Pyrrolobenzodiazepine-antibody conjugates
View Patent ↗The present disclosure relates to pyrrolobenzodiazepines (PBDs) having a labile C2 or N10 protecting group in the form of a linker to an antibody.
1. A conjugate of formula ConjE:
wherein Ab is an antibody that binds to kidney associated antigen 1 (KAAG1), the antibody comprising a VH domain comprising a VH CDR1 amino acid sequence of SEQ ID NO.5, a VH CDR2 amino acid sequence of SEQ ID NO.6, and a VH CDR3 amino acid sequence of SEQ ID NO.7; and
wherein the drug loading (p) is from 1 to 8.
2. The conjugate according to claim 1 , wherein the antibody comprises a VH domain having the amino acid sequence of SEQ ID NO. 1.
3. The conjugate according to claim 1 , wherein the antibody comprises:
a VL domain comprising a VL CDR1 amino acid sequence of SEQ ID NO.8, a VL CDR2 amino acid sequence of SEQ ID NO.9, and a VL CDR3 amino acid sequence of SEQ ID NO.10.
4. The conjugate according to claim 1 , wherein the antibody comprises a VL domain having the amino acid sequence of SEQ ID NO. 2.
5. The conjugate according to claim 1 , wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO. 3 or SEQ ID NO. 11.
6. The conjugate according to claim 1 , wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
7. The conjugate according to claim 1 , wherein the antibody is an intact antibody.
8. The conjugate according to claim 1 , wherein the antibody is humanised, deimmunized, or resurfaced.
9. The conjugate according to claim 1 , wherein the antibody is a fully human monoclonal IgG1 antibody.
10. The conjugate of claim 9 , wherein the antibody is a fully human monoclonal IgG1,κ antibody.
11. The conjugate according to claim 1 , wherein the drug loading (p) is 1, 2, 3, or 4.
12. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable diluent, carrier or excipient.
13. The pharmaceutical composition of claim 12 , comprising a mixture of antibody-drug conjugates, wherein the average drug loading (p) per antibody in the mixture of antibody-drug conjugates is about 2 to about 5.
14. The pharmaceutical composition of claim 12 , further comprising a therapeutically effective amount of a chemotherapeutic agent.
15. A method of treating a kidney associated antigen 1 (KAAG1)-overexpressing cancer in a patient comprising administering to the patient the conjugate of claim 1 .
16. The method of claim 15 , which further comprises administering to the patient a chemotherapeutic agent in combination with the conjugate.
17. The method of claim 15 , wherein the cancer is ovarian cancer, breast cancer, prostate cancer, or renal cancer.