# US 2013/0280282 A1 · Dr5 ligand drug conjugates

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- Number: US 2013/0280282 A1
- Document ID: US20130280282A1
- Status: Published application
- Kind: A1
- Application number: 13/804,922
- Filed: 2013-03-14
- Published: 2013-10-24
- Earliest claimed: 2012-04-24
- Assignees: Daiichi Sankyo Company, Limited; Seattle Genetics, Inc.
- Applicants: Daiichi Sankyo Co., Ltd.; Seattle Genetics, Inc.
- Inventors: Toshiaki Ohtsuka; Kimihisa Ichikawa; Ayumi Yada
- Web page: https://patentgrep.com/patent/US20130280282A1

## CPC

- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/68031: {the drug being an auristatin}
- A61P 35/00: Antineoplastic agents
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- 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

Ligand Drug Conjugates are provided having a DR5 binding moiety attached via linking groups and/or spacers to a therapeutic agent that are effective in treatment of various cancers.

## Claims

### Claim 1

A ligand drug conjugate having the formula:
L-(LU-D)p (I)
or a pharmaceutically acceptable salt thereof, having specificity for target cells expressing DR5, wherein:
L is a Ligand unit which is an anti-DR5 antibody comprising (a) a heavy chain immunoglobulin having the CDR1 consisting of amino residues 1-5 of SEQ ID NO:11, the CDR2 consisting of amino acid residues 1-17 of SEQ ID NO:12, and the CDR3 consisting of amino acid residues 1-13 of SEQ ID NO:13; and (b) a light chain immunoglobulin having the CDR1 consisting of amino residues 1-16 of SEQ ID NO:14, the CDR2 consisting of amino acid residues 1-7 of SEQ ID NO:15, and the CDR3 consisting of amino acid residues 1-9 of SEQ ID NO:16; and
(LU-D) is a Linker unit-Drug unit moiety, wherein
LU is a Linker unit, and
D is a Drug unit, wherein the Drug unit is an auristatin; and
the subscript p is an integer of from 1 to 20.

### Claim 2 (depends on 1)

The ligand drug conjugate of claim 1, wherein the auristatin is auristatin E, AEB, AEVB, AFP, MMAF, or MMAE.

### Claim 3 (depends on 1)

The ligand drug conjugate of claim 1, having the formula:
or a pharmaceutically acceptable salt form thereof, wherein:
S is a sulfur atom of the Ligand unit;
each W is independently an Amino Acid unit;
the subscript w is an integer of from 0 to 12;
Y is a Spacer unit; and
the subscript y is 0, 1, or 2.

### Claim 4 (depends on 3)

The ligand drug conjugate of claim 3, wherein Ww is valine-citrulline.

### Claim 5 (depends on 1)

The ligand drug conjugate of claim 1, having the formula:
or a pharmaceutically acceptable salt form thereof, wherein:
mAb is the anti-DR5 antibody;
S is a sulfur atom of the antibody; and
p is an integer of from 1 to 8.

### Claim 6 (depends on 1)

The ligand drug conjugate of claim 1, wherein the anti-DR5 antibody comprises a heavy chain variable region comprising amino acid residues 1-122 of SEQ ID NO:9 and a light chain variable region comprising amino acid residues 1-114 of SEQ ID NO:10.

### Claim 7 (depends on 1)

The ligand drug conjugate of claim 1, wherein the anti-DR5 antibody comprises a heavy chain consisting of amino residues 1-452 of SEQ ID NO:9 and a light chain consisting of amino acid residues 1-219 of SEQ ID NO:10.

### Claim 8 (depends on 1)

The ligand drug conjugate of claim 1, wherein the anti-DR5 antibody comprises a heavy chain consisting of amino residues 1-451 of SEQ ID NO:9 and a light chain consisting of amino acid residues 1-219 of SEQ ID NO:10.

### Claim 9 (depends on 1)

The ligand drug conjugate of claim 1, wherein p is from 1 to 8.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising the ligand drug conjugate of claim 1, in admixture with a pharmaceutically acceptable excipient.

### Claim 11 (depends on 1)

A composition comprising a mixture of ligand drug conjugates of claim 1, wherein the average p value is between 1 and 20.

### Claim 12 (depends on 11)

The composition of claim 11, wherein the average p value is from about 3.5 to about 4.5.

### Claim 13 (depends on 1)

An anti-tumor agent comprising the ligand drug conjugate of claim 1, as an effective ingredient.

### Claim 14 (depends on 1)

A method of treating cancer that expresses a DR5 protein comprising administering to a subject in need thereof an effective amount of a ligand drug conjugate of claim 1.

### Claim 15 (depends on 14)

A method in accordance with claim 14, wherein said cancer that expresses a DR5 protein is selected from the group consisting of melanoma, colorectal cancer, non-small cell lung carcinoma, uterine cancer, pancreatic cancer, prostate cancer, breast cancer, ovarian cancer, and hematological cancer.

### Claim 16 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is pancreatic cancer.

### Claim 17 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is melanoma.

### Claim 18 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is breast cancer.

### Claim 19 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is ovarian cancer.

### Claim 20 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is colorectal cancer.

### Claim 21 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is renal cancer.

### Claim 22 (depends on 15)

A method in accordance with claim 15, wherein said cancer that expresses a DR5 protein is glioblastoma.