Anti-DLL3 antibodies and drug conjugates for use in melanoma
Anti-DLL3 antibodies and antibody drug conjugates for use in the diagnosis and treatment of melanoma.
1. A method of treating melanoma in a subject, wherein the melanoma is characterized as having a DLL3 expression level above a threshold index value, the method comprising the step of administering to the subject an anti-DLL3 antibody drug conjugate, wherein the antibody drug conjugate comprises the formula M-[L-D]n wherein:
M comprises an anti-DLL3 antibody comprising three CDRs of a light chain variable region amino acid sequence of SEQ ID NO: 405 and three CDRs of a heavy chain variable region amino acid sequence of SEQ ID NO: 407;
L comprises a linker;
D comprises a pyrrolobenzodiazepine (PBD); and
n is an integer from 1 to 8.
2. The method of claim 1 , wherein the melanoma is refractory melanoma.
3. The method of claim 2 , wherein the melanoma is dacarbazine-refractory melanoma, vemurafenib-refractory melanoma, trametinib-refractory melanoma or dasatinib-refractory melanoma.
4. The method of claim 1 , wherein the melanoma comprises wild type BRAF.
5. The method of claim 1 , wherein the melanoma comprises mutated BRAF.
6. The method of claim 1 , wherein the melanoma comprises wild type NRAS.
7. The method of claim 1 , wherein the melanoma comprises mutated NRAS.
8. The method of claim 1 , wherein the antibody drug conjugate (ADC) comprises an anti-DLL3 antibody that is a chimeric antibody, a CDR-grafted antibody, or a humanized antibody.
9. 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: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407.
10. The method of claim 1 , wherein the melanoma is stage II melanoma.
11. The method of claim 1 , wherein the patient has previously undergone tumor resection.
12. The method of claim 1 , wherein the linker comprises a cleavable linker.
13. The method of claim 12 , wherein the cleavable linker comprises a dipeptide.
14. The method of claim 13 , wherein the dipeptide is Val-Ala.
15. The method of claim 1 , wherein the PBD is PBD1:
16. The method of claim 1 , wherein the anti-DLL3 antibody comprises:
(a) residues 24-34 of SEQ ID NO: 405 for CDR-L1, residues 50-56 of SEQ ID NO: 405 for CDR-L2, residues 89-97 of SEQ ID NO: 405 for CDR-L3, residues 31-35 of SEQ ID NO: 407 for CDR-H1, residues 50-65 of SEQ ID NO: 407 for CDR-H2 and residues 95-102 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to Kabat;
(b) residues 24-34 of SEQ ID NO: 405 for CDR-L1, residues 50-56 of SEQ ID NO: 405 for CDR-L2, residues 89-97 of SEQ ID NO: 405 for CDR-L3, residues 26-32 of SEQ ID NO: 407 for CDR-H1, residues 52-56 of SEQ ID NO: 407 for CDR-H2 and residues 95-102 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to Chothia; or
(c) residues 30-36 of SEQ ID NO: 405 for CDR-L1, residues 46-55 of SEQ ID NO: 405 for CDR-L2, residues 89-96 of SEQ ID NO: 405 for CDR-L3, residues 30-35 of SEQ ID NO: 407 for CDR-H1, residues 47-58 of SEQ ID NO: 407 for CDR-H2 and residues 93-101 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to MacCallum.
17. A method of treating melanoma in a subject, wherein the melanoma is dacarbazine-refractory melanoma, vemurafenib-refractory melanoma, trametinib-refractory melanoma or dasatinib-refractory melanoma, the method comprising the step of administering to the subject an anti-DLL3 antibody drug conjugate, wherein the antibody drug conjugate comprises a humanized anti-DLL3 antibody conjugated to one or more pyrrolobenzodiazepines (PBDs), and wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407.
18. The method of claim 17 , wherein the PBD is PBD1:
19. The method of claim 18 , wherein the melanoma comprises wild type BRAF.
20. The method of claim 18 , wherein the melanoma comprises mutated BRAF.
21. The method of claim 18 , wherein the melanoma comprises wild type NRAS.
22. The method of claim 18 , wherein the melanoma comprises mutated NRAS.
23. The method of claim 17 , wherein the melanoma is stage II melanoma.
24. The method of claim 17 , wherein the patient has previously undergone tumor resection.
25. A method of treating stage II melanoma in a subject, the method comprising the step of administering to the subject an anti-DLL3 antibody drug conjugate, wherein the antibody drug conjugate comprises a humanized anti-DLL3 antibody conjugated to one or more pyrrolobenzodiazepines (PBDs), wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407; and wherein the PBD is PBD1:
26. The method of claim 25 , wherein the melanoma is refractory melanoma.
27. The method of claim 25 , wherein the melanoma is dacarbazine-refractory melanoma, vemurafenib-refractory melanoma, trametinib-refractory melanoma or dasatinib-refractory melanoma.
28. The method of claim 25 , wherein the patient has previously undergone tumor resection.