# US 2019/0169276 A1 · Humanized tau antibodies in alzheimer's disease

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- Number: US 2019/0169276 A1
- Document ID: US20190169276A1
- Status: Published application
- Kind: A1
- Application number: 16/181,088
- Filed: 2018-11-05
- Published: 2019-06-06
- Earliest claimed: 2014-11-19
- Assignees: Axon Neuroscience SE
- Applicants: Axon Neuroscience SE
- Inventors: Michal Novak; Eva Kontsekova; Branislav Kovacech; Rostislav Skrabana
- Web page: https://patentgrep.com/patent/US20190169276A1

## CPC

- C07K 16/18: against material from animals or humans
- 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
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- 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 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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 2800/2821: Alzheimer
- G01N 2800/50: Determining the risk of developing a disease
- G01N 2800/7047: Fibrils-Filaments-Plaque formation
- 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)
- 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

The present invention is in the fields of biochemistry, molecular biology, and Alzheimer's disease diagnosis, prevention, and treatment. Provided herein are humanized antibodies against human tau that are capable of discriminating between normal (healthy) and pathological (disease-associated) tau.

## Claims

### Claim at position 1

1-179. (canceled)

### Claim 180

A composition comprising a humanized anti-tau antibody, or a tau-binding fragment thereof, and a second therapeutic agent,
wherein the antibody or binding fragment comprises:
a heavy chain variable region comprising CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NOs. 1, 2, and 3, respectively, and a framework from human immunoglobulin M65092 (SEQ ID NO. 71);
a light chain variable region comprising CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NOs. 4, 5, and 6, respectively, and a framework from human immunoglobulin X72449 (SEQ ID NO. 65); and
heavy chain and light chain constant regions each from a human immunoglobulin;
wherein said heavy chain framework has been substituted at one or more positions selected from 9, 21, 27, 28, 30, 38, 48, 67, 68, 70, and 95; said light chain framework has either not been substituted or has been substituted at position 5; and wherein said positions are according to Kabat.

### Claim 181 (depends on 180)

The composition of claim 180, wherein heavy chain position 9 is occupied by P, position 21 is occupied by P, position 27 is occupied by Y, position 28 is occupied by I, position 30 is occupied by T, position 38 is occupied by K, position 48 is occupied by I, position 67 is occupied by K, position 68 is occupied by A, position 70 is occupied by L, and/or position 95 is occupied by F.

### Claim 182 (depends on 180)

The composition of claim 180, wherein light chain position 5 is occupied by S.

### Claim 183 (depends on 180)

The composition of claim 180, wherein the sequence of the heavy chain variable region is selected from SEQ ID NOs. 13-25 (RHA through RHM); and the sequence of the light chain variable region is SEQ ID NO. 26 (RKA).

### Claim 184 (depends on 180)

The composition of claim 180, wherein the sequence of the heavy chain variable region is selected from SEQ ID NOs. 13-25 (RHA through RHM); and the sequence of the light chain variable region is SEQ ID NO. 27 (RKB).

### Claim 185 (depends on 180)

The composition of claim 180, wherein the sequence of the heavy chain variable region comprises SEQ ID NO. 16 and the sequence of the light chain variable region comprises SEQ ID NO. 26.

### Claim 186 (depends on 180)

The composition of claim 180, wherein the antibody is of the IgG1 or IgG4 isotype.

### Claim 187 (depends on 180)

The composition of claim 180, wherein the light chain comprises a human kappa constant region.

### Claim 188 (depends on 180)

The composition of claim 180, wherein the second therapeutic agent is selected from one or more of a tau-peptide, a beta-amyloid peptide, an N-terminal amyloid beta peptide, an anti-tau antibody, an antibody against beta-amyloid, bapineuzumab, solaneuzumab, gantenerumab, crenezumab, IVIG immunoglobulin, a compound preventing hyperphosphorylation of tau, an active or passive immunization therapy targeting tau aggregates, and any pharmaceutically acceptable salts thereof.

### Claim 189 (depends on 180)

The composition of claim 180, wherein the second therapeutic agent is selected from one of more of an amyloid-beta aggregation inhibitor, a gamma-secretase inhibitor, a gamma-secretase modulator, Tramiprosate, semagacestat, tarenflurbil, and any pharmaceutically acceptable salts thereof.

### Claim 190 (depends on 180)

The composition of claim 180, wherein the second therapeutic agent is aducanumab.

### Claim 191 (depends on 180)

The composition of claim 180, wherein the second therapeutic agent is selected from one of more of an acetylcholinesterase inhibitor, donepezil, rivastigmine, galantamine, tacrine, nutritive supplements, N-Methyl-D-aspartate (NMDA) receptor antagonists, memantine, an inhibitor of DNA repair, pirenzepine or a metabolite thereof, a transition metal chelator, a growth factor, a hormone, a non-steroidal anti-inflammatory drug (NSAID), an antioxidant, a lipid lowering agent, a selective phosphodiesterase inhibitor, an inhibitor of tau aggregation, an inhibitor of a protein kinase, an anti-mitochondrial dysfunction drug, a neurotrophin, an inhibitors of a heat shock protein, an inhibitor of Lipoprotein-associated phospholipase A2, an anti-apoptotic compound, a metal chelator, an inhibitor of DNA repair, 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), a secretase activator, a beta-secretase inhibitor, a gamma-secretase inhibitor, a beta-amyloid peptide, an anti-beta-amyloid antibody, a neurotransmitter, a beta-sheet breaker, an anti-inflammatory molecule, a BACE inhibitor, a muscarinic antagonist, a cholinesterase inhibitor, a gamma secretase inhibitor, a gamma secretase modulator, an HMG-CoA reductase inhibitor, a non-steroidal anti-inflammatory agent, an NMDA receptor antagonist, an anti-amyloid antibody, vitamin E, a nicotinic acetylcholine receptor agonist, a CB1 receptor inverse agonist, a CB1 receptor antagonist, an antibiotic, a histamine H3 antagonist, an AMPA agonist, a PDE4 inhibitor, a GABAA inverse agonist, an inhibitor of amyloid aggregation, a glycogen synthase kinase beta inhibitor, a promoter of alpha secretase activity, a PDE-10 inhibitor, a cholesterol absorption inhibitor, and any pharmaceutically acceptable salts thereof.

### Claim 192 (depends on 180)

A method of treating Alzheimer's Disease or another tauopathy in a subject having, suspected of having, or being prone to have Alzheimer's Disease or another tauopathy, comprising administering to the subject a therapeutically effective amount of the composition according to claim 180.

### Claim 193 (depends on 180)

A method of promoting clearance of tau aggregates from the brain of a subject having, suspected of having, or being prone to have Alzheimer's Disease or another tauopathy, comprising administering to the subject a therapeutically effective amount of the composition according to claim 180.

### Claim 194 (depends on 180)

A method of slowing progression of AD or another tauopathy in a subject having Alzheimer's Disease or another tauopathy, comprising administering to the subject a therapeutically effective amount of the composition according to claim 180.

### Claim 195 (depends on 180)

A method of ameliorating the symptoms of AD or another tauopathy in a subject having Alzheimer's Disease or another tauopathy, comprising administering to the subject a therapeutically effective amount of the composition according to claim 180.

### Claim 196 (depends on 180)

A method of treatment, comprising administering to a subject a therapeutically effective amount of the composition according to claim 180.

### Claim 197 (depends on 180)

A method of evaluating a subject having, suspected of having, or being prone to have Alzheimer's Disease or another tauopathy, the method comprising the step of detecting binding of the composition according to claim 180 to a component of a biological sample from the subject, wherein the detection of binding to the biological sample is indicative of Alzheimer's Disease or another tauopathy in the subject.

### Claim 198

A method of treating Alzheimer's Disease or another tauopathy in a subject having, suspected of having, or being prone to have Alzheimer's Disease or another tauopathy, comprising administering to the subject a therapeutically effective amount of a humanized anti-tau antibody, or a tau-binding fragment thereof, and a second therapeutic agent,
wherein the antibody or binding fragment comprises:
a heavy chain variable region comprising CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NOs. 1, 2, and 3, respectively, and a framework from human immunoglobulin M65092 (SEQ ID NO. 71);
a light chain variable region comprising CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NOs. 4, 5, and 6, respectively, and a framework from human immunoglobulin X72449 (SEQ ID NO. 65); and
heavy chain and light chain constant regions each from a human immunoglobulin;
wherein said heavy chain framework has been substituted at one or more positions selected from 9, 21, 27, 28, 30, 38, 48, 67, 68, 70, and 95; said light chain framework has either not been substituted or has been substituted at position 5; and wherein said positions are according to Kabat.

### Claim 199 (depends on 198)

The method of claim 198, wherein the humanized anti-tau antibody, or tau-binding fragment thereof, and the second therapeutic agent are administered sequentially or simultaneously.