# US 12,215,151 B2 · Methods of treating cancer using antibodies and molecules that immunospecifically bind to BTN1A1

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- Number: US 12,215,151 B2
- Document ID: US12215151B2
- Status: Granted
- Kind: B2
- Application number: 16/618,050
- Filed: 2018-05-30
- Published: 2020-04-30
- Granted: 2025-02-04
- Earliest claimed: 2017-05-31
- Assignees: Stcube, Inc.
- Applicants: Stcube & Co., Inc.
- Inventors: Stephen Sunghan Yoo; Yong-Sik Bong; Kyu Lee Han; Michael Joseph Surace
- Web page: https://patentgrep.com/patent/US12215151B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- G01N 33/57515: of the breast
- G01N 33/5752: of the lungs
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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 2333/70532: B7 molecules, e.g. CD80, CD86
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- 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)
- 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

Provided herein are methods for treating cancer using molecules having an antigen binding fragment that immunospecifically binds to BTN1A1, such as anti-BTN1A1 antibodies. These molecules include those having an antigen binding fragment that immunospecifically binds to glycosylated BTN1A1, such as anti-glycosylated BTN1A1 antibodies. Also included are molecules having an antigen binding fragment that immunospecifically bind to BTN1A1 dimers, such as anti-BTN1A1 dimer antibodies. Also provided are methods for treating anti-PD-1 therapy or anti-PD-L1 therapy resistant or refractory cancers.

## Claims

### Claim 1

A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1, wherein the cancer expresses PD-L1 at a level lower than or equal to a PD-L1 reference level; wherein the PD-L1 reference level is the average or medium expression level of PD-L1 in a population of healthy individuals; and wherein the antigen binding fragment comprises:
(i) a heavy chain variable region (VH) comprising a VH complementarity-determining region (CDR) 1, a VH CDR2, and a VH CDR3 having an amino acid sequence of a VH CDR1, a VH CDR2, and a VH CDR3, respectively, of a VH having an amino acid sequence of SEQ ID NO:31; and
(ii) a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 having an amino acid sequence of a VL CDR1, a VL CDR2, and a VL CDR3, respectively, of a VL having an amino acid sequence of SEQ ID NO:33.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antigen binding fragment thereof comprises:
(a) a VH comprising: a VH CDR1 having the amino acid sequence of SEQ ID NO:35, a VH CDR2 having the amino acid sequence of SEQ ID NO:36; and a VH CDR3 having the amino acid sequence of SEQ ID NO:37; and a VL comprising: a VL CDR1 having the amino acid sequence of SEQ ID NO:47; a VL CDR2 having the amino acid sequence of SEQ ID NO:48; and a VL CDR3 having the amino acid sequence of SEQ ID NO:49; or
(b) a VH comprising: a VH CDR1 having the amino acid sequence of SEQ ID NO:38, a VH CDR2 having the amino acid sequence of SEQ ID NO:39; and a VH CDR3 having the amino acid sequence of SEQ ID NO:40; and a VL comprising: a VL CDR1 having the amino acid sequence of SEQ ID NO:50; a VL CDR2 having the amino acid sequence of SEQ ID NO:51; and a VL CDR3 having the amino acid sequence of SEQ ID NO:52; or
(c) a VH comprising: a VH CDR1 having the amino acid sequence of SEQ ID NO:41, a VH CDR2 having the amino acid sequence of SEQ ID NO:42; and a VH CDR3 having the amino acid sequence of SEQ ID NO:43; and a VL comprising: a VL CDR1 having the amino acid sequence of SEQ ID NO:53; a VL CDR2 having the amino acid sequence of SEQ ID NO:54; and a VL CDR3 having the amino acid sequence of SEQ ID NO:55; or
(d) a VH comprising: a VH CDR1 having the amino acid sequence of SEQ ID NO:44, a VH CDR2 having the amino acid sequence of SEQ ID NO:45; and a VH CDR3 having the amino acid sequence of SEQ ID NO:46; and a VL comprising: a VL CDR1 having the amino acid sequence of SEQ ID NO:56; a VL CDR2 having the amino acid sequence of SEQ ID NO:57; and a VL CDR3 having the amino acid sequence of SEQ ID NO:58.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antigen binding fragment thereof comprises a VL comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:33.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antigen binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:33.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antigen binding fragment thereof comprises a VH comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antigen binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:31.

### Claim 7 (depends on 1)

The method of claim 1, wherein the antigen binding fragment thereof comprises a VL comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:33; and a VH comprising an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:31.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or the antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO: 33; and a VH comprising the amino acid sequence of SEQ ID NO:31.

### Claim 9 (depends on 1)

The method of claim 1, wherein the molecule is an antibody.

### Claim 10 (depends on 1)

The method of claim 1, wherein the molecule is a monoclonal antibody or a humanized antibody.

### Claim 11 (depends on 9)

The method of claim 9, wherein the antibody is an IgG, IgM, or IgA.

### Claim 12 (depends on 1)

The method of claim 1, wherein the molecule comprising the antigen binding fragment that immunospecifically binds to BTN1A1 is a Fab′, a F(ab′) 2, a F(ab′) 3, a monovalent scFv, or a bivalent scFv.

### Claim 13 (depends on 1)

The method of claim 1, further comprising administering to the subject a radiation therapy.

### Claim 14 (depends on 13)

The method of claim 13, wherein the radiation therapy is a high-dose radiation therapy.

### Claim 15 (depends on 1)

The method of claim 1, further comprising administering to the subject a therapeutically effective amount of an anti-PD-1 therapy or an anti-PD-L1 therapy.

### Claim 16 (depends on 1)

The method of claim 1, wherein the cancer is a breast cancer, a neuroendocrine prostate cancer (NEPC), a diffuse large B-cell lymphoma, a melanoma, a cancer from the National Cancer Institute cancer panel (NCI 60), a uveal melanoma, a pancreas cancer, an ovarian cancer, a uterine cancer, a lung adenocarcinoma, a desmoplastic small-round-cell tumor, a bladder cancer, a colorectal cancer, a lung squamous cell carcinoma, a liver cancer, a lung cancer, a stomach cancer, a cholangiocarcinoma, an esophagus squamous cell carcinoma, a head and neck cancer, a sarcoma, a prostate cancer, a liver cancer, a pancreas cancer, a pheochromocytoma or paraganglioma (PCPG), a cervical cancer, a glioma, or an acute myeloid leukemia (AML).

### Claim 17 (depends on 1)

The method of claim 1, wherein the cancer is a breast cancer or a lung cancer.

### Claim 18 (depends on 1)

The method of claim 1, wherein the cancer is a mammary carcinoma or a Lewis lung carcinoma.

### Claim 19 (depends on 1)

The method of claim 1, wherein the cancer expresses BTN1A1 at a level higher than or equal to a BTN1A1 reference level; wherein the BTN1A1 reference level is the average or medium expression level of BTN1A1 in a population of healthy individuals.

### Claim 20 (depends on 1)

The method of claim 1, wherein the treatment produces at least one therapeutic effect selected from a group consisting of a reduction in size of a tumor, a reduction in number of metastatic lesions over time, a complete response, a partial response, and a stable disease.