Antibodies and immunoconjugates
The invention provides immunoconjugates and methods of using the same.
1. An immunoconjugate comprising a structure selected from:
wherein p is from 1 to 4 and Ab is an antibody that binds Ly6E comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 6, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8; an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 3; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 4; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 5.
2. The immunoconjugate of claim 1 , wherein Ab is an antibody that binds Ly6E comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1.
3. The immunoconjugate of claim 1 , wherein the antibody is a monoclonal antibody.
4. The immunoconjugate of claim 1 , wherein the antibody is a humanized or chimeric antibody.
5. The immunoconjugate of claim 1 , wherein the antibody is an antibody fragment that binds to Ly6E.
6. The immunoconjugate of claim 1 , wherein the antibody is an IgG1, IgG2a or IgG2b antibody.
7. The immunoconjugate of claim 1 , wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C.
8. The immunoconjugate of claim 7 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 77 or 79.
9. The immunoconjugate of claim 1 , wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.
10. The immunoconjugate of claim 9 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 76 or 78.
11. The immunoconjugate of claim 1 , wherein the antibody comprises a K149C mutation in the light chain constant region.
12. The immunoconjugate of claim 11 , wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 78.
13. The immunoconjugate of claim 1 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 10 and a light chain comprising the sequence of SEQ ID NO: 9.
14. The immunoconjugate of claim 1 , wherein p ranges from 1 to about 2.
15. The immunoconjugate of claim 1 , wherein p is about 2.
16. An immunoconjugate comprising the structure:
wherein Ab is an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 10 and the light chain comprises the sequence of SEQ ID NO: 9; and p is 1 to about 2.
17. The immunoconjugate of claim 16 , wherein p is about 2.
18. A pharmaceutical formulation comprising the immunoconjugate of claim 1 and a pharmaceutically acceptable carrier.
19. A method of treating a Ly6E-positive cancer comprising administering to an individual with a Ly6E-positive cancer an effective amount of the pharmaceutical formulation of claim 18 .
20. The method of claim 19 , wherein the cancer is selected from breast cancer, metastatic breast cancer, Her2 negative breast cancer, triple negative breast cancer, pancreatic cancer, colon cancer, colorectal cancer, melanoma, ovarian cancer, non-small cell lung cancer, and gastric cancer.
21. A method of inhibiting proliferation of a Ly6E-positive cell, comprising exposing the Ly6E-positive cell to an immunoconjugate of claim 1 under conditions permissive for binding of the immunoconjugate to an antigen on the surface of the cell, thereby inhibiting proliferation of the cell.
22. The immunoconjugate of claim 2 , wherein the antibody is a monoclonal antibody.
23. The immunoconjugate of claim 2 , wherein the antibody is an antibody fragment that binds to Ly6E.
24. The immunoconjugate of claim 2 , wherein the antibody is an IgG1, IgG2a or IgG2b antibody.
25. The immunoconjugate of claim 2 , wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A 118C and S400C.
26. The immunoconjugate of claim 25 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 77 or 79.
27. The immunoconjugate of claim 2 , wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C.
28. The immunoconjugate of claim 27 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 76 or 78.
29. The immunoconjugate of claim 2 , wherein the antibody comprises a K149C mutation in the light chain constant region.
30. The immunoconjugate of claim 29 , wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 78.
31. The immunoconjugate of claim 2 , wherein p ranges from 1 to about 2.
32. The immunoconjugate of claim 2 , wherein p is about 2.
33. A pharmaceutical formulation comprising the immunoconjugate of claim 2 and a pharmaceutically acceptable carrier.
34. A method of treating a Ly6E-positive cancer comprising administering to an individual with a Ly6E-positive cancer an effective amount of the pharmaceutical formulation of claim 33 .
35. The method of claim 34 , wherein the cancer is selected from breast cancer, metastatic breast cancer, Her2 negative breast cancer, triple negative breast cancer, pancreatic cancer, colon cancer, colorectal cancer, melanoma, ovarian cancer, non-small cell lung cancer, and gastric cancer.
36. A pharmaceutical formulation comprising the immunoconjugate of claim 16 and a pharmaceutically acceptable carrier.
37. A method of treating a Ly6E-positive cancer comprising administering to an individual with a Ly6E-positive cancer an effective amount of the pharmaceutical formulation of claim 36 .
38. The method of claim 37 , wherein the cancer is selected from breast cancer, metastatic breast cancer, Her2 negative breast cancer, triple negative breast cancer, pancreatic cancer, colon cancer, colorectal cancer, melanoma, ovarian cancer, non-small cell lung cancer, and gastric cancer.