Antibodies binding AXL
The present invention relates to anti-AXL antibodies, immunoconjugates, compositions and method of treatment of cancer with such anti-AXL antibodies, immunoconjugates, or compositions.
1. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising a cytotoxic agent and an antibody which binds to human AXL and comprises a heavy chain variable (VH) region and a light chain variable (VL) region selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively,
b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively, and
c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.
2. The method of claim 1 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively.
3. The method of claim 1 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively.
4. The method of claim 1 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.
5. The method of claim 1 , wherein the antibody comprises a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2,
b) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26, and
c) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.
6. The method of claim 5 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2.
7. The method of claim 5 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26.
8. The method of claim 5 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.
9. The method of claim 1 , wherein the antibody binds to;
an epitope within the Ig1-like domain of human AXL, wherein said epitope comprises or requires one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL, and wherein the numbering of positions are in relation to human AXL having the amino acid sequence set forth in SEQ ID NO: 130.
10. The method of claim 1 , wherein the antibody comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
11. The method of claim 1 , wherein the antibody is an ADCC-deficient antibody, a stabilized IgG4 antibody or a monovalent antibody.
12. The method of claim 1 , wherein the antibody is a single chain antibody.
13. The method of claim 1 , wherein the cytotoxic agent is MMAE.
14. The method of claim 1 , wherein the cytotoxic agent is linked to said antibody with a cleavable linker.
15. The method of claim 14 , wherein the linker is mc-vc-PAB.
16. The method of claim 1 , wherein the cytotoxic agent is MMAE and the linker is mc-vc-PAB.
17. The method of claim 1 , wherein the cancer is a solid tumor expressing AXL or an AXL-expressing hematological cancer.
18. The method according to claim 1 , wherein the cancer is selected from the group consisting of colorectal cancer, bladder cancer, bone cancer, breast cancer, cancers of the central nervous system, cervical cancer, connective tissue cancer, endometrium cancer, epidermoid carcinoma, fibroblast cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, muscle cancer, neural tissue cancer, ovarian cancer, pancreatic cancer, skin cancer, and soft tissue sarcoma.
19. The method of claim 18 , wherein the cancer is lung cancer.
20. The method of claim 18 , wherein the cancer is skin cancer.
21. The method of claim 18 , wherein the cancer is a sarcoma.
22. The method of claim 18 , wherein the cancer is cervical cancer.
23. The method of claim 18 , wherein the cancer is endometrium cancer.
24. The method of claim 18 , wherein the cancer is ovarian cancer.
25. A method for inhibiting growth and/or proliferation of a tumor cell expressing AXL, comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising a cytotoxic agent and an antibody which binds to human AXL and comprises a heavy chain variable (VH) region and a light chain variable (VL) region selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively,
b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively, and
c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.
26. The method of claim 25 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively.
27. The method of claim 25 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively.
28. The method of claim 25 , wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.
29. The method of claim 25 , wherein the antibody comprises a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2,
b) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26, and
c) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.
30. The method of claim 29 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2.
31. The method of claim 29 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26.
32. The method of claim 29 , wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.
33. The method of claim 25 , wherein the antibody binds to an epitope within the Ig1-like domain of human AXL, wherein said epitope comprises one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL, and wherein the numbering of positions are in relation to human AXL having the amino acid sequence set forth in SEQ ID NO: 130.
34. The method of claim 25 , wherein the antibody comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
35. The method of claim 25 , wherein the antibody is an ADCC-deficient antibody, a stabilized IgG4 antibody or a monovalent antibody.
36. The method of claim 25 , wherein the antibody is a single chain antibody.
37. The method of claim 25 , wherein the cytotoxic agent is MMAE.
38. The method of claim 25 , wherein the cytotoxic agent is linked to said antibody with a cleavable linker.
39. The method of claim 38 , wherein the linker is mc-vc-PAB.
40. The method of claim 39 , wherein the cytotoxic agent is MMAE and the linker is mc-vc-PAB.
41. The method of claim 25 , wherein the tumor cell is from a solid tumor expressing AXL or an AXL-expressing hematological cancer.
42. The method according to claim 25 , wherein the tumor cell is from a cancer selected from the group consisting of colorectal cancer, bladder cancer, bone cancer, breast cancer, cancers of the central nervous system, cervical cancer, connective tissue cancer, endometrium cancer, epidermoid carcinoma, fibroblast cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, muscle cancer, neural tissue cancer, ovarian cancer, pancreatic cancer, skin cancer, and soft tissue sarcoma.
43. A method for inhibiting growth and/or proliferation of a tumor cell expressing AXL comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising (a) a cytotoxic agent and an antibody which binds to human AXL and comprises variable heavy chain (VH) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37, and 38, respectively, and variable light chain (VL) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 39, GAS, and SEQ ID NO: 40, wherein the cytotoxic agent is MMAE, and wherein the MMAE is linked to the antibody with a mc-vc-PAB linker.
44. The method of claim 43 , wherein the antibody comprises VH and VL regions comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 2, respectively.
45. A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising a cytotoxic agent and an antibody which binds to human AXL and comprises the variable heavy chain (VH) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID Nos: 36, 37, and 38, respectively, and the variable light chain (VL) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID No: 39, GAS, and SEQ ID No: 40, wherein the cytotoxic agent is MMAE, and wherein the MMAE is linked to the antibody with a mc-vc-PAB linker.
46. The method of claim 45 , wherein the antibody comprises VH and VL regions comprising the amino acid sequences set forth in SEQ ID Nos: 1 and 2, respectively.