# US 10,865,382 B2 · Reducing immune tolerance induced by PD-L1

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- Number: US 10,865,382 B2
- Document ID: US10865382B2
- Status: Granted
- Kind: B2
- Application number: 16/404,349
- Filed: 2019-05-06
- Published: 2019-10-17
- Granted: 2020-12-15
- Earliest claimed: 2015-03-02
- Assignees: Innovative Cellular Therapeutics, Inc.
- Applicants: Innovative Cellular Therapeutics Co., Ltd.
- Inventors: Zhao Wu
- Web page: https://patentgrep.com/patent/US10865382B2

## CPC

- C07K 16/30: from tumour cells
- 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}
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/70503: {Immunoglobulin superfamily}
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70521: {CD28, CD152}
- C07K 16/2803: {against the immunoglobulin superfamily}
- C12N 5/0636: {T lymphocytes}
- C12N 5/0638: {Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]}
- C07K 2319/00: Fusion polypeptide
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C12N 2510/02: Cells for production
- 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 reducing immune tolerance associated with CAR T cell therapy. Embodiments of the present disclosure include isolated nucleic acid sequence comprising a nucleic acid sequence that encodes modified programmed cell death protein 1 (PD-1) and a nucleic acid sequence that encodes chimeric antigen receptor (CAR).

## Claims

### Claim 1

A pharmaceutical composition comprising an antitumor effective amount of a population of human T cells, wherein the human T cells of the population include human T cells that comprise an isolated nucleic acid sequence comprising a nucleic acid sequence that encodes modified programmed cell death protein 1 (PD-1) and a nucleic acid sequence that encodes chimeric antigen receptor (CAR), wherein the modified PD-1 comprises amino acid sequence SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 12, or SEQ ID NO: 14, wherein the modified PD-1 and the CAR are expressed as gene products that are separate polypeptides; and wherein the modified PD-1 is a dominant negative PD-1.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein an inhibitory effect of PD-L1 on cytokine production of the human T cells of the population is less than an inhibitory effect of PD-L1 on cytokine production of human T cells that do not comprise at least a part of the nucleic acid sequence that encodes the modified PD-1.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the CAR is specific for a tumor antigen that is present on a cancer cell, and wherein the cancer cell or a cell associated with the cancer cell expresses PD-LI.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3, wherein the tumor antigen comprises CD19.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the nucleic acid sequence that encodes the modified PD-1 comprises substitution or deletion of one or more nucleotides as compared to a nucleic acid sequence encoding an intracellular part of wild-type PD-1.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the nucleic acid sequence that encodes the modified PD-1 comprises deletion of multiple nucleotides as compared to a nucleic acid sequence encoding an intracellular part of wild-type PD-1.

### Claim 7 (depends on 5)

The pharmaceutical composition of claim 5, wherein the nucleic acid sequence that encodes the modified PD-1 comprises a nucleic acid encoding a truncated PD-1 that does not include an intracellular domain.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the modified PD-1 comprises one or more point mutations as compared to wild-type PD-1.

### Claim 9 (depends on 8)

The pharmaceutical composition of claim 8, wherein the one or more point mutations comprise one or two amino acid point mutations of phosphorylation sites of wild-type PD-1.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the modified PD-1 comprises a mutation of Tyrosine residue 223 and/or a mutation of Tyrosine residue 248 as compared to wildtype PD-1.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein the modified PD-1 comprises amino acid sequence SEQ ID NO: 13.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1 for use in the treatment of cancer.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein the nucleic acid sequence encoding modified PD-1 comprises SEQ ID NO: 4.

### Claim 14 (depends on 10)

The pharmaceutical composition of claim 10, wherein the modified PD-1 comprises a mutation of Tyrosine residue 223.

### Claim 15 (depends on 10)

The pharmaceutical composition of claim 10, wherein the modified PD-1 comprises a mutation of Tyrosine residue 248.

### Claim 16 (depends on 10)

The pharmaceutical composition of claim 10, wherein the modified PD-1 comprises a mutation of Tyrosine residue 223 or a mutation of Tyrosine residue 248.

### Claim 17

A pharmaceutical composition comprising an antitumor effective amount of a population of human T cells, wherein the human T cells of the population include human T cells that comprise an isolated nucleic acid sequence comprising a nucleic acid sequence that encodes modified programmed cell death protein 1 (PD-1) and a nucleic acid sequence that encodes chimeric antigen receptor (CAR), wherein the modified PD-1 comprises amino acid sequence SEQ ID NO: 9, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 14 and inhibits activities of the wild-type PD-1 on the human T cells induced by PD-L1 of a tumor cell.

### Claim 18 (depends on 1)

The pharmaceutical composition of claim 1, wherein the modified PD-1 comprises amino acid sequence SEQ ID NO: 9.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1, wherein the modified PD-1 comprising amino acid sequence SEQ ID NO: 12.

### Claim 20 (depends on 1)

The pharmaceutical composition of claim 1, wherein the modified PD-1 comprising amino acid sequence SEQ ID NO: 14.