Linkers, conjugates and applications thereof
View Patent ↗The present disclosure relates to a linker molecule for targeting molecule-drug conjugate, and the corresponding conjugate, the preparation and use thereof.
1. A conjugate, wherein the conjugate has the structure of the following:
wherein each g is independently an integer of 1 to 6;
each i, i1, i2, i3, and i4 is independently an integer of 2 to 8;
each j is independently an integer of 8 to 12;
R 11 is C 1-10 alkyl;
z is 1 to 4;
opSu is
or a mixture thereof; and
A is an anti-human monoclonal HER2 antibody connected to the rest of the conjugate through a modified heavy chain and/or light chain C-terminal, wherein the modified heavy chain and/or light chain C-terminal is modified to comprise Leu-Pro-Xaa-Thr (SEQ ID NO:22), wherein Xaa is any natural or unnatural single amino acid.
2. The conjugate of claim 1 ,
wherein each g is 1.
3. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 1 , and at least one pharmaceutically acceptable carrier.
4. A method of treating a disease in a subject in need thereof, wherein the disease is a HER2-positive tumor, wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 1 to the subject.
5. The method of claim 4 , wherein the HER2-positive tumor is selected from breast cancer, gastric cancer, lung cancer, ovarian cancer, and urothelial cancer.
6. The conjugate of claim 1 , wherein each i, i1, i2, i3, and i4 is 4; and
each j is 8 or 12.
7. A conjugate, wherein the conjugate has the structure:
wherein i is 4, j is 8 or 12, R 11 is methyl, g is 1,
opSu is
or a mixture thereof,
A is an anti-human monoclonal HER2 antibody connected to the rest of the conjugate through a modified heavy chain and/or light chain C-terminal, wherein the modified heavy chain and/or light chain C-terminal is modified to comprise Leu-Pro-Xaa-Thr (SEQ ID NO:22), wherein Xaa is any natural or unnatural single amino acid, and z is 2.
8. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 7 , and at least one pharmaceutically acceptable carrier.
9. The conjugate of claim 7 , wherein the antibody comprises the light chain amino acid sequence of SEQ ID NO: 19 and the heavy chain amino acid sequence of SEQ ID NO:2 or the heavy chain sequence amino acid sequence of SEQ ID NO:21.
10. The conjugate of claim 7 , wherein j is 8.
11. The conjugate of claim 7 , wherein j is 12.
12. The conjugate of claim 7 , wherein Xaa is Glu.
13. The conjugate of claim 1 , wherein Xaa is Glu.
14. The conjugate of claim 1 , wherein the modified heavy chain and/or light chain C-terminal is modified to comprise Gly-Ala-Leu-Pro-Xaa-Thr (SEQ ID NO:23).
15. The conjugate of claim 7 , wherein the modified heavy chain and/or light chain C-terminal is modified to comprise Gly-Ala-Leu-Pro-Xaa-Thr (SEQ ID NO:23).
16. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 9 , and at least one pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 10 , and at least one pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 11 , and at least one pharmaceutically acceptable carrier.
19. A method of treating a disease in a subject in need thereof, wherein the disease is a HER2-positive tumor, wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 7 to the subject.
20. The method of claim 19 , wherein the HER2-positive tumor is selected from breast cancer, gastric cancer, lung cancer, ovarian cancer, and urothelial cancer.
21. A method of treating a disease in a subject in need thereof, wherein the disease is a HER2-positive tumor, wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 9 to the subject.
22. The method of claim 21 , wherein the HER2-positive tumor is selected from breast cancer, gastric cancer, lung cancer, ovarian cancer, and urothelial cancer.
23. A method of treating a disease in a subject in need thereof, wherein the disease is a HER2-positive tumor, wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 10 to the subject.
24. The method of claim 23 , wherein the HER2-positive tumor is selected from breast cancer, gastric cancer, lung cancer, ovarian cancer, and urothelial cancer.
25. A method of treating a disease in a subject in need thereof, wherein the disease is a HER2-positive tumor, wherein the method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the conjugate of claim 11 to the subject.
26. The method of claim 25 , wherein the HER2-positive tumor is selected from breast cancer, gastric cancer, lung cancer, ovarian cancer, and urothelial cancer.