Engraftment of stem cells with a combination of an agent that targets stem cells and modulation of immunoregulatory signaling

• US 10,406,179 B2
• Filed: 08/26/2015
• Issued: 09/10/2019
• Est. Priority Date: 08/26/2014
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Shizuru, Judith A., Weissman, Irving L., Weiskopf, Kipp Andrew, Ring, Aaron Michael, Chhabra, Akanksha, Schnorr, Peter
• Primary Examiner(s): Gamett, Daniel C
• Application Number:
  US15/504,264
• Publication Number:
  US 20170224737A1
• Time in Patent Office: 1,476 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/1774 Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/74 Inducing cell proliferation
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

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.

Claims

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.