Methods and compositions based on diphtheria toxin-interleukin-3 conjugates
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 treating a human that has been diagnosed with chronic myelomonocytic leukemia (CMML), comprising administering to said human a pharmaceutical composition comprising a human interleukin (IL)-3-diphtheria toxin conjugate.
2. The method of claim 1 , wherein administration of said human IL-3-diphtheria toxin conjugate results in inhibition of the growth of CMML cells in said human.
3. The method of claim 1 , wherein the conjugate is administered at a dose of 4 μg/kg to 12.5 μg/kg.
4. The method of claim 1 , wherein the conjugate is administered at a dose of 5.3 μg/kg, 7.1 μg/kg, 9.4 μg/kg, or 12.5 μg/kg.
5. The method of claim 1 , wherein the conjugate is administered at a dose that is the maximum tolerated dose.
6. The method of claim 1 , wherein the conjugate is administered at least two times a week or at least three times a week.
7. The method of claim 1 , wherein the conjugate is administered over a period of two weeks or more.
8. The method of claim 1 , wherein the conjugate is administered three times in one week.
9. The method of claim 1 , wherein the conjugate is administered once every day for five days.
10. The method of claim 1 , wherein the conjugate is administered for multiple cycles.
11. The method of claim 1 , wherein the human has abnormal cytogenetics.
12. The method of claim 1 , wherein the conjugate is a chemical conjugate or wherein the conjugate is a recombinantly expressed protein.
13. The method of claim 1 , wherein the conjugate is expressed as a single polypeptide comprising the catalytic and translocation domains of diphtheria toxin and human IL-3.
14. The method of claim 1 , wherein the conjugate comprises amino acid residues 1 to 388 of diphtheria toxin linked via a peptide bond to human IL-3.
15. The method of claim 1 , wherein the human is in a state of remission from CMML.
16. The method of claim 1 , wherein the human has previously been treated with a therapeutic agent and/or has undergone radiation therapy.
17. The method of claim 1 , wherein the human is currently being administered a therapeutic agent other than a human IL-3-diphtheria toxin conjugate and/or is undergoing radiation therapy.
18. The method of claim 1 , wherein the human has relapsed from previous CMML treatment, wherein the human has failed previous CMML treatment, or wherein the human is susceptible to adverse reactions from other CMML treatment.
19. The method of claim 18 , wherein the previous CMML treatment comprises azacitidine and/or decitabine.
20. The method of claim 19 , wherein the conjugate is administered at a dose of 4 μg/kg to 12.5 μg/kg.
21. The method of claim 19 , wherein the conjugate is administered at a dose of 5.3 μg/kg, 7.1 μg/kg, 9.4 μg/kg, or 12.5 μg/kg.
22. The method of claim 19 , wherein the conjugate is administered at a dose that is the maximum tolerated dose.
23. The method of claim 19 , wherein the conjugate is administered at least two times a week or at least three times a week.
24. The method of claim 19 , wherein the conjugate is administered over a period of two weeks or more.
25. The method of claim 19 , wherein the conjugate is administered three times in one week.
26. The method of claim 19 , wherein the conjugate is administered once every day for five days.
27. The method of claim 19 , wherein the conjugate is administered for multiple cycles.
28. The method of claim 1 , wherein the human is refractory to chemotherapy.
29. The method of claim 28 , wherein the chemotherapy comprises azacitidine and/or decitabine.
30. The method of claim 29 , wherein the conjugate is administered at a dose of 4 μg/kg to 12.5 μg/kg.
31. The method of claim 29 , wherein the conjugate is administered at a dose of 5.3 μg/kg, 7.1 μg/kg, 9.4 μg/kg, or 12.5 μg/kg.
32. The method of claim 29 , wherein the conjugate is administered at a dose that is the maximum tolerated dose.
33. The method of claim 29 , wherein the conjugate is administered at least two times a week or at least three times a week.
34. The method of claim 29 , wherein the conjugate is administered over a period of two weeks or more.
35. The method of claim 29 , wherein the conjugate is administered three times in one week.
36. The method of claim 29 , wherein the conjugate is administered once every day for five days.
37. The method of claim 29 , wherein the conjugate is administered for multiple cycles.
38. The method of claim 1 , wherein the human has not been previously treated for CMML.
39. The method of claim 1 , further comprising administering azacitidine and/or decitabine to said human.
40. The method of claim 39 , wherein the conjugate is administered at a dose of 4 μg/kg to 12.5 μg/kg.
41. The method of claim 39 , wherein the conjugate is administered at a dose of 5.3 μg/kg, 7.1 μg/kg, 9.4 μg/kg, or 12.5 μg/kg.
42. The method of claim 39 , wherein the conjugate is administered at a dose that is the maximum tolerated dose.
43. The method of claim 39 , wherein the conjugate is administered at least two times a week or at least three times a week.
44. The method of claim 39 , wherein the conjugate is administered over a period of two weeks or more.
45. The method of claim 39 , wherein the conjugate is administered three times in one week.
46. The method of claim 39 , wherein the conjugate is administered once every day for five days.
47. The method of claim 39 , wherein the conjugate is administered for multiple cycles.