ROR1 antibody immunoconjugates
Provided herein are immunoconjugates comprising an anti-ROR1 antibody or an antigen-fragment fragment thereof and a drug moiety. These immunoconjugates are useful for treating ROR1 expressing cancers.
1. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is
ADC-A, having the structure
wherein Ab in the structure is the antibody.
2. The immunoconjugate of claim 1 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
3. The immunoconjugate of claim 2 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
4. A pharmaceutical composition comprising the immunoconjugate of claim 1 and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
6. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 1 .
7. A method of making the immunoconjugate of claim 1 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating monomethyl auristatin E (MMAE) to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
8. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-E, having the structure
wherein Ab in the structure is the antibody.
9. The immunoconjugate of claim 8 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
10. The immunoconjugate of claim 8 , wherein the ratio of the cytoxic drug moiety to the antibody is 1 to 7.
11. A pharmaceutical composition comprising the immunoconjugate of claim 8 and a pharmaceutically acceptable excipient.
12. The pharmaceutical composition of claim 11 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
13. A method of treating a ROR 1 -expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 8 .
14. A method of making the immunoconjugate of claim 8 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating monomethyl auristatin E (MMAE) to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:5.
15. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-H, having the structure,
wherein Ab in the structure is the antibody.
16. The immunoconjugate of claim 15 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
17. The immunoconjugate of claim 16 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
18. A pharmaceutical composition comprising the immunoconjugate of claim 15 and a pharmaceutically acceptable excipient.
19. The pharmaceutical composition of claim 18 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton'tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2(Bcl-2) inhibitor, mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
20. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 15 .
21. A method of making the immunoconjugate of claim 15 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating azonafide to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO: 6.
22. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-J, having the structure
wherein Ab in the structure is the antibody.
23. The immunoconjugate of claim 22 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
24. The immunoconjugate of claim 23 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
25. A pharmaceutical composition comprising the immunoconjugate of claim 22 and a pharmaceutically acceptable excipient.
26. The pharmaceutical composition of claim 25 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (MTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
27. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 22 .
28. A method of making the immunoconjugate of claim 22 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating Duocarmycin TM to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
29. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-K, having the structure
wherein Ab in the structure is the antibody.
30. The immunoconjugate of claim 29 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
31. The immunoconjugate of claim 30 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
32. A pharmaceutical composition comprising the immunoconjugate of claim 29 and a pharmaceutically acceptable excipient.
33. The pharmaceutical composition of claim 32 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
34. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 29 .
35. A method of making the immunoconjugate of claim 29 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating pyrrolobenzodiazepine (PBD) to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
36. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-L, having the structure
wherein Ab in the structure is the antibody.
37. The immunoconjugate of claim 36 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
38. The immunoconjugate of claim 37 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
39. A pharmaceutical composition comprising the immunoconjugate of claim 36 and a pharmaceutically acceptable excipient.
40. The pharmaceutical composition of claim 39 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
41. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 36 .
42. A method of making the immunoconjugate of claim 36 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and conjugating monomethyl auristatin E (MMAE) to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
43. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-M, having the structure
wherein Ab in the structure is the antibody.
44. The immunoconjugate of claim 43 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
45. The immunoconjugate of claim 44 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
46. A pharmaceutical composition comprising the immunoconjugate of claim 43 and a pharmaceutically acceptable excipient.
47. The pharmaceutical composition of claim 46 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
48. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 43 .
49. A method of making the immunoconjugate of claim 43 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating monomethyl auristatin E (MMAE) to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
50. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-N, having the structure
wherein Ab in the structure is the antibody.
51. The immunoconjugate of claim 50 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
52. The immunoconjugate of claim 51 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
53. A pharmaceutical composition comprising the immunoconjugate of claim 50 and a pharmaceutically acceptable excipient.
54. The pharmaceutical composition of claim 53 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
55. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 50 .
56. A method of making the immunoconjugate of claim 50 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and conjugating PNU-159682 to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
57. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-O, having the structure
wherein Ab in the structure is the antibody.
58. The immunoconjugate of claim 57 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
59. The immunoconjugate of claim 58 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
60. A pharmaceutical composition comprising the immunoconjugate of claim 57 and a pharmaceutically acceptable excipient.
61. The pharmaceutical composition of claim 60 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
62. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 57 .
63. A method of making the immunoconjugate of claim 57 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating PNU-159682 to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
64. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-P, having the structure
wherein Ab in the structure is the antibody.
65. The immunoconjugate of claim 64 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
66. The immunoconjugate of claim 65 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
67. A pharmaceutical composition comprising the immunoconjugate of claim 64 and a pharmaceutically acceptable excipient.
68. The pharmaceutical composition of claim 67 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
69. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 64 .
70. A method of making the immunoconjugate of claim 64 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and conjugating PNU-159682 to the antibody; wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
71. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-Q, having the structure
wherein Ab in the structure is the antibody.
72. The immunoconjugate of claim 71 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
73. The immunoconjugate of claim 72 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
74. A pharmaceutical composition comprising the immunoconjugate of claim 71 and a pharmaceutically acceptable excipient.
75. The pharmaceutical composition of claim 74 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
76. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 71 .
77. A method of making the immunoconjugate of claim 71 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating monomethyl auristatin E (MMAE) to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.
78. An immunoconjugate comprising an antibody conjugated to a cytotoxic drug moiety, wherein the V H and V L of the antibody comprise the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, and the immunoconjugate is ADC-R, having the structure
wherein Ab in the structure is the antibody.
79. The immunoconjugate of claim 78 , wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 3 and 4, respectively.
80. The immunoconjugate of claim 79 , wherein the ratio of the cytotoxic drug moiety to the antibody is 1 to 7.
81. A pharmaceutical composition comprising the immunoconjugate of claim 78 and a pharmaceutically acceptable excipient.
82. The pharmaceutical composition of claim 81 , further comprising an additional therapeutic agent selected from the group consisting of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, a mammalian target of rapamycine (mTOR) inhibitor, and a phosphoinositide 3-kinase (PI3K) inhibitor.
83. A method of treating a ROR1-expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 78 .
84. A method of making the immunoconjugate of claim 78 , comprising:
providing an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1); and
conjugating PNU-159682 to the antibody;
wherein the heavy chain of the antibody comprises the amino acid sequence of SEQ ID NO:5 and the light chain of the antibody comprises the amino acid sequence of SEQ ID NO:6.