# US 10,308,721 B2 · Anti-DLL3 antibodies and drug conjugates for use in melanoma

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- Number: US 10,308,721 B2
- Document ID: US10308721B2
- Status: Granted
- Kind: B2
- Application number: 15/120,499
- Filed: 2015-02-23
- Published: 2017-05-18
- Granted: 2019-06-04
- Earliest claimed: 2014-02-21
- Assignees: Abbvie Stemcentrx LLC
- Applicants: Abbvie Stemcentrx LLC
- Inventors: Samuel Williams; Laura Saunders; Kathryn A Loving
- Web page: https://patentgrep.com/patent/US10308721B2

## CPC

- C07K 16/3053: {Skin, nerves, brain}
- A61K 47/68035: {the drug being a pyrrolobenzodiazepine}
- A61K 47/6817: {Toxins}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6865: {the tumour determinant being from skin, nerves or brain cancer cell}
- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G01N 33/5751: of the skin, e.g. melanoma
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/53: Hinge
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12Q 2600/158: Expression markers
- G01N 2333/47: Assays involving proteins of known structure or function as defined in the subgroups
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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-DLL3 antibodies and antibody drug conjugates for use in the diagnosis and treatment of melanoma.

## Claims

### Claim 1

A method of treating melanoma in a subject, wherein the melanoma is characterized as having a DLL3 expression level above a threshold index value, the method comprising the step of administering to the subject an anti-DLL3 antibody drug conjugate, wherein the antibody drug conjugate comprises the formula M-[L-D]n wherein:
M comprises an anti-DLL3 antibody comprising three CDRs of a light chain variable region amino acid sequence of SEQ ID NO: 405 and three CDRs of a heavy chain variable region amino acid sequence of SEQ ID NO: 407;
L comprises a linker;
D comprises a pyrrolobenzodiazepine (PBD); and
n is an integer from 1 to 8.

### Claim 2 (depends on 1)

The method of claim 1, wherein the melanoma is refractory melanoma.

### Claim 3 (depends on 2)

The method of claim 2, wherein the melanoma is dacarbazine-refractory melanoma, vemurafenib-refractory melanoma, trametinib-refractory melanoma or dasatinib-refractory melanoma.

### Claim 4 (depends on 1)

The method of claim 1, wherein the melanoma comprises wild type BRAF.

### Claim 5 (depends on 1)

The method of claim 1, wherein the melanoma comprises mutated BRAF.

### Claim 6 (depends on 1)

The method of claim 1, wherein the melanoma comprises wild type NRAS.

### Claim 7 (depends on 1)

The method of claim 1, wherein the melanoma comprises mutated NRAS.

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody drug conjugate (ADC) comprises an anti-DLL3 antibody that is a chimeric antibody, a CDR-grafted antibody, or a humanized antibody.

### Claim 9 (depends on 1)

The method of claim 1, 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 10 (depends on 1)

The method of claim 1, wherein the melanoma is stage II melanoma.

### Claim 11 (depends on 1)

The method of claim 1, wherein the patient has previously undergone tumor resection.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

The method of claim 12, wherein the cleavable linker comprises a dipeptide.

### Claim 14 (depends on 13)

The method of claim 13, wherein the dipeptide is Val-Ala.

### Claim 15 (depends on 1)

The method of claim 1, wherein the PBD is PBD1:

### Claim 16 (depends on 1)

The method of claim 1, wherein the anti-DLL3 antibody comprises:
(a) 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;
(b) 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 26-32 of SEQ ID NO: 407 for CDR-H1, residues 52-56 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 Chothia; or
(c) residues 30-36 of SEQ ID NO: 405 for CDR-L1, residues 46-55 of SEQ ID NO: 405 for CDR-L2, residues 89-96 of SEQ ID NO: 405 for CDR-L3, residues 30-35 of SEQ ID NO: 407 for CDR-H1, residues 47-58 of SEQ ID NO: 407 for CDR-H2 and residues 93-101 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to MacCallum.

### Claim 17

A method of treating melanoma in a subject, wherein the melanoma is dacarbazine-refractory melanoma, vemurafenib-refractory melanoma, trametinib-refractory melanoma or dasatinib-refractory melanoma, the method comprising the step of administering to the subject an anti-DLL3 antibody drug conjugate, wherein the antibody drug conjugate comprises a humanized anti-DLL3 antibody conjugated to one or more pyrrolobenzodiazepines (PBDs), and 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 18 (depends on 17)

The method of claim 17, wherein the PBD is PBD1:

### Claim 19 (depends on 18)

The method of claim 18, wherein the melanoma comprises wild type BRAF.

### Claim 20 (depends on 18)

The method of claim 18, wherein the melanoma comprises mutated BRAF.

### Claim 21 (depends on 18)

The method of claim 18, wherein the melanoma comprises wild type NRAS.

### Claim 22 (depends on 18)

The method of claim 18, wherein the melanoma comprises mutated NRAS.

### Claim 23 (depends on 17)

The method of claim 17, wherein the melanoma is stage II melanoma.

### Claim 24 (depends on 17)

The method of claim 17, wherein the patient has previously undergone tumor resection.

### Claim 25

A method of treating stage II melanoma in a subject, the method comprising the step of administering to the subject an anti-DLL3 antibody drug conjugate, wherein the antibody drug conjugate comprises a humanized anti-DLL3 antibody conjugated 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; and wherein the PBD is PBD1:

### Claim 26 (depends on 25)

The method of claim 25, wherein the melanoma is refractory melanoma.

### Claim 27 (depends on 25)

The method of claim 25, wherein the melanoma is dacarbazine-refractory melanoma, vemurafenib-refractory melanoma, trametinib-refractory melanoma or dasatinib-refractory melanoma.

### Claim 28 (depends on 25)

The method of claim 25, wherein the patient has previously undergone tumor resection.