CN101361968A - 白介素-22在治疗脂肪肝中的应用 - Google Patents
白介素-22在治疗脂肪肝中的应用 Download PDFInfo
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- CN101361968A CN101361968A CNA2007100445927A CN200710044592A CN101361968A CN 101361968 A CN101361968 A CN 101361968A CN A2007100445927 A CNA2007100445927 A CN A2007100445927A CN 200710044592 A CN200710044592 A CN 200710044592A CN 101361968 A CN101361968 A CN 101361968A
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Abstract
本发明公开了白介素－22在治疗脂肪肝中的应用，所述的用途可通过降低转氨酶水平实现。本发明还公开了白介素－22在降低转氨酶水平中的应用，通过这种应用可产生治疗脂肪肝的功效。
Description
技术领域
本发明涉及白介素-22(Interleukin-22)的医药用途。具体涉及白介素-22在制备治疗脂肪肝(Fatty liver disease，FLD)的组合物中的用途。
背景技术
脂肪肝(Fatty liver disease，FLD)是指肝细胞内脂肪堆积过多引起的肝脏病变。正常肝内脂肪占肝脏含量的3％—4％，当脂肪含量超过5％时，即为脂肪肝，严重的脂肪肝其脂肪含量高达40％—50％。脂肪肝的形成主要是由于肝脏脂肪代谢紊乱所致。而脂肪肝主要的脂肪是甘油三酯，它的特点是泡性脂肪变性(macvovesicular steatosis)。脂肪肝可以进一步引起肝纤维化(fibrosis)，和肝硬化(cirrhosis)和肝癌(hepatocellutar carcinoma)。在美国，大约31％的成年人用核磁共振方法(magnetic)诊断有脂肪肝，在中国大约有5.2％到11.4％患有脂肪肝。流行病学调查表明，越发达的地区，脂肪肝发病率越高。NAFLD在糖尿病人中发病率为50％，在肥胖病人中(体重指数BMI>30)高达三分之二。
脂肪肝可分为两种：一种是酒精性脂肪肝(Alcoholic fatty liverdisease，AFLD)，由于过量饮酒所引起(乙醇摄入量超过>20g/天)，长期和过量的乙醇在肝细胞代谢，其毒性代谢产物导致肝脏脂肪代谢紊乱而导致脂肪肝。酒精可以改变NADH/NAD+的氧化还原电位，从而抑制脂肪酸的氧化和三羧酸循环反应(tricarboxylicacid cycle)。其次，酒精可以在抑制肝脂肪氧化的同时还可以促进脂肪的合成。酒精还可以抑制PPAR α(peroxisomeproliferators-activated receptor-α)转录因子活化(You et al.2004，Am.J.Gastrointest.Liver Physiol.287：G1-G6)。第二种FLD是非酒精性脂肪肝(non-alcoholic fatty liver disease，NAFLD)，NAFLD包括非酒精性脂肪肝和非酒精性脂肪变性肝炎(steatohepatitis)。而非酒精性脂肪肝又分为肥胖性脂肪肝、糖尿病性脂肪肝、营养过剩和营养不良性脂肪肝、妊娠性脂肪肝、药物性脂肪肝、高脂血症脂肪肝、中老年脂肪肝、以及其他类型脂肪肝。在脂肪肝人中常见的脂肪肝合并症有：脂肪肝伴胆囊炎、脂肪肝伴胆石症、脂肪肝伴肥胖症、脂肪肝伴高血压、脂肪肝伴糖尿病、脂肪肝伴冠心病等合并症。
临床主要诊断采用，超声波，CT(Computerized tomography)和mRI扫描手段，肝组织活检(liver biopsy)。脂肪肝最普通的血清学指标是转氨酶活性升高，丙氨酸转氨酶Alanine transaminase(ALT)和草氨酸转氨酶Aspartale transaminase(AST)的升高。同时，碱性磷酸酶alkalinephosphatase/γ-glutamyl transferas(GGT)也可能升高。转氨酶升高指示肝脏代谢功能的降低，同时也可以作为脂肪肝的指针。
目前认为NAFLD的病因主要是由直接和间接的因素引起：直接的病因有：代谢综合症包括，胰岛素抵抗，脂肪代谢疾病等。间接的病因有：药物引起：比如，糖皮质激素类药物，激素，Tamoxifen，Methotrexate，zidouvdine，Aminodarone，ASA(水杨酸类)，四环素类，Didanosine，吗啡类Cocaine，Perhexilene，Hypervitaminosis A，Diltizem；毒素：蘑菇类毒素(Amanitaphalloides Lepiota)；石油化工类物质(Petrochemicals)；磷酸基类；Bacillus Cereus toxin；有机溶剂；间接性疾病引起：Lipodystrophy(脂肪代谢紊乱)，Dysbetalipoproteinemia，Weber-Christian disease，Wolman’s disease，妊娠性急性脂肪肝，Reye’s syndrome，自发性免疫疾病引起：如炎症性肠病(inflammatory Bowel disease IBD)，关节炎，红斑狼疮等.感染引起：病毒引起：HIV，HBV，细菌引起：急剧体重减轻，如：饥饿，gastric by pass，肠道手术。
目前临床主要治疗方法有：抗氧化，如维生素C，维生素E；甲硫氨酸(Methione)的代谢中的化合物，如甜菜碱(Betaine)；甲福明二甲双胍(Metformin)，它可增加对胰岛素敏感性，同类药物还有：噻唑烷二酮类药物(Thiazolidinediones TZD)，血管紧张素转移酶抑制剂(Angiotensin-converting Enzyme Inhibitors)，如血管紧张素II(AngiotensinII)受体的抑制剂；具有细胞保护，抗细胞凋亡，免疫调节功能的尿脱氧胆酸(Urodeoxycholic acid)；己酮可可碱(Pentoxifylline)可通过抑制炎症因子，比如肿瘤坏死因子(TNF α)的产生取得疗效；其他还有曲格列酮(Troglitazone)，咯格列酮(Rosiglitazone)，吡格列酮(Pioglitazone)。目前，所有的治疗方法对脂肪肝的疗效都不够理想。
白介素-22(Interleukin-22，IL-22)是一种T细胞分泌的糖蛋白，又名白介素10诱导的T细胞因子(IL-10-related T cell-derived induciblefactor，IL-TIF)。白介素22mRNA的表达最初证明在小鼠的IL-9刺激后的T细胞株和IL-9刺激的肥大细胞株(mast cells)，以及concanavalinA激活后的脾细胞。人白介素22mRNA的表达主要在外周自分离的T细胞并通过抗CD-3的抗体或ConA刺激。白介素22mRNA在激活后的NK细胞也有表达。活化的T细胞主要是CD4+，特别是由CD28通路的Th1细胞。
白介素-22由179个氨基酸残基组成，Dumoutier等最先报道了克隆小鼠和人的白介素-22基因(Dumoutier，et al，JI，164：1814-1819，2000)。此外，Dumoutier还取得了IL-22的专利(US专利号6,359,117和6,274,710)。Gurney也取得了IL-22在治疗人胰腺病变方面的应用专利(US专利号6,551,799)。
白介素-22主要在胸腺、大脑、活化的T细胞和肥大细胞、lectin刺激后的脾细胞(Duroutier JI 2002)、白介素-2/白介素-12刺激后的NK细胞(Wolk，K JI 2002)，以及LPS刺激后的多个器官和组织中表达(Dumoutier PNAS paper)，包括肠道，肝，胃，肾，肺，心脏，胸腺，脾都可测到IL-22的表达升高。
IL-22通过结合IL-22RI受体和IL-10R2受体，发挥生物学功能。IL-22R1是IL-22特异的受体，它表达在皮肤，肾，消化系统(胰腺，小肠，肝，大肠，结肠)以及呼吸系统(肺，支气管)。以公开的研究表明，白介素22是一个免疫调节剂。
目前并未发现白介素-22可以在治疗脂肪肝中发挥积极的作用。
发明内容
本发明旨在提供白介素-22在治疗脂肪肝中的新用途。
本发明的第二个目的是提供白介素-22在降低转氨酶水平中的作用。
在本发明的第一方面，提供了一种白介素-22在制备用于治疗脂肪肝的组合物中的用途。
在另一优选例中，所述的组合物还用于降低转氨酶水平。
在另一优选例中，所述的组合物包括药物组合物或保健品组合物。
在另一优选例中，所述的白介素-22包括哺乳动物白介素-22、和/或重组哺乳动物白介素-22。
在另一优选例中，所述的脂肪肝包括酒精性脂肪肝、和/或非酒精性脂肪肝。
在另一优选例中，所述的组合物包括选自下组的额外组分：具有减肥功能、减低血脂或降血糖的提取物或化合物，炎症性细胞因子(inflammatorycytokines)的抑制剂和抗体药物，增加糖和脂肪代谢的激素，调节代谢的蛋白因子，或其混合。
在另一优选例中，所述的具有减肥功能、减低血脂或降血糖的物质(提取物或化合物)包括茶叶提取物、他汀类化合物(如辛伐他汀、普伐他汀、洛伐他汀)、抗氧化类药物、胰岛素增敏类药物、血管紧张素转移酶抑制剂、和/或免疫调节功能类药物。
在另一优选例中，所述的调节代谢的蛋白因子包括胰岛素，胰高糖素(glucagon)，瘦素(leptin)，和/或脂联素(adiponectin)等。
在另一优选例中，所述的组合物选自：粉剂、颗粒剂、胶囊剂、注射剂、酊剂、口服液或片剂。
在本发明的第二部分，提供了一种白介素-22在制备降低转氨酶水平的组合物中的用途。
在另一优选例中，所述的组合物还可用于治疗脂肪肝。
据此，本发明提供了白介素-22在治疗脂肪肝中的积极作用。
附图说明
图1显示了人白介素-22的mRNA序列。
图2显示了小鼠白介素-22的mRNA序列.
图3显示了人白介素-22的蛋白质序列。
图4显示了小鼠白介素-22的蛋白质序列。
图5显示了白介素-22对肥胖小鼠ob/ob小鼠血清中转氨酶水平的影响。
图6显示了白介素-22对治疗非酒精性脂肪肝的作用；
其中A为注射载体溶液(对照组)的肥胖小鼠ob/ob组织切片用苏木精-曙红(hematoxylin-eosin)的染色结果，B为注射IL-22(IL-22治疗组)的肥胖小鼠ob/ob组组织切片用苏木精-曙红的染色结果。
图7显示了白介素-22对治疗酒精诱导的脂肪肝的作用；
其中A为注射载体溶液(对照组)的小鼠肝组织切片用“油红0”方法染色的结果，A为注射IL-22(IL-22治疗组)的小鼠肝组织切片用“油红0”方法染色的结果。
具体实施方式
发明人经过深入的研究，发现无论对于酒精性脂肪肝还是非酒精性脂肪肝，白介素-22都有积极的治疗效果；发明人还发现白介素-22能有效降低血清中转氨酶的水平。
如本文所用，术语“组合物”包括(1)治疗脂肪肝的组合物和/或(2)降低转氨酶水平的组合物。
如本发明所用，“白介素-22”是指一种蛋白质，该蛋白质(a)具有与Dumoutier等人在US Patent No.359,117中描述的人/鼠白介素-22基本相同的氨基酸序列和(b)具有与天然白介素-22相同的生物学活性。本发明的白介素-22包括，但不限于：人白介素-22、重组人白介素、鼠白介素-22和/或重组鼠白介素-22。
术语“氨基酸序列基本相同”是指序列相同或由一个或多个氨基酸改变(缺失、增加、取代)引起的不同，但这种改变基本上不降低其生物学活性，即可以通过结合IL-22靶细胞受体而发生生物学功能。任何符合“基本相同”要求的白介素-22均包括在本发明内，无论它是糖基化的(即来源于天然的或来源于真核生物表达系统的)或是非糖基化的(即来源于原核生物表达系统或化学合成的)。
术语“治疗”是指基于治愈、缓解、改善、减轻、影响治疗对象疾病、症状、疾病体质(predisposition)的目的而给予需要治疗的对象本发明的白介素-22。
术语“治疗对象”是指鼠、人及其他哺乳动物。
术语“治疗有效量”是指能够在治疗对象体内达到治疗目的的白介素-22的量。本领域的普通技术人员应理解，所述“治疗有效量”可随白介素-22的给药途径、所用药物辅料以及与其他药物联合用药情况的不同而有所不同。
本发明的白介素-22是用基因重组技术克隆表达的。表达的宿主细胞包括原核细胞、酵母细胞或者高等真核生物细胞。适用的原核宿主细胞包括，但不限于：G+或G-菌，如大肠杆菌E.coli.，能够通过公共途径得到的E.coli.菌株包括：K12 MM294(ATCC 31，446)、X1776(ATCC 31，537)、W3110(ATCC27，325)和K5 772(ATCC 53，635)等。其他可用的原核细胞包括但不限于：欧式杆菌(Erwinia)、克雷伯杆菌(Klebsiella)、变形杆菌(Proteus)、沙门杆菌(Salmonella)如鼠伤寒杆菌(Salmonella typhimurium)、沙雷菌属(Serratia)如粘质沙雷菌(Serratia marcescans)、志贺菌属(Shigella)、枯草杆菌.(B.subtilis)、地衣芽胞杆菌(B.licheniformis)、假单胞菌属(Pseudomonas)如绿脓杆菌(P.aeruginosa)、链球菌(Streptomyces)。E.coli.W3110因其常被用作重组DNA产品的发酵宿主而被推荐为优选。
除了原核细胞，真核细胞如丝状真菌(filamentous fungi)或酵母菌(yeast)等同样适用于表达或者克隆本发明的白介素-22。酿酒酵母菌(Saccharomyces)就是一种常用的低等真核宿主微生物，其他宿主如非洲粟酒裂殖酵母菌(Schizosaccharomyces pombe)(Beach and Nurse，Nature，290：140[1981]；EP 139，383)；克鲁维酵母菌(Kluyveromyces hosts)(U.S.Pat.No.4，943，529；Flee et al.，Bio/Technology，9：968-975(1991))如K.lactis(MW98-8C，CBS683，CBS4574；Louvencourt et al.，J.Bacteriol.，154(2)：737-742[1983])，K.fragilis(ATCC12，424)，K.waltii(ATCC56，500)，K.drosophilarum(ATCC 36，906；Van den Berg et al.，Bio/Technolog，8：135(1990))，K.thermotolerans，K.marxianus；yarrowia(EP 402，226)；巴氏毕赤酵母菌(Pichia Pastoris)(EP 183.070；Sreekrishnaet al.，J.Basic Microbiol.，28：265-278[1988])；念珠菌(Candida)；Trichoderma reesia(EP 244,234)；脉胞菌(Neurospora crassa)(Case etal.，Proc.Natl.Acad.Sci.USA，76：5259-5263[1979])；施万异样霉菌(schwanni omyces)如Schwanniomyces occidentalis(EP 394,538)；丝状真菌(filamentous fungi)如Neurospora，青霉菌(Penicillium)，Tolypocladium(WO 91/00357)，曲霉菌(Aspergjllus)如A.nidulans(Balanceet al.，Biochem.Biophys.Res.Commum.，112：284-289[1983]；Tilburm etal.，Gene，26：205-221[1983]；Yelton et al.，Proc.Natl.Acad.Sci.USA，81：1470-1474[1984])和黑曲霉(A.niger)(Kelly and Hynes，EMBO J.，4：475-479[1985])。甲基营养酵母菌(Methylotropic yeasts)同样可用于表达本发明的白介素-22，包括但不限于各种能够在甲醇中生长的酵母菌如汉逊酵母菌(Hansenula)，念珠菌(Candida)，克勒克酵母菌(kloeckera)，毕赤酵母菌(Pichia)，酿酒酵母菌(Saccharomyces)，球拟酵母菌(Torulopsis)，红酵母菌(Rhodotorula)。属于甲基营养酵母菌类的典型菌种参见C.Anthony，The Biochemistry of Methylotrophs，269(1982)。
用于表达糖基化的本发明的白介素-22的宿主细胞来源于多细胞有机体。无脊椎动物细胞的例子包括昆虫细胞如Drosophila S2和Spodoptera Sf9，植物细胞。适用的哺乳动物宿主细胞的例子包括中华仓鼠卵巢细胞(CHO)，COS细胞。特别是，经SV40转化的猴肾CV1细胞株(COS-7，ATCC CRL 1651)；人胚胎肾细胞株293(Graham et al.，J.Gen Virol.，36：59(1977))；CHO/-DHFR(Urlaub and Chasin，Proc.Natl.Acad.Sci.USA，77：4216(1980))；小鼠睾丸滋养细胞(TM4，Mather，Biol.Reprod.，23：243-251(1980))；人肺细胞(WI38，ATCC CCL 75)；人肝细胞(Hep G2，HB 8065)；小鼠乳腺癌细胞(MMT 060562，ATCC CCL5 1)。本领域的普通技术人员应知如何选择合适的宿主细胞。
上述宿主细胞经白介素-22表达载体或克隆载体转染或者转化后可在传统的营养基(nutrient media)中培养，所述营养基经修饰后适于诱导启动子(promoter)、选择性转化体(selecting transformant)或者扩增白介素-22编码基因序列。培养条件如培养基、温度、pH等的选择对本领域的普通技术人员来说则是应知的。如何使细胞培养繁殖力最大化的一般原则、方案以及操作技术可参见Mammalian Cell Biotechnology：a Practical Approach，M.Butler，cd.(IRL Press，1991)and Sambrook et al.，supra.。
本领域的普通技术人员应熟知真核细胞转染和原核细胞转化的方法，例如CaCl2法、磷酸钙沉淀法、脂质体媒介法或电穿孔法。根据使用的宿主细胞的不同，本领域的普通技术人员可选择相应的标准转化技术，例如CaCl2法(Sambrooket al.，supra.)或电穿孔法通常用于原核细胞；根癌农杆菌(Agrobacteriumtumefaciens)感染主要用于某些植物细胞的转化(Shaw et al.，Gene，23：315(1983)and WO 89/05859)；对于没有细胞壁的哺乳动物细胞，则可以使用磷酸钙沉淀法(Graham and van der Eb，Virology，52：456-457(1978))；有关哺乳动物宿主细胞转染的全面描述可参见U.S.Pat.N..4,399,216。有关如何转化酵母细胞可参见Van Solingen et al.，J.Bact.，130：946(1977)和Hsiao et al.，Proc.Natl.Acad.Sci.(USA)，76：3829(1979).。其他将DNA引入细胞的方法，如核酸微量注射、电穿孔、完整细菌细胞原生质体融合(bacterial protoplast fusion with intact cells)、或者聚阳离子法(polycations)如1，5-二甲基-1，5-二氮十一亚甲基聚甲溴化物(polybrene)、聚鸟氨酸(polyornithine)等皆可用于本发明中。有关各种哺乳动物细胞转化技术的描述可参见Keown et al.，Methods in Enzymology，185：527-537(1990)和Mansour et al.，Nature，336：348-352(1988)。
编码本发明的白介素-22的核苷酸序列(即cDNA或基因组DNA)可被插入一可复制载体(replicable vector)进行基因克隆(DNA扩增)或者表达。各种载体如质粒、粘粒(cosmid，装配型质粒)、病毒颗粒或噬菌体等均可通过公共途径获得。运用本领域的公知技术，可将本发明的白介素-22的编码核苷酸序列按常规步骤插入可复制载体上适宜的限制性核酸内切酶位点。一个可复制载体通常包括但不限于以下部件：一条或多条信号序列(signal sequence)，一个复制起点(origin of replication)，一条或多条标记基因(marker gene)，一个增强子元件(enhancer element)，一个启动子(promoter)，以及一段转录中止序列(transcription termination sequence)。本领域的普通技术人员可运用本领域标准的连接技术(ligation techniques)构建含有一个或多个上述部件的合适的可复制载体。
本发明的白介素-22不但可以通过基因重组直接表达，也可以通过与异种多肽形成融和多肽的方式生产，后者可以是一段位于成熟蛋白质或多肽N端的信号序列，也可以是位于成熟蛋白质或多肽N端的具有特异性切割位点的其他多肽片段。通常情况下，这段信号序列是上述可复制载体的一部分，或者它也可以是插入可复制载体的本发明的白介素-22编码核苷酸序列的一部分。所述信号序列可以是原核信号序列，例如碱性磷酸酶，青霉素酶，lpp，或者热稳定肠毒素II前导序列。在酵母分泌系统(yeast secretion)中，该信号序列可以是酵母转化酶前导序列(yeast invertase leader)，α因子前导序列(包括酿酒酵母菌和克鲁维酵母菌α因子前导序列，参见U.S.Pat.No.5,010,182)，或酸性磷酸酶前导序列，C.albicans葡萄糖淀粉酶前导序列(EP 362,179)。在哺乳动物表达系统中，哺乳动物信号序列可直接用于分泌目标蛋白质，此类序列包括来源于相同或相近物种哺乳动物分泌蛋白的信号序列以及病毒分泌前导序列。
表达载体和克隆载体均含有一段核苷酸序列，该序列使载体能够在一个或多个相应的宿主细胞内复制。与各种细菌、酵母或病毒宿主细胞对应的核苷酸序列为本领域普通技术人员所公知。例如，质粒pBR322的复制起点适用于大多数G细菌，2.mu.质粒复制起点适用于酵母细胞，而各种病毒复制起点(SV40，多形瘤病毒，腺病毒，VSV或BPV)则适用于哺乳动物细胞内的克隆载体。
表达载体和克隆载体通常含有一段选择基因，又名“选择标记”。典型的选择基因编码产生的蛋白质(a)对某些抗生素或毒素如氨苄青霉素，新霉素，氨甲蝶呤，四环素等具有抗性；(b)能弥补营养缺陷型缺乏(auxotrophicdeficiencies)(c)补充复合型培养基不能提供的关键营养物质如杆菌宿主细胞需要的D-丙氨酸消旋酶的编码基因。
适用于哺乳动物宿主细胞的选择基因应该可以将有能力吸纳本发明的白介素-22编码基因的宿主细胞区分出来，如DHFR或胸(腺嘧啶核)苷激酶。适用的以野生型DHFR为选择基因的宿主细胞是无DHFR活性的CHO细胞株，该细胞株的制备及繁殖方法可参见Urlaub et al.，Proc.Natl.Acad.Sci.USA，77：4216(1980)。适用于酵母细胞的选择基因是在酵母质粒Yrp7中表达的trpl基因(Stinchcomb et al.，Nature，282：39(1979)；Kingsman et al.，Gene，7：141(1979)；Tschemperet al.，Gene，10：157(1980))。trpl基因可用于筛选不能在色氨酸中生长的酵母菌突变株如ATCC No.44047或PEP4-1(Jones，Genetics，85：12(1977))。
表达载体和克隆载体通常含有一个可人工操纵地连接到本发明的白介素-22编码核苷酸序列上的启动子，以指导mRNA的合成。与各种宿主细胞对应的启动子为本领域普通技术人员所公知。适用于原核宿主细胞的启动子包括β-内酰胺酶和乳糖启动子系统(Chang et al.，Nature，275：615(1978)；Goeddelet al.，Nature，281：544(1979))，碱性磷酸酶，色氨酸(trp)启动子系统(Goeddel，Nucleic Acids Res.，8：4057(1980)；EP 36,776)，杂合启动子如tac启动子(deBoer et al.，Proc.Natl.Acad.Sci.USA，80：21-25(1983))。细菌宿主细胞启动子同样包含一段可人工操纵地连接到本发明的白介素-22编码基因序列的Shine-Dalgarno(S.D.)序列。
适用于酵母宿主细胞的启动子序列包括3-磷酸甘油酸激酶启动子(Hitzeman et al.，J.Biol.Chem.，255：2073(1980))或其他糖酵解酶的启动子(Hess et al.，J.Adv.Enzvme Reg.，7：149(1968)；Holland，Biochemistry，17：4900(1978))，如烯醇化酶，甘油醛-3-磷酸脱氢酶，己糖激酶，丙酮酸脱羧酶，果糖磷酸激酶，葡糖-6-磷酸异构酶，3-磷酸甘油酸变位酶，丙酮酸激酶，丙糖磷酸异构酶，葡糖磷酸异构酶，和葡糖激酶。
还有一些可诱导的酵母启动子，它们能更好地根据生长情况来调节转录，包括醇脱氢酶2，异细胞色素C，酸性磷酸酶，氮素代谢相关降解酶，金属硫蛋白，甘油醛-3-磷酸，麦芽糖和半乳糖代谢酶等的启动子。有关适用于酵母表达系统的载体和启动子的进一步描述参见EP 73,657。
启动子可以控制哺乳动物宿主细胞内可复制载体上本发明的白介素-22编码基因序列的转录。所述启动子包括来自于多形瘤病毒，禽痘病毒(UK2,211,504)，腺病毒，牛乳头(状)瘤病毒，禽类肉瘤病毒，巨细胞病毒，逆转录病毒，乙肝病毒，或猿猴空泡病毒(SV40)等病毒基因组的启动子，来自于异种哺乳动物的启动子如肌动蛋白启动子或免疫球蛋白启动子，以及来自于热休克蛋白的启动子，前提是这些启动子同宿主细胞表达体系相容。
通过在可复制载体中插入增强子可增强本发明的白介素-22的编码核苷酸序列在高等真核生物表达体系中的转录。增强子是一种DNA分子的顺式作用元件，通常为10到300个bp，通过作用于启动子而增强DNA分子的转录。目前已知很多增强子序列来自于哺乳动物基因(珠蛋白，弹性蛋白酶，白蛋白，α-胎蛋白，胰岛素)。而使用较多的是来自于真核病毒细胞的增强子，如位于复制起点下游(late side)的SV40增强子(100-270bp)，巨细胞病毒早期启动子增强子，位于复制起点下游的多形瘤病毒增强子，腺病毒增强子。增强子可被剪切插入位于可复制载体上的本发明的白介素-22的编码核苷酸序列的5’端或3’端，优选位于启动子的5’端。
真核宿主细胞(酵母细胞、真菌细胞、昆虫细胞、植物细胞、动物细胞、人类细胞，或者来源于其他多细胞有机体的有核细胞)中的表达载体同样含有中止转录和稳定mRNA所需的核苷酸序列。此类序列通常取自真核或者病毒DNA或cDNA非翻译区的5’端，有时也可取自3’端。所述“非翻译区”包含的核苷酸片段可转录产生位于本发明的白介素-22 mRNA非翻译区的聚腺苷酰化片段。
其他可在重组脊椎动物培养体系中用于合成本发明的白介素-22的方法、载体和宿主细胞可参见Gething et al.，Nature，293：620-625(1981)；Manteiet al.，Nature，281：40-46(1979)；EP 117,060；以及EP 117,058。
用途
白介素-22可用作治疗脂肪肝的组合物中的活性成分。所述的白介素-22可包括哺乳动物白介素-22、和/或重组哺乳动物白介素-22，或其混合。优选地，包括人白介素-22、重组人白介素、鼠白介素-22和/或重组鼠白介素-22。
组合物中的活性成分除了上述的白介素-22，还可以含有有助于治疗脂肪肝的额外组分，例如炎症性细胞因子(inflammatory cytokines)的抑制剂和抗体药物，增加糖和脂肪代谢的激素，和/或调节代谢的蛋白因子如:胰岛素，胰高糖索(glucagon)，瘦素(leptin)，脂联素(adiponectin)等。
在本发明的组合物中，还可以包括其它具有减肥功能、减低血脂或降血糖的物质(提取物或化合物)，例如茶叶提取物、他汀类化合物(如辛伐他汀、普伐他汀、洛伐他汀)、抗氧化类药物、胰岛素增敏类药物、血管紧张素转移酶抑制剂、和/或免疫调节功能类药物。
本发明白介素-22还可用作降低转氨酶水平的组合物中的活性成分。所述的白介素-22可包括哺乳动物白介素-22、和/或重组哺乳动物白介素-22，或其混合。优选地，包括人白介素-22、重组人白介素、鼠白介素-22和/或重组鼠白介素-22。
本发明的降低转氨酶水平的组合物中还可以包括其它具有降低转氨酶水平作用的物质。
本发明的白介素-22的编码核苷酸序列可被应用于基因治疗中。在基因治疗过程中，基因被导入细胞中以期在体内合成具有治疗效果的基因表达产物，比如替代原有的缺陷基因。“基因治疗”包括传统的基因疗法，即通过一次治疗而长期有效；也包括给予基因治疗药物，后者包括一次或者多次地给予有效的DNA或者mRNA。反义RNA和DNA亦可被用作基因治疗药物以阻断体内某些基因的表达。业已证实，尽管反义寡核苷酸短片段被细胞膜吸收有限，导致其胞内浓度降低，它仍然可以在细胞内发挥抑制剂的作用(Zamecnjk et al.，Proc.Natl.Acad.Sci.USA 83：4143-4146[1986]))所述寡核苷酸片段经修饰例如用不带电荷的基团取代其带负电荷的磷酸二酯基团后，可提高其细胞膜吸收度。
本发明的白介素-22可被用作治疗药物。本领域的普通技术人员可按本领域的常规方法将其制备成各种药学上有效的制剂(formulation)，其中包含有效量的白介素-22和药学上可接受的载体。
当制成冻干制剂或溶液剂时，本发明的药物组合物中还需要加入其他一些生理上可接受的载体、赋形剂、稳定剂等以便于储存(Remington’sPharmaceutical Sciences16th edition，Osol，A.Ed.(1980))。所述“生理上可接受”的载体、赋形剂、稳定剂等其药用剂量和浓度应对给药对象(人、鼠及其他哺乳动物)无毒，包括缓冲剂如磷酸盐、柠檬酸盐及其他有机酸；抗氧化剂如抗坏血酸(Vit C)；低分子量(少于10个氨基酸残基)多肽；蛋白质如血清白蛋白，明胶或免疫球蛋白；亲水聚合物如聚乙烯吡咯烷酮(PVP)，氨基酸如氨基乙酸、谷氨酸盐、天冬酰胺酸、精氨酸或赖氨酸；单糖、二糖和其他碳水化合物如葡萄糖、甘露糖或糊精；鳌合剂如EDTA；糖醇(sugaralcohols)如甘露醇、山梨醇；成盐抗衡离子(counterions)如钠离子；和/或非离子型表面活性剂如TWEEN.TM.，PLURONICS.TM.或PEG.等。
含有本发明的白介素-22的制剂在体内给药前必须经过灭菌。该步骤可在冻干和再组成(reconstitution)之前或之后借助灭菌过滤膜(sterilefiltration membranes)过滤完成。
本发明的药物组合物通常被置于一配备有“灭菌入口”(sterile accessport)的容器中，例如，一个有瓶塞的静脉溶液瓶，所述塞子可被皮下注射针穿透。
本发明的药物组合物可按本领域的常规途径给药，包括但不限于：静脉注射或输注、腹腔注射、脑内注射、肌内注射、眼内注射、动脉注射或输注、局部给药或者通过缓释系统(sustained release systems)给药。
本发明的药物组合物的剂量和浓度范围可因实际使用情况的不同而变化。本领域的普通技术人员应知如何根据实际需求去选择合适的剂量和给药途径。本发明人所做的动物实验已为白介素-22在人体的用量范围提供了一个可信的指导，例如，重组鼠白介素-22在剂量大于30ug/kg/d时可见显著的降血脂效果，并呈量效关系(实施例3)。对于不同种系，例如人和鼠之间药物剂量范围的调整原则，可参见Mordenti，J.and Chappell，W.“The use ofinterspecies scaling in toxicokinetics”In Toxicokinetics and New DrugDevelopment，Yacobi et al.；Pergamon Press，New York 1989，pp.42-96.。
当本发明的白介素-22体内给药时，其通常剂量范围为每天1ng/kg—100mg/kg哺乳动物体重，优选范围10ug/kg/d—100ug/kg/d，根据给药途径的不同而有所不同。对于某些特定剂量和给药方法的指导参见U.S.Pat.Nos.4657760；5206344；或5225212。可以预见的是，不同的白介素-22制剂将对不同的病种有效；当药物作用靶点(器官或组织)发生变化时，给药方式也需要做相应的调整。
含有本发明的白介素-22的微胶囊可用于本发明的白介素-22的缓释给药。重组蛋白的微囊缓释给药技术已成功应用于重组人生长激素(rhGH)、重组人干扰素(rhIFN)、白介素-2和MNrgp120(Johnson et al.，Nat.Med.，2：795-799(1996)；Yasuda，Biomed.Ther 27：1221-1223(1993)；WO 97/03692，WO96/40072，WO 96/07399；U.S.Pat.No.5654010。
本发明的白介素-22的缓释制剂可用具有良好生物兼容性和宽泛生物可降解性的乳酸羟基乙酸高聚物(PLGA)制备。PLGA的降解产物，乳酸和羟基乙酸可被人体很快清除。而且，该高聚物的降解能力可随其分子量和组成的不同，从几个月延长到几年(Lewis，“Controlled release of bioactive agents formlactide/glycolide polymer，”in：M.Chasin and R.Langer(Eds.)，Biodegradable Polymers as Drug Delivery Systems(Marcel Dekker：New York，1990)，pp.1-41))。
本发明的白介素-22还可用各种活化的分子量为5,000—100,000的聚乙二醇(PEG)修饰以使之高分子化，延长其半衰期。具体操作可参见Greenwald etal.，Bioorg.Med.Chem.Lett.1994，4，2465；Caliceti et al.，IL Farmaco，1993，48，919；Zalipsky and Lee，《聚乙二醇化学：生物技术与生物医学应用》，J.M.Harris编，Plenum Press，N.Y.，1992。优选使用多臂树权型活性PEG(CN ZL02101672.0，WO9932139，PCT/US95/0755，PCT/US94/13013，US Pat：4,640,835，4,496,689，4,301,144，4,670,417，4,791,192，4,179,337)。
本发明的IL-22还可以做成嵌合分子(Chimeric Molecule)或融合蛋白(Fusion Protein)从而增强其生物学活性或延长其体内的生物半衰期。比如与人的整个和部分免疫球蛋白基因(Fc)相连进行表达。IL-22的部分可以用整个或部分IL-22cDNA序列。生产表达Fc融合蛋白可见US Pat：5,428,130。IL-22基因可以放在Fc的N-末端，也可以放在Fc的C-末端进行表达。
共价修饰的IL-22蛋白质也包括在本发明内。化学共价修饰包括改变N-末端或C-末端或其他氨基酸加上一个化学分子。这种修饰也包括改变IL-22的氨基酸序列。改变IL-22本身的糖基化状态(Glycosalytion)，包括增加糖基化或减少糖基化，或者直接通过化学反应改变糖基化状态，比如专利WO87/05330。
其他制剂技术如纳米制剂(US60/544,693)、喷雾剂(CN00114318.2，PCT/CN02/00342)、吸入剂等同样包括在本发明的保护范围之内。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
本发明的主要优点在于：
1、白介素-22具有明显的治疗脂肪肝的作用。
2、白介素-22具有明显的降低转氨酶水平的作用。
下面将结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆:实验室手册(New York：Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则所有的百分比和份数按重量计。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
人和小鼠白介素-22基因克隆
人白介素-22基因的克隆：取正常人的外周血单核细胞，用anti-CD3mAb刺激并培养过夜。提取tRNA的方法采用超速离心法。cDNA通过用dT为引物合成。人白介素-22基因用引物包括有意义链(5’-GCAGAATCTGAACAGGTTC-3’)和反意义链(5’-GGCATCTAATTGTTATTTCTAG-3’)，进行PCR扩增。扩增后的人白介素-22的DNA再克隆到大肠杆菌表达载体。
小鼠白介素-22基因的克隆：C57BL/6雌性小鼠，注射LPS(5mg/kg，sc)，20小时后取脾，抽取RNA。CDNA通过用dT引物合成。小鼠白介素-22用引物包括有意义链(5’-CTCTCACTTATCAACTGTTGAC-3’)和反意义链引物(5’-GATGATGGACGTTAGCTTCTCAC-3’)，进行PCT扩增后再克隆到大肠杆菌表达载体pET21(+)。
人和小鼠白介素-22基因通过DNA测序确认无误，见图1和2。
实施例2
人和鼠白介素-22蛋白的表达
大肠杆菌BL21(E.Coli)用来表达重组蛋白。大肠杆菌在高压下用匀浆破坏。含白介素-22的包含体以离心方法获得。包含体在缓冲液体(含50mMTris-HCl pH 8.0，NaCl 100mM，EDTA 1mM，DTT 1mM，Sodium Deoxycholate 0.5％)中充分洗涤。包含体进一步在8M尿素，50mM Mes，10mM EDTA和0.1mM DTT，PH 6.5中溶解。溶解后的包含体在100mM Tris HCL，2mM EDTA，0.5m L-arginine，1mM还原型谷胱甘肽，0.1mM氧化型谷胱甘肽，PH8.0还原复位20小时4次。然后经过浓缩，并进一步在Superdex75(Amersham)柱层析纯化。重组后的蛋白质用Tris-HCl 20mM、NaCl 50mM PH 7.0洗脱。白介素-22的纯度用SD3-PAGE胶染色(纯度>95％)，见图3和4。并定量分装在-80℃保存。
实施例3
重组白介素-22降低肥胖小鼠ob/ob小鼠血清中转氨酶的水平
取8—12周的肥胖小鼠ob/ob，体重范围35—50g，连续注射实施例2制得的重组白介素-22，300ug/kg/d，14天，对照组小鼠注射相同体积的载体溶液(0.1％BSA，PBS)。在第15天时将实验动物处死，取血清，测定血中丙氨酸转氨酶(ALT)和草氨酸转氨酶(AST)的活性。结果见图5所示。
结果表明，注射IL-22可明显降低血清中甘油三酯浓度的同时，显著降低血清中AST，ALT酶的活性。
实施例4
重组白介素-22对治疗肥胖小鼠ob/ob(非酒精性的)脂肪肝的作用
取8—12周的肥胖小鼠ob/ob，体重范围35—50g，IL-22治疗组小鼠连续注射实施例2制得的重组白介素-22，300ug/kg/d，14天；对照组小鼠注射相同体积的载体溶液(0.1％BSA，PBS)。在第15天时将实验动物处死，取肝脏在10％甲醛中固定，进行病理分析。组织切片用苏木精-曙红(hematoxylin-eosin)染色。结果见图6所示。
结果表明，注射载体溶液的肥胖小鼠ob/ob组可见明显的脂肪变性和脂肪肝变。而注射IL-22的肥胖小鼠ob/ob组可显著地降低肝脏的脂肪变性的程度。显示出白介素-22对非酒精性脂肪肝明显的治疗作用。
实施例5
重组白介素-22对治疗酒精诱导的脂肪肝的作用
取C57BC/6小鼠，周龄8-12周。用液体饲料喂养(Lieber.et al.1989，Hepatology 10：501-510)，液体饲料含蛋白质20％，10％脂肪，碳水化合物45％。乙醇25％饲养(百分比以总热量计算)。小鼠喂养2-3周后：动物随机分为两组：一组是对照组，注射相同体积的载体溶液(0.1％BSA，PBS)；一组为IL-22治疗组，注射实施例2制得的重组小鼠IL-22蛋白300ug/kg/d。2周后处死动物。取小鼠肝脏进行病理分析，肝组织切片用“油红O”方法染色，结果见图6所示。
结果表明，重组白介素-22对治疗小鼠酒精诱导的脂肪肝有显著的作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种白介素-22在制备用于治疗脂肪肝的组合物中的用途。
2.如权利要求1所述的用途，其特征在于，所述的组合物还用于降低转氨酶水平。
3.如权利要求1所述的用途，其特征在于，所述的组合物包括药物组合物或保健品组合物。
4.如权利要求1所述的用途，其特征在于，所述的白介素-22包括哺乳动物白介素-22、和/或重组哺乳动物白介素-22。
5.如权利要求1所述的用途，其特征在于，所述的脂肪肝包括酒精性脂肪肝、和/或非酒精性脂肪肝。
6.如权利要求1所述的用途，其特征在于，所述的组合物包括选自下组的额外组分：具有减肥功能、减低血脂或降血糖的提取物或化合物，炎症性细胞因子的抑制剂和抗体药物，增加糖和脂肪代谢的激素，调节代谢的蛋白因子，或其混合。
7.如权利要求6所述的用途，其特征在于，所述的具有减肥功能、减低血脂或降血糖的提取物或化合物包括茶叶提取物、他汀类化合物、抗氧化类药物、胰岛素增敏类药物、血管紧张素转移酶抑制剂、和/或免疫调节功能类药物；所述的调节代谢的蛋白因子包括胰岛素，胰高糖素，瘦素，和/或脂联素。
8.如权利要求1所述的用途，其特征在于，所述的组合物选自：粉剂、颗粒剂、胶囊剂、注射剂、酊剂、口服液或片剂。
9.一种白介素-22在制备降低转氨酶水平的组合物中的用途。
10.如权利要求9所述的用途，其特征在于，所述的组合物还可用于治疗脂肪肝。
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| EP20080797018 EP2185202B1 (en) | 2007-08-06 | 2008-08-01 | Use of interleukin-22 in the treatment of fatty liver disease |
| AU2008284116A AU2008284116B2 (en) | 2007-08-06 | 2008-08-01 | Use of interleukin-22 in the treatment of fatty liver disease |
| CA2695734A CA2695734C (en) | 2007-08-06 | 2008-08-01 | Use of interleukin-22 in the treatment of fatty liver disease |
| JP2010520208A JP5546453B2 (ja) | 2007-08-06 | 2008-08-01 | 脂肪肝疾患の治療におけるインターロイキン−２２の使用 |
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| US12/672,274 US20110262385A1 (en) | 2007-08-06 | 2008-08-01 | Use of interleukin-22 in the treatment of fatty liver disease |
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| US15/694,670 US10786551B2 (en) | 2007-08-06 | 2017-09-01 | Use of interleukin-22 in the treatment of fatty liver disease |
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2007
- 2007-08-06 CN CN2007100445927A patent/CN101361968B/zh active Active
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- 2008-08-01 CA CA2695734A patent/CA2695734C/en active Active
- 2008-08-01 JP JP2010520208A patent/JP5546453B2/ja active Active
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| CA2695734C (en) | 2017-02-14 |
| WO2009020844A1 (en) | 2009-02-12 |
| JP5546453B2 (ja) | 2014-07-09 |
| JP2010535786A (ja) | 2010-11-25 |
| EP2185202A4 (en) | 2013-11-06 |
| EP2185202A1 (en) | 2010-05-19 |
| AU2008284116B2 (en) | 2014-01-09 |
| US20140377222A1 (en) | 2014-12-25 |
| US20180028614A1 (en) | 2018-02-01 |
| US10786551B2 (en) | 2020-09-29 |
| AU2008284116A1 (en) | 2009-02-12 |
| US20110262385A1 (en) | 2011-10-27 |
| EP2185202B1 (en) | 2015-05-06 |
| CA2695734A1 (en) | 2009-02-12 |
| CN101361968B (zh) | 2011-08-03 |
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