Anti-DLL3 antibody drug conjugates and methods of use
View Patent ↗Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat tumors having neuroendocrine features are provided.
1. A method of treating a tumor comprising neuroendocrine features in a subject, wherein the tumor is characterized by elevated expression of ASCL1, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:
M comprises an anti-DLL3 antibody;
L comprises an optional linker;
D comprises a cytotoxic agent; and
n is an integer from 1 to 20.
2. The method of claim 1 , wherein the tumor shows suppressed Notch signaling.
3. The method of claim 1 , wherein the tumor shows elevated levels of DLL3 and/or HES6 as compared to normal tissue or non-tumorigenic cells.
4. The method of claim 3 , wherein the tumor shows reduced levels of one or more markers selected from the group consisting of HES1, HEY1, JAG1, and Notch receptor.
5. The method of claim 3 , wherein the tumor shows elevated levels of one or more markers selected from the group consisting of neuron-specific enolase (ENO2), CD56 (NCAM1), synaptophysin (SYP), chomogranin A (CHGA), dopa decarboxylase (DDC), PGP9.5 (UCHL1), calcitonin (CALCA), somatostatin (SST), and NK2 homeobox 1 (NKX2-1).
6. The method of claim 1 , wherein the tumor is characterized by a poorly differentiated neuroendocrine phenotype.
7. The method of claim 1 , wherein the tumor occurs in lung, genitourinary tract, gastrointestinal tract, thyroid, or kidney.
8. The method of claim 7 , wherein the tumor comprises small cell lung cancer.
9. The method of claim 7 , wherein the tumor is a large cell neuroendocrine carcinoma.
10. The method of claim 9 , wherein the anti-DLL3 antibody competes for binding to human DLL3 protein with an antibody comprising a light chain variable region set forth as SEQ ID NO: 84 and a heavy chain variable region set forth as SEQ ID NO: 85.
11. The method of claim 9 , wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 84 for CDR-L 1, residues 50-56 of SEQ ID NO: 84 for CDR-L2, residues 89-97 of SEQ ID NO: 84 for CDR-L3, residues 31-35 of SEQ ID NO: 85 for CDR-H1, residues 50-65 of SEQ ID NO: 85 for CDR-H2 and residues 95-102 of SEQ ID NO: 85 for CDR-H3, wherein the residues are numbered according to Kabat.
12. The method of claim 11 , wherein D comprises a pyrrolobenzodiazepine (PBD).
13. The method of claim 9 , wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 212 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 213.
14. The method of claim 7 , wherein the tumor comprises ovarian cancer.
15. The method of claim 7 , wherein the tumor comprises prostate cancer.
16. The method of claim 15 , wherein the anti-DLL3 antibody competes for binding to human DLL3 protein with an antibody comprising a light chain variable region set forth as SEQ ID NO: 84 and a heavy chain variable region set forth as SEQ ID NO: 85.
17. The method of claim 15 , wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 84 for CDR-L 1, residues 50-56 of SEQ ID NO: 84 for CDR-L2, residues 89-97 of SEQ ID NO: 84 for CDR-L3, residues 31-35 of SEQ ID NO: 85 for CDR-H1, residues 50-65 of SEQ ID NO: 85 for CDR-H2 and residues 95-102 of SEQ ID NO: 85 for CDR-H3, wherein the residues are numbered according to Kabat.
18. The method of claim 17 , wherein D comprises a pyrrolobenzodiazepine (PBD).
19. The method of claim 15 , wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 212 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 213.
20. The method of claim 7 , wherein the tumor comprises medullary thyroid cancer.
21. The method of claim 7 , wherein the tumor comprises renal cancer.
22. The method of claim 1 , wherein M comprises an anti-DLL3 antibody that specifically binds to an epitope within the DSL domain of a DLL3 protein set forth as SEQ ID NO: 3 or 4.
23. The method of claim 1 , wherein the anti-DLL3 antibody specifically binds to an epitope comprising amino acids G203, R205 and P206 (SEQ ID NO: 10).
24. The method of claim 1 , wherein the anti-DLL3 antibody is a chimeric antibody, a CDR-grafted antibody, or a humanized antibody.
25. The method of claim 1 , wherein the anti-DLL3 antibody competes for binding to human DLL3 protein with an antibody comprising a light chain variable region set forth as SEQ ID NO: 84 and a heavy chain variable region set forth as SEQ ID NO: 85.
26. The method of claim 1 , wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 84 for CDR-L 1, residues 50-56 of SEQ ID NO: 84 for CDR-L2, residues 89-97 of SEQ ID NO: 84 for CDR-L3, residues 31-35 of SEQ ID NO: 85 for CDR-H1, residues 50-65 of SEQ ID NO: 85 for CDR-H2 and residues 95-102 of SEQ ID NO: 85 for CDR-H3, wherein the residues are numbered according to Kabat.
27. The method of claim 1 , wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 212 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 213.
28. The method of claim 1 , wherein D comprises a pyrrolobenzodiazepine (PBD).
29. A method of treating large cell neuroendocrine carcinoma in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:
M comprises an anti-DLL3 antibody, wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 84 for CDR-L1, residues 50-56 of SEQ ID NO: 84 for CDR-L2, residues 89-97 of SEQ ID NO: 84 for CDR-L3, residues 31-35 of SEQ ID NO: 85 for CDR-H1, residues 50-65 of SEQ ID NO: 85 for CDR-H2 and residues 95-102 of SEQ ID NO: 85 for CDR-H3, wherein the residues are numbered according to Kabat;
L comprises a linker;
D comprises a pyrrolobenzodiazepine (PBD); and
n is an integer from 1 to 20.
30. A method of treating prostate cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of an anti-DLL3 antibody drug conjugate (ADC), or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate (ADC) comprises the formula M-[L-D]n, wherein:
M comprises an anti-DLL3 antibody, wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 84 for CDR-L1, residues 50-56 of SEQ ID NO: 84 for CDR-L2, residues 89-97 of SEQ ID NO: 84 for CDR-L3, residues 31-35 of SEQ ID NO: 85 for CDR-H1, residues 50-65 of SEQ ID NO: 85 for CDR-H2 and residues 95-102 of SEQ ID NO: 85 for CDR-H3, wherein the residues are numbered according to Kabat;
L comprises a linker;
D comprises a pyrrolobenzodiazepine (PBD); and
n is an integer from 1 to 20.