# US 11,111,295 B2 · Antibody for anti-claudin 18A2 and use thereof

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- Number: US 11,111,295 B2
- Document ID: US11111295B2
- Status: Granted
- Kind: B2
- Application number: 16/316,331
- Filed: 2017-07-10
- Published: 2019-08-01
- Granted: 2021-09-07
- Earliest claimed: 2016-07-08
- Assignees: Cafa Therapeutics Limited
- Applicants: Cafa Therapeutics Limited
- Inventors: Peng Wang; Hua Jiang; Linlin Yang; Zhimin Shi; Huamao Wang; Zonghai Li
- Web page: https://patentgrep.com/patent/US11111295B2

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/282: Platinum compounds
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7115: Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/15: Natural-killer [NK] cells; Natural-killer T [NKT] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/4202: {Receptors, cell surface antigens or cell surface determinants}
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- C12N 5/0634: {Cells from the blood or the immune system}
- C12N 5/10: Cells modified by introduction of foreign genetic material
- C12N 15/85: for animal cells
- A61K 2239/38: characterised by the dose, timing or administration schedule
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 2319/00: Fusion polypeptide
- C07K 2319/03: containing a transmembrane segment
- 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 in the present invention is an antibody for anti-claudin 18A2 and an immune effector cell targeting claudin 18A2. Also provided are methods for inducing cell death and treating tumours.

## Claims

### Claim 1

An antibody or antigen binding unit thereof that specifically binds to claudin 18A2, wherein,
(a) HCDR1 is SEQ ID NO:31, HCDR2 is SEQ ID NO:32, HCDR3 is SEQ ID NO:33, LCDR1 is SEQ ID NO:34, LCDR2 is SEQ ID NO:35, and LCDR3 is SEQ ID NO:36;
(b) HCDR1 is SEQ ID NO:37, HCDR2 is SEQ ID NO:38, HCDR3 is SEQ ID NO:39, LCDR1 is SEQ ID NO: 40, LCDR2 is SEQ ID NO: 41, and LCDR3 is SEQ ID NO:42;
(c) HCDR1 is SEQ ID NO:43, HCDR2 is SEQ ID NO:44, HCDR3 is SEQ ID NO:45, LCDR1 is SEQ ID NO:46, LCDR2 is SEQ ID NO:47, and LCDR3 is SEQ ID NO:48;
(d) HCDR1 is SEQ ID NO:49, HCDR2 is SEQ ID NO:50, HCDR3 is SEQ ID NO:51, LCDR1 is SEQ ID NO:52, LCDR2 is SEQ ID NO:53, and LCDR3 is SEQ ID NO:54;
(e) HCDR1 is SEQ ID NO:31, HCDR2 is SEQ ID NO:83, HCDR3 is SEQ ID NO:33, LCDR1 is SEQ ID NO:34, LCDR2 is SEQ ID NO:35, and LCDR3 is SEQ ID NO:36;
(f) HCDR1 is SEQ ID NO:31, HCDR2 is SEQ ID NO:84, HCDR3 is SEQ ID NO:33, LCDR1 is SEQ ID NO:34, LCDR2 is SEQ ID NO:35, and LCDR3 is SEQ ID NO: 36; or
(g) HCDR1 is SEQ ID NO:49, HCDR2 is SEQ ID NO:85, HCDR3 is SEQ ID NO:51, LCDR1 is SEQ ID NO:52, LCDR2 is SEQ ID NO:53, and LCDR3 is SEQ ID NO: 54.

### Claim 2 (depends on 1)

The antibody or antigen binding unit of claim 1, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein
VH comprises an amino acid sequence of SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:11, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:23, SEQ ID NO:27 or SEQ ID NO:29; and
VL comprises an amino acid sequence of SEQ ID NO:1, SEQ ID NO:5, SEQ ID NO:9, SEQ ID NO:13, SEQ ID NO:21 or SEQ ID NO:25.

### Claim 3 (depends on 2)

The antibody or antigen binding unit of claim 2, wherein:
(a) VH comprises an amino acid sequence of SEQ ID NO:3 and VL comprises an amino acid sequence of SEQ ID NO:1;
(b) VH comprises an amino acid sequence of SEQ ID NO:7 and VL comprises an amino acid sequence of SEQ ID NO:5;
(c) VH comprises an amino acid sequence of SEQ ID NO:11 and VL comprises an amino acid sequence of SEQ ID NO:9;
(d) VH comprises an amino acid sequence of SEQ ID NO:15 and VL comprises an amino acid sequence of SEQ ID NO:13;
(e) VH comprises an amino acid sequence of SEQ ID NO:17 and VL comprises an amino acid sequence of SEQ ID NO:1;
(f) VH comprises an amino acid sequence of SEQ ID NO:19 and VL comprises an amino acid sequence of SEQ ID NO:1;
(g) VH comprises an amino acid sequence of SEQ ID NO:23 and VL comprises an amino acid sequence of SEQ ID NO:21;
(h) VH comprises an amino acid sequence of SEQ ID NO:27 and VL comprises an amino acid sequence of SEQ ID NO:25; or
(i) VH comprises an amino acid sequence of SEQ ID NO:29 and VL comprises an amino acid sequence of SEQ ID NO:25.

### Claim 4 (depends on 1)

The antibody or antigen binding unit of claim 1, which is a humanized antibody, a chimeric antibody, a fully humanized antibody, a monoclonal antibody, a single chain antibody, a multivalent antibody, a chimeric antigen receptor, an scFv, an Fv, a Fab, or a F(ab′)2.

### Claim 5 (depends on 1)

The antibody of claim 1, having
(a) a heavy chain comprising an amino acid sequence of SEQ ID NO:63 and a light chain comprising an amino acid sequence of SEQ ID NO:65;
(b) a heavy chain comprising an amino acid sequence of SEQ ID NO:59 and a light chain comprising an amino acid sequence of SEQ ID NO:61; or
(c) a heavy chain comprising an amino acid sequence of SEQ ID NO:67 and a light chain comprising an amino acid sequence of SEQ ID NO:65.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising the antibody or antigen binding unit of claim 1, and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1)

A nucleic acid encoding the antibody or antigen binding fragment of claim 1.

### Claim 8 (depends on 7)

An expression vector comprising the nucleic acid of claim 7.

### Claim 9 (depends on 8)

A host cell comprising the expression vector of claim 8.

### Claim 10 (depends on 9)

A method for producing an antibody or antigen binding unit that specifically binds to claudin 18A2, comprising culturing the host cell of claim 9 under suitable conditions, and obtaining the product expressed by the host cell.

### Claim 11 (depends on 1)

A method for preparing an anti-claudin 18A2 targeting drug, an anti-claudin 18A2 antibody-drug conjugate, a multifunctional anti-claudin 18A2 antibody, a reagent for diagnosing a tumor expressing claudin 18A2, or an anti claudin 18A2 chimeric antigen receptor modified immune cell, wherein the method comprises providing the antibody or antigen binding unit of claim 1 and incorporating said antibody or antigen binding unit into the claudin 18A2 targeting drug, the anti-claudin 18A2 antibody-drug conjugate, the multifunctional anti-claudin 18A2 antibody, the reagent for diagnosing a tumor expressing claudin 18A2, or the anti claudin 18A2 chimeric antigen receptor modified immune cell.

### Claim 12 (depends on 1)

A chimeric antigen receptor comprising the following sequentially linked components: the antibody or antigen binding unit of claim 1, a transmembrane region, and an intracellular signal region.

### Claim 13 (depends on 12)

The chimeric antigen receptor of claim 12, wherein the intracellular signal region is selected from: an intracellular signal region sequence of CD3ζ, FcεRIγ, CD27, CD28, CD137, CD134, MyD88, CD40, and combinations thereof; and/or the transmembrane region comprises a transmembrane region of CD8 or CD28.

### Claim 14 (depends on 12)

A nucleic acid encoding the chimeric antigen receptor of claim 12.

### Claim 15 (depends on 14)

An expression vector comprising the nucleic acid of claim 14.

### Claim 16 (depends on 15)

A virus comprising the vector of claim 15.

### Claim 17 (depends on 12)

A chimeric antigen receptor-modified immune cell having the chimeric antigen receptor of claim 12 expressed on the surface.

### Claim 18 (depends on 17)

The chimeric antigen receptor-modified immune cell of claim 17, wherein the immune cell is selected from a T lymphocyte, a NK cell, and a NKT lymphocyte.

### Claim 19 (depends on 18)

The chimeric antigen receptor-modified immune cell of claim 18, further comprising:
(a) an encoding sequence for an exogenous cytokine;
(b) another expressed chimeric antigen receptor which does not contain CD3ζ but contains an intracellular signal domain of CD28, an intracellular signal domain of CD137, or a combination of the both;
(c) an expressed chemokine receptor;
(d) an expressed siRNA which can reduce expression of PD-1;
(e) an expressed protein which can block PD-L1;
(f) a knock-out of endogenous PD-1 in the immune cell by gene editing techniques;
(g) an expressed safety switch; or
(h) an expressed Type I interferon.

### Claim 20 (depends on 1)

A multifunctional immunoconjugate comprising:
an antibody or antigen binding unit of claim 1; and
a functional molecule linked thereto, wherein the functional molecule is selected from a molecule targeting a surface marker on a tumor, a tumor-inhibiting molecule, a molecule targeting a surface marker of an immune cell, and a detectable label.

### Claim 21 (depends on 20)

The multifunctional immunoconjugate of claim 20, which is bifunctional and wherein the function molecule is a molecule targeting-a surface marker of an immune cell that is a T cell.

### Claim 22 (depends on 20)

A nucleic acid encoding the multifunctional immunoconjugate of claim 20.

### Claim 23 (depends on 1)

A kit comprising:
a container, and
the antibody or antigen binding unit of claim 1.

### Claim 24 (depends on 6)

The composition of claim 6, further comprising a Type I interferon.

### Claim 25 (depends on 1)

A method for inducing the death of a cell comprising a claudin 18A2 peptide, comprising contacting the cell with the antibody or antigen binding unit of claim 1.

### Claim 26 (depends on 1)

A method for treating a tumor in an individual in need thereof, comprising administering to the individual an effective amount of the antibody or antigen binding unit of claim 1.

### Claim 27 (depends on 26)

The method of claim 26, wherein the tumor is a solid tumor.

### Claim 28 (depends on 26)

The method of claim 26, wherein the tumor is associated with gastric cancer, esophageal cancer, intestinal cancer, pancreatic cancer, nephroblastoma, lung cancer, ovarian cancer, colon cancer, rectal cancer, liver cancer, head and neck cancer, chronic myelogenous leukemia, or gallbladder cancer.

### Claim 29 (depends on 26)

The method of claim 26, further comprising administering to the individual an additional therapeutic agent selected from epirubicin, oxaliplatin, and 5-fluorouracil.