Non-genotoxic conditioning regimen for stem cell transplantation

Inactive Publication Date: 2018-08-02
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0018]Following transplantation with donor stem cells, the recipient may be a chimera or mixed chimera for the donor cells. The methods of the invention allow effective stem cell engraftment in the absence of non-selective ablation methods, e.g. radiation or chemotherapy, which

Problems solved by technology

Current methods to clear niche space rely on radiation and/or chemotherapy, which can impart toxic adverse effects that greatly limit

Method used

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  • Non-genotoxic conditioning regimen for stem cell transplantation
  • Non-genotoxic conditioning regimen for stem cell transplantation
  • Non-genotoxic conditioning regimen for stem cell transplantation

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Example 1

A Non-Genotoxic Conditioning Regimen for Haploidentical Hematopoietic Stem Cell Transplantation Materials and Methods

[0138]Mice. All donor and recipient mice were between 8 and 12 weeks of age. Donor mice were AKR×Hz F1 mice bred by the Shizuru lab. AKR×Hz F1 mice are double positive for 45.1 and 45.2, and H2Kb and H2Kk. Recipient mice were CB6F1 from JAX. CB6F1 mice are single positive for 45.2 and double positive for H2Kb and H2Kd. All procedures were approved by the International Animal Care and Use Committee. Mouse strains were maintained at Stanford University's Research Animal Facility.

[0139]Antibodies. All antibodies for in vivo conditioning were purchased from Bio X Cell, including anti-CD47 (clone 3 / clone mIAP410), anti-CD117 (clone ACK2), anti-CD40L (clone MR-1), and anti-CD122 (clone TM-b1).

[0140]BM Transplant. Recipient CB6F1 mice were given a priming dose of 100 ug of anti-CD47 intraperitoneally on Day −8. On Day −6, mice were given a 500 μg retro-orbital injec...

Example

Example 2

Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance

[0144]Replacing a patient's diseased blood system by hematopoietic cell transplantation (HCT) can treat or cure genetic disorders of the blood and immune system, including leukemia, autoimmune diseases and immunodeficiencies. In HCT, a patient's blood and immune systems are typically ablated using toxic “conditioning regimens” (chemotherapy and / or radiation) and then replaced with donor cells containing hematopoietic stem cells (HSCs) to regenerate a healthy blood system. While HCT is a foundational treatment, its use and safety are hindered by graft vs. host disease (which can be overcome by transplanting purified HSCs devoid of contaminating donor T cells) and lethal toxicities caused by the conditioning regimens. Therefore, a decisive goal is to achieve HCT conditioning with more specific, safer agents (e.g., monoclonal antibodies), obviating the need for toxic chemo...

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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.

Description

CROSS REFERENCE[0001]This application claims benefit of U.S. Provisional Patent Application No. 62 / 452,218, filed Jan. 30, 2017, which applications are incorporated herein by reference in their entirety.[0002]Stem cells provide the means for organisms to maintain and repair certain tissues, through the ability of these cells to self-renew and to generate differentiated cells. Clinically, bone marrow and hematopoietic stem cell transplantation are widely used as a means of providing patients with the capacity to generate blood cells, usually where the patient has been depleted of endogenous stem cells by high dose chemotherapy or radiation.[0003]Hematopoietic cell transplantation (HCT) generally involves the intravenous infusion of autologous or allogeneic blood forming cells, the active subset of which are hematopoietic stem cells (HSC); these are collected from bone marrow, peripheral blood, or umbilical cord blood and transplanted to reestablish hematopoietic function in patients ...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61P37/06A61K39/395
CPCA61K39/001A61P37/06A61K39/39541A61K2039/505A61K2035/122C07K16/2803C07K16/2866C07K16/2875A61K38/177A61K38/13A61K2035/124
Inventor WEISSMAN, IRVING L.SHIZURU, JUDITH A.CHHABRA, AKANKSHAGEORGE, BENSON M.
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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