CN104740608A - Use of soluble CTLA4 (cytotoxic T lymphocyte-associated antigen-4) molecule in preparation of drug for treatment of rheumatoid arthritis - Google Patents
Use of soluble CTLA4 (cytotoxic T lymphocyte-associated antigen-4) molecule in preparation of drug for treatment of rheumatoid arthritis Download PDFInfo
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Abstract
The invention discloses use of a soluble CTLA4 (cytotoxic T lymphocyte-associated antigen-4) molecule in the preparation of a drug for treatment of rheumatoid arthritis, and specifically provides the use of the soluble CTLA4molecule in preparation of the drug for treatment of active rheumatoid arthritis (ra) in adults, wherein biological or non biological preparation disease modifying anti-rheumatic drugs (DMARDs) have poor therapeutic effects on the active rheumatoid arthritis (ra) in adults, and the DMARDs can be one of amethopterin, cyclophosphamide, azathioprine, cyclosporine A or tumor necrosis factor alpha (TNF alpha) blocking agent or antagonist or a combination thereof. Preferably, the soluble CTLA4 molecule is CTLA4Ig. The experimental results show that CTLA4Ig can significantly improve the symptoms, physical signs and laboratory indicators of rheumatoid arthritis compared with placebo.
Description
Technical field
The invention belongs to field of biological pharmacy, more specifically, the invention discloses soluble CTLA 4 molecule for the preparation of the purposes in treatment immune disease medicine.
Background technology
Rheumatoid arthritis is a kind of progressivity rheumatism, and the adult of the Chinese Home that interferes with the development about 2% (Utsinger, P.D., et al., 1985Rheuma toid Arthritis, p.140).The feature of this disease is the struvite synovitis continued, and this causes the corrosion of cartilage and bone, thus causes the structural deformities in joint, periphery.Comprise arthroncus, joint tenderness, inflammation, morning stiff and pain with the symptom of rheumatoid arthritis, particularly bending time pain.The experimenter with advanced joint inflammation is subject to the impact of structural damage, comprises destruction of joint and bone corrosion (see Principals of Internal Medicine, Harrison, 13th edition, pages1648-1655).In addition, patient can also show other clinical symptoms of various organ lesion, comprises skin, pathological changes that kidney, heart, lung, central nervous system unify eye, and this is due to the vasculitis relevant to self-immunprocess.
Other symptom relevant to rheumatoid arthritis comprises erythrocyte sedimentation rate to be increased, and serum C-reactive protein (CRP) and/or IL-2 receptor (IL-2r) level raise.Erythrocyte sedimentation rate nearly all suffer from the patient of Active rheumatoid arthritis all increase.Serum C-reactive protein level also raises, and relevant with the probability that progressivity joint injury occurs to disease activity degree.In addition, the solubility IL-2f level that in the serum of Active rheumatoid arthritis patient and synovial fluid, a kind of T cell by activating produces also raises (see Principals ofInternal Medicine, Harrison, 13th edition, page1650).
Rheumatoid arthritis is also considered to the autoimmune disease of a kind of T cell mediation, and it relates to the antigen-non-specific cell-cell interaction between T lymphocyte and antigen-presenting cell.In general, the common stimulation responses that the intensity of t cell response is caused by the interaction between T cell surface molecular and its part measures (Mueller, et al., 1989Ann.Rev.Immunol.7:445-480).Crucial costimulatory signal is by its part on T cell surface receptor CD28 and CTLA4 and antigen-presenting cell, as the interaction between B7 correlation molecule CD80 (i.e. B7-1) and CD86 (i.e. B7-2) provides (Linsley, P.and Ledbetter, J.1993Ann.Rev.I mmunol.11:191-212).
When not stimulating altogether, the activation of T cell causes anergy t cell response (Schwartz, R.H., 1992Cell71:1065-1068), and wherein immune system becomes stimulation nonreply.
Because rheumatoid arthritis is considered to the disease of immune system of a kind of T cell mediation, a kind of strategy of the novel agent of exploitation treatment rheumatoid arthritis is qualification blocks the costimulatory signal between T lymphocyte and antigen-presenting cell molecule by the interaction blocked between endogenous CD28 or CTLA4 and B7.Possible molecule comprises modified and with the affinity higher than wild type CTLA4 or CD28 in conjunction with B7, thus blocks the soluble CTL A 4 of costimulatory signal.
The soluble form of CD28 and CTLA4, by merging variable region (V) like cell extracellular portion and immunoglobulin (Ig) constant region of CD28 and CTLA4, obtaining CD28Ig and CTLA4Ig and building.Nucleotide and the aminoacid sequence of CTLA4Ig are shown in Fig. 1, and this protein amino acid sequence, from the methionine of+1 or from the alanine of-1, stops with the lysine of+357.CTLA4Ig is relative to CD28Ig, and the combination of positive with CD80 in CD86 positive cell more by force (Linsley, P., et al., 1994Immunity1:793-80).Have been found that many T cell dependent immune response by CTLA4Ig in vivo with extracorporeal blocking (Linsley, P., et al., 1991b, supra; Linsley, P., et al., 1992a Science257:792-795; Linsley, P., et al., 1992b J.Exp.Med.176:1595-1604; Lenschow, D.J., et al.1992Science257:789-792; Tan, P., et al., 1992J.Exp.Med.177:165-173; Turka, L.A., 1992Proc.Natl.Acad.Sci.USA89:11102-11105).
The treatment of the rheumatism such as current rheumatoid arthritis comprises and gives nonspecific cytotoxicity immunosuppressive drug, as methotrexate, cyclophosphamide, azathioprine, Ciclosporin A and tumor necrosis factor α (TNF α) blocker or antagonist.These immunosuppressive drugs suppress the whole immune system of experimenter, and long-term prescription increases the risk infected.And these medicines only delay the progress of rheumatoid arthritis, when treating discontinuous, can recur at faster speed.In addition, the long-term treatment of these nonspecific drugs produces toxic side effects, comprises the tendency that some malignant tumor, diabetes and liver dysfunction occur.These medicines also can lose efficacy gradually after effective 2-5 (Kelley ' s Textbook of Rheumatology, 6thEdition, p1001-1022).
As selection, as the therapeutic agent of Non-specific immune suppression and anti-inflammatory agent for relief of symptoms.These medicines are dose dependents, can not prevent progression of disease.These medicines comprise steroid compound, as prednisone and methyl meticortelone.The life-time service of steroid is also with serious toxic side effects.(Kelley′s Textbook of Rheumatology，6thEdition，p829-833)。
Therefore, the treatment modest efficacy of current rheumatoid arthritis, causes serious toxicity side effect, and can not life-time service continuously.
Summary of the invention
The invention provides the method by giving experimenter's soluble CTLA 4 molecule treatment rheumatoid arthritis, the B7 molecule of this soluble CTLA 4 molecule on B7 positive cell is combined, thus suppresses CTLA4 and/or CD28 of endogenous B7 molecule in T cell to be combined.Soluble CTLA 4 molecule for the inventive method is CTLA4Ig.More preferably, the invention provides the activities of adults rheumatoid arthritis improving antirheumatic (DMARDs) unsatisfactory curative effect by giving the biological or non-biological agents state of an illness of experimenter's soluble CTLA 4 molecule treatment, wherein DMARDs can be methotrexate, cyclophosphamide, azathioprine, Ciclosporin A or tumor necrosis factor α (TNF α) blocker or antagonist one or a combination set of.
The present invention also provides a kind of pharmaceutical composition being used for the treatment of the disease of immune system such as rheumatism, comprise a kind of pharmaceutically suitable carrier and biologically effective reagent, as solvable CTLA4 molecule, said composition can be used for the medicine preparing treatment rheumatoid arthritis, and the especially biological or non-biological agents state of an illness improves the activities of adults rheumatoid arthritis of antirheumatic (DMARDs) unsatisfactory curative effect.
The present invention also comprises the test kit of the pharmaceutical composition containing treatment disease of immune system.In one embodiment, with the test kit treatment disease of immune system comprising one or more pharmaceutical compositions of the present invention, as rheumatoid arthritis, the especially biological or non-biological agents state of an illness improves the activities of adults rheumatoid arthritis of antirheumatic (DMARDs) unsatisfactory curative effect.Such as, the soluble CTL A 4 mutating molecule that the B7 molecule on B7 positive cell that this pharmaceutical composition comprises a kind of effective dose is combined, thus CTLA4 and/or CD28 of blocking-up B7 molecule in T cell is combined.In addition, this test kit can immunosuppressant containing one or more and pharmaceutical composition coupling of the present invention, comprise, but be not limited to, corticosteroid, nonsteroidal antiinflammatory drug (as Cox-2 inhibitor), ciclosporin, prednisone, azathioprine, methotrexate, TNF alpha blocker or antagonist, infliximab, any biological reagent, hydroxyl chloroquine, sulfasalazine (sulphasalazopryine), golden salt, etanercept and anakinra being positioned inflammatory cytokine.
The present invention includes the pharmaceutical composition being used for the treatment of disease of immune system, wherein comprise the soluble CTLA 4 molecule of pharmacy effective dose.In certain embodiments, disease of immune system is interacted by CD28/CTLA4/B7 and mediates.Soluble CTLA 4 molecule preferably has the CTLA4 molecule of wild-type sequence and/or has the soluble CTLA 4 molecule of one or more sudden change at the extracellular domain of CTLA4.This pharmaceutical composition can comprise soluble CTL A 4 protein molecular and/or nucleic acid molecules, and/or the carrier of these molecules of encoding.In preferred embodiments, described soluble CTLA 4 molecule starts with the alanine of the methionine of (SEQ ID Nos:1-2) shown in Fig. 1+1 or-1, the CTLA4Ig stopped with the lysine of+357; In preferred embodiment, described soluble CTLA 4 molecule starts with the methionine of+1 shown in Fig. 1, the CTLA4Ig stopped with the lysine of+357.
These compositionss can comprise other treatment agent further, include, but are not limited to drug toxicity, enzyme, antibody or conjugate.
As the standard practices in this area, provide the pharmaceutical composition comprised with well known to a person skilled in the art the molecule of the present invention that suitable carrier or adjuvant mix.These pharmaceutical compositions preferably comprise suitable carrier and adjuvant, the activity of this molecule is kept and material unresponsive with the immune system of experimenter when comprising any ought combination with molecule of the present invention (such as, as soluble CTLA 4 molecule, CTLA4Ig).These carriers and adjuvant can be including but not limited to, ion-exchanger, aluminum, aluminium stearate, lecithin, serum albumin are as human serum albumin, and buffer substance is if the partial glyceride mixtures of phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid, phosphate buffer, water, emulsion (as oil/water emulsion), salt or electrolyte are as protamine sulfate, sodium dihydrogen phosphate, dibastic sodium phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvidon, cellulose base materials and Polyethylene Glycol.Other carriers can comprise sterile solution, tablet, comprise coated tablet and capsule.These carriers generally containing excipient as the clay of starch, milk, sugar (as sucrose, glucose, maltose), some type, gelatin, stearic acid or its salt, magnesium stearate or magnesium stearate calcium, Pulvis Talci, plant fat or oil, natural gum, ethylene glycol or other known excipients.These carriers also can comprise aromatic and coloring agent or other compositions.The compositions comprising these carriers is prepared by conventional method known in the art.These compositionss also can at various fluid compositions such as liposomees, and prepares in the various polymer composition such as polymeric microspheres.
The invention provides the various local or the systemic manner that give soluble CTLA 4 molecule, these methods comprise but intravenous, intramuscular, intraperitoneal, oral, suck and subcutaneous methods, and implantable pump, continuous infusion, gene therapy, liposome, suppository, localized contact, carrier, capsule and injecting method.Usually be lyophilized preservation with the therapeutic agent of carrier compound, use the water of pH neutral (pH is about 7-8, as pH7.5) or buffer to rebuild before administration, also can high protein concentration injection form preserve.
As standard practices of the present invention, compositions of the present invention can give experimenter with any pharmaceutically acceptable form.
According to enforcement of the present invention, these methods comprise and give experimenter soluble CTLA 4 molecule of the present invention, to regulate the interaction of CD28 and/or CTLA4 positive cell and B7 positive cell, the soluble CTLA 4 molecule of the present invention of B7 positive cell and effective dose or its fragment or derivant are contacted, to form soluble CTL A 4/B7 complex, the interaction of these complex interference endogenous CD28 and CTLA4 positive cell and B7 family molecule.
Soluble CTLA 4 molecule can be blocked the combination of their the respective ligand bindings in endogenous B7 and experimenter with effective dose and being enough to.Therefore, the blocking-up of endogenous B7/ ligand binding suppresses the interaction of B7 positive cell and CD28 and/or CTLA4 positive cell.
The dosage of therapeutic agent depends on many factors, includes, but not limited to the type of affected tissue, the type of subject autoimmune disease, the order of severity of disease, the health of experimenter and the reaction to this agent therapy.Therefore, the dosage of these reagent can be different according to each experimenter and administering mode.The dosage of soluble CTLA 4 molecule can be 0.1-20mg/kg weight in patients/day, preferred 0.5-10.0mg/kg/ day.
The present invention also comprises and treats disease of immune system by compositions of the present invention together with other medicament.Such as, can comprise with the medicament of molecule therapeutic alliance rheumatism of the present invention, but be not limited to, immunosuppressant is as corticosteroid, ciclosporin (Mathiesen1989CaocerLett.44 (2): 151-156), prednisone, azathioprine, methotrexate (R.Handschumacher,: " Drugs Used for Immunosuppression " P1264-1276), TNF alpha blocker or antagonist (New England Journal of Medicine, vol.340:253-259,1999, The Lancet vol.354:1932-39, 1999, Annalsof Internal Medicine, vol.130:478-486), or other any target is due to the biological preparation of inflammatory cytokine, nonsteroidal antiinflammatory drug/Cox-2 inhibitor, hydroxyl chloroquine, sulfasalazine, gold salt, etanercept, infliximab, adalimumab, tocilizumab, rapamycin, Mycophenolate Mofetic, azathioprine, fujimycin 506, basiliximab, cyclophosphamide, β-1a interferon, β-1b interferon, glatiramer acetate, mitoxantrone hydrochloride, anakinra and/or other biological preparation.
Soluble CTLA 4 molecule also can use with one or more agent combination following, replys: sCD154 is (also referred to as CD40L (CD40L) with immunity moderation, CD154, T-BAM, TRAP), solubility CD29, Soluble CD40, solubility CD80 (as ATCC68627), solubility CD86, sCD28 (as 68628), solubility CD56, soluble T hy-1, solubility CD3, sTCR, solubility VLA-4, solubility VCAM-1, solubility LECAM-1, soluble E LAM-1, solvable CD44, the antibody reacted with gp39 is (as ATCC HB-10916, ATCC HB-12055 and ATCC HB-12056), the antibody (as ATCC HB-9110) reacted with CD40, the antibody reacted with B7 is (as ATCCHB-253, ATCC CRL-2223, ATCC CRL-2226, ATCC HB-301, ATCCHB11341 etc.), the antibody (as the mAb9.3 that (J.Clin.Immun.4 (1): 18-22,1980) such as ATCC HB-11944 or Martin describe) reacted with CD28, the antibody (as ATCC HB-9579 and ATCC TIB-213) reacted with LFA-1, the antibody reacted with LFA-2, the antibody reacted with IL-2, the antibody reacted with IL-12, with the antibody of IFN gamma reaction, the antibody reacted with CD2, the antibody reacted with CD48, the antibody (as ICAM-1 (ATCC CRL-2252), ICAM-2and ICAM-3) reacted with any ICAM, the antibody reacted with CTLA4 (as ATCCHB-304), the antibody reacted with Thy-1, the antibody reacted with CD3, the antibody reacted with CD29, the antibody reacted with TCR, the antibody reacted with VLA-4, the antibody reacted with VCAM-1, the antibody reacted with LECAM-1, the antibody reacted with ELAM-1, the antibody reacted with CD44.In certain embodiments, monoclonal antibody is preferred.In other embodiments, preferred antibody fragment.Those skilled in the art will readily appreciate that, this combination can comprise soluble CTLA 4 molecule of the present invention and other immunosuppressant a kind of, soluble CTLA 4 molecule and two kinds of other immunosuppressant, soluble CTLA 4 molecule and three kinds of other immunosuppressant etc., the judgement of optimum combination and dosage can adopt the known method of the present invention to measure and optimization.
Soluble CTLA 4 molecule of the present invention, can as unique active component or administration together with the other medicines in immunomodulating regimens or other antiinflammatory, be used for the treatment of or prevent allogeneic or heteroplastic acute or chronic rejection or struvite or autoimmune disease, or inducing tolerance.Such as, it can with following reagent coupling: calcineurin inhibitor, as Ciclosporin A or FK506; Inhibitive ability of immunity macrolide as rapamycin or derivatives thereof, as 40-O-(2-hydroxyl) ethyl rapamycin; Lymphocyte homing agent is as FTY720 or its analog; Corticosteroid; Cyclophosphamide; Mizoribine; Mycophenolic acid; 15-deoxyspergualine or its analog; Inhibitive ability of immunity monoclonal antibody, as MHC, CD2, CD3, CD4, CD11a/CD18, CD7, CD25, CD27, B7, CD40, CD45, CD58, CD137, ICOS, CD150 (SLAM), the monoclonal antibody of the lymphocyte receptors such as OX40,4-1BB or its part; Or other immunomodulating complex, as CTLA4/CD28-Ig; Or other adhesion molecule inhibitors, as mAbs or low-molecular-weight depressor, comprise LFA-1 antagonist, select protein antagonist and VLA-4 antagonist.This compound may be used for the complex with interference CD40 and part thereof especially, as the antibody of CD40 and the antibody coupling of CD40-L.
According to foregoing teachings, present invention also offers the method for another aspect as defined above, comprise and jointly giving, as simultaneously or the sequential soluble CTLA 4 molecule of the present invention giving the free form or pharmaceutical acceptable salt for the treatment of effective dose as CTLA4Ig, and the second drug substance, this second drug substance is immunosuppressant such as noted before, immunomodulating or anti-inflammatory drug.Further provide the therapeutic combination for above-mentioned any method, as test kit, comprise the soluble CTLA 4 molecule of free form or pharmaceutical acceptable salt, it and at least one comprise immunosuppressant, immunomodulating or anti-inflammatory drug pharmaceutical composition simultaneously or sequential use.This test kit can comprise the explanation of administration.
Accompanying drawing explanation
Fig. 1: CTLA4Ig sequence;
Fig. 2: ACR result in embodiment 1;
Fig. 3: embodiment 2ACR result.
Detailed description of the invention
The following examples are in order to demonstrate the invention and help those skilled in the art carry out and use the present invention.The scope that these embodiments do not limit the present invention in any way.
CTLA4Ig can prepare with reference to method disclosed in ZL01812229.9, and its preparation can be prepared by formula disclosed in ZL2006800530510.4 and obtain, and also can be prepared according to formula disclosed in ZL200610147281.9 and obtain.
Embodiment 1CTLA4Ig treats the invalid rheumatoid arthritis of DMARDs
219 one or more DMARDs Endodontic failure rheumatoid arthritis patients of example are divided into two groups at random, accept CTLA4Ig10mg/kg or placebo (the adjuvant preparations. Control of active substance) venous transfusion, within the 0th, 2,4,8,12 week, respectively infuse once.
Curative effect index is the ACR20 standard that Americanism damp disease association (ACR) defines.ACR20 is defined as compared with baseline, arthroncus, counting of touching a tender spot improve at least 20%, and the scoring of pain degree, Physician Global, Patient Global's scoring, the scoring of HAQ function/deformity, any three improvement at least 20%, ACR50 in acute phase reactant (ESR or CRP) five indices and ACR70 are in like manner defined as improvement at least 50% and 70% respectively.
Result of the test display CTLA4Ig significantly can improve the symptom of rheumatoid arthritis, sign and lab index compared with placebo.Related data is as following table 1-4 and Fig. 2:
Table 1 reaches the Proportion of patients that ACR20 improves
| Time | CTLA4Ig | Placebo | P |
| 2 weeks | 15.45% | 10.09 | 0.2337 |
| 4 weeks | 35.45 | 14.68 | 0.0004 |
| 8 weeks | 62.73 | 12.84 | <0.0001 |
| 12 weeks | 56.36 | 17.43 | <0.0001 |
Table 2 reaches the Proportion of patients of ACR20, ACR50, ACR70
The improvement situation (treatment front and back difference, unit: mm/hr) of table 3 erythrocyte sedimentation rate (ESR):
| Time | CTLA4Ig | Placebo | P |
| 2 weeks | 7.91±22.82 | 6.04±25.17 | 0.3644 |
| 4 weeks | 10.31±22.82 | 3.65±25.06 | 0.0149 |
| 8 weeks | 16.29±19.84 | 3.56±28.34 | <0.0001 |
| 12 weeks | 19.26±23.82 | 7.06±26.53 | <0.0001 |
The improvement (treatment front and back difference, unit: mg/L) of table 4C reactive protein (CRP):
| Time | CTLA4Ig | Placebo | P |
| 2 weeks | 11.13±23.63 | -4.40±23.67 | <0.0001 |
| 4 weeks | 11.28±24.60 | -3.11±20.98 | <0.0001 |
| 8 weeks | 15.97±24.36 | -3.12±22.19 | <0.0001 |
| 12 weeks | 14.82±31.18 | 0.16±25.07 | <0.0001 |
Embodiment 2CTLA4Ig treatment biology or the non-biological agents state of an illness improve the activities of adults rheumatoid arthritis of antirheumatic DMARDs unsatisfactory curative effect
Adult is defined as: 18 years old and more than;
Activity definition is:
Active Rheumatoid Arthritis diagnostic criteria (based on 28 joints)
1. arthroncus >=4;
2. joint tenderness >=6;
3. follow up a case by regular visits to morning on the same day stiff persistent period >=45 minutes;
4. erythrocyte sedimentation rate testing result abnormal (normal value: man 0 ~ 15mm/hr, female 0 ~ 20mm/hr);
5. c reactive protein testing result abnormal (normal value: < 5mg/L).
Allly meet the 1. item and 2. item simultaneously, and 3. ~ 5. person any one of item, can active stage RA be diagnosed as.
28 joints comprise 10 proximal interphalangeal joint (PIP), 10 metacarpophalangeal joints (MCP), 2 carpal joint, 2 elbow joinies, 2 shoulder joint and 2 knee joints.
Biological or the non-biological agents state of an illness of 440 examples has been selected to improve the activities of adults rheumatoid arthritis patients of antirheumatic DMARDs unsatisfactory curative effect, test group patient by 10mg/kg consumption venoclysis CTLA4Ig, 0,2,4 weeks each once, every 4 weeks subsequently once, until 12 weeks.
MTX matched group patient MTX dosage was adjusted to 15mg/ week in the 4th week, Weekly administration once, to 12 weeks.Basic condition, correlated results see the following form 5-8 and Fig. 3:
Table 5: baseline period data: basic condition
Table 6 basic condition
Table 712 all ACR improvement rates result
| CTLA4Ig | MTX | P | Difference (95%CI) | |
| ACR20 | 70.61% | 46.36% | <0.0001 | 24.24(13.71,34.78) |
| ACR50 | 40.30% | 22.73% | 0.0009 | 17.58(8.12,27.03) |
| ACR70 | 16.67% | 7.27% | 0.0138 | 9.39(3.09,15.70) |
The all ACR of table 812 mark each sub-project scoring and improve (before treatment-treatment after)
Good therapeutic effect is had to the activities of adults rheumatoid arthritis that biological or the non-biological agents state of an illness improve antirheumatic (DMARDs) unsatisfactory curative effect as can be seen from table 7-8 and Fig. 3: CTLA4Ig.
Claims (5)
1. soluble CTLA 4 molecule improves the purposes in the activities of adults rheumatoid arthritis medicine of antirheumatic DMARDs unsatisfactory curative effect at preparation treatment biology or the non-biological agents state of an illness.
2. soluble CTLA 4 molecule according to claim 1, its aminoacid sequence as shown in Figure 1, from the methionine of+1 or from the alanine of-1, stops with the lysine of+357.
3. the purposes described in claim 1 or 2, wherein the dosage of soluble CTLA 4 molecule is 0.1-20mg/kg weight in patients/day.
4. purposes according to claim 3, the dosage of soluble CTLA 4 molecule is 0.5-10.0mg/kg/ day.
5. purposes according to claim 4, wherein the dosage of soluble CTLA 4 molecule is 10.0mg/kg/ day.
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| CN1318086C (en) * | 2000-07-03 | 2007-05-30 | 布里斯托尔-迈尔斯斯奎布公司 | Methods for treating rheumatic diseases using soluble CTLA4 molecule |
| CN101198347A (en) * | 2005-04-06 | 2008-06-11 | 布里斯托尔-迈尔斯斯奎布公司 | Methods for treating immune disorders associated with graft transplantation with soluble CTLA4 mutant molecules |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1441810A (en) * | 2000-05-26 | 2003-09-10 | 布里斯托尔-迈尔斯斯奎布公司 | Soluble CTL A4 mutant molecules and use thereof |
| CN1318086C (en) * | 2000-07-03 | 2007-05-30 | 布里斯托尔-迈尔斯斯奎布公司 | Methods for treating rheumatic diseases using soluble CTLA4 molecule |
| CN101198347A (en) * | 2005-04-06 | 2008-06-11 | 布里斯托尔-迈尔斯斯奎布公司 | Methods for treating immune disorders associated with graft transplantation with soluble CTLA4 mutant molecules |
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Address after: Shanghai city 201203 libing road Pudong New Area Zhangjiang hi tech Park No. 399 Applicant after: Three country Kin Pharmaceutical (Shanghai) Limited by Share Ltd Address before: Shanghai city 201203 libing road Pudong New Area Zhangjiang hi tech Park No. 399 Applicant before: Shanghai CP Guojian Pharmaceutical Co., Ltd. |
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Application publication date: 20150701 |