Disulfide bridging conjugates
Provided are bispecific conjugates having the general formula: pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and their use in the treatment of cancer.
1. An antibody Fab conjugate having a Formula I or a Formula II:
or a pharmaceutically acceptable salt thereof, wherein each n is independently an integer from 2 to 20; each m is independently an integer from 2 to 15; and wherein each FAB fragment is connected to a pyrrolidine-dione moiety or a CH 2 -quinoxalinyl moiety through native cysteine residues in the Fab fragment.
2. The antibody Fab conjugate of claim 1 , wherein n is an integer from 2 to 12.
3. The antibody Fab conjugate of claim 2 , wherein n is an integer from 4 to 10.
4. The antibody Fab conjugate of claim 3 , wherein n is 8.
5. The antibody Fab conjugate of claim 1 wherein m is an integer from 2 to 10.
6. The antibody Fab conjugate of claim 5 , wherein m is an integer from 4 to 8.
7. The antibody Fab conjugate of any one of claim 6 , wherein m is 6.
8. The antibody Fab conjugate of claim 7 , wherein the FAB fragment comprises a CD3 binding region.
9. A pharmaceutical composition comprising the antibody Fab conjugate of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
10. A method of treating prostate cancer or adenocarcinoma, comprising administering to a subject in need thereof a conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, or the composition of claim 9 .
11. The method of claim 10 , wherein the subject has prostate cancer.
12. The method of claim 10 , wherein the subject has an adenocarcinoma.
13. A method of inducing cell death of a PSMA-expressing cell, comprising contacting the PSMA-expressing cell with the conjugate of claim 1 .
14. The method of claim 13 , wherein the FAB fragment comprises a CD3 binding region.
15. The method of claim 13 , wherein the conjugate induces cell death in an effector-cell-dependent manner.
16. The method of claim 15 , wherein the effector cell is a peripheral blood mononuclear cell.
17. The antibody Fab conjugate of claim 1 , which is of Formula I.
18. The antibody Fab conjugate of claim 1 , which is of Formula II.