# US 11,299,525 B2 · Chimeric antigen receptor-modified immune effector cell carrying PD-L1 blocking agent

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- Number: US 11,299,525 B2
- Document ID: US11299525B2
- Status: Granted
- Kind: B2
- Application number: 15/775,769
- Filed: 2016-10-31
- Published: 2018-11-15
- Granted: 2022-04-12
- Earliest claimed: 2015-11-13
- Assignees: Crage Medical Co., Limited
- Applicants: CRAGE medical Co., Limited
- Inventors: Zonghai Li; Zeyan Pan; Zhimin Shi; Bo Song; Peng Wang
- Web page: https://patentgrep.com/patent/US11299525B2

## CPC

- C07K 14/4747: {Apoptosis related proteins}
- A61K 39/17: Newcastle disease virus
- 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 40/4204: {Epidermal growth factor receptors [EGFR]}
- A61P 35/00: Antineoplastic agents
- C12N 5/0638: {Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]}
- C12N 5/10: Cells modified by introduction of foreign genetic material
- C12N 15/62: DNA sequences coding for fusion proteins
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- 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

Provided is a chimeric antigen receptor-modified immune effector cell carrying a procedural death ligand 1 (PD-L1) blocking agent. Also provided is a method for secreting and expressing a PD-L1 blocking agent using the immune effector cell as a carrier to improve the anti-tumour effect of the chimeric antigen receptor-modified immune effector cell.

## Claims

### Claim 1

An immune effector cell modified to express:
(i) a chimeric antigen receptor (CAR); and
(ii) a PD-L1 blocking agent that is chosen from:
(a) a soluble PD-1;
(b) a fusion peptide of soluble PD-1 and CH3 domain of hIgG4e1-Fc; or
(c) a fusion peptide of soluble PD-1 and hIgG4e1-Fc,
wherein the PD-L1 blocking agent is not a component of the CAR, and
wherein the soluble PD-1 comprises a signal peptide and an extracellular region of PD-1 but does not comprise a transmembrane domain of PD-1.

### Claim 2 (depends on 1)

The immune effector cell according to claim 1, wherein the signal peptide is encoded by the nucleic acid sequence set forth in SEQ ID NO: 1.

### Claim 3 (depends on 1)

The immune effector cell according to claim 1, wherein the CH3 domain of hIgG4e1-Fc is encoded by the nucleotide sequence as shown in SEQ ID NO: 3; and/or the sequence of hIgG4e1-Fc comprises a Ser to Pro mutation at position 288.

### Claim 4 (depends on 1)

The immune effector cell according to claim 1, wherein the CAR comprises an extracellular antigen-binding region, a transmembrane region, and intracellular signaling region, wherein the extracellular antigen-binding region is an antibody that specifically binds to an antigen highly expressed in a tumor.

### Claim 5 (depends on 4)

The immune effector cell according to claim 4, wherein the intracellular signaling region is the sequence of the intracellular signaling region of CD3ζ, FcεRIγ, CD27, CD28, 4-1BB, CD134, CD40; or Myd88; or a combination thereof.

### Claim 6 (depends on 4)

The immune effector cell according to claim 4, wherein the transmembrane region is a CD8 transmembrane region, or a CD28 transmembrane region.

### Claim 7 (depends on 4)

The immune effector cell according to claim 4, wherein the antigen highly expressed in the tumor is: EGFR, GPC3, HER2, EphA2, Claudin18.1, Claudin18.2, Claudin6, GD2, EpCAM, mesothelin, CD19, CD20, ASGPR1, EGFRvIII, de4 EGFR, CD19, CD33, IL13R, LMP1, PLAC1, NY-ESO-1, MAGE4, MUC1, MUC16, LeY, CEA, CAIX, or CD123.

### Claim 8 (depends on 1)

The immune effector cell according to claim 1, wherein the immune effector cell comprises a T lymphocyte, NK cell, NKT cell, or Treg cell.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the immune effector cell of claim 1.

### Claim 10 (depends on 1)

The immune effector cell according to claim 1, wherein the extracellular region of PD-1 is encoded by the nucleotide sequence as shown in SEQ ID NO: 2.

### Claim 11 (depends on 4)

The immune effector cell according to claim 4, wherein the tumor is a tumor expressing PD-L1.