Anti-DLL3 antibodies
View Patent ↗Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat proliferative disorders are provided.
1. An isolated monoclonal antibody, which specifically binds to an epitope within the DSL domain of a DLL3 protein set forth as SEQ ID NO: 3 or 4, wherein the isolated monoclonal antibody is a chimeric antibody, a CDR-grafted antibody, or a humanized antibody.
2. The isolated monoclonal antibody of claim 1 , wherein the epitope comprises amino acids G203, R205 and P206 (SEQ ID NO: 10).
3. The isolated monoclonal antibody of claim 1 , which specifically binds to tumor initiating cells.
4. The isolated monoclonal antibody of claim 1 , which is an internalizing antibody.
5. The isolated monoclonal antibody of claim 1 , which is selected from the group consisting of a primatized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti-idiotypic antibody, diabody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
6. The isolated monoclonal antibody of claim 1 , which competes for binding to human DLL3 protein with an antibody comprising a light chain variable region set forth as SEQ ID NO: 60 and a heavy chain variable region set forth as SEQ ID NO: 61.
7. The isolated monoclonal antibody of claim 1 , which 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.
8. The isolated monoclonal antibody of claim 1 , which comprises residues 24-34 of SEQ ID NO: 60 for CDR-L1, residues 50-56 of SEQ ID NO: 60 for CDR-L2, residues 89-97 of SEQ ID NO: 60 for CDR-L3, residues 31-35 of SEQ ID NO: 61 for CDR-H1, residues 50-65 of SEQ ID NO: 61 for CDR-H2 and residues 95-102 of SEQ ID NO: 61 for CDR-H3, wherein the residues are numbered according to Kabat.
9. The isolated monoclonal antibody of claim 1 , which comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 210 or a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 211.
10. The isolated monoclonal antibody of claim 9 , which comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 210 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 211.
11. The isolated monoclonal antibody of claim 1 , which 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.
12. The isolated monoclonal antibody of claim 1 , which comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 212 or a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 213.
13. The isolated monoclonal antibody of claim 12 , which 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. A pharmaceutical composition comprising the isolated monoclonal antibody of claim 1 and a pharmaceutically acceptable carrier.
15. An isolated monoclonal antibody, which competes for binding to human DLL3 protein with (a) an antibody comprising a light chain variable region set forth as SEQ ID NO: 60 and a heavy chain variable region set forth as SEQ ID NO: 61; or (b) 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, wherein the isolated antibody is a chimeric antibody, a CDR-grafted antibody, or a humanized antibody.
16. The isolated monoclonal antibody of claim 15 , which inhibits the binding of an antibody comprising a light chain variable region set forth as SEQ ID NO: 60 and a heavy chain variable region set forth as SEQ ID NO: 61, or of 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, by at least about 40%.
17. The isolated monoclonal antibody of claim 15 , which specifically binds to tumor initiating cells.
18. The isolated monoclonal antibody of claim 15 , which is an internalizing antibody.
19. The isolated monoclonal antibody of claim 15 , which is selected from the group consisting of a primatized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti-idiotypic antibody, diabody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
20. A pharmaceutical composition comprising the isolated monoclonal antibody of claim 15 and a pharmaceutically acceptable carrier.
21. An isolated antibody comprising 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, wherein the isolated antibody is a chimeric antibody, a CDR-grafted antibody, or a humanized antibody.
22. The antibody of claim 21 , which is selected from the group consisting of a monoclonal antibody, primatized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, anti-idiotypic antibody, diabody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
23. The isolated antibody of claim 21 , which comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 212 or a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 213.
24. The isolated antibody thereof of claim 23 , which 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.
25. The isolated antibody of claim 24 , which comprises human constant regions.
26. The isolated antibody of claim 25 , which comprises a human IgG1 heavy chain constant region.
27. The isolated antibody of claim 25 , which comprises a human kappa light chain constant region.
28. The isolated antibody of claim 21 , which is an internalizing antibody.
29. A pharmaceutical composition comprising the isolated monoclonal antibody of claim 21 and a pharmaceutically acceptable carrier.
30. An isolated antibody, which specifically binds to human DLL3, the antibody comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises the sequence of SEQ ID NO: 212, or wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 213.