# US 10,478,509 B2 · Anti-DLL3 antibody drug conjugates for treating cancer

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- Number: US 10,478,509 B2
- Document ID: US10478509B2
- Status: Granted
- Kind: B2
- Application number: 15/946,459
- Filed: 2018-04-05
- Published: 2018-11-08
- Granted: 2019-11-19
- Earliest claimed: 2013-02-22
- Assignees: Abbvie Stemcentrx LLC; MedImmune, LLC
- Applicants: Abbvie Stemcentrx LLC; Medimmune Limited
- Inventors: Michael Torgov; Philip Wilson Howard
- Web page: https://patentgrep.com/patent/US10478509B2

## CPC

- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/68035: {the drug being a pyrrolobenzodiazepine}
- 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 5/00: Drugs for disorders of the endocrine system
- A61P 5/38: of the suprarenal hormones
- A61P 11/00: Drugs for disorders of the respiratory system
- 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 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/30: from tumour cells
- C07K 16/3023: {Lung}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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

Provided are novel antibody drug conjugates (ADCs), and methods of using such ADCs to treat proliferative disorders.

## Claims

### Claim 1

A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs), wherein the one or more PBDs is/are:

### Claim 2 (depends on 1)

The method of claim 1, wherein the cancer is lung cancer.

### Claim 3 (depends on 2)

The method of claim 2, wherein the cancer is small cell lung cancer.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cancer comprises a neuroendocrine tumor.

### Claim 5 (depends on 4)

The method of claim 4, wherein the cancer is large cell neuroendocrine carcinoma.

### Claim 6 (depends on 1)

The method of claim 1, wherein the cancer is thyroid cancer.

### Claim 7 (depends on 1)

The method of claim 1, wherein the cancer is prostate cancer.

### Claim 8 (depends on 1)

The method of claim 1, wherein the linker comprises a cleavable linker.

### Claim 9 (depends on 1)

The method of claim 1, wherein the anti-DLL3 antibody is covalently linked to more than one PBD.

### Claim 10 (depends on 1)

The method of claim 1, wherein the ADC has a drug loading of 2.

### Claim 11 (depends on 1)

The method of claim 1, wherein the anti-DLL3 antibody is a chimeric antibody, CDR-grafted antibody, or humanized antibody.

### Claim 12 (depends on 1)

The method of claim 1, wherein the anti-DLL3 antibody comprises three CDRs of a light chain variable region set forth as SEQ ID NO: 405 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 407.

### Claim 13 (depends on 12)

The method of claim 12, wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 405 for CDR-L1, residues 50-56 of SEQ ID NO: 405 for CDR-L2, residues 89-97 of SEQ ID NO: 405 for CDR-L3, residues 31-35 of SEQ ID NO: 407 for CDR-H1, residues 50-65 of SEQ ID NO: 407 for CDR-H2, and residues 95-102 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to Kabat.

### Claim 14 (depends on 13)

The method of claim 13, wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407.

### Claim 15 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition comprises a DAR of 2+/−0.4.

### Claim 16 (depends on 15)

The method of claim 15, wherein the pharmaceutical composition comprises less than 30% of non-predominant ADC species.

### Claim 17

A method of reducing the frequency of tumor initiating cells in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs), wherein the one or more PBDs is/are:

### Claim 18 (depends on 17)

The method of claim 17 wherein the reduction in frequency is determined using
(a) flow cytometric analysis of tumor cell surface markers known to enrich for tumor initiating cells or immunohistochemical detection of tumor cell surface markers known to enrich for tumor initiating cells;
(b) in vitro or in vivo limiting dilution analysis;
(c) in vivo limiting dilution analysis comprising transplant of live human tumor cells into immunocompromised mice; or
(d) in vitro limiting dilution analysis comprising limiting dilution deposition of live human tumor cells into in vitro colony supporting conditions.

### Claim 19

A method of sensitizing a tumor in a subject for treatment with an anti-cancer agent, to said subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs), wherein the one or more PBDs is/are:

### Claim 20

A method of inhibiting metastasis in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs), wherein the one or more PBDs is/are:

### Claim 21 (depends on 20)

The method of claim 20 wherein the subject undergoes a debulking procedure before or after the administration of the pharmaceutical composition.

### Claim 22

A method of performing maintenance therapy to reduce cancer recurrence in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs), wherein the one or more PBDs is/are:

### Claim 23

A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising:
wherein Ab comprises an anti-DLL3 antibody.

### Claim 24 (depends on 23)

The method of claim 23, wherein Ab is covalently linked to more than one PBD.

### Claim 25 (depends on 23)

The method of claim 23, wherein the ADC has a drug loading of 2.

### Claim 26 (depends on 23)

The method of claim 23, wherein the cancer is small cell lung cancer.

### Claim 27

A method of treating lung cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs),
wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407;
wherein the one or more PBDs is/are:
and
wherein the pharmaceutical composition comprises a DAR of 2+/−0.4.

### Claim 28 (depends on 27)

The method of claim 27, wherein the lung cancer is small cell lung cancer.

### Claim 29

A method of treating lung cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody drug conjugate (ADC) comprising:
wherein Ab comprises an anti-DLL3 antibody comprising a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407; and
wherein the pharmaceutical composition comprises a DAR of 2+/−0.4.

### Claim 30 (depends on 29)

The method of claim 29, wherein the lung cancer is small cell lung cancer.