# US 2021/0275589 A1 · Co-receptor systems for treating infectious diseases

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- Number: US 2021/0275589 A1
- Document ID: US20210275589A1
- Status: Published application
- Kind: A1
- Application number: 17/258,245
- Filed: 2019-07-12
- Published: 2021-09-09
- Earliest claimed: 2018-07-13
- Applicants: Nanjing Legend Biotech Co. Ltd.
- Inventors: Ming Zeng; Lu Chen; Shu Wu; Lili Chen; Xun Liu
- Web page: https://patentgrep.com/patent/US20210275589A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 16/2812: {against CD4}
- 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 40/4224: {Molecules with a "CD" designation not provided for elsewhere}
- A61K 40/4236: {Chemokines}
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 14/70521: {CD28, CD152}
- C07K 14/7158: {for chemokines}
- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- C12N 5/0636: {T lymphocytes}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- C12N 2510/00: Genetically modified cells
- C12N 2740/16043: viral genome or elements thereof as genetic vector
- 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)
- 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)
- 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

Immune cells (such as T cells) comprising a chimeric receptor (CR), a chimeric co-receptor (CCOR), and/or a co-receptor (COR) are provided.

## Claims

### Claim 1

An engineered immune cell comprising:
a) a chimeric receptor (CR) comprising: i) a CR antigen binding domain specifically recognizing a CR target antigen; ii) a CR transmembrane domain, and iii) an intracellular CR signaling domain; and
b) a chimeric co-receptor (CCOR) comprising: i) a CCOR antigen binding domain specifically recognizing a CCOR target antigen; ii) a CCOR transmembrane domain; and iii) an intracellular CCOR co-stimulatory domain,
wherein the CR target antigen is CCR5 or CXCR4 and the CCOR target antigen is CD4, or wherein the CR target antigen is CD4 and the CCOR target antigen is CCR5 or CXCR4.

### Claim 2

An engineered immune cell comprising:
a chimeric receptor (CR) comprising: i) a CR antigen binding domain specifically recognizing a CR target antigen; ii) a CR transmembrane domain, and iii) an intracellular CR signaling domain,
wherein the CR target antigen is selected from the group consisting of CCR5, CXCR4 and CD4.

### Claim 3 (depends on 1, 2)

The engineered immune cell of claim 1 or 2, wherein the CCR5, CXCR4 or CD4 is in tandem with a broadly neutralizing antibody.

### Claim 4 (depends on 3)

The engineered immune cell of claim 3, the broadly neutralizing antibody is VRC01, PGT121, 3BNC117 or 10-1074.

### Claim 5 (depends on 1, 2, 3, 4)

The engineered immune cell of any one of claims 1-4, further comprising one or more co-receptors (“COR”).

### Claim 6

An engineered immune cell comprising:
a) a first nucleic acid encoding a chimeric receptor (CR), wherein the CR comprises: i) a CR antigen binding domain specifically recognizing a CR target antigen; ii) a CR transmembrane domain, and iii) an intracellular CR signaling domain; and
b) second nucleic acid encoding a chimeric co-receptor (CCOR), wherein the CCOR comprises: i) a CCOR antigen binding domain specifically recognizing a CCOR target antigen; ii) a CCOR transmembrane domain; and iii) an intracellular CCOR co-stimulatory signaling domain;
wherein the CR target antigen is CCR5 or CXCR4 and the CCOR target antigen is CD4, or wherein the CR target antigen is CD4 and the CCOR target antigen is CCR5 or CXCR4.

### Claim 7

An engineered immune cell comprising:
a nucleic acid encoding a chimeric receptor (CR), wherein the CR comprises: i) a CR antigen binding domain specifically recognizing a CR target antigen; ii) a CR transmembrane domain, and iii) an intracellular CR signaling domain,
wherein the CR target antigen is selected from the group consisting of CCR5, CXCR4 and CD4.

### Claim 8 (depends on 6, 7)

The engineered immune cell of claim 6 or claim 7, wherein the CCR5, CXCR4 or CD4 is in tandem with a broadly neutralizing antibody.

### Claim 9 (depends on 8)

The engineered immune cell of claim 8, the broadly neutralizing antibody is VRC01, PGT121, 3BNC117, 10-1074.

### Claim 10 (depends on 6, 7, 8, 9)

The engineered immune cell of claim 6-9, further comprising one or more nucleic acid(s) encoding one or more co-receptors (“COR”).

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The engineered immune cell of any one of claims 1-10, wherein the CR is a chimeric antigen receptor (“CAR”).

### Claim 12 (depends on 11)

The engineered immune cell of claim 11, wherein the CR transmembrane is derived from CD8α.

### Claim 13 (depends on 11)

The engineered immune cell of claim 11, wherein the intracellular CR signaling domain is derived from CD3ζ.

### Claim 14 (depends on 11, 12, 13)

The engineered immune cell of any one of claims 11-13, wherein the CR further comprises an intracellular CR co-stimulatory domain.

### Claim 15 (depends on 14)

The engineered immune cell of claim 14, wherein the intracellular CR co-stimulatory signaling domain comprises a cytoplasmic domain of 4-1-BB.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The engineered immune cell of any one of claims 1-10, wherein the CR does not comprise an intracellular co-stimulatory domain.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The engineered immune cell of any one of claims 1-10, wherein the CR is a chimeric T cell receptor (“cTCR”).

### Claim 18 (depends on 17)

The engineered immune cell of claim 17, wherein the CR transmembrane domain is derived from the transmembrane domain of a TCR subunit selected from the group consisting of TCRα, TCRβ, TCRγ, TCRδ, CD3γ, CD3ε, and CD3δ.

### Claim 19 (depends on 18)

The engineered immune cell of claim 18, wherein the CR transmembrane domain is derived from the transmembrane domain of CD3ε.

### Claim 20 (depends on 17, 18, 19)

The engineered immune cell of any one of claims 17-19, wherein the intracellular CR signaling domain is derived from the intracellular signaling domain of a TCR subunit selected from the group consisting of TCRα, TCRβ, TCRγ, TCRδ, CD3γ, CD3ε, and CD3δ.

### Claim 21 (depends on 20)

The engineered immune cell of claim 20, wherein the intracellular CR signaling domain is derived from the intracellular signaling domain of CD3ε.

### Claim 22 (depends on 17, 18, 19, 20, 21)

The engineered immune cell of any one of claims 17-21, wherein the CR transmembrane domain and intracellular CR signaling domain are derived from the same or different TCR subunit(s).

### Claim 23 (depends on 17, 18, 19, 20, 21, 22)

The engineered immune cell of any one of claims 17-22, wherein the CR further comprises a portion of an extracellular domain of a TCR subunit.

### Claim 24 (depends on 17, 18, 19, 20, 21, 22, 23)

The engineered immune cell of any one of claims 17-23, wherein the CR comprises the CR antigen binding domain fused to the N-terminus of CD3ε.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The engineered immune cell of any one of claims 1-24, wherein the CR target antigen is CD4.

### Claim 26 (depends on 1, 5, 6)

The engineered immune cell of any one of claims 1, 5, 6, and 10-25, wherein the CCOR target antigen is CD4.

### Claim 27 (depends on 1, 5, 6)

The engineered immune cell of any one of claims 1, 5, 6, and 10-24 and 26, wherein the CR target antigen is CCR5 or CXCR4 and the CCOR target antigen is CD4.

### Claim 28 (depends on 1, 5, 6)

The engineered immune cell of any one of claims 1, 5, 6, and 10-25, wherein the CR target antigen is CD4 and the CCOR target antigen is CCR5 or CXCR4.

### Claim 29 (depends on 25, 26, 27, 28)

The engineered immune cell of claim 25-28, wherein the CR antigen binding domain or the CCOR antigen binding domain specifically recognizes domain 1 of CD4 (CD4 D1).

### Claim 30 (depends on 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The engineered immune cell of any one of claims 5 and 10-29, wherein the one or more COR is selected from the group consisting of CXCR5, α4β7, and CCR9.

### Claim 31 (depends on 30)

The engineered immune cell of claim 30, wherein the one or more COR comprises both α4β7 and CCR9.

### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The engineered immune cell of any one of claims 1-31, wherein the engineered immune cell is modified to reduce or eliminate expression of CCR5 within the cell.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The engineered immune cell of any one of claims 1-32, wherein the engineered immune cell is modified to express an anti-HIV antibody.

### Claim 34 (depends on 33)

The engineered immune cell of claim 33, wherein the anti-HIV antibody is a broadly neutralizing antibody.

### Claim 35 (depends on 34)

The engineered immune cell of claim 34, wherein the broadly neutralizing antibody is VRC01, PGT121, 3BNC117 10-1074.

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The engineered immune cell of any one of claims 1-35, wherein the CR antigen binding domain is scFv or sdAb.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)

The engineered immune cell of any one of claims 1-36, wherein the CCOR antigen binding domain is scFv or sdAb.

### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

The engineered immune cell of any one of claims 1-37, wherein the engineered immune cell is selected from the group consisting of a cytotoxic T cell, a helper T cell, a natural killer cell, a γδT cell and a natural killer T cell.

### Claim 39 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

A pharmaceutical composition comprising the engineered immune cell of any one of claims 1-37 and a pharmaceutically acceptable carrier.

### Claim 40 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)

The pharmaceutical composition of claim 39, wherein the pharmaceutical composition comprises at least two different types of engineered immune cells according to any one of claims 1-38.

### Claim 41 (depends on 39, 40)

A method of treating an infectious disease in an individual, comprising administering to the individual an effective amount of a pharmaceutical composition of claim 39 or 40.

### Claim 42 (depends on 41)

The method of claim 41, wherein the infectious disease is an infection by a virus selected from the group consisting of HIV and HTLV.

### Claim 43 (depends on 42)

The method of claim 42, wherein the infectious disease is HIV.

### Claim 44 (depends on 41, 42, 43)

The method of claim 41-43, further comprising administering to the individual a second anti-infectious agent.

### Claim 45 (depends on 39, 40)

A method of treating a cancer in an individual, comprising administering to the individual an effective amount of a pharmaceutical composition of claim 39 or 40.

### Claim 46 (depends on 45)

The method of claim 45, wherein the cancer is T cell lymphoma.

### Claim 47 (depends on 45, 46)

The method of claim 45 or 46, further comprising administering to the individual a second anti-cancer agent.

### Claim 48 (depends on 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 41-47, wherein the individual is a human.

### Claim 49 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)

A method of making an engineered immune cell of any one of claims 1-38, comprising:
a) providing a population of immune cells;
b) introducing into the population of immune cells a first nucleic acid encoding the CR.

### Claim 50

The method of claim49, further comprising:
c) introducing into the population of immune cells a second nucleic acid encoding the CCOR.

### Claim 51

The method of claim50, further comprising introducing into the population of immune cells one or more nucleic acids encoding one or more CORs.

### Claim 52 (depends on 49, 50, 51)

The method of any one of claims 49-51, wherein the first nucleic acid, the second nucleic acid, and/or the COR encoding nucleic acids are introduced into the cell via a viral vector.

### Claim 53 (depends on 49, 50, 51, 52)

The method of any one of claims 49-52, further comprising introducing into the population of immune cells a nucleic acid encoding a broadly neutralizing antibody (bNAb) or a HIV fusion inhibition peptide

### Claim 54 (depends on 49, 50, 51, 52, 53)

The method of any one of claims 49-53, further comprising inactivating the CCR5 gene in the cell.

### Claim 55 (depends on 54)

The method of claim 54, wherein the CCR5 gene is inactivated by using the method selected from the group consisting of: CRISPR/Cas9, TALEN, ZFN, siRNA, and antisense RNA.

### Claim 56 (depends on 49, 50, 51, 52, 53, 54, 55)

The method of any one of claims 49-55, further comprising obtaining the population of immune cells from the peripheral blood of an individual.

### Claim 57 (depends on 56)

The method of claim 56, wherein the population of immune cells are further enriched for CD4+ cells.

### Claim 58 (depends on 56, 57)

The method of claim 56 or 57, wherein the population of immune cells are further enriched for CD8+ cells.