IP Library › Granted Patent US 12,370,243
Granted Patent B2
US 12,370,243 · App. 17/185,386 · Granted Jul 29, 2025

Non-genotoxic conditioning regimen for stem cell transplantation

Inventors: Irving L. Weissman (Stanford, CA); Judith A. Shizuru (Palo Alto, CA); Akanksha Chhabra (San Francisco, CA); Benson M. George (Palo Alto, CA)
Assignee: The Board of Trustees of the Leland Stanford Junior University
A61K39/001A61K39/39541A61P37/06C07K16/2803C07K16/2866C07K16/2875A61K2035/122A61K2039/505
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,370,243
App. No.
17/185,386
Granted
Jul 29, 2025
Kind
B2
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.

Claims (15)

1. A method of providing for engraftment of HLA-mismatched hematopoietic stem cells in an immunocompetent human subject, the method comprising a conditioning regimen of:

contacting said subject concomitantly with (i) an antibody that specifically binds to CD117 and (ii) an agent that blocks interaction between CD47 and SIRPα; in a dose effective to ablate targeted endogenous hematopoietic stem cells from bone marrow of said subject;

introducing a cellular composition comprising exogenous allogeneic hematopoietic stem cells mismatched at one or more major MHC loci to said subject, following a wash-out period of time sufficient to reduce the serum level of (i) and (ii) to non-toxic levels in the subject, the cellular composition comprising: exogenous hematopoietic stem cells mismatched at one or more major MHC loci; and

concomitantly contacting said subject with (iii) an agent that induces transient immunosuppression, wherein the agent is an anti-CD40L antibody; and

contacting the subject with (iv) an agent the depletes NK cells, wherein the agent (iv) is administered prior to or concurrently with the exogenous stem cells;

wherein the exogenous stem cells engraft in the absence of myeloablative conditioning.

2. The method of claim 1 , wherein the agent that blocks interaction between CD47 and SIRPα is selected from: a soluble SIRPα polypeptide; an antibody specific for CD47, an antibody specific for SIRPα, and a soluble CD47 polypeptide.

3. The method of claim 1 , wherein the subject is haploidentical relative to the exogenous stem cells.

4. The method of claim 1 , wherein an agent (iv) that selectively depletes NK cells is selected from an antibody specific for one or more of CD122 and CD56.

5. The method of claim 1 , wherein the agent (iv) is an antibody selected from an antibody specific for CD2, CD52, CD45; or anti-thymocyte globulin (ATG).

6. The method of claim 1 , wherein an agent (iv) further comprises an agent that selectively depletes T cells, selected from an antibody specific for one or more of CD3, CD4, and CD8.

7. The method of claim 5 , wherein the cellular composition comprises at least 50% hematopoietic stem cells selected for CD34 + expression from bone marrow, cord blood, or peripheral blood.

8. The method of claim 6 , wherein the cellular composition comprises at least 50% hematopoietic stem cells selected for CD34 + expression from bone marrow, cord blood, or peripheral blood.

9. The method of claim 5 , wherein the cellular composition comprises hematopoietic stem cells derived from pluripotent cells in vitro.

10. The method of claim 5 , wherein the cellular composition comprises at least 10 5 CD34 + cells/kg of recipient body weight.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 5, 2021
From: WEISSMAN, IRVING L.; SHIZURU, JUDITH A.; CHHABRA, AKANKSHA; GEORGE, BENSON M.
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 056144/0526 →
Continuity (3)
Division 15884017 · Jan 30, 2018
Provisional Application 62452218 · Jan 30, 2017
Related Publication 20210177949A1 · Jun 17, 2021
References Cited (35)
US 5877299A · Thomas · 1999 [cited by applicant]
US 10406179B2 · Shizuru · 2019 [cited by applicant]
US 20050112122A1 · Greiner · 2005 [cited by applicant]
US 20060147428A1 · Sachs · 2006 [cited by applicant]
US 20130189253A1 · Danska · 2013 [cited by applicant]
US 20170151327A1 · Lui · 2017 [cited by applicant]
US 20190134217A1 · Nixon · 2019 [cited by applicant]
WO WO2003054019 · 2003 [cited by applicant]
WO WO2004002425 · 2004 [cited by applicant]
WO WO2005021734 · 2005 [cited by applicant]
WO WO2008067115 · 2008 [cited by applicant]
WO WO2016033201 · 2016 [cited by applicant]
WO WO2016094679 · 2016 [cited by applicant]
WO WO2016154588 · 2016 [cited by applicant]
WO WO2016164502 · 2016 [cited by applicant]
Bartolovic et al., “Inhibitory effect of imatinib on normal progenitor cells in vitro” Blood, Jan. 15, 2004, pp. 523-529, vol. 103, No. 2, The American Society of Hematology, Washington, D.C. [cited by applicant]
Burt et al., “Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation”, Blood, Nov. 15, 1998, pp. 3505-3514, vol. 92(10), The American Society of … [cited by applicant]
Chen et al., “Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure”, Blood, Sep. 15, 2004, pp. 1671-1678, 104(6), The American Society of Hematology, … [cited by applicant]
Chhabra et al. (2014) “Successful Engraftment of Hematopoietic Stem Cells into Immunocompetent Recipients Using Only Anti-CD117 Antibody and CD47 Blockade as Conditioning” Blood, 2014,v.124, p. 2410. [cited by applicant]
Chhabra et al., “Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy,” Sci Transl Med, Aug. 10, 2016, pp. 1-11, vol. 8, No. 35, American Association for the Advancement of … [cited by applicant]
Czechowicz et al., “Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches.” Science, Nov. 23, 2007, pp. 1296-1299, vol. 318, No. 5854, AAAS, Washington, DC. [cited by applicant]
Gaspar et al., “Successful Reconstitution of Immunity in ADA-SCID by tem Cell Gene Therapy Following Cessation of PEG-ADA and Use of Mild Preconditioning”, Molecular Therapy, Oct. 2006, pp. 505-513, vol. 14(4), The Amer… [cited by applicant]
Ishikawa et al., “An assay for long-term engrafting human hemopoietic cells based on newborn NOD/SCID Beta 2-microglobulin(null) mice”, Experimental Hematology, Jan. 22, 2002, pp. 488-494, 30(5), Elsevier, Amsterdam, Ne… [cited by applicant]
Jacobsohn et al., “Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children”, The Lancet, Jul. 10, 2004, pp. 156-162, 364(9429), The Lancet, London, United Kingdom. [cited by applicant]
Kim et al (2003) “Successful allogenic hematopoietic stem cell transplantation using triple agent immunosuppression in serve aplastic anemia patients” Bone Marrow Transplantation, v.31, pp. 79-86. [cited by applicant]
Kraft et al. “Ability of Anti C-knit Targeting Monoclonal Antibody ACK-2 To Target hematopoietic stem cells and Facilitate Engraftment of human CD34+ Engraftment and Hematolymphoid Development in Immunodeficient Mice: A… [cited by applicant]
Kraft et al., “Effect and kinetics of depleting ACK-2 anti c-kit monoclonal antibody on hematopoiesis and hematopoietic progenitors and ability to condition for bone marrow transplantation” Blood, (Ash Annual Meeting Ab… [cited by applicant]
Kraft et al., “196—Ability Of Anti C-Kit Targeting Monoclonal Antibody Ack-2 To Target Hematopoietic Stem Cells, And Facilitate Engraftment Of Human CD34+ Engraftment And Hematolymphoid Development In Immunodeficient Mi… [cited by applicant]
Kraft et al., “378—Adult human hematopoietic cells differentiate into mature T cells via a CD3-4+8-intermediate within the mouse thymic microenvironment; a new model system for the study of human thymocyte development f… [cited by applicant]
Murray et al. {2002) “Non-Cancer Therapeutic Anti Bodies” Expert Opinion On Therapeutic Patents, vo 1, 12. no. 3. pp. 401-417. [cited by applicant]
Partridge et al. “Enhanced Engraftment of Hematopoietic Stem Cells (HSCs) by Inhibition of Mammalian Target of Rapamycin” (2013) Molecular Therapy,v.21, Suppl S160-S161. [cited by applicant]
Quesenberry et al., “Stem cell homing: Rolling, crawling, and nesting”, PNAS, Dec. 1998, pp. 15155-15157 vol. 95, National Academy of Sciences, Washington, D.C. [cited by applicant]
Remberger et al. {1999) “Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies uring conditioning for unrelated hematopoietic stem cell transplantation” Bone Marrow Transplantation… [cited by applicant]
Xue et al., “Antibody targeting KIT as pre-transplantation conditioning in immunocompetent mice,” Blood, Sep. 2, 2010, pp. 5419-5422, vol. 116(24), The American Society of Hematology, Washington, D.C. [cited by applicant]
Duncan et al. (2005) “Transplant-related immunosuppression: a review of immunosuppression and pulmonary infections”. Proc Am Thorac Soc. :2(5):449-455. [cited by applicant]