion of an antibody heavy or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived.
  • Non-limiting examples of functional fragments include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab′) fragments, F(ab) 2 fragments, F(ab) 2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody.
  • scFv single-chain Fvs
  • Fab fragments F(ab′) fragments, F(ab) 2 fragments, F(ab) 2 fragments, disulfide-linked Fvs (dsFv)
  • dsFv disulfide-linked Fvs
  • antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen-binding site that binds to a tau-pS413 protein or peptide (e.g., one or more CDRs of an anti-tau-pS413 antibody).
  • Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Pluckthun and Skerra, 1989, Meth. Enzymol.
  • the antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule.
  • a “Fab fragment” is comprised of one light chain and the C H 1 and variable regions of one heavy chain.
  • the heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.
  • An “Fab fragment” can be the product of papain cleavage of an antibody.
  • An “Fc” region contains two heavy chain fragments comprising the C H 1 and C H 2 domains of an antibody.
  • the two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the C H 3 domains.
  • a “Fab′ fragment” contains one light chain and a portion or fragment of one heavy chain that contains the VH domain and the C H 1 domain and also the region between the C H 1 and C H 2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab′ fragments to form a F(ab′) 2 molecule.
  • a “F(ab′) 2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the C H 1 and C H 2 domains, such that an interchain disulfide bond is formed between the two heavy chains.
  • a F(ab′) 2 fragment thus is composed of two Fab′ fragments that are held together by a disulfide bond between the two heavy chains.
  • An “F(ab′) 2 fragment” can be the product of pepsin cleavage of an antibody.
  • Fv fragment or “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
  • the term “monoclonal antibody,” as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains that are often specific for different epitopes.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.
  • humanized antibody refers to forms of antibodies that contain sequences from both human and non-human (e.g., murine, rat) antibodies.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence.
  • the humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function.
  • “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).
  • variable region means the segment of IgG chains which is variable in sequence between different antibodies.
  • a “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination.
  • the variable region of the heavy chain may be referred to as “VH.”
  • the variable region of the light chain may be referred to as “VL.”
  • the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • CDRs complementarity determining regions
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991) (“Kabat 1”); Kabat (1978) Adv. Prot. Chem. 32:1-75 (“Kabat 2”); Kabat, et al., (1977) J. Biol. Chem.
  • CDR refers to one of three hypervariable regions (H1, H2, or H3) within the non-framework region of the antibody V H ⁇ -sheet framework, or one of three hypervariable regions (L1, L2, or L3) within the non-framework region of the antibody VL n-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable domains (see Kabat 1-3, supra).
  • CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved n-sheet framework, and thus are able to adapt to a different conformation (see Chothia 1-2, supra). Both Kabat and Chothia methodologies for defining CDR sequences within antibody variable regions are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (Al-Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79).
  • the CDRs are as defined by the AbM numbering system. In still other embodiments, the CDRs are as defined by the Chothia numbering system. In yet other embodiments, the CDRs are as defined by the Contact numbering system. In yet still other embodiments, the CDRs are as defined by any numbering system that is known to those skilled in the art.
  • Constantly modified variants or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g. charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity of the protein.
  • Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene , The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)).
  • substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in TABLE 3.
  • epitope is defined in the context of a molecular interaction between an “antigen binding molecule,” such as an antibody (Ab), and its corresponding “antigen” (Ag).
  • “epitope” refers to the area or region on an Ag to which an Ab specifically binds, i.e. the area or region in physical contact with the Ab. Physical contact may be defined through distance criteria (e.g. a distance cut-off of 4 ⁇ ) for atoms in the Ab and Ag molecules.
  • Epitopes may be linear epitopes or conformational epitopes. Linear epitopes are formed by a continuous sequence of amino acids in a protein.
  • Conformational epitopes are formed of amino acids that are discontinuous in the protein sequence, but which are brought together upon folding of the protein into its three-dimensional structure. Induced epitopes are formed when the three-dimensional structure of the protein is in an altered conformation, such as following activation or binding of another protein or ligand.
  • isolated nucleic acid means a DNA or RNA polynucleotide of genomic, mRNA, cDNA, or synthetic origin or some combination thereof which is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, or is linked to a polynucleotide to which it is not linked in nature.
  • Isolated nucleic acid molecules “comprising” specified nucleic acid sequences may include, in addition to the specified sequences, coding sequences for up to ten or even up to twenty or more other proteins or portions or fragments thereof, or may include operably linked regulatory sequences that control expression of the coding region of the recited nucleic acid sequences, and/or may include vector sequences or non-coding sequences.
  • control sequences refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism.
  • the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to use promoters, polyadenylation signals, and enhancers.
  • a nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence.
  • DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or
  • a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • cell As used herein, the expressions “cell,” “host cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include progeny.
  • Treat” or “treatment” means to administer an agent, such as a composition containing any of the antibodies or antigen binding fragments thereof of the present invention, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity.
  • the agent is administered in an amount effective to alleviate one or more disease symptoms in the treated subject or population, whether by inducing the regression of or inhibiting, delaying or slowing the progression of such symptom(s) by any clinically measurable degree.
  • the amount of an agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject.
  • Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom.
  • the term further includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder.
  • the terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms.
  • the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom.
  • Tau is a protein encoded by the MAPT gene, which is located on chromosome 17 (17q21) in the human genome.
  • the tau protein is one of the microtubule-binding proteins abundantly expressed in the central nervous system.
  • the tau protein has been found to be a major constituent protein in the paired helical filaments and straight filaments forming NFT in AD, one of the most prominent neurodegenerative diseases, and its intracellular accumulation has been demonstrated in a variety of neuropathological conditions.
  • the diseases caused by such intracellular accumulation of tau are collectively referred to as “tauopathies” (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • Tauopathies include neurodegenerative diseases such as Alzheimer's disease (AD), corticobasal degeneration (CBD) or corticobasal syndrome (CBS), progressive supranuclear palsy, Pick's disease, argyrophilic grain dementia (argyrophilic grain disease), multiple system tauopathy with dementia (MSTD), chromosome 17-linked frontotemporal dementia with Parkinsonism (FTDP-17), neurofibrillary tangle dementia, diffuse neurofibrillary tangles with calcification (DNTC), white matter tauopathy with globular glial inclusions (WMT-GGI), frontotemporal lobar degeneration with tau-positive inclusions (FTLD-tau).
  • AD Alzheimer's disease
  • CBD corticobasal degeneration
  • CBS corticobasal syndrome
  • Pick's disease argyrophilic grain dementia
  • MSTD multiple system tauopathy with dementia
  • FTDP-17 chromosome 17-linked frontotemporal dementia with Parkinsonism
  • DNTC diffuse neuro
  • Tauopathies also include non-neurodegenerative diseases including: infectious diseases such as Economo's encephalitis sequela and subacute sclerosing panencephalitis; and trauma-induced conditions such as boxer's encephalopathy (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • infectious diseases such as Economo's encephalitis sequela and subacute sclerosing panencephalitis
  • trauma-induced conditions such as boxer's encephalopathy (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • the MAPT gene has been identified as consisting of 13 exons disposed on the genome, which can be expressed as multiple different protein isoforms via alternative splicing (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • the structure of tau comprises an N-terminal acidic domain containing 0-2 repetitive sequences (N) of 29 amino acids depended on alternative splicing of exon 2 and exon 3 (N0-N2), an intermediate domain rich in proline, and a C-terminal microtubule-binding domain (encoded by exons 9 to 12) containing 3 (3R) or 4 (4R) repetitive sequences (R) that contribute to microtubule binding (Alistair Burns et al. (Edit), Dementia, 3rd Edition, 2005, CRC Press, pp. 408-464; Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Supp1.6), 2010, pp. 46-51).
  • human tau has six representative isoforms: 3R0N (352 amino acids), 3R1N (381 amino acids), 3R2N (410 amino acids), 4R0N (383 amino acids), 4R1N (412 amino acids), and 4R2N (441 amino acids), depending on the number of 29 amino acid repetitive sequences (N) and microtubule-binding repetitive sequences (R) that it contains.
  • N 29 amino acid repetitive sequences
  • R microtubule-binding repetitive sequences
  • “Ser413” refers to the serine residue at the 413th amino acid position in 4R2N (defined in SEQ ID NO:1), which corresponds to the serine at the 384th amino acid position in 4R1N (defined in SEQ ID NO:2), the 355th amino acid position in 4R0N (defined in SEQ ID NO:3), the 382nd amino acid position in 3R2N (defined in SEQ ID NO:4), the 353rd amino acid position in 3R1N (defined in SEQ ID NO:5), and the 324th amino acid position in 3R0N (defined in SEQ ID NO:6).
  • tau accumulated in neurodegenerative diseases is characterized by being highly modified via phosphorylation.
  • tauopathy In patients exhibiting mild cognitive impairment, a correlation is observed between the level of phosphorylated tau in the spinal fluid and the degree of pituitary atrophy, suggesting phosphorylated tau as a highly reliable biomarker for neurodegeneration in patients with tauopathy (Wendy Noble et al., Expert Opinion on Drug Discovery, 2011, Vol. 6, No. 8, pp. 797-810).
  • tauopathy Wang et al., Expert Opinion on Drug Discovery, 2011, Vol. 6, No. 8, pp. 797-810
  • there are a large number of sites which can be phosphorylated in tau while virtually no information exists regarding which antibodies for which phosphorylation sites are effective to treat tauopathy.
  • an antibody as an active compound for a therapeutic or prophylactic agent
  • the brain is the target organ to be treated in cognitive disorders such as AD
  • systemic administration by intravenous or subcutaneous routes is generally thought to result in a low migration rate of antibodies from the blood to the brain, due to the presence of the blood-brain barrier.
  • antibodies used for treatment of cognitive disorders are expected to require high dosages, compared to treatment for diseases involving other organs.
  • anti-tau-pS413 antibodies include WO 2013/180238 and WO 2018/254390, the entirety of which disclosures are incorporated by reference herein. Distinct from the prior disclosures, the present invention provides higher affinity anti-tau-pS413 antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof.
  • V1-AFM e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V
  • These high affinity anti-tau-pS413 antibodies or antigen binding fragments thereof show increased binding potency compared to previously disclosed anti-tau-pS413 antibodies (e.g., at least 10- to 40-fold increase) to recombinant tau-pS413 protein or peptide, tau transgenic mouse brains, AD patients' brain homogenates, and AD patients' CSF samples.
  • Such high affinity antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof can also effectively prevent the development of tau pathology in hu-iPSC neurons induced by seeding of AD brain homogenates.
  • optimized (e.g., higher affinity) versions of the previously disclosed anti-tau-pS413 antibodies were obtained by affinity maturation to improve potency or by structure-based modeling to identify one or more amino acid mutations (e.g., K54E or K54D) that lowers pI (isoelectric point), improves affinity, and increases production of the antibody molecule.
  • the optimized (e.g., higher affinity) anti-tau-pS413 antibodies can be obtained by affinity maturation.
  • the optimized (e.g., higher affinity) anti-tau-pS413 antibodies can be obtained by structure-based modeling to identify one or more amino acid mutations (e.g., K54E or K54D) that lowers pI, improves affinity, and increases production of the antibody molecule.
  • the optimized (e.g., higher affinity) anti-tau-pS413 antibodies can be obtained by affinity maturation and structure-based modeling to identify one or more amino acid mutations (e.g., K54E or K54D) that lowers pI, improves affinity, and increases production of the antibody molecule.
  • the heavy chain constant region of the optimized (e.g., higher affinity) anti-tau-pS413 antibodies is switched from IgG4-S228P isotype to IgG1-LALA to improve colloidal stability and lower viscosity while maintaining reduced Fc effector function.
  • a half-life extension YTE mutation is integrated into the Fc region to increase half-life of the optimized (e.g., higher affinity) anti-tau-pS413 antibodies.
  • the heavy chain constant region of the optimized (e.g., higher affinity) anti-tau-pS413 antibodies is switched from IgG4-S228P isotype to IgG1-LALA and a half-life extension YTE mutation is integrated into the Fc region.
  • an optimized (e.g., higher affinity) anti-tau-pS413 antibody e.g., V1-AFM-hIgG1-LALA-YTE, V2-AFM-hIgG1-LALA-YTE, V3-AFM-hIgG1-LALA-YTE, V4-AFM-hIgG1-LALA-YTE, V5-AFM-hIgG1-LALA-YTE, V6-AFM-hIgG1-LALA-YTE, V7-AFM-hIgG1-LALA-YTE, or V8-AFM-hIgG1-LALA-YTE) is obtained by 1) affinity maturation, 2) structure-based modeling to identify a mutation (e.g., K54E or K54D) that lowers pI, improves affinity, and increases production of the antibody molecule, 3) switching isotype to IgG1-LALA to improve colloidal stability and lower viscosity while
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:87; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:88; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:83; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:84; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:85.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:94; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:89; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:90; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:91.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:98; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:99; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:100; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:97.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:104; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:105; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:106; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:101; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:102; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:103.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • the CDRs are as defined by the Kabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:28.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:20.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:32.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:36.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:40.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, 60, 61, 62, 63, 64, 65, 66, 67, or 68. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:60. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:61.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:62. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:63. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:64. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:65. In still another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:66.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:67. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:68. In certain embodiments, the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:57 or 58. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:57. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, 60, 61, 62, 63, 64, 65, 66, 67, or 68, and a light chain constant region having the amino acid sequence of SEQ ID NO:57 or 58. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:60, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:61, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:62, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:63, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:64, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:65, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:66, and a light chain constant region having the amino acid sequence of SEQ ID NO:57. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:67, and a light chain constant region having the amino acid sequence of SEQ ID NO:57. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:68, and a light chain constant region having the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In still another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:60, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In one embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:61, and a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:62, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:63, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In still another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:64, and a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:65, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:66, and a light chain constant region having the amino acid sequence of SEQ ID NO:58. In yet another embodiment, the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:67, and a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:68, and a light chain constant region having the amino acid sequence of SEQ ID NO:58.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:71 and a heavy chain comprising the amino acid sequence of SEQ ID NO:72.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO:75 and a heavy chain comprising the amino acid sequence of SEQ ID NO:76.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof consists of two light chains comprising the amino acid sequence of SEQ ID NO:71 and two heavy chains comprising the amino acid sequence of SEQ ID NO:72.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof consists of two light chains comprising the amino acid sequence of SEQ ID NO:73 and two heavy chains comprising the amino acid sequence of SEQ ID NO:74.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof consists of two light chains comprising the amino acid sequence of SEQ ID NO:75 and two heavy chains comprising the amino acid sequence of SEQ ID NO:76.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof consists of two light chains consisting of the amino acid sequence of SEQ ID NO:71 and two heavy chains consisting of the amino acid sequence of SEQ ID NO:72.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof consists of two light chains consisting of the amino acid sequence of SEQ ID NO:73 and two heavy chains consisting of the amino acid sequence of SEQ ID NO:74.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen-binding fragment thereof consists of two light chains consisting of the amino acid sequence of SEQ ID NO:75 and two heavy chains consisting of the amino acid sequence of SEQ ID NO:76.
  • the lysine residue at the C-terminus of the heavy chain constant region is present. In other embodiments, the lysine residue at the C-terminus of the heavy chain constant region is absent.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 1 ⁇ 10 ⁇ 8 M or less, 9 ⁇ 10 ⁇ 9 M or less, 8 ⁇ 10 ⁇ 9 M or less, 7 ⁇ 10 ⁇ 9 M or less, 6 ⁇ 10 ⁇ 9 M or less, 5 ⁇ 10 ⁇ 9 M or less, 4 ⁇ 10 ⁇ 9 M or less, 3 ⁇ 10 ⁇ 9 M or less, or 2 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 1 ⁇ 10 ⁇ 8 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 9 ⁇ 10 ⁇ 9 M or less for tau-pS413. In other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 8 ⁇ 10 ⁇ 9 M or less for tau-pS413. In certain embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 7 ⁇ 10 ⁇ 9 M or less for tau-pS413. In some embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 6 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 5 ⁇ 10 ⁇ 9 M or less for tau-pS413. In yet other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 4 ⁇ 10 ⁇ 9 M or less for tau-pS413. In still other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 3 ⁇ 10 ⁇ 9 M or less for tau-pS413. In yet still other embodiments, the antibody or antigen binding fragment thereof has an equilibrium dissociation constant (KD) of 2 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the KD is measured by Surface Plasmon Resonance (SPR) assay. In certain embodiments, the KD is measured by Surface Plasmon Resonance (SPR) assay with the antibody or antigen binding fragment thereof being immobilized. In other embodiments, the KD is measured by Surface Plasmon Resonance (SPR) assay with the antigen being immobilized. In one embodiment, the KD is measured by Biacore. In another embodiment, the KD is measured by KinExA. In one specific embodiment, the KD is measured by Biacore with the antibody or antigen binding fragment thereof being immobilized.
  • SPR Surface Plasmon Resonance
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 1 ⁇ 10 ⁇ 8 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 9 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 8 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 7 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 6 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 5 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 4 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 3 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; and has a KD of 2 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the KD is measured by Biacore with the antibody or antigen binding fragment thereof being immobilized.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 1 ⁇ 10 ⁇ 8 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 9 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 8 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 7 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 6 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 5 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 4 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 3 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; and has a KD of 2 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the KD is measured by Biacore with the antibody or antigen binding fragment thereof being immobilized.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 1 ⁇ 10 ⁇ 8 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 9 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 8 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 7 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 6 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 5 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 4 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 3 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the antibody or antigen binding fragment thereof that binds to tau-pS413 comprises a VH comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56 and a VL comprising at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; and has a KD of 2 ⁇ 10 ⁇ 9 M or less for tau-pS413.
  • the KD is measured by Biacore with the antibody or antigen binding fragment thereof being immobilized.
  • the present disclosure further includes functional fragments of the anti-tau-pS413 antibodies disclosed herein.
  • functional fragments e.g., antigen-binding fragments such as tau-pS413-binding fragments
  • functional fragments include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab′) fragments, F(ab) 2 fragments, F(ab′)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody.
  • antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen-binding site that binds to a tau-pS413 antigen (e.g., one or more CDRs of an anti-tau-pS413 antibody).
  • Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Pluckthun and Skerra, 1989, Meth. Enzymol. 178:497-515; Day, Advanced Immunochemistry (2d ed. 1990); Hudson et al., 2003, Nature Med. 9:129-34.
  • Immunoglobulins may be assigned to different classes depending on the amino acid sequences of the constant domain of their heavy chains. There are at least five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g. IgG-1, IgG-2, IgG-3 and IgG-4; IgA-1 and IgA-2.
  • the invention comprises antibodies and antigen binding fragments of any of these classes or subclasses of antibodies.
  • the antibody or antigen binding fragment comprises a heavy chain constant region, e.g. a human constant region, such as ⁇ 1, ⁇ 2, ⁇ 3, or ⁇ 4 human heavy chain constant region or a variant thereof.
  • the antibody or antigen binding fragment comprises a light chain constant region, e.g. a human light chain constant region, such as lambda or kappa human light chain region or variant thereof.
  • the antibodies disclosed herein can also be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or effector function (e.g., antigen-dependent cellular cytotoxicity).
  • the antibodies disclosed herein can be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody.
  • the numbering of residues in the Fc region is that of the EU index of Kabat.
  • the antibodies disclosed herein also include antibodies with modified (or blocked) Fc regions to provide altered effector functions. See, e.g., U.S. Pat. No. 5,624,821; WO2003/086310; WO2005/120571; WO2006/0057702. Such modification can be used to enhance or suppress various reactions of the immune system, with possible beneficial effects in diagnosis and therapy. Alterations of the Fc region include amino acid changes (substitutions, deletions and insertions), glycosylation or deglycosylation, and adding multiple Fc. Changes to the Fc can also alter the half-life of antibodies in therapeutic antibodies, enabling less frequent dosing and thus increased convenience and decreased use of material. See Presta (2005) J. Allergy Clin. Immunol. 116:731 at 734-35.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 is modified with two amino acid substitutions, L234A and L235A (sometimes referred to as “LALA” mutations) that reduce/ablate effector function.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 is modified with three amino acid substitutions, L234A, L235A and D265S that reduce/ablate effector function.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 is modified with three amino acid substitutions, M252Y, S254T, and T256E that increase half-life of the antibody in serum.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 is modified with five amino acid substitutions, L234A, L235A, M252Y, S254T, and T256E that reduce/ablate effector function and increase half-life of the antibody in serum.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 is modified with six amino acid substitutions, L234A, L235A, D265S, M252Y, S254T, and T256E that reduce/ablate effector function and increase half-life of the antibody in serum.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 is modified with the amino acid substitution N297A, which eliminates a glycosylation site and reduces/ablates effector function.
  • the constant domain (CH1-hinge-CH2-CH3) of human wild type IgG1 with the amino acid substitution N297Q which eliminates a glycosylation site and reduces/ablates effector function.
  • the antibody is an IgG4 isotype antibody comprising a Serine to Proline mutation at an amino acid position corresponding to position 228 (S228P; EU index) in the hinge region of the heavy chain constant region. This mutation has been reported to abolish the heterogeneity of inter-heavy chain disulfide bridges in the hinge region (Angal et al. supra; position 241 is based on the Kabat numbering system).
  • the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is increased or decreased. This approach is described further in U.S. Pat. No. 5,677,425. The number of cysteine residues in the hinge region of CH1 is altered, for example, to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • the antibody is modified to increase its biological half-life.
  • Various approaches are possible. For example, one or more of the following amino acid mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375.
  • the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody.
  • one or more amino acids selected from amino acid residues at positions 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260.
  • one or more amino acids selected from amino acid residues at positions 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351.
  • the Fc region is modified to increase or decrease the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase or decrease the affinity of the antibody for an Fc ⁇ receptor by modifying one or more amino acids at the following positions: 238, 239, 243, 248, 249, 252, 254, 255, 256, 258, 264, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439.
  • ADCC antibody dependent cellular
  • the Fc region is modified to decrease the ability of the antibody to mediate effector function and/or to increase anti-inflammatory properties by modifying amino acid residues at positions 243 and 264. In one embodiment, the Fc region of the antibody is modified by changing the amino acid residues at positions 243 and 264 to alanine. In one embodiment, the Fc region is modified to decrease the ability of the antibody to mediate effector function and/or to increase anti-inflammatory properties by modifying amino acid residues at positions 243, 264, 267 and 328.
  • the antibody comprises a particular glycosylation pattern.
  • an aglycosylated antibody can be made (i.e., the antibody lacks glycosylation).
  • the glycosylation pattern of an antibody may be altered to, for example, increase the affinity or avidity of the antibody for an antigen.
  • modifications can be accomplished by, for example, altering one or more of the glycosylation sites within the antibody sequence.
  • one or more amino acid substitutions can be made that result removal of one or more of the variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation may increase the affinity or avidity of the antibody for antigen. See, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861.
  • an antibody may also be made in which the glycosylation pattern includes hypofucosylated or afucosylated glycans, such as a hypofucosylated antibodies or afucosylated antibodies have reduced amounts of fucosyl residues on the glycan.
  • the antibody may also include glycans having an increased amount of bisecting GlcNAc structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such modifications can be accomplished by, for example, expressing the antibody in a host cell in which the glycosylation pathway was been genetically engineered to produce glycoproteins with particular glycosylation patterns.
  • the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (a (1,6)-fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates.
  • FUT8 a (1,6)-fucosyltransferase
  • the Ms704, Ms705, and Ms709 FUT8 ⁇ / ⁇ cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No.
  • EP 1176195 describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the ⁇ -1,6 bond-related enzyme.
  • EP 1,176,195 also describes cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662).
  • PCT Publication WO 03/035835 describes a variant CHO cell line, Lec13 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields et al. (2002) J. Biol. Chem. 277:26733-26740).
  • Antibodies with a modified glycosylation profile can also be produced in chicken eggs, as described in PCT Publication WO 06/089231.
  • antibodies with a modified glycosylation profile can be produced in plant cells, such as Lemna (U.S. Pat. No. 7,632,983). Methods for production of antibodies in a plant system are disclosed in the U.S. Pat. Nos.
  • PCT Publication WO 99/54342 describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., ⁇ (1,4)-N-acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech. 17:176-180).
  • glycoprotein-modifying glycosyl transferases e.g., ⁇ (1,4)-N-acetylglucosaminyltransferase III (GnTIII)
  • the fucose residues of the antibody can be cleaved off using a fucosidase enzyme; e.g., the fucosidase ⁇ -L-fucosidase removes fucosyl residues from antibodies (Tarentino et al. (1975) Biochem. 14:5516-23).
  • a fucosidase enzyme e.g., the fucosidase ⁇ -L-fucosidase removes fucosyl residues from antibodies (Tarentino et al. (1975) Biochem. 14:5516-23).
  • Antibodies disclosed herein further include those produced in lower eukaryote host cells, in particular fungal host cells such as yeast and filamentous fungi have been genetically engineered to produce glycoproteins that have mammalian- or human-like glycosylation patterns (see, for example, Choi et al, (2003) Proc. Natl. Acad. Sci. 100: 5022-5027; Hamilton et al., (2003) Science 301: 1244-1246; Hamilton et al., (2006) Science 313: 1441-1443).
  • a particular advantage of these genetically modified host cells over currently used mammalian cell lines is the ability to control the glycosylation profile of glycoproteins that are produced in the cells such that compositions of glycoproteins can be produced wherein a particular N-glycan structure predominates (see, e.g., U.S. Pat. Nos. 7,029,872 and 7,449,308).
  • These genetically modified host cells have been used to produce antibodies that have predominantly particular N-glycan structures (see, for example, Li et al., (2006) Nat. Biotechnol. 24: 210-215).
  • the anti-tau-pS413 antibodies or antigen binding fragments thereof disclosed herein can also be conjugated to one or more agents (e.g., a peptide or chemical moiety).
  • the chemical moiety may be, inter alia, a polymer, a radionuclide, or a therapeutic or prophylactic agent.
  • the chemical moiety is a polymer which increases the half-life of the antibody molecule in the body of a subject.
  • Suitable polymers include, but are not limited to, hydrophilic polymers which include but are not limited to polyethylene glycol (PEG) (e.g., PEG with a molecular weight of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa or 40 kDa), dextran and monomethoxypolyethylene glycol (mPEG).
  • PEG polyethylene glycol
  • mPEG monomethoxypolyethylene glycol
  • the antibodies and antibody fragments disclosed herein may be pegylated, for example to increase its biological (e.g., serum) half-life.
  • the antibody, or fragment thereof typically is reacted with a reactive form of polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment.
  • PEG polyethylene glycol
  • the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer).
  • polyethylene glycol is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide.
  • the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See, e.g., EP 0 154 316 and EP 0 401 384.
  • the antibodies and antibody fragments disclosed herein may also be conjugated to detectable substances including, but not limited to, various enzymes, such as, but not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as, but not limited to, streptavidin/biotin or avidin/biotin; fluorescent materials, such as, but not limited to, umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; luminescent materials, such as, but not limited to, luminol; bioluminescent materials, such as, but not limited to, luciferase, luciferin, or aequorin; chemiluminescent material, such as, but not limited to, an acridinium based compound or
  • the antibodies or antigen binding fragments thereof can be recombinantly fused or chemically conjugated (covalent or non-covalent conjugations) to a heterologous protein or polypeptide (or fragment thereof, for example, to a polypeptide of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 amino acids) to generate fusion proteins.
  • fusion proteins comprising an antigen-binding fragment of an antibody provided herein (e.g., a Fab fragment, Fc fragment, Fv fragment, F(ab) 2 fragment, a VH domain, a VH CDR, a VL domain, or a VL CDR) and a heterologous protein, polypeptide, or peptide.
  • an antibody that binds to a cell surface receptor expressed by a particular neuron cell type may be fused or conjugated to a modified antibody provided herein.
  • the present disclosure also includes methods of using the high affinity anti-tau-pS413 antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein.
  • These antibodies can be used in treating, diagnosing, or monitoring progress of tauopathy, or decreasing the amount of tau-pS413 in the brain of a subject having tauopathy.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of the antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein.
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof described herein e.g., various isotypes of V1-AFM, V2-AFM
  • a method of decreasing the amount of tau-pS413 in the brain of a subject having tauopathy comprising administering to the subject in need thereof an effective amount of the antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof of described herein.
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof of described herein e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein to treat tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein to decrease the amount of tau-pS413 in the brain of a subject having tauopathy.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for the treatment of tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for the preparation of a medicament to treat tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for use in a method for treating tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for use in a method for decreasing the amount of tau-pS413 in the brain of a subject having tauopathy.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:87; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:88; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:83; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:84; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:85.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:94; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:89; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:90; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:91.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:98; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:99; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:100; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:97.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:104; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:105; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:106; and a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:101; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:102; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:103.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:28.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:20.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:32.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:36.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:40.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a light chain comprising the amino acid sequence of SEQ ID NO:71 and a heavy chain comprising the amino acid sequence of SEQ ID NO:72.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74.
  • a method of treating tauopathy in a subject comprising administering to the subject an effective amount of an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises: a light chain comprising the amino acid sequence of SEQ ID NO:75 and a heavy chain comprising the amino acid sequence of SEQ ID NO:76.
  • the method further comprises administering to the subject an additional agent.
  • the additional agent is an agent effective to treat the same or different disorder as the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein are being used to treat.
  • the additional agent is an agent effective to mitigate one or more side effects of the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein.
  • Exemplary additional agents include, but are not limited to:
  • cholinesterase inhibitors such as donepezil, galantamine, rovastigmine, and tacrine
  • NMDA receptor antagonists such as memantine
  • amyloid beta peptide aggregation inhibitors antioxidants, gamma-secretase modulators, nerve growth factor (NGF) mimics or NGF gene therapy, PPAR ⁇ agonists, HMS-CoA reductase inhibitors (statins), ampakines, calcium channel blockers, GABA receptor antagonists, glycogen synthase kinase inhibitors, intravenous immunoglobulin, muscarinic receptor agonists, nicotinic receptor modulators, active or passive amyloid beta peptide for immunization, phosphodiesterase inhibitors, serotonin receptor antagonists, anti-amyloid beta peptide antibodies, growth hormone, neurotrophic factor, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-4/5, fibroblast growth factor (FGF)-2 and
  • combination therapies noted above encompass combined administration (where two or more agents are included in the same or separate formulations), and separate administration, in which case, administration of the anti-tau-pS413 antibody or antigen binding fragment thereof can occur prior to, simultaneously, and/or following, administration of the additional agent and/or adjuvant.
  • the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein can also be used in combination with other interventional therapies such as, but not limited to, radiation therapy, behavioral therapy, or other therapies known in the art and appropriate for the neurological disorder to be treated or prevented, for example, regenerative medicine approaches that use biotechnologies including gene therapy, gene-modified cell therapy, cell therapy and tissue engineering to restore or establish normal brain function.
  • Anti-tau-pS413 antibodies or fragments thereof may also be useful in diagnostic assays for tau-pS413, e.g., detecting its existence in specific neuron cells, brain tissues, CSF, or interstitial fluid (ISF). Such diagnostic methods may be useful in various disease diagnoses or monitoring progress of the disease.
  • particular embodiments include ELISA assays incorporating the use of an anti-tau-pS413 antibody or antigen binding fragment thereof disclosed herein.
  • An exemplary method comprises the following steps:
  • a substrate e.g., surface of a microtiter plate well, e.g., a plastic plate
  • a detectably labeled second antibody e.g., enzyme-linked antibody
  • the anti-tau-pS413 antibodies described herein can be the first antibody or the second antibody, or both the first and the second antibodies in the above exemplary method.
  • the anti-tau-pS413 antibody described herein is the first antibody, and the second antibody is a different antibody that is specific to tau or phosphorylated tau.
  • the anti-tau-pS413 antibody described herein is the second antibody, and the first antibody is a different antibody that is specific to tau or phosphorylated tau.
  • the labeled anti-tau-pS413 antibody is labeled with peroxidase which reacts with ABTS (e.g., 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)) or 3,3′,5,5′-tetramethylbenzidine to produce a color change which is detectable.
  • ABTS e.g., 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)
  • 3,3′,5,5′-tetramethylbenzidine e.g., 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)
  • 3,3′,5,5′-tetramethylbenzidine e.g., 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)
  • 3,3′,5,5′-tetramethylbenzidine e.g., 2,2′-a
  • An anti-tau-pS413 antibody described herein may be used in a Western blot or immune-protein blot procedure.
  • An exemplary method comprises the following steps:
  • Such a membrane may take the form of a nitrocellulose or vinyl-based (e.g., polyvinylidene fluoride (PVDF)) membrane to which proteins to be tested for the presence of tau-pS413 in a non-denaturing PAGE (polyacrylamide gel electrophoresis) gel or SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) gel have been transferred (e.g., following electrophoretic separation in the gel).
  • PVDF polyvinylidene fluoride
  • Detection of the bound antibody or fragment may be by binding the antibody or fragment with a secondary antibody (an anti-immunoglobulin antibody) which is detectably labeled and, then, detecting the presence of the secondary antibody.
  • a secondary antibody an anti-immunoglobulin antibody
  • the anti-tau-pS413 antibodies and antigen binding fragments thereof disclosed herein may also be used for immunohistochemistry.
  • Such a method forms part of the present disclosure and comprises, e.g., (1) contacting a cell or tissue to be tested for the presence of tau-pS413 with an anti-tau-pS413 antibody or antigen binding fragment thereof described herein; and (2) detecting the anti-tau-pS413 antibody or antigen binding fragment thereof on or in the cell or in the tissue. If the anti-tau-pS413 antibody or fragment itself is detectably labeled, it can be detected directly. Alternatively, the anti-tau-pS413 antibody or fragment may be bound by a detectably labeled secondary antibody which is detected.
  • the anti-tau-pS413 antibodies and antigen binding fragments thereof disclosed herein may also be used for in vivo imaging.
  • Such a method may include injection of a radiolabeled anti-tau-pS413 antibodies or antigen-binding fragment thereof into the body of a patient to be tested for the presence of tauopathy associated with the presence of tau-pS413 followed by nuclear imaging of the body of the patient to detect the presence of the labeled anti-tau-pS413 antibody or fragment, e.g., at loci comprising a high concentration of the anti-tau-pS413 antibody or fragment which are bound to tau-pS413 in the brain.
  • Imaging techniques include SPECT imaging (single photon emission computed tomography) or PET imaging (positron emission tomography).
  • Labels include e.g., iodine-123 ( 123 I) and technetium-99m ( 99m Tc), e.g., in conjunction with SPECT imaging or 11 C, 13 N, 15 O or 18 F, e.g., in conjunction with PET imaging or Indium-111 (See e.g., Gordon et al., (2005) International Rev. Neurobiol. 67:385-440).
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein to diagnose tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein to monitor progress of tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for the diagnosis of tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for the monitor of progress of tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for use in a method for diagnosing tauopathy in a subject.
  • an antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragment thereof as disclosed herein for use in a method for monitoring progress of tauopathy in a subject.
  • the method of diagnosing tauopathy in a subject comprises administering to the subject an effective amount of the antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein; and imaging the brain of the subject.
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the method of diagnosing tauopathy in a subject comprises obtaining a sample of CSF or ISF from a subject; running an immunodiagnostic assay (e.g., ELISA) with the antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein; and determining whether the subject has tauopathy.
  • an immunodiagnostic assay e.g., ELISA
  • the method of monitoring progress of tauopathy in a subject comprises administering to the subject an effective amount of the antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein; and imaging the brain of the subject.
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the method of monitoring progress of tauopathy in a subject comprises obtaining a sample of CSF or ISF from a subject; running an immunodiagnostic assay (e.g., ELISA) with the antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein; and determining progress of tauopathy in the subject.
  • an immunodiagnostic assay e.g., ELISA
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5
  • the tauopathy is a neurodegenerative disease, including but not limited to Alzheimer's disease (AD), corticobasal degeneration (CBD) or corticobasal syndrome (CBS), progressive supranuclear palsy, Pick's disease, argyrophilic grain dementia (argyrophilic grain disease), multiple system tauopathy with presenile dementia (MSTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), dementia with neurofibrillary tangles, diffuse neurofibrillary tangle with calcification (DNTC), white matter tauopathy with globular glial inclusions (WMT-GGI), or frontotemporal lobar degeneration with tau pathology (FTLD-tau).
  • AD Alzheimer's disease
  • CBD corticobasal degeneration
  • CBS corticobasal syndrome
  • Pick's disease argyrophilic grain dementia
  • MSTD multiple system tauopathy with presenile dementia
  • FTDP-17 frontotemporal dementia and parkinsonism
  • the tauopathy is AD. In another embodiment, the tauopathy is CBD. In yet another embodiment, the tauopathy is progressive supranuclear palsy. In still another embodiment, the tauopathy is Pick's disease. In one embodiment, the tauopathy is argyrophilic grain dementia. In another embodiment, the tauopathy is MSTD. In yet another embodiment, the tauopathy is FTDP-17. In still another embodiment, the tauopathy is dementia with neurofibrillary tangles. In one embodiment, the tauopathy is DNTC. In another embodiment, the tauopathy is WMT-GGI. In yet another embodiment, the tauopathy is FTLD-tau.
  • the tauopathy is a non-neurodegenerative disease, including but not limited to infectious diseases, such as Economo's encephalitis sequela and subacute sclerosing panencephalitis, and trauma-induced conditions, such as boxer's encephalopathy.
  • infectious diseases such as Economo's encephalitis sequela and subacute sclerosing panencephalitis
  • trauma-induced conditions such as boxer's encephalopathy.
  • the tauopathy is Economo's encephalitis sequela.
  • the tauopathy is subacute sclerosing panencephalitis.
  • the tauopathy is boxer's encephalopathy.
  • isolated nucleic acids and vectors comprising polynucleotide sequences encoding such high affinity antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) disclosed herein or antigen binding fragments thereof, cells (e.g., host cells) comprising such isolated nucleic acids or vectors, and methods of making such high affinity antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof.
  • high affinity antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or
  • nucleic acid encoding various polypeptides disclosed herein.
  • the isolated nucleic acid encodes the VH (e.g., SEQ ID NO:44, 48, 52, 56, or 24) of various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed herein.
  • VH e.g., SEQ ID NO:44, 48, 52, 56, or 24
  • various antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the isolated nucleic acid encodes the VL (e.g., SEQ ID NO:32, 36, 40, 28, or 20) of various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed herein.
  • VL e.g., SEQ ID NO:32, 36, 40, 28, or 20
  • various antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the isolated nucleic acid encodes the VH (e.g., SEQ ID NO:44, 48, 52, 56, or 24) and the VL (e.g., SEQ ID NO:32, 36, 40, 28, or 20) of various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed herein.
  • VH e.g., SEQ ID NO:44, 48, 52, 56, or 24
  • VL e.g., SEQ ID NO:32, 36, 40, 28, or 20
  • various antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the isolated nucleic acid encodes the heavy chain (e.g., SEQ ID NO:72, 74 or 76) of various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed herein.
  • various antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof disclosed herein e.g., various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed
  • the isolated nucleic acid encodes the light chain (e.g., SEQ ID NO:71, 73, or 75) of various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed herein.
  • various antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof disclosed herein e.g., various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed
  • the isolated nucleic acid encodes the heavy chain (e.g., SEQ ID NO:72, 74 or 76) and the light chain (e.g., SEQ ID NO:71, 73, or 75) of various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof disclosed herein.
  • various antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • antigen binding fragments thereof disclosed herein e.g., various antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AF
  • the isolated nucleic acid encodes a VH domain comprising the VH-CDR1, VH-CDR2 and VH-CDR3 as disclosed in TABLE 5.
  • the isolated nucleic acid encodes a VL domain comprising the VL-CDR1, VL-CDR2 and VL-CDR3 as disclosed in TABLE 6.
  • the isolated nucleic acid encodes a VH domain comprising the VH-CDR1, VH-CDR2 and VH-CDR3 as disclosed in TABLE 5 and a VL domain comprising the VL-CDR1, VL-CDR2 and VL-CDR3 as disclosed in TABLE 6.
  • the isolated nucleic acid comprises a nucleotide sequence as set forth in SEQ ID NO:107. In another specific embodiment, the isolated nucleic acid comprises a nucleotide sequence as set forth in SEQ ID NO:108.
  • the nucleic acids further encode a signal sequence.
  • an expression vector comprising one or more of the various isolated nucleic acids disclosed herein, wherein the nucleic acid(s) is operably linked to control sequences that are recognized by a host cell when the host cell is transfected with the expression vector.
  • host cell comprising one or more of the various isolated nucleic acids or the various expression vectors disclosed herein.
  • the host cell comprises one or more of the various isolated nucleic acids disclosed herein.
  • the host cell comprises one or more of the various expression vectors disclosed herein.
  • kits for making the antibody comprising: culturing a host cell comprising an expression vector encoding the antibody or antigen binding fragment thereof in culture medium under conditions wherein the antibody or antigen binding fragment thereof is expressed.
  • Also provided are methods of making the antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragment thereof disclosed herein, comprising: expressing an expression vector that comprises one or more isolated nucleic acid(s) disclosed herein under conditions wherein the antibody or antigen binding fragment thereof is expressed.
  • the antibody e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • methods of making the antibody comprising: expressing one or more isolated nucleic acid(s) disclosed herein under conditions wherein the antibody or antigen binding fragment thereof is expressed.
  • the method further comprises isolating the antigen or antigen binding fragment thereof from the host cell or culture medium, or in vitro expression system.
  • Mammalian cell lines available as hosts for expression of the antibodies or fragments disclosed herein are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). These include, inter alia, Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, HEK-293 cells and a number of other cell lines.
  • Other cell lines that may be used are insect cell lines, such as Sf9 cells, amphibian cells, bacterial cells, plant cells and fungal cells.
  • the antibody or antigen binding fragment thereof is produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody or antigen binding fragment thereof in the host cells or, more preferably, secretion of the antibody or antigen binding fragment thereof into the culture medium in which the host cells are grown.
  • Antibodies can be recovered from the culture medium using standard protein purification methods.
  • glycoproteins produced in a particular cell line or transgenic animal will have a glycosylation pattern that is characteristic for glycoproteins produced in the cell line or transgenic animal. Therefore, the particular glycosylation pattern of an antibody will depend on the particular cell line or transgenic animal used to produce the antibody.
  • all antibodies encoded by the nucleic acid molecules provided herein, or comprising the amino acid sequences provided herein comprise the instant invention, independent of the glycosylation pattern the antibodies may have.
  • antibodies with a glycosylation pattern comprising only non-fucosylated N-glycans may be advantageous, because these antibodies have been shown to typically exhibit more potent efficacy than their fucosylated counterparts both in vitro and in vivo (See for example, Shinkawa et al., J. Biol. Chem. 278: 3466-3473 (2003); U.S. Pat. Nos. 6,946,292 and 7,214,775). These antibodies with non-fucosylated N-glycans are not likely to be immunogenic because their carbohydrate structures are a normal component of the population that exists in human serum IgG.
  • composition comprising the anti-tau-pS413 antibodies (e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM) or antigen binding fragments thereof described herein and a pharmaceutically acceptable carrier.
  • anti-tau-pS413 antibodies e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • a pharmaceutically acceptable carrier e.g., various isotypes of V1-AFM, V2-AFM, V3-AFM, V4-AFM, V5-AFM, V6-AFM, V7-AFM, or V8-AFM
  • the composition further comprises an additional agent.
  • the additional agent is an agent effective to treat the same or different disorder as the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein are being used to treat.
  • the additional agent is an agent effective to relieve side effects of the anti-tau-pS413 antibodies or antigen-binding fragments thereof disclosed herein.
  • Exemplary additional agents include, but are not limited to: cholinesterase inhibitors (such as donepezil, galantamine, rovastigmine, and tacrine), NMDA receptor antagonists (such as memantine), amyloid beta peptide aggregation inhibitors, antioxidants, gamma-secretase modulators, nerve growth factor (NGF) mimics or NGF gene therapy, PPAR ⁇ agonists, HMS-CoA reductase inhibitors (statins), ampakines, calcium channel blockers, GABA receptor antagonists, glycogen synthase kinase inhibitors, intravenous immunoglobulin, muscarinic receptor agonists, nicotinic receptor modulators, active or passive amyloid beta peptide for immunization, phosphodiesterase inhibitors, serotonin receptor antagonists, anti-amyloid beta peptide antibodies, growth hormone, neurotrophic factor, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-4
  • the antibody or antigen binding fragment thereof is admixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary , Mack Publishing Company, Easton, Pa. (1984).
  • Formulations of therapeutic and diagnostic agents may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics , McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy , Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications , Marcel Dekker, NY; Lieberman, et al.
  • Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with another agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index (LD 50 /ED 50 ).
  • antibodies exhibiting high therapeutic indices are desirable.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration.
  • composition comprising an antibody or antibody fragment disclosed herein is administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (Nov. 1, 2002)).
  • the mode of administration can vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral, intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.
  • the anti-tau-pS413 antibody or antigen binding fragment thereof can be administered by an invasive route such as by injection (see above).
  • the anti-tau-pS413 antibody or antigen binding fragment thereof, or pharmaceutical composition thereof is administered intravenously, subcutaneously, intrathecally, intramuscularly, or intracerebrally.
  • the anti-tau-pS413 antibody or antigen binding fragment thereof, or pharmaceutical composition thereof is administered intravenously.
  • the anti-tau-pS413 antibody or antigen binding fragment thereof, or pharmaceutical composition thereof is administered subcutaneously.
  • the anti-tau-pS413 antibody or antigen binding fragment thereof, or pharmaceutical composition thereof is administered intrathecally. In still another specific embodiment, the anti-tau-pS413 antibody or antigen binding fragment thereof, or pharmaceutical composition thereof, is administered intramuscularly. In still another specific embodiment, the anti-tau-pS413 antibody or antigen binding fragment thereof, or pharmaceutical composition thereof, is administered intracerebrally.
  • compositions can be administered with medical devices known in the art.
  • a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.
  • compositions disclosed herein may also be administered by infusion.
  • the administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the ratio of the therapeutic antibody that crosses the blood-brain barrier, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix.
  • the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects.
  • the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance in selecting appropriate doses of therapeutic antibodies is available (see, e.g., Wawrzynczak (1996) Antibody Therapy , Bios Scientific Pub.
  • Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. In general, it is desirable that a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized and fully human antibodies are may be desirable.
  • the anti-tau-pS413 antibodies or antigen binding fragments thereof may be coadministered with one or more additional agents.
  • the antibody may be linked to the agent (as an immunocomplex) or can be administered separately from the agent (fixed dose). In the latter case (separate administration), the antibody can be administered before, after, or concurrently with the agent or can be co-administered with other known therapies.
  • kits comprising an antibody (e.g., an anti-tau-pS413 antibody) provided herein, or a composition (e.g., a pharmaceutical composition) thereof, packaged into suitable packaging material.
  • a kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.
  • packaging material refers to a physical structure housing the components of the kit.
  • the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, etc.).
  • Kits provided herein can include labels or inserts.
  • Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g., a box), or attached to, for example, an ampoule, tube, or vial containing a kit component.
  • Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media, or memory type cards.
  • Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location, and date.
  • Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Kits can also be designed for cold storage. A kit can further be designed to contain antibodies provided herein, or cells that contain nucleic acids encoding the antibodies provided herein. The cells in the kit can be maintained under appropriate storage conditions until ready to use.
  • Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies , Oxford Univ. Press, New York, N.Y.; Kontermann and Dubel (eds.) (2001) Antibody Engineering , Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem.
  • Fluorescent reagents suitable for modifying nucleic acids including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probes (2003) Catalogue , Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue , St. Louis, Mo.).
  • HmzTa1505-hIgG4-S228P is a humanized antibody that was generated from the mouse parental antibody Ta1505-mIgG2a, the details of which are documented in WO 2018/254390.
  • Affinity maturation of HmzTa1505-hIgG4-S228P was performed via yeast display screening of a structure-based designed affinity maturation library.
  • the library design was guided by the apo Ta1505 Fab crystal structure with the introduction of 79:7:7:7 non-equimolar (doped) partially randomized mutations at the DNA level to solvent-exposed heavy chain and light chain CDR residues.
  • Three initial libraries were created and screened; the libraries consisted of mutations in CDR-H1/H2 (9 residues total), CDR-H3 (8 residues total), and CDR-VL (12 residues total).
  • FACS sorting of yeast cells labeled with biotinylated tau-pS413 peptide and anti-kappa light chain was used to isolate leads with increased affinity while maintaining phospho-specificity.
  • FACS sorted outputs from the initial libraries were later combined to generate a final combined VH/VL yeast display library for synergistic improvement and screened in the same manner. Thirty hits from the combined library were reformatted to hIgG4-S228P isotype and produced recombinantly, followed by Biacore and protein analytics.
  • V1-AFM-hIgG4-S228P which showed a 10-fold improvement in monovalent affinity and >40 ⁇ improvement in binding to phosphorylated Tau in AD patient cerebrospinal fluid (CSF), compared to HmzTa1505-hIgG4-S228P (see TABLE 8).
  • VH or VL from the top hits of affinity maturation were switched and matched with VL or VH of another top hit to generate more antibody variants.
  • K54E or K54D An additional mutation (K54E or K54D) in various VHs was identified via structure-based design with the goal of identifying mutations that lowered the isoelectric point (pI) while maintaining or improving the affinity.
  • the designs were guided by computational saturation mutagenesis and a co-crystal of Ta1505 Fab bound to a tau-pS413 peptide.
  • V6-AFM exhibited improved monovalent affinity to tau-pS413 on all 3 isotypes tested (hIgG1-LALA, hIgG1-LALA-YTE, and hIgG4-S228P) (see TABLE 8).
  • V6-AFM even exhibited improved production of the antibody molecules on IgG1-LALA isotype (data not shown) and IgG1-LALA-YTE isotype ( FIG. 6 ), compared with V1-AFM.
  • K54E mutation in the VH of V2-AFM was replaced with K54D.
  • both E and D mutations at position 54 reduced the pI to 7.58.
  • K54E and K54D mutations increased the KD of the reference antibody by 1.9- and 1.4-fold, respectively.
  • heavy chain isotype constant regions e.g., IgG1, IgG1-LALA, IgG1-LALA-YTE, IgG4, IgG4-S228P
  • IgG1, IgG1-LALA, IgG1-LALA-YTE, IgG4, IgG4-S228P were added to the VH of various exemplary antibodies.
  • Sequence alignment among exemplary VHs is shown in FIG. 1 A
  • sequence alignment among exemplary VLs is shown in FIG. 1 B .
  • SPR assay was used to determine the monovalent binding affinities of mAbs to a tau-pS413 peptide (SEQ ID NO:109).
  • Antibodies were amine coupled to a CMS sensor chip at approximately 1000 RUs each.
  • Binding assays were performed using HBS-EP running buffer containing 3 mM EDTA and 0.05% Tween-20, pH 7.4. Titrating concentrations (200 nM top for HmzTa1505-hIgG4-S228P, 80 nM top for all other mAbs, 6-point, 2.5-fold dilution series and two zeros) of the tau-pS413 peptide were injected over the immobilized mAbs.
  • Binding specificity of the high affinity antibodies described herein was assessed with various tau peptides by a peptide-coated ELISA. Plates were coated with 50 ⁇ l of 1 ⁇ g/ml peptides 69AXY, 70AXY, 74AXY, 84AWK, 25AWF, or 24AWF in PBS for overnight at 4° C. On the next day, the plates were washed 3 times, blocked with 200 ⁇ l of superblock for 1 hr at room temperature, then washed 3 times again. Antibodies were diluted at 1:5 serial dilution in ELISA buffer starting from 10 ⁇ g/ml.
  • the plates were incubated with 50 ⁇ l of serially diluted antibodies at room temperature for 1 hr and washed 3 times. Then the plates were incubated with 50 ⁇ l of goat anti-mouse IgG-HRP (Southern Biotech, cat #1030-05) or goat anti-human IgG-HRP (Jackson Immunologics, cat #109-036-0980) diluted 1:3000 in ELISA buffer for 45 minutes at room temperature, washed 5 times, then developed with ABTS for 5 mins at room temperature and read at OD 405 nM.
  • goat anti-mouse IgG-HRP Pacificn Biotech, cat #1030-05
  • goat anti-human IgG-HRP Jackson Immunologics, cat #109-036-0980
  • FIGS. 2 A- 2 F The bindings of exemplary antibodies (V8-AFM-IgG1-LALA, V8-AFM-IgG1-LALA-YTE, V8-AFM-IgG4-S228P, V5-AFM-IgG4-S228P) are shown in FIGS. 2 A- 2 F .
  • they all specifically bind to a tau peptide with phosphorylated serine 413 [PD17(p)PS413 (24AWF), SEQ ID NO:77] ( FIG. 2 A ) but do not bind to the same peptide without phosphorylated serine 413, [PD17 (25AWF), SEQ ID NO:78] ( FIG. 2 B ).
  • FIGS. 2 C- 2 F A control antibody, humanized antibody against RSV does not bind to any of the tested peptides ( FIGS. 2 A- 2 F ).
  • SPR assay was used to determine the binding affinity of the high affinity antibodies described herein to human and cynomolgus monkey (cyno) FcRn at pH 6.0 and 7.4.
  • Anti-human kappa antibody was amine coupled to a CMS chip. Each antibody was captured to 200-300 RUs.
  • Binding assays were performed using PBS running buffer containing 0.05% Tween-20, adjusted to either pH 6.0 or 7.4. Titration samples were also prepared using the corresponding pH buffer for the assay. Titrating concentrations (1200 nM top, 6-point, 3-fold dilution series and two zeros) of human or cyno FcRn were injected over the captured mAbs.
  • Binding affinities of various anti-tau-pS413 antibodies described herein for endogenous tau species were determined in brain homogenates and CSF samples from AD patients and preclinical models. Briefly, samples were pre-incubated with different concentrations of various anti-tau-pS413 antibodies, or respective isotype controls. Following a one-hour pre-incubation period, the antigen-antibody (Ag-Ab) mixture was added to plates pre-coated with a total tau capture antibody (Innotest ELISA kit). Unbound (“free”) tau-pS413 in the brain homogenate or CSF sample was then detected by biotinylated Ta1505-mIgG2a antibody.
  • Ag-Ab antigen-antibody
  • P2 extracts were prepared as follows. Ten grams of pre-frontal cortex tissue (ABS Inc) were immersed in artificial CSF buffer (aCSF: 119 mM NaCl, 2.5 mM KCl, 1 mM NaH 2 PO 4 , 1.3 mM MgSO 4 , 2.5 mM CaCl 2 , 26 mM NaHCO 3 , 11 mM glucose, 10 mM HEPES, pH 7.4 and sterile water) with protease and phosphatase inhibitors (Pierce) at the dilution of tissue/buffer 1:5 (w/v). Tissue was homogenized by GentleMACS Dissociator.
  • CSF buffer aCSF: 119 mM NaCl, 2.5 mM KCl, 1 mM NaH 2 PO 4 , 1.3 mM MgSO 4 , 2.5 mM CaCl 2 , 26 mM NaHCO 3 , 11 mM glucose, 10 mM HEPES, pH 7.
  • the lysed tissue was centrifuged at 3000 g for 20 minutes at 4° C.
  • the supernatants were transferred to polycarbonate 50 ml centrifuge tubes and spun at 27,000 g for 20 minutes at 4° C.
  • the supernatants were collected (51 fraction) and further centrifuged at 150,000 g for 20 minutes at 4° C.
  • the pellets were resuspended, P2 fraction, in aCSF buffer with protease and phosphatase inhibitors and sonicated for a few seconds using a probe sonicator.
  • the concentration of the P2 fraction was determined by BCA protein assay (Pierce) and the P2 fraction were aliquoted and stored at ⁇ 80° C.
  • FIG. 3 A illustrates the raw data showing the decreased levels of “free” unbound antigen in P2 extracts of AD brain homogenates with increasing concentrations of mAbs, but not isotype control.
  • FIG. 3 B illustrates the transformed data where the absorbance (OD) values of isotype control hIgG OD values (“total”) were subtracted from test mAbs (“free”) and normalized to calculate the occupancy EC50's of the profiled mAbs (TABLE 10).
  • the high affinity anti-tau-pS413 antibodies described herein also bind to tau species in brain homogenates from mutant tau mice (rTg(tauP301L)4510) (Ramsden M et al., 2005 , J. Neurosci. 25 (46) 10637-10647) and in the CSF from post-mortem AD patients and African Green Monkeys. Tissue homogenates were prepared using 1% sarkosyl buffer with several high-speed centrifugation steps to enrich for insoluble proteins including tau. Binding measures could not be assessed in CSF of the tau mutant mice because of the limited volume.
  • the “effective” binding potencies of HmzTa1505-hIgG4-S228P and V8-AFM-hIgG1-LALA-YTE for the endogenous tau in the various biological specimens are about 2- to about 10-fold higher than the respective potencies for recombinant phosphorylated tau protein monomer used as standard (TABLE 11). These results suggest anti-tau-pS413 antibodies bind with an avidity component to the target tau species.
  • the binding potencies of V8-AFM-hIgG1-LALA-YTE for these biological tau species are also about 30- to about 200-fold higher than those of HmzTa1505-hIgG4-S228P (TABLE 11).
  • the immunodepletion was performed using Dynabeads protein G after pre-incubation of 4 ⁇ g of total protein of P2 extract with various concentration of mAbs or corresponding isotype control (3 nM to 3 pM) of tau antibodies or isotype control for 4 hours.
  • mAbs or corresponding isotype control 3 nM to 3 pM
  • tau antibodies or isotype control for 4 hours.
  • neurons were immuno-stained with MC1 antibody, a tau mAb specific for pathological tau conformation (provided by Dr. Peter Davies, Department of Pathology, Albert Einstein College of Medicine). Tau pathology was quantified with high-content image analysis based on immuno-staining of MC1 antibody (Representative images in FIG. 4 D ).
  • This neutralization assay consists of immuno-depleting tau species from P2 extracts with HmzTa1505-hIgG4-S228P, V1-AFM-hIgG4-S228P, V8-AFM-hIgG1-LALA-YTE, or corresponding isotype control before seeding the P2 extract in hiPSC neurons (as described in the schematic representation of FIG. 4 A ).
  • the immuno-depleted samples were tested in AlphaLISA® assay to confirm the successful immuno-depletion of total tau (Tau5/HT7 antibody pair, FIG. 4 C ) or tau-pS413 species (pTa1505 IgG2a/HT7 antibody pair, FIG. 4 B ) with HmzTa1505-hIgG4-S228P, V1-AFM-hIgG4-S228P, or V8-AFM-hIgG1-LALA-YTE.
  • immunodepleted samples were incubated with HT7 (Thermofisher) acceptor beads (final concentration 20 ⁇ g/mL) and Tau5 (Thermofisher) or Ta1505 biotinylated antibody (0.6 ⁇ g/mL) for 2 hrs in immunoassay buffer at room temperature.
  • streptavidin donor beads final concentration 40 ⁇ g/mL were added to the plate and incubated for an additional 1 hr at room temperature with gentle shaking and then the plates were read on Envision plate reader (Perkin Elmer).
  • Tg4510 mice WT:Car mice were injected into the hippocampus with Sarkosyl Insoluble (SI) Tau preparation from rTg(tauP301L)4510 mice (Car:Car) mice to elicit the transmission and of tau pathology around the injection site and spreading to other brain regions. Mice were then treated weekly with antibody injections.
  • FIG. 5 showed a reduced pathology with high doses of both V8-AFM-mIgG1 and Ta1505-mIgG1 and a trend towards a dose response reduction in tau pathology in the ipsilateral hippocampus. While administration of V8-AFM-mIgG1 did not show significantly better reduction in tau pathology, drug exposures were unexpectedly lower in the V8-AFM-mIgG1 groups. In particular, for each dose level, the V8-AFM-mIgG1 group showed 20-fold lower PK levels than the Ta1505-mIgG1 group (TABLE 12). As a result, we could not directly compare the efficacious doses.
  • Example 8 Ex-Vivo Detection of Target Engagement by Anti-Tau-pS413 Antibodies in CSF Samples from Heathy Volunteers and AD Patients
  • ECL electro-chemiluminescent
  • Meso Scale Discovery S-Plex Platform An ultra-sensitive electro-chemiluminescent (ECL) assay on the Meso Scale Discovery S-Plex Platform was developed to measure a baseline level of tau-pS413 in human CSF and free (i.e., unbound) tau-pS413 in the presence of tau-pS413-specific antibodies. The method can be used to demonstrate target engagement by anti-tau-pS413 antibodies as a reduction in free tau-pS413 signal.
  • biotinylated mouse monoclonal anti-tau-pS413 antibody Ta1505 was coated onto MSD 96-well S-PLEX SECTOR Plates (Mesoscale Discovery, cat No.
  • MSD Diluent 101 (Mesoscale Discovery Cat No. R51AD) and incubated for 1 hour at room temperature on orbital shaker (700 rpm). Color enhancement and development steps were performed following MSD S-PLEX protocol. Plates were read on MESO SECTORTM S600 instrument for electro-chemiluminescent signal (A.U.).
  • the ex-vivo binding of anti-tau-pS413 antibody was evaluated by quantitating tau-pS413 after incubating human non-AD or AD CSF samples with V8-AFM-hIgG1-LALA-YTE at titrated concentrations (0.085 fM to 50 nM) using the tau-pS413 MSD S-PLEX assay.
  • the assay signal reduced with increasing concentration of V8-AFM-hIgG1-LALA-YTE ( FIG. 7 A ).
  • the antibody reached 100% target occupancy at a concentration from about 1.85 nM to about 50 nM.
  • the percent reduction of the free tau-pS413 (not bound by V8-AFM-hIgG1-LALA-YTE) levels was calculated based on a maximum signal produced without V8-AFM-hIgG1-LALA-YTE and a minimum signal produced without 50 nM V8-AFM-hIgG1-LALA-YTE (both the maximum level and the minimum level subtracted a background level without CSF samples but with the buffer only).

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US20230167168A9 (en) 2023-06-01
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DOP2022000295A (es) 2023-02-15
US11702467B2 (en) 2023-07-18
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