EP3638694A1 - Compositions et méthodes de traitement de tauopathies - Google Patents

Compositions et méthodes de traitement de tauopathies

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Publication number
EP3638694A1
EP3638694A1 EP17743107.9A EP17743107A EP3638694A1 EP 3638694 A1 EP3638694 A1 EP 3638694A1 EP 17743107 A EP17743107 A EP 17743107A EP 3638694 A1 EP3638694 A1 EP 3638694A1
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European Patent Office
Prior art keywords
seq
amino acid
acid sequence
disease
human tau
Prior art date
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EP17743107.9A
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German (de)
English (en)
Inventor
Giridhar TIRUCHERAI
Michael Frans BURGESS
Masano Tlaneci HUANG
Lori S. Burton
Yong Quan
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Publication of EP3638694A1 publication Critical patent/EP3638694A1/fr
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    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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

Definitions

  • the present application relates generally to dosage regimens and formulations for the clinical use of anti-tau antibodies.
  • Protein accumulation, modifications, and aggregation are pathological aspects of numerous neurodegenerative diseases.
  • Pathologically modified and aggregated tau including hyperphosphorylated tau conformers are an invariant hallmark of tauopathies and correlate with disease severity.
  • the microtubule associated protein tau is abundant in the central nervous system and is produced primarily by neurons. Tau promotes the assembly of, maintains the structure of, and stabilizes microtubules.
  • the tau proteins are derived from alternative mRNA splice variants that originate from a single gene and result in mature proteins that vary in size from 352 to 441 amino acids. While the fetal brain contains a single tau isoform (Tau-352), six tau isoforms exist in the adult human brain. They differ from one another in having three or four microtubule binding repeats of 31-32 amino acids each, and two, one, or no amino terminal inserts of 29 amino acids each.
  • Tauopathies are a class of neurodegenerative diseases resulting from the pathological aggregation of Tau protein in so-called neurofibrillary tangles (NFT) in the brain.
  • NFT neurofibrillary tangles
  • tauopathies include progressive supranuclear palsy, Alzheimer's disease, frontotemporal dementia (FTD), corticobasal degeneration, and frontotemporal lobar degeneration.
  • This disclosure relates, in part, to dosage regimens and formulations of anti-human tau antibodies or tau-binding fragments thereof and their use in the treatment of a tauopathy.
  • this disclosure provides a method of treating a tauopathy in a human subject in need thereof.
  • the method involves administering to the human subject an anti- human tau antibody at a fixed dose of 2000 mg.
  • the anti-human tau antibody comprises an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL).
  • the VH comprises VH complementarity determining regions (VH- CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16; VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:17; and VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19; VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:20; and VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • the anti -human tau antibody is administered to the human subject intravenously. In certain cases, the fixed dose of 2000 mg of the anti-human tau antibody is administered once every four weeks.
  • a method of treating a tauopathy in a human subject in need thereof involves administering to the human subject an anti- human tau antibody at a fixed dose of 150 mg.
  • the anti-human tau antibody comprises an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL).
  • the VH comprises VH complementarity determining regions (VH- CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16; VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:17; and VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19; VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:20; and VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • the anti -human tau antibody is administered to the human subject intravenously.
  • the fixed dose of 150 mg of the anti-human tau antibody is administered once every four weeks.
  • a method of treating a tauopathy in a human subject in need thereof involves administering to the human subject an anti- human tau antibody at a fixed dose of 210 mg.
  • the anti-human tau antibody comprises an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL).
  • the VH comprises VH complementarity determining regions (VH- CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16; VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:17; and VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • the VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19; VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:20; and VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • the anti -human tau antibody is administered to the human subject intravenously.
  • the fixed dose of 210 mg of the anti-human tau antibody is administered once every four weeks.
  • a method of treating a tauopathy in a human subject in need thereof involves administering to the human subject an anti- human tau antibody at a fixed dose of 2100 mg.
  • the anti-human tau antibody comprises an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL).
  • the VH comprises VH complementarity determining regions (VH- CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16; VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:17; and VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19; VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:20; and VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • the anti -human tau antibody is administered to the human subject intravenously.
  • the fixed dose of 2100 mg of the anti-human tau antibody is administered once every four weeks.
  • a method of treating a tauopathy in a human subject in need thereof involves administering to the human subject an anti -human tau antibody at a fixed dose of 4200 mg.
  • the anti-human tau antibody comprises an
  • VH immunoglobulin heavy chain variable region
  • VL immunoglobulin light chain variable region
  • the VH comprises VH complementarity determining regions (VH- CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16; VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:17; and VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • the VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19; VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:20; and VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • the anti -human tau antibody is administered to the human subject intravenously.
  • the fixed dose of 4200 mg of the anti-human tau antibody is administered once every four weeks.
  • the following embodiments apply to all of the above aspects.
  • the tauopathy is progressive supranuclear palsy, Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism- dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Straussler- Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angi
  • the tauopathy is progressive supranuclear palsy. In another instance, the tauopathy is Alzheimer's disease.
  • the VH of the anti-human tau antibody comprises or consists of SEQ ID NO: 12
  • the VL of the anti- human tau antibody comprises or consists of SEQ ID NO: 13.
  • the anti- human tau antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of SEQ ID NO: 14, and the light chain comprises or consists of SEQ ID NO: 15.
  • this disclosure features a pharmaceutical composition comprising an anti-human tau antibody.
  • the pharmaceutical composition comprises an anti-human tau antibody at a concentration of 50 mg/ml or 60 mg/ml; histidine at a concentration of 20 mM, sucrose at a concentration of 250 mM, polysorbate-80 at a concentration of 0.05% (w/v).
  • the pharmaceutical composition further comprises 50 ⁇ diethylenetriamine pentaacetic acid (DTP A).
  • DTP A diethylenetriamine pentaacetic acid
  • the anti-human tau antibody comprises a VH and a VL.
  • the VH comprises a VH-CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; a VH-CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; and a VH-CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 18.
  • the VL comprises a VL-CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; a VL-CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO:20; and a VL-CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:21.
  • the pharmaceutical composition has a pH of 6.0.
  • the VH of the anti-human tau antibody comprises or consists of SEQ ID NO: 12 and the VL of the anti-human tau antibody comprises or consists of SEQ ID NO: 13.
  • the anti-human tau antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of SEQ ID NO: 14 and the light chain comprises or consists of SEQ ID NO: 15.
  • the pharmaceutical composition is used in for treating a tauopathy in a human subject in need thereof by intravenously administering to the human subject any of the above-described pharmaceutical compositions.
  • the anti-human tau antibody of the pharmaceutical composition is administered to a human subject at a fixed dose of 150 mg once every four weeks.
  • the anti-human tau antibody of the pharmaceutical composition is administered to a human subject at a fixed dose of 210 mg once every four weeks. In yet other embodiments, the anti-human tau antibody of the pharmaceutical composition is administered to a human subject at a fixed dose of 700 mg once every four weeks. In further embodiments, the anti-human tau antibody of the pharmaceutical composition is administered to a human subject at a fixed dose of 2000 mg once every four weeks. In other embodiments, the anti-human tau antibody of the pharmaceutical composition is administered to a human subject at a fixed dose of 2100 mg once every four weeks. In another embodiment, the anti-human tau antibody of the pharmaceutical composition is administered to a human subject at a fixed dose of 4200 mg once every four weeks.
  • the pharmaceutical composition is administered for at least 12 weeks (e.g., 12 weeks, 16 weeks, 20 weeks, 24 weeks, 30 weeks, 32 weeks, 36 weeks, 40 weeks, 48 weeks, 52 weeks).
  • the tauopathy is progressive supranuclear palsy, Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism- dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type
  • Fig. 1 provides the sequences of different forms of extracellular Tau (eTau), eTaul (SEQ ID NO:7); eTau2 (SEQ ID NO:8), eTau3 (SEQ ID NO:9), and eTau4 (SEQ ID NO: 10), compared to the human Tau-441 isoform (2N4R) sequence (SEQ ID NO:6).
  • Fig. 2 is a schematic representation of the study design for the single ascending dose study described in Example 1.
  • Fig. 3 is a graph depicting the exposure-response model (Bayesian Emax) of CSF concentration versus eTau suppression.
  • Fig. 4 is a schematic representation of the study design for the multiple ascending dose study described in Example 3.
  • Fig. 5 is a table providing the baseline demographic characteristics of the patients in the multiple ascending dose study described in Example 3.
  • Fig. 6 is a table providing a summary of the adverse events for the multiple ascending dose study described in Example 3.
  • Fig. 7 is a table providing a summary of the serum PK parameters for BIIB092 (at day 57 of the study).
  • Fig. 8 is a graphical depiction of the mean change in eTau concentrations over time. There was a dose-dependent relationship between BIIB092 dose and the extent of eTau suppression in the CSF.
  • FIG. 9 is a table providing CSF free eTau as a percentage of baseline with BIIB092 dose. Detailed Description
  • This disclosure features dosage regimens and formulations of anti-human tau antibodies and tau-binding fragments thereof and their use in the treatment of tauopathies (e.g., disorders related to aggregates of tau such as progressive supranuclear palsy,
  • Alzheimer's disease amyotrophic lateral sclerosis/parkinsonism- dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute s
  • Tau is a protein that plays a critical role in the pathogenesis of several disorders collectively referred to as tauopathies.
  • tauopathies There are several different isoforms of the microtubule-associated protein, which are provided below:
  • eTau Extracellular Tau
  • CSF cerebrospinal fluid
  • ISF interstitial fluid
  • eTau is a polypeptide having a sequence set forth in one of SEQ ID NOS.: 7-10 of Figure 1.
  • the eTau species varies from 171 amino acids for eTaul to 67 amino acids for eTau4.
  • tau lacks a signal sequence, tau has been found released into culture medium from neuroblastoma cells, tau-expressing non-neuronal cells, induced pluripotent stem cell-derived human neurons, and mouse primary neurons.
  • tau may be secreted unconventionally or associated with exosomes or other membrane vesicles.
  • eTau has also been detected in the brain ISF of both wild type and P301S tau-expressing mice in microdialysis studies. It has also been seen in the brain ISF of patients following traumatic brain injury. eTau has been shown to regulate ⁇ production and to increase neuronal hyperactivity (Bright et al., Neurobiology and Aging, 36:693-709 (2015)). Treatment with an eTau-neutralizing antibody reduces eTau-mediated neuronal hyperactivity. See, e.g., WO 2014/02877.
  • eTau-driven neuronal hyperactivity increase leads not only to increased ⁇ secretion but also to a further increase in eTau secretion and thus, eTau and ⁇ create a feed forward disease mechanism that perpetuates the disease.
  • neutralizing eTau can inhibit the spread of tau and tau pathology in the brain, reduce central nervous system ⁇ levels and the resulting neuronal hyperactivity, and potentially slow the clinical progression into dementia.
  • antibodies that bind tau are used to neutralizing tau.
  • these antibodies bind to an epitope within amino acids 1-25, 1-18, 9-18, 13-24, 15-44, or 15-24 of SEQ ID NO:6.
  • an anti-tau antibody binds to an epitope within AGTYGLGDRK (SEQ ID NO: 11).
  • BIIB092 An exemplary anti-human tau antibody is designated "BIIB092.”
  • BIIB092 is a humanized IgG4/kappa antibody that recognizes human tau.
  • the heavy chain variable domain of the BIIB092 antibody has the following amino acid sequence:
  • the light chain variable domain of the BIIB092 antibody has the following amino acid sequence:
  • the heavy chain of the BIIB092 antibody has the following amino acid sequence:
  • the light chain of the BIIB092 antibody has the following amino acid sequence:
  • the anti-human tau antibody or tau-binding fragment thereof comprises the three light chain variable domain CDRs of BIIB092. In some embodiments, the anti-human tau antibody or tau-binding fragment thereof comprises the three heavy chain variable domain CDRs of BIIB092. In still other embodiments, the anti -human tau antibody or tau-binding fragment thereof comprises the three heavy chain variable domain CDRs and the three light chain variable domain CDRs of BIIB092.
  • the CDRs can be based on any CDR definition in the art, e.g., the definitions of Kabat, Chothia, Chothia from Abysis, enhanced Chothia/AbM, or based on the contact definition. CDR sequences of BIIB092 are provided in Table 1 below.
  • the anti-human tau antibody or tau-binding fragment thereof comprises a VH CDRl comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 16, a VH CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 17; and a VH CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 18; a VL CDRl comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 19, a VL CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:20; and a VL CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:21.
  • the anti-human tau antibody or tau-binding fragment thereof comprises a VH comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the anti-human tau antibody or tau-binding fragment thereof comprises a VL comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the anti -human tau antibody or tau-binding fragment thereof comprises a VH comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 12 and a VL comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 13.
  • the anti-human tau antibody or tau-binding fragment thereof comprises a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-human tau antibody or tau-binding fragment thereof comprises a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the anti-human tau antibody or tau-binding fragment thereof comprises a heavy chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 14 and a light chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 15.
  • the anti-human tau antibody is an IgG antibody.
  • the anti-human tau antibody has heavy chain constant region chosen from, e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE.
  • the anti- human tau antibody is of the IgG4 isotype.
  • the anti-human tau antibody is of the IgGl isotype.
  • the anti-human tau antibody is of the IgG2 isotype.
  • the anti-human tau antibody is of the IgG3 isotype.
  • the anti-human tau antibody has a light chain constant region chosen from, e.g., a human kappa light chain constant region or a human lambda light chain constant region.
  • the anti-human tau antibody is an
  • IgG4/human kappa light chain antibody IgG4/human kappa light chain antibody.
  • the anti-human tau antibody is a full-length (whole) antibody or substantially full-length.
  • the protein can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains.
  • the anti-human tau antibody is a tau-binding fragment.
  • the tau-binding antibody fragment is a Fab, a Fab', an F(ab')2, a Facb, an Fv, a single chain Fv (scFv), a sc(Fv)2, or a diabody.
  • the heavy chain and light chain of the anti-human tau antibodies disclosed herein may also include signal sequences.
  • the signal sequences can be selected from those known in the art, for example, MDMRVPAQLLGLLLLWFPGSRC (SEQ ID NO:22) or
  • Antibodies such as BIIB092, or tau-binding fragments thereof can be made, for example, by preparing and expressing synthetic genes that encode the recited amino acid sequences or by mutating human germline genes to provide a gene that encodes the recited amino acid sequences. Moreover, this antibody and other anti -human tau antibodies can be produced, e.g., using one or more of the following methods. Methods of Producing Anti-Human tau Antibodies
  • Anti-human tau antibodies or tau-binding fragments may be produced in bacterial or eukaryotic cells. Some antibodies, e.g., Fab's, can be produced in bacterial cells, e.g., E. coli cells. Antibodies can also be produced in eukaryotic cells such as transformed cell lines (e.g., CHO, 293E, COS). In addition, antibodies (e.g., scFv's) can be expressed in a yeast cell such as Pichia (see, e.g., Powers et al., J Immunol Methods . 251 : 123-35 (2001)), Hanseula, or Saccharomyces.
  • a yeast cell such as Pichia (see, e.g., Powers et al., J Immunol Methods . 251 : 123-35 (2001)), Hanseula, or Saccharomyces.
  • a polynucleotide or polynucleotides encoding the antibody is/are constructed, introduced into an expression vector or expression vectors, and then expressed in suitable host cells.
  • the nucleotide sequences of the light and heavy chain genes can be recoded without changing (or minimally changing - e.g., removal of a C-terminal residue of the heavy or light chain) the amino acid sequence.
  • the areas for potential recoding include those associated with translation initiation, codon usage, and possible unintended mRNA splicing.
  • Polynucleotides encoding an anti- human tau antibody comprising the VH and/or VL, HC and/or LC of the tau antibodies described herein would be readily envisioned by the ordinarily skilled artisan.
  • Standard molecular biology techniques are used to prepare the recombinant expression vector(s), transfect the host cells, select for transformants, culture the host cells, and recover the anti -human tau antibody.
  • the expression vector should have characteristics that permit amplification of the vector in the bacterial cells. Additionally, when E. coli such as JM109, DH5a, HB101, or XL 1 -Blue is used as a host, the vector must have a promoter, for example, a lacZ promoter (Ward et al, 341 :544-546 (1989), araB promoter (Better et al, Science, 240: 1041-1043 (1988)), or T7 promoter that can allow efficient expression in E. coli.
  • a promoter for example, a lacZ promoter (Ward et al, 341 :544-546 (1989), araB promoter (Better et al, Science, 240: 1041-1043 (1988)
  • T7 promoter that can allow efficient expression in E. coli.
  • vectors examples include, for example, M13-series vectors, pUC-series vectors, pBR322, pBluescript, pCR-Script, pGEX-5X-l (Pharmacia), "QIAexpress system"
  • the expression vector may contain a signal sequence for antibody secretion.
  • the pelB signal sequence (Lei et al., J. Bacteriol, 169:4379 (1987)) may be used as the signal sequence for antibody secretion.
  • calcium chloride methods or electroporation methods may be used to introduce the expression vector into the bacterial cell.
  • the expression vector includes a promoter necessary for expression in these cells, for example, an SV40 promoter (Mulligan et al, Nature, 277: 108 (1979)) (e.g., early simian virus 40 promoter), MMLV-LTR promoter, EF la promoter (Mizushima et al , Nucleic Acids Res. , 18:5322 (1990)), or CMV promoter (e.g., human cytomegalovirus immediate early promoter).
  • SV40 promoter Mulligan et al, Nature, 277: 108 (1979)
  • MMLV-LTR promoter e.g., early simian virus 40 promoter
  • EF la promoter e.g., EF la promoter
  • CMV promoter e.g., human cytomegalovirus immediate early promoter
  • the recombinant expression vectors may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin, or methotrexate, on a host cell into which the vector has been introduced.
  • vectors with selectable markers include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.
  • the anti-human tau antibodies are produced in mammalian cells.
  • mammalian host cells for expressing an antibody include Chinese Hamster Ovary (CHO cells) (including dhfir CHO cells, described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in Kaufman and Sharp (1982) Mol. Biol.
  • the cell is a mammary epithelial cell.
  • the mammalian cell is a CHO-DG44I cell.
  • a recombinant expression vector encoding both the anti-human tau antibody heavy chain and the anti-human tau antibody light chain of an anti-human tau antibody is introduced into dhfr ⁇ CHO cells by calcium phosphate-mediated transfection.
  • the antibody heavy and light chain genes are each operatively linked to enhancer/promoter regulatory elements (e.g., derived from SV40, CMV, adenovirus and the like, such as a CMV enhancer/ AdMLP promoter regulatory element or an SV40 enhancer/ AdMLP promoter regulatory element) to drive high levels of transcription of the genes.
  • enhancer/promoter regulatory elements e.g., derived from SV40, CMV, adenovirus and the like, such as a CMV enhancer/ AdMLP promoter regulatory element or an SV40 enhancer/ AdMLP promoter regulatory element
  • the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
  • the selected transformant host cells are cultured to allow for expression of the antibody heavy and light chains and the antibody is recovered from the culture medium.
  • Antibodies can also be produced by a transgenic animal.
  • U.S. Pat. No. 5,849,992 describes a method of expressing an antibody in the mammary gland of a transgenic mammal.
  • a transgene is constructed that includes a milk-specific promoter and nucleic acids encoding the antibody of interest and a signal sequence for secretion.
  • the milk produced by females of such transgenic mammals includes, secreted-therein, the antibody of interest.
  • the antibody can be purified from the milk, or for some applications, used directly. Animals are also provided comprising one or more of the nucleic acids described herein.
  • the antibodies of the present disclosure can be isolated from inside or outside (such as medium) of the host cell and purified as substantially pure and homogenous antibodies. Methods for isolation and purification commonly used for antibody purification may be used for the isolation and purification of antibodies, and are not limited to any particular method. Antibodies may be isolated and purified by appropriately selecting and combining, for example, column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel
  • Chromatography includes, for example, affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reverse-phase chromatography, and adsorption
  • Chromatography can be carried out using liquid phase chromatography such as HPLC and FPLC.
  • Columns used for affinity chromatography include protein A column and protein G column. Examples of columns using protein A column include Hyper D, POROS, and Sepharose FF (GE Healthcare Biosciences).
  • the present disclosure also includes antibodies that are highly purified using these purification methods.
  • any of the anti-human tau antibodies described herein can be formulated as a pharmaceutical composition.
  • the pharmaceutical composition can comprise 10 mg/mL, 60 mg/mL or 50 mg/mL of an anti-human tau antibody described herein.
  • the pharmaceutical composition comprises 50 mg/mL of an anti -human tau antibody described herein.
  • the pharmaceutical composition includes histidine at a concentration of 20 mM, sucrose at a concentration of 250 mM, and polysorbate-80 at a concentration of 0.05% (w/v).
  • the pharmaceutical composition further includes 50 ⁇ diethylenetriamine pentaacetic acid (DTP A).
  • DTP A diethylenetriamine pentaacetic acid
  • the pharmaceutical composition has a pH of 6.0.
  • the anti-human tau antibody of the pharmaceutical composition comprises an immunoglobulin heavy chain variable region (VH) comprising VH
  • VH-CDRs complementarity determining regions
  • VL immunoglobulin light chain variable region
  • the VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16;
  • VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 17;
  • VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • the VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19;
  • VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 20; and
  • VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • the anti-human tau antibody of the pharmaceutical composition comprises a VH comprising or consisting of SEQ ID NO: 12. In certain cases, the anti -human tau antibody of the pharmaceutical composition comprises a VL comprising or consisting of SEQ ID NO: 13. In certain cases, the anti-human tau antibody of the pharmaceutical composition comprises a VH comprising or consisting of SEQ ID NO: 12 and a VL comprising or consisting of SEQ ID NO: 13.
  • the anti-human tau antibody of the pharmaceutical composition comprises a heavy chain comprising or consisting of SEQ ID NO: 14. In certain cases, the anti-human tau antibody of the pharmaceutical composition comprises a light chain comprising or consisting of SEQ ID NO: 15. In certain cases, the anti-human tau antibody of the pharmaceutical composition comprises a heavy chain comprising or consisting of SEQ ID NO: 14 and a light chain comprising or consisting of SEQ ID NO: 15.
  • Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles in the human brain.
  • Exemplary tauopathies include progressive supranuclear palsy, Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism- dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann- Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy
  • the anti-human tau antibodies described herein are used to treat progressive supranuclear palsy.
  • the anti-human tau antibodies described herein are used to treat Alzheimer's disease.
  • the disclosure features methods of treating human subjects with a tauopathy (see above) with an anti-human tau antibody disclosed herein or a pharmaceutical composition disclosed herein.
  • the tauopathy is progressive supranuclear palsy.
  • the tauopathy is Alzheimer's disease.
  • the method comprises administering to the human subject in need thereof an anti-human tau antibody in an amount effective to reduce significantly the level of tau (e.g., total Tau and/or free Tau) in an extracellular fluid (e.g., cerebrospinal fluid (CSF), interstitial fluid (ISF), blood, or a blood fraction (e.g., serum or plasma)) in the individual.
  • an extracellular fluid e.g., cerebrospinal fluid (CSF), interstitial fluid (ISF), blood, or a blood fraction (e.g., serum or plasma)
  • eTau extracellular Tau
  • Total Tau includes free Tau and Tau that is bound to an anti -human tau antibody.
  • the method comprises administering to the human subject in need thereof an anti -human tau antibody in an amount effective to reduce significantly the level of free eTau.
  • the level of tau e.g., total Tau and/or free Tau
  • the level of tau is significantly reduced within 36 hours of administration of the anti-human tau antibody.
  • the level of tau e.g., total Tau and/or free Tau
  • the level of free eTau is significantly reduced within 24 hours of administration of the anti-human tau antibody.
  • an effective amount of an anti-human tau antibody is an amount that is effective to reduce significantly the level of tau (e.g., total Tau and/or free Tau) in an extracellular fluid within 48 hours, 36 hours, within 24 hours, within 12 hours, within 8 hours, within 4 hours, within 2 hours, within 1 hour, within 30 minutes, within 15 minutes, or within 5 minutes, of administration of the anti-human tau antibody.
  • level of tau e.g., total Tau and/or free Tau
  • an effective amount of an anti-human tau antibody is an amount that is effective to reduce significantly the level of Tau (e.g., total Tau and/or free Tau) in an extracellular fluid within from 5 minutes to about 10 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 30 minutes, from about 30 minutes to about 1 hour, from about 1 hour to about 2 hours, from about 2 hours to about 4 hours, from about 4 hours to about 8 hours, from about 8 hours to about 12 hours, from about 12 hours to about 24 hours, from about 24 hours to about 36 hours, from about 24 to about 48 hours, or from about 36 hours to about 48 hours.
  • Tau e.g., total Tau and/or free Tau
  • a significant reduction in the level of tau (e.g., total Tau and/or free Tau) in an extracellular fluid (e.g., CSF, ISF, blood, or a blood fraction (e.g., serum or plasma)) of an individual is an at least 30% reduction, at least 35% reduction, at least 40% reduction, at least 45% reduction, at least 50% reduction, an at least 55% reduction, an at least 60% reduction, an at least 65% reduction, an at least 70% reduction, an at least 75% reduction, an at least 80% reduction, an at least 85% reduction, an at least 90% reduction, an at least 95% reduction, or a greater than 90% reduction.
  • the significant reduction is a statistically significant reduction.
  • the significant reduction is a clinically significant reduction.
  • the level of tau (e.g., total Tau and/or free Tau) in an extracellular fluid is reduced to a normal, control level (e.g., about 100 pg/ml).
  • the level of Tau (e.g., total Tau and/or free Tau) in an extracellular fluid is reduced to an undetectable level.
  • the extracellular fluid is CSF.
  • the extracellular fluid is ISF.
  • the extracellular fluid is plasma.
  • the extracellular fluid is whole blood.
  • the extracellular fluid is serum.
  • an anti-human tau antibody described herein is administered to the human subject at a fixed dose of 2000 mg. In certain instances, an anti -human tau antibody is administered to the human subject at a fixed dose of 2100 mg. In other instances, an anti -human tau antibody is administered to the human subject at a fixed dose of 150 mg. In further instances, an anti -human tau antibody is administered to the human subject at a fixed dose of 4200 mg. In certain embodiments, the above-noted fixed doses of an anti-human tau antibody described herein are administered to the human subj ect once every four weeks.
  • an anti-human tau antibody described herein is administered to the human subject as part of a pharmaceutical composition.
  • the pharmaceutical composition comprises 50 mg/mL of the anti-human tau antibody, 20 mM histidine, 250 mM sucrose, and 50 ⁇ DTP A.
  • the pharmaceutical composition has a pH of 6.0.
  • the pharmaceutical composition is administered to the human subject in an amount sufficient to deliver a fixed dose of 2000 mg of the anti -human tau antibody.
  • the pharmaceutical composition is administered to the human subject in an amount sufficient to deliver a fixed dose of 2100 mg of the anti -human tau antibody.
  • the pharmaceutical composition is administered to the human subject in an amount sufficient to deliver a fixed dose of 700 mg of the anti-human tau antibody.
  • the pharmaceutical composition is administered to the human subject in an amount sufficient to deliver a fixed dose of 150 mg of the anti-human tau antibody. In certain embodiments, the pharmaceutical composition is administered to the human subject in an amount sufficient to deliver a fixed dose of 210 mg of the anti-human tau antibody. In certain embodiments, the pharmaceutical composition is administered to the human subject in an amount sufficient to deliver a fixed dose of 4200 mg of the anti -human tau antibody.
  • the anti-human tau antibody is administered to the human subject in need thereof by an intravenous route.
  • the anti-human tau antibody comprises an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL), wherein the VH comprises VH complementarity determining regions (VH-CDRs), wherein VH-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 16; VH-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 17; and VH-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 18; and the VL comprises VL-CDRs, wherein VL-CDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 19; VL-CDR2 comprises or consists of the amino acid sequence of SEQ ID NO:20; and VL-CDR3 comprises or consists of the amino acid sequence of SEQ ID NO:21.
  • VH immunoglobulin heavy chain variable region
  • VL immunoglobulin light chain variable region
  • the VH of the anti-human tau antibody comprises or consists of SEQ ID NO: 12 and the VL comprises or consists of SEQ ID NO: 13.
  • the anti-human tau antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of SEQ ID NO: 14 and the light chain comprises or consists of SEQ ID NO: 15.
  • Example 1 A Single Ascending Dose Study of an Anti-Human Tau Antibody. BIIB092
  • BIIB092 is a humanized antibody that recognizes human extracellular Tau (eTau).
  • the purposes of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB092 as well as the pharmacodynamic (PD) effects of BIIB092 on extracellular tau (eTau) after a single intravenous (IV) infusion of BIIB092 in healthy human subjects.
  • PK pharmacokinetics
  • PD pharmacodynamic
  • BIIB092 was tested to determine its efficacy in preventing transmission of tau pathology by binding and reducing free eTau in human CSF.
  • suppression of CSF eTau at 28 days ranged from 65% to 96% at doses ranging from 70mg to 4200mg.
  • BIIB092 has utility for the treatment of human tauopathies (e.g., progressive supranuclear palsy).
  • Single doses of BIIB092 administration were safe and well tolerated at doses up to 4200mg.
  • Example 2 Bavesian Emax Model
  • Bayesian Emax An exposure-response model (Bayesian Emax) of CSF concentration versus eTau suppression was constructed (see, FIG. 3).
  • the Bayesian Emax model captured the observed eTau suppression reasonably well.
  • Example 3 Multiple Ascending Dose Study of an Anti -Human Tau Antibody. BIIB092. in Patients with Progressive Supranuclear Palsy
  • FIG. 4 The baseline demographic characteristics for this study are shown in FIG. 4.
  • This study was a randomized, double-blind, placebo-controlled, multiple ascending dose trial of 48 patients with PSP, of whom 12 (25%) received placebo.
  • Three ascending dose panels (150 mg, 700 mg, and 2100 mg) comprised of 8 patients per panel, were administered IV infusions of BIIB092 (6 patients) or placebo (2 patients) Q4W for 12 weeks; an additional 24 patients were treated with BIIB092 at a dose of 2100 mg (18 patients) or placebo (6 patients) administered Q4W for 12 weeks. See, FIG. 5. All patients were also offered the opportunity to participate in an open-label extension study.
  • Safety assessments and serum and CSF samples were collected over the 12 weeks.
  • PK parameters in serum and CSF
  • PD measures Concentrations of CSF free eTau
  • corresponding change and percent change from baseline were evaluated.
  • Clinical outcome measures including the PSP Rating Scale and Schwab and England Activities of Daily Living Scale were also employed.
  • Example 4 BIIB092 Dose Selection Based on Simulated PK and eTau Suppression
  • eTau concentrations were converted to percent suppression, relative to each subject's baseline value, prior to summarization based on the simulations.
  • Table 1 below shows summary statistics of percent suppression of eTau relative to baseline levels at 4 weeks, 12 weeks, 24 weeks, and 48 weeks following the 2000 mg Q4W dosing regimen.
  • Table 2 shows summary statistics of percent suppression of eTau relative to baseline levels at 4 weeks, 12 weeks, 24 weeks, and 48 weeks following the 700 mg Q4W dosing regimen.
  • the 2000 mg dose of BIIB092 is associated with slightly higher suppression (3 to 5%) at trough than the 700 mg dose.
  • Ninety percent of all subjects that are dosed with the 2000 mg Q4W dose are expected to have a percentage suppression of eTau at or above 96% at trough.
  • Ninety percent of all subjects that are dosed the 700 mg Q4W dose are expected have a percentage suppression of eTau at or above 93% at trough.
  • dosing BIIB092 can also be done on a less frequent basis, e.g., once every 12 weeks (Q12W). Simulations were performed using the same PK-PD model for a 2000 mg dose, administered Q12W.
  • Q12W dosing is also expected to be associated with robust and persistent lowering of eTau and may be preferred by patients and caregivers.
  • BIIB092 was evaluated at 10 mg/mL in 20 mM
  • Formulations targeted to 10 mg/mL all exhibited protein concentrations between 9.8 - 1 1.4 mg/mL. Note that the measured concentrations of the sorbitol formulations (E4 - E6) were approximately 0.5 mg/mL higher than those of the sucrose formulations (El - E3), but this merely reflects slightly higher concentrations from sample preparation.
  • Formulation E7 targeted to 20 mg/mL ranged from 19.0 - 20.2 mg/mL
  • E8 targeted to 50 mg/mL
  • Protein content by A280 demonstrated no significant trends in protein concentration throughout the stability time points for any of the formulations tested.
  • Particle increases were especially pronounced in the E7 and E8 formulations (with 20 mg/mL and 50 mg/mL of API, respectively); particles at 10 ⁇ in E7 increased from 12 counts at the initial time point to 1 161 counts for the nine month / 25°C/60% RH sample, particles at 10 ⁇ in E8 increased from 18 counts at the initial time point to 1003 counts for the nine month / 25°C/60% RH sample. Particle counts in these two samples at other longer range stability time points and conditions were also much higher than the initial particle counts. Differences between storage temperatures are likely due to variability of the method. For the formulations E4 - E6, which were only tested out to three months, particle counts out to that time point were comparable to those observed in El - E3, and smaller than those observed in E7 - E8.
  • formulations E2 and E3 exhibited the highest main peak purity, indicating the least aggregation and fragmentation of the API in these formulations.
  • the percent LMW did not appear to change significantly (increases of between 0.1 - 0.3% for some formulations and time points / conditions, others saw no
  • Percent acidic variants increased over time for all formulations, and demonstrated greater increases with increasing temperature, and appeared to be lower with lower pH. Conversely, percent basic variants, while increasing over time and with higher stability temperature, demonstrated lower variants with increasing pH. There did not appear to be any significant differences in either percent acidic or percent basic variants in samples formulated at higher concentrations (E7 - 20 mg/mL, E8 - 50 mg/mL) versus comparable sample at 10 mg/mL at the same pH (6.0).
  • Proline and lysine hydroxylation although present in significant abundance in the reformulated samples, did not appear to change with time, regardless of storage temperature. Hydroxylation of PI 89 was very consistent and unchanged at all time points. Interestingly, this proline hydroxylation was lower in the frozen reference standard. The levels of proline hydroxylation in reference standard measured by UV (1.1- 1.6%) were reasonably similar to those measured by LC/MS (1.0%). Measurement of K121 hydroxylation produced much larger differences in quantities. However, because no consistent trends could be observed, it is concluded these differences represent analytical noise. The levels of lysine hydroxylation in reference standard measured by UV (4.1 - 7.9%) were reasonably similar to those measured in the parent material by LC/MS (2.8%).
  • Methionine oxidation at heavy chain site M425 was fairly conducive to analysis. Small, but consistent, levels of oxidation were seen in all formulations. Oxidation increased slowly as a function of time and temperature, but was not affected by the pH or formulation components. Even after two months at 40°C / 75% RH, the oxidation increased only by about 0.5%. The levels of modification in reference standard measured by UV (0.2 -0.6%) were very similar to those measured in the parent material by LC/MS (0.3%).

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Abstract

L'invention concerne des schémas posologiques et des formulations d'anticorps anti-tau humains. Ces formulations et schémas posologiques trouvent une utilisation dans le traitement de tauopathies telles que la paralysie supranucléaire progressive et la maladie d'Alzheimer.
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US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
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US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5827690A (en) 1993-12-20 1998-10-27 Genzyme Transgenics Corporatiion Transgenic production of antibodies in milk
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ES2686550T3 (es) * 2010-10-11 2018-10-18 Biogen International Neuroscience Gmbh Anticuerpos anti-tau humanos
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EP3007726B1 (fr) * 2013-06-10 2020-04-08 Ipierian, Inc. Méthodes de traitement d'une tauopathie
JP6629201B2 (ja) * 2013-11-27 2020-01-15 アイピエリアン，インコーポレイティド タウオパチーの処置方法
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