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WO1993018136A1 - Procede de maintien de cellules souche hematopoietiques - Google Patents

Procede de maintien de cellules souche hematopoietiques Download PDF

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Publication number
WO1993018136A1
WO1993018136A1 PCT/US1993/002043 US9302043W WO9318136A1 WO 1993018136 A1 WO1993018136 A1 WO 1993018136A1 US 9302043 W US9302043 W US 9302043W WO 9318136 A1 WO9318136 A1 WO 9318136A1
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WO
WIPO (PCT)
Prior art keywords
cells
hematopoietic
cell
patient
peripheral blood
Prior art date
Application number
PCT/US1993/002043
Other languages
English (en)
Inventor
Charles Sardonini
Wu Ying-Jye
Karl Nocka
Stephen Ip
Original Assignee
Cytomed, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cytomed, Inc. filed Critical Cytomed, Inc.
Priority to AU37938/93A priority Critical patent/AU3793893A/en
Publication of WO1993018136A1 publication Critical patent/WO1993018136A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/125—Stem cell factor [SCF], c-kit ligand [KL]
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/22—Colony stimulating factors (G-CSF, GM-CSF)
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]

Definitions

  • the present invention provides a process for ⁇ n vitro support of mammalian hematopoietic cells derived from peripheral blood.
  • the present invention provides for a process for in vitro support of mammalian hematopoietic cells derived from peripheral blood. These cells can be used in addition to or in place of bone marrow cells for transplatation. Specifically, the cells are stem cells and/or progenitor cells and they are maintained in a culture medium which contains at least one cytokine effective for supporting such cells. Additionally, the cells may be contained in a number of culture vessels such as a stir tank or airlift bioreactor (with or without the use of microcarrier beads), blood bags or growth chambers in which there is a continuous or periodic addition or perfusion of growth medium.
  • culture vessels such as a stir tank or airlift bioreactor (with or without the use of microcarrier beads), blood bags or growth chambers in which there is a continuous or periodic addition or perfusion of growth medium.
  • PBMC peripheral blood mononuclear cells
  • CFU-GM granulocyte-macrophage progenitor cells
  • Table I Maximum expansion values for the total cells, CFU-GM, and BFU-e exhibited by previously frozen bone marrow, fresh PBMC's and frozen PBMC's in various small scale bioreactors. All expansion values were normalized to a value of 1.0 at the start of the experiments. Also listed is the timepoint at which the maximum expansion occurred. PBMC's were obtained from patients treated _in. vivo with G-CSF.
  • An object of the present invention -provides for the in vitro support of mammalian hematopoietic cells derived from peripheral blood.
  • the cells are maintained in a culture medium which contains at least one cytokine effective for supporting such cells.
  • Preferred embodiments of this aspect of the present invention provide a process for supporting mammalian hematopoietic cells derived from peripheral blood which are progenitor cells, and a process for supporting hematopoietic cells which are derived from peripheral blood which are stem cells.
  • Applicants' invention provides for the support of hematopoietic stem and progenitor cells derived from PBMC without prior selection of progenitor cell populations as used in expanding cells derived from bone marrow.
  • stem cell as used herein and by those skilled in the art means cells which are not committed and which give rise to more differentiated cells and other stem cells.
  • progenitor cells as used herein and by those skilled in the art means a committed or specialized precursor with proliferative capability.
  • supporting as used herein and by those skilled in the art with respect to stem, progenitor and other hematopoietic cells means maintaining and/or expanding and/or promoting some differentiation of such cells.
  • cytokines effective for supporting the expansion of cells in accordance with the present invention:interleukin (IL)-l; IL-3; IL-6; granulocyte/ macrophage-colony stimulating factor (GM-CSF); human or murine stem cell factor (sometimes referred to as human or murine mast cell growth factor (MGF) or a c-kit ligand) .
  • IL interleukin
  • IL-3 IL-3
  • IL-6 granulocyte/ macrophage-colony stimulating factor
  • GM-CSF granulocyte/ macrophage-colony stimulating factor
  • human or murine stem cell factor sometimes referred to as human or murine mast cell growth factor (MGF) or a c-kit ligand
  • Another aspect of the present invention provides for a process of supporting hematopoietic cells wherein the cells are maintained in a culture medium containing a combination of cytokines effective for supporting such cells.
  • cytokines effective for supporting such cells.
  • the following are representative of some examples of such combinations of cytokines: IL-3 and GM-CSF; IL-3, GM-CSF- and stem cell factor.
  • the representative examples of cytokines and combinations thereof are merely intended to be examples of some cytokines and is not intended to limit the present invention.
  • a process for supporting mammalian hematopoietic cells by maintaining the cells in a culture medium which contains at least one cytokine effective for supporting such cells, wherein the culture is maintained within a large scale cell culture system, for example, a stirred tank (spinner vessel) bioreactor or an airlift bioreactor.
  • the bioreactor used is the stirred tank bioreactor which may be utilized with or without micro-carrier beads to aid in the expansion of the cells in the bioreactor.
  • Such cells may be derived from peripheral blood or from bone marrow.
  • the use of large reactors provides distinct advantages over conventional T-flask cultures in the expansion of progenitor and stem cells on a large scale where the cells have been derived from either peripheral blood or bone marrow.
  • a spinner vessel or airlift bioreactor An advantage of a spinner vessel or airlift bioreactor is that the large number of cells necessary for transplantation can be cultured in one or a few vessels whereas culturing these cells in T-flasks would require many vessels. This significantly reduces the amount of labor required to perform these in vitro cultures and reduces the likelihood of contamination observed from these additional manipulations. In addition, improved expansion of the cells is obtained.
  • Figures 1 and 2 are examples of the expansion of cells in spinner vessels and airlift bioractors.
  • stir vessel spinner vessel
  • airlift bioreactor as used herein and by those skilled in the art means any vessel used to contain cells using a sparged or bubbled gas for medium agitation and/or aeration containing at least one port for the addition and removal of medium or other nutrients.
  • microcarrier bead as used herein and by those skilled in the art means any bead (porous or non-porous) used to support or enhance the proliferation of cells in agitated vessels.
  • cytokines which may be employed in the present invention: IL-1 may be employed in an amount effective to support the cells, generally, such amount is at least 20 pg/ml and need not exceed 1 ng/ml, preferably 1 ng/ml; IL-6 may be employed in in an amount effective to support the cells, generally, such amount is at least 1 pg/ml and need not exceed 50 ng/ml preferably 10 ng/ml; IL-3 may be employed in an amount effective to support the cells, generally, such amount is at least 500 pg/ml and need not exceed 50 ng/ml, preferably 500 pg/ml; GM-CSF may be employed in an amount effective to support the cells, generally, such amount is at least 100 pg/ml and need not exceed 1 ng/ml, preferably 200 pg/ml; c-kit ligand may be employed in an amount effective to support the cells, generally, such amount is at least 1.0 ng/ml and need not
  • hematopoietic cells may be derived from peripheral blood withdrawn from a mammal in particular, a human.
  • a preferred embodiment of the present invention provides that the mammal has been treated with cytokines to enrich progenitor cells prior to the withdrawal of blood.
  • the cells supported in accordance with the present invention may be used in a variety of ways.
  • such cells may be employed as part of cell replacement therapy.
  • the expanded and cultivated cells may be infused alone or added to bone marrow cells for bone marrow transplant procedures.
  • the expanded cells produced in accordance with the present invention may be used in cell replacement therapy.
  • Such a procedure would involve treating the patient with one or a combination of cytokines in particular G-CSF or by using other agents which increase the number of stem cells or progenitor cells in the peripheral blood.
  • Peripheral blood leukocytes are then harvested by leukapheresis three times at intervals of three days before starting chemotherapy.
  • Peripheral blood mononuclear cells are obtained by density centrifugation. A typical leukapheresis results in approximately
  • the total PBMC harvest for the process is typically 3 x 10 cells
  • PBMC's amounting to 3.2 x 10 CFU-GM would be required for the starting population. Since fewer enriched PBMC's would be required, two thirds of the current leukapheresis process could be avoided. Providing an increased amount of CFU-GM would benefit the patient by providing a greater number of the progenitors necessary to provide engraftment.
  • the cells may be expanded in accordance with the invention before or after freezing thereof. After chemotherapy, the expanded cells are reinfused into a patient by procedures known in the art.
  • Fresh peripheral blood leukocytes were obtained by leukapheresis from a patient being treated with G-CSF therapy.
  • Tissue culture medium used was IMDM with 10% FBS, 100 units/mL penicillin, 100 mcg/mL streptomycin and cytokines.
  • Added cytokines included IL-3 (0.5 ng/mL), GM-CSF (0.25 ng/mL), and c-kit ligand (also known as stem cell factor) (100 ng/mL) and were added at a rate of three times per week regardless of the medium feed schedule.
  • Medium was replaced as necessary in order to keep the cell concentration under 10 cells/mL.
  • medium was replaced on a weekly basis by removing one half of the volume of the culture, centrifuging and adding back the cells with fresh medium.
  • the cultures were split 1 to 2 in order to reduce the cell concentration. This was performed by removing and discarding half of the volume of the culture (along with cells) and replacing the volume with fresh medium. Cell counts were obtained every 2-3 days.
  • Fresh and frozen PBMC's obtained as described in Example 1 were seeded into 250 mL stirred tank bioreactors at a density of 5.0 x 10 viable cells/mL. Tissue culture medium and cytokine compositions and feed schedules were performed as described in Example 1.
  • CFU-GM granulocyte-macrophage
  • BFU-e erythrocyte progenitor cells
  • methylcellulose colony assays (CytoMed) .
  • Cells were seeded into six well plates at densities ranging from 2.0 x 10 4 to 1.0 x 105 cells per plate using a volume of 1.0 ml. For each experiment, duplicate wells each at two different seeding densities were used to evaluate rogenitor cell concentrations. Assay plates were scored for the presence of CFU-GM and BFU-e colonies at day 14. Colony assays were performed on both spinner vessels as well as fresh and frozen PBMC seed cultures.
  • n is the number of 1 to 2 splits.
  • the increase in CFU-GM and BFU-e was calculated using the increase in the total cell number on the appropriate day as well as the concentration of protenitor cells determined in the colony assays.
  • One vessel was operated as a suspension bioreactor while the second vessel was operated with 2.5 g/L of microcarrier beads for cell culture in order to support the growth of anchorage-dependent cells.
  • the medium feeding schedule for both vessels was performed as described in Example 1.
  • Added cytokines included IL-3 (0.5 ng/ml), GM-CSF (0.25 ng/mL), and kit ligand (stem cell factor) (100 ng/mL). Cytokines were added independent of the media changes at a rate of three times per week.
  • CFU-GM Granulocyte-macrophage
  • BFU-e erythrocyte progenitor assays were performed by inoculating cells into 35 mm culture dishes in duplicate as described in Exampe 2. Plates were scored for the presence of colonies at day 14. Assays were performed weekly in spinner vessels with and without microcarriers as well as freshly thawed bone marrow.
  • Results of the total cell increase for the vessels with and without microcarrier beads are presented in Table 1 and Figure 1.
  • the vessels with and without microcarrier beads exhibited a maximum total cell expansion of 35 and 8 fold respectively.
  • the maximum expansion of both CFU-GM and BFU-e progenitors were observed on day 7.
  • the CFU-GM population increased from >a normalized value of 1.0 to values of 2.5 and 1.8 for the suspension and microcarrier cultures respectively.
  • the BFU-e population increased from 1.0 to 1.6 and 1.9 for the two cultures respectively.
  • Bone marrow obtained and processed as described in Example 3 was inoculated into an airlift bioreactor at a concentration of 1.1 x 10 cells/mL using IMDM with 10% FBS with added cytokines at a volume of 575 mL. Medium and cytokine concentrations, feeding rates, and progenitor assays were followed as described in Example 3.
  • Results for the increase in total cells and progenitors are presented in Table 1 and Figure 2.
  • the total cell increase in the airlift bioreactor was 5.3 fold on day 21.
  • the CFU-GM population expanded maximally on day 15 to a value of 2.1 compared to a normalized starting value of 1.0. No increase in BFU-e progenitors were observed over what was initially seeded into the culture.
  • the increase in total cell number was calculated using

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Abstract

L'invention concerne un procédé de maintien in vitro de cellules hématopoïétiques mammifères dérivées de sang périphérique. Les cellules hématopoïétiques peuvent être des cellules souche et/ou des cellules mère et lesdites cellules sont conservées dans un milieu de culture contenant au moins une cytokine efficace dans le maintien desdites cellules. De plus, l'invention concerne un procédé de traitement d'un patient au moyen d'une thérapie de remplacement cellulaire par administration à ce dernier des cellules hématopoïétiques dérivées du sang périphérique et conservées in vitro.
PCT/US1993/002043 1992-03-05 1993-03-05 Procede de maintien de cellules souche hematopoietiques WO1993018136A1 (fr)

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AU37938/93A AU3793893A (en) 1992-03-05 1993-03-05 Process for supporting hematopoietic progenitor cells

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US84660692A 1992-03-05 1992-03-05
US07/846,606 1992-03-05

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0587754A4 (fr) * 1991-06-07 1994-11-30 Immunex Corp Procede d'amelioration d'une transplantation autologue.
US5399493A (en) * 1989-06-15 1995-03-21 The Regents Of The University Of Michigan Methods and compositions for the optimization of human hematopoietic progenitor cell cultures
WO1995010291A1 (fr) * 1993-10-08 1995-04-20 Cellpro Ii Procedes de collecte et de cryoconservation de granulocytes humains
US5437994A (en) * 1989-06-15 1995-08-01 Regents Of The University Of Michigan Method for the ex vivo replication of stem cells, for the optimization of hematopoietic progenitor cell cultures, and for increasing the metabolism, GM-CSF secretion and/or IL-6 secretion of human stromal cells
WO1995026507A1 (fr) * 1994-03-25 1995-10-05 Board Of Regents, The University Of Texas System Expansion differentielle de cellules souches foetales dans la circulation sanguine maternelle, pour l'analyse genetique prenatale
WO1996000777A1 (fr) * 1994-06-30 1996-01-11 Boehringer Ingelheim International Gmbh Procede de production et de culture de cellules precurseurs hematopoietiques
US5605822A (en) * 1989-06-15 1997-02-25 The Regents Of The University Of Michigan Methods, compositions and devices for growing human hematopoietic cells
US5631219A (en) * 1994-03-08 1997-05-20 Somatogen, Inc. Method of stimulating hematopoiesis with hemoglobin
US5635386A (en) * 1989-06-15 1997-06-03 The Regents Of The University Of Michigan Methods for regulating the specific lineages of cells produced in a human hematopoietic cell culture
US5846529A (en) * 1993-08-23 1998-12-08 Nexell Therapeutics, Inc. Infusion of neutrophil precursors for treatment of neutropenia
WO1999038008A1 (fr) * 1998-01-23 1999-07-29 Prolifaron, Inc. Procedes et compositions d'identification de substances mimetiques de facteurs de croissance, de facteurs de croissance et d'inhibiteurs
US6037174A (en) * 1993-08-23 2000-03-14 Nexell Therapeutics, Inc. Preparation of serum-free suspensions of human hematopoietic cells or precursor cells
US6242417B1 (en) 1994-03-08 2001-06-05 Somatogen, Inc. Stabilized compositions containing hemoglobin
US6835566B2 (en) 1998-02-23 2004-12-28 Aastrom Biosciences, Inc. Human lineage committed cell composition with enhanced proliferative potential, biological effector function, or both; methods for obtaining same; and their uses
US9856287B2 (en) 2009-06-22 2018-01-02 Amgen Inc. Refolding proteins using a chemically controlled redox state
US10577392B2 (en) 2009-06-25 2020-03-03 Amgen Inc. Capture purification processes for proteins expressed in a non-mammalian system
US11299701B2 (en) 2019-03-19 2022-04-12 Olympus Corporation Culture-medium-monitoring apparatus

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US5004681A (en) * 1987-11-12 1991-04-02 Biocyte Corporation Preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood
US5061620A (en) * 1990-03-30 1991-10-29 Systemix, Inc. Human hematopoietic stem cell
US5154921A (en) * 1990-07-13 1992-10-13 Dana-Farber Cancer Institute, Inc. Promotion of maturation of hematopoietic progenitor cells
US5192553A (en) * 1987-11-12 1993-03-09 Biocyte Corporation Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood and methods of therapeutic use

Patent Citations (5)

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US5004681A (en) * 1987-11-12 1991-04-02 Biocyte Corporation Preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood
US5192553A (en) * 1987-11-12 1993-03-09 Biocyte Corporation Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood and methods of therapeutic use
US5004681B1 (en) * 1987-11-12 2000-04-11 Biocyte Corp Preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood
US5061620A (en) * 1990-03-30 1991-10-29 Systemix, Inc. Human hematopoietic stem cell
US5154921A (en) * 1990-07-13 1992-10-13 Dana-Farber Cancer Institute, Inc. Promotion of maturation of hematopoietic progenitor cells

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Title
BIOSIS ABSTRACT, ACTA HAEMATOLOGICA JAPONICA, Volume 53, No. 7, issued 1990, OKANO et al., "A Novel Liquid Culture System for In-Vitro Expansion of Human and Murine Hemopoietic Stem Cells Using IL-6 and IL-3", pages 1213-1221. *
BIOSIS ABSTRACT, BIOTECHNOLOGY PROGRESS, Volume 9, No. 2, issued 1993, SARDONINI et al., "Expansion and Differentiation of Human Hematopoietic Cells from Static Cultures Through Small-Scale Bioreactors", pages 131-137. *
BIOSIS ABSTRACT, BLOOD, Volume 81, No. 3 issued 1993, SROUR et al., "Long-Term Generation and Expansion of Human Primitive Hematopoietic Progenitor Cells In-Vitro", pages 661-669. *
BIOSIS ABSTRACT, EXPERIMENTAL HEMATOLOGY, (New York), Volume 20, No. 3, issued 1992, MUENCH et al., "Interactions Among Colony-Stimulating Factors IL-1 Beta IL6 and Kit-Ligand in the Regulation of Primitive Murine Hematopoietic Cells", page 339-349. *
BIOSIS ABSTRACT, HOKKAIDO JOURNAL OF MEDICAL SCIENCE, Volume 67, No. 5, issued 1992, HAN, M., "Synergistic Effects of Murine Stem Cell Factor in Combination with a Variety of Cytokines on the Expansion of Murine Hematopoietic Progenitor Cells in Short-Term Suspension Cultures", pages 674-683. *
BIOSIS ABSTRACT, LEUKEMIA (BASINGSTOKE), Volume 6, No. 10, issued 1992, TERSTAPPEN et al., "Differentiation and Maturation of Growth Factor Expanded Human Hematopoietic Progenitors Assessed by Multidimensional Flow Cytometry", pages 1001-1010. *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5399493A (en) * 1989-06-15 1995-03-21 The Regents Of The University Of Michigan Methods and compositions for the optimization of human hematopoietic progenitor cell cultures
US5437994A (en) * 1989-06-15 1995-08-01 Regents Of The University Of Michigan Method for the ex vivo replication of stem cells, for the optimization of hematopoietic progenitor cell cultures, and for increasing the metabolism, GM-CSF secretion and/or IL-6 secretion of human stromal cells
US5605822A (en) * 1989-06-15 1997-02-25 The Regents Of The University Of Michigan Methods, compositions and devices for growing human hematopoietic cells
US6667034B2 (en) 1989-06-15 2003-12-23 The Regents Of The University Of Michigan Methods for regulating the specific lineages of cells produced in a human hematopoietic cell culture, methods for assaying the effect of substances on lineage-specific cell production, and cell compositions produced by these cultures
US5635386A (en) * 1989-06-15 1997-06-03 The Regents Of The University Of Michigan Methods for regulating the specific lineages of cells produced in a human hematopoietic cell culture
EP0587754A4 (fr) * 1991-06-07 1994-11-30 Immunex Corp Procede d'amelioration d'une transplantation autologue.
US5846529A (en) * 1993-08-23 1998-12-08 Nexell Therapeutics, Inc. Infusion of neutrophil precursors for treatment of neutropenia
US6037174A (en) * 1993-08-23 2000-03-14 Nexell Therapeutics, Inc. Preparation of serum-free suspensions of human hematopoietic cells or precursor cells
US6010697A (en) * 1993-08-23 2000-01-04 Nexell Therapeutics, Inc. Infusion of neutrophil precursors for treatment of neutropenia
WO1995010291A1 (fr) * 1993-10-08 1995-04-20 Cellpro Ii Procedes de collecte et de cryoconservation de granulocytes humains
US5631219A (en) * 1994-03-08 1997-05-20 Somatogen, Inc. Method of stimulating hematopoiesis with hemoglobin
US6242417B1 (en) 1994-03-08 2001-06-05 Somatogen, Inc. Stabilized compositions containing hemoglobin
US5580724A (en) * 1994-03-25 1996-12-03 Board Of Regents, The University Of Texas System Differential expansion of fetal stem cells in maternal circulation for use in prenatal genetic analysis
WO1995026507A1 (fr) * 1994-03-25 1995-10-05 Board Of Regents, The University Of Texas System Expansion differentielle de cellules souches foetales dans la circulation sanguine maternelle, pour l'analyse genetique prenatale
US5905041A (en) * 1994-06-30 1999-05-18 Boehringer Ingelheim International Gmbh Process for preparing and cultivating hematopoietic progenitor cells
WO1996000777A1 (fr) * 1994-06-30 1996-01-11 Boehringer Ingelheim International Gmbh Procede de production et de culture de cellules precurseurs hematopoietiques
WO1999038008A1 (fr) * 1998-01-23 1999-07-29 Prolifaron, Inc. Procedes et compositions d'identification de substances mimetiques de facteurs de croissance, de facteurs de croissance et d'inhibiteurs
US6835566B2 (en) 1998-02-23 2004-12-28 Aastrom Biosciences, Inc. Human lineage committed cell composition with enhanced proliferative potential, biological effector function, or both; methods for obtaining same; and their uses
US9856287B2 (en) 2009-06-22 2018-01-02 Amgen Inc. Refolding proteins using a chemically controlled redox state
US12269843B2 (en) 2009-06-22 2025-04-08 Amgen Inc. Refolding proteins using a chemically controlled redox state
US10577392B2 (en) 2009-06-25 2020-03-03 Amgen Inc. Capture purification processes for proteins expressed in a non-mammalian system
US11407784B2 (en) 2009-06-25 2022-08-09 Amgen Inc. Capture purification processes for proteins expressed in a non-mammalian system
US12312381B2 (en) 2009-06-25 2025-05-27 Amgen Inc. Capture purification processes for proteins expressed in a non-mammalian system
US11299701B2 (en) 2019-03-19 2022-04-12 Olympus Corporation Culture-medium-monitoring apparatus

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