Methods for treating myelodysplastic syndrome with a human interleukin-3-diphtheria toxin conjugate
View Patent ↗The present invention provides methods for inhibiting interleukin-3 receptor-expressing cells, and, in particular, inhibiting the growth of such cells by using a diphtheria toxin-human interleukin-3 conjugate (DT-IL3) that is toxic to cells expressing the interleukin-3 receptor. In preferred embodiments, the DT-IL3 conjugate is a fusion protein comprising amino acids 1-388 of diphtheria toxin fused via a peptide linker to full-length, human interleukin-3. In certain embodiments, the methods of the present invention relate to the administration of a DT-IL3 conjugate to inhibit the growth of cancer cells and/or cancer stem cells in humans, which cells express one or more subunits of the interleukin-3 receptor. Exemplary cells include myeloid leukemia cancer stem cells. In other embodiments, the methods of the present invention relate to ex vivo purging of bone marrow or peripheral blood to remove cells that express one or more subunits of the interleukin-3 receptor such that the purged bone marrow or peripheral blood is suitable, e.g., for autologous stem cell transplantation to restore hematopoietic function.
1. A method for reducing blasts in a human diagnosed with myelodysplastic syndrome (MDS), comprising administering to a human in need of such reduction a pharmaceutical composition comprising a human interleukin 3 (IL-3)-diphtheria toxin conjugate in which the conjugate is administered at a dose of about 0.1 μg/kg to about 50 μg/kg.
2. The method of claim 1 , wherein the method results in an improvement in hematopoietic function and/or an improvement in the marrow blast index.
3. The method of claim 2 , wherein the reduction is measured by conventional measurements, including blood tests; blast count; blast percentage; physical examination; complete blood count; flow cytometric analyses; bone marrow aspirate; bone marrow analyses; hematopoietic function; marrow blast index; the amount of normal white blood cells, red blood cells, and/or platelets; histology; immunohistochemistry; frequency of transfusion; and/or bone marrow biopsy.
4. The method of claim 1 , wherein the blasts express the IL-3 receptor.
5. The method of claim 4 , wherein the reduction reduces the amount of IL-3R-expressing blasts.
6. The method of claim 1 , wherein the reduction reduces the amount of IL-3R-expressing cells.
7. The method of claim 1 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 50 μg/kg.
8. The method of claim 1 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 12.5 μg/kg.
9. The method of claim 1 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 20 μg/kg.
10. The method of claim 1 , wherein the conjugate is administered at a dose of about 5.3 μg/kg.
11. The method of claim 1 , wherein the conjugate is administered at a dose of about 7.1 μg/kg.
12. The method of claim 1 , wherein the conjugate is administered at a dose of about 9.4 μg/kg.
13. The method of claim 1 , wherein the conjugate is administered at a dose of about 12.5 μg/kg.
14. The method of claim 1 , wherein the conjugate is administered at a dose that is the maximum tolerated dose.
15. The method of claim 1 , wherein the conjugate is administered at least two times a week.
16. The method of claim 9 , wherein the conjugate is administered at least three times a week.
17. The method of claim 1 , wherein the conjugate is administered over a period of two weeks or more.
18. The method of claim 16 , wherein the conjugate is administered over a period of two weeks or more.
19. The method of claim 1 , wherein the human has abnormal cytogenetics.
20. The method of claim 1 , wherein the conjugate is a chemical conjugate.
21. The method of claim 1 , wherein the conjugate is a recombinantly expressed protein.
22. The method of claim 21 , wherein the conjugate is expressed as a single polypeptide comprising the catalytic and translocation domains of diphtheria toxin and human IL-3.
23. The method of claim 22 , wherein the conjugate comprises amino acid residues 1 to 388 of diphtheria toxin linked via a peptide bond to human IL-3.
24. The method of claim 22 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 12.5 μg/kg.
25. The method of claim 22 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 20 μg/kg.
26. The method of claim 1 , wherein the conjugate is administered once every day for five days.
27. The method of claim 26 , wherein the conjugate is administered for multiple cycles.
28. A method for improving hematopoietic function in a human diagnosed with MDS, comprising administering to a human in need of such improvement a pharmaceutical composition comprising a human IL-3-diphtheria toxin conjugate in which the conjugate is administered at a dose of about 0.1 μg/kg to about 50 μg/kg.
29. The method of claim 28 , wherein the method results in a stabilization in the amount of blasts and/or an improvement in the marrow blast index.
30. The method of claim 29 , wherein the stabilization is measured by conventional measurements, including blood tests; blast count; blast percentage; physical examination; complete blood count; flow cytometric analyses; bone marrow aspirate; bone marrow analyses; hematopoietic function; marrow blast index; the amount of normal white blood cells, red blood cells, and/or platelets; histology; immunohistochemistry; frequency of transfusion; and/or bone marrow biopsy.
31. The method of claim 28 , wherein the conjugate is a chemical conjugate.
32. The method of claim 28 , wherein the conjugate is a recombinantly expressed protein.
33. The method of claim 32 , wherein the conjugate is expressed as a single polypeptide comprising the catalytic and translocation domains of diphtheria toxin and human IL-3.
34. The method of claim 33 , wherein the conjugate comprises amino acid residues 1 to 388 of diphtheria toxin linked via a peptide bond to human IL-3.
35. The method of claim 28 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 50 μg/kg.
36. The method of claim 28 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 12.5 μg/kg.
37. The method of claim 28 , wherein the conjugate is administered at a dose of about 4 μg/kg to about 20 μg/kg.
38. The method of claim 28 , wherein the conjugate is administered at a dose that is the maximum tolerated dose.
39. The method of claim 37 , wherein the conjugate is administered at least two times a week.
40. The method of claim 39 , wherein the conjugate is administered over a period of two weeks or more.
41. The method of claim 28 , wherein the conjugate is administered once every day for five days.
42. The method of claim 41 , wherein the conjugate is administered for multiple cycles.
43. The method of claim 28 , wherein the conjugate is administered at a dose of about 5.3 μg/kg.
44. The method of claim 28 , wherein the conjugate is administered at a dose of about 7.1 μg/kg.
45. The method of claim 28 , wherein the conjugate is administered at a dose of about 9.4 μg/kg.
46. The method of claim 28 , wherein the conjugate is administered at a dose of about 12.5 μg/kg.
47. The method of claim 1 or 28 , wherein the MDS is refractory.
48. The method of claim 1 or 28 , wherein the MDS is in remission.
49. The method of claim 1 or 28 , wherein the human has been previously treated with a therapeutic agent and/or has undergone radiation therapy.
50. The method of claim 1 or 28 , wherein the human is currently being administered a therapeutic agent and/or is undergoing radiation therapy.
51. The method of claim 1 or 28 , wherein the human has relapsed from MDS.
52. The method of claim 1 or 28 , wherein the human has failed MDS treatment.
53. The method of claim 1 or 28 , wherein the human is elderly.
54. The method of claim 53 , wherein the human is susceptible to adverse reactions from other therapies.
55. The method of claim 1 or 28 , wherein the human is refractory to chemotherapy.
56. The method of claim 1 or 28 , wherein the human has not been previously treated for MDS.