SEZ6 modulators and methods of use
View Patent ↗Novel modulators, including antibodies and derivatives thereof, and methods of using such modulators to treat proliferative disorders are provided.
1. A monoclonal antibody that comprises the same antigen-binding site as, and competes for binding to a human SEZ6 protein with, an antibody comprising a light chain variable region of SEQ ID NO: 168 and a heavy chain variable region of SEQ ID NO: 169.
2. The monoclonal antibody of claim 1 , wherein mutating at least one of amino acids T352, S353, and H375 in the SEZ6 protein shows loss of binding of the antibody to the SEZ6 protein.
3. The monoclonal antibody of claim 1 , selected from the group consisting of a chimeric antibody, CDR-grafted antibody, humanized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
4. The monoclonal antibody of claim 1 , wherein the antibody comprises a light chain variable region and a heavy chain variable region, and
wherein the light chain variable region has three complementarity determining regions of SEQ ID NO: 190 and the heavy chain variable region has three complementarity determining regions of SEQ ID NO: 191.
5. The monoclonal antibody of claim 4 , comprising residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.
6. The monoclonal antibody of claim 4 , comprising residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia.
7. The monoclonal antibody of claim 4 , comprising residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum.
8. The monoclonal antibody of claim 4 , comprising a light chain variable region set forth as SEQ ID NO: 190 and a heavy chain variable region set forth as SEQ ID NO: 191.
9. The monoclonal antibody of claim 1 , which is conjugated to a cytotoxic agent.
10. The monoclonal antibody of claim 9 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
11. The monoclonal antibody of claim 10 , wherein the cytotoxic agent is a calicheamicin.
12. The monoclonal antibody of claim 2 , which is conjugated to a cytotoxic agent.
13. The monoclonal antibody of claim 12 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
14. The monoclonal antibody of claim 13 , wherein the cytotoxic agent is a calicheamicin.
15. The monoclonal antibody of claim 4 , which is conjugated to a cytotoxic agent.
16. The monoclonal antibody of claim 15 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
17. The monoclonal antibody of claim 16 , wherein the cytotoxic agent is a calicheamicin.
18. An antibody drug conjugate comprising a monoclonal antibody conjugated, linked or otherwise associated with a cytotoxic agent, wherein the monoclonal antibody comprises the same antigen-binding site as, and competes for binding to a human SEZ6 protein with, an antibody comprising a light chain variable region of SEQ ID NO: 168 and a heavy chain variable region of SEQ ID NO: 169.
19. The antibody drug conjugate of claim 18 , wherein mutating at least one of amino acids T352, S353, and H375 in the SEZ6 protein shows loss of binding of the antibody to the SEZ6 protein.
20. The antibody drug conjugate of claim 18 , wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody, CDR-grafted antibody, humanized antibody, human antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
21. The antibody drug conjugate of claim 18 , wherein the antibody comprises a light chain variable region and a heavy chain variable region, and
wherein the light chain variable region has three complementarity determining regions of SEQ ID NO: 190 and the heavy chain variable region has three complementarity determining regions of SEQ ID NO: 191.
22. The antibody drug conjugate of claim 21 , wherein the monoclonal antibody comprises residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.
23. The antibody drug conjugate of claim 21 , wherein the monoclonal antibody comprises residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia.
24. The antibody drug conjugate of claim 21 , wherein the monoclonal antibody comprises residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum.
25. The antibody drug conjugate of claim 21 , wherein the light chain variable region comprises SEQ ID NO: 190 and the heavy chain variable region comprises SEQ ID NO: 191.
26. The antibody drug conjugate of claim 18 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
27. The antibody drug conjugate of claim 26 , wherein the cytotoxic agent is a calicheamicin.
28. The antibody drug conjugate of claim 19 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
29. The antibody drug conjugate of claim 28 , wherein the cytotoxic agent is a calicheamicin.
30. The antibody drug conjugate of claim 21 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
31. The antibody drug conjugate of claim 30 , wherein the cytotoxic agent is a calicheamicin.
32. The antibody drug conjugate of claim 18 , wherein the antibody drug conjugate comprises the formula: Ab-[L-D]n wherein:
(a) Ab comprises the monoclonal antibody;
(b) L comprises an optional linker;
(c) D comprises a drug, which is the cytotoxic agent; and
(d) n is an integer from 1 to 20.
33. The antibody drug conjugate of claim 32 , wherein mutating at least one of amino acids T352, S353, and H375 in the SEZ6 protein shows loss of binding of the antibody to the SEZ6 protein.
34. The antibody drug conjugate of claim 32 , wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody, CDR-grafted antibody, humanized antibody, human antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.
35. The antibody drug conjugate of claim 32 , wherein the antibody comprises a light chain variable region and a heavy chain variable region, and
wherein the light chain variable region has three complementarity determining regions of SEQ ID NO: 190 and the heavy chain variable region has three complementarity determining regions of SEQ ID NO: 191.
36. The antibody drug conjugate of claim 35 , wherein the monoclonal antibody comprises residues 24-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 31-35 of SEQ ID NO: 191 for CDR-H1, residues 50-65 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Kabat.
37. The antibody drug conjugate of claim 35 , wherein the monoclonal antibody comprises residues 23-34 of SEQ ID NO: 190 for CDR-L1, residues 50-56 of SEQ ID NO: 190 for CDR-L2, residues 89-97 of SEQ ID NO: 190 for CDR-L3, residues 26-32 of SEQ ID NO: 191 for CDR-H1, residues 50-58 of SEQ ID NO: 191 for CDR-H2 and residues 95-102 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to Chothia.
38. The antibody drug conjugate of claim 35 , wherein the monoclonal antibody comprises residues 30-36 of SEQ ID NO: 190 for CDR-L1, residues 46-55 of SEQ ID NO: 190 for CDR-L2, residues 89-96 of SEQ ID NO: 190 for CDR-L3, residues 30-35 of SEQ ID NO: 191 for CDR-H1, residues 47-58 of SEQ ID NO: 191 for CDR-H2 and residues 93-101 of SEQ ID NO: 191 for CDR-H3, wherein the residues are numbered according to MacCallum.
39. The antibody drug conjugate of claim 35 , wherein the light chain variable region comprises SEQ ID NO: 190 and the heavy chain variable region comprises SEQ ID NO: 191.
40. The antibody drug conjugate of claim 32 , wherein the cytotoxic agent comprises a calicheamicin, a duocarmycin, an auristatin, an amanitin, a pyrrolobenzodiazepine, or a radioisotope.
41. The antibody drug conjugate of claim 40 , wherein the cytotoxic agent is a calicheamicin.