Ligand-cytotoxic drug conjugate, preparation method thereof, and uses thereof

• US 10,562,977 B2
• Filed: 01/22/2015
• Issued: 02/18/2020
• Est. Priority Date: 01/29/2014
• Status: Active Grant

• Current Assignee: Jiangsu Hengrui Medicine Company Limited, Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.)
• Original Assignee: Shanghai Hengrui Pharmaceutical Co., Ltd. (Jiangsu Hengrui Pharmaceuticals Co., Ltd.)
• Inventors: Wang, Yali, Zhang, Lianshan, Liang, Jindong, Li, Ang, Yang, Fanglong
• Primary Examiner(s): Canella, Karen A.
• Application Number:
  US15/113,610
• Publication Number:
  US 20170002090A1
• Time in Patent Office: 1,853 Days
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2851 against the lectin superfamily, e.g. CD23, CD72
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2884 against CD44
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/32 against translation products of oncogenes

Abstract

Ligand-cytotoxic drug conjugates, pharmaceutical compositions, preparation methods, and pharmaceutical uses thereof are provided. More specifically, a ligand-cytotoxic drug conjugate of general formula Pc-(X-Y-D)_n is provided. The ligand-cytotoxic drug conjugate can be used to treat cancer via receptor modulation.

Claims

1. A ligand-cytotoxic drug conjugate of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

PcX—

Y-D)_n 

 

(I)

wherein Pc is an antibody;

Y is an interval unit;

D is a cytotoxic drug;

n is selected from 1 to 8;

X is a connecting unit linked to at least one of an N-terminal amino group of the antibody of the ligand Pc and an ε

-amino group of a lysine residue of the antibody of the ligand Pc, wherein the connecting unit X has the following structure;

2. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X₁ is H or alkyl.

3. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein X₂ is alkyl or aryl.

4. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the antibody is specific for a cell surface antigen expressed on at least one of a target cell and tissue of a proliferative disease.

5. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein the cell surface antigen is selected from the group consisting of:

HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), CD20, CD22, CD30, CD33, CD44, Lewis Y, CD56, CD105, VEGFR, and GPNMB.

6. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 5, wherein the cell surface antigen is selected from the group consisting of:

HER2 (ErbB2), CD22, CD30, CD33, CD44, CD56, Lewis Y, and GPNMB.

7. The ligand-conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the antibody is selected from the group consisting of:

Trastuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96, Glematumamab and Pertuzumab.

8. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 7, wherein the antibody is capable of binding to a HER2 protein, wherein the antibody comprises:

1) a light chain comprising CDR-L1, CDR-L2 and CDR-L3 sequences defined according to Kabat numbering system, wherein;

i) CDR-L1 is a CDR of SEQ ID NO;

7;

ii) CDR-L2 is a CDR of SEQ ID NO;

8;

iii) CDR-L3 is a CDR of SEQ ID NO;

9; and

2) a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 sequences defined according to Kabat numbering system, wherein;

iv) CDR-H1 is a CDR of SEQ ID NO;

10;

v) CDR-H2 is a CDR of SEQ ID NO;

11;

vi) CDR-H3 is a CDR of SEQ ID NO;

12.

9. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 8, wherein the antibody capable of binding to the HER2 protein comprises a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence of SEQ ID NO:

13, and the heavy chain comprises the amino acid sequence of SEQ ID NO;

14.

10. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the cytotoxic drug is selected from the group consisting of tubulin inhibitors, topoisomerase inhibitors, DNA alkylating agents, tyrosine kinase inhibitors, and DNA synthesis inhibitors.

11. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 10, wherein the cytotoxic drug is a tubulin inhibitor selected from the group consisting of maytansinoids, calicheamicin, taxanes, vincristine, colchicine, and Dolastatins/Auristatins.

12. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein D is selected from the group consisting of Dolastatins/Auristatins having a structure of formula (D₁):

13. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein D is maytansine having a structure of formula (D_M):

14. The ligand-cytotoxic drug conjugate or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the interval unit —

Y—

has a structure of the following formula;

16. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, having a structure of formula (III):

20. A process of preparing an antibody-cytotoxic drug conjugate of formula (III) according to claim 16:

21. A pharmaceutical composition comprising the ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. A method for modulating a receptor in vitro, the method comprising contacting the receptor with an effective amount of the pharmaceutical composition according to claim 21, wherein the receptor is selected from the group consisting of:

HER2 (ErbB2), CD22, CD30, CD33, CD44, CD56, Lewis Y, and GPNMB.

23. A method of treating cancer in a human subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 21, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary gland cancer, lung cancer, colon cancer, renal cancer, rectal cancer, thyroid cancer, pancreatic cancer, prostate cancer, bladder cancer, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma and relapsed anaplastic large cell lymphoma.

24. A method of treating cancer in a subject in the need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 21, wherein the cancer is a tumor-associated receptor overexpressed cancer, wherein the tumor-associated receptor is one or more selected from the group consisting of:

HER2 (ErbB2), CD22, CD30, CD33, CD44, CD56, Lewis Y, and GPNMB.

25. The process according to claim 20, wherein the compound of formula (IE) is a compound of formula (IV):

15. A compound of formula (II):

PcX-T)_n 

 

(II)

wherein;

Pc is an antibody;

T is selected from the group consisting of H, t-butyl, acetyl, n-propionyl, isopropionyl, triphenylmethyl, methoxymethyl, and 2-(trimethylsilyl)ethoxymethyl;

n is selected from 1 to 8; and

X is a connecting unit linked to at least one of an N-terminal amino group of the antibody Pc and an ε

-amino group of a lysine residue of the antibody Pc, wherein the connecting unit X has the following structure;

17. A ligand-cytotoxic drug conjugate or a pharmaceutically acceptable salt or solvate thereof selected from the group consisting of:

18. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 17, wherein Pc is selected from the group consisting of Trastuzumab, Inotuzumab and Brentuximab.

19. The ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 17, selected from the group consisting of:

26. A pharmaceutical composition comprising the ligand-cytotoxic drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to claim 19, and one or more pharmaceutically acceptable carriers, diluents or excipients.

27. A method of treating cancer in a human subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 26, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary gland cancer, lung cancer, colon cancer, renal cancer, rectal cancer, thyroid cancer, pancreatic cancer, prostate cancer, bladder cancer, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma and relapsed anaplastic large cell lymphoma.

28. The method according to claim 27, wherein the cancer is selected from the group consisting of breast cancer, Hodgkin'"'"'s lymphoma, and relapsed anaplastic large cell lymphoma.