WO2021179959A1 - Pharmaceutical composition comprising jak3/jak1/tbk1 inhibitor and methotrexate and use thereof - Google Patents
Pharmaceutical composition comprising jak3/jak1/tbk1 inhibitor and methotrexate and use thereof Download PDFInfo
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- WO2021179959A1 WO2021179959A1 PCT/CN2021/078693 CN2021078693W WO2021179959A1 WO 2021179959 A1 WO2021179959 A1 WO 2021179959A1 CN 2021078693 W CN2021078693 W CN 2021078693W WO 2021179959 A1 WO2021179959 A1 WO 2021179959A1
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- WIPO (PCT)
- Prior art keywords
- jak1
- jak3
- methotrexate
- pharmaceutical composition
- pharmaceutically acceptable
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Definitions
- the invention belongs to the technical field of medicine, and specifically relates to a drug combination comprising JAK3/JAK1/TBK1 inhibitor and methotrexate, and its use and method for treating autoimmune diseases, especially rheumatoid arthritis.
- Autoimmune diseases refer to diseases caused by the body's immune response to self-antigens and damage to its own tissues.
- Common autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn’s disease, systemic lupus erythematosus, Multiple sclerosis, type I diabetes, allergic diseases, chronic obstructive pulmonary disease, asthma, leukemia, lymphoma diseases, etc.
- RA Rheumatoid arthritis
- RA Rheumatoid arthritis
- the etiology of the disease is unknown.
- the peak age of the disease is between 30 and 50 years old. Generally, there are more women than men.
- the overall incidence rate in my country is 0.32% to 0.36%.
- Methotrexate (methotrexate, MTX) has the following structure, and its chemical name is: S-(+)-N-2-[4-[[(2,4-diamino-6pteridinyl)methyl]methan Amino]benzoyl]glutamic acid.
- MTX is a classic disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA. It is recommended by major rheumatology societies and guidelines worldwide as the first choice for early RA.
- DMARD disease-modifying anti-rheumatic drug
- MTX reduces the chemotaxis of neutrophils by inhibiting the synthesis of thymine and inhibits the release of inflammatory cytokines, thereby alleviating disease symptoms and slowing the progression of joint damage. Since RA cannot be cured, the safety of long-term use of the drug requires special attention. Clinical studies have confirmed that the main side effects of long-term use of MTX are gastrointestinal reactions, bone marrow suppression, liver damage, kidney damage, etc.
- JAKs are a small family in the superfamily of non-receptor tyrosine protein kinases in the cytoplasm, including four known members of JAK1, JAK2, JAK3 and TYK2. JAKs function by interacting with tyrosine kinase-related receptors and transcription factor signal transducers and activators of transcription (STAT): the tyrosine kinase-related receptors on the cell membrane do not themselves Kinase activity, but the intracellular segment has the binding site of JAKs.
- STAT transcription factor signal transducers and activators of transcription
- the tyrosine residues of various target proteins are phosphorylated by the activation of the bound JAKs to realize the signal from the outside of the cell. Transfer to the cell; after activation of JAKs, the tyrosine residues on the catalytic receptor undergo phosphorylation modification and then form a "parking site" with the surrounding amino acid sequence.
- the STAT protein is recruited to this "parking site", and finally JAKs catalyze the phosphorylation modification of STAT protein.
- the activated STAT protein enters the nucleus in the form of a dimer and binds to the target gene to regulate gene transcription.
- JAK3 is specifically expressed in hematopoietic cells by binding to the ⁇ co-chain ( ⁇ c) of cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 , Regulate cell signal transduction.
- JAK1 can interact with IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, IFN- ⁇ , IFN- ⁇ , IL-6 in the gp130 family, and other receptors containing ⁇ c, etc. Combine.
- JAK1 and JAK3 are considered to be more related to immune regulation.
- the abnormal activation of the two is involved in a variety of autoimmune diseases (including but not limited to lymphoma, arthritis, psoriasis, Crohn’s disease, erythema). Lupus, etc.) play a key role in the etiology and course of the disease. Therefore, the development of inhibitors of JAK1 and JAK3 has become a hot spot in the treatment of RA.
- autoimmune diseases including but not limited to lymphoma, arthritis, psoriasis, Crohn’s disease, erythema).
- Lupus, etc. play a key role in the etiology and course of the disease. Therefore, the development of inhibitors of JAK1 and JAK3 has become a hot spot in the treatment of RA.
- TBK1 (TANK binding kinase 1) is a serine/threonine kinase that activates its substrates IRF3 and IRF7 transcription factors by directly phosphorylating specific sites, and induces them to localize to the nucleus to promote the transcription of type I IFN genes.
- the expression of type I IFN may cause damage to the body.
- RANKL/NF ⁇ B is considered to be one of the most important signaling pathways for osteoclast differentiation.
- Increased levels of soluble RANKL in the synovial fluid of RA patients cause abnormal activation of NF ⁇ B, which will lead to an increase in the number of activated osteoclasts, excessive bone resorption and Increased risk of bone destruction.
- Studies have shown that the activation of NF ⁇ B can be enhanced by the kinase activity of TBK1, and inhibition of TBK1 activity can inhibit RANKL-induced osteoclast differentiation.
- the compound represented by formula (I) is a new molecular entity drug exclusively discovered by Shenzhen Chips Biotechnology Co., Ltd., with a novel mechanism.
- Patent (CN105399685A) and literature (Shan S., et al. 2019, IntImmunopharmacol. 77:105914.) studies have shown that the compound represented by formula (I) is a selective inhibitor of JAK3/JAK1/TBK1, through the target Inhibition reduces the activation of STATs and IRF3, thereby inhibiting the activation of CD4 + T cells, the function of helper T cells 17, the expression of type I interferon (interferon, IFN), and the receptor activator of nuclear factor ⁇ B.
- Nuclear factor kappa B ligand (RANKL) induces osteoclast differentiation to achieve the therapeutic effect of alleviating RA.
- MTX and JAK3/JAK1/TBK1 inhibitors are different in the mechanism of alleviating RA.
- the present invention combines these two drugs with different mechanisms. It is unexpectedly found that the two have a significant synergistic effect on RA, which can reduce Single drug dose, reduce the patient's drug tolerance and reduce possible adverse reactions to provide new and better medication options.
- the inventors unexpectedly discovered through research that the combination of MTX or its pharmaceutically acceptable salt with JAK3/JAK1/TBK1 inhibitors has a synergistic effect for RA and other autoimmune diseases.
- the first aspect of the present invention provides a pharmaceutical composition containing MTX or a pharmaceutically acceptable salt thereof and a JAK3/JAK1/TBK1 inhibitor.
- the pharmaceutical composition can effectively alleviate autoimmunity including RA
- the treatment effect of the symptoms of sexual diseases is significantly better than the effect of any single component.
- JAK3/JAK1/TBK1 inhibitors used in the present invention include the compounds described in CN105399685A, the entire contents of which are incorporated herein by reference.
- the compound in CN105399685A includes a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof,
- R 1 is halogen or C1-C6 alkyl
- R 2 is one or more substituents selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane Carbonyl and C1-C6 alkylamino;
- R 3 is hydrogen or halogen
- R 4 is hydrogen or C1-C4 alkyl
- X is NH, O or S
- Y is CO or S(O) 2 ;
- Z is a covalent bond, CH 2 or (CH 2 ) 2 ;
- n is an integer from 1 to 4.
- Ring A is a benzene ring, a pyridine ring or a piperidine ring.
- the JAK3/JAK1/TBK1 inhibitor is N-(3-(5-chloro-2-(4-fluoro-3-(N-methacrylamido)phenylamino)pyrimidinyl-4 -Amino)propyl)-4-cyanobenzamide, its structural formula is as shown in formula (II):
- the pharmaceutical composition according to the present invention comprises a JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof.
- the weight ratio of the MTX or its pharmaceutically acceptable salt (calculated as MTX) to the JAK3/JAK1/TBK1 inhibitor is 1:100-1:500.
- the effective dose of the MTX or its pharmaceutically acceptable salt is 0.1 mg/kg to 0.5 mg/kg.
- the effective dose of the JAK3/JAK1/TBK1 inhibitor is 20-100 mg/kg; preferably 15-90 mg/kg; most preferably 20-80 mg/kg.
- the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof can be administered separately, simultaneously or sequentially.
- halogen refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, and bromine; most preferably chlorine.
- the alkyl group refers to a saturated branched or branched chain hydrocarbon group; in particular, C1-C4 alkyl refers specifically to methyl, ethyl, propyl, isopropyl, butyl, 1-isobutyl, 2- Isobutyl, tert-butyl; the C1-C6 alkyl group includes a 5-carbon alkyl group and a 6-carbon alkyl group in addition to the aforementioned C1-C4 alkyl group, and specific examples thereof will not be repeated here.
- the alkyl group in the compound of the present invention may be optionally substituted or unsubstituted, and the substituent may include an alkyl group, a halogen, an alkoxy group, a hydrocarbyl group, a hydroxyl group, and the like.
- the "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” in the present invention refers to an acid addition salt prepared by reacting the compound represented by the aforementioned formula (I) or MTX with a pharmaceutically acceptable acid, or A salt formed by the reaction between a compound having an acidic group and a pharmaceutically acceptable base.
- the pharmaceutically acceptable acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.) and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, Tartaric acid, citric acid or benzoic acid, etc.);
- the pharmaceutically acceptable base is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, ammonia or ammonium bicarbonate.
- the stereoisomers include conformational isomers, enantiomers and diastereomers.
- composition of the present invention may also include pharmaceutically acceptable excipients.
- compositions according to the present invention can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions).
- any excipient known and widely used in the art can be used.
- carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
- disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.
- disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oils, etc.
- adsorption promoters such as lactose, white sugar, sodium chloride, glucose
- any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders, Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
- carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc
- binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
- disintegrants such as agar and kelp powder.
- the solution and suspension can be sterilized, and it is best to add an appropriate amount of sodium chloride, glucose or glycerin, etc., to make an injection that is isotonic with blood.
- any carriers commonly used in the art can also be used.
- usual dissolving agents, buffering agents and analgesics can also be added.
- the content of the JAK3/JAK1/TBK1 inhibitor of the present invention and methotrexate or its pharmaceutically acceptable salt in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually alone can be a mass percentage 1-45%, preferably 1-30% by mass.
- the present invention provides a medicine kit containing the above-mentioned pharmaceutical composition.
- the MTX and JAK3/JAK1/TBK1 inhibitors are unit preparations with the same or different specifications, respectively, and the preparations are not particularly limited and can be any preparations, especially those described in the present invention above. Dosage form.
- the MTX and JAK3/JAK1/TBK1 inhibitors are preferably provided in separate containers.
- the weight ratio of the MTX to the JAK3/JAK1/TBK1 inhibitor is 1:100 to 1:500.
- the MTX and JAK3/JAK1/TBK1 inhibitor are administered simultaneously, separately or sequentially.
- the present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating autoimmune diseases.
- the autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymph Tumor disease and so on.
- the present invention provides a method for treating autoimmune diseases, which includes the step of administering a therapeutically effective amount of the above-mentioned pharmaceutical composition or kit to a patient in need.
- composition and kit of the present invention can be prepared by conventional methods in the art.
- the autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic disease, chronic obstructive pulmonary disease, asthma, leukemia, lymph Tumor disease and so on.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a JAK3/JAK1/TBK1 inhibitor and methotrexate, which has a synergistic effect for autoimmune diseases including RA.
- the present invention also relates to a kit containing the pharmaceutical composition, so that the JAK3/JAK1/TBK1 inhibitor and methotrexate can be administered separately or simultaneously.
- the pharmaceutical composition or the kit according to the present invention can reduce a single drug dose, thereby reducing toxicity, reducing the patient's drug tolerance and reducing possible adverse reactions, and providing new and better drug options for autoimmune diseases.
- Figure 1 The efficacy of MTX and JAK3/JAK1/TBK1 inhibitors in the CIA rat model.
- Figure 2 H&E staining and microscopic observation of the sections of the knee joint (Figure 2A) and ankle joint (Figure 2B) of CIA rats after the administration.
- the present invention discloses the combination of MTX or its pharmaceutically acceptable salt and JAK3/JAK1/TBK1 inhibitor and its use in the treatment of autoimmune diseases including RA.
- SD rats Three-month-old male Sprague Dawley (SD) rats were purchased from Guangdong Medical Experimental Animal Center.
- Bovine type II collagen and incomplete Freund's adjuvant were purchased from Chondrex.
- JAK3/JAK1/TBK1 inhibitor N-(3-(5-chloro-2-(4-fluoro-3-(N-methacrylamido)phenylamino)pyrimidinyl-4-amino)propyl) -4-Cyanobenzamide, code CS12192) was synthesized by Shenzhen Microchip Biotechnology Co., Ltd.; methotrexate was purchased from Shanghai Yuanye Biotechnology Co., Ltd.
- Tissue fixative solution and EDTA decalcification solution were purchased from Salarbio.
- Hematoxylin and eosin staining solutions were purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd.
- test animals were numbered and divided into 5 groups, each with 8 animals, including the normal control group, model group, MTX group, CS12192 group and MTX+CS12192 group. Gavage was started on the day of the second immunization.
- the MTX group was given 0.2 mg MTX per kilogram of body weight once a day; the CS12192 group was given 40 mg per kilogram of body weight twice a day and CS12192; the MTX+CS12192 group was given 0.2 mg per kilogram of body weight per day.
- MTX once, and give 40mg CS12192 per kilogram of body weight twice a day.
- the front and back paws of each test animal were collected, fixed in tissue fixative for 24 hours, and 3 days after decalcification treatment, paraffin embedding and sectioning were performed, and the tissue was cut into 5 ⁇ m thick.
- the sections were deparaffinized and stained with H&E.
- the pathological changes of the knee joint and ankle joint tissues of the tested animals were observed under the microscope, including whether the synovial tissue was proliferated, whether inflammatory cells were infiltrated, and whether there was granulation tissue formation.
- the average inflammation scores of the two single-drug groups of MTX and CS12192 were 4.14 and 4, respectively.
- the P values were 0.027 and 0.018, respectively.
- MTX+CS12192 is the combination medication group.
- the average inflammation score at the end of the experiment is 1.86.
- the P value is 0.00010, indicating that the combination medication has a statistically significant improvement in the condition of CIA; while the combination medication group and MTX and MTX have a P value of 0.00010. Comparing the two single-drug groups of CS12192 (P values were 0.020 and 0.0093), there were still statistical or significant statistical differences.
- Figure 1B shows the changes in the weight of the animals recorded in the experiment. Due to the development of the disease, the average weight of the model group at the end of the experiment was significantly lower than that of the blank control group, and the average weight gain of each administration group was higher than that of the model group. improve.
- Figure 2 shows that the knee joints and ankle joints of each group of animals were collected after the administration, fixed, sliced and H&E stained, and then the pathological changes were observed under a microscope.
- Figure 2A is the knee joint
- Figure 2B is the ankle joint.
- significant disease changes can be observed in the model: synovial tissue abnormal proliferation, massive inflammatory cell infiltration and granulation tissue formation; CS12192 or MTX alone
- the improvement of the disease by the drug can be observed, but a certain amount of synovial tissue abnormal proliferation or inflammatory cell infiltration can still be found; while in the CS12192+MTX combined drug group, the pathological features of arthritis are basically not found.
- the combination of MTX and JAK3/JAK1/TBK1 inhibitors can achieve a significant synergistic effect that is superior to that of single drugs in collagen-induced arthritis rat models. There are no obvious side effects in animal models, and the safety is acceptable.
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Abstract
Description
Claims (10)
- 一种药物组合物,其特征在于,其包含JAK3/JAK1/TBK1抑制剂和甲氨蝶呤(MTX)或其药学上可接受的盐。A pharmaceutical composition characterized in that it comprises a JAK3/JAK1/TBK1 inhibitor and methotrexate (MTX) or a pharmaceutically acceptable salt thereof.
- 根据权利要求1所述的药物组合物,其特征在于,所述JAK3/JAK1/TBK1抑制剂为式(I)所示化合物或其立体异构体或其药学上可接受的盐:The pharmaceutical composition according to claim 1, wherein the JAK3/JAK1/TBK1 inhibitor is a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof:其中,in,R 1为卤素或C1-C6烷基; R 1 is halogen or C1-C6 alkyl;R 2为一个或多个取代基,所述取代基选自氢、羟基、氰基、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6的卤代烷基、C1-C6的烷基羰基和C1-C6烷基氨基; R 2 is one or more substituents selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane Carbonyl and C1-C6 alkylamino;R 3为氢或卤素; R 3 is hydrogen or halogen;R 4为氢或C1-C4烷基; R 4 is hydrogen or C1-C4 alkyl;X为NH、O或S;X is NH, O or S;Y为CO或S(O) 2; Y is CO or S(O) 2 ;Z为共价键、CH 2或(CH 2) 2; Z is a covalent bond, CH 2 or (CH 2 ) 2 ;n为1到4的整数;n is an integer from 1 to 4;环A为苯环、吡啶环或哌啶环。Ring A is a benzene ring, a pyridine ring or a piperidine ring.
- 根据权利要求2所述的药物组合物,其特征在于,所述JAK3/JAK1/TBK1抑制剂为N-(3-(5-氯-2-(4-氟-3-(N-甲基丙烯酰胺基)苯基氨基)嘧啶基-4-氨基)丙基)-4-氰基苯甲酰胺,其结构式如式(II)所示:The pharmaceutical composition according to claim 2, wherein the JAK3/JAK1/TBK1 inhibitor is N-(3-(5-chloro-2-(4-fluoro-3-(N-methylpropene) Amido)phenylamino)pyrimidinyl-4-amino)propyl)-4-cyanobenzamide, the structural formula of which is shown in formula (II):
- 根据权利要求1-4任一项所述的药物组合物,其特征在于,所述JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其药学上可接受的盐混合存在于所述药物组合物中或二者包含于所述组合物的不同部分,以使得JAK3/JAK1/TBK1抑制剂和甲氨蝶呤或其药学上可接受的盐可以同时或分开使用。The pharmaceutical composition according to any one of claims 1 to 4, wherein the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are mixed in the pharmaceutical composition Either or both are included in different parts of the composition, so that the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof can be used simultaneously or separately.
- 一种药盒,其特征在于,其包含治疗有效量的权利要求1-4中任一项所述的药物组合物。A kit, characterized in that it contains a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-4.
- 根据权利要求5所述的药盒,其特征在于,所述JAK3/JAK1/TBK1抑制剂与甲氨蝶呤或其药学上可接受的盐分别是具有相同或不同规格的单位制剂。The kit according to claim 5, wherein the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are unit preparations with the same or different specifications, respectively.
- 根据权利要求5-6任一项所述的药盒,其特征在于,所述JAK3/JAK1/TBK1抑制剂与甲氨蝶呤或其药学上可接受的盐分别置于单独容器中提供。The kit according to any one of claims 5-6, wherein the JAK3/JAK1/TBK1 inhibitor and methotrexate or a pharmaceutically acceptable salt thereof are provided in separate containers.
- 根据权利要求5-7任一项所述的药盒,其特征在于,按照JAK3/JAK1/TBK1抑制剂50mg/kg,以MTX计,甲氨蝶呤或其药学上可接受的盐0.1mg/kg~0.5mg/kg来确定所述药盒中提供的甲氨蝶呤或其药学上可接受的盐与JAK3/JAK1/TBK1抑制剂的用量。The kit according to any one of claims 5-7, wherein according to the JAK3/JAK1/TBK1 inhibitor 50mg/kg, in terms of MTX, methotrexate or its pharmaceutically acceptable salt 0.1mg/kg kg-0.5 mg/kg to determine the dosage of methotrexate or its pharmaceutically acceptable salt and JAK3/JAK1/TBK1 inhibitor provided in the kit.
- 根据权利要求1-4任一项所述的药物组合物或权利要求5-8任一项所述的药盒在制备治疗自身免疫性疾病的药物中的用途。Use of the pharmaceutical composition according to any one of claims 1 to 4 or the kit according to any one of claims 5-8 in the preparation of a medicament for the treatment of autoimmune diseases.
- 根据权利要求9所述的用途,其中所述自身免疫性疾病包括类风湿性关节炎、银屑病、克罗恩病、系统性红斑狼疮、多发性硬化症、Ⅰ型糖尿病、过敏性疾病、慢性阻塞性肺病、哮喘、白血病、淋巴瘤疾病。The use according to claim 9, wherein the autoimmune diseases include rheumatoid arthritis, psoriasis, Crohn’s disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, allergic diseases, Chronic obstructive pulmonary disease, asthma, leukemia, lymphoma disease.
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