# US 2023/0056470 A1 · Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases

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- Number: US 2023/0056470 A1
- Document ID: US20230056470A1
- Status: Published application
- Kind: A1
- Application number: 17/786,265
- Filed: 2020-12-03
- Published: 2023-02-23
- Earliest claimed: 2019-12-20
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Mirek DOSTALEK; Claire FABRE; Fariba KHANSHAN
- Web page: https://patentgrep.com/patent/US20230056470A1

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- 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
- A61P 35/00: Antineoplastic agents
- C07K 16/245: {IL-1}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2818: {against CD28 or CD152}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- 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 2317/31: multispecific
- C07K 2317/565: Complementarity determining region [CDR]
- 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

## Abstract

Therapies using TGF-β inhibitors and/or PD-1 inhibitors are disclosed. These drugs at certain doses (including flat dosing) and regimens can be used to treat or prevent proliferative diseases such as solid tumors, including pancreatic cancers. Further combination and uses thereof are also disclosed.

## Claims

### Claim 1

A method of treating a proliferative disease in a subject in need thereof comprising administering to the subject a TGF-β antibody at a dose of about 16 mg/kg to about 50 mg/kg, once every two or three weeks, wherein the TGF-β antibody comprises a heavy chain CDR1, CDR2, and CDR3, of SEQ ID NOs: 1, 2, and 3, respectfully, and a light chain CDR1, CDR2, and CDR3, of SEQ ID NOs: 4, 5, and 6, respectfully.

### Claim 2 (depends on 1)

The method of claim 1, wherein the TGF-β antibody is administered at a dose of about 20 mg/kg.

### Claim 3 (depends on 1, 2)

The method of claim 1 or 2, wherein the TGF-β antibody is administered at a dose of about 30 mg/kg.

### Claim 4

A method of treating a proliferative disease in a subject in need thereof comprising administering to the subject a TGF-β antibody at a dose of about 1200 mg to about 1600 mg, once every two or three weeks, wherein the TGF-β antibody comprises a heavy chain CDR1, CDR2, and CDR3, of SEQ ID NOs: 1, 2, and 3, respectfully, and a light chain CDR1, CDR2, and CDR3, of SEQ ID NOs: 4, 5, and 6, respectfully.

### Claim 5 (depends on 4)

The method of claim 4, wherein the TGF-β antibody is administered at a dose of about 1400 mg.

### Claim 6 (depends on 4, 5)

The method of claim 4 or 5, wherein the TGF-β antibody is administered every two weeks.

### Claim 7

A method of treating a proliferative disease comprising administering to a subject in need thereof a TGF-β antibody at a dose of about 1900 mg to about 2300 mg, once every two or three weeks, wherein the TGF-β antibody comprises a heavy chain CDR1, CDR2, and CDR3, of SEQ ID NOs: 1, 2, and 3, respectfully, and a light chain CDR1, CDR2, and CDR3, of SEQ ID NOs: 4, 5, and 6, respectfully.

### Claim 8 (depends on 7)

The method of claim 7, wherein the TGF-β antibody is administered at a dose of about 2100 mg.

### Claim 9 (depends on 7, 8)

The method of claim 7 or 8, wherein the TGF-β antibody is administered every three weeks.

### Claim 10 (depends on 7, 8)

The method of claim 7 or 8, wherein the TGF-β antibody is administered every two weeks.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the TGF-β antibody comprises the heavy chain variable region and the light chain variable region set out in amino acid sequence SEQ ID NOs: 7 and 8, respectively.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The method of any one of claims 1 to 11, wherein the TGF-β antibody comprises the heavy chain and light chain set out in amino acid sequence of SEQ ID NOs: 9 and 10, respectively.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The method of any one of claims 1 to 12, wherein the TGF-β antibody is a monoclonal antibody.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The method of any one of claims 1 to 13, wherein the antibody is a multispecific antibody.

### Claim 15 (depends on 14)

The method of claim 14, wherein the multispecific antibody is a bispecific antibody.

### Claim 16 (depends on 14)

The method of claim 14, wherein the multispecific antibody is a trispecific antibody.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The method of any one of claims 1 to 16, wherein the TGF-β inhibitor is administered over a period of about 20 to about 40 minutes.

### Claim 18 (depends on 17)

The method of claim 17, wherein the TGF-β inhibitor is administered over a period of about 30 minutes.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

The method of any one of claims 1 to 18, wherein the subject is about 70 kg.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The method of any one of claims 1 to 19, further comprising administering to the subject a checkpoint inhibitor.

### Claim 21 (depends on 20)

The method of claim 20, wherein the checkpoint inhibitor is a PD1 inhibitor.

### Claim 22 (depends on 21)

The method of claim 21, wherein the PD1 inhibitor is an anti-PD1 antibody.

### Claim 23 (depends on 22)

The method of claim 22, wherein the anti-PD1 antibody is spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, REGN2810, TSR-042, PF-06801591, BGB-A317, BGB-108, INCSHR1210, AMP-224, or any combination thereof.

### Claim 24 (depends on 22, 23)

The method of claim 22 or 23, wherein the anti-PD1 antibody is spartalizumab.

### Claim 25 (depends on 24)

The method of claim 24, wherein spartalizumab is administered at a flat dose.

### Claim 26 (depends on 25)

The method of claim 25, wherein spartalizumab is administered at a dose of about 300 mg or about 400 mg, once every three weeks or once every four weeks.

### Claim 27 (depends on 23, 24, 25, 26)

The method of any one of claims 23 to 26, wherein spartalizumab is administered at a dose of about 300 mg spartalizumab, once every three weeks.

### Claim 28 (depends on 23, 24, 25, 26)

The method of any one of claims 23 to 26, wherein spartalizumab is administered at a dose of about 400 mg spartalizumab, once every four weeks.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1 to 28, wherein the TGF-β inhibitor and/or PD1 inhibitor is administered intravenously.

### Claim 30 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 20 to 29, wherein the TGF-β inhibitor is administered on the same day as the checkpoint inhibitor.

### Claim 31 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 20 to 29, wherein the TGF-β inhibitor is administered before the checkpoint inhibitor is administered.

### Claim 32 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 20 to 29, wherein the TGF-β inhibitor is administered after the checkpoint inhibitor is administered.

### Claim 33 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 20 to 29, wherein the TGF-β inhibitor is administered at the same time as the checkpoint inhibitor.

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The method of any one of claims 1 to 33, wherein the proliferative disease is a cancer.

### Claim 35 (depends on 34)

The method of claim 34, wherein the cancer is a myelofibrosis, a leukemia, a lymphoma, a myeloma, a lung cancer, a skin cancer, an ovarian cancer, a mesothelioma, a gastrointestinal cancer, a bladder cancer, a soft tissue sarcoma, a bone cancer, a kidney cancer, a liver cancer, a cholangiocarcinoma, a sarcoma, a myelodysplastic syndrome (e.g., low risk or high risk myelodysplastic syndrome), a prostate cancer, a breast cancer (e.g., triple negative breast cancer), a colorectal cancer, a nasopharyngeal cancer, a duodenal cancer, an endometrial cancer, a pancreatic cancer, a head and neck cancer, an anal cancer, a gastro-esophageal cancer, a thyroid cancer, a cervical cancer, or a neuroendocrine tumor.

### Claim 36 (depends on 35)

The method of claim 35, wherein the cancer is a pancreatic cancer.

### Claim 37 (depends on 36)

The method of claim 36, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

### Claim 38 (depends on 35)

The method of claim 35, wherein the cancer is a gastrointestinal cancer.

### Claim 39 (depends on 38)

The method of claim 38, wherein the gastrointestinal cancer is colorectal cancer.

### Claim 40 (depends on 35)

The method of claim 35, wherein the cancer is myelofibrosis.

### Claim 41 (depends on 35)

The method of claim 35, wherein the cancer is myelodysplastic syndrome.

### Claim 42 (depends on 35)

The method of claim 35, wherein the cancer is breast cancer.

### Claim 43 (depends on 42)

The method of claim 42, wherein the breast cancer is triple negative breast cancer.

### Claim 44 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The method of any one of claims 1 to 43, wherein the TGF-β inhibitor and/or checkpoint inhibitor is given until remission.

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The method of any one of claims 1 to 44, further comprising administering to the subject one or more anticancer therapies.

### Claim 46 (depends on 45)

The method of claim 45, wherein the anticancer therapy is a standard of care therapy or an anticancer therapeutic.

### Claim 47

A method of treating pancreatic ductal adenocarcinoma comprising administering to a subject in need thereof a TGF-β antibody at a dose of 2100 mg, once every two or three weeks, wherein the TGF-β antibody comprises the heavy chain and light chain set out in amino acid sequence of SEQ ID NOs: 9 and 10, respectively.

### Claim 48

A method of treating colorectal cancer comprising administering to a subject in need thereof a TGF-β antibody at a dose of 2100 mg, once every two or three weeks, wherein the TGF-β antibody comprises the heavy chain and light chain set out in amino acid sequence of SEQ ID NOs: 9 and 10, respectively.

### Claim 49

A method of treating pancreatic ductal adenocarcinoma comprising administering to a subject in need thereof a TGF-β antibody at a dose of 1400 mg, once every two weeks, wherein the TGF-β antibody comprises the heavy chain and light chain set out in amino acid sequence of SEQ ID NOs: 9 and 10, respectively.

### Claim 50

A method of treating colorectal cancer comprising administering to a subject in need thereof a TGF-β antibody at a dose of 1400 mg, once every three weeks, wherein the TGF-β antibody comprises the heavy chain and light chain set out in amino acid sequence of SEQ ID NOs: 9 and 10, respectively.

### Claim 51 (depends on 47, 48, 49, 50)

The method of any one of claims 47 to 50, further comprising administering spartalizumab at a dose of about 300 mg once every three weeks.

### Claim 52 (depends on 47, 48, 49, 50)

The method of any one of claims 47 to 50, further comprising administering spartalizumab at a dose of about 400 mg once every four weeks.

### Claim 53

A pharmaceutical composition comprising a TGF-β antibody and a pharmaceutically acceptable excipient, wherein the TGF-β antibody comprises the heavy chain and light chain set out in amino acid sequence of SEQ ID NOs: 9 and 10, respectively.

### Claim 54 (depends on 53)

The pharmaceutical composition of claim 53, wherein the TGF-β antibody is present at a concentration of 100 mg/mL.

### Claim 55 (depends on 53, 54)

The pharmaceutical composition of claim 53 or 54, further comprising (a) a histidine buffer at a concentration of 20 mM with a pH of 5.5; (b) sucrose at a concentration of 220 mM; and (c) a surfactant or polysorbate 20 present at a concentration of 0.04% (w/w).