Claims (99)
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
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
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,
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
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
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
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
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
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
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
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
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
87. A method of treating a human receptor tyrosine kinase like orphan receptor 1 (ROR1) expressing cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the immunoconjugate of claim 1.
Show 86 dependent claims
2. The immunoconjugate of claim 1 , wherein the heavy chain and light chain of the antibody Ab 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 n is an integer from 1 to 5 .
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 rapamycin (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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
85. The immunoconjugate of claim 3 , wherein n is 4.
86. The immunoconjugate of claim 1 , wherein Ab comprises: a heavy chain comprising an amino acid sequence at least 95% identical to that of SEQ ID NO: 3, and a light chain comprising an amino acid sequence at least 95% identical to that of SEQ ID NO: 4.
88. A method of making the immunoconjugate of claim 1 , comprising the steps: (i) reducing the cysteine residues of Ab of claim 1 by contacting Ab with a reducing agent; and (ii) conjugating one or more thiol groups of the reduced cysteine moieties of the product of step (i) with the maleimide group of the following linker/payload moiety: 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E (MC-VC-PAB-MMAE).
89. The method of claim 87 , wherein the human receptor tyrosine kinase like orphan receptor 1 (ROR1) expressing cancer is a lymphoma.
90. The method of claim 89 , wherein the lymphoma is selected from diffuse large β-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL).
91. The method of claim 87 , further comprising administering to the patient one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are selected from rituximab, cyclophosphamide, vincristine, prednisone, gemcitabine, daunorubicin hydrochloride, and a Bruton's tyrosine kinase (BTK) inhibitor.
92. The immunoconjugate of claim 86 , wherein Ab comprises: a V H comprising the amino acid sequence of SEQ ID NO: 5, and a V L comprising the amino acid sequence of SEQ ID NO: 6.
93. A method of making the immunoconjugate of claim 3 , comprising the steps: (i) reducing the cysteine residues of Ab of claim 3 by contacting Ab with a reducing agent; and (ii) conjugating one or more thiol groups of the reduced cysteine moieties of the product of step (i) with the maleimide group of the following linker/payload moiety: 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E (MC-VC-PAB-MMAE).
94. A method of making the immunoconjugate of claim 86 , comprising the steps: (i) reducing the cysteine residues of Ab of claim 86 by contacting Ab with a reducing agent; and (ii) conjugating one or more thiol groups of the reduced cysteine moieties of the product of step (i) with the maleimide group of the following linker/payload moiety: 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E (MC-VC-PAB-MMAE).
95. A method of making the immunoconjugate of claim 92 , comprising the steps: (i) reducing the cysteine residues of Ab of claim 92 by contacting Ab with a reducing agent; and (ii) conjugating one or more thiol groups of the reduced cysteine moieties of the product of step (i) with the maleimide group of the following linker/payload moiety: 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E (MC-VC-PAB-MMAE).
96. The immunoconjugate of claim 86 , wherein n is 4.
97. The immunoconjugate of claim 92 , wherein n is 4.
98. The method of claim 90 , wherein the lymphoma is diffuse large β-cell lymphoma (DLBCL).
99. The method of claim 98 , further comprising administering to the patient one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are selected from rituximab, cyclophosphamide, vincristine, prednisone, daunorubicin hydrochloride, and gemcitabine.
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Citations
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