# US 11,077,202 B2 · Anti-CDH6 antibody and anti-CDH6 antibody-drug conjugate

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- Number: US 11,077,202 B2
- Document ID: US11077202B2
- Status: Granted
- Kind: B2
- Application number: 17/010,162
- Filed: 2020-09-02
- Published: 2020-12-17
- Granted: 2021-08-03
- Earliest claimed: 2017-05-15
- Assignees: Daiichi Sankyo Company, Limited
- Applicants: Daiichi Sankyo Company, Limited
- Inventors: Atsuko Saito; Tsuyoshi Hirata; Kensuke Nakamura
- Web page: https://patentgrep.com/patent/US11077202B2

## CPC

- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0021: {Intradermal administration, e.g. through microneedle arrays or needleless injectors}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- 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 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/68033: {the drug being a maytansine}
- A61K 47/68037: {the drug being a camptothecin [CPT] or derivatives}
- 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 47/6861: {the tumour determinant being from kidney or bladder cancer cell}
- A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate}
- A61P 13/12: of the kidneys
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C12N 5/16: Animal cells
- C12N 5/163: {one of the fusion partners being a B or a T lymphocyte}
- A61K 2039/505: {comprising antibodies}
- 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 2317/40: characterized by post-translational modification
- C07K 2317/41: Glycosylation, sialylation, or fucosylation
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12N 2510/02: Cells for production
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

It is an object of the present invention to provide an antibody binding to CDH6 and having internalization activity, an antibody-drug conjugate of the antibody and a drug having antitumor activity, a pharmaceutical product comprising the antibody-drug conjugate and having therapeutic effects on a tumor, a method for treating a tumor using the antibody, the antibody-drug conjugate or the pharmaceutical product, and the like. The present invention provides an anti-CDH6 antibody having internalization activity, an antibody-drug conjugate of the antibody and a drug having antitumor activity, a pharmaceutical product comprising the antibody or the antibody-drug conjugate, and a method for treating a tumor.

## Claims

### Claim 1

An antibody-drug conjugate comprising (i) an antibody or a functional fragment thereof that specifically binds to the amino acid sequence of SEQ ID NO: 4 and possesses internalization ability that permits cellular uptake of the antibody, and (ii) a drug conjugated to the antibody or functional fragment thereof via a linker;
wherein the antibody or functional fragment thereof comprises a light chain comprising a CDRL1, a CDRL2, and a CDRL3 and a heavy chain comprising a CDRH1, a CDRH2, and a CDRH3 selected from the group consisting of:
(a) CDRL1 comprising SEQ ID NO: 12, CDRL2 comprising SEQ ID NO: 13, and CDRL3 comprising SEQ ID NO: 14, and CDRH1 comprising SEQ ID NO: 17, CDRH2 comprising SEQ ID NO: 18, and CDRH3 comprising SEQ ID NO: 19;
(b) CDRL1 comprising SEQ ID NO: 22, CDRL2 comprising SEQ ID NO: 23, and CDRL3 comprising SEQ ID NO: 24, and CDRH1 comprising SEQ ID NO: 27, CDRH2 comprising SEQ ID NO: 28, and CDRH3 comprising SEQ ID NO: 29;
(c) CDRL1 comprising SEQ ID NO: 32, CDRL2 comprising SEQ ID NO: 33, and CDRL3 comprising SEQ ID NO: 34, and CDRH1 comprising SEQ ID NO: 37, CDRH2 comprising SEQ ID NO: 38, and CDRH3 comprising SEQ ID NO: 39;
(d) CDRL1 comprising SEQ ID NO: 42, CDRL2 comprising SEQ ID NO: 43, and CDRL3 comprising SEQ ID NO: 44, and CDRH1 comprising SEQ ID NO: 47, CDRH2 comprising SEQ ID NO: 48, and CDRH3 comprising SEQ ID NO: 49; and
(e) CDRL1 comprising SEQ ID NO: 12, CDRL2 comprising SEQ ID NO: 13, and CDRL3 comprising SEQ ID NO: 14, and CDRH1 comprising SEQ ID NO: 17, CDRH2 comprising SEQ ID NO: 60, and CDRH3 comprising SEQ ID NO: 19.

### Claim 2 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the drug is an antitumor compound.

### Claim 3 (depends on 2)

The antibody-drug conjugate according to claim 2, wherein the antitumor compound is an antitumor compound represented by the following formula:

### Claim 4 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the linker has a structure selected from the group consisting of the following formulas (a) to (f):
-(Succinimid-3-yl-N)—CH2CH2—C(═O)-GGFG-NH—CH2CH2CH2—C(═O)—, (a)
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG-NH—CH2CH2CH2—C(═O)—, (b)
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG-NH—CH2—O—CH2—C(═O)—, (c)
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG-NH—CH2CH2—O—CH2—C(═O)—, (d)
-(Succinimid-3-yl-N)—CH2CH2—C(═O)—NH—CH2CH2O—CH2CH2O—CH2CH2—C(═O)-GGFG-NH—CH2CH2CH2—C(═O)—, and (e)
-(Succinimid-3-yl-N)—CH2CH2—C(═O)—NH—CH2CH2O—CH2CH2O—CH2CH2O—CH2CH2O—CH2CH2—C(═O)-GGFG-NH—CH2CH2CH2—C(═O)—, (f)
wherein the antibody is connected to the terminus of -(Succinimid-3-yl-N), the antitumor compound is connected to the carbonyl group of the —CH2CH2CH2—C(═O)— moiety of (a), (b), (e) or (f), the CH2—O—CH2—C(═O)— moiety of (c) or the CH2CH2—O—CH2—C(═O)— moiety of (d) with the nitrogen atom of the amino group at position 1 as a connecting position, GGFG represents an amino acid sequence consisting of glycine-glycine-phenylalanine-glycine linked through peptide bonds, and
-(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.

### Claim 5 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the linker is represented by any formula selected from the group consisting of the following formulas (c), (d) and (e):
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG-NH—CH2—O—CH2—C(═O)—, (c)
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG-NH—CH2CH2—O—CH2—C(═O)—, and (d)
-(Succinimid-3-yl-N)—CH2CH2—C(═O)—NH—CH2CH2O—CH2CH2O—CH2CH2—C(═O)-GGFG-NH—CH2CH2CH2—C(═O)—. (e)

### Claim 6 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the linker is represented by the following formula (c) or (e):
-(Succinimid-3-yl-N)—CH2CH2CH2CH2CH2—C(═O)-GGFG-NH—CH2—O—CH2—C(═O)—, (c)
and
-(Succinimid-3-yl-N)—CH2CH2—C(═O)—NH—CH2CH2O—CH2CH2O—CH2CH2—C(═O)-GGFG-NH—CH2CH2CH2—C(═O)—. (e)

### Claim 7 (depends on 1)

The antibody-drug conjugate according to claim 1, which has a structure represented by the following formula:
wherein AB represents the antibody or the functional fragment of the antibody, n represents the average number of units of the drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a sulfhydryl group derived from the antibody.

### Claim 8 (depends on 7)

The antibody-drug conjugate according to claim 7, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 1 to 10.

### Claim 9 (depends on 7)

The antibody-drug conjugate according to claim 7, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 2 to 8.

### Claim 10 (depends on 7)

The antibody-drug conjugate according to claim 7, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 5 to 8.

### Claim 11 (depends on 1)

The antibody-drug conjugate according to claim 1, which has a structure represented by the following formula:
wherein AB represents the antibody or the functional fragment of the antibody, n represents the average number of units of the drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a sulfhydryl group derived from the antibody.

### Claim 12 (depends on 11)

The antibody-drug conjugate according to claim 11, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 1 to 10.

### Claim 13 (depends on 11)

The antibody-drug conjugate according to claim 11, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 2 to 8.

### Claim 14 (depends on 11)

The antibody-drug conjugate according to claim 11, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 5 to 8.

### Claim 15 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the antibody is an antibody comprising a light chain and a heavy chain in any one combination selected from the group consisting of the following combinations (1) to (4), or a functional fragment of the antibody:
(1) a light chain consisting of the amino acid sequence at positions 21 to 233 in SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in SEQ ID NO: 69,
(2) a light chain consisting of the amino acid sequence at positions 21 to 233 in SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in SEQ ID NO: 73,
(3) a light chain consisting of the amino acid sequence at positions 21 to 233 in SEQ ID NO: 65 and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in SEQ ID NO: 73, and
(4) a light chain consisting of the amino acid sequence at positions 21 to 233 in SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in SEQ ID NO: 77.

### Claim 16 (depends on 15)

The antibody-drug conjugate according to claim 15, wherein the antibody is an antibody comprising a light chain consisting of the amino acid sequence at positions 21 to 233 in SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in SEQ ID NO: 69, or a functional fragment of the antibody.

### Claim 17 (depends on 15)

The antibody-drug conjugate according to claim 15, wherein the antibody is an antibody comprising a light chain consisting of the amino acid sequence at positions 21 to 233 in SEQ ID NO: 61 and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in SEQ ID NO: 77, or a functional fragment of the antibody.

### Claim 18 (depends on 15)

The antibody-drug conjugate according to claim 15, wherein the antibody comprises a light chain consisting of amino acids 21 to 233 of SEQ ID NO: 61 and a heavy chain consisting of amino acids 20 to 471 of SEQ ID NO: 73.

### Claim 19 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the heavy chain or the light chain has undergone one or two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamic acid to pyroglutamic acid, and a deletion of one or two amino acids from the carboxyl terminus.

### Claim 20 (depends on 1)

The antibody-drug conjugate according to claim 1, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 1 to 10.

### Claim 21 (depends on 20)

The antibody-drug conjugate according to claim 20, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 2 to 8.

### Claim 22 (depends on 21)

The antibody-drug conjugate according to claim 21, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 5 to 8.

### Claim 23 (depends on 22)

The antibody-drug conjugate according to claim 22, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 7 to 8.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising the antibody-drug conjugate according to claim 1, a salt thereof, or a hydrate of the conjugate or the salt.

### Claim 25 (depends on 24)

The pharmaceutical composition according to claim 24, which is an antitumor drug.

### Claim 26 (depends on 25)

The pharmaceutical composition according to claim 25, wherein the tumor is a tumor expressing CDH6.

### Claim 27 (depends on 25)

The pharmaceutical composition according to claim 25, wherein the tumor is renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer, small-cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor or neuroblastoma.

### Claim 28

An antibody-drug conjugate, comprising the formula:
wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of the drug-linker structure conjugated to the antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 1 to 10.

### Claim 29

An antibody-drug conjugate, comprising the formula:
wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 75 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of the drug-linker structure conjugated to the antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 1 to 10.

### Claim 30

An antibody-drug conjugate, comprising the formula:
wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 79 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of the drug-linker structure conjugated to the antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated per antibody is in the range of from 1 to 10.