NZ710786B2 - Tau immunotherapy - Google Patents
Tau immunotherapy Download PDFInfo
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- NZ710786B2 NZ710786B2 NZ710786A NZ71078614A NZ710786B2 NZ 710786 B2 NZ710786 B2 NZ 710786B2 NZ 710786 A NZ710786 A NZ 710786A NZ 71078614 A NZ71078614 A NZ 71078614A NZ 710786 B2 NZ710786 B2 NZ 710786B2
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- 238000009169 immunotherapy Methods 0.000 title description 3
- 102000004965 antibodies Human genes 0.000 claims abstract 36
- 108090001123 antibodies Proteins 0.000 claims abstract 36
- 102000005614 monoclonal antibodies Human genes 0.000 claims 13
- 108010045030 monoclonal antibodies Proteins 0.000 claims 13
- NFGXHKASABOEEW-UHFFFAOYSA-N (+)-methoprene Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims 8
- 229960000070 antineoplastic Monoclonal antibodies Drugs 0.000 claims 6
- 108091006028 chimera Proteins 0.000 claims 6
- 229960000060 monoclonal antibodies Drugs 0.000 claims 6
- 125000003275 alpha amino acid group Chemical group 0.000 claims 5
- 230000035772 mutation Effects 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 206010001897 Alzheimer's disease Diseases 0.000 description 6
- 210000002682 Neurofibrillary Tangles Anatomy 0.000 description 6
- 210000002569 neurons Anatomy 0.000 description 6
- 210000004688 Microtubules Anatomy 0.000 description 4
- 102000028664 Microtubules Human genes 0.000 description 4
- 108091022031 Microtubules Proteins 0.000 description 4
- 201000011240 frontotemporal dementia Diseases 0.000 description 4
- 230000001537 neural Effects 0.000 description 4
- 210000004727 Amygdala Anatomy 0.000 description 2
- 210000004556 Brain Anatomy 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- 210000001353 Entorhinal Cortex Anatomy 0.000 description 2
- 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 description 2
- 210000001320 Hippocampus Anatomy 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- 206010022114 Injury Diseases 0.000 description 2
- 210000000478 Neocortex Anatomy 0.000 description 2
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 2
- 201000011585 Pick's disease Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 230000000087 stabilizing Effects 0.000 description 2
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 206010048327 Supranuclear palsy Diseases 0.000 description 1
- 230000000626 neurodegenerative Effects 0.000 description 1
- 200000000025 progressive disease Diseases 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
Classifications
-
- 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
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal 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
- A61K39/0005—Vertebrate antigens
- A61K39/0007—Nervous system antigens; Prions
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6843—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
-
- 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
-
- 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
-
- 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
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2821—Alzheimer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
Abstract
The invention provides antibodies to tau. The antibodies inhibit or delay tau-associated pathologies and associated symptomatic deterioration.
Description
/165271
TAU IMMUNOTHERAPY
TAU IMMUNOTHERAPY
CROSS-REFERENCE TO RELATED APPLICATIONS CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a non-provisional of 61/780,624 filed March 13, 2013 and The present application is a non-provisional of 61/780,624 filed March 13, 2013 and
61/800,382, filed March 15, 2013, each incorporated by reference in its entirety for all purposes.
61/800,382, filed March 15, 2013, each incorporated by reference in its entirety for all purposes.
BACKGROUND
BACKGROUND
Tau is a well-known human protein that can exist in phosphorylated forms (see, e.g.,
Tau is a well-known human protein that can exist in phosphorylated forms (see, e.g.,
Goedert, Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988); Goedert, EMBO J. 8:393- Goedert, Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988); Goedert, EMBO J. 8:393-
399(1989); Lee, Neuron 2:1615-1624(1989); Goedert, Neuron 3:519-526(1989); Andreadis,
399(1989); Lee, Neuron 2:1615-1624(1989); Goedert, Neuron 3:519-526(1989); Andreadis,
Biochemistry 31:10626-10633(1992). Tau has been reported to have a role in stabilizing
Biochemistry 31:10626-10633(1992). Tau has been reported to have a role in stabilizing
microtubules, particularly in the central nervous system. Total tau (t-tau, i.e., phosphorylated
microtubules, particularly in the central nervous system. Total tau (t-tau, i.e., phosphorylated
and and unphosphorylated forms) and phospho-tau (p-tau, i.e., phosphorylated tau) are released by unphosphorylated forms) and phospho-tau (p-tau, i.e., phosphorylated tau) are released by
the brain in response to neuronal injury and neurodegeneration and have been reported to occur
the brain in response to neuronal injury and neurodegeneration and have been reported to occur
at at increased levels in the CSF of Alzheimer's patients relative to the general population (Jack et increased levels in the CSF of Alzheimer's patients relative to the general population (Jack et
al, Lancet Neurol 9: 119-28 (2010)).
al, Lancet Neurol 9 : 119-28 (2010)).
Tau is the principal constituent of neurofibrillary tangles, which together with plaques are [0003] Tau is the principal constituent of neurofibrillary tangles, which together with plaques are
a hallmark characteristic of Alzheimer's disease. The tangles constitute abnormal fibrils
a hallmark characteristic of Alzheimer's disease. The tangles constitute abnormal fibrils
measuring 10 nm in diameter occurring in pairs wound in a helical fashion with a regular
measuring 10 nrn in diameter occurring in pairs wound in a helical fashion with a regular
periodicity periodicity of 80 nm. The tau within neurofibrillary tangles is abnormally phosphorylated of 80 nm. The tau within neurofibrillary tangles is abnormally phosphorylated
(hyperphosphorylated) with phosphate groups attached to specific sites on the molecule. Severe
(hyperphosphorylated) with phosphate groups attached to specific sites on the molecule. Severe
involvement of neurofibrillary tangles is seen in the layer II neurons of the entorhinal cortex, the
involvement of neurofibrillary tangles is seen in the layer II neurons of the entorhinal cortex, the
CA1 and subicular regions of the hippocampus, the amygdala, and the deeper layers (layers III,
CA1 and subicular regions of the hippocampus, the amygdala, and the deeper layers (layers III,
V, and superficial VI) of the neocortex in Alzheimer's disease. Hyperphosphorylated tau has also
V, and superficial VI) of the neocortex in Alzheimer's disease. Hyperphosphorylated tau has also
been reported to interfere with microtubule assembly, which may promote neuronal network
been reported to interfere with microtubule assembly, which may promote neuronal network
breakdown.
breakdown.
Tau inclusions are part of the defining neurophathology of several neurodegenerative
Tau inclusions are part of the defining neurophathology of several neurodegenerative
diseases including Alzheimer's disease, frontotemporal lobar degeneration, progressive
diseases including Alzheimer's disease, frontotemporal lobar degeneration, progressive
supranuclear palsy and Pick's disease.
supranuclear palsy and Pick's disease.
SHEET (RULE 26)
SUBSTITUTE SUBSTITUTE SHEET (RULE 26)
2014/165271
Claims (1)
- SUMMARY OF THE CLAIMED INVENTION • [0005] The invention provides monoclonal antibodies that compete for binding to tau with The invention provides monoclonal antibodies that compete for binding to tau with monoclonal antibody 16B5. Some antibodies are humanized, chimeric, veneered or human monoclonal antibody 16B5. Some antibodies are humanized, chimeric, veneered or human antibodies. Some antibodies are of human IgG isotype (e.g., IgGl, IgG2, or IgG4). Some such antibodies. Some antibodies are of human IgG isotype (e.g., IgGl, IgG2, or IgG4). Some such antibodies have a human IgGl constant region having the sequence of SEQ ID NO: 29. Some antibodies have a human IgG1 constant region having the sequence of SEQ ID NO: 29. Some antibodies have a human kappa constant region having the sequence of SEQ ID NO: 32. Some antibodies have a human kappa constant region having the sequence of SEQ ID NO: 32. Some antibodies have at least one mutation in the constant region. antibodies have at least one mutation in the constant region. [0006] Some of the antibodies are a humanized, chimeric or veneered form of monoclonal Some of the antibodies are a humanized, chimeric or veneered form of monoclonal antibody 16B5. Some antibodies have the three light chain CDRs as defined by Kabat and three antibody 16B5. Some antibodies have the three light chain CDRs as defined by Kabat and three heavy chain CDRs as defined by Kabat of monoclonal antibody 16B5. Some antibodies bind to heavy chain CDRs as defined by Kabat of monoclonal antibody 16B5. Some antibodies bind to tau in phosphorylated and unphosphorylated forms. tau in phosphorylated and unphosphorylated forms. The invention further provides monoclonal antibodies that specifically bind to an The invention further provides monoclonal antibodies that specifically bind to an epitope within residues 24-46 of SEQ ID NO: 1 (Swiss-Prot No. P10636-8). Some such epitope within residues 24-46 of SEQ ID NO: 1 (Swiss-Prot No. P10636-8). Some such antibodies are human, humanized, chimeric, or veneered antibodies. Some antibodies antibodies are human, humanized, chimeric, or veneered antibodies. Some antibodies specifically specifically bind to an epitope within residues 25-44 of SEQ ID NO: 1. Some antibodies bind to an epitope within residues 25-44 of SEQ ID NO: 1. Some antibodies specifically bind to an epitope within residues 30-39 of SEQ ID NO: 1. Some antibodies bind to specifically bind to an epitope within residues 30-39 of SEQ ID NO: 1. Some antibodies bind to tau in phosphorylated and unphosphorylated forms. tau in phosphorylated and unphosphorylated forms. The invention further provides monoclonal antibodies comprising a mature heavy chain The invention further provides monoclonal antibodies comprising a mature heavy chain variable region having an amino acid sequence at least 90% (e.g., at least 95%, at least 98%, at variable region having an amino acid sequence at least 90% (e.g., at least 95%, at least 98%, at least 99%) identical to SEQ ID NO: 15 and a mature light chain variable region at least 90% (e.g., least 99%) identical to SEQ ID NO: 15 and a mature light chain variable region at least 90% (e.g., at at least 95%, at least 98%, at least 99%) identical to SEQ ID NO:22. In certain embodiments, least 95%, at least 98%, at least 99%) identical to SEQ ID NO:22. In certain embodiments, the monoclonal antibody comprises three Kabat CDRs of SEQ ID NO: 15 and three Kabat CDRs the monoclonal antibody comprises three Kabat CDRs of SEQ ID NO: 15 and three Kabat CDRs of SEQ ID NO:22. In some antibodies, the mature heavy chain variable region has an amino of SEQ ID NO:22. In some antibodies, the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO: 15 and the mature light chain variable region has an acid sequence designated SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:21, 22, or 23. amino acid sequence designated SEQ ID NO:21, 22, or 23. In some antibodies, at least one of positions HI3, H48 and H91 is occupied by K, M In some antibodies, at least one of positions HI3, H48 and H91 is occupied by K, M and F, respectively, and at least one of positions LI, L4, L36 and L43 is occupied by N, L, F and and F, respectively, and at least one of positions LI, L4, L36 and L43 is occupied by N, L, F and S, respectively. In some antibodies, positions H13, H48 and H91 are occupied by K, M and F, S, respectively. In some antibodies, positions H13, H48 and H91 are occupied by K, M and F, respectively, and at least two of positions LI, L4, L36 and L43 are occupied by N, L, F and S, respectively, and at least two of positions LI, L4, L36 and L43 are occupied by N, L, F and S, (RULE 26) SUBSTITUTE SUBSTITUTE SHEET (RULE 26) SHEET PCT/1JS
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361780624P | 2013-03-13 | 2013-03-13 | |
US61/780,624 | 2013-03-13 | ||
US201361800382P | 2013-03-15 | 2013-03-15 | |
US61/800,382 | 2013-03-15 | ||
PCT/US2014/025044 WO2014165271A2 (en) | 2013-03-13 | 2014-03-12 | Tau immunotherapy |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ710786A NZ710786A (en) | 2021-04-30 |
NZ710786B2 true NZ710786B2 (en) | 2021-08-03 |
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