Methods and compositions for mobilizing stem cells

Abstract

The present invention relates to methods and compositions for mobilizing hematopoietic stem cells and/or progenitor cells, and related methods of conditioning for engraftment of transplanted hematopoietic stem cells and/or progenitor cells, and methods of treating diseases requiring hematopoietic stem cell and/or progenitor cell transplantation.

What is claimed is: 
     
         1 . A method of mobilizing hematopoietic stem cells and/or progenitor cells in a subject, comprising administering to the subject a combination of a CXCR2 agonist and a CXCR4 antagonist, in amounts effective to mobilize hematopoietic stem cells and/or progenitor cells into the subject's peripheral blood. 
     
     
         2 . The method according to  claim 1 , wherein the CXCR2 agonist is selected from the group consisting of Gro-beta, Gro-betaΔ4 and analogs or derivatives thereof. 
     
     
         3 . The method according to  claim 1 , wherein the CXCR4 antagonist is selected from the group consisting of Plerixafor and analogs or derivatives thereof. 
     
     
         4 . The method according to  claim 1 , wherein the CXCR2 agonist is selected from the group consisting of Gro-beta, Gro-betaΔ4 and analogs or derivatives thereof; and wherein the CXCR4 antagonist is selected from the group consisting of Plerixafor and analogs or derivatives thereof 
     
     
         5 . The method according to  claim 1 , further comprising administering to the subject a cytokine selected from the group consisting of recombinant granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and glycosylated or pegylated forms thereof. 
     
     
         6 . The method according to  claim 1 , wherein the mobilized hematopoietic stem cells comprise CD34 +  peripheral blood stem cells. 
     
     
         7 . The method according to  claim 1 , wherein the subject exhibits poor mobilization in response to administration of G-CSF alone. 
     
     
         8 . A method of treating a disease requiring peripheral blood stem cell transplantation in a subject in need of such treatment, comprising: (a) administering to a peripheral blood stem cell donor a combination of a CXCR2 agonist and a CXCR4 antagonist, in amounts effective to mobilize circulating peripheral blood stem cells in the donor; and (b) transplanting the mobilized circulating peripheral blood stem cells from the donor into the subject in need of a peripheral blood stem cell transplantation. 
     
     
         9 . The method according to  claim 8 , wherein the CXCR2 agonist is selected from the group consisting of Gro-beta, Gro-betaΔ4 and analogs or derivatives thereof; and wherein the CXCR4 antagonist is selected from the group consisting of Plerixafor and analogs or derivatives thereof 
     
     
         10 . The method according to  claim 8 , further comprising administering to the subject a cytokine selected from the group consisting of recombinant granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and glycosylated or pegylated forms thereof. 
     
     
         11 . The method according to  claim 8 , wherein the mobilized hematopoietic stem cells comprise CD34 +  peripheral blood stem cells. 
     
     
         12 . The method according to  claim 11 , further comprising harvesting the CD34+ peripheral blood stem cells from the donor prior to transplantation into the subject. 
     
     
         13 . The method according to  claim 12 , wherein harvesting the mobilized hematopoietic stem cells comprises apheresis. 
     
     
         14 . The method according to  claim 13 , wherein the apheresis procedure is performed within an hour of administration of the CXCR2 agonist and the CXCR4 antagonist to the donor. 
     
     
         15 . The method according to  claim 8 , wherein the donor and the subject are the same individual. 
     
     
         16 . The method according to  claim 8 , wherein the donor and the subject are different individuals. 
     
     
         17 . A method of conditioning a subject for engraftment of transplanted peripheral blood stem cells, comprising administering to the subject a combination of at least one CXCR2 agonist, and at least one CXCR4 antagonist in amounts effective to deplete hematopoietic stem cells from the subject's stem cell niche for subsequent engraftment in the subject's stem cell niche of transplanted peripheral blood stem cells, thereby conditioning the subject for engraftment of transplanted peripheral blood stem cells. 
     
     
         18 . The method of  claim 17 , wherein the CXCR2 agonist is selected from the group consisting of Gro-beta, Gro-betaΔ4 and analogs or derivatives thereof; and wherein the CXCR4 antagonist is selected from the group consisting of Plerixafor and analogs or derivatives thereof. 
     
     
         19 . The method according to  claim 17 , wherein the subject is a patient presenting with a hematological malignancy. 
     
     
         20 . The method according to  claim 19 , wherein the hematological malignancy is selected from the group consisting of acute lymphoid leukemia, acute myeloid leukemia, chronic lymphoid leukemia, chronic myeloid leukemia, diffuse large B-cell non-Hodgkin's lymphoma, mantle cell lymphoma, lymphoblastic lymphoma, Burkitt's lymphoma, follicular B-cell non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, lymphocyte predominant nodular Hodgkin's lymphoma, multiple myeloma, and juvenile myelomonocytic leukemia.