# US 2019/0169274 A1 · Human anti-tau antibodies

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- Number: US 2019/0169274 A1
- Document ID: US20190169274A1
- Status: Published application
- Kind: A1
- Application number: 16/020,346
- Filed: 2018-06-27
- Published: 2019-06-06
- Earliest claimed: 2012-12-21
- Assignees: Biogen MA Inc.; Biogen International Neuroscience GmbH
- Applicants: Biogen MA Inc.; Biogen International Neuroscience GmbH
- Inventors: Paul H. Weinreb; Feng Chen; Ellen A. Garber Stark; Jan Grimm; Fabio Montrasio
- Web page: https://patentgrep.com/patent/US20190169274A1

## CPC

- C07K 16/18: against material from animals or humans
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 49/00: Preparations for testing in vivo
- A61K 49/16: Antibodies; Immunoglobulins; Fragments thereof
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/41: Glycosylation, sialylation, or fucosylation
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- G01N 2333/47: Assays involving proteins of known structure or function as defined in the subgroups
- G01N 2800/2814: Dementia; Cognitive disorders
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided are novel human tau-specific antibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for tau are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for tau targeted immunotherapy and diagnosis, respectively.

## Claims

### Claim at position 1

-42. (canceled)

### Claim 43

A polynucleotide linked to a heterologous nucleic acid, wherein the polynucleotide is selected from the group consisting of:
(a) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau;
(b) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;
(c) a polynucleotide encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VH when paired with the VL binds to tau;
(d) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau;
(e) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:221 binds to tau;
(f) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:222 binds to tau;
(g) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:46, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;
(h) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:221, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;
(i) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:222, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;
(j) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:46;
(k) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:221;
(l) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:222;
(m) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:91, 92, and 93, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau;
(n) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:94, 95, and 96, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau; and
(o) a polynucleotide encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:91, 92, and 93, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs: 94, 95, and 96, respectively, wherein the VH when paired with the VL binds to tau.

### Claim 44 (depends on 43)

The polynucleotide of claim 43, wherein the heterologous nucleic acid is a regulatory element.

### Claim 45 (depends on 44)

The polynucleotide of claim 44, wherein the regulatory element is a promoter, an enhancer, a ribosome binding site, or a transcription terminator.

### Claim 46 (depends on 43)

The polynucleotide of claim 43, wherein the heterologous nucleic acid is a secretory signal peptide.

### Claim 47 (depends on 46)

The polynucleotide of claim 46, wherein the secretory signal peptide is a mammalian signal peptide.

### Claim 48 (depends on 47)

The polynucleotide of claim 47, wherein the mammalian signal peptide is from tissue plasminogen activator.

### Claim 49 (depends on 43)

A host cell comprising the polynucleotide of claim 43.

### Claim 50 (depends on 49)

The host cell of claim 49, wherein the host cell is a Chinese Hamster Ovary (CHO) cell.

### Claim 51

A cDNA comprising a polynucleotide encoding a polypeptide comprising any one of:
(a) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau; or
(b) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau.

### Claim 52 (depends on 51)

The cDNA of claim 51, wherein the polypeptide comprises:
an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in any one of SEQ ID NO: 44 or 45; or
an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in any one of SEQ ID NO:46, 221, or 222.

### Claim 53

An expression vector comprising a heterologous promoter operably linked to a polynucleotide encoding a polypeptide comprising:
(a) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau; or
(b) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau.

### Claim 54 (depends on 53)

The expression vector of claim 53, wherein the polypeptide comprises:
an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in any one of SEQ ID NO: 44 or 45; or
an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in any one of SEQ ID NO:46, 221, or 222.

### Claim 55 (depends on 53)

The expression vector of claim 53, wherein the expression vector is a plasmid, phage, or virus.

### Claim 56 (depends on 53)

The expression vector of claim 53, wherein the expression vector is a retrovirus.

### Claim 57 (depends on 53)

The expression vector of claim 53, wherein the heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter.

### Claim 58 (depends on 53)

The expression vector of claim 53, wherein the heterologous promoter is the cytomegalovirus immediate early promoter.

### Claim 59 (depends on 53)

The expression vector of claim 53, wherein the polypeptide comprises a signal peptide.

### Claim 60 (depends on 59)

The expression vector of claim 59, wherein the signal peptide is a heterologous signal peptide.

### Claim 61 (depends on 53)

A host cell comprising the expression vector of claim 53.

### Claim 62 (depends on 61)

The host cell of claim 61, wherein the heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter and the second heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter.

### Claim 63 (depends on 61)

A method for preparing an anti-human tau antibody or human tau-binding fragment thereof, the method comprising:
culturing the host cell of claim 61 in a cell culture; and
isolating the anti-human tau antibody or human tau-binding fragment thereof from the cell culture.

### Claim 64 (depends on 63)

The method of claim 63, further comprising formulating the anti-human tau antibody or human tau-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject.

### Claim 65 (depends on 64)

The method of claim 64, wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration.

### Claim 66

A method of treating a neurodegenerative tauopathy in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an anti-tau antibody or tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment thereof comprises:
a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and
a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222.

### Claim 67 (depends on 66)

The method of claim 66, wherein:
the VH comprises an amino acid sequence set forth in any one of SEQ ID NO: 44 or 45; and
the VL comprises an amino acid sequence set forth in any one of SEQ ID NO:46, 221, or 222.

### Claim 68 (depends on 66)

The method of claim 66, wherein the antibody or antigen-binding fragment thereof comprises a human IgG1 heavy chain constant region and a human lambda light chain constant region.

### Claim 69 (depends on 66)

The method of claim 66, neurodegenerative tauopathy is selected from the group consisting of 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, frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Sträussler-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, progressive supranuclear palsy, subacute sclerosing panencephalitis, Tangle only dementia, multi-infarct dementia, and ischemic stroke.

### Claim 70

A method of treating abnormal accumulation or deposition of tau in the central nervous system in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an anti-tau antibody or tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment thereof comprises:
a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and
a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222.

### Claim 71

A method for in vivo detection of tau deposition in the brain, the method comprising: administering to a human subject an antibody or antigen-binding fragment thereof that specifically binds to tau, wherein the antibody or antigen-binding fragment thereof comprises: a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222, wherein the antibody or antigen-binding fragment thereof is attached to a detectable label; and
detecting the detectable label in the brain of the human subject, to thereby detect tau deposition in the brain of the human subject.

### Claim 72

A method of diagnosing or monitoring the progression of a neurodegenerative tauopathy, the method comprising:
measuring the level of pathologically modified or aggregated tau in a sample from a human subject with an anti-tau antibody or tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment thereof comprises a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222; and
comparing the level of modified or aggregated tau to a reference standard that indicates the level of the pathologically modified or aggregated tau in one or more control subjects,
wherein a difference or similarity between the level of pathologically modified or aggregated tau and the reference standard indicates that the human subject has a neurodegenerative tauopathy.

### Claim 73

An antibody or antigen-binding fragment thereof that binds to human tau and comprises:
a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222,
wherein the antibody or antigen-binding fragment thereof comprises polyethylene glycol or a detectable label selected from the group consisting of an enzyme, a radioisotope, a fluorescent compound, a chemiluminescent compound, a bioluminescent compound, and a heavy metal.

### Claim 74

An anti-tau single chain antibody or scFv antibody comprising:
a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and
a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222.