Conjugate of biotin-modified dimer and phthalocyanine dye

Patent metadata

Field	Value
Publication number	US-12115223-B2
Application number	US-202117237709-A
Country	US
Kind code	B2
Filing date	Apr 22, 2021
Priority date	Apr 22, 2021
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

[Object] It is an object of the present invention to provide a conjugate of a biotin-modified dimer and a phthalocyanine dye, which is used in photoimmunotherapy.
[Means for Solution] A compound represented by the following formula (1) or a salt thereof:

wherein X represents a substituent having a hydrophilic group, a cationic group or an amino group at the terminus thereof, or —OH, and other groups have the meanings as defined in the description.

First claim

The invention claimed is:

1. A complex comprising (a) a compound represented by the following formula (1) or a salt thereof:

wherein
X represents a substituent having a hydrophilic group, a cationic group or an amino group at the terminus thereof, or —OH,
X1a, X1b, X2a and X2b each independently represent O or NH,
Y 1 and Y 2 each independently represent C or S,
Z 1 and Z 2 each independently represent O, S or NH,
V 1 and V 2 each independently represent S or S + —O − ,
n1 and n2 each independently represent an integer of 0 or 1,
L 1 and L 2 each independently represent a divalent linking group,
L 3 represents a trivalent linking group,
L 4 , L 5 , and L 6 each independently represent a divalent linking group, and (b) a conjugate of mutant streptavidin, comprising a molecular probe conjugated to mutant streptavidin.

2. The compound according to claim 1 or a salt thereof, which is represented by the following formula (2):

wherein each symbol is as defined in claim 1 .

3. The complex according to claim 1 , wherein X1a, X1b, X2a and X2b represent NH; Y 1 and Y 2 represent C; Z 1 and Z 2 represent NH; and V 1 and V 2 represent S.

4. The complex according to claim 1 , wherein L 1 and L 2 each independently represent a divalent linking group consisting of a combination of groups selected from —CONH—, —NHCO—, —COO—, —OCO—, —CO—, —O—, and an alkylene group containing 1 to 10 carbon atoms.

5. The complex according to claim 1 , wherein L 4 represents a group consisting of a combination of groups selected from —CONH—, —NHCO—, —COO—, —OCO—, —CO—, —O—, —NH—, and an alkylene group containing 1 to 10 carbon atoms.

6. The complex according to claim 1 , wherein L 5 represents

a triazole group, —S—, —CONH—, —NHCO—, —COO—, —OCO—, —CO—, —O—, —NH—, an alkylene group containing 1 to 10 carbon atoms, or a group consisting of a combination of these groups.

7. The complex according to claim 1 , wherein L 6 represents —Si(R 1 )(R 2 )—O—, —CONH—, —NHCO—, —COO—, —OCO—, —CO—, —O—, —NH—, an alkylene group containing 1 to 10 carbon atoms, or a group consisting of a combination of these groups.

8. The complex according to claim 1 , wherein the substituent having a hydrophilic group, a cationic group or an amino group at the terminus thereof, which is represented by X, is any one of the following:

9. The complex according to claim 8 , wherein the substituent having a hydrophilic group, a cationic group or an amino group at the terminus thereof, which is represented by X, is the Formula 4-3.

10. The complex according to claim 8 , wherein the substituent having a hydrophilic group, a cationic group or an amino group at the terminus thereof, which is represented by X, is the Formula 4-4.

11. A therapeutic agent comprising the complex according to claim 1 and a pharmaceutically acceptable carrier.

12. A therapeutic kit comprising: (1) the complex according to claim 1 , wherein the conjugate of mutant streptavidin comprises the amino acid sequence as set forth in SEQ ID NO: 1 (provided that a part of or the entire histidine tag at the C-terminus may be deleted).

13. The therapeutic kit according to claim 12 , wherein the molecular probe is an anti-EREG antibody, an anti-CEA antibody, or an anti-HER2 antibody.

14. The complex according to claim 1 , wherein L 5 is [Formula 3]

15. A method of suppressing proliferation of cancer cells which comprises:
administering a complex of the complex of claim 1 , and wherein the conjugate of mutant streptavidin comprises the amino acid sequence as set forth in SEQ ID NO: 1 (provided that a part of or the entire histidine tag at the C-terminus may be deleted), to a subject; and
irradiating the cells with an excitation light in an amount effective for suppression of cell proliferation or induction of cell death.

16. The method according to claim 15 , wherein the subject is affected with cancer or solid tumor.

17. The method according to claim 15 , wherein wavelength of irradiation light is 660 to 740 nm.

18. The method according to claim 15 , wherein light irradiation amount is 1 to 500 J/cm 2 .

19. The method according to claim 15 , wherein the molecular probe is an anti-EREG antibody, an anti-CEA antibody, or an anti-HER2 antibody.

20. A complex of claim 1 , wherein the compound of (a) is any one of the following:

Assignees

• Univ Tokyo
• Savid Therapeutics Inc

Inventors

• Kanai Motomu
• Yamatsugu Kenzo
• TATSUMI Toshifumi
• Takahashi Kazuki
• Kodama Tatsuhiko
• Sugiyama Akira
• Yamashita Takefumi
• TSUKAGOSHI Masanobu
• Toda Yuzo
• Nishigaki Junji

Classifications

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K41/0071

  PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines · CPC title

• A61K47/6898

  using avidin- or biotin-conjugated antibodies · CPC title

• A61K47/6853

  Carcino-embryonic antigens · CPC title