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NZ722668B2 - Anti-her3 antibody-drug conjugate - Google Patents
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NZ722668B2 - Anti-her3 antibody-drug conjugate - Google Patents

Anti-her3 antibody-drug conjugate Download PDF

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Publication number
NZ722668B2
NZ722668B2 NZ722668A NZ72266815A NZ722668B2 NZ 722668 B2 NZ722668 B2 NZ 722668B2 NZ 722668 A NZ722668 A NZ 722668A NZ 72266815 A NZ72266815 A NZ 72266815A NZ 722668 B2 NZ722668 B2 NZ 722668B2
Authority
NZ
New Zealand
Prior art keywords
cancer
antibody
drug conjugate
ch2ch2
conjugate according
Prior art date
Application number
NZ722668A
Other versions
NZ722668A (en
Inventor
Reimar Abraham
Sabine Blum
Thore Hettmann
Suguru Ueno
Original Assignee
Daiichi Sankyo Company Limited
Daiichi Sankyo Europe Gmbh
Filing date
Publication date
Application filed by Daiichi Sankyo Company Limited, Daiichi Sankyo Europe Gmbh filed Critical Daiichi Sankyo Company Limited
Priority claimed from PCT/JP2015/002020 external-priority patent/WO2015155998A1/en
Publication of NZ722668A publication Critical patent/NZ722668A/en
Publication of NZ722668B2 publication Critical patent/NZ722668B2/en

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    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Abstract

Provided is an antibody-drug conjugate in which exatecan is conjugated to an anti-HER3 antibody via a linker having a structure represented by the formula: -L1-L2-LP-NH-(CH2)n1-La-(CH2)n2-C(=O)- or -L1-L2-LP- (the anti-HER3 antibody is connected to the terminal of L1, the antitumor compound is connected to the carbonyl group of -(CH2)n2-C(=O)- moiety or the C terminal of LP, with the nitrogen atom of the amino group at position 1 as a connecting position).

Claims (49)

Claims [
1.Claim 1] An antibody-drug conjugate wherein an antitumor compound represented by the following formula [Chem. 1] is conjugated to an anti-HER3 antibody by a thioether bond which is formed at a disulfide bond moiety present in a hinge part of the antiHER3 antibody via a linker having a structure represented by the following formula: -L1 -L2 -LP -NH-(CH2)n1 -La -(CH2)n2 -C(=O)- or -L1 -L2 -LP - wherein, the anti-HER3 antibody is connected to the terminal of L1 , the antitumor compound is connected to the carbonyl group of -(CH2)n2 - C(=O)- moiety or the C terminal of LP , with the nitrogen atom of the amino group at position 1 as a connecting position, wherein, n1 represents an integer of 0 to 6, n2 represents an integer of 0 to 5, L1 represents -(Succinimidyl-N)-(CH2)n3 -C(=O)-, wherein n3 represents an integer of 2 to 8, L2 represents -NH-(CH2CH2-O)n4 -CH2CH2-C(=O)- or a single bond, wherein n4 represents an integer of 1 to 6, LP represents a peptide residue consisting of 2 to 7 amino acids, La represents -O- or a single bond, -(Succinimidyl-N)- has a structure represented by the following formula: 228 [Chem. 2] which is connected to the anti-HER3 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.
2.[Claim 2] The antibody-drug conjugate according to claim 1, wherein the peptide residue of LP is a peptide residue comprising an amino acid selected from phenylalanine, glycine, valine, lysine, citrulline, serine, glutamic acid, and aspartic acid.
3.[Claim 3] The antibody-drug conjugate according to claim 1 or 2, wherein LP is a peptide residue selected from the following group: -GGF-, -DGGF-, -(D-)D-GGF-, -EGGF-, -GGFG-, -SGGF-, -KGGF-, -DGGFG-, -GGFGG-, -DDGGFG-, -KDGGFG-, and -GGFGGGF-; wherein, "(D-)D" represents D-aspartic acid.
4.[Claim 4] The antibody-drug conjugate according to claim 1 or 2, wherein LP is a peptide residue comprising 4 or 5 amino acids.
5.[Claim 5] The antibody-drug conjugate according to any one of claims 1 to 4, wherein LP is -GGFG- or -DGGFG-.
6.[Claim 6] The antibody-drug conjugate according to any one of claims 1 to 4, wherein LP is -GGFG-.
7.[Claim 7] The antibody-drug conjugate according to any one of claims 1 to 6, wherein n3 is an integer of 2 to 5 and L2 is a single bond. 229
8.[Claim 8] The antibody-drug conjugate according to any one of claims 1 to 7, wherein the linker is -L1 -L2 -LP -NH-(CH2)n1 -La -(CH2)n2 -C(=O)-.
9.[Claim 9] The antibody-drug conjugate according to claim 8, wherein n3 is an integer of 2 to 5, L2 is -NH-(CH2CH2-O)n4 -CH2CH2-C(=O)-, and n4 is 2 or 4.
10.[Claim 10] The antibody-drug conjugate according to claim 8 or 9, wherein -NH-(CH2)n1 -La -(CH2)n2 -C(=O)- is a partial structure having a chain length of 4 to 7 atoms.
11.[Claim 11] The antibody-drug conjugate according to claim 8 or 9, wherein -NH-(CH2)n1 -La -(CH2)n2 -C(=O)- is a partial structure having a chain length of 5 or 6 atoms.
12.[Claim 12] The antibody-drug conjugate according to claim 10, wherein -NH- (CH2)n1 -La -(CH2)n2 -C(=O)- is any one of the following: -NH-CH2CH2-C(=O)-, -NH-CH2CH2CH2-C(=O)-, -NH-CH2CH2CH2CH2-C(=O)-, -NH-CH2CH2CH2CH2CH2-C(=O)-, -NH-CH2-O-CH2-C(=O)-, and -NH-CH2CH2-O-CH2-C(=O)-.
13.[Claim 13] The antibody-drug conjugate according to claim 12, wherein -NH-(CH2)n1 - La -(CH2)n2 -C(=O)- is any one of the following: -NH-CH2CH2CH2-C(=O)-, -NH-CH2-O-CH2-C(=O)-, and -NH-CH2CH2-O-CH2-C(=O)-.
14.[Claim 14] The antibody-drug conjugate according to claim 1, wherein the druglinker structure moiety in which a drug is connected to -L1 -L2 -LPNH-(CH2)n1 -La -(CH2)n2 -C(=O)- or -L1 -L2 -LP - is one drug-linker structure selected from the following group: -(Succinimidyl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NHDX), -(Succinimidyl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)- (NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2- C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NHCH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NHCH2CH2CH2CH2CH2-C(=O)-(NH-DX), 230 -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-NHCH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-NHCH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-NHCH2CH2CH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-OCH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2- O-CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-OCH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-OCH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-OCH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)- (NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-OCH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2- C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-GGFG-(NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-DGGFG-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-(NH-DX), and -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-(NH-DX); wherein, -(Succinimidyl-N)- has a structure represented by the following formula: [Chem. 3] which is connected to the anti-HER3 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, -(NH-DX) represents a group represented by the following formula, 231 with the nitrogen atom of the amino group at position 1 being a connecting position, [Chem. 4] -GGFG- represents a tetrapeptide residue of -Gly-Gly-Phe-Gly- and -DGGFG- represents a pentapeptide residue of -Asp-Gly-Gly-Phe-Gly-.
15.[Claim 15] The antibody-drug conjugate according to claim 14, wherein a druglinker structure moiety is one drug-linker structure selected from the following group: -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NHCH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-NHCH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-OCH2-C(=O)-(NH-DX), -(Succinimidyl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2OCH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX), and -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-(NH-DX).
16.[Claim 16] The antibody-drug conjugate according to claim 15, wherein the druglinker structure moiety is: -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NHCH2CH2CH2-C(=O)-(NH-DX).
17.[Claim 17] The antibody-drug conjugate according to claim 15, wherein the druglinker structure moiety is: -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-NHCH2CH2CH2-C(=O)-(NH-DX).
18.[Claim 18] The antibody-drug conjugate according to claim 15, wherein the druglinker structure moiety is: 232 -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-OCH2-C(=O)-(NH-DX).
19.[Claim 19] The antibody-drug conjugate according to claim 15, wherein the druglinker structure moiety is: -(Succinimidyl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2OCH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).
20.[Claim 20] The antibody-drug conjugate according to claim 15, wherein the druglinker structure moiety is: -(Succinimidyl-N)-CH2CH2CH2CH2CH2-C(=O)-DGGFG-(NH-DX).
21.[Claim 21] The antibody-drug conjugate according to any one of claims 1 to 20, wherein the antibody comprises the CDRH1 to CDRH3 and CDRL1 to CDRL3 of U1-49, U1-53, U1-59, U1-7 or U1-9 in the heavy and light chains, respectively.
22.[Claim 22] The antibody-drug conjugate according to any one of claims 1 to 20, wherein the antibody comprises the heavy chain variable region and the light chain variable region of U1-49, U1-53, U1-59, U1-7 or U1-9 on the heavy and light chains, respectively.
23.[Claim 23] The antibody-drug conjugate according to any one of claims 1 to 20, wherein the antibody comprises the amino acid sequences represented by SEQ ID Nos: 42 and 44, SEQ ID Nos: 54 and 56, SEQ ID Nos: 70 and 72, SEQ ID Nos: 92 and 94, or, SEQ ID Nos: 96 and 98, in the heavy and light chains, respectively.
24.[Claim 24] The antibody-drug conjugate according to any one of claims 1 to 20, wherein the antibody comprises the amino acid sequences represented by SEQ ID Nos: 583 and 584 in the heavy and light chains, respectively.
25.[Claim 25] The antibody-drug conjugate according to claim 24, wherein the antiHER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.
26.[Claim 26] The antibody-drug conjugate according to any one of claims 1 to 25, wherein the average number of units of the selected one drug-linker structure conjugated per antibody is in a range of from 2 to 8.
27.[Claim 27] The antibody-drug conjugate according to any one of claims 1 to 25, wherein the average number of units of the selected one drug-linker structure conjugated per antibody is in a range of from 3 to 8.
28.[Claim 28] A medicine comprising the antibody-drug conjugate according to any one of claims 1 to 25, a salt thereof or a hydrate thereof.
29.[Claim 29] An antitumor medicine and/or anticancer medicine comprising the antibody-drug conjugate according to any one of claims 1 to 25, a salt 233 thereof or a hydrate thereof.
30.[Claim 30] The antitumor medicine and/or anticancer medicine according to claim 29, for the treatment of lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.
31.[Claim 31] A pharmaceutical composition comprising the antibody-drug conjugate according to any one of claims 1 to 25, a salt thereof or a hydrate thereof as an active ingredient, and a pharmaceutically acceptable formulation ingredient.
32.[Claim 32] The pharmaceutical composition according to claim 31, for the treatment of lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.
33.[Claim 33] Use of the antibody-drug conjugate according to any one of claims 1 to 25, a salt thereof or a hydrate thereof, in the manufacture of a medicament for treating a tumor and/or cancer.
34.[Claim 34] The use according to claim 33, wherein the tumor and/or cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus 234 cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.
35.[Claim 35] The antibody-drug conjugate according to claim 1, wherein the antibodydrug conjugate is represented by the following formula: wherein n is an average number of units of the drug-linker structure conjugated per anti-HER3 antibody, and wherein the anti-HER3 antibody comprises the amino acid sequences represented by SEQ ID No: 583 and 584 in the heavy and light chains, respectively.
36.[Claim 36] The antibody-drug conjugate according to claim 35, wherein the antiHER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.
37.[Claim 37] The antibody-drug conjugate according to claim 35 or 36, wherein n is in a range from 2 to 8.
38.[Claim 38] The antibody-drug conjugate according to claim 35 or 36, wherein n is in a range from 3 to 8.
39.[Claim 39] A medicine comprising the antibody-drug conjugate according to any one of claims 35 to 38, a salt thereof or a hydrate thereof.
40.[Claim 40] An antitumor medicine and/or anticancer medicine comprising the antibody-drug conjugate according to any one of claims 35 to 38, a salt thereof or a hydrate thereof.
41.[Claim 41] The antitumor medicine and/or anticancer medicine according to claim 40, for the treatment of lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval 235 cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.
42.[Claim 42] A pharmaceutical composition comprising the antibody-drug conjugate according to any one of claims 35 to 38, a salt thereof or a hydrate thereof as an active ingredient, and a pharmaceutically acceptable formulation ingredient.
43.[Claim 43] The pharmaceutical composition according to claim 42, for the treatment of lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.
44.[Claim 44] Use of the antibody-drug conjugate according to any one of claims 35 to 38, a salt thereof or a hydrate thereof in the manufacture of a medicament for treating a tumor and/or cancer.
45.[Claim 45] The use according to claim 44, wherein the tumor and/or cancer is lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, cervical cancer, head and neck cancer, esophageal cancer, epidermoid cancer, peritoneal cancer, adult glioblastoma multiforme, hepatic cancer, hepatocellular carcinoma, colon cancer, rectal cancer, colon and rectal cancer, endometrial cancer, uterus cancer, salivary cancer, renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anus carcinoma, or penis cancer.
46.[Claim 46] A method for producing an antibody-drug conjugate represented by the following formula: 236 wherein n is an average number of units of the drug-linker structure conjugated per anti-HER3 antibody, and wherein the anti-HER3 antibody comprises the amino acid sequences represented by SEQ ID No: 583 and 584 in the heavy and light chains, respectively, and wherein the method comprises the step of treating the anti-HER3 antibody in a reducing condition and thereafter reacting the anti-HER3 antibody with a compound represented by the following formula: .
47.[Claim 47] The method according to claim 46, wherein the anti-HER3 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.
48.[Claim 48] The method according to claim 46 or 47, wherein n is in a range from 2 to 8.
49.[Claim 49] The method according to claim 46 or 47, wherein n is in a range from 3 to 8.
NZ722668A 2015-04-10 Anti-her3 antibody-drug conjugate NZ722668B2 (en)

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