# US 10,766,955 B2 · Anti-TGF-β antibodies and their use

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- Number: US 10,766,955 B2
- Document ID: US10766955B2
- Status: Granted
- Kind: B2
- Application number: 15/875,532
- Filed: 2018-01-19
- Published: 2018-08-30
- Granted: 2020-09-08
- Earliest claimed: 2017-01-20
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Gary Shapiro; Kevin Brower; Patrick Finn; Richard C. Gregory; Rao Koduri; Feng Liu; Natalia Malkova; Parminder Mankoo; Jack R. Pollard; Huawei Qiu; Joachim Theilhaber; Christopher Winter; Marcella Yu
- Web page: https://patentgrep.com/patent/US10766955B2

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/30: from tumour cells
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- 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 2317/76: 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 invention provides an improved pan-TGF-β antibody for treatment of conditions that are mediated by TGF-β, including autoimmune diseases, fibrotic conditions, and cancers. Also provided are methods and uses of the antibody in conjunction with other immunomodulatory agents such as an anti-PD-1 antibody.

## Claims

### Claim 1

A method of inhibiting TGF-β signal transduction in a patient in need thereof, comprising administering to the patient a therapeutic amount of an isolated monoclonal antibody, wherein the antibody binds to human TGF-β1, TGF-β2, and TGF-β3 and comprises the heavy chain complementarity-determining regions (CDR) 1-3 in SEQ ID NO:1 and the light chain CDR1-3 in SEQ ID NO:2, and wherein the antibody comprises a human IgG4 constant region having a proline at position 228 (EU numbering).

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient has cancer.

### Claim 3 (depends on 2)

The method of claim 2, wherein the cancer is selected from the group consisting of melanoma, lung cancer, cutaneous squamous cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, head and neck cancer, hepatocellular carcinoma, urothelial cancer, and renal cell carcinoma.

### Claim 4 (depends on 2)

The method of claim 2, wherein the cancer is characterized by overexpression of one or more of smooth muscle α2 actin (ACTA2), vimentin (VIM), matrix Gla protein (MGP), and ZW10 interacting kinetochore protein (ZWINT).

### Claim 5 (depends on 2)

The method of claim 2, wherein the cancer is a mesenchymal tumor.

### Claim 6 (depends on 2)

The method of claim 2, wherein the antibody alleviates an immunosuppressive tumor microenvironment in a cancer tissue in the patient.

### Claim 7 (depends on 1)

The method of claim 1, wherein the antibody comprises a heavy chain variable domain (VH) amino acid sequence corresponding to residues 1-120 of SEQ ID NO:1 and a light chain variable domain (VL) amino acid sequence corresponding to residues 1-108 of SEQ ID NO:2.

### Claim 8 (depends on 7)

The method of claim 7, wherein the antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.

### Claim 9

A method of treating cancer or increasing an immune response in a patient in need thereof, comprising administering to the patient (1) a therapeutically effective amount of an isolated monoclonal antibody, and (2) a therapeutically effective amount of an inhibitor of an immune checkpoint protein, wherein the antibody binds to human TGF-β1, TGF-β2, and TGF-β3 and comprises the heavy chain complementarity-determining regions (CDR) 1-3 in SEQ ID NO:1 and the light chain CDR1-3 in SEQ ID NO:2, and wherein the antibody comprises a human IgG4 constant region having a proline at position 228 (EU numbering).

### Claim 10 (depends on 9)

The method of claim 9, wherein the immune checkpoint protein is PD-1, PD-L1, or PD-L2.

### Claim 11 (depends on 10)

The method of claim 10, wherein the inhibitor of the immune checkpoint protein is an anti-PD-1 antibody.

### Claim 12 (depends on 11)

The method of claim 11, wherein the anti-PD-1 antibody comprises:
a) the heavy chain CDR1-3 in SEQ ID NO:5 and the light chain CDR1-3 in SEQ ID NO:6;
b) a VH amino acid sequence corresponding to residues 1-117 of SEQ ID NO:5 and a VL amino acid sequence corresponding to residues 1-107 of SEQ ID NO:6; or
c) a heavy chain amino acid sequence set forth in SEQ ID NO:5 and a light chain amino acid sequence set forth in SEQ ID NO:6.

### Claim 13 (depends on 12)

The method of claim 12, wherein the anti-TGF-β antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.

### Claim 14 (depends on 9)

The method of claim 9, wherein the cancer is refractory to anti-PD-1 or anti-PD-L1 antibody treatment.

### Claim 15 (depends on 9)

The method of claim 9, wherein the cancer is advanced or metastatic melanoma, or cutaneous squamous cell carcinoma.

### Claim 16 (depends on 9)

The method of claim 9, wherein the cancer is a mesenchymal subtype of a solid tumor.

### Claim 17 (depends on 9)

The method of claim 9, wherein the cancer is characterized by overexpression of one or more of smooth muscle α2 actin (ACTA2), vimentin (VIM), matrix Gla protein (MGP), and ZW10 interacting kinetochore protein (ZWINT).

### Claim 18 (depends on 9)

The method of claim 9, wherein the cancer is selected from the group consisting of melanoma, lung cancer, cutaneous squamous cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, head and neck cancer, hepatocellular carcinoma, urothelial cancer, and renal cell carcinoma.

### Claim 19 (depends on 9)

The method of claim 9, wherein the antibody comprises a heavy chain variable domain (VH) amino acid sequence corresponding to residues 1-120 of SEQ ID NO:1 and a light chain variable domain (VL) amino acid sequence corresponding to residues 1-108 of SEQ ID NO:2.

### Claim 20 (depends on 19)

The method of claim 19, wherein the antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.

### Claim 21

A method of treating cancer in a patient in need thereof, comprising administering to the patient (1) a therapeutically effective amount of an isolated monoclonal antibody, and (2) a therapeutically effective amount of an antibody to PD-1 or PD-L1, wherein the isolated monoclonal antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.

### Claim 22 (depends on 21)

The method of claim 21, wherein the cancer is refractory to anti-PD-1 or anti-PD-L1 antibody treatment.

### Claim 23 (depends on 21)

The method of claim 21, wherein the antibody to PD-1 or PD-L1 is an antibody to PD-1 comprising a heavy chain amino acid sequence set forth in SEQ ID NO:5 and a light chain amino acid sequence set forth in SEQ ID NO:6.

### Claim 24 (depends on 21)

The method of claim 21, wherein the cancer is advanced or metastatic melanoma, or cutaneous squamous cell carcinoma.

### Claim 25 (depends on 21)

The method of claim 21, wherein the cancer is a mesenchymal subtype of a solid tumor.

### Claim 26 (depends on 21)

The method of claim 21, wherein the cancer is colorectal cancer.

### Claim 27 (depends on 21)

The method of claim 21, wherein the cancer is urothelial cancer.

### Claim 28 (depends on 21)

The method of claim 21, wherein the cancer is non-small cell lung cancer.

### Claim 29 (depends on 21)

The method of claim 21, wherein the cancer is hepatocellular carcinoma.

### Claim 30 (depends on 21)

The method of claim 21, wherein the cancer is ovarian cancer.

### Claim 31 (depends on 21)

The method of claim 21, wherein the cancer is cervical cancer.

### Claim 32 (depends on 21)

The method of claim 21, wherein the cancer is pancreatic cancer.

### Claim 33 (depends on 21)

The method of claim 21, wherein the cancer is prostate cancer.