Antibody-drug conjugate produced by binding through linker having hydrophilic structure

Patent metadata

Field	Value
Publication number	US-9872924-B2
Application number	US-201314436458-A
Country	US
Kind code	B2
Filing date	Oct 17, 2013
Priority date	Oct 19, 2012
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

As an antitumor drug which is excellent in terms of antitumor effect and safety, there is provided an antibody-drug conjugate in which an antitumor compound represented by the following formula (I) is conjugated to an antibody via a linker having a structure represented by the following formula: -L 1 -L 2 -L P -NH—(CH 2 )n 1 -L a -L b -L c - or -L 1 -L 2 -L P - wherein the antibody is connected to the terminal of L 1 , the antitumor compound is connected to the terminal of L c or L P , and any one or two or more of linkers of L 1 , L 2 , and L P has a hydrophilic structure.

First claim

The invention claimed is:

1. An antibody-drug conjugate comprising an antitumor compound represented by the following formula:

wherein the antitumor compound is conjugated to an antibody via a linker having a structure represented by the following formula:
-L 1 -L 2 -L P -NH—(CH 2 )n 1 -L a -L b -L c - or -L 1 -L 2 -L P -
wherein the antibody is connected to the terminal of L 1 , the antitumor compound is connected to the terminal of L c or L P ,
wherein
n 1 represents an integer of 0 to 6,
L 1 represents -(Succinimid-3-yl-N)—(CH 2 )n 2 -C(═O)—, -(Succinimid-3-yl-N)—CH[—(CH 2 )n 3 -COOH]—C(═O)—, —CH 2 —C(═O)—NH—(CH 2 )n 4 -C(═O)—,
—C(═O)-cyc.Hex(1,4)-CH 2 —(N-ly-3-Succinimid)-, or —C(═O)—(CH 2 )n 5 -C(═O)—,
wherein n 2 represents an integer of 2 to 8, n 3 represents an integer of 1 to 8, n 4 represents an integer of 1 to 8, n 5 represents an integer of 1 to 8,
L 2 represents —NH—(CH 2 —CH 2 —O)n 6 -CH 2 —CH 2 —C(═O)—, —N[—(CH 2 CH 2 —O)n 7 -CH 2 CH 2 —OH]—CH 2 —C(═O)—, —S—(CH 2 )n 8 -C(═O)—, or a single bond,
wherein n 6 represents an integer of 0 to 6, n 7 represents an integer of 1 to 4, n 8 represents an integer of 1 to 6,
L P represents: (i) a peptide residue consisting of 3 to 8 amino acids wherein the peptide residue has a hydrophilic amino acid other than glycine at the N terminal, or (ii) a peptide residue comprising GGFGG (SEQ ID NO: 40) or GGFGGG (SEQ ID NO: 41),
L a represents —C(═O)—NH—, —NR 1 —(CH 2 )n 9 -, —O—, or a single bond,
wherein n 9 represents an integer of 1 to 6, R 1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, —(CH 2 )n a -COOH, or —(CH 2 )n b -OH, n a represents an integer of 1 to 4, n b represents an integer of 1 to 6,
L b represents —CR 2 (—R 3 )—, —O—, —NR 4 —, or a single bond,
wherein R 2 and R 3 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, —(CH 2 )n c -NH 2 , —(CH 2 )n d -COOH, or —(CH 2 )n e -OH, R 4 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, n c represents an integer of 0 to 6, n d represents an integer of 1 to 4, n e represents an integer of 1 to 4, provided that when n c is 0, R 2 and R 3 are not the same as each other,
L c represents —CH 2 — or —C(═O)—,
-(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,
—(N-ly-3-Succinimid)- has a structure represented by the following formula:

which is connected to L 2 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,
cyc.Hex(1,4) represents a 1,4-cyclohexylene group,
when L 2 is —S—(CH 2 )n 8 -C(═O)—, L 1 is —C(═O)-cyc.Hex(1,4)-CH 2 —(N-ly-3-Succinimid)-.

2. The antibody-drug conjugate according to claim 1 , wherein
L 1 is -(Succinimid-3-yl-N)—(CH 2 )n 2 -C(═O)—, -(Succinimid-3-yl-N)—CH[—(CH 2 )n 3 -COOH]—C(═O)—, or —CH 2 —C(═O)—NH—(CH 2 )n 4 -C(═O)—,
wherein n 2 represents an integer of 2 to 8, n 3 represents an integer of 1 to 8, n 4 represents an integer of 1 to 8,
L 2 is —NH—(CH 2 —CH 2 —O)n 6 -CH 2 —CH 2 —C(═O)—, —N[—(CH 2 CH 2 —O)n 7 -CH 2 CH 2 —OH]—CH 2 —C(═O)—, or a single bond,
wherein n 6 represents an integer of 0 to 6, n 7 represents an integer of 1 to 4,
L P is (i) a peptide residue consisting of 3 to 8 amino acids wherein the peptide residue has a hydrophilic amino acid other than glycine at the N terminal, or (ii) a peptide residue comprising GGFGG (SEQ ID NO: 40) or GGFGGG (SEQ ID NO: 41),
each of L a and L b is a single bond, and
L c is —C(═O)—.

3. The antibody-drug conjugate according to claim 1 , wherein L P is a peptide residue having a hydrophilic amino acid other than glycine at the N terminal.

4. The antibody-drug conjugate according to claim 3 , wherein the hydrophilic amino acid other than glycine is aspartic acid, glutamic acid, lysine, serine, threonine, glutamine, asparagine, histidine, tyrosine, or arginine.

5. The antibody-drug conjugate according to claim 3 , wherein the N-terminal hydrophilic amino acid other than glycine in L P is glutamic acid, aspartic acid, or lysine.

6. The antibody-drug conjugate according to claim 4 , wherein the peptide residue following the N-terminal hydrophilic amino acid in L P is an amino acid residue comprising an amino acid selected from phenylalanine, glycine, valine, lysine, citrulline, serine, glutamic acid, and aspartic acid.

7. The antibody-drug conjugate according to claim 6 , wherein a peptide residue following the N-terminal hydrophilic amino acid in L P is a peptide residue consisting of 3 or 4 amino acids.

8. The antibody-drug conjugate according to claim 7 , wherein the peptide residue following the N-terminal hydrophilic amino acid in L P is GGF or GGFG (SEQ ID NO. 33).

9. The antibody-drug conjugate according to claim 8 , wherein L P is DGGF (SEQ ID NO. 34), KGGF (SEQ ID NO. 35), EGGF (SEQ ID NO. 36), DGGFG (SEQ ID NO. 37), KGGFG (SEQ ID NO. 38), or EGGFG (SEQ ID NO. 39).

10. The antibody-drug conjugate according to claim 8 , wherein L P is DGGFG (SEQ ID NO. 37), KGGFG (SEQ ID NO. 38), or EGGFG (SEQ ID NO. 39).

11. The antibody-drug conjugate according to any one of claims 1 to 10 , wherein the linker is a linker having a structure represented by -L 1 -L 2 -L P -NH—(CH 2 )n 1 -L a -L b -L c .

12. The antibody-drug conjugate according to claim 11 , wherein L c is —C(═O)—.

13. The antibody-drug conjugate according to claim 12 , wherein L 1 is -(Succinimid-3-yl-N)—(CH 2 )n 2 -C(═O)—, n 2 is an integer of 2 to 5, and L 2 is a single bond.

14. The antibody-drug conjugate according to claim 13 , wherein n 2 is 5.

15. The antibody-drug conjugate according to claim 14 , wherein n 1 is 1 to 3.

16. The antibody-drug conjugate according to claim 15 , wherein the structure of the —NH—(CH 2 )n 1 -L a -L b -L c - moiety in the linker is
—NH—CH 2 —C(═O)—,
—NH—(CH 2 ) 2 —C(═O)—,
—NH—(CH 2 ) 3 —C(═O)—,
—NH—CH 2 —O—CH 2 —C(═O)—, or
—NH—(CH 2 ) 2 —O—CH 2 —C(═O)—.

17. The antibody-drug conjugate according to claim 15 , wherein
the structure of the —NH—(CH 2 )n 1 -L a -L b -L c - moiety in the linker is
—NH—CH 2 —C(═O)—,
—NH—(CH 2 ) 2 —C(═O)—, or
—NH—(CH 2 ) 3 —C(═O)—.

18. The antibody-drug conjugate according to any one of claims 1 to 10 , wherein the linker is a linker having a structure represented by -L 1 -L 2 -L c -.

19. The antibody-drug conjugate according to claim 18 , wherein L 1 is -(Succinimid-3-yl-N)—(CH 2 )n 2 -C(═O)—, n 2 is an integer of 2 to 5, and L 2 is a single bond.

20. The antibody-drug conjugate according to claim 19 , wherein n 2 is 5.

21. The antibody-drug conjugate according to claim 1 , wherein the peptide residue consists of 4 to 8 amino acids in the linker.

22. The antibody-drug conjugate according to claim 1 , wherein L P is GGFGG (SE

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Naito Hiroyuki
• Nakada Takashi
• Yoshida Masao
• Ashida Shinji
• Masuda Takeshi
• Miyazaki Hideki
• Kasuya Yuji
• Abe Yuki
• Ogitani Yusuke

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07K16/00

  Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies · CPC title