# US 12,178,786 B2 · Combination of cellular immunotherapy

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- Number: US 12,178,786 B2
- Document ID: US12178786B2
- Status: Granted
- Kind: B2
- Application number: 16/966,789
- Filed: 2019-02-02
- Published: 2021-04-22
- Granted: 2024-12-31
- Earliest claimed: 2018-02-02
- Assignees: Crage Medical Co., Limited
- Applicants: CRAGE medical Co., Limited
- Inventors: Zonghai Li; Xiuqi Wu
- Web page: https://patentgrep.com/patent/US12178786B2

## CPC

- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/4261: {Proteoglycans, e.g. glypican, brevican or CSPG4}
- A61P 35/00: Antineoplastic agents
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 16/2815: {against CD8}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/303: {Liver or Pancreas}
- A61K 2039/844: {Liver}
- A61K 2239/31: characterized by the route of administration
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/53: Liver
- C07K 2319/03: containing a transmembrane segment
- 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
- 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)

## Abstract

Provided in the present invention is a method for treating tumor. An immune effector cell and a second treatment agent are applied to individual suffering from tumor, wherein the immune effector cell expresses a receptor for recognizing tumor antigen, and wherein the second treatment agent is a compound of formula I or a pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A method for treating a tumor or for reducing the growth, survival or viability of cancer cells, characterized in that an immune effector cell and a second therapeutic agent are administered to a human suffering from a tumor, wherein the immune effector cell expresses a receptor recognizing glypican-3 (GPC3) and the second therapeutic agent comprises a compound of formula II:
wherein the immune effector cell is a T cell,
wherein the receptor comprises a chimeric antigen receptor (CAR),
wherein the chimeric antigen receptor comprises an antibody or a fragment thereof that specifically recognizes a tumor antigen, the transmembrane region of CD28, the co-stimulatory signal domain of CD28, and the intracellular domain of CD3ζ,
wherein the antibody specifically recognizing a tumor antigen comprises HCDR1, HCDR2, HCDR3 respectively represented by SEQ ID NOs: 15, 16, 17, and LCDR1, LCDR2, LCDR3 respectively represented by SEQ ID NOs: 18, 19, 20.

### Claim 2 (depends on 1)

The method according to claim 1, characterized in that the human is not subjected or is subjected to lymphocyte clearance before administering the immune effector cell to the human suffering from a tumor.

### Claim 3 (depends on 1)

The method according to claim 1, characterized in that the second therapeutic agent is administered at a dose of 100-1000 mg per day.

### Claim 4 (depends on 3)

The method according to claim 3, characterized in that the dose of the immune effector cell per administration is about 1×105-1×108 cells/kg subject weight.

### Claim 5 (depends on 1)

The method according to claim 1, characterized in that the immune effector cell and the second therapeutic agent are administered in no particular order.

### Claim 6 (depends on 1)

The method according to claim 1, characterized in that the tumor comprises: breast cancer, glioma, blood cancer, colon cancer, rectal cancer, renal cell carcinoma, liver cancer, lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vagina cancer, vulva cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumor, bladder cancer, renal or ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, a combination of the cancers, and the metastatic foci of the cancer.

### Claim 7

A kit for treating a tumor, characterized in that the kit comprises:
1) an immune effector cell expressing a receptor that recognizes glypican-3 (GPC3),
wherein the immune effector cell is a T cell,
wherein the receptor comprises a chimeric antigen receptor (CAR),
wherein the chimeric antigen receptor comprises an antibody or a fragment thereof that specifically recognizes a tumor antigen, the transmembrane region of CD28, the co-stimulatory signal domain of CD28, and the intracellular domain of CD3ζ,
wherein the antibody specifically recognizing a tumor antigen comprises HCDR1, HCDR2, HCDR3 respectively represented by SEQ ID NOs: 15, 16, 17, and LCDR1, LCDR2, LCDR3 respectively represented by SEQ ID NOs: 18, 19, 20;
2) a second therapeutic agent;
3) a container for containing the above substances of 1) and 2); and
4) instructions for using the kit to treat a tumor in a human;
wherein the immune effector cell and the second therapeutic agent comprises a compound of formula II:

### Claim 8 (depends on 1)

The method according to claim 1, wherein the second therapeutic agent is administered at a dose of 400-800 mg per day.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the second therapeutic agent is administered 1-3 times per day.

### Claim 10 (depends on 1)

The method according to claim 1, characterized in that the immune effector cell is administered during the administration of the second therapeutic agent or the second therapeutic agent is administered orally.

### Claim 11 (depends on 1)

The method according to claim 1, characterized in that the amino acid sequence of the antibody specifically recognizing the tumor antigen has at least 90% identity with the sequence of SEQ ID NO: 14.

### Claim 12 (depends on 1)

The method according to claim 1, characterized in that the amino acid sequence of the chimeric antigen receptor having the antibody that specifically recognizes the tumor antigen has at least 90% identity with the sequence of SEQ ID NO: 22.

### Claim 13 (depends on 2)

The method according to claim 2, characterized in that the lymphatic clearance comprises administering one or more chemotherapeutic agents including cyclophosphamide and/or fludarabine.

### Claim 14 (depends on 1)

The method according to claim 1, characterized in that the immune effector cell is administered about 5×108 cells/subject every time for 2 consecutive days.

### Claim 15 (depends on 1)

The method according to claim 1, characterized in that the immune effector cell is administered twice.

### Claim 16 (depends on 3)

The method according to claim 3, characterized in that the dose of the immune effector cell per administration is about 1×105-1×107 cells/kg subject weight.