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US20080292601A1 - Treatment of graft-versus-host disease with il-10 expressing cells - Google Patents

Treatment of graft-versus-host disease with il-10 expressing cells Download PDF

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US20080292601A1
US20080292601A1 US12/127,743 US12774308A US2008292601A1 US 20080292601 A1 US20080292601 A1 US 20080292601A1 US 12774308 A US12774308 A US 12774308A US 2008292601 A1 US2008292601 A1 US 2008292601A1
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cells
stem cells
marrow stem
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therapeutic agent
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Sun Uk SONG
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Homeotherapy Co Ltd
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    • 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
    • A61K38/20—Interleukins [IL]
    • A61K38/2066—IL-10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/22—Immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/418—Antigens related to induction of tolerance to non-self
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0662—Stem cells
    • C12N5/0663—Bone marrow mesenchymal stem cells (BM-MSC)
    • 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
    • A61K2035/122—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells for inducing tolerance or supression of immune responses
    • 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
    • A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration

Definitions

  • the present invention relates to a therapeutic agent for treating acute or chronic graft-versus-host disease.
  • the present invention also relates to a therapeutic agent for treating acute or chronic graft-versus-host disease that contains mesenchymal stem cells as an active ingredient.
  • GVHD graft-versus-host disease
  • graft-versus-host disease can be classified largely into acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD).
  • cGVHD is the most major and common side effect, occurring in 20%-70% of patients living past 100 days following blood and marrow progenitor cell transplantation, and a major cause of death following transplantation. Because cGVHD and aGVHD are not successive diseases, aGVHD requires a different approach and cGVHD is becoming the bigger problem due to developments in blood and marrow progenitor cell transplantation therapeutic methods.
  • cGVHD in the case of homogenous transplantations, occurs usually 4-6 months following transplantation and its occurrence within 80 days or after 1 year is uncommon. Accordingly, it can be seen that a homogeneous reaction is a major prerequisite for causing cGVHD and the pathogenesis of cGVHD goes through a long incubation period or the effect on the target organ shows up slowly.
  • Clinical symptoms of cGVHD include changes in the skin such as erythema, dryness, itchiness, pigmentation change, and maculopapular rashes; changes in hair such as thinning of hair and loss of hair, and changes in the mouth such as inflamed gums, mucositis, and lip atrophy. Aside from the various lesions appearing on the eyes, reproductive organs, liver, lungs, gastrointestinal tracts, fascia, skeletal system, serous membranes, and so forth.
  • cGVHD is generally defined as GVHD that occurs after 100 days following bone marrow transplantation
  • the manifested conditions are more important to the diagnosis than the manifested time period.
  • classification can be made between a progressive onset in which aGVHD not having been cured since occurrence shifts to cGVHD, a quiescent onset in which cGVHD appears after aGVHD has been fully cured, and de novo in which it occurs without prior appearance of aGVHD.
  • the morbidity and death rate is highest in the progressive onset, next is quiescent onset, and it is lowest in the case of de novo.
  • lichenous shaped rashes in the skin and mucous coat of the mouth are the first symptoms, and while it may appear on the same parts as in aGVHD, the lesions are papulous, invasive, and covered with white scales.
  • the lymphocyte infiltration shows an over consolidated band. Aside from that, the gall bladder duct is diminished, and while bile accumulation can be seen, because there may be cases in which it may be mixed with legions related to the medication or viral hepatitis, there may be cases in which it is difficult to differentiate from cGVHD.
  • mesenchymal stem cells can be propagated in an undifferentiated situation as primordial cells of the original mesoderm and be separated from various organs such as bone marrow, fat tissue, liver, tendon, synovial membrane, and umbilical cord, a single marker that can precisely define it as a mesenchymal stem cell is not in existence.
  • CD14, CD34, and CD45 are well known as markers for bone marrow and SH-2(CD105), SH-3(CD73), SH-4, and Th7-1 are well known as markers for mesenchyma.
  • MHC mesenchymal stem cells or mesenchymal stromal cells
  • MHC class can induce manifestation through interferon gamma (IFN- ⁇ ), and because it does not manifest FAS or FAS L(CD40) type costimulatory molecules, it does not induce immunological reactions, and is free from cytolysis due to cytotoxic T lymphocytes (CTL) and natural killer (NK) cells.
  • CTL cytotoxic T lymphocytes
  • NK natural killer cells.
  • mesenchymal stem cells suppress proliferation of T cells through density reliance at time of mixed lymphocyte reaction (MLR) and suppress proliferation of B cells as well as formation of immunoglobulin
  • MLR mixed lymphocyte reaction
  • B cells as well as formation of immunoglobulin
  • MHC compatibility is not a necessity for MSC immune suppression.
  • MLR mixed lymphocyte reaction
  • MSC that exists in the body is very rare, development of technology that isolates it is important.
  • density gradient centrifugal separation, method using monoclonal antibodies specifically for Sca-1 or STRO-1, and separation method according to cell size are known methods for separating MSC.
  • the inventors herein have previously developed an effective MSC separation method (Republic of Korea Public Patent No. 10-0802011) that does not require a particular mechanical device or reagent, and the above method is characterized by the fact that marrow taken from the individual is cultivated, and the cultured upper liquid is further cultivated by repeatedly removing to a new container.
  • U.S. Pat. No. 6,544,506 presents a GVHD prevention and treatment method that has as its distinctive feature the removal of cytotoxic T lymphocytes by injecting non-alloreactive anti-cytotoxic lymphocytes in organ transplantation patients.
  • U.S. Pat. No. 6,936,281 describes a GVHD treatment method using mesenchymal stem cells.
  • U.S. Pat. No. 7,173,016 describes a GVHD treatment method that includes the step of injecting adenosine deaminase inhibitors.
  • 6,328,960 describes a GVHD treatment method that has as its distinctive feature the injection of mesenchymal stem cells in an amount that can lessen the immunological reaction of effector cells against the antigens in the target organ transplantation patient in order to lessen the effector cell's immunological reaction against the alloantigen in the target transplantation patient.
  • U.S. Pat. No. 6,368,636 describes a method of lessening the immunological reaction caused by effector cells, which includes the step of contacting the effector cells with the upper liquid of the mesenchymal stem cells in an injection amount that can reduce the immunological reaction against alloantigen.
  • a goal of this invention is to provide a therapeutic agent for acute or chronic graft-versus-host disease.
  • Another goal of this invention is to provide a treatment method for acute or chronic graft-versus-host disease.
  • this invention provides a therapeutic agent that includes mesenchymal or marrow stem cells for treating acute or chronic graft-versus-host disease.
  • this invention also includes a method for treating graft-versus-host disease that includes the step of injecting an effective dose of mesenchymal or marrow stem cells in patients with acute or chronic graft-versus-host disease.
  • the present invention is directed to a method of inhibiting activity of T-cell from donor marrow in a subject identified as suffering from graft-versus-host disease, comprising administering to the subject in need thereof a therapeutically effective amount of a population of homogeneous clonal marrow stem cells.
  • a dosage of the stem cells per each administration may be between 1 ⁇ 10 4 cells/kg body weight to 1 ⁇ 10 8 cells/kg weight.
  • the stem cells may be isolated using a subfractionation culturing method.
  • the stem cells may express CD29, CD44, and CD105 cell surface antigens, but not HLA-DR cell surface antigen.
  • the stem cells may express CD29, CD44, CD73 CD90, CD105, and CD166 cell surface antigens but not CD106, CD119, or HLA-DR cell surface antigens.
  • the homogeneous clonal marrow stem cells may secrete interleukin-10 at a concentration of at least about 5 ng/ml.
  • the invention is directed to a method of treating symptoms of graft-versus-host disease in a subject identified as suffering from graft-versus-host disease, comprising administering to the subject in need thereof a therapeutically effective amount of a population of homogeneous clonal marrow stem cells.
  • the symptom of graft-versus-host disease may be in the gastrointestinal tract, sclerotic skin, limitation of oral intake, dryness of eyes, liver symptoms, shortness of breath, or tightness of arms or legs.
  • the gastrointestinal symptom may be elevated daily volume of stool or inflamed colon.
  • the liver symptom may be raised alkaline phosphatase level in blood serum.
  • the invention is directed to a method of inhibiting activity of T-cell from donor marrow in a subject identified as suffering from graft-versus-host disease, comprising:
  • the container may be treated with a coating.
  • the coating may be collagen, poly-lysine, fibrinogen, or gelatin.
  • the invention is directed to a method of treating symptoms of graft-versus-host disease in a subject identified as suffering from graft-versus-host disease, comprising:
  • a dosage of the cells may be between 1 ⁇ 10 4 cell/kg to 1 ⁇ 10 8 cell/kg.
  • the cells may express CD29, CD44, and CD105 cell surface antigens, but not HLA-DR cell surface antigens.
  • the cells may express CD29, CD44, CD73 CD90, CD105, and CD166 cell surface antigens but not CD106, CD119, or HLA-DR cell surface antigens.
  • the population of cells may secrete interleukin-10 at a concentration of at least about 5 ng/ml.
  • FIG. 1 shows a diagram of the procedure of isolating clonal marrow stem cells or mesenchymal stromal cells by subfractionation culturing method used in this invention.
  • FIG. 2 shows a FACS phenotyping result of cell surface epitopes on the clonal marrow stem cells isolated by subfractionation culturing method and used for the treatment of a GVHD patient.
  • FIGS. 3A-3B show graphs of the amount of (A) TGF- ⁇ and (B) IL-10 secreted from the clonal marrow stem cells (cMSC-15) used in the treatment of the GVHD patient and control mesenchymal stem cells isolated by the conventional density gradient centrifugation method.
  • FIG. 4 shows a graph of the changes in the volume of daily stool amount and activity of alkaline phosphatase after the administration of clonal marrow stem cells in the GVHD patient.
  • FIGS. 5A-5D show colonoscopy pictures of the GVHD patient who was injected with the clonal marrow stem cells.
  • A is a picture prior to treatment
  • B is a picture taken 10 days after treatment
  • C is a picture taken 1 month after treatment
  • D is a picture taken 3 months after treatment.
  • bodily sample refers to any sample obtained from a mammal from which is desired to isolate a single type of cell.
  • Such bodily sample includes bone marrow sample, peripheral blood, cord blood, fatty tissue sample, and cytokine-activated peripheral blood.
  • clonal marrow stem cells refers to cells that are derived from a single stem cell. This phrase is used interchangeably with “multi-lineage stem cell”, which are obtained by subfractionation culturing methods.
  • homogeneous population of cells generally indicates that the same type of cells are present within the population.
  • Substantially homogeneous may mean about 80% homogeneity, or about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%. 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% homogeneity.
  • homogeneity of the cells is attributed to the expansion of the cells from a single cell origin. No MSC-specific antigen is currently available and therefore no MSC-specific antibody is available.
  • the “homogeneous population of stem cells” refers to stem cells that are derived from a single cell identified as a stem cell later by such characterization studies.
  • lower density cell refers to cells that have lower density than others in the sample, and are the object of isolation.
  • the lower density cell includes without limitation, multi-lineage stem cells, progenitor cells, other marrow stromal cells.
  • mammal for purposes of discussing the source of the cells and treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, rats, mice, rabbits, and so on.
  • the mammal is human.
  • MLC multi-lineage stem cell
  • MLSC/PC refers to multi-lineage stem cell or progenitor cell.
  • MSC refers to marrow stromal cells or mesenchymal stem cells, or marrow stem cells which terms are used interchangeably.
  • sample of cells refers to any sample in which is contained a mixture of different types of cells, including bone marrow sample, peripheral blood, cord blood, fatty tissue sample, and cytokine-activated peripheral blood.
  • a preferred method of obtaining the cells for use in treating Graft Versus Host Disease is by a “subfractionation culturing method”, which method is used to isolate a highly homogeneous population of clonal marrow stem cells or multi-lineage stem cells (MLSCs) from a bodily sample or source such as human bone marrow.
  • a bodily sample or source such as human bone marrow.
  • Bone marrow MSCs have been known to be difficult to isolate without contamination by hematopoietic cells. For application in clinical settings, it is important to have a homogeneous population of MSCs in order to prevent immunogenic problems and to evaluate the clinical effects correctly. Conventionally, isolation of homogeneous populations of MSCs was carried out by MSC-specific antibody column purification. However, even this method is not adequate as no such perfect MSC-specific antibody is yet available.
  • the inventive subfractionation culturing method is a simple, effective, and economic protocol to isolate highly homogeneous MLSCs from a bodily sample, preferably a bone marrow sample.
  • mononuclear cells isolated/fractionated by conventional density gradient centrifugation method of MSC isolation can also be subjected to the D1 dish to obtain single cell-derived colonies and then to isolate homogeneous populations of stem or progenitor cells ( FIG. 1 ). Therefore, the subfractionation culturing method can be used with the mononuclear cells fractionated by the conventional density gradient centrifugation method.
  • the present application describes diversity of characteristics in cell surface protein expression of the isolated single-cell derived stem cell lines, which indicates that there are several different types of multi-lineage stem or progenitor cells that exist in biological samples, and in particular bone marrow samples, which are exemplified.
  • the isolated MLSCs were generally negative or dimly positive for CD34, HLA-DR, CD31, CD166, HLA Class I and highly positive for CD44, CD29, CD105.
  • some cell lines from D4 and D5 dishes exhibited distinctive levels of surface proteins, which indicates that there could be several different types of multi-lineage stem or progenitor cells in bone marrow ( FIG. 1 ). These MSCs having different surface markers may represent different differentiation potential of the cells.
  • isolation of single-cell derived homogeneous stem cells by the subfractionation culturing method makes it possible to isolate tissue-specific stem or committed progenitor cells, as long as these groups of cells exist in the bone marrow or other specifically isolated bodily sample, and culture conditions do not change their potential during cell expansion.
  • the safety and efficacy of MSC treatment and cell engraftment process is improved by being able to characterize subpopulations of cells with specific properties, as shown in the present application.
  • the subfractionation culturing method By eliminating density gradient centrifugation and mononuclear cell fractionation steps and without requiring the use of antibodies to separate stem cells, or particular enzymes, the subfractionation culturing method generates more homogeneous populations of MSCs or MLSCs in a simple, effective, and economic procedure and safer applications for therapeutic settings.
  • marrow stem cells may be obtained using the subfractionation culturing method as described above. Further, it is preferable that the obtained MSC's express any or all of CD29, CD44, CD105 cell surface antigens. It is also preferable that any or all of HLA-DR cell surface antigens be not expressed in the MSC's. More preferably, any and all of CD29, CD44, CD90, CD105, and CD166 cell surface antigens are expressed on the MSC's, any or all of the CD106, CD119, and HLA-DR cell surface antigens are not expressed on the MSC's.
  • the inventively used MSC's express Interleukin-10 (IL-10).
  • IL-10 is expressed at over 5 ng/ml or over 10 ng/ml after culturing at the time of treatment.
  • the invention is directed to using cell obtained by the subfractionation culturing method, which includes: 1) the step of obtaining bone marrow from an individual; 2) the step of cultivating the bone marrow; 3) the step of moving only the upper liquid in 2) to a new container and culturing; and 4) the step of separating only the upper liquid of 3) and repeatedly culturing in a culture container that has been optionally treated with coating.
  • the repeated culturing in the above step 4) may be carried out for about 1 to 4 hours at 37° C. and then repeatedly cultured for about 2 to 3 times for about 12 to 36 hours at 37° C. and then cultured for about 24 to 72 hours at 37° C., and for the upper liquid to be moved to a new culture container each time.
  • collagen, gelatin, fibrinogen or polylysine-coated culture dishes were used in order to obtain more adherent stem cells. Applicant has discovered that any charged culture surface, either positive or negative, helps the attachment of stem cells to it, compared to the surface of an uncoated dish. More cells were attached to a collagen or polylysine-coated culture dish than uncoated dish, approximately by about two to three fold respectively (data not shown).
  • the bottom of a culture dish can be coated by either positively charged amino acids, such as polylysine, polyarginine, or negatively charged amino acids, such as polyaspartate, polyglutamate, or a combination thereof to help stem or progenitor cells adhere better to the bottom of the dish.
  • positively charged amino acids such as polylysine, polyarginine
  • negatively charged amino acids such as polyaspartate, polyglutamate, or a combination thereof to help stem or progenitor cells adhere better to the bottom of the dish.
  • the culture container is treated with a coating, and while any material than can improve the attachment of cells to the container may be used, it is particularly preferred that collagen, poly-lysine, fibrinogen, or gelatin be used. More preferably, collagen or poly-lysine may be used. Even more preferably, collagen may be used. In addition, it is desirable for the cells to be repeatedly cultured for about 3 to 6 times in a culture container that has been treated with collagen and even more desirable for the cells to be repeatedly cultivated about 4 to 5 times.
  • composition of the therapeutic agent may be made using conventional knowledge in the industry. For example, it can be used in a non oral form of water or a sterilized liquid solution pharmaceutically permissible as well as a suspended injection.
  • pharmaceutical preparation by combining it with a carrier or media that is pharmaceutically permissible, specifically sterile water or a physiological saline solution, vegetable oil, emulsifier, suspensions, surfactant, stabilizer, excipient, vehicle, preservative, binder, and so on, and blending it in a unit capacity format that is generally accepted as being required in a pharmaceutical application can be considered.
  • sterilized composites for injection can be prescribed based on known pharmaceutical applications using supporting liquids such as injectible distilled water.
  • an example can be physiological saline solution, glucose, or isotonic solutions including supportive medications such as D-sorbitol, D-mannose, D-manitol, chloride, or natrium.
  • supportive medications such as D-sorbitol, D-mannose, D-manitol, chloride, or natrium.
  • an example can be alcohol, specifically ethanol or poly alcohol such as propylene glycol, or a non-ionized surfactant such as polysorbate 80TM or HCO-50.
  • sesame oil or soybean oil can be considered and can be used jointly with a benzyl benzoate or benzyl alcohol.
  • a buffering agent such as phosphate buffering solution, sodium acetate buffering solution, or analgesic solution such as Novocain or stabilizer such as benzyl alcohol, phenol, or antioxidant.
  • the prepared injection liquid is to be charged in a commonly accepted adequate ampoule.
  • the administration into the body of the patient is non-oral, and more specifically while it is basic to administer into the vein 1 or 3 times, greater injection is also allowable. Additionally, the administration length can be short or long. More specifically, injection type or transdermal type can be considered. As an example of injection type, while it may be administered through intravenous injection, arterial injection, selectable arterial injection, intramuscular injection, intraperitoneal injection, hypodermic injection, intracerebral injection, cerebral injection, or bone marrow injection, and intravenous injection is desirable. In the case of intravenous injection, because transplantation methods using common blood transfusion have become possible, the patient does not require surgery and furthermore because topical anesthesia is not required, the burden is light on both patient and doctor. When future development of emergency medicine is considered, administration during emergency transportation or at the critical site can be considered.
  • this invention provides a method for treating patients with graft-versus-host disease that includes the step of administering mesenchymal or marrow stem cells, in an effective dose for treatment, to the above mentioned patient suffering from graft-versus-host disease.
  • the effective dose per injection of the clonal marrow cells for treatment of GVHD or the symptoms of GVHD in a mammal and in particular human being may be between 1 ⁇ 10 4 cells/kg body weight and 1 ⁇ 10 8 cells/kg body weight; between 1 ⁇ 10 4 cells/kg body weight and 1 ⁇ 10 8 cells/kg body weight; between 2 ⁇ 10 4 cells/kg body weight and 1 ⁇ 10 8 cells/kg body weight; between 2.5 ⁇ 10 4 cells/kg body weight and 1 ⁇ 10 8 cells/kg body weight; between 2 ⁇ 10 4 cells/kg body weight and 1 ⁇ 10 7 cells/kg body weight; between 2.5 ⁇ 10 4 cells/kg body weight and 1 ⁇ 10 7 cells/kg body weight; between 2 ⁇ 10 4 cells/kg body weight and 3 ⁇ 10 6 cells/kg body weight; between 2.5 ⁇ 10 4 cells/kg body weight and 3 ⁇ 10 6 cells/kg body weight; between 2 ⁇ 10 4 cells/kg body weight and 2 ⁇ 10 6 cells/kg body weight; between 2.5 ⁇ 10 4 cells/kg body weight and 2 ⁇ 10 6 cells/kg body weight; between 2 ⁇
  • non oral administration method is preferred. While whole body or partial body administration is possible, whole body administration is preferred and intravenous injection is most preferred.
  • the inventors herein were able to improve the condition of acute or chronic graft-versus-host disease patients who were unresponsive to treatment by administering mesenchymal or marrow stem cells separated using the methods ( FIG. 1 ) described in U.S. Patent Application Publication US2006/0286669, filed Jun. 19, 2006, “Isolation of Multi-Lineage Stem Cells”, the contents of which are incorporated herein by reference in their entirety.
  • GVHD vascular endothelial hypertension
  • GI gastrointestinal
  • ALT alanine aminotranferease
  • AST aspartate aminotransferase
  • a subject may exhibit multiple symptoms depending on the tissue that is affected by the graft-versus-host disease. Some patients have 4-5 symptoms others may have 1-2 symptoms. Therefore, the present invention is directed to treating any and all of the symptoms associated with GVHD as manifested any tissue in the subject. As the manifestations or symptoms are treated, it is believed that GVHD disease itself is also treated thereby.
  • the following description provides details of the application of the subfractionation culturing technology and using the homogeneous clonal marrow stem cells obtained thereby to administer to an individual identified as suffering from the symptoms of GVHD. Without being bound by theory, it is believed that the administered stem cells secrete IL-10 in the subject, which counteracts or inactivates the ill effects of the donor's T-cells, thereby treating GVHD and the symptoms of GVHD.
  • cMSC-15 After separating the mesenchymal or marrow stem cell from the mother of the above patient suffering from chronic graft-versus-host disease using the subfractionation culturing method and establishing it as the cell line of monoclonal origin, it was named cMSC-15. A cell surface antigen analysis was carried out through parenchyma cell analysis to determine whether the above cell line was an actual mesenchymal or marrow stem cell ( FIG. 2 ).
  • the inventors herein after cultivating the above established mesenchymal or marrow stem cell to an amount sufficient for treatment, applied it in the treatment of a patient whose life was in a critical situation due to the onset of chronic graft-versus-host disease.
  • the above patient was an 18 year old woman who was diagnosed with acute myelogenous leukemia and after reaching remission through induction therapy, received allogeneic bone marrow transplantation.
  • CsA Cyclosporine A
  • MMF Mycophenolate mofetil
  • steroids the condition of the patient deteriorated due to continuing hematochezia, increased bilirubin, and dryness of skin, mouth, and eyes, and because of the activation of cytomegalovirus (CMV) due to treatment side effects and BK virus being found even in the urine and blood due to infection of the BK virus, a treatment using Cideforvir was started.
  • CsA Cyclosporine A
  • MMF Mycophenolate mofetil
  • CMV cytomegalovirus
  • the inventors herein administered the above mentioned cultivated mesenchymal or marrow stem cells through intravenous injection one time after receiving an emergency clinical permit from the Korean Food and Drug Administration. No adverse/negative reactions were observed during or after the administration, and the symptoms of the patient slowly improved after the 1 st administration, and a 2 nd administration was given after 3 weeks. Afterwards, the patient's symptoms improved and the patient was discharged 34 days after the 2 nd administration in a state of having stopped taking steroids and only taking immunological suppressants.
  • the inventors herein measured the amount of stool and activity of alkaline phosphatase in the blood, which are major indicators of Graft-Versus-Host-Disease ( FIG. 4 ).
  • the amount of stool had considerably reduced, and the activity of alkaline phosphatase in the blood, which is a serological index had also fallen to normal levels (60-220 ng/ml).
  • a colonoscopy analysis was carried out to verify whether symptoms had improved ( FIG. 5 ). As can be seen in FIG. 5 , with the passage of time following administration of mesenchymal or marrow stem cells in this invention, ulcers had much improved from a colonoscopy data.
  • mesenchymal or marrow stem cells separated using the subfractionation culturing method of this invention is effective in treating chronic graft-versus-host disease.
  • marrow provider's mother of treatment target chronic graft-versus-host disease patient
  • bone marrow was extracted by inserting an injection needle into the hip bone.
  • 15 ml of DMEM (Dulbecco's modified Eagle's Medium, GIBCO-BRL, Life-technologies, MD, USA) which included 20% FBS and 1% penicillin/streptomycin and 2 ml of the marrow extracted from the above mentioned marrow provider was put into a 100 mm culture container and cultivated for 2 hours in a 37° C., 5% CO 2 cell cultivator. After cultivation, the culture container was slightly leaned so that the cells attached to the bottom would not fall out and the maximum amount of the upper layer culture liquid in the culture container was moved to a new container.
  • the culture liquid that was taken was moved to a culture container (Becton Dickinson) and cultivated for 2 hours at 37° C.
  • the culture liquid was again moved to a new container and after 24 hours was moved to another new container and after 24 hours was moved to a new container again.
  • This single clone was treated with trypsin, separated, and moved to a 6-well culture container with a cell number of 10 2 to 6 ⁇ 10 2 per well. After cultivating for 4 to 5 days in a 37° C., 5% CO 2 cell cultivator when it had grown 80%, it was treated with 0.25% trypsin/1 mM EDTA (GIBCO-BRL) and after gathering was moved and successively cultivated in a 75 cm 2 culture container. Cell lines with monoclonal origins were acquired as above and named cMSC-15.
  • Example 1 In order to verify whether the cMSC-15 cells that were separated from the marrow using the method in the above Example 1 were mesenchymal or marrow stem cells, a flow cytometry (BD Biosciences) was used to find out if cell surface antigens with stem cell characteristics existed.
  • Stem cells that were successively cultivated for 6 to 7 days in a 75 cm 2 culture container was treated with 0.25% trypsin and the cells were gathered.
  • the cells were washed 2 times with a 1 ⁇ PBS/0.4% BSA to remove trypsin as well as culture liquids.
  • the cells were collected using centrifugal separation and after measuring the number of cells, 1 ⁇ 10 6 cells were gathered in a 1.5 ml tube and blocked for 1 hour in room temperature using goat serum (Vector).
  • the cells were washed 2 times with a 1 ⁇ PBS/0.4% BSA and treated with a phycoerythrin (PE) attached anti-CD14, CD29, CD31, CD34, CD44, CD73, CD90, CD105, CD106, CD119, CD133, CD166, HLA-DR, HLA Class 1 and STRO-1 antibody (Serotec Ltd, Kidington, OX, UK) each and reacted for 40 minutes at 4° C. After the cells were washed 2 times with a 1 ⁇ PBS/0.4% BSA, they were suspended in 0.5 ml 1 ⁇ PBS/0.4% BSA, loaded in the flow cytometry and analyzed.
  • PE phycoerythrin
  • CD29 which is an integrin antigen specific for mesenchymal stem cells, as well as CD44 and CD105, which are matrix receptor antigens also specific for mesenchymal stem cells showed a positive reaction.
  • CD90, CD166, and HLA-Class 1 cell surface antigens were expressed, and CD106, CD119, as well as HLA-DR cell surface antigens were not expressed.
  • an expression level was weakly positive ( FIG. 2 ). Expression of such cell surface antigens was maintained in the cells that has undergone 6 successive cultivations. This indicates that the separated cells, even if they are successively cultivated, the antigens specific for mesenchymal stem cells would be continually expressed.
  • the inventors herein in order to find out more about the characteristics of the isolated mesenchymal stem cells using the subfractionation culturing method in this invention, analyzed the expression levels of immunological suppression related cytokines.
  • the expressed amount of the TGF- ⁇ and IL-10 secreted in the culture liquid was analyzed using an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the cMSC-15 cells obtained using the subfractionation culturing method showed increased expression over 5 times compared with the control group ( FIG. 3 ). This indicates that there is a correlation between the treatment effectiveness of graft-versus-host disease and the IL-10 expression level of mesenchymal or marrow stem cells.
  • the patient was an 18 year old woman who was diagnosed with acute myelogenous leukemia and after reaching remission through induction therapy, received an allogeneic bone marrow transplantation.
  • CsA Cyclosporine A
  • MMF Mycophenolate mofetil
  • steroids the condition of the patient deteriorated due to continuing hematochezia, increased bilirubin, and dryness of skin, mouth, and eyes, and because of the activation
  • the mesenchymal or marrow stem cells of the patient's mother which were isolated as described in Example 1 was cultivated in the GMP facilities and administered to the patient using intravenous injection. No adverse/negative reactions were observed during or after the administration, and the symptoms of the patient slowly improved after the 1 st administration, and a 2 nd administration in the same amount as the 1 st was given after 3 weeks. Afterwards, the patient's symptoms improved considerably and the patient was discharged 34 days after the 2 nd administration in a state of having stopped taking steroids, left with only taking MMF 1.5 g/day as an immunological suppressant.
  • the inventors herein measured the amount of stool and activity of alkaline phosphatase in the blood which is a major indicator ( FIG. 4 ).
  • the activation of alkaline phosphatase in the blood was accomplished using a commercial kit (Sigma Chemical Company, USA).
  • This invention as it is in regards to a therapeutic agent for treating acute or chronic graft-versus-host disease that includes mesenchymal or marrow stem cells as the active ingredient, the therapeutic agent in this invention can very effectively treat host-versus-host disease which has been very difficult to treat, especially the deadly acute or chronic graft-versus-host disease which occurs frequently as a side effect after bone marrow transplantation surgery.

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WO2011007348A2 (fr) 2009-07-13 2011-01-20 Biogencell, Ltd. Procédé d'utilisation de cellules directrices pour l'activation et la différentiation de cellules souches/progénitrices spécifiques
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US9439929B2 (en) 2005-06-17 2016-09-13 Inha-Industry Partnership Institute Treatment of graft-versus-host disease
WO2009040666A3 (fr) * 2007-05-25 2009-12-30 Sun Uk Song Traitement de la maladie de rejet de greffe
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