WO2001087058A1 - Souris chimerique ayant une immunite creee par utilisation de cellules positives cd34 humaines et utilisation de cette souris - Google Patents
Souris chimerique ayant une immunite creee par utilisation de cellules positives cd34 humaines et utilisation de cette souris Download PDFInfo
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- WO2001087058A1 WO2001087058A1 PCT/JP2001/004034 JP0104034W WO0187058A1 WO 2001087058 A1 WO2001087058 A1 WO 2001087058A1 JP 0104034 W JP0104034 W JP 0104034W WO 0187058 A1 WO0187058 A1 WO 0187058A1
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Classifications
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- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/01—Animal expressing industrially exogenous proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/74—Inducing cell proliferation
Definitions
- the present invention relates to a chimeric mouse capable of producing a human antibody, a method for producing a human antibody using the chimeric mouse, and a human antibody prepared by the method.
- a chimeric antibody comprising the variable region of a mouse antibody and the constant region of a human antibody was prepared, and only the complementarity-determining region (CDR) essential for antigen-binding activity was prepared.
- CDR complementarity-determining region
- a humanized antibody transplanted into a human antibody was produced.
- the least antigenic antibodies are human antibodies derived from human antibody-producing cells, and homogeneous human antibodies, human monoclonal antibodies, are useful in the field of therapeutics.
- a method for producing a human monoclonal antibody a method is known in which human antibody-producing cells are obtained from a human having the desired antibody in the blood, and then the cells are immortalized to obtain a human antibody-producing cell clone.
- Japanese Patent Laid-Open No. 5-25058 Japanese Patent Laid-Open No. 5-25058
- cells producing an antibody having a desired activity had to be separated, and it was difficult to arbitrarily obtain a human antibody suitable for the purpose.
- transgenic mice having a human antibody gene repertoire have been produced, and then antigen-specific human antibody-producing mouse cells have been obtained by immunization with an antigen, which has been immortalized by fusion with myeloma cells, etc.
- SCID mice severe combined immunodeficiency disease mice have been used because they do not readily cause rejection and do not produce mouse-derived antibodies. SCID mice were found to have extremely low blood levels of immunoglobulin than 17 mice, which are allotype common genes for immunoglobulin heavy chains of Balb / c mice (Nature, 301, 527 (1983)). This mouse has severe immunodeficiency and has been shown to be deficient in mature T cells and B cells, the primary cells responsible for the immune system (J. Immunol. 132, 1084).
- T cells and B cells require the expression of T cell receptors and membrane-type immunoglobulin molecules, respectively.
- genes that are indispensable for expressing these molecules are required. Abnormalities are found in the group of enzymes (recombinases) responsible for remodeling, and in particular, it has been shown that the substrate specificity of recombinase is defective (J. Immunol. 134, 227 (1985)).
- recombinases enzymes responsible for remodeling
- SC ID-hu mice (Nature, 251, 791 (1991)) transplanted with small pieces of human fetal thymus and fetal liver while retaining histological structure under the renal capsule, and human peripheral blood lymphocytes (perip A hu-PBL-SCID mouse (Science 247, 564 (1990)) in which heral blood lymphocyte (PBL) has been transplanted intraperitoneally is known. It has been reported that hu-PBL-SCID mice can induce specific human antibodies against tetanus toxin and hepatitis B virus C antigen (J. Exp. Med. 173, 147 (1991)).
- peripheral blood lymphocytes are already differentiated lymphocytes, their survival period is short, and chimeric mice into which they have been transferred cannot immunize for a long period of time, and peripheral blood lymphocytes have already adapted themselves. Since the cells are mature and differentiated, they have the drawback that they cannot produce antibodies (autoantibodies) against human components.
- the antibody class produced is often IgM, and it has been difficult to obtain IgG class antibodies with higher binding affinity by inducing affinity maturation.
- IgG-class antibodies have been desired because of the production method and ease of purification. Disclosure of the invention
- the present invention has been made in view of such circumstances, and has been designed to construct a chimeric mouse capable of producing any desired antibody including human autoantibodies and immunizing for a long period of time, and It is intended to prepare antibodies.
- the present invention provides a chimeric mouse having a human immune system constructed by transferring human CD34-positive cells into a SCID mouse, a method for preparing a human antibody using the chimeric mouse, and a method prepared by the method.
- Human antibodies are provided.
- mature human B cells and human B cells constructed by transferring human CD34-positive cells collected from human cord blood to SCID mice.
- the hematopoietic stem cells that provide the chimeric mouse induced to produce IgG are pluripotent cells that develop and differentiate all cells of the blood cell lineage. All lymphocytes such as cells and T cells are also derived from hematopoietic stem cells.
- the present inventors have paid attention to such characteristics of hematopoietic stem cells, and thought that by transferring human hematopoietic stem cells to mice, the problems of the conventional method of transferring peripheral blood lymphocytes can be solved.
- chimeric mice into which human hematopoietic stem cells have been transferred have more sustained immunity than conventional methods using short-lived peripheral blood lymphocytes, because they continuously develop and differentiate human T cells and human B cells in the body.
- autoantibodies can be used as in the conventional method of transferring peripheral blood lymphocytes that have matured and differentiated by adaptation in the human body into mice. We thought that there was no disadvantage that it could not be produced.
- the present inventors have attempted to produce a chimeric mouse into which human hematopoietic stem cells have been transferred based on such an idea.
- CD34-positive cells were prepared from human cord blood, and this was used as a cell group containing hematopoietic stem cells, and this was transferred from the tail vein of a recipient mouse to produce a chimeric mouse.
- recipient mice N0D-SCID mice that had lost mouse antibody-producing ability and were less likely to cause rejection due to reduced NK cell activity were selected.
- the present inventors immunized the thus obtained chimeric mouse with an antigen and examined production of human antibodies. As a result, it was found that the chimeric mouse produced antigen-specific human IgM and human IgG.
- the present inventors transplanted cells prepared by the hybrid agglutination method (RT0C method) of CD34-positive human cells and mouse thymus stoma cells into the N0D-SCID mouse under both kidney capsules. It has been found that mature T cells can be induced from CD34-positive human cells in the mouse body. That is, the present inventors succeeded in producing a chimeric mouse having a completely reconstituted human immune system. Since this chimeric mouse has human-derived mature B cells and mature T cells, it is possible to prepare an antibody against any antigen including a human self component by using the chimeric mouse. Efficient IgG production can be achieved by stimulating immunocompetent cells such as spleen cells with helper factors such as human CD40 ligand to induce antibody class switching.
- R0C method hybrid agglutination method
- the present invention has been completed based on the above findings, and has been constructed by transferring human CD34-positive cells to SCID mice and has a chimeric mouse capable of producing human antibodies, and preparation of human antibodies using the chimeric mice.
- a method, and a human antibody prepared by the method are provided.
- the present invention provides
- chimeric mice having human-derived mature B cells and mature T cells and capable of producing human antibodies
- mice that continuously retain human T cells and / or B cells derived from human CD34-positive cells
- a method for preparing a human antibody (a) immunizing the chimeric mouse according to any of (4) to (7) or a lymphocyte prepared from the chimeric mouse with an antigen, and
- step (b) recovering a human antibody produced by the immunization in the step (a), which binds to the antigen.
- step (9) The method according to (8), wherein in the step (a), a substance that activates CD40 is administered to a chimeric mouse or to a lymphocyte.
- human CD34-positive cells refers to a group of cells including hematopoietic stem cells having CD34 as an antigen on the surface of the cells.
- a chimeric mouse capable of producing a human antibody means a chimeric mouse capable of producing a human antibody that binds to an antigen upon administration of the antigen.
- a chimeric mouse having human antibody-producing ability is produced by transferring human CD34-positive cells to a mouse (SCID mouse) exhibiting severe combined immunodeficiency disease.
- the origin of the CD34-positive cells used in the present invention is not particularly limited, but those derived from human umbilical cord blood can be suitably used.
- the human CD34-positive cells may be cells immediately after being separated from human umbilical cord blood, or cells that have been once cultured and cryopreserved.
- the culture may be performed using a mouse bone marrow stromal cell line (eg, HESS-5) as a feeder cell and adding human SCF, human TP0, and human F2 (2xperimental Hematology 27, 904 (1999)).
- the addition amount of these molecules is preferably about 50 ng / ml.
- Human CD34-positive cells can be prepared using a commercially available kit, for example, as described in Example 1.
- a normal SCID mouse can be used as a mouse into which human CD34-positive cells are transferred.
- transplanted C D3-positive cells may be damaged by the action of NK cells, which may reduce the engraftment rate of the transferred cells.
- NOD-SCID mice which are SCID mice with reduced NK cell activity.
- SCID mice and NOD-SCID mice are already known from the literature (Nature, 301, 527 (1983), J. Immunol. 154, 180 (1995)) and can be obtained from experimental animal suppliers (for example, , Jackson Laboratory 1).
- cell-specific antibody it is also effective to administer a cell-specific antibody to the mouse for the purpose of further reducing the activity of NK cells.
- the cell-specific antibody include, but are not limited to, anti-ashi mouth (Ml antibody).
- human peripheral blood lymphocytes are also effective to transfer radiation-irradiated (preferably about 15 Gy) human peripheral blood lymphocytes as accessory cells when transferring the cells. It is.
- the number of accessory cells for transfer is preferably about the same as the number of transferred cells.
- the human peripheral blood lymphocytes may be from the same or different from the CD34 positive cells.
- the method of transferring human CD34-positive cells or accessory cells to mice is not limited as long as these cells can be introduced into the bloodstream, but tail vein injection is preferred because of the simplicity of the technique. .
- both the B cells and the T cells in the mouse be human-derived cells.
- human CD34-positive cells are transferred to recipient mice and hybrid agglutination (RT0C method: Immunol. Letter 71, 61 (2000)) J. Exp. Med. 176, 845 (1992)) may be transferred.
- RT0C method for example, after treating mouse fetal thymus with deoxyguanosine (dGuo), epithelial cells are collected, reaggregated with human CD34-positive cells, and cultured for about one week.
- human CD34-positive cells By transferring human CD34-positive cells to the SCID mouse from the tail vein and transplanting the human CD34-positive cell aggregate prepared by the hybrid agglutination method under the renal capsule of the SCID mouse, a complete human immune system is obtained.
- Fig. 1 shows an outline of the hybrid agglutination method using human CD34-positive cells and mouse thymus stromal cells.
- soluble T cell-derived factors for example, soluble T cell-derived factors
- T cell-derived factor for example, human CD40 ligand (hCD40L) can be used. So far, it has been reported that IgG-class antibody-producing cells were obtained by adding hCD40 L, IL-4 and IL-10 to the ⁇ ' ⁇ / ⁇ culture system (Blood 92, 4501). (1998)).
- hCD4 OL (2 ⁇ g) or anti-CD40 antibody (2 ⁇ g) may be administered 10 times every other day (every two days).
- the anti-CD40 antibody may be administered preferably at a dose of 1 to 50 g / head, more preferably 5 to 30 g / heads, and most preferably 10 to 20 g / head, for a total of about 10 doses.
- hCD40L for example, those purified from a transformed Hela cell producing the same molecule can be used.
- Anti-hCD40 antibodies include, for example, mouse Purified monoclonal antibodies derived from Supri doma (5C3) can be used.
- the chimeric mouse thus produced can produce a human antibody that binds to the antigen by administering the antigen.
- Administration of the antigen and recovery of the produced human antibody can be performed by methods known to those skilled in the art (see Example 3).
- lymphocytes prepared from the chimeric mouse with / 72 can also be used.
- Known methods can be used for sensitizing the antigen with In ⁇ ' ⁇ (Arai, Experimental Medicine, 6, 897-903 (1988)).
- Lymphocytes to be sensitized may be, for example, those derived from spleen cells.
- helper factors it is effective to use helper factors to expand antigen-specific antibody-producing cells and induce class switches for efficient IgG production.
- hu-SCID chimeric mouse into which CD34-positive cells have been transferred
- spleen cells are collected, and the antigen together with helper factor is obtained in vitro.
- Soluble hCD40L, IL-4 and IL-10 can be used as helper factors.
- the amount of these molecules added to the culture system is preferably about 10 ⁇ g / ml for soluble hCD40L, and about 0.5 to 50 ng / ml for IL-4 and IL-10.
- the antibody titer and antibody class of the antibody secreted into the culture supernatant are determined by adding the test solution to a plate on which the antigen has been coated, and then using labeled anti-human immunoglobulin class antibodies. It can be evaluated by the method.
- FIG. 1 is a diagram showing an outline of a hybrid agglutination method using human CD34-positive cells and mouse thymus stromal cells.
- FIG. 2 is a diagram showing a human antigen-specific antibody titer in NOD-SCID mouse serum. The vertical axis shows the DNP-specific antibody titer in the serum collected each week.
- FIG. 3 shows the amounts of IgM class and IgG class antibodies in the anti-DNP-KLH antibody.
- the vertical axis represents the amount of the antibody (ng / ml).
- FIG. 4 is a view showing T cell functional differentiation induction (IL-2 production ability) from human CD34-positive cells.
- A shows a culture of lymphocytes differentiated in 0 by the human / mouse hybrid agglutination method
- (B) shows a culture of lymphocytes differentiated in Fira.
- the horizontal axis represents the number of weeks elapsed after transplantation, and the vertical axis represents the amount of IL-2 produced (pg / ml).
- the leukocyte layer containing lymphocytes separated at the interface between the two layers was collected and washed three times with PBS (Washing buffer) containing 1% BSA-0.02% EDTA.
- the obtained leukocyte cell fraction was separated using a MACS CD34i femoral unomagnetic isolation kit (Miltenyi Biotec, Glodbach, Germany) to obtain CD34-positive cells.
- cells were labeled with magnetic beads according to the instruction manual, washed with a washing buffer, and VS + column was attached to a MACS separator to separate CD34-positive cells.
- the collected cells were again subjected to positive selection on the RS column.
- the separated cells were replaced with PBS after counting the number of cells, and used for the subsequent operations.
- Example 2 Preparation of mouse into which human lymphocytes had been transferred
- An 8-week-old NOD / sci-scid (N0D-SCID) mouse (J. Immunol. 154, 180 (1995)) was irradiated with a half-lethal X-ray of 3.5 Gty, and human CD34 positive prepared in Example 1 Cells were transferred from the tail vein of mice at a rate of 500,000 cells per animal.
- 15 Gy of X-irradiated human peripheral blood lymphocytes were transferred from the tail vein of mice as accessory cells at a rate of 500,000 cells per mouse.
- T cell-independent (TI) antigen Ficol DNP J. Immunol. 114, 704 (1975) 50 ⁇ g / head or T-cell dependent (TD) antigen KLH-DNP or OVA-DNP (Methods Med. Res. 10, 94 (1964)) (25 g / head) was mixed with an equal amount of complete Freund's adjuvant (Difco Laboratories) and administered intraperitoneally. Thereafter, immunization was similarly performed at two-week intervals. However, incomplete Freund's adjuvant (Difco Laboratories) was used as the adjuvant.
- complete Freund's adjuvant Difco Laboratories
- Blood was collected by orbital sampling every other week after the start of immunization, and the antibody titer derived from the transferred human cells and the frequency of appearance of human T cells and human B cells in peripheral blood were measured.
- the antibody titer was determined by separating the serum from the collected blood and using an ELISA method using a KLH-DNP-coated plastic plate. That is, a plate coated with DNP bound to a carrier was blocked with 3% BSA at room temperature for 2 hours, 100/1/100 serum diluted 10-50-fold was added, and the mixture was reacted at room temperature for 2 hours.
- mice immunized with DNP-Ficoll a T cell-independent antigen (TI), DNP-specific antibody titers were detected in three of the five immunized mice, one of which was Showed a very high antibody titer (FIG. 2A).
- the DNP-specific antibody titers were 1 in 4 for DNP-0VA and 4 for MP-KLH. High antibody titers were confirmed (Fig. 2B, C) .o
- IgG class antibodies were detected in anti-DNP-KLH antibodies (Fig. 3).
- the appearance frequency of human T cells and human B cells was determined by collecting lymphocyte fractions from collected peripheral blood using Ficoll (Pharmacia) and staining with various antibodies specific for human T cells or human B cells. Measured by flow cytometry overnight (FACS). For B cells, a subset of B cells was obtained using the B cell markers PE-anti-CD19, FITC-anti-CD5, FITC-anti-IgM, FITC-anti-IgG, and FITC-anti-CD40. ⁇ The degree of differentiation was analyzed. T cells were analyzed using PE-anti-CD2 antibody, FITC-anti-CD3 antibody, and FITC-anti-CM antibody (all antibodies were Becton Dickinson). The reaction was performed at 0 ° for 20 minutes.
- the cells were suspended in 0.5 ml of FACS buffer and analyzed by FACScan (Becton Dickinson) using the fluorescence intensity of the antibody reacting with each cell as an index. Upon analysis, CD45-positive cells were gated to calculate the percentage of cells with each T or B cell marker.
- the thymus was collected from a 15-day-old BALB / c mouse embryo and subjected to organ culture (FTOC) on a nuclepore Track-Etoh Membrane (Corning) for 4 days in the presence of 1.3 # 1-dexoxyguanosine (dGuo; Sigma) for lymphocytes. Spheres and dendritic cells were removed. After removing deoxyguanosine from the medium and culturing for an additional day, the thymic tissue was treated with PBS containing 0.25% trypsin (sigma) and 0.02% EDTA (Wako Pure Chemical Industries), and the released thymic supporting epithelial cells (stoma) were removed. Mouth cells).
- the stromal cells After mixing the stromal cells with human CD34-positive cells at a ratio of 1: 4, the mixture was centrifuged at 2000 rpm, and the resulting aggregates (human / mouse hybrid reag aggregate; hu / m hybrid) ⁇ nuclepore Track-Ethoh Membrane Cultured for 2 weeks (RTOC) o After 2 weeks of RTOC, the hu / m hybrid was transplanted under the renal capsule of NOD-SCID mice. The differentiation status of human T cells in the transplanted hu / m hybrid was analyzed by FACScan using T cell specific antibodies (anti-CDla, anti-CD anti-CD8, anti-CD3, anti-CD45).
- the IL-2 producing ability was measured by measuring the concentration of hlL-2 produced in the culture supernatant by the stimulation of PMA (phorbol myristate acetate) and IM (ionomycin) using an ELISA kit.
- PMA phorbol myristate acetate
- IM ionomycin
- a cell suspension mainly composed of lymphocytes was prepared by aseptically cutting out the re-aggregated constructs transferred under the kidney capsule and removing unnecessary cell clumps and dead cell clumps using a nylon mesh. .
- These cells are RPMI After adjusting the concentration of 5 x l0 6 / ml in culture medium were seeded at 100ml / Ueru in U-bottom 96-well plates.
- PA final concentration: 20 ng / ml
- IM final concentration: 200 ng / ml
- An ELISA kit for measuring IL-2 Endogen Human Interleukin-2 ELISA kit was used for the measurement.
- mice transfected with human CD34-positive cells were prepared by the method described in Example 2, and 8 weeks later, the mice were intraperitoneally administered (primary immunization) with DNP-KLH (100 mg) and the anti-human CD40 antibody (20 ju g) (5C3: Pharmingen) was administered subcutaneously. Thereafter, the anti-human CD40 antibody (20 ig) alone was administered every other day for 10 times until the 11th week. At 11 weeks, DNP-KLH was again administered intraperitoneally (Booth Yuichi). At 12 weeks, the spleen was removed from the mouse under anesthesia, and the following analysis was performed.
- a chimeric mouse having human antibody-producing ability into which human CD34-positive cells have been transferred, a method for preparing the same, and a method for preparing a human antibody using the chimeric mouse are provided.
- the chimeric mouse of the present invention is different from a conventional chimeric mouse prepared by transferring human peripheral blood lymphocytes (PBL), in which undifferentiated hematopoietic stem cells are transferred and lymphocytes are differentiated in the body. These lymphocytes are not adapted to themselves (humans) like the human peripheral blood lymphocytes in the conventional method. Therefore, the chimeric mouse of the present invention can produce human antibodies against any antigen including human self components.
- PBL peripheral blood lymphocytes
- the chimeric mice of the present invention into which CD34-positive cells have been transfected have no EBV mixture. It is known that existing dendritic cells have low antigen-presenting ability, and it is difficult to elicit an efficient immune response.On the other hand, in the chimeric mouse of the present invention, B cells, Immunocompetent cells such as T cells and dendritic cells continuously differentiate and proliferate, and can perform immunization for a long period of time.
- EBV Epstein-Barr virus
- the antibody obtained in the present invention is composed of a complete human immunoglobulin component containing a sugar chain portion.
- mouse-type sugar chains are bound to produce antibodies in mouse B cells. Therefore, there was a possibility that an anti-mouse-type sugar chain antibody would be produced in a drug requiring repeated administration.
- the human antibody produced by the present invention has a human-type sugar chain, production of such a neutralizing antibody is unlikely to occur, and the utility is high.o
- helper factor in the present invention, it is possible to obtain an IgG class antibody having high binding activity. This is very significant when antibodies are used as pharmaceuticals because of the ease of production and purification.
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AU2001256746A AU2001256746A1 (en) | 2000-05-15 | 2001-05-15 | Chimeric mouse having immunity constructed by using human cd34-positive cells and use thereof |
US10/276,572 US20040016007A1 (en) | 2000-05-15 | 2001-05-15 | Chimeric mouse having immunity constructed by using human cd34-positive cells and use thereof |
EP01930151A EP1285577A4 (en) | 2000-05-15 | 2001-05-15 | CHIMERIC MOUSE HAVING IMMUNITY CREATED BY USE OF HUMAN CD34 POSITIVE CELLS AND USE THEREOF |
US11/602,446 US20070067854A1 (en) | 2000-05-15 | 2006-11-20 | Chimeric mouse having an immune system constructed with human CD34+ cells and use thereof |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1321477A1 (en) * | 2001-12-22 | 2003-06-25 | Ulf Grawunder | Method for the generation of genetically modified vertebrate precursor lymphocytes and use thereof for the production of heterologous binding proteins |
WO2003068819A1 (en) * | 2001-12-22 | 2003-08-21 | 4-Antibody Ag | Method for the generation of genetically modified vertebrate precursor lymphocytes and use thereof for the production of heterologous binding proteins |
WO2004006664A1 (ja) * | 2002-07-16 | 2004-01-22 | Japan Science And Technology Agency | 非癌部肝臓組織が移植されたモデル動物およびその作製方法 |
JPWO2004110139A1 (ja) * | 2003-06-16 | 2006-08-03 | 株式会社産学連携機構九州 | ヒト由来免疫担当細胞の製造方法 |
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JP3964278B2 (ja) * | 2002-07-16 | 2007-08-22 | 独立行政法人科学技術振興機構 | 肝硬変モデル動物およびその作製方法 |
US20070025961A1 (en) * | 2003-06-03 | 2007-02-01 | Kenzo Bamba | Composition for stabilizing survival of transplanted hematopoietic stem cell, kit for obtaining the composition, method of stabilizing survival of transplanted hematopoietic stem cell, human monoclonal antibody or human polyclonal antibody and method of producing the same, gene encoding human monoclonal antibody and transf |
US8883507B2 (en) | 2005-10-18 | 2014-11-11 | The Regents Of The University Of Colorado | Conditionally immortalized long-term hematopoietic stem cells and methods of making and using such cells |
AU2008224950B2 (en) * | 2007-03-13 | 2013-10-03 | National Jewish Medical And Research Center | Methods for generation of antibodies |
WO2009020923A1 (en) | 2007-08-03 | 2009-02-12 | Musc Foundation For Research Development | Human monoclonal antibodies and methods for producing the same |
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JP5812861B2 (ja) | 2008-08-28 | 2015-11-17 | タイガ バイオテクノロジーズ,インク. | Mycの修飾物質、該mycの修飾物質を使用する方法、およびmycを調節する薬剤を同定する方法 |
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US10149898B2 (en) | 2017-08-03 | 2018-12-11 | Taiga Biotechnologies, Inc. | Methods and compositions for the treatment of melanoma |
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US6353150B1 (en) * | 1991-11-22 | 2002-03-05 | Hsc Research And Development Limited Partnership | Chimeric mammals with human hematopoietic cells |
CA2170357A1 (en) * | 1993-08-25 | 1995-03-02 | David Digiusto | Method for producing a highly enriched population of hematopoietic stem cells |
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EP1321477A1 (en) * | 2001-12-22 | 2003-06-25 | Ulf Grawunder | Method for the generation of genetically modified vertebrate precursor lymphocytes and use thereof for the production of heterologous binding proteins |
WO2003068819A1 (en) * | 2001-12-22 | 2003-08-21 | 4-Antibody Ag | Method for the generation of genetically modified vertebrate precursor lymphocytes and use thereof for the production of heterologous binding proteins |
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US7741077B2 (en) | 2001-12-22 | 2010-06-22 | 4-Antibody Ag | Method for the generation of genetically modified vertebrate precursor lymphocytes and use thereof for the production of heterologous binding proteins |
WO2004006664A1 (ja) * | 2002-07-16 | 2004-01-22 | Japan Science And Technology Agency | 非癌部肝臓組織が移植されたモデル動物およびその作製方法 |
JPWO2004110139A1 (ja) * | 2003-06-16 | 2006-08-03 | 株式会社産学連携機構九州 | ヒト由来免疫担当細胞の製造方法 |
JP4609855B2 (ja) * | 2003-06-16 | 2011-01-12 | 国立大学法人九州大学 | ヒト由来免疫担当細胞の製造方法 |
US7960175B2 (en) | 2003-06-16 | 2011-06-14 | Kyushu University, National University Corporation | Process for producing human-origin immunocompetent cell |
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EP1285577A4 (en) | 2007-05-09 |
US20040016007A1 (en) | 2004-01-22 |
US20070067854A1 (en) | 2007-03-22 |
AU2001256746A1 (en) | 2001-11-26 |
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