# US 2020/0399364 A1 · Anti-claudin 18.2 antibodies and uses thereof

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- Number: US 2020/0399364 A1
- Document ID: US20200399364A1
- Status: Published application
- Kind: A1
- Application number: 15/733,553
- Filed: 2019-03-06
- Published: 2020-12-24
- Earliest claimed: 2018-03-08
- Assignees: Phanes Therapeutics, Inc.
- Applicants: Phanes Therapeutics, Inc.
- Inventors: Minghan WANG; Hui ZOU; Haiqun JIA
- Web page: https://patentgrep.com/patent/US20200399364A1

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61P 35/00: Antineoplastic agents
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Anti-CLDN18.2 antibodies and antigen-binding fragments thereof are described. Also described are nucleic acids encoding the antibodies, compositions comprising the antibodies, and methods of producing the antibodies and using the antibodies for treating or preventing diseases such as cancer and/or an inflammatory disease.

## Claims

### Claim 1

An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of:
a. SEQ ID NOs: 33, 34, 35, 63, 64 and 65, respectively, or SEQ ID NOs: 93, 94, 95, 123, 124 and 125, respectively;
b. SEQ ID NOs: 21, 22, 23, 51, 52 and 53, respectively, or SEQ ID NOs: 81, 82, 83, 111, 112 and 113, respectively;
c. SEQ ID NOs: 24, 25, 26, 54, 55 and 56, respectively, or SEQ ID NOs: 84, 85, 86, 114, 115 and 116, respectively;
d. SEQ ID NOs: 27, 28, 29, 57, 58 and 59, respectively, or SEQ ID NOs: 87, 88, 89, 117, 118 and 119, respectively;
e. SEQ ID NOs: 30, 31, 32, 60, 61 and 62, respectively, or SEQ ID NOs: 90, 91, 92, 120, 121 and 122, respectively;
f. SEQ ID NOs: 36, 37, 38, 66, 67 and 68, respectively, or SEQ ID NOs: 96, 97, 98, 126, 127 and 128, respectively;
g. SEQ ID NOs: 39, 40, 41, 69, 70 and 71, respectively, or SEQ ID NOs: 99, 100, 101, 129, 130 and 131, respectively;
h. SEQ ID NOs: 42, 43, 44, 72, 73 and 74, respectively, or SEQ ID NOs: 102, 103, 104, 132, 133 and 134, respectively;
i. SEQ ID NOs: 45, 46, 47, 75, 76 and 77, respectively, or SEQ ID NOs: 105, 106, 107, 135, 136 and 137, respectively; or
j. SEQ ID NOs: 48, 49, 50, 78, 79 and 80, respectively, or SEQ ID NOs: 108, 109, 110, 138, 139 and 140, respectively;
wherein the antibody or antigen-binding fragment thereof specifically binds claudin 18.2 (CLDN18.2).

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1, comprising a heavy chain variable region having a polypeptide sequence at least 95% identical to SEQ ID NO: 9, 1, 3, 5, 7, 11, 13, 15, 17 or 19, or a light chain variable region having a polypeptide sequence at least 95% identical to SEQ ID NO: 10, 2, 4, 6, 8, 12, 14, 16, 18 or 20.

### Claim 4 (depends on 1)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1, comprising:
a. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:9, and a light chain variable region having the polypeptide sequence of SEQ ID NO:10;
b. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:1, and a light chain variable region having the polypeptide sequence of SEQ ID NO:2;
c. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:3, and a light chain variable region having the polypeptide sequence of SEQ ID NO:4;
d. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:5, and a light chain variable region having the polypeptide sequence of SEQ ID NO:6;
e. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:7, and a light chain variable region having the polypeptide sequence of SEQ ID NO:8;
f. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:11, and a light chain variable region having the polypeptide sequence of SEQ ID NO:12;
g. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:13, and a light chain variable region having the polypeptide sequence of SEQ ID NO:14;
h. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:15, and a light chain variable region having the polypeptide sequence of SEQ ID NO:16;
i. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:17, and a light chain variable region having the polypeptide sequence of SEQ ID NO:18;
j. a heavy chain variable region having the polypeptide sequence of SEQ ID NO:19, and a light chain variable region having the polypeptide sequence of SEQ ID NO:20.

### Claim 5 (depends on 1)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof is capable of inducing effector-mediated tumor cell lysis.

### Claim 6 (depends on 1)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof is chimeric or human or humanized.

### Claim 7

(canceled)

### Claim 8 (depends on 6)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 6, wherein the isolated humanized antibody or antigen-binding fragment thereof comprises:
(a) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:142, and a light chain variable region having the polypeptide sequence of SEQ ID NO:144;
(b) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:142, and a light chain variable region having the polypeptide sequence of SEQ ID NO:145;
(c) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:143, and a light chain variable region having the polypeptide sequence of SEQ ID NO:144;
(d) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:143, and a light chain variable region having the polypeptide sequence of SEQ ID NO:145;
(e) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:146, and a light chain variable region having the polypeptide sequence of SEQ ID NO:148;
(f) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:146, and a light chain variable region having the polypeptide sequence of SEQ ID NO:149;
(g) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:146, and a light chain variable region having the polypeptide sequence of SEQ ID NO:150;
(h) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:147, and a light chain variable region having the polypeptide sequence of SEQ ID NO:148;
(i) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:147, and a light chain variable region having the polypeptide sequence of SEQ ID NO:149;
(j) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:147, and a light chain variable region having the polypeptide sequence of SEQ ID NO:150;
(k) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:151, and a light chain variable region having the polypeptide sequence of SEQ ID NO:153;
(l) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:152, and a light chain variable region having the polypeptide sequence of SEQ ID NO:153;
(m) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:154, and a light chain variable region having the polypeptide sequence of SEQ ID NO:157;
(n) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:155, and a light chain variable region having the polypeptide sequence of SEQ ID NO:157;
(o) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:156, and a light chain variable region having the polypeptide sequence of SEQ ID NO:158;
(p) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:159, and a light chain variable region having the polypeptide sequence of SEQ ID NO:163;
(q) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:159, and a light chain variable region having the polypeptide sequence of SEQ ID NO:164;
(r) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:160, and a light chain variable region having the polypeptide sequence of SEQ ID NO:163;
(s) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:160, and a light chain variable region having the polypeptide sequence of SEQ ID NO:164;
(t) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:161, and a light chain variable region having the polypeptide sequence of SEQ ID NO:165; or
(u) a heavy chain variable region having the polypeptide sequence of SEQ ID NO:162, and a light chain variable region having the polypeptide sequence of SEQ ID NO:165.

### Claim 9 (depends on 1)

The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof is capable of inducing effector-mediated tumor cell lysis through antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent phagocytosis (ADPC), and/or complement-dependent cytotoxicity (CDC), and/or mediating the recruitment of conjugated drugs, and/or forming a bispecific antibody with another mAb or antigen-binding fragment thereof with cancer-killing effect.

### Claim 10 (depends on 1)

An isolated nucleic acid encoding the monoclonal antibody or antigen-binding fragment thereof of claim 1.

### Claim 11 (depends on 10)

A vector comprising the isolated nucleic acid of claim 10.

### Claim 12 (depends on 11)

A host cell comprising the vector of claim 11.

### Claim 13 (depends on 1)

A pharmaceutical composition, comprising the isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.

### Claim 14

(canceled)

### Claim 15 (depends on 13)

A method of treating cancer or targeting CLDN18.2 on a cancer cell surface in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 13.

### Claim 16 (depends on 15)

The method of claim 15, wherein the cancer is selected from the group consisting of a lung cancer, a gastric cancer, an esophageal cancer, a bile duct cancer, a cholangiocarcinoma, a colon cancer, a hepatocellular carcinoma, a renal cell carcinoma, a bladder urothelial carcinoma, a metastatic melanoma, a breast cancer, an ovarian cancer, a cervical cancer, a head and neck cancer, a pancreatic cancer, a glioma, a glioblastoma, and other solid tumors, and a hon-Hodgkin's lymphoma (NHL), an acute lymphocytic leukemia (ALL), a chronic lymphocytic leukemia (CLL), a chronic myelogenous leukemia (CIVIL), a multiple myeloma (MM), an acute myeloid leukemia (AML), and other liquid tumors.

### Claim 17 (depends on 13)

A method of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 13.

### Claim 18 (depends on 1)

A method of producing the monoclonal antibody or antigen-binding fragment thereof of claim 1, comprising culturing a cell comprising a nucleic acid encoding the monoclonal antibody or antigen-binding fragment thereof under conditions to produce the monoclonal antibody or antigen-binding fragment thereof and recovering the antibody or antigen-binding fragment thereof from the cell or culture.

### Claim 19 (depends on 1)

A method of producing a pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment of claim 1, comprising combining the monoclonal antibody or antigen-binding fragment thereof with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition.

### Claim 20 (depends on 1)

A method of determining a level of CLDN18.2 in a subject, the method comprising:
a. obtaining a sample from the subject;
b. contacting the sample with an isolated monoclonal antibody or antigen-binding fragment thereof of claim 1; and
c. determining a level of CLDN18.2 in the subject.

### Claim 21 (depends on 20)

The method of claim 20, wherein the sample is a tissue sample or a blood sample.

### Claim 22 (depends on 21)

The method of claim 21, wherein the tissue sample is a cancer tissue sample.

### Claim 23

(canceled)

### Claim 24 (depends on 1)

An isolated bispecific antibody or antigen-binding fragment thereof comprising the monoclonal antibody or antigen-binding fragment thereof of claim 1.

### Claim 25 (depends on 24)

An isolated nucleic acid encoding the bispecific antibody or antigen-binding fragment thereof of claim 24.

### Claim 26 (depends on 25)

A vector comprising the isolated nucleic acid of claim 25.

### Claim 27 (depends on 26)

A host cell comprising the vector of claim 26.

### Claim 28 (depends on 24)

A pharmaceutical composition comprising the isolated bispecific antibody or antigen-binding fragment thereof of claim 24 and a pharmaceutically acceptable carrier.