Charged linkers and their uses for conjugation

Patent metadata

Field	Value
Publication number	US-10696700-B2
Application number	US-201816228310-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Feb 28, 2014
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

Cell binding agent-drug conjugates comprising phosphinate-based charged linkers and methods of using such linkers and conjugates are provided.

First claim

What is claimed is:

1. A compound of formula (III):

wherein Cb represents a cell-binding agent which is an antibody, or a fragment thereof;
n is an integer from 1 to 20; and
the compound of formula (III) is formed by reacting a functional group on the cell-binding agent with Y in a compound of formula (I):

wherein Z is a thiol, disulfide, unsubstituted or substituted pyridyldisulfide, unsubstituted or substituted amino, —ONH 2 , carboxy, aldehyde, ketone, azide, unsubstituted or substituted maleimido, haloacetyl, halogen, hydrazine, hydrazide or hydroxy group;
M is H, Na, K, N + R 1 R 2 R 3 or a pharmaceutical salt thereof;
R 1 and R 2 are the same or different and are a linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
R 3 is absent, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
or R 1 , R 2 and R 3 are respectively a chain of atoms selected from the group consisting of C, N, O, S, Si, and P, and R 1 , R 2 and R 3 optionally covalently connect among each other;
R 4 , and R 5 , are the same or different and are absent, H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p-1 OCH 2 CH 3 , wherein p-1 is an integer from 1 to about 1000, or a combination thereof; and
Y is an unsubstituted or substituted N-hydroxysuccinimide ester, hydrazide, p-nitrophenyl ester, dinitrophenyl ester, pentafluorophenyl ester, pyridyldisulfide, nitropyridyldisulfide, unsubstituted or substituted maleimido, β-maleimidopropionamido, haloacetate, or carboxylic acid halide.

2. The compound of claim 1 , wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that binds the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment that binds to the target cell, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment that binds to the target cell.

3. The compound of claim 1 , wherein the cell-binding agent binds to target cells which are selected from the group consisting of tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing the CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD 51, CD52, CD56, CD66, CD70, CD74, CD79, CD80, CD98, CD125, CD221, CD227, CD262, CD309, CD326, CEACAM3, CEACAM5 (carcinoembryonic antigen), DLL4 (A-like-4), EGFR, CTLA4, CXCR4 (CD184), Endoglin (CD105), EPCAM (epithelial cell adhesion molecule), ERBB2 (Epidermal Growth Factor Receptor 2), FCGR1, FOLR (folate receptor,), GD2 ganglioside, G-28 (a cell surface antigen glyvolipid), GD3 idiotype, Heat shock proteins, HER1, HER2, HLA-DR10, HLA-DRB, human chorionic gonadotropin, IGF1R (insulin-like growth factor 1 receptor), IL-2 receptor (interleukin 2 receptor), IL-6R (interleukin 6 receptor), Integrins (αvβ3, α5β1, α6β4, α11β3, α5β5, αvβ5), MAGE-1, MAGE-2, MAGE-3, MAGE 4, anti-transferrin receptor, p9′7, MS4A1 (membrane-spanning 4-domains subfamily A member 1), MUC1 or MUC1-KLH, MUC16 (CA125), CEA, gp100, MART 1, MPG, MS4A1 (membrane-spanning 4-domains subfamily A), Nucleolin, Neu oncogene product, P21, Paratope of anti-(N-glycolylneuraminic acid), PLAP-like testicular alkaline phosphatase, PSMA, PSA, ROBO4, TAG 72 (tumor associated glycoprotein 72), T cell transmembrane protein, Tie (CD202b), TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (tumor necrosis apoprosis inducing ligand receptor 1), VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), CanAg, CALLA, and cells expressing insulin growth factor receptor, and epidermal growth factor receptor.

4. The compound of claim 3 , wherein the tumor cells are selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, testicular cancer cells, or any cells that grow and divide at an unregulated, quickened pace to cause cancers.

5. The compound of claim 1 , wherein Z is an unsubstituted or substituted pyridyldisulfide, unsubstituted or substituted amino, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido.

6. The compound of claim 1 , wherein R 1 and R 2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms.

7. The compound of claim 1 , wherein R 3 , R 4 and R 5 are absent.

8. The compound of claim 1 , wherein R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, and R 4 and R 5 are absent.

9. The compound of claim 8 , wherein p is an integer from 1 to 24.

10. The compound of claim 1 , wherein M is H.

11. The compound of claim 1 , wherein
Z is an unsubstituted or substituted pyridyldisulfide, unsubstituted or substituted amino, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido;
R 1 and R 2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 3 , R 4 and R 5 are absent; and
M is H.

12. The compound of claim 1 , wherein
Z is an unsubstituted pyridyldisulfide, unsubstituted or substituted amino, —ONH 2 , ketone, azide, or unsubstituted maleimido;
R 1 and R 2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 3 , R 4 and R 5 are absent; and
M is H.

13. The compound of claim 1 , wherein
Z is an unsubstituted or substituted pyridyldisulfide, unsubstituted or substituted amino, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido;
R 1 and R 2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.

14. The compound of claim 1 , wherein
Z is an unsubstituted pyridyldisulfide, unsubstituted or substituted amino, —ONH 2 , ketone, azide, or unsubstituted maleimido;
R 1 and R 2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.

15. The compound of claim

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert Yongxin
• Li Xing
• Huang Yuangyuang
• Yang Qingliang

Classifications

• A61K47/6803

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

• A61K38/07

  Tetrapeptides · CPC title

• A61K47/6809

  Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07F9/302

  Acyclic unsaturated acids · CPC title