# US 2019/0314513 A1 · Duocarmycin adcs showing improved in vivo antitumor activity

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- Number: US 2019/0314513 A1
- Document ID: US20190314513A1
- Status: Published application
- Kind: A1
- Application number: 16/456,177
- Filed: 2019-06-28
- Published: 2019-10-17
- Earliest claimed: 2014-01-10
- Assignees: Synthon Biopharmaceuticals B.V.
- Applicants: Synthon Biopharmaceuticals B.V.
- Inventors: Willem DOKTER; Peter Johannes GOEDINGS; Gijsbertus Franciscus Maria VERHEIJDEN; Patrick Henry BEUSKER
- Web page: https://patentgrep.com/patent/US20190314513A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6801: {Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent}
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6871: {the antibody targeting an enzyme}
- 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 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/32: against translation products of oncogenes
- C07K 16/40: against enzymes
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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

The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumours and haematological malignancies expressing HER2, in particular breast cancer, gastric cancer, bladder cancer, ovarian cancer, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer or osteosarcoma, and acute lymphoblastic leukaemia. In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of human solid tumours with HER2 IHC 2+ or 1+ and HER2 FISH negative tissue status. Advantageously, the present invention relates to duocarmycin-containing ADCs for use in the treatment of triple negative breast cancer (TNBC).

## Claims

### Claim at position 1

1-15. (canceled)

### Claim 16

A method of treating bladder cancer in a human patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I)
wherein
anti-HER2 Ab is an anti-HER2 antibody or antibody fragment able to bind HER2,
n is 0, 1, 2, or 3,
m represents an average DAR of from 1 to 4,
R1 is selected from the group consisting of
y is 1-16, and
R2 is selected from the group consisting of
and
wherein the patient has HER2 expressing bladder cancer.

### Claim 17 (depends on 16)

The method according to claim 16, wherein
n is 0 or 1,
R1 is selected from the group consisting of
and
R2 is

### Claim 18 (depends on 17)

The method according to claim 17, wherein
anti-HER2 Ab is an anti-HER2 monoclonal antibody,
m represents an average DAR of from 2 to 3,
R1 is
and
y is 1, 2, 3, or 4.

### Claim 19 (depends on 16)

The method according to claim 16, wherein said bladder cancer is HER2 positive.

### Claim 20 (depends on 19)

The method according to claim 19, wherein said bladder cancer is IHC 3+.

### Claim 21 (depends on 16)

The method according to claim 16, wherein said anti-HER2 Ab is trastuzumab.

### Claim 22 (depends on 16)

The method according to claim 16, wherein the compound of formula (I) is a compound of formula (II)

### Claim 23 (depends on 22)

The method according to claim 22, wherein the compound of formula (II) has an average DAR of from 2.5 to 2.9.

### Claim 24 (depends on 22)

The method according to claim 22, wherein the compound of formula (II) has an average DAR of from 2.6 to 2.9.

### Claim 25 (depends on 16)

The method according to claim 16, further comprising administering an effective amount of a therapeutic antibody or a chemotherapeutic agent, or a combination thereof.

### Claim 26 (depends on 25)

The method according to claim 25, wherein the therapeutic antibody is pertuzumab and the chemotherapeutic agent is a taxane or an anthracycline.