# US 10,869,888 B2 · Modified cell expansion and uses thereof

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- Number: US 10,869,888 B2
- Document ID: US10869888B2
- Status: Granted
- Kind: B2
- Application number: 16/387,166
- Filed: 2019-04-17
- Published: 2019-10-17
- Granted: 2020-12-22
- Earliest claimed: 2018-04-17
- Assignees: Innovative Cellular Therapeutics, Inc.
- Applicants: Innovative Cellular Therapeutics Co., Ltd.
- Inventors: Lei Xiao; Zhiyuan Cao; Chengfei Pu
- Web page: https://patentgrep.com/patent/US10869888B2

## CPC

- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 38/191: {Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta}
- A61K 38/204: {IL-6}
- A61K 38/208: {IL-12}
- 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 40/4211: {CD19 or B4}
- A61K 40/4257: {Mucins, e.g. MUC-1}
- A61P 35/00: Antineoplastic agents
- C07K 14/82: Translation products from oncogenes
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/3092: {against tumour-associated mucins}
- C12N 15/86: Viral vectors
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C12N 2740/16043: viral genome or elements thereof as genetic vector
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present disclosure relates to compositions and methods for enhancing T cell response and/or CAR cell expansion and/or maintenance in vivo and/or in vitro. For example, a method of enhancing T cell-based therapy comprises administering genetically modified T cells comprising a first chimeric antigen receptor (CAR) and a second CAR, wherein a binding domain of the first CAR binds a first antigen, and a binding domain of the second CAR binds a second antigen. The first antigen is different from the second antigen. In embodiments, the first CAR binds a surface molecule or antigen of a white blood cell.

## Claims

### Claim 1

A method of enhancing expansion of cells in a subject, the method comprising:
administering an effective amount of a composition to the subject having a form of cancer expressing a tumor antigen, wherein the composition comprises a first population of cells comprising a first chimeric antigen receptor (CAR) binding a first antigen, and a second population of cells comprising a second CAR binding a second antigen, the first and second population of cells comprising T cells, the first and second CAR comprising an antigen binding domain, a transmembrane domain, a costimulatory domain, and a CD3 zeta domain, and the first antigen comprising CD19 or BCMA and the second antigen comprising a solid tumor antigen; and
allowing the first and second population of cells to expand, wherein expansion of the second population of cells in the subject is enhanced as compared to a subject administered a composition comprising the second population of cells without the first population of cells.

### Claim 2 (depends on 1)

The method of claim 1, wherein the solid tumor antigen is tMUC 1, PRLR, CLCA1, MUC12, GUCY2C, GPR35, CR1L, MUC 17, TMPRSS11B, MUC21, TMPRSS11E, CD207, SLC30A8, CFC1, SLC12A3, SSTR1, GPR27, FZD10, TSHR, SIGLEC15, SLC6A3, KISS1R, QRFPR, GPR119, CLDN6, UPK2, ADAM12, SLC45A3, ACPP, MUC21, MUC16, MS4A12, ALPP, CEA, EphA2, FAP, GPC3, IL13-Rα2, Mesothelin, PSMA, ROR1, VEGFR-II, GD2, FR-α, ErbB2, EpCAM, EGFRvIII, B7-H3, or EGFR.

### Claim 3 (depends on 2)

The method of claim 2, wherein the solid tumor antigen comprises tumor associated tMUC1.

### Claim 4 (depends on 1)

The method of claim 1, wherein the co-stimulatory domain comprises the intracellular domain of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that binds CD83, or a combination thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the first CAR comprises a scFv binding CD19, an intracellular domain of 4-1BB or CD28, and a CD3 zeta domain, and the second CAR comprises a scFv binding tMUC1, an intracellular domain of 4-1BB or CD28, and a CD3 zeta domain.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5 or 6 and the antigen binding domain of the second CAR comprises amino acid sequence SEQ ID NO: 8, 11, 70, or 439.

### Claim 7 (depends on 1)

The method of claim 1, wherein the second population of cells comprises a lentiviral vector encoding the second CAR and a dominant negative form of PD-1.

### Claim 8 (depends on 1)

The method of claim 1, wherein the first population of cells comprises a lentiviral vector encoding the first CAR and a therapeutic agent.

### Claim 9 (depends on 8)

The method of claim 8, wherein the therapeutic agent comprises a cytokine.

### Claim 10 (depends on 9)

The method of claim 9, wherein the cytokine is IL6 and/or IFN-γ.

### Claim 11 (depends on 9)

The method of claim 9, wherein the cytokine is at least one of IL6, IL12, TNF-α, or IFN-γ.

### Claim 12 (depends on 1)

The method of claim 1, wherein the method further comprises treating the subject having solid tumor cancer.

### Claim 13 (depends on 12)

The method of claim 12, wherein the solid tumor cancer is cholangiocarcinoma, pancreatic cancer, breast cancer, colorectal cancer, thyroid cancer, or prostate cancer.

### Claim 14 (depends on 1)

The method of claim 1, wherein the solid tumor antigen is tMUC1.

### Claim 15 (depends on 1)

The method of claim 1, wherein the solid tumor antigen is GUCY2C.

### Claim 16 (depends on 1)

The method of claim 1, wherein the solid tumor antigen is TSHR.

### Claim 17 (depends on 1)

The method of claim 1, wherein the solid tumor is CLND18.2.

### Claim 18 (depends on 1)

The method of claim 1, wherein the solid tumor antigen is ACPP.

### Claim 19 (depends on 1)

The method of claim 1, wherein the first CAR comprises amino acid sequence SEQ ID NO: 5.

### Claim 20 (depends on 1)

The method of claim 1, wherein the first CAR comprises amino acid sequence encoded by nucleic acid sequence SEQ ID NO: 28.

### Claim 21 (depends on 1)

The method of claim 1, wherein the second CAR comprises amino acid sequence SEQ ID NO: 8.

### Claim 22 (depends on 1)

The method of claim 1, wherein the first CAR comprises amino acid sequence encoded by nucleic acid sequence SEQ ID NO: 279.

### Claim 23 (depends on 1)

The method of claim 1, wherein the second CAR comprises amino acid sequence SEQ ID NO: 11.

### Claim 24 (depends on 1)

The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the solid tumor antigen comprises GUCY2C.

### Claim 25 (depends on 1)

The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the solid tumor antigen comprises TSHR.

### Claim 26 (depends on 1)

The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the solid tumor antigen comprises ACPP.

### Claim 27 (depends on 1)

The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the antigen binding domain of the second CAR comprises amino acid sequence SEQ ID NO: 11.

### Claim 28 (depends on 1)

The method of claim 1, wherein the antigen binding domain of the first CAR comprises amino acid sequence SEQ ID NO: 5, and the antigen binding domain of the second CAR comprises amino acid sequence SEQ ID NO: 8.