Hematopoietic stem cell engraftment with a combination of agents
The present invention provides a clinically applicable method of bone marrow conditioning for stem cell transplantation or therapeutic treatment of hematologic malignancies.
1 . A method for providing hematopoietic stem cell engraftment in a mammalian subject, the method comprising:
(i) administering to the subject an effective dose of an anti-CD117 antibody;
(ii) administering to the subject an effective dose of a hypomethylating agent; and
(iii) infusing a cellular composition comprising exogenous hematopoietic stem cells to the subject,
wherein the administration of the anti-CD117 antibody and the administration of the hypomethylating agent ablate targeted endogenous hematopoietic stem cells in the subject, and the exogenous hematopoietic stem cells are engrafted to the subject in the absence of myeloablative conditioning.
2 . The method of claim 1 , wherein the anti-CD117 antibody is a monoclonal antibody, and optionally is an aglycosylated IgG antibody.
3 . The method of claim 2 , wherein the dose of the anti-CD117 antibody is from about 0.1 mg/kg to about 25 mg/kg.
4 . The method of claim 2 , wherein the anti-CD117 antibody is administered as a single dose.
5 . The method of claim 1 , wherein the hypomethylating agent blocks the activity of DNA methyltransferase, and wherein the hypomethylating agent is a cytosine analog.
6 . The method of claim 5 , wherein the hypomethylating agent is 5-azacytidine, decitabine, guadecitabine, or 5-fluro-2′-deoxycytidine.
7 . The method of claim 6 , wherein the daily dose of the hypomethylating agent is from about 0.1 mg/kg to about 10 mg/kg.
8 . The method of claim 1 , wherein the hypomethylating agent is administered daily for a period of from 1 to 9 days, or for a period of 5 days.
9 . The method of claim 1 , wherein the hypomethylating agent and the anti-CD117 antibody are administered concomitantly.
10 . The method of claim 1 , wherein the hypomethylating agent is administered subsequent to the administration of the anti-CD117 antibody, and the interval of time between administration of the anti-CD117 antibody and administration of the hypomethylating agent is between 1 and 10 days.
11 . The method of claim 1 , wherein the infusion of the cellular composition comprising the exogenous hematopoietic stem cells is performed from after about 12 hours to after about 10 days when the administration of the hypomethylating agent is completed.
12 . The method of claim 1 , wherein the exogenous hematopoietic stem cells are autologous or allogeneic relative to the subject, and are optionally genetically engineered ex vivo.
13 . The method of claim 1 , wherein the exogenous hematopoietic stem cells are obtained from bone marrow, cord blood, or peripheral blood and selected for CD34+ expression; optionally wherein the cellular composition comprises at least 50% CD34+ cells.
14 . The method of claim 13 , wherein the cellular composition comprises at least 105 CD34+ cells/kg of recipient body weight.
15 . The method of claim 1 , wherein the subject has a hematologic malignancy, a blood disorder, or has received an organ transplant from the same donor of the hematopoietic stem cells.
16 . A method of treatment for a hematologic malignancy in a subject, the method comprising:
(i) administering to the subject an effective dose of an anti-CD117 antibody; and
(ii) administering to the subject an effective dose of a hypomethylating agent,
wherein the administration of the anti-CD117 antibody and the administration of the hypomethylating agent ablate targeted endogenous hematopoietic stem cells in the subject.
17 . The method of claim 16 , wherein the anti-CD117 antibody is an aglycosylated IgG antibody, and wherein the dose of the anti-CD117 antibody is from about 0.1 mg/kg to about 25 mg/kg.
18 . The method of claim 16 , wherein the hypomethylating agent is 5-azacytidine, decitabine, guadecitabine, or 5-fluro-2′-deoxycytidine, and wherein the daily dose of the hypomethylating agent is from about 0.1 mg/kg to about 10 mg/kg.
19 . The method of claim 16 , wherein the hematologic malignancy is a leukemia or pre-leukemia.
20 . The method of claim 19 , wherein the hematologic malignancy is myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), or chronic myelomonocytic leukemia (CMML).