# US 8,569,462 B2 · Antibodies specific for TGF-beta and methods for treating thereof

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- Number: US 8,569,462 B2
- Document ID: US8569462B2
- Status: Granted
- Kind: B2
- Application number: 13/486,983
- Filed: 2012-06-01
- Published: 2012-12-13
- Granted: 2013-10-29
- Earliest claimed: 2012-06-01
- Assignees: Xoma Technology Ltd.
- Applicants: Daniel Bedinger; Shireen S. Khan; Amer Mirza; Ajay J. Narasimha; Toshihiko Takeuchi
- Inventors: Daniel Bedinger; Shireen S. Khan; Amer Mirza; Ajay J. Narasimha; Toshihiko Takeuchi
- Web page: https://patentgrep.com/patent/US8569462B2

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/08: Vasodilators for multiple indications
- 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 9/12: Antihypertensives
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/08: Bronchodilators
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/10: for impotence
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- 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 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/12: for cataracts
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/30: characterized by aspects of specificity or valency
- C07K 2317/55: Fab or Fab'
- 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 2317/64: comprising a combination of variable region and constant region components
- 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: 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
- 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)

## Abstract

The present disclosure relates, in general, to materials and methods for antibodies specific for transforming growth factor beta (TGFβ), including TGFβ1, TGFβ2 and TGFβ3, and uses of these antibodies in the treatment of subjects having cancer, an eye disease, condition or disorder, fibrosis, including ophthalmic fibrosis or fibrosis of the eye, and other conditions or disorders related to TGFβ expression.

## Claims

### Claim 1

An antibody that binds transforming growth factor beta (TGFβ)1, TGFβ2 and TGFβ3 comprising:
(a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 19, or a variant thereof in which one or two amino acids have been changed;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 20, or a variant thereof in which one or two amino acids have been changed;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 21, or a variant thereof in which one or two amino acids have been changed;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 22, or a variant thereof in which one or two amino acids have been changed;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 23, or a variant thereof in which one or two amino acids have been changed; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 24, or a variant thereof in which one or two amino acids have been changed.

### Claim 2 (depends on 1)

The antibody of claim 1, in which one or more heavy chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.

### Claim 3

An antibody that binds transforming growth factor beta (TGFβ)1, TGFβ2 and TGFβ3 comprising a light chain variable region and a heavy chain variable region, wherein
(a) the light chain variable region comprises at least a CDR1 amino acid sequence set out in SEQ ID NO: 22, a CDR2 amino acid sequence set out in SEQ ID NO: 23, and a CDR3 amino acid sequence set out in SEQ ID NO: 24; and wherein
(b) the heavy chain variable region comprises at least a CDR1 amino acid sequence set out in SEQ ID NO: 19, a CDR2 amino acid sequence set out in SEQ ID NO: 20, and a CDR3 amino acid sequence set out in SEQ ID NO: 21.

### Claim 4 (depends on 1, 3)

The antibody of claim 1 or 3, further comprising a heavy chain constant region, wherein the heavy chain constant region is a modified or unmodified IgG, IgM, IgA, IgD, IgE, a fragment thereof, or combinations thereof.

### Claim 5 (depends on 1, 3)

The antibody of claim 1 or 3, in which one or more light chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.

### Claim 6 (depends on 1, 3)

The antibody of claim 1 or 3, wherein the antibody is XPA.42.089 having a heavy chain variable region amino acid sequence set out in SEQ ID NO: 6 and a light chain variable region amino acid sequence set out in SEQ ID NO: 8.

### Claim 7 (depends on 1, 3)

The antibody of claim 1 or 3, further comprising a human light chain constant region attached to said light chain variable region.

### Claim 8 (depends on 1, 3)

An antibody of claim 1 or 3 that binds TGFβ1 and TGFβ2 with an affinity Kd of 10 −6 M or less.

### Claim 9 (depends on 1, 3)

An antibody of claim 1 or 3, wherein the antibody binds to TGFβ1 and TGFβ2 with greater affinity than TGFβ3.

### Claim 10 (depends on 1, 3)

An antibody of claim 1 or 3, wherein the antibody neutralizes activity of TGFβ1 and TGFβ2 to a greater extent than TGFβ3.

### Claim 11 (depends on 1, 3)

The antibody of claim 1 or 3 that comprises a heavy chain variable region amino acid sequence set forth in SEQ ID NO: 6 and a light chain variable region amino acid sequence set forth in SEQ ID NO: 8.

### Claim 12 (depends on 1, 3)

A sterile pharmaceutical composition comprising the antibody of claim 1 or 3 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1, 3, 12)

A composition comprising an antibody of claim 1 or 3 or a pharmaceutical composition of claim 12 for use in treating a condition or disorder associated with TGFβ expression.

### Claim 14 (depends on 1, 3, 12)

A method for treating a disease, condition or disorder associated with TGFβ expression comprising the step of administering to a subject in need thereof a therapeutically effective amount of an antibody of claim 1 or 3 or a pharmaceutical composition of claim 12.

### Claim 15 (depends on 1, 3, 12)

A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an antibody of claim 1 or 3 or a pharmaceutical composition of claim 12.

### Claim 16 (depends on 15)

The method of claim 15, wherein the antibody or composition increases the number of natural killer (NK) cells in a tumor and/or improves NK cell cytolytic activity.

### Claim 17 (depends on 15)

The method of claim 15, wherein the antibody or composition decreases the number of regulatory T cells in a tumor and/or inhibits regulatory T cell function.

### Claim 18 (depends on 15)

The method of claim 15, wherein the antibody or composition increases the number of cytotoxic T cells (CTLs) in a tumor and/or enhances CTL function.

### Claim 19 (depends on 15)

The method of claim 15, wherein the antibody decreases the number of myeloid-derived suppressor cells (MDSC) in a tumor and/or inhibits MDSC function.

### Claim 20 (depends on 15)

The method of claim 15, wherein the antibody decreases the number of dendritic cells (DC) in a tumor and/or inhibits the tolerogenic function of dendritic cells.

### Claim 21 (depends on 15)

The method of claim 15, wherein the cancer is selected from the group consisting of lung cancer, prostate cancer, breast cancer, hepatocellular cancer, esophageal cancer, colorectal cancer, pancreatic cancer, bladder cancer, kidney cancer, ovarian cancer, stomach cancer, fibrotic cancer, glioma and melanoma.