WO2005094886A1 - Gpiアンカー蛋白質アゴニストによる調節性t細胞分化誘導・増殖方法およびそのための医薬組成物 - Google Patents
Gpiアンカー蛋白質アゴニストによる調節性t細胞分化誘導・増殖方法およびそのための医薬組成物 Download PDFInfo
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
- C07K16/2803—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 immunoglobulin superfamily
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- 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
- C07K16/2803—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 immunoglobulin superfamily
- C07K16/2809—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 immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
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- 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
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
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- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5047—Cells of the immune system
- G01N33/505—Cells of the immune system involving T-cells
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- C07K2317/74—Inducing cell proliferation
Definitions
- the present invention relates to a novel method for regulating immunity, particularly a method for regulating immunity by inducing differentiation and promoting proliferation of regulatory ⁇ cells (sometimes called inhibitory ⁇ cells).
- the present invention relates to a pharmaceutical composition for use in a method.
- ⁇ cells One cell group that plays a central role in the immune system as a host defense system against various pathogens is ⁇ cells.
- ⁇ Cells are roughly divided into CD4-positive helpers ⁇ cells and CD8-positive cytotoxic ⁇ cells, the former mainly due to the pattern of cytokinin production at specific stages of differentiation and maturation after antigen stimulation.
- -Th1 cells that produce ⁇
- Th2 cells that produce IL-4, etc.
- the former contributes to cell-mediated immunity and the latter contributes to the activation of the humoral immune system, and is deeply involved in host defense. Immune responses are deeply involved in the elimination of pathogens and the acquisition of infectious resistance under a subtle balance by the actions of T cells with these different properties.
- the latter include induction of cell death or induction of non-responsiveness to autoantigens (Rocha, B., and H. von Boehmer. 1991. Science. 251: 1225-1228 .; Jenkins, MK, and RH Schwartz. 1987. J. Exp. Med. 165: 302-319.), Together with an active suppression mechanism by regulatory T cells (Shevach, EM 2000. Annu. Rev. Immunol. 18: 423- 449.) are known. Regulatory T cells are defined as having an inhibitory effect on other T cells. The immune response is based on a subtle balance, for example, it is known that the Thl cells and Th2 cells described above antagonize each other's immune response, and that one acts as a regulatory T cell for the other.
- CD4 + CD25 + which is mainly used for mice and rats. It has been studied in non-human species. That is, CD4 positive spleen cell power of normal mice or rats is also CD25 positive, RT6.1 positive (expressed in most of mature rat T cells), CD5 strong positive, or CD45RB weak positive (mouse) or CD45RC weak positive (rat) It was found that removing cells from the cells and transferring the remaining T cells to immunodeficient animals induced organ-specific autoimmune disease.
- CD4 + CD25 + regulatory T cells were identified in mice and rats as described above, while the presence of similar cells in humans was reported in 2001 by several groups (Jonuleit , H. et al "2001. J. Exp. Med. 193: 1285-1294; Levings, MK et al., 2001. J. Exp. Med. 193: 1295—1301; Dieckmann, D. et al., 2001. J. Exp. Med. 193: 1303-1310; Taama, LS et al., 2001. Eur. J. Immunol. 31: 1122—1131; Stephens, LA et al "2001. Eur. J. Immunol. 31: 1247-1245; Baecher-Allan, C.
- potent CD4 + CD25 + regulatory T cells can be stimulated by anti-CD3 antibody stimulation, stimulation by anti-CD3 and anti-CD28 antibodies, stimulation by allogeneic mature DCs, etc. No DNA synthesis and no production of cytodynamics was observed, ie, CD4 + CD25 + regulatory T cells were in anergy to antigen stimulation.
- CD4 + CD25 + regulatory T cells can increase their DNA synthesis ability by stimulating the site of cytokines such as IL-2, IL-4 and IL-15 in addition to anti-CD3 and anti-CD28 antibodies. Increasing powers Less than that of CD4 + CD25-negative T cells.
- CD4 + CD25 + T cells are stimulated by anti-CD3 antibodies or allogeneic mature DCs to stimulate CD4 + CD25 + regulatory T cells.
- the proliferation inhibitory effect of CD4 positive CD25 negative T cells is observed depending on the number of CD4 positive CD25 positive regulatory T cells.
- CD4-positive CD25-positive regulatory T cells can produce inhibitory cytokins such as IL-10 and TGF-1, but the growth inhibitory effect on CD4-positive CD25-negative cells is It has been reported that the antibody is not released by the sum antibody, and that the inhibitory effect requires direct cell contact between CD4-positive CD25-negative ⁇ cells and CD4-positive CD25-positive regulatory ⁇ cells.
- the existence of CD4 + CD25 + regulatory ⁇ cells in mice, rats and humans has been reported and their characterization has been advanced, but their detailed mechanisms of inhibition and inhibitory action have not yet been elucidated. No markers specific to the cells have been found.
- Trl cells are also anergic, like CD4 + CD25 + regulatory T cells. T cells suppressive mechanisms are influenced by IL-10 and TGF-1 that they produce. May be explainable power Whether the Trl cells and the CD4 + CD25 + regulatory T cells are completely different T cell subsets, or whether they are the same cells at different stages of dyad activity. Tsu, and it is clarified.
- CD4 + CD25 + T cells were isolated from CD4 + and CD25 + T cells. It was confirmed that CD4 + CD25 + T cells from which blood was separated had other cell surface markers and functions similar to those of the same cells in mice and rats. This suggested the existence of CD4 + CD25 + regulatory T cells in humans. These cells are a rare cell population that makes up only 5-10% of peripheral blood CD4-positive T cells and are unresponsive to activated 'proliferative stimuli.
- Regulatory T cells can suppress an autoimmune disease (autoimmune encephalomyelitis, colitis) by transferring them to experimental animals (Kohm, AP et al., 2002. J. Immunol.
- the proteins that make up biological membranes include the transmembrane type, which is present in the cell membrane by the hydrophobic portion contained in the amino acid sequence of its own, and the proteins that are modified by lipids, Some parts are connected to the membrane using the part as an anchor.
- GPI anchor protein (A)
- Glycosylphosphatidylinositol anchored protein belongs to the latter, in which the C-terminal part of the protein is modified, and the oligosaccharide chain and the inositol phospholipid complex lipid covalently bind, and bind to the membrane via the hydrophobic part of the lipid. Te ru.
- GPI anchor proteins There are more than 200 GPI anchor proteins that have been reported so far, and their functions are diverse, such as antigens, enzymes, receptors, and cell adhesion factors (Hiroo Ikezawa, 1999. Protein Nucleic Acid Enzyme. 44: 1321-1328).
- GPI anchor proteins are also expressed on T cells, and it has been reported that these GPI anchor proteins are involved in T cell activation (Horejsi, V. et al., 1998. Immunol. Letter 63: o3—73; Loertscher, R. ana Lavery, P. 2002. Transplant Immunol. 9: 93-96) o
- the GPI anchor protein reported to be involved in T cell activation is Thy- 1 (Kroczek, RA et al., 1986. J. Immunol. 136: 4379-4384), Ly-6 (Malek, TR et al., 1986. J. Exp. Med., 164: 709—722), Qa — 2 (Hahn, AB et al., 1989. J.
- lipid rafts present on T cell membranes play an important role in T cell receptor (TCR) signaling! /! (Xavier, R. et al., 1998) Immunity. 8: 723—732; Montixi, C. et al "1998.
- GPI anchor proteins are thought to transmit a common signal via lipid rafts, regardless of their type (Hale, G. 2001. Cytotherapy. 3: 137-143). ). Indeed, it has been reported that signal transduction factors phosphorylated by GPI anchor protein cross-linking are highly common (Rosemarie, A, et al., 2000. Int. Immunol.
- CD59 is a GPI anchor protein of about 20 kDa, structurally belongs to the Ly6 family, and is expressed in cells of various tissues including the blood system. CD59 binds to C9, one of the complement components, and inhibits the binding of C9 to C5b-8, the final stage of late complement assembly. This suppresses the formation of a membrane-damaging complex on the cell membrane and protects the cells from injury by the complement system. Furthermore, in T cells, in addition to the above-described inhibitory effect of the complement system, it is also known to be involved in adhesion by interacting with CD2 (Lovelan, B. 2002. "CD59” in Leukocyte Typing VII, Oxford University Press: 807-809).
- CD55 is a GPI-anchored protein of about 70 kDa, and is widely expressed in systemic tissues including the blood system. CD55 binds to C3b and C4b, one of the complement components, to inhibit the formation of C3 convertase, and binds to C3bBb and C4b2a to promote the degradation of C3 convertase and regulate complement Injury by the complement system as a factor is known to protect cells! /, Ru (Loveian, B. 2002.'Shishi D5o in Leukocyte Typing VII, Oxford University
- T cells like other GPI anchor proteins, act as costimulators by cross-linking of the CD59 antigen. Do not activate T cells alone. ⁇ When stimulated with low doses of PMA, anti-CD55 antibodies are used to crosslink CD55 to expand CD4 + and CD8 + T cells (Davis, LS et. al., 1988. J. Immunol. 141: 2246-2252) 0 In the costimulation with CD55, the presence of the GPI anchor is essential, and CD55 is fused with the transmembrane domain of CD46 instead of the GPI anchor.
- CD48 is a 45 kDa GPI-anchored protein that belongs to the immunoglobulin superfamily. It is widely expressed on leukocytes, and its expression is enhanced in lymphocytes by activation. It is known that CD48 is involved in cell adhesion by binding to CD2 in mice. ⁇ The affinity between CD48 and CD2 is very low in humans. For the link to the disease, It is known that the frequency of CD48-positive lymphocytes decreases in patients with paroxysmal nocturnal hemoglobinuria (Lo, MF, Sandrin, M. 2002. "CD48" in Leukocyte Typing VII, Oxford
- CD48 expressed on T cells as a costimulatory molecule has been specifically investigated in mice.
- CD48 When CD48 is cross-linked by anti-CD48 antibody when stimulated with anti-CD3 antibody, proliferation of T cells is enhanced (Kato, K. et al., 1992. J. Exp. Med. 176: 1241-1249)
- T cell stimulating ability is enhanced in antigen presenting cells transfected with CD2, a ligand of CD48 (Moran, M. et al., 1998. Immunity 9: 787-796) and that costimulation from CD48 by binding of CD2 is important for induction of cytotoxic T cells (Musgrave, BL et al, 2003. J. Interferon Cytokine). Res.
- Patent Document 1 International Publication No. W099 / 12972
- Patent Document 2 Japanese Patent Publication No. 2
- Non-Patent Document l Masuyama, J. et al. (2002) J. Immunol, 169, 3710
- Non-Patent Document 2 Hale, G. et al., (1983) Blood, 62, 873
- Non-Patent Document 3 Xia, M.Q., et al., (1991) European J. Immunol, 21,1677
- Non-Patent Document 4 Kirchhoff, C et al., (1993) Molecular Reproduction and Development, 34,
- Non-Patent Document 5 Pangolis GA et al., (2001) Medical Oncology, 18, 99
- Non-Patent Document 6 Hederere RA et al., (2000) International Immunology, 12, 505
- Non-Patent Document 7 Valentin H et al., (1992) Transplantation, 54, 97
- Non-Patent Document 8 Rowan WC et al., (1994) International Immunology, 7, 69
- Non-Patent Document 9 Kirchhoff C et al., (2001) Cells Tissues Organs, 168, 93
- the object of the present invention is to provide regulatory T cells having immunoregulatory ability, a method for inducing the regulatory T cells, and a pharmaceutical composition containing the regulatory T cells. Specifically, a method for inducing differentiation and / or promoting proliferation of regulatory T cells via a GPI anchor protein including CD59, CD55 and CD48, regulatory T cells induced by the method, and regulatory T cells It relates to the use of cells for autoimmune diseases, allergic diseases or transplant immune response modulation.
- the present inventors have found that regulatory T cells are induced to differentiate and / or promote proliferation by an antibody against CD52 (International Publication No. WO2004 / 087210 (Japanese Patent Application No. 2003-95765, Japanese Patent Application No. 413786)).
- the present inventors focused on GPI anchor proteins expressed in T cells.
- GPI-anchored proteins especially CD59, CD55 and CD48
- they have an effect of inducing differentiation and / or promoting proliferation of regulatory T cells.
- the present invention is as follows:
- a method of promoting differentiation induction and / or proliferation of regulatory T cells which comprises stimulating a GPI anchor protein other than CD52 present on the surface of immune cells with an agonist of the protein;
- CD3 agonist is an anti-CD3 antibody or a fragment thereof
- the anti-CD3 antibody is a humanized antibody or a human antibody
- the immune cells are peripheral blood mononuclear cells
- a cell-containing substance containing regulatory T cells obtained by promoting induction and / or proliferation by the method according to any one of 1 to 10 above;
- a pharmaceutical composition for immunosuppression comprising regulatory T cells obtained by promoting induction and / or proliferation by the method according to any one of 1 to 10 above;
- the GPI anchor protein is selected from the group consisting of CD55, CD59 and CD48; 19.A method for screening a drug having a T cell differentiation-inducing and / or proliferation-promoting effect by using an interaction with a GPI-anchor protein other than CD52 as an index, comprising expressing a GPI-anchor protein other than CD52. The method comprising contacting the cells with the candidate conjugate and detecting these interactions or the GPI-anchored protein stimulation response;
- GPI anchor protein is selected from the group consisting of CD55, CD59 and CD48;
- a pharmaceutical composition for inducing and / or promoting proliferation of regulatory T cells comprising as an active ingredient an agonist of a GPI anchor protein other than CD52;
- composition according to 27 above, wherein the above-mentioned agonist is an anti-GPI anchor protein antibody or a fragment thereof;
- composition according to the above 30, wherein the antibody is a humanized antibody or a human antibody;
- composition according to 27 further comprising a CD3 agonist
- composition for preventing or treating an autoimmune disease, an allergic disease or a transplant immune response.
- T cells activated by costimulation through GPI anchor proteins including CD59, CD55 and CD48 are induced to differentiate into regulatory T cells and / or promote proliferation.
- These regulatory T cells are useful as active ingredients in pharmaceutical compositions for regulating autoimmune diseases, allergic diseases and transplant immune responses.
- FIG. 1 shows the results of examining the inhibitory effect of regulatory T cells induced by anti-CD59 antibody on the proliferation of CD4-positive T cells stimulated by anti-CD3 antibodies.
- FIG. 2 shows the results of examining the inhibitory effect of regulatory T cells induced by anti-CD55 antibody on the proliferation of CD4-positive T cells stimulated by anti-CD3 antibody.
- FIG. 3 shows the results of examining the inhibitory effect of regulatory T cells induced by an anti-CD48 antibody on the proliferation of CD4-positive T cells stimulated by an anti-CD3 antibody.
- the present invention relates to an effect of inducing differentiation and / or promoting proliferation of regulatory T cells, and an immunosuppressive effect through the effect of an agonist of a GPI anchor protein. Therefore, a pharmaceutical composition for the above-mentioned effect, which contains a GPI-anchored protein as an active ingredient, and induces and / or promotes the proliferation of regulatory T cells using the above-mentioned agonist.
- the present invention relates to a method and an immunosuppressive method through the method. Stimulation of the GPI anchor protein on the cell surface of immune cells (especially T cells) by its agonist induces the induction of regulatory T cell differentiation, and the proliferation of regulatory T cells while maintaining their function is stimulated. As a result, an in vivo immunosuppressive effect is obtained.
- the GPI-anchored protein agonist is a substance that interacts with the GPI-anchored protein, and stimulates the GPI-anchored protein present on the surface of immune cells to convert the protein.
- GPI anchor proteins As described above, more than 200 types of GPI anchor proteins have been found, among which Thy-1, Ly-6 and Qa-2 in mice, and CD52, CD55, CD59, CD73, CD48 and BY55 / in humans. It has been reported that it is expressed on CD160 isotonic T cells and is involved in the activation of the cells.
- the GPI anchor protein of the present invention is preferably CD55, CD59, CD73, CD48 and BY55 / CD160 when used for humans, regardless of which GPI anchor protein is present on the surface of T cells. It is not limited to these.
- the signal induced by the stimulation of the GPI-anchored protein induces a response such as cell division into regulatory T cells and / or proliferation while retaining the characteristics of regulatory T cells.
- GPI-anchored protein agonists include natural or synthetic ligands for GPI-anchored proteins, i.e., any molecule that induces intracellular signals through the GPI-anchored protein, antibodies to the GPI-anchored protein, and fragments thereof. Is also included. Such an antibody may recognize any site of the GPI anchor protein as long as it can induce an intracellular signal via the GPI anchor protein.
- antibodies to CD55, CD59, or CD48 can also be included in the GPI anchor protein algorithm.
- the antibody used in the present invention may be a polyclonal antibody or a monoclonal antibody prepared by a method known to those skilled in the art, for example, as described in "New Chemistry Laboratory Course 1, Protein I, 389-406, Tokyo Chemical Doujinshi ").
- the antibody used in the present invention can also be easily obtained by combining the steps of evaluating the ability to induce differentiation and proliferation of regulatory T cells described in Examples of the present invention. It is also possible to use commercially available products.
- Preferred antibodies for use in the present invention include, by way of example, anti-CD55, anti-CD59, and anti-CD48 antibodies, various of which are commercially available, for example, from Serotec.
- MEM-43 anti-CD59 antibody commercially available from Wako !, anti-CD55 antibody 1C6 clone, commercially available from Serotec !, anti-CD48 antibody MEM102 clone, and the like.
- a so-called human iridase antibody obtained by transplanting the variable region of an antibody against the GPI anchor protein into the framework of a human antibody can be used as an agonist of the GPI anchor protein of the present invention.
- a mouse that retains a human antibody gene that has not been rearranged and produces a human antibody specific to the antigen upon sensitization of the antigen eg, Tomizuka et al., 2000. Proc. Natl. Acad. Sci. USA , 97: 722
- the antibody can be used in the present invention.
- the differentiation of regulatory T cells is induced by allowing the GPI anchor protein to act in addition to the CD3 agonist on immune cells that express the CD3 and GPI anchor proteins. And / or promote cell proliferation. That is, the CD3 signal transduction system, which is the main stimulus transmission pathway involved in T cell sorting, is the main stimulus pathway, and the pathway via the GPI anchor protein is the so-called accessory stimulation pathway.
- causing stimulation through the GPI anchor protein in addition to stimulation through CD3 may be referred to as GPI anchor protein co-stimulation.
- CD3 agonist refers to the action of a CD3 molecule expressed on the surface of an immune cell to induce signal transduction into a cell via CD3, and the signal transduction promotes differentiation of the cell. Then ⁇ ⁇ means any substance that can induce a reaction.
- Examples of CD3 agonists include agonistic anti-CD3 antibodies such as OKT3 (ATCC CRL-8001), UCHT1 (BD PharMingen), and HIT3a (BD PharMingen).
- agonists against various T cell antigen receptors in particular, antibodies having agonist action or fragments thereof also cause complex formation of ⁇ cell antigen receptor and CD3, and signal transduction into cells via CD3. Because , Can be used as a CD3 agonist in the present invention.
- OT145 Pieris et al., 1986, Proc. Natl. Acad. Sci. USA., 83 (20): 7888_92
- a substance that recognizes a T cell antigen receptor and exerts an agonist action such as a soluble HLA molecule or a tetramer molecule of an HLA molecule and an antigen peptide, can also be used.
- the pharmaceutical composition containing the agonist of the GPI anchor protein as an active ingredient and the pharmaceutical composition containing the agonist and the CD3 agonist as the active ingredients provided by the present invention can be used as immunosuppressants.
- the pharmaceutical composition may further be useful as an agent targeting a specific mechanism of action of the immune system, or as an agent for inducing differentiation and / or promoting proliferation of regulatory T cells.
- the pharmaceutical composition provided by the present invention may be administered in vivo, or may be an immune cell, particularly a T cell, or an immune cell collected from a patient or another human.
- an immune cell particularly a T cell
- an immune cell collected from a patient or another human for in vitro treatment of peripheral blood, umbilical cord blood, bone marrow cells, lymph fluid, lymph node cells, and thymocytes containing the same.
- the pharmaceutical composition of the present invention can be formulated by a known method. That is, a pharmaceutical preparation containing various additives acceptable for the therapeutic effect, for example, a carrier, a pH buffer, a stabilizer, an excipient and the like is produced. Such formulations preferably include a physiologically acceptable diluent or carrier, and suitable carriers include physiological saline, phosphate buffered saline, phosphate buffered saline. These include, but are not limited to, glucose solutions and buffered saline. Alternatively, the agonist of the GPI anchor protein may be provided in a freeze-dried (freeze-dried) state, and reconstituted by adding the above buffer aqueous solution when necessary. Examples of the dosage form of the above preparation include oral administration using tablets, capsules, granules, powders, syrups and the like, and parenteral administration using injections, drops and suppositories.
- the administration method and dosage of the pharmaceutical composition are determined in the course of preclinical tests and clinical tests. Can be determined as appropriate.
- the power varies depending on symptoms, age, body weight, etc.
- Oral administration is usually about 0.01 mg to 1000 mg per day for an adult, and these can be administered once or in several divided doses.
- about 0.01 mg to 1000 mg can be administered by subcutaneous injection, intramuscular injection or intravenous injection.
- the disease to be treated is a disease in which a treatment that produces an immunosuppressive effect is required, and specifically, a transplant immune response, ie, graft-versus-host disease (GvHD) or graft rejection, Allergic diseases, and autoimmune diseases such as rheumatism.
- a transplant immune response ie, graft-versus-host disease (GvHD) or graft rejection, Allergic diseases, and autoimmune diseases such as rheumatism.
- the pharmaceutical composition of the present invention and the method of the present invention can also be used for treatment before and after organ or cell transplantation for the treatment or prevention of graft versus host disease or transplant rejection.
- immune cells collected from the patient or another human in need of the above treatment or prevention or peripheral blood, umbilical cord blood, bone marrow cells, lymph fluid, lymph containing the immune cells Treating node cells or thymocytes in vitro, with GPI-anchored protein agonists, or in some cases with the agonists and CD3 agonists to expand regulatory T cells and repopulate the expanded cells
- GPI-anchored protein agonists or in some cases with the agonists and CD3 agonists to expand regulatory T cells and repopulate the expanded cells
- the conditions for stimulating the immune cells with an agonist are as follows: when an intracellular signal is transmitted via a GPI anchor protein by a GPI anchor protein agonist and stimulation is also performed by a CD3 agonist, Stimulation may be performed with each agonist in an amount sufficient for the intracellular signal to be transmitted through the cell.
- the amount varies depending on the type of the agonist, and an appropriate amount of the agonist to be used and the time for stimulating the agonist can be determined by those skilled in the art by a simple test.
- the time for the stimulation is generally 12 hours or more, more preferably 24 hours or more, for example, preferably about 3 days.
- the present invention also includes a method for in vitro differentiation and proliferation of regulatory T cells by the above method, and a regulatory T cell obtained thereby, provided that the same T cell is returned to the same person or another human. I do.
- regulatory T cells derived from one individual that is, regulatory T cells having a uniform genetic trait, can be obtained in a therapeutically effective amount, which was difficult to obtain by conventional techniques. It is.
- the present invention provides a method for contacting a cell expressing a GPI anchor protein with a candidate conjugate for the development of a drug having an effect of inducing differentiation and / or promoting proliferation of regulatory T cells. And detecting the interaction or the GPI-anchored protein stimulus response, and screening for a compound that becomes an agonist of the GPI-anchored protein using the interaction with the GPI-anchored protein as an index.
- the GPI-anchored protein-stimulated response is, for example, the activity of inducing differentiation or promoting proliferation of regulatory T cells.
- Example 1 Regulation of Tile CD59 Pile Secondary Stimulation Induction of T cells
- CD4-positive T cells were prepared from peripheral blood mononuclear cells by negative selection using MACS CD4 + T Cell Isolation Kit (Miltenyi Biotec) according to the manufacturer's instructions. Got The CD4-positive T cells were suspended in RPMI 1640 medium (GIBCO) supplemented with 10% FCS and 15 mM HEPES buffer, and the plate was immobilized with the aforementioned anti-CD3 antibody and anti-CD59 antibody. Seed at 5 cells / well and in a CO incubator at 37 ° C / 5% CO environment
- the inhibition was performed as follows. 1 x 10 5 cells / well of CD4-positive T cells were seeded together with 4 x 10 5 cells / well of peripheral blood mononuclear cells irradiated with X-rays (5,000 rads) on a 96-well U bottom plate (ICN). was added to a final concentration of 25 ng / ml and cultured for 3 days.
- the regulatory T cells mosquitoes ⁇ Ena force ivy group was added mosquitoes ⁇ the X-ray irradiation (5,000 rads) anti CD59 antibodies co-stimulation cell as a control group and regulatory T cells in l ⁇ 2xl0 5 cells / well
- the inhibitory activity was evaluated by comparing [] thymidine incorporation.
- [ 3 H] thymidine incorporation was performed by adding 0.2 Ci / well of [ 3 H] thymidine on the third day of culture, collecting the cells 8 hours later, and counting the [ 3 H] thymidine incorporated in the cells by a beta plate. (PerkinElmer). All cells used for a single assay were from the same donor.
- the anti-CD59 antibody costimulator cells suppressed the proliferation of CD4-positive T cells stimulated by the anti-CD3 antibody depending on the number of added costimulator cells. This revealed that regulatory T cells were induced by the anti-CD59 antibody costimulation.
- Example 2 Pile CD55 Pellet regulation induced by co-stimulation T cell induction
- CD25-negative non-activated cells showed no inhibitory activity, but CD25-positive activated cells. Inhibited the proliferation of CD4-positive T cells induced by anti-CD3 antibody stimulation depending on the number of activated cells. It was revealed that cells activated by anti-CD55 antibody costimulation acquired the properties of regulatory T cells.
- An anti-CD48 antibody (clone MEM102, Serotec) was used instead of the CD59 antibody.
- the anti-CD48 antibody costimulator cells suppressed the proliferation of CD4-positive T cells by anti-CD3 antibody stimulation in a cell-dependent manner, and the anti-CD48 antibody costimulated decreased the regulatory T cells. It was found to be induced.
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US10/594,638 US20070178072A1 (en) | 2004-03-31 | 2005-03-30 | Method for inducing differentiation of regulatory t cells usinggip-anchored protein agonist and pharmaceutical composition therefor ( as amended |
JP2006511747A JPWO2005094886A1 (ja) | 2004-03-31 | 2005-03-30 | Gpiアンカー蛋白質アゴニストによる調節性t細胞分化誘導・増殖方法およびそのための医薬組成物 |
EP05727887A EP1749538A4 (en) | 2004-03-31 | 2005-03-30 | METHOD FOR DETERMINING THE DIFFERENTIATION OF REGULATORY T CELLS AND THEIR PROLIFERATION WITH GPI ANCHOR PROTEIN AGONISTS AND MEDICINAL COMPOSITION THEREFOR |
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JP2018509908A (ja) * | 2015-03-18 | 2018-04-12 | シアトル ジェネティックス, インコーポレイテッド | Cd48抗体及びその複合体 |
WO2018067964A1 (en) * | 2016-10-07 | 2018-04-12 | Genzyme Corporation | Early post-transfection isolation of cells (epic) for biologics production |
US10317329B2 (en) | 2015-10-09 | 2019-06-11 | Genzyme Corporation | Early post-transfection isolation of cells (EPIC) for biologics production |
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US8409565B2 (en) * | 2006-02-14 | 2013-04-02 | Francesca Levi-Schaffer | Therapeutic target and diagnostic marker for asthma and related conditions |
WO2010078329A1 (en) * | 2008-12-30 | 2010-07-08 | President And Fellows Of Harvard College | Methods and compositions for the treatment of pathogenic diseases |
WO2011151941A1 (ja) | 2010-06-04 | 2011-12-08 | 国立大学法人東京大学 | 制御性t細胞の増殖または集積を誘導する作用を有する組成物 |
US9533039B2 (en) | 2010-09-27 | 2017-01-03 | Regeneron Pharmaceuticals, Inc. | Methods of treating systemic lupus erythematosus (SLE) using anti-CD48 antibodies |
AR083044A1 (es) | 2010-09-27 | 2013-01-30 | Regeneron Pharma | Anticuerpos anti-cd48 y usos de los mismos |
EP2785828B1 (en) | 2011-12-01 | 2020-04-08 | The University of Tokyo | Human-derived bacteria that induce proliferation or accumulation of regulatory t cells |
WO2019040513A1 (en) * | 2017-08-22 | 2019-02-28 | Agonox, Inc. | METHODS AND COMPOSITIONS RELATED TO CD55 BINDING AGENT |
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JP2003102471A (ja) * | 2001-10-01 | 2003-04-08 | Kirin Brewery Co Ltd | 調節性t細胞の分化誘導・増殖促進方法 |
WO2004087210A1 (ja) * | 2003-03-31 | 2004-10-14 | Kirin Beer Kabushiki Kaisha | 抗cd52抗体による調節性t細胞分化誘導・増殖方法およびそのための医薬組成物 |
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WO2004087210A1 (ja) * | 2003-03-31 | 2004-10-14 | Kirin Beer Kabushiki Kaisha | 抗cd52抗体による調節性t細胞分化誘導・増殖方法およびそのための医薬組成物 |
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Cited By (5)
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JP2018509908A (ja) * | 2015-03-18 | 2018-04-12 | シアトル ジェネティックス, インコーポレイテッド | Cd48抗体及びその複合体 |
US10317329B2 (en) | 2015-10-09 | 2019-06-11 | Genzyme Corporation | Early post-transfection isolation of cells (EPIC) for biologics production |
US11635363B2 (en) | 2015-10-09 | 2023-04-25 | Genzyme Corporation | FLARE (flow cytometry attenuated reporter expression) technology for rapid bulk sorting |
WO2018067964A1 (en) * | 2016-10-07 | 2018-04-12 | Genzyme Corporation | Early post-transfection isolation of cells (epic) for biologics production |
US11685943B2 (en) | 2016-10-07 | 2023-06-27 | Genzyme Corporation | Early post-transfection isolation of cells (EPIC) for biologics production |
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EP1749538A4 (en) | 2009-11-11 |
EP1749538A1 (en) | 2007-02-07 |
JPWO2005094886A1 (ja) | 2008-02-14 |
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