# US 11,298,359 B2 · Anti-HER3 antibody-drug conjugate

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- Number: US 11,298,359 B2
- Document ID: US11298359B2
- Status: Granted
- Kind: B2
- Application number: 16/264,395
- Filed: 2019-01-31
- Published: 2019-05-23
- Granted: 2022-04-12
- Earliest claimed: 2014-04-10
- Assignees: Daiichi Sankyo Company, Limited; Daiichi Sankyo Europe GmbH
- Applicants: Daiichi Sankyo Company, Limited; Daiichi Sankyo Europe GmbH
- Inventors: Thore Hettmann; Reimar Abraham; Sabine Blum; Suguru Ueno
- Web page: https://patentgrep.com/patent/US11298359B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 47/68037: {the drug being a camptothecin [CPT] or derivatives}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6857: {the tumour determinant being from lung cancer cell}
- A61K 47/6861: {the tumour determinant being from kidney or bladder cancer cell}
- A61K 47/6863: {the tumour determinant being from stomach or intestines cancer cell}
- A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/3015: {Breast}
- C07K 16/3023: {Lung}
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- 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
- 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)

## Abstract

To provide an antitumor drug having excellent therapeutic effect, which is excellent in terms of antitumor effect and safety. Provided is an antibody-drug conjugate in which an antitumor compound represented by the following formula is conjugated to an anti-HER3 antibody via a linker having a structure represented by the formula: -L1-L2-LP-NH—(CH2)n1-La-(CH2)n2-C(═O)— or -L1-L2-LP- (the anti-HER3 antibody is connected to the terminal of L1, the antitumor compound is connected to the carbonyl group of —(CH2)n2-C(═O)— moiety or the C terminal of LP, with the nitrogen atom of the amino group at position 1 as a connecting position).

## Claims

### Claim 1

An antibody-drug conjugate, wherein a linker and an antitumor compound represented by any one of the following formulae and anti-HER3 antibody are connected:
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG (SEQ ID NO: 585)-NH—CH2CH2CH2—C(═O)-(NH-DX), or
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-DGGFG (SEQ ID NO: 590)-NH—CH2CH2CH2—C(═O)-(NH-DX);
wherein
-(Succinimid-3-yl-N)— has a structure represented by the following formula:
which is connected to the antibody at position 3 thereof and is connected to a methylene group in the linker structure containing this structure on the nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula:
wherein the nitrogen atom of the amino group at position 1 is the connecting position.

### Claim 2 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein an average number of units of the drug-linker structure conjugated per antibody is in a range of from 2 to 8.

### Claim 3 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein an average number of units of the drug-linker structure conjugated per antibody is in a range of from 3 to 8.

### Claim 4 (depends on 1)

A drug containing the antibody-drug conjugate according to claim 1 or a salt thereof.

### Claim 5 (depends on 4)

A method of treating cancer in an individual comprising administering to an individual with cancer the drug according to claim 4.

### Claim 6 (depends on 5)

The method of claim 5, wherein the cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.

### Claim 7 (depends on 1)

A pharmaceutical composition containing the antibody-drug conjugate according to claim 1 or a salt thereof as an active component, and a pharmaceutically acceptable formulation component.

### Claim 8 (depends on 7)

A method of treating cancer in an individual comprising administering to an individual with cancer the pharmaceutical composition according to claim 7.

### Claim 9 (depends on 8)

The method according to claim 8, wherein the cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.

### Claim 10 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody comprises the CDRH1 to CDRH3 and CDRL1 to CDRL3 of U1-49, U1-53, U1-59, U1-7 or U1-9 in the heavy and light chains, respectively.

### Claim 11 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody comprises the heavy chain variable region and the light chain variable chain of U1-49, U1-53, U1-59, U1-7 or U1-9 on the heavy and light chains, respectively.

### Claim 12 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody comprises the amino acid sequences represented by SEQ ID Nos: 42 and 44, SEQ ID Nos: 54 and 56, SEQ ID Nos: 70 and 72, SEQ ID Nos: 92 and 94, or SEQ ID Nos: 96 and 98, in the heavy and light chains, respectively.

### Claim 13 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody comprises the amino acid sequences represented by SEQ ID Nos: 583 and 584 in the heavy and light chains, respectively.

### Claim 14 (depends on 10)

A pharmaceutical composition comprising the antibody-drug conjugate according to claim 10, a salt thereof as an active ingredient, and a pharmaceutically acceptable formulation ingredient.

### Claim 15 (depends on 14)

A method of treating cancer in an individual comprising administering to an individual with cancer the pharmaceutical composition according to claim 14.

### Claim 16 (depends on 15)

The method of claim 15, wherein the cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.

### Claim 17 (depends on 13)

The antibody-drug conjugate according to claim 13, wherein the antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.