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Devices and methods for selecting apoptosis-signaling resistant cells, and uses thereof

a technology of apoptosis signaling and resistant cells, applied in the direction of drug compositions, separation processes, immunological disorders, etc., can solve the problems of life-threatening situations, loss of some beneficial stem cells, and negative selection of stem cell populations, so as to improve the clinical outcome of hematopoietic stem cells

Inactive Publication Date: 2018-07-26
CELLECT BIOTHERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a device and method for improving the success of transplanting stem and progenitor cells. The device is used to contact a population of cells containing stem and progenitor cells with an apoptosis-inducing ligand, and the remaining cells are then used for transplantation. The technical effect of this invention is to enhance the clinical outcome of hematopoietic stem and progenitor cells transplantation.

Problems solved by technology

Nevertheless, this procedure is currently employed for life threatening conditions because of its severe toxicity effects of which Graft versus host disease (GvHD) is the most critical.
The use of non-myeloablative preconditioning has improved significantly, yet not sufficiently, life-threatening situations caused by vital organ dysfunction, failure of engraftment and intractable infections.
Using such a positive selection method results in loss of some of the beneficial stem cells.
Therefore, exposure of a transplant population to TNF family apoptosis-inducing ligands such as FasL, Trail, Tweak or TNF-α results in negatively selecting the stem cell population, as cell populations sensitive for TNF-family ligand induced apoptosis undergo apoptosis and are removed from the transplant.
However, transplantation of allogeneic T cells into partially immunosuppressed recipients supports durable engraftment, which mediates a potentially lethal graft versus host reaction (GvH) or graft versus host disease (GvHD).
Extensive efforts have been invested in dissociation between T cell subsets that mediate GvH and support engraftment; however the experimental evidence has been so far inconclusive.
Acute GvHD is usually treated by immunosuppressive therapy, which has negative effects on hematopoietic reconstitution, whereas there is no current effective therapy for the chronic reaction.
Intensive efforts to achieve more selective T cell depletion (TCD) using various cell surface markers have failed.
However, there are several major hurdles to this approach to selective elimination.

Method used

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  • Devices and methods for selecting apoptosis-signaling resistant cells, and uses thereof
  • Devices and methods for selecting apoptosis-signaling resistant cells, and uses thereof
  • Devices and methods for selecting apoptosis-signaling resistant cells, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Ex Vivo Exposure of Umbilical Cord Blood Cells to Death Ligands

Apoptotic Activity of Death Receptor Activation In Vitro

[0136]The primary activity of the TNF superfamily is transduction of apoptotic signals. Fresh umbilical cord blood (UCB) obtained from term deliveries upon informed consent were exposed to FasL and TNF-α for various periods of time in liquid culture without supplementation of growth factors. Gated CD34+ progenitors within the bulk UCB cultures displayed reduced rates of apoptosis, with increasing susceptibility as a function of time (FIG. 1A), however apoptotic cell death is not enhanced by exposure to death ligands of the TNF family. It has been previously suggested that insensitivity to apoptotic signaling is caused by low-level expression of the receptors in hematopoietic progenitors. The analysis revealed lower expression of the Fas and TNF receptors in gated CD34+ and isolated lin− progenitors than in the bulk UCB population (FIG. 1B). More focused evaluation o...

example 2

Ex Vivo Exposure of Mobilized Peripheral Blood Cells to Death Ligands

[0145]APOPTOTIC activity of death receptor activation in vitro

[0146]A prevalent source of hematopoietic progenitors for transplantation is peripheral blood following mobilization with granulocyte colony stimulating factor (G-CSF) or antagonists of c-kit and CXCR4. The mobilized mononuclear cells are subsequently collected from peripheral blood by apheresis, containing a substantial number of CD34+ progenitors. Cells harvested from the peripheral blood are generally activated, therefore the periods of exposure to death ligands for selective depletion are significantly shorter. An additional difference from data presented for UCB cells is the use of cryopreserved mPB samples, the thawing of which is associated with apoptotic death of 15-25% of the cells. Fas is expressed in ˜25% of CD34+ progenitors (FIG. 6A) and considerable fractions of B lymphocytes and myeloid cells (50-65%, FIG. 6B). The TNF receptors are expres...

example 3

Pretransplant Depletion of T Cells Prevents Lethal GvHD

Prevention of Lethal GvHD by Ex Vivo Selective Depletion of Host-Sensitized T Cells

[0151]Both physical depletion of T cells from donor inoculum and FasL-mediated elimination of host-reactive T cells reliably prevent GVHD. Haploidentical murine transplants (parent to child) represent the extreme risk of GvHD, characterized by high levels of mortality. In first stage experiments were recapitulated using depletion of T cells by apoptotic signals following sensitization to host antigens. Antigen-specific sensitization in vitro for 2-3 days causes T cell receptor (TCR)-mediated stimulation of responsive T cells who concomitantly upregulate Fas and its cognate ligand, resulting in execution of the apoptotic cascade in parallel to downregulation of protective antiapoptotic mechanisms. To compare this procedure to tested approach using brief exposure to apoptotic ligands ex vivo without prolonged incubation, the donors were pre-immunize...

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PUM

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Abstract

The present invention discloses a device and a kit adapted for selection of cells that are resistant to receptor-mediated apoptosis and a method for using the device and kit. The device enables negative selection of mature immune cells which induce graft versus host disease (GvHD) out of a heterogeneous cell population which is introduced into the device. The device enables an efficient cell selection in simplified and cheaper setting by an off the shelf product—a solution that currently do not exist. The present invention further discloses uses for the device.

Description

[0001]A Sequence Listing in ASCII text file format of 9547 bytes in size, created on Sep. 7, 2017, with the file name “2017-09-07SequenceListing_YARKONI4A” is incorporated herein by reference.[0002]The present invention relates to the field of medical devices and more specifically, to devices aimed at selecting cells that are resistant to apoptosis signaling, methods of using the devices and uses thereof.BACKGROUND OF THE INVENTION[0003]Stem cells are cells that can both divide and differentiate into diverse specialized cell types and self-renew to produce more stem cells. In mammals, stem cells are found as either embryonic stem cells, which are isolated from the inner cell mass of blastocysts, or adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues.[0004]Unlike all current treatments relying upon surgical intervention or drugs that modulate physiological activities,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N5/00A61K35/51A61K35/28A61K35/30A61K35/12B01D15/00
CPCA61K35/51A61K35/30C12N2501/599B01D15/00C12N5/0081A61K35/12A61K35/28C12N2501/25A61P35/00A61P37/06
Inventor YARKONI, SHAIASKENASY, NADIR
Owner CELLECT BIOTHERAPEUTICS LTD
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