WO2004044127A2 - Stem cell populations - Google Patents
Stem cell populations Download PDFInfo
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- WO2004044127A2 WO2004044127A2 PCT/US2003/033368 US0333368W WO2004044127A2 WO 2004044127 A2 WO2004044127 A2 WO 2004044127A2 US 0333368 W US0333368 W US 0333368W WO 2004044127 A2 WO2004044127 A2 WO 2004044127A2
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- WO
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- Prior art keywords
- cells
- population
- tgf
- positive
- beta
- Prior art date
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- 210000000130 stem cell Anatomy 0.000 title description 7
- 210000004027 cell Anatomy 0.000 claims abstract description 65
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims abstract description 23
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims abstract description 23
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 20
- 210000005260 human cell Anatomy 0.000 claims abstract description 4
- 210000004700 fetal blood Anatomy 0.000 claims description 3
- 238000000684 flow cytometry Methods 0.000 claims description 3
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims description 2
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims description 2
- 210000001185 bone marrow Anatomy 0.000 claims description 2
- 230000000779 depleting effect Effects 0.000 claims description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 9
- 108091005735 TGF-beta receptors Proteins 0.000 description 4
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 4
- 101000981881 Brevibacillus parabrevis ATP-dependent glycine adenylase Proteins 0.000 description 2
- 101000981889 Brevibacillus parabrevis Linear gramicidin-PCP reductase Proteins 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000023750 transforming growth factor beta production Effects 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 102100025470 Carcinoembryonic antigen-related cell adhesion molecule 8 Human genes 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000914320 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 8 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 102100038081 Signal transducer CD24 Human genes 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors
Definitions
- This invention relates to stem cell populations and methods of obtaining such populations.
- TGF-beta plays a role in controlling cell cycles in many human cell types.
- TGF-beta has diverse functionality, which includes both proliferative and differentiative aspects.
- TGF-beta functions differently in different cell types. In some cases, it plays a role in stimulating cells to grow. In other cases, it plays an opposite role, maintaining the cells in a state of quiescence (a non-cycling state).
- the dominant role of TGF-beta in the most primitive of hematopoietic stem cells is to maintain quiescence. Early hematopoietic stem cells bear TGF-beta receptors.
- TGF-beta production methods of the invention do not interfere, interact, or otherwise disturb TGF-beta receptors on the surface of these target cells.
- Enrichment is enhanced by lineage depletion (using positive or negative selection to remove Lin+ cells, using, e.g., an antibody) as is described in Kraus U.S. Patent No. 5,925,567, the disclosure of which is hereby incorporated herein by reference.
- methods of the invention yield enriched stem cell containing populations, which can be expanded, and can be of value to patients in need of cellular therapy, e.g., cancer therapy, immunotherapy, and gene therapy.
- the invention features a population of human cells containing at least 1% TGF-beta positive/Lineage depleted cells.
- the TGF-beta positive/Lineage depleted cells can be derived from human cord blood, bone marrow or other sources. At least 5%, preferably at least 50%, and more preferably at least 90% of the cells in the population are TGF-beta positive/Lineage depleted cells.
- the cell population may be further stem cell enriched by selecting cells that are also CD45+/CD34+/CD38-.
- Lineage positive cells can be removed from the starting population of relatively undifferentiated cells by negative selection.
- Target cells can be expanded following selection, e.g., by the methods described in U.S. Patent No. 5,925,567.
- TGF- ⁇ positive/Lineage depleted cells can again be removed from the target cell population to further purify the target cell population.
- the removing step can be performed using flow cytometry, e.g., using fluorescent activated cell sorting.
- the method includes (a) selecting TGF-beta positive cells by positive selection; and (b) depleting TGF-beta positive cells of Lineage minus cells by negative selection.
- steps (a) and (b) are performed sequentially.
- the invention further features methods of treating a patient in need of cellular therapy by administering to the patient an aliquot of one of the cell populations described above.
- Fig. 1 is a dot plot showing the population profile of a Human Cord Blood Lineage Negative (CD2/3/4/8/14/16/19/24/56/66b/GlyA) Cell Population that includes a subpopulation (0.16%) which is co-positive for 1D11.
- Fig. 2 is a dot plot showing the population of Fig. 1, back-gated into a forward/side scatter plot, indicating that 67% of the Lin-/1D11+ cells fall within the primitive leucocyte gate.
- Figs. 3 and 3 A are dot plots showing the presence of mouse Lin- /Rholo/Holo/c-Kit+Sca+ hematopoietic stem cells (Fig. 3 A) in lineage-depleted bone marrow cell preparations (Fig. 3).
- Isolation and enrichment can be performed using a variety of immuno- selection strategies, including panning, magnetic particles, magnetic beads, chromatographic-like techniques, cell sorting, and high-speed cell sorting.
- suitable strategies include flow cytometry and fluorescent activated cell sorting.
- This population can be expanded, e.g., using the target cell expansion methods described in U.S. Patent No. 5,925,567, the disclosure of which is incorporated herein by reference.
- HCB obtained from full term infants was red cell depleted according to standard procedures and cryopreserved.
- the processed cord was later thawed and lineage depleted by immunomagnetic means using a cocktail of lineage antibodies that included CD2/CD3/CD14/CD16/CD19/CD24/CD56/CD66b/GlyA (StemCell Technologies).
- a sample of the purified fraction was incubated with 80 ug/ml of anti-TGF-beta antibody (IDl 1) that had been conjugated with ALEXA-488 (Molecular Probes) fluorochrome.
- IDl 1 anti-TGF-beta antibody
- ALEXA-488 Molecular Probes fluorochrome
- the purified anti-TGF-beta positive/LIN- populations of the invention are separated from lineage depleted HCB using a high speed cell sorter (e.g., Cytomation). These cells can be functionally characterized in CFC, HPP and NOD/scid engraftrnent assays.
- the method represents a 100 to 1,000 fold enrichment in the target population.
- Other embodiments are within the scope of the following claims.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Hematology (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Developmental Biology & Embryology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Cell Biology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Populations of human cells comprising at least 1% TGF-beta positive/Lineage depleted cells are provided. The invention also features methods of obtaining such populations.
Description
STEM CELL POPULATIONS
TECHNICAL FIELD
This invention relates to stem cell populations and methods of obtaining such populations.
BACKGROUND
TGF-beta plays a role in controlling cell cycles in many human cell types. TGF-beta has diverse functionality, which includes both proliferative and differentiative aspects. TGF-beta functions differently in different cell types. In some cases, it plays a role in stimulating cells to grow. In other cases, it plays an opposite role, maintaining the cells in a state of quiescence (a non-cycling state). The dominant role of TGF-beta in the most primitive of hematopoietic stem cells is to maintain quiescence. Early hematopoietic stem cells bear TGF-beta receptors.
SUMMARY
We have found that a rare population of lineage-minus hematopoietic stem cells are stained positive using an antibody to the TGF-beta receptor. As a result, we can identify and isolate specific and rare populations of hematopoietic stem cells using an antibody to TGF-beta, which can be used alone or in combination with means for selecting a sub-set of cells that are also positive for TGF-beta production; these cells are preferable to cells that bear the TGF-beta receptor but do not substantially express TGF-beta protein. TGF-beta production methods of the invention do not interfere, interact, or otherwise disturb TGF-beta receptors on the surface of these target cells. Enrichment is enhanced by lineage depletion (using positive or negative selection to remove Lin+ cells, using, e.g., an antibody) as is described in Kraus U.S. Patent No. 5,925,567, the disclosure of which is hereby incorporated herein by reference.
Thus, methods of the invention yield enriched stem cell containing populations, which can be expanded, and can be of value to patients in need of cellular therapy, e.g., cancer therapy, immunotherapy, and gene therapy.
Accordingly, in one aspect, the invention features a population of human cells containing at least 1% TGF-beta positive/Lineage depleted cells.
Some implementations include one or more of the following features. The TGF-beta positive/Lineage depleted cells can be derived from human cord blood, bone marrow or other sources. At least 5%, preferably at least 50%, and more preferably at least 90% of the cells in the population are TGF-beta positive/Lineage depleted cells. The cell population may be further stem cell enriched by selecting cells that are also CD45+/CD34+/CD38-.
Lineage positive cells can be removed from the starting population of relatively undifferentiated cells by negative selection. Target cells can be expanded following selection, e.g., by the methods described in U.S. Patent No. 5,925,567. After the expanding step, TGF-β positive/Lineage depleted cells can again be removed from the target cell population to further purify the target cell population. The removing step can be performed using flow cytometry, e.g., using fluorescent activated cell sorting.
In a preferred embodiment, the method includes (a) selecting TGF-beta positive cells by positive selection; and (b) depleting TGF-beta positive cells of Lineage minus cells by negative selection.
In some implementations, steps (a) and (b) are performed sequentially. The invention further features methods of treating a patient in need of cellular therapy by administering to the patient an aliquot of one of the cell populations described above.
Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.
DESCRIPTION OF DRAWINGS
Fig. 1 is a dot plot showing the population profile of a Human Cord Blood Lineage Negative (CD2/3/4/8/14/16/19/24/56/66b/GlyA) Cell Population that includes a subpopulation (0.16%) which is co-positive for 1D11.
Fig. 2 is a dot plot showing the population of Fig. 1, back-gated into a forward/side scatter plot, indicating that 67% of the Lin-/1D11+ cells fall within the primitive leucocyte gate.
Figs. 3 and 3 A are dot plots showing the presence of mouse Lin- /Rholo/Holo/c-Kit+Sca+ hematopoietic stem cells (Fig. 3 A) in lineage-depleted bone marrow cell preparations (Fig. 3).
DETAILED DESCRIPTION Using antibodies directed at the cell surfaces of lineage positive cells, we, in one of the steps of the invention, deplete a large number of differentiated cell types from a sample containing rare hematopoietic stem cells. This procedure leads to an enrichment of stem cells, and the other primary step, employing an anti-TGF-beta antibody as a positive selector, yields a population of cells highly enriched in a rare population of hematopoietic stem cells.
Using this procedure, we have identified within a sub-compartment of lineage depleted (LIN-) hematopoietic cells a population of anti-TGF-beta (e.g., IDl 1 Genzyme) positive cells.
Isolation and enrichment can be performed using a variety of immuno- selection strategies, including panning, magnetic particles, magnetic beads, chromatographic-like techniques, cell sorting, and high-speed cell sorting. For example, suitable strategies include flow cytometry and fluorescent activated cell sorting.
This population can be expanded, e.g., using the target cell expansion methods described in U.S. Patent No. 5,925,567, the disclosure of which is incorporated herein by reference.
Example
HCB obtained from full term infants was red cell depleted according to standard procedures and cryopreserved. The processed cord was later thawed and lineage depleted by immunomagnetic means using a cocktail of lineage antibodies that included CD2/CD3/CD14/CD16/CD19/CD24/CD56/CD66b/GlyA (StemCell Technologies). Following lineage depletion, a sample of the purified fraction was incubated with 80 ug/ml of anti-TGF-beta antibody (IDl 1) that had been conjugated with ALEXA-488 (Molecular Probes) fluorochrome. Using a Facscan (Becton
Dickinson), a 0.16% population with differential logarithmic expression levels was identified (Fig. 1).
Upon back-gating this population into the bi-variant Side Scatter versus
Forward Scatter dot plot, we learned that greater than 66% of the cells of the anti- TGF-beta positive population fell inside a primitive leukocyte region (Fig. 2). This region correlates with mouse Lin-/Rholo/Holo/c-Kit+Sca+ hematopoietic stem cells in cell preparations (Figs. 3 -3 A).
Given the differential positivity and relatively high concentration of antibody employed, we hypothesize that the anti-TGF-beta antibody is, in our methods, both bound to surface TGF-beta, and internalized within the cytoplasm of the cells. The purified anti-TGF-beta positive/LIN- populations of the invention are separated from lineage depleted HCB using a high speed cell sorter (e.g., Cytomation). These cells can be functionally characterized in CFC, HPP and NOD/scid engraftrnent assays.
The method represents a 100 to 1,000 fold enrichment in the target population. Other embodiments are within the scope of the following claims.
Claims
1. A population of human cells comprising at least 1% TGF-beta positive/Lineage depleted cells.
2. The population of claim 1 wherein the TGF-beta positive/Lineage depleted cells are derived from human cord blood or bone marrow.
3. The population of claim 1 wherein at least 5% of the cells in the population are TGF-beta positive/Lineage depleted cells.
4. The population of claim 1 wherein at least 50% of the cells in the population are TGF-beta positive/Lineage depleted cells.
5. The population of claim 1 wherein at least 90% of the cells in the population are TGF-beta positive/Lineage depleted cells.
6. The population of claim 1 further comprising CD45+/CD34+/CD38- cells.
7. A method of obtaining a target cell population comprising removing TGF-β positive/lineage depleted cells from a starting population containing relatively differentiated cells.
8. The method of claim 7 further comprising removing lineage positive cells from the starting population by negative selection.
9. The method of claim 7 further comprising, after the removing step, expanding target cells of the target cell population.
10. The method of claim 9 further comprising, after the expanding step, removing TGF-β positive/lineage depleted cells from the target cell population to further purify the target cell population.
11. The method of claim 7 wherein the removing step is performed using flow cytometry.
12. The method of claim 11 wherein the removing step is performed using fluorescent activated cell sorting.
13. A method of obtaining a cell population comprising
(a) selecting TGF-beta positive cells by positive selection; and
(b) depleting TGF-beta positive cells of Lineage minus cells by negative selection
14. The method of claim 13 wherein steps (a) and (b) are performed sequentially.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003284314A AU2003284314A1 (en) | 2002-11-08 | 2003-10-20 | Stem cell populations |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42483502P | 2002-11-08 | 2002-11-08 | |
| US60/424,835 | 2002-11-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2004044127A2 true WO2004044127A2 (en) | 2004-05-27 |
| WO2004044127A3 WO2004044127A3 (en) | 2004-07-08 |
Family
ID=32312880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2003/033368 WO2004044127A2 (en) | 2002-11-08 | 2003-10-20 | Stem cell populations |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003284314A1 (en) |
| WO (1) | WO2004044127A2 (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11608486B2 (en) | 2015-07-02 | 2023-03-21 | Terumo Bct, Inc. | Cell growth with mechanical stimuli |
| US11613727B2 (en) | 2010-10-08 | 2023-03-28 | Terumo Bct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
| US11624046B2 (en) | 2017-03-31 | 2023-04-11 | Terumo Bct, Inc. | Cell expansion |
| US11629332B2 (en) | 2017-03-31 | 2023-04-18 | Terumo Bct, Inc. | Cell expansion |
| US11634677B2 (en) | 2016-06-07 | 2023-04-25 | Terumo Bct, Inc. | Coating a bioreactor in a cell expansion system |
| US11667876B2 (en) | 2013-11-16 | 2023-06-06 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
| US11667881B2 (en) | 2014-09-26 | 2023-06-06 | Terumo Bct, Inc. | Scheduled feed |
| US11685883B2 (en) | 2016-06-07 | 2023-06-27 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
| US11795432B2 (en) | 2014-03-25 | 2023-10-24 | Terumo Bct, Inc. | Passive replacement of media |
| US11965175B2 (en) | 2016-05-25 | 2024-04-23 | Terumo Bct, Inc. | Cell expansion |
| US12043823B2 (en) | 2021-03-23 | 2024-07-23 | Terumo Bct, Inc. | Cell capture and expansion |
| US12152699B2 (en) | 2022-02-28 | 2024-11-26 | Terumo Bct, Inc. | Multiple-tube pinch valve assembly |
| US12234441B2 (en) | 2017-03-31 | 2025-02-25 | Terumo Bct, Inc. | Cell expansion |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5925567A (en) * | 1995-05-19 | 1999-07-20 | T. Breeders, Inc. | Selective expansion of target cell populations |
-
2003
- 2003-10-20 WO PCT/US2003/033368 patent/WO2004044127A2/en not_active Application Discontinuation
- 2003-10-20 AU AU2003284314A patent/AU2003284314A1/en not_active Abandoned
Cited By (22)
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| US11746319B2 (en) | 2010-10-08 | 2023-09-05 | Terumo Bct, Inc. | Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
| US11613727B2 (en) | 2010-10-08 | 2023-03-28 | Terumo Bct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
| US11773363B2 (en) | 2010-10-08 | 2023-10-03 | Terumo Bct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
| US11667876B2 (en) | 2013-11-16 | 2023-06-06 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
| US11708554B2 (en) | 2013-11-16 | 2023-07-25 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
| US11795432B2 (en) | 2014-03-25 | 2023-10-24 | Terumo Bct, Inc. | Passive replacement of media |
| US12065637B2 (en) | 2014-09-26 | 2024-08-20 | Terumo Bct, Inc. | Scheduled feed |
| US11667881B2 (en) | 2014-09-26 | 2023-06-06 | Terumo Bct, Inc. | Scheduled feed |
| US11608486B2 (en) | 2015-07-02 | 2023-03-21 | Terumo Bct, Inc. | Cell growth with mechanical stimuli |
| US11965175B2 (en) | 2016-05-25 | 2024-04-23 | Terumo Bct, Inc. | Cell expansion |
| US11634677B2 (en) | 2016-06-07 | 2023-04-25 | Terumo Bct, Inc. | Coating a bioreactor in a cell expansion system |
| US11999929B2 (en) | 2016-06-07 | 2024-06-04 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
| US11685883B2 (en) | 2016-06-07 | 2023-06-27 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
| US12077739B2 (en) | 2016-06-07 | 2024-09-03 | Terumo Bct, Inc. | Coating a bioreactor in a cell expansion system |
| US11624046B2 (en) | 2017-03-31 | 2023-04-11 | Terumo Bct, Inc. | Cell expansion |
| US11629332B2 (en) | 2017-03-31 | 2023-04-18 | Terumo Bct, Inc. | Cell expansion |
| US11702634B2 (en) | 2017-03-31 | 2023-07-18 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
| US12234441B2 (en) | 2017-03-31 | 2025-02-25 | Terumo Bct, Inc. | Cell expansion |
| US12359170B2 (en) | 2017-03-31 | 2025-07-15 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
| US12043823B2 (en) | 2021-03-23 | 2024-07-23 | Terumo Bct, Inc. | Cell capture and expansion |
| US12152699B2 (en) | 2022-02-28 | 2024-11-26 | Terumo Bct, Inc. | Multiple-tube pinch valve assembly |
| US12209689B2 (en) | 2022-02-28 | 2025-01-28 | Terumo Kabushiki Kaisha | Multiple-tube pinch valve assembly |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004044127A3 (en) | 2004-07-08 |
| AU2003284314A1 (en) | 2004-06-03 |
| AU2003284314A8 (en) | 2004-06-03 |
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