Modulators and methods of use
View Patent ↗Novel modulators, including antibodies and derivatives thereof, and methods of such modulators to treat hyperproliferative disorders are provided.
1. A chimeric, CDR-grafted, humanized antibody, or fragment thereof, that comprises the same antigen-binding site as, and competes for binding to human EFNA4 with, an antibody comprising a heavy chain variable region set forth as SEQ ID NO: 113 and a light chain variable region set forth as SEQ ID NO: 115.
2. The antibody of claim 1 , which is a neutralizing antibody.
3. The antibody of claim 1 , which is an internalizing antibody.
4. The antibody of claim 1 , which is a depleting antibody.
5. The antibody of claim 1 comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as SEQ ID NOs: 12, 25, and 38.
6. The antibody of claim 1 comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one light chain variable region comprises three CDRs set forth as SEQ ID NOs: 51, 74, and 87.
7. The antibody of claim 1 comprising:
(a) a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 12, 25, and 38; and
(b) a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 51, 74, and 87.
8. The antibody of claim 7 comprising a heavy chain variable region having an amino acid sequence that is at least 60% identical to SEQ ID NO: 157 and a light chain variable having an amino acid sequence that is at least 60% identical to SEQ ID NO: 159.
9. The antibody of claim 8 comprising a heavy chain variable region set forth as SEQ ID NO: 157 and a light chain variable region set forth as SEQ ID NO: 159.
10. The antibody of claim 1 comprising a heavy chain variable region set forth as SEQ ID NO: 113 or 157.
11. The antibody of claim 1 comprising a light chain variable region set forth as SEQ ID NO: 115 or 159.
12. The antibody of claim 1 comprising a heavy chain variable region set forth as SEQ ID NO: 113 or 157, and a light chain variable region set forth as SEQ ID NO: 115 or 159.
13. The antibody of claim 1 , which is conjugated, linked or otherwise associated with a cytotoxic agent.
14. The antibody of claim 9 , which is conjugated, linked or otherwise associated with a cytotoxic agent.
15. A pharmaceutical composition comprising the antibody of claim 1 .
16. A pharmaceutical composition comprising the antibody of claim 9 .
17. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 31-35 of SEQ ID NO: 113 for CDR-H1, residues 50-65 of SEQ ID NO: 113 for CDR-H2, and residues 95-102 of SEQ ID NO: 113 for CDR-H3, wherein the residues are numbered according to Kabat.
18. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one light chain variable region comprises three CDRs set forth as residues 24-34 of SEQ ID NO: 115 for CDR-L1, residues 50-56 of SEQ ID NO: 115 for CDR-L2, and residues 89-97 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to Kabat.
19. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 31-35 of SEQ ID NO: 113 for CDR-H1, residues 50-65 of SEQ ID NO: 113 for CDR-H2, and residues 95-102 of SEQ ID NO: 113 for CDR-H3, and wherein the at least one light chain variable region comprises three CDRs set forth as residues 24-34 of SEQ ID NO: 115 for CDR-L1, residues 50-56 of SEQ ID NO: 115 for CDR-L2, and residues 89-97 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to Kabat.
20. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 26-32 of SEQ ID NO: 113 for CDR-H1, residues 53-55 of SEQ ID NO: 113 for CDR-H2, and residues 96-101 of SEQ ID NO: 113 for CDR-H3, wherein the residues are numbered according to Chothia.
21. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one light chain variable region comprises three CDRs set forth as residues 26-32 of SEQ ID NO: 115 for CDR-L1, residues 50-52 of SEQ ID NO: 115 for CDR-L2, and residues 91-96 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to Chothia.
22. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 26-32 of SEQ ID NO: 113 for CDR-H1, residues 53-55 of SEQ ID NO: 113 for CDR-H2, and residues 96-101 of SEQ ID NO: 113 for CDR-H3, and wherein the at least one light chain variable region comprises three CDRs set forth as residues 26-32 of SEQ ID NO: 115 for CDR-L1, residues 50-52 of SEQ ID NO: 115 for CDR-L2, and residues 91-96 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to Chothia.
23. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 30-35 of SEQ ID NO: 113 for CDR-H1, residues 47-58 of SEQ ID NO: 113 for CDR-H2, and residues 93-101 of SEQ ID NO: 113 for CDR-H3, wherein the residues are numbered according to MacCallum.
24. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one light chain variable region comprises three CDRs set forth as residues 30-36 of SEQ ID NO: 115 for CDR-L1, residues 46-55 of SEQ ID NO: 115 for CDR-L2, and residues 89-96 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to MacCallum.
25. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 30-35 of SEQ ID NO: 113 for CDR-H1, residues 47-58 of SEQ ID NO: 113 for CDR-H2, and residues 93-101 of SEQ ID NO: 113 for CDR-H3, and wherein the at least one light chain variable region comprises three CDRs set forth as residues 30-36 of SEQ ID NO: 115 for CDR-L1, residues 46-55 of SEQ ID NO: 115 for CDR-L2, and residues 89-96 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to MacCallum.
26. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs of a heavy chain variable region set forth as SEQ ID NO: 113.
27. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one light chain variable region comprises three CDRs of a light chain variable region set forth as SEQ ID NO: 115.
28. The antibody of claim 1 , comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs of a heavy chain variable region set forth as SEQ ID NO: 113 and wherein the at least one light chain variable region comprises three CDRs of a light chain variable region set forth as SEQ ID NO: 115.
29. The antibody of claim 28 , wherein each respective CDR is defined according to the CDR definition of Kabat, Chothia, or MacCallum.
30. An antibody conjugate comprising the antibody of claim 1 , which antibody is conjugated, linked or otherwise associated with a cytotoxic agent.
31. An antibody conjugate comprising the antibody of claim 9 , which antibody is conjugated, linked or otherwise associated with a cytotoxic agent.
32. A pharmaceutical composition comprising the antibody conjugate of claim 30 .
33. A pharmaceutical composition comprising the antibody conjugate of claim 31 .
34. A chimeric, CDR-grafted, humanized antibody, or fragment thereof, comprising at least one heavy chain variable region and at least one light chain variable region, wherein the at least one heavy chain variable region comprises three CDRs set forth as residues 31-35 of SEQ ID NO: 113 for CDR-H1, residues 50-65 of SEQ ID NO: 113 for CDR-H2, and residues 95-102 of SEQ ID NO: 113 for CDR-H3, and wherein the at least one light chain variable region comprises three CDRs set forth as residues 24-34 of SEQ ID NO: 115 for CDR-L1, residues 50-56 of SEQ ID NO: 115 for CDR-L2, and residues 89-97 of SEQ ID NO: 115 for CDR-L3, wherein the residues are numbered according to Kabat.
35. The antibody of claim 34 , comprising a heavy chain variable region set forth as SEQ ID NO: 157 and a light chain variable region set forth as SEQ ID NO: 159.
36. An antibody conjugate comprising the antibody of claim 34 , which antibody is conjugated, linked or otherwise associated with a cytotoxic agent.