# US 10,501,531 B2 · Tau immunotherapy

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- Number: US 10,501,531 B2
- Document ID: US10501531B2
- Status: Granted
- Kind: B2
- Application number: 14/776,724
- Filed: 2014-03-12
- Published: 2016-02-04
- Granted: 2019-12-10
- Earliest claimed: 2013-03-13
- Assignees: Prothena Biosciences Limited
- Applicants: Prothena Biosciences Limited
- Inventors: Peter Seubert; Philip James Dolan, III; Yue Liu; Robin Barbour
- Web page: https://patentgrep.com/patent/US10501531B2

## CPC

- C07K 16/18: against material from animals or humans
- A61K 39/0007: {Nervous system antigens; Prions}
- A61K 47/6843: {the antibody targeting a 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}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/55: {characterised by the host/recipient, e.g. newborn with maternal antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/55: Fab or Fab'
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- G01N 2333/47: Assays involving proteins of known structure or function as defined in the subgroups
- G01N 2800/2821: Alzheimer
- 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

The invention provides antibodies to tau. The antibodies inhibit or delay tau-associated pathologies and associated symptomatic deterioration.

## Claims

### Claim 1

An antibody comprising a mature heavy chain variable region comprising three heavy chain CDRs of the amino acid sequence encoded by SEQ ID NO:25, the mature heavy chain variable region being at least 90% identical to the sequence encoded by SEQ ID NO:25 and a mature light chain variable region comprising three light chain CDRs of SEQ ID NO:22 provided positions L36 and L43 can be occupied by F and S respectively, the mature light chain variable region being at least 90% identical to SEQ ID NO:22.

### Claim 2 (depends on 1)

The monoclonal antibody of claim 1 that is of human IgG isotype.

### Claim 3 (depends on 2)

The monoclonal antibody of claim 2, wherein the isotype is IgG1.

### Claim 4 (depends on 2)

The monoclonal antibody of claim 2, having at least one mutation in the constant region.

### Claim 5 (depends on 2)

The monoclonal antibody of claim 2 that is of human IgG2 or IgG4 isotype.

### Claim 6 (depends on 1)

The antibody of claim 1, comprising CDRH1 of SEQ ID NO:11 or SEQ ID NO:24, CDRH-2 of SEQ ID NO:12 and CDRH-3 of SEQ ID NO:13 and CDR-L1 of SEQ ID NO:17, CDR-L2 of SEQ ID NO:18 and CDR-L3 of SEQ ID NO:19.

### Claim 7 (depends on 6)

The antibody of claim 6, wherein the mature heavy chain variable region has an amino acid sequence at least 99% identical to the sequence encoded by SEQ ID NO:25 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:21, 22, or 23.

### Claim 8 (depends on 6)

The antibody of claim 6, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.

### Claim 9 (depends on 8)

The antibody of claim 8, wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcγ receptor relative to the natural human constant region.

### Claim 10 (depends on 8)

The antibody of claim 8, wherein the heavy chain constant region is of IgG1 isotype.

### Claim 11 (depends on 6)

The antibody of claim 6, provided at least one of positions H13, H48 and H91 is occupied by K, M and F respectively and at least one of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively.

### Claim 12 (depends on 11)

The antibody of claim 11, provided positions H13, H48 and H91 are occupied by K, M and F respectively and at least two of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively.

### Claim 13 (depends on 12)

The antibody of claim 12, provided positions H13, H48 and H91 are occupied by K, M and F respectively, and at least three of positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively.

### Claim 14 (depends on 13)

The antibody of claim 13, provided positions H13, H48 and H91 are occupied by K, M and F respectively, and positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively.

### Claim 15 (depends on 14)

The antibody of claim 14, comprising a mature heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 95% identical to SEQ ID NO:22.

### Claim 16 (depends on 14)

The antibody of claim 14, comprising a mature heavy chain variable region having an amino acid sequence at least 96% identical to the amino acid sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 96% identical to SEQ ID NO:22.

### Claim 17 (depends on 14)

The antibody of claim 14, comprising a mature heavy chain variable region having an amino acid sequence at least 97% identical to the amino acid sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 97% identical to SEQ ID NO:22.

### Claim 18 (depends on 14)

The antibody of claim 14, comprising a mature heavy chain variable region having an amino acid sequence at least 98% identical to the amino acids sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 98% identical to SEQ ID NO:22.

### Claim 19 (depends on 14)

The antibody of claim 14, comprising a mature heavy chain variable region having an amino acid sequence at least 99% identical to the amino acids sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 99% identical to SEQ ID NO:22.

### Claim 20 (depends on 19)

The antibody of claim 19, wherein the mature heavy chain variable region has an amino acid sequence at least 99% identical to the sequence encoded by SEQ ID NO:25 and the mature light chain variable region has the amino acid sequence encoded by designated SEQ ID NO:22.

### Claim 21 (depends on 6, 15)

The antibody of any one of claims 6 and 15, wherein the antibody is a Fab fragment.

### Claim 22 (depends on 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The antibody of any one of claims 6-15, wherein the mature heavy chain variable region has the amino acid sequence encoded by the nucleic acid sequence of SEQ ID NO:25.

### Claim 23 (depends on 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

A polynucleotide comprising a nucleic acid encoding the heavy and/or light chains of an antibody as described in any one of claims 6-15, 7, 20 and 16-19.

### Claim 24

A method of humanizing an antibody, comprising:
determining the sequences of the heavy and light chain variable regions of a mouse antibody;
synthesizing a nucleic acid encoding a humanized heavy chain comprising CDRs of the mouse antibody heavy chain and a nucleic acid encoding a humanized light chain comprising CDRs of the mouse antibody light chain; and
expressing the nucleic acids in a host cell to produce a humanized antibody,
wherein the mouse antibody is characterized by a mature heavy chain variable region of SEQ ID NO:10 and a mature light chain variable region of SEQ ID NO:16.

### Claim 25

A method of producing a humanized, chimeric or veneered antibody, comprising:
culturing cells transformed with nucleic acids encoding the heavy and light chains of the antibody, so that the cell secretes the antibody; and
purifying the antibody from cell culture media,
wherein the antibody is a humanized, chimeric or veneered form of a mouse antibody, which is characterized by a mature heavy chain variable region of SEQ ID NO:10 and a mature light chain variable region of SEQ ID NO:16.

### Claim 26

A method of producing a cell line producing a humanized, chimeric or veneered antibody, comprising;
introducing a vector encoding heavy and light chains of an antibody and a selectable marker into cells;
propagating the cells under conditions to select for cells having increased copy number of the vector;
isolating single cells from the selected cells; and
banking cells cloned from a single cell selected based on yield of antibody; wherein the antibody is a humanized, chimeric or veneered form of a mouse antibody, which is characterized by a mature heavy chain variable region of SEQ ID NO:10 and a mature light chain variable region of SEQ ID NO:16.