IL3Rα antibody conjugates and uses thereof
The present invention provides antibodies that bind to the IL-3 receptor alpha subunit alpha (Il3Rα) chain, and compositions comprising such antibodies. The present invention provides methods for inhibiting or reducing an IL3Rα-expressing cell population, the methods comprising contacting a population of IL3Rα-expressing cells (e.g., cancer cells and/or cancer stem cells) with an antibody that binds to IL3Rα. The present invention also provides antibody conjugates comprising an antibody that binds to an IL3Rα chain linked to a cytotoxic agent or anticellular agent and compositions comprising such conjugates. The present invention also provides methods for preventing, treating and/or managing a disorder associated with IL3Rα-expressing cells (e.g., a hematological cancer), the methods comprising administering to a subject in need thereof an antibody that binds to IL3Rα.
1. An antibody conjugate comprising an antibody that binds to the human IL-3 receptor alpha chain, wherein the antibody is conjugated to a cytotoxic agent, and wherein the antibody comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies.
2. A pharmaceutical composition comprising the antibody conjugate of claim 1 , and a pharmaceutically acceptable carrier or excipient.
3. A pharmaceutical composition comprising an antibody conjugate that binds to the human IL-3 receptor alpha chain in an amount effective to reduce cancer cells in an animal with myeloid leukemia, wherein the antibody conjugate comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies, and wherein the antibody is conjugated to a cytotoxic agent.
4. The pharmaceutical composition of claim 3 , wherein the animal is an animal model for myeloid leukemia.
5. A pharmaceutical composition comprising an antibody conjugate that binds to the human IL3-receptor alpha chain in an amount effective to reduce cancer stem cells in an animal with myeloid leukemia, wherein the antibody conjugate comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies, and wherein the antibody is conjugated to a cytotoxic agent.
6. A method of treating acute myeloid leukemia, the method comprising administering the pharmaceutical composition of any claims 2 , 3 , and 5 .
7. A method of treating acute myeloid leukemia, the method comprising administering the pharmaceutical composition of claim 4 .
8. The pharmaceutical composition of claim 3 or 5 , wherein the antibody conjugate is in an amount effective to reduce myeloid leukemia cells in an animal with myeloid leukemia by 25% relative to a negative control.
9. An antibody conjugate comprising an antibody that binds to the human IL-3 receptor alpha chain, wherein the antibody is conjugated to a cytotoxic agent, and wherein the antibody comprises a V H domain and a V L domain having the amino acid sequences of SEQ ID NO: 2 and 7; SEQ ID NO: 12 and 17; SEQ ID NO: 22 and 27; or SEQ ID NO: 32 and 37, respectively.
10. A method of treating acute myeloid leukemia comprising administering to a patient diagnosed with acute myeloid leukemia an antibody that binds to the human IL-3 receptor alpha chain, in an amount sufficient to inhibit the proliferation of acute myeloid leukemia cells in the patient, wherein the antibody is conjugated to a cytotoxic agent, and wherein the antibody comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies.
11. The method of claim 10 , wherein the acute myeloid leukemia cells are reduced in the patient.
12. The method of claim 10 , wherein the acute myeloid leukemia cells do not increase in the patient.
13. The method of claim 11 , wherein the method further comprises detecting acute myeloid leukemia cells.
14. The method of claim 13 , wherein the detection utilizes a specimen from the patient.
15. The method of claim 14 , wherein the specimen is from a blood sample or a bone marrow sample.
16. The method of claim 13 , wherein the detection utilizes an imaging technique.
17. The method of claim 16 , wherein the technique is accomplished using radionuclide imaging, fluorescent imaging, CT scan or MRI scan.
18. The method of claim 10 , wherein the method further comprises detecting acute myeloid leukemia stem cells.
19. The method of claim 18 , wherein the detection utilizes a specimen from the patient.
20. The method of claim 19 , wherein the specimen is from a blood sample or a bone marrow sample.
21. The method of claim 18 , wherein the detection utilizes an imaging technique.
22. The method of claim 21 , wherein the technique is accomplished using radionuclide imaging, fluorescent imaging, CT scan or MRI scan.
23. The method of claim 10 , wherein the antibody results in a decrease in viability of acute myeloid leukemia stem cells.
24. The method of claim 10 , wherein the antibody results in a decrease in growth of acute myeloid leukemia stem cells.
25. The method of claim 10 , wherein the antibody modulates acute myeloid leukemia stem cells.
26. The method of claim 10 , wherein the antibody results in the differentiation of acute myeloid leukemia stem cells.
27. The method of claim 10 , wherein the antibody results in asymmetric cell division of acute myeloid leukemia stem cells.
28. The method of claim 10 , wherein the antibody binds to the target that is expressed on a acute myeloid leukemia stem cell.
29. The method of claim 10 , wherein the patient has been diagnosed with acute myeloid leukemia and has undergone cancer therapy.
30. The method of claim 10 , wherein the patient has undergone cancer therapy.
31. The method of claim 30 , wherein the patient is in remission from cancer.
32. The method of claim 30 , wherein the patient has relapsed from cancer.
33. The method of claim 30 , wherein the patient has failed cancer treatment.
34. A method of treating acute myeloid leukemia, comprising:
(a) administering to a patient diagnosed with acute myeloid leukemia an antibody or a fragment thereof that binds to the human IL-3 receptor alpha chain, in an amount sufficient to reduce acute myeloid leukemia stem cells in the patient, wherein the antibody is conjugated to a cytotoxic agent, and
(b) detecting the acute myeloid leukemia stem cells,
wherein the antibody comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies.
35. The method of claim 34 , wherein there is a reduction in acute myeloid leukemia cells in the patient.
36. The method of claim 34 , wherein acute myeloid leukemia cells do not increase in the patient.
37. The method of claim 35 , wherein the method further comprises detecting acute myeloid leukemia cells.
38. The method of claim 37 , wherein the detection utilizes a specimen from the patient.
39. The method of claim 38 , wherein the specimen is from a blood sample or a bone marrow sample.
40. The method of claim 37 , wherein the detection utilizes an imaging technique.
41. The method of claim 40 , wherein the technique is accomplished using radionuclide imaging, fluorescent imaging, CT scan or MRI scan.
42. The method of claim 34 , wherein the antibody results in a decrease in viability of acute myeloid leukemia stem cells.
43. The method of claim 34 , wherein the antibody results in a decrease in growth of acute myeloid leukemia stem cells.
44. The method of claim 34 , wherein the antibody modulates acute myeloid leukemia stem cells.
45. The method of claim 34 , wherein the antibody results in the differentiation of acute myeloid leukemia stem cells.
46. The method of claim 34 , wherein the antibody results in asymmetric cell division of acute myeloid leukemia stem cells.
47. The method of claim 34 , wherein the antibody binds to the target that is expressed on an acute myeloid leukemia stem cell.
48. A method of treating hematologic cancer, the method comprising administering the antibody of claim 2 , 3 , or 5 .
49. A method of treating hematologic cancer comprising administering to a patient diagnosed with hematologic cancer an antibody that binds to the human IL-3 receptor alpha chain, in an amount sufficient to inhibit the proliferation of hematologic cancer cells in the patient, wherein the antibody is conjugated to a cytotoxic agent, and wherein the antibody comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies.
50. A method of treating hematologic cancer, comprising:
(a) administering to a patient diagnosed with hematologic cancer an antibody or a fragment thereof that binds to the human IL-3 receptor alpha chain, in an amount sufficient to reduce hematologic cancer stem cells in the patient, wherein the antibody is conjugated to a cytotoxic agent, and
(b) detecting the hematologic cancer stem cells,
wherein the antibody comprises the V H and V L domains of the 26292, 32701, 32716 or 32703 antibodies.