# US 10,501,550 B2 · Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof

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- Number: US 10,501,550 B2
- Document ID: US10501550B2
- Status: Granted
- Kind: B2
- Application number: 15/369,290
- Filed: 2016-12-05
- Published: 2017-05-25
- Granted: 2019-12-10
- Earliest claimed: 2014-06-06
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Changyu Wang; Nils Lonberg; Alan J. Korman; Mark J. Selby; Mohan Srinivasan; Karla A. Henning; Michelle Minhua Han; Guodong Chen; Richard Huang; Indrani Chakraborty; Haichun Huang; Susan Wong; Huiming Li
- Web page: https://patentgrep.com/patent/US10501550B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/6863: {Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- 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 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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 2317/52: Constant or Fc region; Isotype
- C07K 2317/53: Hinge
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/74: Inducing cell proliferation
- C07K 2317/75: Agonist effect on antigen
- 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
- G01N 2333/70578: NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95
- G01N 2333/7151: for tumor necrosis factor [TNF]; for lymphotoxin [LT]
- 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

Provided herein are antibodies, or antigen binding portions thereof, that bind to glucocorticoid-inducible TNF receptor (GITR). Also provided are uses of these proteins in therapeutic applications, such as in the treatment of cancer. Further provided are cells that produce antibodies, polynucleotides encoding the heavy and/or light chain variable region of the antibodies, and vectors comprising the polynucleotides encoding the heavy and/or light chain variable region of the antibodies.

## Claims

### Claim 1

A method for inhibiting the growth of a tumor in a human subject comprising administering to the subject an effective amount of an antibody which binds to human glucocorticoid-inducible TNF receptor (GITR), wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 13, and a light chain variable region sequence comprising SEQ ID NO: 14.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 15 and a light chain sequence comprising SEQ ID NO: 16, wherein the heavy chain sequence optionally lacks the C-terminal lysine.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 17 and a light chain sequence comprising SEQ ID NO: 19.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 18 and a light chain sequence comprising SEQ ID NO: 19.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody binds to a cell expressing membrane-bound human GITR with a KD of 10 nM or less as determined by Scatchard analysis.

### Claim 7 (depends on 1)

The method of claim 1, wherein the antibody binds to human GITR on activated human T cells.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody binds to GITR on 3A9 cells ectopically expressing human GITR.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody stimulates a T cell response.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody is a human IgG antibody.

### Claim 11 (depends on 10)

The method of claim 10, wherein the antibody is a human IgG1, an IgG2, or an IgG4 antibody.

### Claim 12 (depends on 1)

The method of claim 1, wherein the tumor is from a cancer selected from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.

### Claim 13 (depends on 12)

The method of claim 12, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.

### Claim 14 (depends on 1)

The method of claim 1, further comprising administering one or more additional therapy.

### Claim 15 (depends on 14)

The method of claim 14, wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.

### Claim 16 (depends on 3)

The method of claim 3, wherein the tumor is from a cancer from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.

### Claim 17 (depends on 16)

The method of claim 16, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.

### Claim 18 (depends on 3)

The method of claim 3, further comprising administering one or more additional therapy.

### Claim 19 (depends on 18)

The method of claim 18, wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.

### Claim 20 (depends on 18)

The method of claim 18, wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.

### Claim 21 (depends on 18)

The method of claim 18, wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.

### Claim 22 (depends on 18)

The method of claim 18, wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.

### Claim 23 (depends on 18)

The method of claim 18, wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.

### Claim 24 (depends on 4)

The method of claim 4, wherein the tumor is from a cancer selected from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.

### Claim 25 (depends on 24)

The method of claim 24, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.

### Claim 26 (depends on 4)

The method of claim 4, further comprising administering one or more additional therapy.

### Claim 27 (depends on 26)

The method of claim 26, wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.

### Claim 28 (depends on 26)

The method of claim 26, wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.

### Claim 29 (depends on 26)

The method of claim 26, wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.

### Claim 30 (depends on 26)

The method of claim 26, wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.

### Claim 31 (depends on 26)

The method of claim 26, wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.

### Claim 32 (depends on 5)

The method of claim 5, wherein the tumor is from a cancer from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.

### Claim 33 (depends on 32)

The method of claim 32, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.

### Claim 34 (depends on 5)

The method of claim 5, further comprising administering one or more additional therapy.

### Claim 35 (depends on 34)

The method of claim 34, wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.

### Claim 36 (depends on 34)

The method of claim 34, wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.

### Claim 37 (depends on 34)

The method of claim 34, wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.

### Claim 38 (depends on 34)

The method of claim 34, wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.

### Claim 39 (depends on 34)

The method of claim 34, wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.

### Claim 40

A method of treating cancer comprising administering to a human subject in need thereof a therapeutically effective amount of an antibody which binds to human glucocorticoid-inducible TNF receptor (GITR), wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively.

### Claim 41 (depends on 40)

The method of claim 40, wherein the antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 13, and a light chain variable region sequence comprising SEQ ID NO: 14.

### Claim 42 (depends on 40)

The method of claim 40, wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 15 and a light chain sequence comprising SEQ ID NO: 16, wherein the heavy chain sequence optionally lacks the C-terminal lysine.

### Claim 43 (depends on 40)

The method of claim 40, wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 17 and a light chain sequence comprising SEQ ID NO: 19.

### Claim 44 (depends on 40)

The method of claim 40, wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 18 and a light chain sequence comprising SEQ ID NO: 19.

### Claim 45 (depends on 40)

The method of claim 40, wherein the antibody binds to a cell expressing membrane-bound human GITR with a KD of 10 nM or less as determined by Scatchard analysis.

### Claim 46 (depends on 40)

The method of claim 40, wherein the antibody binds to human GITR on activated human T cells.

### Claim 47 (depends on 40)

The method of claim 40, wherein the antibody binds to GITR on 3A9 cells ectopically expressing human GITR.

### Claim 48 (depends on 40)

The method of claim 40, wherein the antibody stimulates a T cell response.

### Claim 49 (depends on 40)

The method of claim 40, wherein the antibody is a human IgG antibody.

### Claim 50 (depends on 49)

The method of claim 49, wherein the antibody is a human IgG1, an IgG2, or an IgG4 antibody.

### Claim 51 (depends on 40)

The method of claim 40, wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.

### Claim 52 (depends on 51)

The method of claim 51, wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.

### Claim 53 (depends on 40)

The method of claim 40, further comprising administering one or more additional therapy.

### Claim 54 (depends on 53)

The method of claim 53, wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.

### Claim 55 (depends on 53)

The method of claim 53, wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.

### Claim 56 (depends on 53)

The method of claim 53, wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.

### Claim 57 (depends on 53)

The method of claim 53, wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.

### Claim 58 (depends on 53)

The method of claim 53, wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.