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Selective immunodepletion of endogenous stem cell niche for engraftment

a stem cell niche and immunodepletion technology, applied in the direction of antibody medical ingredients, drug compositions, peptides, etc., can solve the problems of poor engraftment, graft failure, microenvironment or marrow stroma dysfunction, etc., to improve the function of targeted tissue, improve the efficiency of engraftment, and eliminate endogenous stem cells

Inactive Publication Date: 2010-09-09
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]Adhesion to the extracellular matrix is mediated by several classes of receptor, the most extensively characterized being integrins. High expression of β1 integrins is required for maintenance of epidermal stem cells, and β1 integrins regulate differentiation of keratinocytes and other cell types through MAP kinase signaling. Integrins can maintain the position of cells in a tissue, and loss or alteration of integrin expression can lead to loss of a position in a niche. The extracellular matrix may also sequester and modulate the local concentration of secreted factors available within the stem cell niche.
[0012]Methods are provided for the engraftment of stem cells, e.g. hematopoietic stem cells, where endogenous stem cells are selectively ablated, thereby opening a niche for the engraftment of donor stem cells. Selective ablation substantially eliminates endogenous stem cells in the targeted tissue, without general ablation of cells in the tissue. The efficiency of engraftment is significantly enhanced by selective ablation, as compared to engraftment obtained without pretreatment. Such selective ablation allows improved function of the targeted tissue during the engraftment period, compared to methods involving non-selective ablation. The methods of the invention thus allow effective stem cell engraftment in the absence of non-selective ablation methods, e.g. radiation or chemotherapy, which have the undesirable effect of ablating differentiated cells involved in the function of the targeted tissue as well as undesirable side effects upon other tissues (e.g. on cells of the gastrointestinal system, hair growth), as well as increasing risk of secondary malignancies.

Problems solved by technology

Trimethoprim-sulfamethoxazole given to prevent Pneumocystis carinii infections is modestly myelosuppressive and only rarely produces graft failure.
Poor engraftment may also result from microenvironment or marrow stroma dysfunction related to the patient's underlying disease or prior therapy.
This mobilization results in a substantial rise in the number of circulating progenitor cells.
Integrins can maintain the position of cells in a tissue, and loss or alteration of integrin expression can lead to loss of a position in a niche.

Method used

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  • Selective immunodepletion of endogenous stem cell niche for engraftment
  • Selective immunodepletion of endogenous stem cell niche for engraftment
  • Selective immunodepletion of endogenous stem cell niche for engraftment

Examples

Experimental program
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Effect test

example 1

Antibody-Based Depletion of Hematopoietic Stem Cells Empties Niches for Efficient Transplantation

[0090]We demonstrate that administration of a depleting antibody specific for c-kit leads to the highly efficient removal of host hematopoietic stem cells (HSCs) and high levels of donor HSC chimerism following transplantation.

[0091]Upon intravenous transplantation, hematopoietic stem cells (HSCs) can home to specialized bone marrow niches, yet engraftment levels rarely exceed 0.5% following transplantation into immunodeficient recipients without toxic conditioning. Here, we provide evidence that, aside from immune barriers, donor HSC engraftment is restricted by occupancy of appropriate niches by host HSCs. Administration of ACK2, a depleting antibody specific for c-kit, led to the transient removal of >98% of endogenous HSCs and transplantation of these animals with donor HSCs led to chimerism levels of up to 90%. Extrapolation of these methods to humans may enable efficient yet mild c...

example 2

Antibody-Mediated Lymphoablation and HSC Transplantation for the Treatment of Agammaglobulinemia

[0132]We sought to determine whether transient depletion of CD4+ T cells from mice that normally reject allogeneic HSCs would allow for minor histocompatibility-mismatched HSC engraftment. Cμ− / − mice, which are a model for agammaglobulinemia and are recalcitrant to sustained donor HSC engraftment in the absence of irradiation, were treated with anti-CD4 antibody (clone GK1.5), which depletes >95% of CD4+ T cells in vivo, prior to transplantation with HSCs from GFP-transgenic mice. Short-term engraftment and B cell reconstitution was seen in all animals treated with anti-CD4 antibody, but was never seen in any of the untreated animals (FIG. 11). This chimerism, however, was lost between 8-12 weeks after transplantation as CD4+ T cell counts returned to normal. Thus, in this system, permanent transplantation tolerance was not generated by ˜0.1-0.2% HSC chimerism.

[0133]Candidate human HSC-sp...

example 3

Purified Hematopoietic Stem Cell Engraftment of Rare Niches Corrects Severe Lymphoid Deficiencies without Host Conditioning

[0135]In the absence of irradiation or other cytoreductive conditioning, endogenous hematopoietic stem cells (HSCs) are thought to fill the unique niches within the bone marrow that allow maintenance of full hematopoietic potential and thus prevent productive engraftment of transplanted donor HSCs. By transplantation of purified exogenous HSCs into unconditioned congenic histocompatible strains of mice, we show that ˜0.1-1.0% of these HSC niches are available for engraftment at any given point and find no evidence that endogenous HSCs can be displaced from the niches they occupy. We demonstrate that productive engraftment of HSCs within these empty niches is inhibited by host CD4+ T cells that recognize very subtle minor histocompatibility differences. Strikingly, transplantation of purified HSCs into a panel of severe combined immunodeficient (SCID) mice leads ...

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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. 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, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment and tolerance.

Description

[0001]Stem cells provide the means for organisms to maintain and repair certain tissues, through the ability of these cells to self-renew and, through asymmetric replication, to generate differentiated cells. The potency of stem cells varies: whereas embryonic stem cells can give rise to all tissues of an organism, somatic stem cells may be limited to a specific lineage. 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. Bone marrow and peripheral blood are currently used as sources of autologous stem cells. In the future, cultured stem cells may provide an alternative to autologous cells for transplants.[0002]In cancer patients, hematopoietic stem cells may be administered as supportive care to circumvent the morbidity and mortality associated with high-dose ablative ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K35/12A61P43/00A61K39/00
CPCA61K2039/505A61K2039/54C07K16/2803C07K2316/96C07K16/2866C07K16/2896C07K16/2812C07K2317/73A61P43/00A61K35/28A61K39/3955C07K16/2815C07K16/32C07K2317/76
Inventor WEISSMAN, IRVING L.CZECHOWICZ, AGNIESZKABHATTACHARYA, DEEPTAKRAFT, DANIEL
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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