# US 11,897,966 B2 · Mesothelin-targetting antibodies, chimeric antigen receptors, and uses thereof

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- Number: US 11,897,966 B2
- Document ID: US11897966B2
- Status: Granted
- Kind: B2
- Application number: 18/062,084
- Filed: 2022-12-06
- Published: 2023-07-27
- Granted: 2024-02-13
- Earliest claimed: 2021-08-16
- Assignees: Utc Therapeutics (Shanghai) Co., Ltd.
- Applicants: Utc Therapeutics (Shanghai) Co., Ltd.
- Inventors: Yangbing Zhao; Gengzhen Zhu; Xiaojun Liu
- Web page: https://patentgrep.com/patent/US11897966B2

## CPC

- A61P 35/00: Antineoplastic agents
- 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 40/4255: {Mesothelin [MSLN]}
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70517: {CD8}
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 2239/48: Blood cells, e.g. leukemia or lymphoma
- A61K 2239/54: Pancreas
- A61K 2239/55: Lung
- A61K 2239/59: Reproductive system, e.g. uterus, ovaries, cervix or testes
- C07K 2317/21: from primates, e.g. man
- C07K 2317/31: multispecific
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2319/02: containing a signal sequence
- C07K 2319/03: containing a transmembrane segment
- 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)
- 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)

## Abstract

Disclosed herein are anti-mesothelin antibodies and antigen-binding fragments, chimeric antigen receptors (“CARs”) having these anti-mesothelin antibodies and antigen-binding fragments (“mesothelin CARs”) and genetically modified immune effector cells having such mesothelin CARs. Polynucleotides encoding the anti-mesothelin antibodies and antigen-binding fragments and mesothelin CARs are also provided herein. Compositions comprising anti-mesothelin antibodies and antigen-binding fragments and mesothelin CARs are also provided herein. The present disclosure also relates to uses of the anti-mesothelin antibodies and antigen-binding fragments and genetically modified immune effector cells having such mesothelin CARs in cancer treatment.

## Claims

### Claim 1

An antibody or antigen-binding fragment thereof that specifically binds mesothelin and comprises a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2 and a VH CDR3, wherein
(a) the VL CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 1, 2, and 3 respectively; and
(b) the VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 4, 5, and 6 respectively.

### Claim 2 (depends on 1)

The antibody or antigen-binding fragment of claim 1, comprising a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 7 and 8, respectively.

### Claim 3 (depends on 1)

The antibody or antigen-binding fragment of claim 1 that is a monoclonal antibody or antigen-binding fragment.

### Claim 4 (depends on 1)

The antibody or antigen-binding fragment of claim 1 that is selected from the group consisting of an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

### Claim 5 (depends on 1)

The antibody or antigen-binding fragment of claim 1 that is selected from the group consisting of a Fab, a Fab′, a F(ab′)2, a Fv, a scFv, and a (scFv)2.

### Claim 6 (depends on 1)

A Chimeric Antigen Receptor (CAR) that specifically binds mesothelin, comprising, from N-terminus to C-terminus:
(a) a mesothelin-binding domain that comprises the antibody or antigen-binding fragment of claim 1;
(b) a transmembrane domain; and
(c) a cytoplasmic domain.

### Claim 7 (depends on 6)

The CAR of claim 6, wherein the transmembrane domain is derived from CD8, CD28, CD3ζ, CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, TCR α chain, TCR β chain, or TCR ζ chain, CD3ε, CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, or CD154.

### Claim 8 (depends on 6)

The CAR of claim 6, wherein the transmembrane domain comprises CD8 transmembrane region or CD28 transmembrane region.

### Claim 9 (depends on 6)

The CAR of claim 6, wherein the cytoplasmic domain comprises a signaling domain derived from CD3ζ, FcRγ, FcγRIIa, FcRβ, CD3γ, CD3δ, CD3ε, CD5, CD22, CD79a, CD79b, DAP10, DAP12, or any combination thereof.

### Claim 10 (depends on 6)

The CAR of claim 6, wherein the cytoplasmic domain further comprises a co-stimulatory domain derived from CD28, 4-1BB (CD137), OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, GITR, TLR, DR3, CD43, or any combination thereof.

### Claim 11 (depends on 6)

The CAR of claim 6, wherein the cytoplasmic domain comprises a CD3ζ signaling domain and a 4-1BB co-stimulatory domain, or the cytoplasmic domain comprises a CD3ζ signaling domain and a CD28 co-stimulatory domain.

### Claim 12 (depends on 6)

The CAR of claim 6, further comprising a CD8 hinge between the antibody or antigen-binding fragment and the transmembrane domain.

### Claim 13 (depends on 6)

The CAR of claim 6, having the amino acid sequence of SEQ ID NO: 12.

### Claim 14 (depends on 6)

A cell expressing the CAR of claim 6.

### Claim 15 (depends on 14)

The cell of claim 14 that is an immune effector cell.

### Claim 16 (depends on 14)

The cell of claim 14 that is derived from a cell isolated from peripheral blood or bone marrow.

### Claim 17 (depends on 14)

The cell of claim 14 that is derived from a cell differentiated in vitro from a stem or progenitor cell is selected from the group consisting of a T cell progenitor cell, a hematopoietic stem and progenitor cell, a hematopoietic multipotent progenitor cell, an embryonic stem cell, and an induced pluripotent cell.

### Claim 18 (depends on 14)

The cell of claim 14, which is a T cell or a NK cell.

### Claim 19 (depends on 18)

The cell of claim 18 that is a cytotoxic T cell, a helper T cell, a gamma delta T, a CD4+/CD8+ double positive T cell, a CD4+ T cell, a CD8+ T cell, a CD4/CD8 double negative T cell, a CD3+ T cell, a naive T cell, an effector T cell, a helper T cell, a memory T cell, a regulator T cell, a Th0 cell, a Th1 cell, a Th2 cell, a Th3 (Treg) cell, a Th9 cell, a Th17 cell, a Thαβ helper cell, a Tfh cell, a stem memory TSCM cell, a central memory TCM cell, an effector memory TEM cell, or an effector memory TEMRA cell.

### Claim 20 (depends on 1)

A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of claim 1.

### Claim 21 (depends on 14)

A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the cell of claim 14.

### Claim 22 (depends on 20)

The method of claim 20, further comprising Obtaining cells from the subject.

### Claim 23 (depends on 20)

The method of claim 20, further comprising administering an additional therapy to the subject.

### Claim 24 (depends on 20)

The method of claim 20, wherein the subject is a human.

### Claim 25 (depends on 20)

The method of claim 20, wherein the cancer is a mesothelin-expressing cancer.

### Claim 26 (depends on 20)

The method of claim 20, wherein the cancer is a solid tumor or a hematological cancer.

### Claim 27 (depends on 20)

The method of claim 20, wherein the cancer is mesothelioma, pancreatic cancer and/or ovarian cancer.

### Claim 28 (depends on 27)

The method of claim 27, wherein the mesothelioma is pleural mesothelioma, peritoneal mesothelioma, or pericardial mesothelioma; the pancreatic cancer is pancreatic ductal carcinoma; and/or the ovarian cancer is ovarian epithelial carcinoma.