Engraftment of stem cells with a combination of an agent that targets stem cells and modulation of immunoregulatory signaling
The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells with a combination of antibodies specific for CD117, and agents that modulate immunoregulatory signaling pathways, e.g. agonists of immune costimulatory molecules, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment, even in immunocompetent recipients.
1. A method of hematopoietic stem cell engraftment in a mammal, the method comprising:
contacting said mammal concomitantly with (i) a monoclonal antibody specific for CD117 and (ii) an agent that blocks interaction between CD47 and SIRPα, wherein the agent is selected from an anti-CD47 antibody, an anti-SIRPα antibody, a soluble SIRPα polypeptide or a fusion protein comprising a SIRPα polypeptide; in a dose effective in ablating hematopoietic stem cells from bone marrow of said mammal; and
introducing exogenous hematopoietic stem cells to said mammal, wherein the exogenous hematopoietic stem cells engraft to provide for long-term multilineage hematopoietic engraftment.
2. The method of claim 1 wherein the agent that blocks interaction between CD47 and SIRPα comprises a soluble SIRPα polypeptide.
3. The method of claim 2 , wherein the soluble SIRPα polypeptide is a high affinity SIRPα variant.
4. The method of claim 3 , wherein the soluble SIRPα polypeptide is CV1.
5. The method of claim 2 , wherein the agent is a fusion protein comprising a SIRPα polypeptide.
6. The method of claim 5 , wherein the agent is a monomer or a dimer.
7. The method of claim 1 wherein the agent that blocks interaction between CD47 and SIRPα is an anti-CD47 antibody.
8. The method of claim 1 , wherein the agent that blocks interaction between CD47 and SIRPα is an anti-SIRPα antibody.
9. The method according to claim 1 , wherein said mammal is a mouse.
10. The method of claim 1 , wherein the engraftment is performed in the absence of myeloablative conditioning.
11. The method of claim 1 , wherein the mammal is immunocompetent.
12. The method according to claim 1 , wherein said exogenous stem cells are allogeneic stem cells.
13. The method of claim 1 , wherein the exogenous stem cells are autologous.
14. The method of claim 1 , wherein said contacting is repeated at least twice.
15. A method of hematopoietic stem cell engraftment in a human, the method comprising:
contacting said human concomitantly with (i) a monoclonal antibody specific for CD117 and (ii) an agent that blocks interaction between CD47 and SIRPα, wherein the agent is selected from an anti-CD47 antibody, an anti-SIRPα antibody, a soluble SIRPα polypeptide or a fusion protein comprising a SIRPα polypeptide; in a dose effective in ablating hematopoietic stem cells from bone marrow of said human; and
introducing exogenous human hematopoietic stem cells to said human, wherein the exogenous hematopoietic stem cells engraft to provide for long-term multilineage hematopoietic engraftment.