CN101815532B - 以白细胞介素6受体抑制剂为有效成分的移植物抗宿主病治疗剂 - Google Patents
以白细胞介素6受体抑制剂为有效成分的移植物抗宿主病治疗剂 Download PDFInfo
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Abstract
本发明提供一种新型移植物抗宿主病(GVHD)治疗剂,其以白细胞介素6(IL-6)受体抑制剂为有效成分。
Description
技术领域
本发明涉及一种移植物抗宿主病治疗剂。更详细而言,本发明涉及一种以白细胞介素6(IL-6)受体抑制剂为有效成分的移植物抗宿主病治疗剂。
背景技术
白血病等造血器官肿瘤的治疗首先是利用抗癌剂进行化疗,对通过通常的化疗难以治愈、或治愈可能性小的患者要进行造血干细胞(外周血干细胞、骨髓细胞等)移植。但是,在造血干细胞移植过程中,被指出会发生移植物抗宿主病(graft-Versus-host disease:GVHD)。
GVHD是因移入或移植的免疫活性细胞对宿主组织的免疫反应而产生的疾病的统称。其产生的主要原因被认为是移入或移植的外周血等中所含的成熟T细胞等免疫活性细胞对受体组织产生免疫应答。GVHD有急性及慢性疾病,其症状有皮肤症状、腹泻、黄疸等,有时还会具有致死的严重作用。
目前,在抑制GVHD时使用以下方法:使用甲氨喋呤或环孢霉素A等免疫抑制剂的方法和从移植细胞群(移植物)除去成熟T细胞的方法等。使用甲氨喋呤或环孢霉素A时它们对生物体带来的副作用成为问题。已知环孢霉素A的副作用是强肾毒性、甲氨喋呤的副作用是骨髓抑制。
另外,利用从移植细胞群除去成熟T细胞的方法可以抑制GVHD,但存在确认到白血病再现等抗肿瘤效果减弱的缺点(非专利文献1)。
白细胞介素6(IL-6)是也称为B细胞刺激因子2(BSF2)或干扰素β2的细胞因子。已知IL-6是作为与B淋巴细胞系细胞的活化相关的分化因子被发现的(非专利文献2),其是对各种细胞功能有影响的多功能细胞因子(非专利文献3)。据报道IL-6诱导T淋巴细胞系细胞的成熟化(非专利文献4)。
IL-6在细胞上介由二种蛋白质传导其生物学活性。其一是IL-6结合的分子量约80kD的配体结合型蛋白质的IL-6受体(非专利文献5,6)。IL-6受体除了跨细胞膜而在细胞膜上发现的膜结合型以外,还主要以其胞外域形成的可溶性IL-6受体存在。
另一个是与非配体结合性的信号传导相关的分子量约130kD的膜蛋白质gp130。IL-6与IL-6受体形成IL-6/IL-6受体复合体,然后与gp 130结合,将IL-6的生物学活性传导到细胞内(非专利文献7)。
IL-6抑制剂是抑制IL-6的生物学活性传导的物质。目前已知有IL-6的抗体(抗IL-6抗体)、IL-6受体的抗体(抗IL-6受体抗体)、gp130的抗体(抗gp130抗体)、IL-6变异体、IL-6或IL-6受体部分肽等。
关于抗IL-6受体抗体,有一些报道(非专利文献8、9,专利文献1~3)。已知通过将作为其中之一的小鼠抗体PM-1(非专利文献10)的互补决定区(CDR:complementarity determining region)移植到人抗体中而得到的人源化PM-1抗体(专利文献4)。
I L-6受体的抗体用于风湿病等炎症疾病的治疗。然而,由于IL-6等炎症性细胞因子会形成复杂的网状,因此,IL-6受体抑制剂对移植物抗宿主病等其它疾病的治疗是否有效尚不清楚。
据报道,实际上,在发现IL-6的GVHD模型小鼠中,即使给予抗IL-6抗体也无法得到治疗效果(非专利文献11)。
另外,以下例示与本申请的发明相关的先行技术文献信息。
非专利文献1:Blood,78:2120-2123,1991
非专利文献2:Hirano,T.et al.,Nature(1986)324,73-76
非专利文献3:Akira,S.et al.,Adv.in Immunology(1993)54,1-78
非专利文献4:Lotz,M.et al.,J.Exp.Med.(1988)167,1253-1258
非专利文献5:Taga,T.et al.,J.Exp.Med.(1987)166,967-981
非专利文献6:Yamasaki,K.et al.,Science(1988)241,825-828
非专利文献7:Taga,T.et al.,Cell(1989)58,573-581
非专利文献8:Novick,D.et al.,Hybridoma(1991)10,137-146
非专利文献9:Huang,Y.W.et al.,Hybridoma(1993)12,621-630
非专利文献10:Hirata,Y.et al.,J,Immunol.(1989)143,2900-2906
非专利文献11:Knulst A.C.et al.,Mediators ofInflammation(1994)3,33-40
专利文献1:国际专利申请公开号WO 95-09873
专利文献2:法国专利申请公开号FR 2694767
专利文献3:美国专利号US 5216128
专利文献4:国际专利申请公开号WO 92-19759
发明内容
关于IL-6受体对GVHD的详细作用尚未明确。另外,IL-6受体抑制剂的给予对GVHD显示何种效果也还未明确。
本发明是鉴于上述情况完成的,其目的在于提供一种新型GVHD治疗剂。
本发明人等为了解决上述目的进行了潜心研究,结果发现,在GVHD模型小鼠中,抗IL-6受体抗体显示出显著的治疗效果,从而完成本发明。
即,本发明具体提供以下的[1]~[5]。
[1]一种移植物抗宿主病(GVHD)治疗剂,其以白细胞介素6(IL-6)受体抑制剂为有效成分。
[2]如[1]所述的GVHD治疗剂,其中,IL-6受体抑制剂为人IL-6受体抑制剂。
[3]如[1]所述的GVHD治疗剂,其中,IL-6受体抑制剂为抗IL-6受体抗体。
[4]如[3]所述的GVHD治疗剂,其中,抗IL-6受体抗体为嵌合抗体、人源化抗体或人抗体。
[5]如[1]~[4]中任一项所述的GVHD治疗剂,其特征在于,治疗外周血干细胞移植后的GVHD。
[6]一种治疗移植物抗宿主病(GVHD)的方法,其包含给予治疗有效量的白细胞介素6(IL-6)受体抑制剂。
附图说明
图1是表示GVHD发作小鼠中,抗IL-6受体抗体给予组与对照组的体重经时变化的图表。
具体实施方式
本发明中,所谓“IL-6受体抑制剂”,是阻断介由IL-6受体的信号传导、抑制IL-6受体的生物学活性的物质。IL-6受体抑制剂可以为与IL-6受体结合而直接抑制IL-6受体的生物学活性的物质,也可以为与gp130等其它物质结合而间接抑制IL-6受体的生物学活性的物质,优选为具有与IL-6受体结合而抑制IL-6与IL-6受体结合的活性的物质。
作为本发明的IL-6受体抑制剂,例如可以举出:抗IL-6受体抗体、可溶性IL-6受体变异体、IL-6受体的部分肽、与它们显示相同活性的低分子物质等,但没有特别限定。作为本发明的IL-6受体抑制剂的优选例,可以举出识别IL-6受体的抗体。
本发明使用的抗IL-6受体抗体的来源没有特别限定,优选源自哺乳动物的抗体。
本发明使用的抗IL-6受体抗体可以使用公知的方法以多克隆或单克隆抗体得到。作为本发明使用的抗IL-6受体抗体,特别优选源自哺乳动物的单克隆抗体。作为源自哺乳动物的单克隆抗体,有杂交瘤细胞所产生的抗体、及利用基因工程的方法由包含抗体基因的表达载体转化得到的宿主所产生的抗体等。该抗体通过与IL-6受体结合,抑制IL-6与IL-6受体的结合从而阻断IL-6的生物学活性向细胞内传导。
作为这种抗体的实例,可以举出:MR16-1抗体(Tamura,T.et al.Proc.Natl.Acad.Sci.USA(1993)90,11924-11928)、PM-1抗体(Hirata,Y.et al.,J,Immunol.(1989)143,2900-2906)、AUK12-20抗体、AUK64-7或AUK146-15抗体(国际专利申请公开号WO 92-19759)、人源化PM-1抗体(tocilizumab)等。其中,作为人IL-6受体的优选的单克隆抗体,可例示PM-1抗体,另外,作为小鼠IL-6受体的优选的单克隆抗体,可以举出MR16-1抗体,但并不限定于此。
产生抗IL-6受体单克隆抗体的杂交细胞瘤基本上可以使用公知技术,如下制作。即,可以将IL-6受体用作致敏性抗原,利用通常的免疫方法免疫其,利用通常的细胞融合法使得到的免疫细胞与公知的亲本细胞融合,利用通常的筛选法筛选单克隆抗体产生细胞,由此制作。
具体而言,如下制作抗IL-6受体抗体即可。例如,用作得到抗体的致敏性抗原的人IL-6受体通过使用欧洲专利申请公开号EP 325474中公开的IL-6受体基因/氨基酸序列来得到,小鼠IL-6受体通过使用日本专利申请公开号特开平3-155795中公开的IL-6受体基因/氨基酸序列来得到。
IL-6受体蛋白质有在细胞膜上表达的受体蛋白质和从细胞膜脱离的受体蛋白质(可溶性IL-6受体)(Yasukawa,K.et al.,J.Biochem.(1900)108,673-676)两种。可溶性IL-6受体由结合在细胞膜上的IL-6受体的实质上的胞外域构成,在欠缺跨细胞膜区或跨细胞膜区和细胞内区域这一点上不同于膜结合型IL-6受体。对于IL-6受体蛋白质,只要是作为本发明使用的抗IL-6受体抗体的制作的致敏性抗原使用,就可以使用任一种IL-6受体。
将IL-6受体的基因序列插入公知的表达载体系而使适当的宿主细胞转化后,用公知的方法从该宿主细胞中或培养上清液中精制目标IL-6受体蛋白质,将该精制IL-6受体蛋白质作为致敏性抗原使用即可。另外,还可以将表达IL-6受体的细胞或IL-6受体蛋白质与其它蛋白质的融合蛋白质作为致敏性抗原使用。
作为被致敏性抗原免疫的哺乳动物,没有特别限定,但是优选考虑与细胞融合时使用的亲本细胞的适合性进行选择,一般使用啮齿类动物,例如小鼠、大鼠、仓鼠等。
对动物免疫致敏性抗原时,利用公知的方法进行。例如,作为一般的方法,通过在哺乳动物的腹腔内或皮下注射致敏抗原来进行。具体而言,优选用PBS(Phosphate-Buffered Saline)或生理盐水等将致敏抗原稀释成适当的量,并根据需要适量混合悬浊物和通常的佐剂例如弗氏完全佐剂,乳化后,每4-21天对哺乳动物进行数次给药。此外,可以在致敏性抗原免疫时使用适当的载体。
由此进行免疫,在确认血清中目标抗体水平上升后,从哺乳动物中取出免疫细胞,用于细胞融合。作为用于细胞融合的优选的免疫细胞,特别举出脾细胞。
作为与上述免疫细胞融合的另一个亲本细胞的哺乳动物的骨髓瘤细胞,适当使用已公知的各种细胞株,例如P3X63Ag8.653(Kearney,J.F.et al.J.Immnol.(1979)123,1548-1550)、P3X63Ag8U.1(CurrentTopics in Microbiology and Immunology(1978)81,1-7)、NS-1(Kohler.G.and Milstein,C.Eur.J.Immunol.(1976)6,511-519)、MPC-11(Margulies.D.H.et al.,Cell(1976)8,405-415)、SP2/0(Shulman,M.et al.,Nature(1978)276,269-270)、FO(de St.Groth,S.F.et al.,J.Immunol.Methods(1980)35,1-21)、S194(Trowbridge,I.S.J.Exp.Med.(1978)148,313-323)、R210(Galfre,G.et al.,Nature(1979)277,131-133)等。
上述免疫细胞与骨髓瘤细胞的细胞融合基本可以利用公知的方法例如Milstein等的方法(Kohler.G.and Milstein,C.,MethodsEnzymol.(1981)73,3-46)等进行。
更具体而言,上述细胞融合在例如细胞融合促进剂的存在下在通常的营养培养液中实施。作为融合促进剂,例如可以使用聚乙二醇(PEG)、仙台病毒(HVJ)等,为了进一步根据需要提高融合效率,还可以添加二甲基亚砜等辅助剂使用。
对于免疫细胞与骨髓瘤细胞的使用比例,例如,优选将免疫细胞设定为骨髓瘤细胞的1~10倍。作为上述细胞融合使用的培养液,例如可以使用上述骨髓瘤细胞株的增殖所优选的RPMI1640培养液、MEM培养液,此外,还可以使用这种细胞培养所使用的一般的培养液,进而,还可以并用胎牛血清(FCS)等血清补液。
细胞融合通过在上述培养液中良好地混合规定量的上述免疫细胞与骨髓瘤细胞,以通常30~60%(w/v)的浓度添加预先加温至37℃左右的PEG溶液例如平均分子量1000~6000左右的PEG溶液并混合,形成目标融合细胞(杂交瘤细胞)。接着,依次添加适当的培养液,重复离心除去上清液的操作,由此可以除去杂交瘤细胞的生育所不优选的细胞融合剂等。
该杂交瘤细胞可以通过用通常的选择培养液例如HAT培养液(包含次黄嘌呤、氨喋呤及胸腺嘧啶脱氧核苷的培养液)进行培养来选择。在该HAT培养液中进行的培养持续的时间为目标杂交瘤细胞以外的细胞(非融合细胞)灭活所需的足够的时间,通常为数日~数周时间。接着,实施通常的有限稀释法,进行产生目标抗体的杂交瘤细胞的筛选及克隆。
另外,除对人以外的动物免疫抗原而得到上述杂交瘤细胞以外,也可以在体外用目标抗原蛋白质或抗原表达细胞使人淋巴细胞致敏,使致敏B淋巴细胞与人骨髓瘤细胞例如U266融合,得到对所希望的抗原或抗原表达细胞具有结合活性的所希望的人抗体(参照日本特公平1-59878)。进而,还可以对具有人抗体基因库的转基因动物给予抗原或抗原表达细胞,按照上述方法得到所希望的人抗体(参照国际专利申请公开号WO93/12227、WO92/03918、WO94/02602、WO94/25585、WO96/34096、WO96/33735)。
由此制得的产生单克隆抗体的杂交瘤细胞可以在通常的培养液中进行传代培养,另外,可以在液氮中长期保存。
由该杂交瘤细胞得到单克隆抗体时,采用利用通常的方法培养该杂交瘤细胞而以其培养上清液的形式得到的方法,或将杂交瘤细胞给予和其具有适合性的哺乳动物使其增殖而以其腹水的形式得到的方法等。前者的方法适用于得到高纯度的抗体,后者的方法适用于抗体的大量生产。
例如,在制作抗IL-6受体抗体产生杂交瘤细胞时,可以利用日本特开平3-139293中公开的方法进行。可以利用以下方法进行:将PM-1抗体产生杂交瘤细胞注入BALB/c小鼠的腹腔内,得到腹水,由该腹水精制PM-1抗体的方法;或用适当的培养基例如10%胎牛血清、含5%BM-Condimed H1(Boehringer Mannheim制)的RPMI1640培养基、杂交瘤细胞SFM培养基(GIBCO-BRL制)、PFHM-II培养基(GIBCO-BRL制)等进行培养,由其培养上清液精制PM-1抗体的方法。
在本发明中,作为单克隆抗体,可以使用以下抗体:由杂交瘤细胞克隆抗体基因并植入适当的载体中,将其导入宿主内,使用基因重组技术而产生的重组型抗体(参照例如Borrebaeck C.A.K.andLarrick J.W.THERAPEUTIC MONOCLONAL ANTIBODIES,Published in theUnited Kingdom by MACMILLAN PUBLISHERS LTD,1990)。
具体而言,从产生目标抗体的细胞例如杂交瘤细胞分离编码抗体的可变(V)区的mRNA。mRNA的分离可以利用公知的方法例如胍超离心法(Chirgwin,J.M.et al.,Biochemistry(1979)18,5294-5299)、AGPC法(Chomczynski,P.et al.,Anal.Biochem.(1987)162,156-159)等制备总RNA,使用mRNA Purification Kit(Pharmacia制)等制备mRNA。另外,可以使用QuickPrep mRNA Purification Kit(Pharmacia制)直接制备mRNA。
使用逆转录酶由得到的mRNA合成抗体V区的cDNA。cDNA的合成可以使用AMV ReVerse Transcriptase First-strand cDNA SynthesisKit等进行。另外,在进行cDNA的合成及扩增时,可以使用5′-AmpliFINDER RACE Kit(Clontech制)及使用PCR的5′-RACE法(Frohman,M.A.et al.,Proc.Natl.Acad.Sci.USA(1988)85,8998-9002;Belyavsky,A.et al.,Nucleic Acids Res.(1989)17,2919-2932)。由得到的PCR产物精制目标DNA片段,与载体DNA连结。进而,由其制作重组载体并导入大肠杆菌等,选择菌落,制备所希望的重组载体。利用公知的方法例如脱氧法确认目标DNA的碱基序列。
如果得到编码目标抗体的V区的DNA,则使其与编码目标抗体稳定区(C区)的DNA连结,将其植入表达载体。或者,也可以将编码抗体的V区的DNA植入包含抗体C区的DNA的表达载体中。
制造本发明使用的抗体时,可以如后面所述将抗体基因以在表达控制区例如增强子、启动子的控制下表达的方式植入表达载体中。接着,可以通过该表达载体转化宿主细胞,使抗体表达。
在本发明中,可以使用以降低对人的异种抗原性等为目的而人为改变的基因重组型抗体,例如嵌合(Chimeric)抗体、人源化(Humanized)抗体等。这些可变抗体可以使用已知的方法进行制造。
嵌合抗体可以通过将如上述操作得到的编码抗体V区的DNA与编码人抗体C区的DNA连结,将其植入表达载体并导入宿主使其产生来得到(参照欧洲专利申请公开号EP 125023、国际专利申请公开号WO92-19759)。使用该已知的方法,可以得到对本发明有用的嵌合抗体。
人源化抗体也被称为重构(reshaped)人抗体或人型抗体,是将人以外的哺乳动物例如小鼠抗体的互补决定区(CDR)移植到人抗体的互补决定区的物质,目前已知其一般的基因重组方法(参照欧洲专利申请公开号EP 125023、国际专利申请公开号WO 92-19759)。
具体而言,利用PCR法由以末端部具有重叠部分的方式制作的数个寡核苷酸合成以连结小鼠抗体的CDR与人抗体的构架区(FR;framework region)的方式设计的DNA序列。通过将得到的DNA与编码人抗体C区的DNA连结然后植入表达载体、将其导入宿主使其产生而得到(参照欧洲专利申请公开号EP 239400、国际专利申请公开号WO92-19759)。
对于介由CDR连结的人抗体的FR,选择互补决定区形成良好的抗原结合部位的区域。根据需要,还可以取代抗体可变区的构架区的氨基酸,以使重构人抗体的互补决定区形成合适的抗原结合部位(Sato,K.et al.,Cancer Res.(1993)53,851-856)。
嵌合抗体、人源化抗体通常使用人抗体C区。作为人抗体重链C区的实例,可以举出Cγ、Cα、Cμ、Cδ、Cε,例如可以使用Cγ1、Cγ2、Cγ3或Cγ4。作为人抗体轻链C区的实例,可以举出κ或λ。另外,为了改善抗体或其产生的稳定性,也可以修饰人抗体C区。
嵌合抗体由源自人以外的哺乳动物的抗体的可变区和源自人抗体的C区构成,另外,人源化抗体由源自人以外的哺乳动物的抗体的互补决定区和源自人抗体的构架区及C区构成,由于它们在人体内的抗原性低,因此作为本发明使用的抗体是有用的。
作为本发明使用的人源化抗体的优选的具体例,可以举出人源化PM-1抗体(tocilizumab)(参照国际专利申请公开号WO 92-19759)。另外,还可以为对人源化PM-1抗体的氨基酸序列进行取代、缺失、附加等而得的取代体。
另外,作为得到人抗体的方法,除先前叙述的方法以外,还已知使用人抗体库、通过淘选得到人抗体的技术。例如,还可以利用噬菌体展示法使人抗体的可变区作为单链抗体(scFv)在噬菌体的表面表达,选择与抗原结合的噬菌体。如果分析选择的噬菌体的基因,则可以确定编码与抗原结合的人抗体的可变区的DNA序列。如果与抗原结合的scFv的DNA序列明确,则可以制作包含该序列的合适的表达载体,得到人抗体。这些方法是众所周知的,可以参考WO 92/01047、WO92/20791、WO 93/06213、WO 93/11236、WO 93/19172、WO 95/01438、WO 95/15388。
如上操作而构筑的抗体基因可以利用公知的方法表达。使用哺乳类细胞时,可以利用常用的有用的启动子、表达的抗体基因、使PolyA信号与其3′侧下游功能性结合的DNA或包含其的载体使其表达。例如,作为启动子/增强子,可以举出人巨细胞病毒早期启动子/增强子(human cytomegalovirus immediate early promoter/enhancer)。
另外,作为其它的可以用于表达本发明使用的抗体的启动子/增强子,使用逆转录病毒、多瘤病毒、腺病毒、猴病毒40(SV40)等病毒启动子/增强子或人延长因子1α(HEF1α)等源自哺乳类细胞的启动子/增强子即可。
例如,使用SV40启动子/增强子时,可以利用Mulligan等的方法(Mulligan,R.C.et al.,Nature(1979)277,108-114)容易地实施,另外,使用HEF1α启动子/增强子时,可以利用Mizushima等的方法(Mizushima,S.and Nagata,S.Nucleic Acids Res.(1990)18,5322)容易地实施。
使用原核细胞作为宿主时,有使用细菌细胞的产生系统。作为细菌细胞,已知大肠杆菌(E.coli)、枯草菌。
为大肠杆菌时,可以使常用的有用的启动子、用于抗体分泌的信号序列、表达的抗体基因功能性结合使其表达。例如,作为启动子,可以举出lacZ启动子、araB启动子。使用lacZ启动子时,利用Ward等的方法(Ward,E.S.et al.,Nature(1989)341,544-546;Ward,E.S.etal.FASEB J.(1992)6,2422-2427)即可,使用araB启动子时,利用Better等的方法(Better,M.et al.Science(1988)240,1041-1043)即可。
作为用于抗体分泌的信号序列,使大肠杆菌的周质产生时,使用pelB信号序列(Lei,S.P.et al J.Bacteriol.(1987)169,4379-4383)即可。将周质产生的抗体分离后,将抗体的结构进行适当的重折叠(refold)后使用(参照例如WO96/30394)。
作为复制的来源,可以使用源自SV40、多瘤病毒、腺病毒、牛乳头瘤病毒(BPV)等的物质,进而,为了使宿主细胞系中基因复制数扩增,表达载体可以包含氨基糖苷磷酸转移酶(APH)基因、胸苷激酶(TK)基因、大肠杆菌黄嘌呤鸟嘌呤磷酸核糖转移酶(Ecogpt)基因、二氢叶酸还原酶(dhfr)基因等作为选择性标记物。
为了制造本发明使用的抗体,可以使用任意的产生体系。用于抗体制造的产生体系,有体外(in Vitro)及体内(in ViVo)产生体系。作为体外产生体系,可以举出使用真核细胞的产生体系及使用原核细胞的产生体系。
使用真核细胞作为宿主时,有使用动物细胞、植物细胞或真菌细胞的的产生体系。作为动物细胞,已知(1)哺乳类细胞,例如CHO、COS、骨髓瘤细胞、BHK(baby hamster kidney)、HeLa、Vero等,(2)两栖类细胞,例如爪蟾卵母细胞,或(3)昆虫细胞,例如sf9、sf21、Tn5等。作为植物细胞,已知源自烟草(Nicotiana tabacum)的细胞,将细胞进行愈伤组织培养即可。作为真菌细胞,已知酵母,例如酵母(Saccharomyces)属,例如酿酒酵母(Saccharomyces cereVisiae);丝状菌,例如曲霉(Aspergillus)属,例如黑曲霉菌(Aspergillusniger)等。
通过转化在这些细胞中导入目标抗体基因,将转化的细胞在体外培养,从而得到抗体。培养利用公知的方法进行。例如,作为培养液,可以使用DMEM、MEM、RPMI1640、IMDM,还可以并用胎牛血清(FCS)等血清辅液。另外,也可以通过将导入抗体基因的细胞移入动物的腹腔等,在体内产生抗体。
另一方面,作为体内的产生体系,可以举出使用动物的产生体系及使用植物的产生体系。使用动物时,有使用哺乳类动物、昆虫的产生体系等。
作为哺乳类动物,可以使用山羊、猪、羊、小鼠、牛等(VickiGlaser,SPECTRUM Biotechnology Applications,1993)。另外,作为昆虫,可以使用蚕。使用植物时,例如可以使用烟草。
将抗体基因导入这些动物或植物中,使动物或植物体内产生抗体并回收。例如,将抗体基因插入编码山羊β酪蛋白之类的乳汁中固有产生的蛋白质的基因中,以融合基因的形式制备。将包含插入有抗体基因的融合基因的DNA片段注入山羊的胚胎内,将该胚胎导入雌性山羊体内。从由接受胚胎的山羊生出的转基因山羊或其子孙产生的乳汁得到所希望的抗体。为了使由转基因山羊产生的包含所希望的抗体的乳汁量增加,也可以对转基因山羊使用合适的激素(Ebert,K.M.etal.,Bio/Technology(1994)12,699-702)。
另外,使用蚕时,使蚕感染插入有目标抗体基因的杆状病毒,由该蚕的体液得到所希望的抗体(Maeda,S.et al.,Nature(1985)315,592-594)。进而,使用烟草时,将目标抗体基因插入植物表达用载体例如pMON530中,将该载体导入根瘤土壤杆菌(Agrobacteriumtumefaciens)之类的细菌中。使烟草例如Nicotiana tabacum感染该细菌。由该烟草的叶得到所希望的抗体(Julian,K.-C.Ma etal.,Eur.J.Immunol.(1994)24,131-138)。
如上所述以体外或体内产生体系产生抗体时,还可以将编码抗体重链(H链)或轻链(L链)的DNA分别植入表达载体中使宿主同时转化,或者,也可以将编码H链或L链的DNA植入单独的表达载体中,使宿主转化(参照国际专利申请公开号WO 94-11523)。
本发明使用的抗体只要适合在本发明中使用,就可以为抗体片段或其修饰物。例如,作为抗体片段,可以举出:用合适的连结子使Fab、F(ab′)2、Fv或H链和L链的Fv连结而成的单链Fv(scFv)。
具体而言,用酶例如木瓜蛋白酶、胃蛋白酶处理抗体生成抗体片段,或构筑编码这些抗体片段的基因,将其导入表达载体后,用适当的宿主细胞使其表达(参照例如Co,M.S.etal.,J.Immunol.(1994)152,2968-2976、Better,M.& Horwitz,A.H.Methods in Enzymology(1989)178,476-496、Plueckthun,A.& Skerra,A.Methods in Enzymology(1989)178,497-515、Lamoyi,E.,Methods in Enzymology(1989)121,652-663、Rousseaux,J.etal.,Methods in Enzymology(1989)121,663-66、Bird,R.E.etal.,TIBTECH(1991)9,132-137)。
scFv通过将抗体的H链V区与L链V区连结而得到。在该scFv中,H链V区和L链V区介由连结子、优选连接肽连结(Huston,J.S.etal.,Proc.Natl.Acad.Sci.U.S.A.(1988)85,5879-5883)。scFv中的H链V区及L链V区可以源自上述记载的抗体中的任一种。作为连结V区的连接肽,例如使用由氨基酸12-19残基构成的任意一条链肽。
编码scFv的DNA可以如下操作来得到:以编码上述抗体的H链或H链V区的DNA、及编码L链或L链V区的DNA为模板,将编码这些序列中的目标氨基酸序列的DNA部分使用规定其两端的引物对利用PCR法进行扩增,接着,进一步组合以分别与H链、L链连结的方式规定的引物对,使编码多肽连接器部分的DNA及其两端扩增,由此得到。
另外,一旦制作编码scFv的DNA,就可以利用常规方法得到包含它们的表达载体及利用该表达载体进行转化的宿主,另外,还可以使用该宿主、利用常规方法得到scFv。
这些抗体片段可以与上述同样操作得的其基因并使其表达,并由宿主产生。本发明的“抗体”还包含它们的抗体片段。
作为抗体的修饰物,还可以使用与聚乙二醇(PEG)等各种分子结合的抗体。本发明的“抗体”还包含它们的抗体修饰物。为了得到这样的抗体修饰物,可以通过对得到的抗体施行化学修饰来得到。这些方法在本领域是已经确立了的方法。
如上操作产生并表达的抗体可以从细胞内外、宿主分离,并精制直至均匀。本发明使用的抗体的分离、精制可以利用亲和色谱法进行。作为亲和色谱中使用的色谱柱,例如可以举出蛋白质A色谱柱、蛋白质G色谱柱。作为蛋白质A色谱柱使用的载体,例如可以举出HyperD、POROS、SepharoseF.F.等。此外,也可以使用通常的蛋白质使用的分离、精制方法,没有任何限定。
通过适当选择并组合例如上述亲和色谱法以外的色谱法、过滤器、超滤、盐析、透析等,可以分离、精制本发明使用的抗体。作为色谱法,例如可以举出离子交换色谱法、疏水层析法、凝胶过滤等。这些色谱法可以使用HPLC(High performance liquid chromatography)。另外,也可以使用反相HPLC(reverse phase HPLC)。
上述得到的抗体的浓度测定可以通过吸光度的测定或ELISA等进行。即,通过吸光度的测定进行时,用PBS(-)进行适当的稀释后,测定280nm的吸光度,按照1mg/ml为1.350D进行计算。另外,通过ELISA进行时,可以如下操作进行测定。即,将用0.1M重碳酸缓冲液(pH9.6)稀释成1μg/ml的山羊抗人IgG(TAG制)100μl加入96孔板(Nunc制),在4℃下培养一晚,使抗体固化。成块后,添加适当稀释的本发明使用的抗体或包含抗体的样品、或作为标准品的人IgG(CAPPEL制)100μl,在室温下培养1小时。
洗净后,加入稀释了5000倍的碱性磷酸酶标记抗人IgG(BIOSOURCE制)100μl,在室温下培养1小时。洗净后,加入基质溶液进行培养后,使用MICROPLATE READER Model 3550(Bio-Rad制)测定405nm处的吸光度,计算目标抗体的浓度。
IL-6受体部分肽是由IL-6受体的氨基酸序列中与IL-6和IL-6受体的结合相关的区域的部分或全部氨基酸序列构成的肽。这样的多肽通常由10~80、优选20~50、更优选20~40个氨基酸残基构成。
IL-6受体部分肽可以通过特定IL-6受体的氨基酸序列中与IL-6和IL-6受体的结合相关的区域,基于以该特定区的一部分或全部氨基酸序列,利用通常已知的方法例如基因工程的方法或肽合成法来制作。
利用基因工程的方法制作IL-6受体部分肽时,可以将编码所希望的多肽的DNA序列植入表达载体,基于上述重组型抗体的表达、产生及精制方法来得到。
利用多肽合成法制作IL-6受体部分肽时,可以使用肽合成通常使用的方法,例如固相合成法或液相合成法。
具体而言,基于续医药品的开发第14卷肽合成监修矢岛治明广川书店1991年记载的方法进行即可。作为固相合成法,使用以下方法:使与欲合成的肽的C末端对应的氨基酸与不溶于有机溶剂的支撑体结合,交替重复使以合适的保护基保护α-氨基及侧链官能团的氨基酸按从C末端到N末端方向的顺序每个氨基酸依次发生缩合的反应、和使结合在树脂上的氨基酸或肽的α-氨基的保护基脱离的反应,从而使肽链延长。固相肽合成法根据使用的保护基的种类大致分为Boc法和Fmoc法。
由此合成目标多肽后,进行去保护反应及将肽链从支撑体切断的反应。对于肽链的切断反应,Boc法中通常可以使用氟化氢或三氟甲基磺酸;或Fmoc法中通常可以使用TFA。在Boc法中,例如在氟化氢中在苯甲醚的存在下处理上述保护多树脂。接着,进行保护基的脱离和从支撑体的切断,回收肽。通过将其冷冻干燥,可以得到粗肽。另一方面,在Fmoc法中,例如可以以与TFA中的上述同样的操作进行去保护反应及将肽链从支持体切断的反应。
得到的粗肽可以使用HPLC进行分离、精制。在其溶出时,使用蛋白质的精制中通常使用的水-乙腈系溶剂在最适的条件下进行即可。分取对应于得到的色谱侧面图的峰的成分,将其进行冷冻干燥。对于这样操作精制得到的肽成分,通过利用质谱分析的分子量解析、氨基酸组成分析、或氨基酸序列解析等进行确定。
本发明的GVHD治疗剂可以在GVHD的治疗及/或预防时使用。本发明的GVHD治疗剂还包含抑制GVHD发病的GVHD预防剂。因此,本发明中的“GVHD治疗”是指GVHD的抑制、GVHD发病率的降低、GVHD的治疗、GVHD症状的改善等。
作为本发明的治疗剂的对象的GVHD可以为任意的GVHD。作为本发明的治疗剂的对象的GVHD包含急性GVHD及慢性GVHD。本发明的GVHD治疗剂对外周血干细胞移植后(同种外周血干细胞移植等)的GVHD、骨髓移植后(同种骨髓移植等)的GVHD等造血干细胞移植后的GVHD等特别有效。
本发明使用的IL-6受体抑制剂的GVHD治疗剂的效果例如可以将信号传导抑制活性作为指标进行评价,但并不限定于此。IL-6受体抑制剂的信号传导抑制活性可以利用通常使用的方法进行评价。具体而言,培养IL-6依赖性人骨髓瘤株(S6B45,KPMM2)、人Lennert淋巴瘤T淋巴瘤细胞株KT3、或者IL-6依赖性细胞MH60.BSF2,在其中加入IL-6,同时使IL-6受体抑制剂共存,由此测定IL-6依赖性细胞的3H-胸腺嘧啶脱氧核苷的取入。另外,培养作为IL-6受体表达细胞的U266,添加125I标记IL-6,同时加入IL-6受体抑制剂,由此测定与IL-6受体表达细胞结合的125I标记IL-6。在上述测定体系中,可以预先准备存在IL-6受体抑制剂的组及不含有IL-6受体抑制剂的阴性对照组,比较两者得到的结果,由此可以评价IL-6受体抑制剂的IL-6受体抑制活性。
给予本发明的GVHD治疗剂的对象是哺乳动物。哺乳动物优选为人。
本发明的GVHD治疗剂可以以医药品的形式给予,可以经口或非经口全身或局部给药。例如,可以选择点滴等静脉内注射、肌内注射、腹腔内注射、皮下注射、栓剂、灌肠、经口性肠溶剂等,可以根据患者的年龄、症状选择合适的给药方式。有效给药量没有特别限定,一次1kg体重选择0.01mg到100mg的范围。或者,每个患者可以选择1~1000mg、优选5~50mg的给药量。作为优选的给药量、给药方法的具体例,有:例如为抗IL-6受体抗体的情况下,每kg体重1个月(4周时间)分1次到数次给药0.5mg~40mg、优选1mg~20mg,例如以2次/周、1次/周、1次/2周、1次/4周等给药时间表用点滴等静脉内注射、皮下注射、肌内注射等方法进行给药的方法等。对于给药时间表,还可以边观察患者的状态及血液检查值的倾向边将给药间隔从2次/周或1次/周延长为1次/2周、1次/3周、1次/4周等,可以进行调整。
如后述实施例所示,本发明的GVHD治疗剂通过在造血干细胞移植前及移植后给予受体,可以显著抑制GVHD的发病。因此,本发明的GVHD治疗剂在造血干细胞移植前给予,进而从GVHD方面考虑,优选在移植后给予。
本发明的GVHD治疗剂还可以与至少1个已知的GVHD治疗剂或治疗法同时给予。例如,可以与用于预防GVHD的免疫抑制剂(环孢霉素、他克莫司、甲氨蝶呤)同时或依次给予。另外,还可以并用从移植细胞群(移植片)除去成熟T细胞的方法。
本发明的GVHD治疗剂中还可以添加保存剂及稳定剂等制剂上容许的载体。制剂上容许的载体是指可以与上述药剂一同给予的材料。作为制剂上容许的材料,例如可以举出:灭菌水或生理盐水、稳定剂、赋形剂、缓冲剂、防腐剂、表面活性剂、络合剂(EDTA等)、结合剂等。
本发明中,作为表面活性剂,可以举出非离子型表面活性剂,作为典型的实例,例如可以举出:脱水山梨醇单辛酸酯、脱水山梨醇单月桂酸酯、脱水山梨醇单棕榈酸酯等脱水山梨醇脂肪酸酯;单辛酸甘油酯、单豆蔻酸甘油酯、单硬脂酸甘油酯等甘油脂肪酸酯;十聚甘油单硬脂酸酯、十聚甘油二硬脂酸酯、十聚甘油单亚油酸酯等聚甘油脂肪酸酯;聚氧乙烯脱水山梨醇单月桂酸酯、聚氧乙烯脱水山梨醇单油酸酯、聚氧乙烯脱水山梨醇单硬脂酸酯、聚氧乙烯脱水山梨醇单棕榈酸酯、聚氧乙烯脱水山梨醇三油酸酯、聚氧乙烯脱水山梨醇三硬脂酸酯等聚氧乙烯脱水山梨醇脂肪酸酯;聚氧乙烯山梨醇四硬脂酸酯、聚氧乙烯山梨醇四油酸酯等聚氧乙烯山梨醇脂肪酸酯;聚氧乙烯单硬脂酸甘油酯等聚氧乙烯甘油脂肪酸酯;聚乙二醇二硬脂酸酯等聚乙二醇脂肪酸酯;聚氧乙烯十二烷基醚等聚氧乙烯烷基醚;聚氧乙烯聚氧丙烯二醇、聚氧乙烯聚氧丙烯丙醚、聚氧乙烯聚氧丙烯十六烷基醚等聚氧乙烯聚氧丙烯烷基醚;聚氧乙烯壬基苯基醚等聚氧乙烯烷基苯基醚;聚氧乙烯蓖麻油、聚氧乙烯固化蓖麻油(聚氧乙烯氢化蓖麻油)等聚氧乙烯固化蓖麻油;聚氧乙烯山梨醇蜂蜡等聚氧乙烯蜂蜡衍生物;聚氧乙烯羊毛脂等聚氧乙烯羊毛脂衍生物;聚氧乙烯硬脂酸酰胺等聚氧乙烯脂肪酸酰胺等具有HLB6~18的化合物等。
另外,作为表面活性剂,还可以举出阴离子表面活性剂,作为典型的实例,例如可以举出:十六烷基硫酸钠、十二烷基硫酸钠、油烯基硫酸钠等具有碳原子数10~18的烷基的烷基硫酸盐;聚氧乙烯十二烷基硫酸钠等环氧乙烷的平均加成摩尔数为2~4且烷基的碳原子数为10~18的聚氧乙烯烷基醚硫酸盐;十二烷基磺基琥珀酸钠等烷基的碳原子数为8~18的烷基磺基琥珀酸盐;天然表面活性剂,例如卵磷脂、甘油磷脂;神经鞘磷脂等鞘磷脂;碳原子数12~18的脂肪酸的蔗糖脂肪酸酯等。
在本发明的药剂中,可以组合添加这些表面活性剂中的1种或2种以上。本发明的制剂中使用的优选的表面活性剂为聚山梨醇酯20、40、60或80等聚氧乙烯脱水山梨醇脂肪酸酯,特别优选聚山梨醇酯20及80。另外,还优选泊洛沙姆(PluronicF-68(注册商标)等)代表的聚氧乙烯聚氧丙烯二醇。
表面活性剂的添加量根据使用的表面活性剂的种类而不同,为聚山梨醇酯20或聚山梨醇酯80的情况下,通常为0.001~100mg/mL,优选为0.003~50mg/mL,更优选为0.005~2mg/mL。
作为本发明的缓冲剂,可以举出:磷酸、柠檬酸缓冲液、醋酸、苹果酸、酒石酸、琥珀酸、乳酸、磷酸钾、葡糖酸、辛酸、去氧胆酸、水杨酸、三乙醇胺、富马酸等其它的有机酸等、或碳酸缓冲液、三羟甲基氨基甲烷缓冲液、组氨酸缓冲液、咪唑缓冲液等。
另外,在溶液制剂领域,还可以通过溶解在公知的水性缓冲液中来制备溶液制剂。缓冲液的浓度通常为1~500mM,优选为5~100mM,更优选为10~20mM。
另外,本发明的治疗剂还可以包含其它低分子量的多肽、血清白蛋白、明胶或免疫球蛋白等蛋白质、氨基酸、多糖及单糖等糖类或碳水化合物、糖醇。
作为本发明中的氨基酸,可以举出:碱性氨基酸,例如精氨酸、赖氨酸、组氨酸、鸟氨酸等、或这些氨基酸的无机盐(优选盐酸盐、磷酸盐的形式、即磷酸氨基酸)。使用游离氨基酸时,优选的pH值通过添加合适的生理上容许的缓冲物质例如无机酸,尤其是盐酸、磷酸、硫酸、醋酸、甲酸或它们的盐进行调整。此时,磷酸盐的使用尤其在得到稳定的冷冻干燥物上特别有利。制备物实质上不含有机酸例如苹果酸、酒石酸、柠檬酸、琥珀酸、富马酸等时或不存在对应的阴离子(苹果酸离子、酒石酸离子、柠檬酸离子、琥珀酸离子、富马酸离子等)时,特别有利。优选的氨基酸为精氨酸、赖氨酸、组氨酸或鸟氨酸。进而,还可以使用酸性氨基酸例如谷氨酸及天冬氨酸;及其盐的形式(优选钠盐)或中性氨基酸例如异亮氨酸、亮氨酸、甘氨酸、丝氨酸、苏氨酸、缬氨酸、蛋氨酸、半胱氨酸或丙氨酸;或芳香族氨基酸例如苯丙氨酸、酪氨酸、色氨酸;或衍生物的N-乙酰色氨酸。
本发明中,作为多糖及单糖等糖类或碳水化合物,例如可以举出:葡聚糖、葡萄糖、果糖、乳糖、木糖、甘露糖、麦芽糖、蔗糖、海藻糖、蜜三糖等。
本发明中,作为糖醇,例如可以举出:甘露醇、山梨醇、肌醇等。
将本发明的药剂制成注射用水溶液时,例如,可以与包含生理盐水、葡萄糖或其它辅助药物(例如D-山梨醇、D-甘露糖、D-甘露醇、氯化钠)的等张液混合,另外该水溶液还可以与适当的溶解辅助剂(例如醇(乙醇等)、多元醇(丙二醇、PEG等)、非离子性表面活性剂(聚山梨醇酯80、HCO-50)等)并用。
根据目标,还可以进一步含有稀释剂、溶解辅助剂、pH调节剂、无痛剂、含硫还原剂、抗氧化剂等。
本发明中,作为含硫还原剂,例如可以举出:N-乙酰半胱氨酸、N-乙酰同型半胱氨酸、硫辛酸、硫代双乙醇、硫代乙醇胺、硫代甘油、硫代山梨醇、硫代葡糖酸及其盐、硫代硫酸钠、谷胱甘肽、及碳原子数1~7的硫代烷酸等具有巯基的化合物等。
另外,作为本发明中的抗氧化剂,例如可以举出:异抗坏血酸、二丁基羟基甲苯、丁基羟基茴香醚、α-生育酚、醋酸生育酚、L-抗坏血酸及其盐、L-抗坏血酸棕榈酸酯、L-抗坏血酸硬脂酸酯、亚硫酸氢钠、亚硫酸钠、没食子酸三戊酯、没食子酸丙酯或乙二胺四乙酸二钠(EDTA)、焦磷酸钠、偏磷酸钠等络合剂。
另外,可根据需要封入微囊(羟甲基纤维素、明胶、聚[甲基丙烯酸甲酯]等微囊)中、或制成胶质药物传递系统(脂质体、白蛋白微球体、微乳、纳米粒子及纳米胶囊等)(参照“Remington′s PharmaceuticalScience 16th edition”,Oslo Ed.,1980等)。进而,将药剂制成缓释药剂的方法是公知的,可以适用于本发明(Langer etal.,J.Biomed.Mater.Res.1981,15:167-277;Langer,Chem.Tech.1982,12:98-105;美国专利第3,773,919号;欧洲专利申请公开(EP)第58,481号;Sidman et al.,Biopolymers 1983,22:547-556;EP第133,988号)。
所使用的制剂上容许的载体根据剂型从上述适当或组合选择,但并不限定于此。
本发明是涉及一种包含将IL-6受体抑制剂给予患GVHD的对象或有发病可能性的对象的工序的治疗及/或预防对象的GVHD的方法。
本发明中,“对象”是指给予本发明的GVHD治疗剂的生物体、该生物体的体内的一部分。生物体没有特别限定,包含动物(例如人、家畜动物、野生动物)。
本发明中,“给药”包含经口或非经口给药。作为经口给药,可以举出以经口剂的形式给药,作为经口剂,可以选择颗粒剂、散剂、片剂、胶囊剂、溶液剂、乳剂、或悬浊剂等剂型。
作为非经口给药,可以举出以注射剂的形式给药,作为注射剂,可以举出:皮下注射剂、肌肉注射剂、静脉内注射剂或腹腔内注射剂等。另外,通过使用基因治疗的方法将包含应给予的寡核苷酸的基因导入生物体内,可以获得本发明方法的效果。另外,还可以将本发明的药剂局部给予欲实施处理的区域。例如也可以通过手术中的局部注射、导管的使用、或编码本发明的肽的DNA的靶向化基因传导给药。
另外,本说明书中引用的全部先行技术文献都作为参照写入本说明书中。
通过实施例进一步详细地说明本发明,但本发明并不限定于此。本领域人员可以进行各种变更、修饰,这些变更、修饰也包含在本发明中。
实施例
实施例1:IL-6受体抗体对GVHD的效果
试验法
将由8周龄的雌性C57BL/6J供体小鼠(日本Charles RiVer)得到的脾细胞6×107cells/mouse经尾静脉移入8周龄的雌性B6D2F1/Crlj受体小鼠(日本Charles RiVer)以引发GVHD。
将受体小鼠分成2组,另一方面,在移入脾细胞的1天前尾静脉给予抗小鼠IL-6受体抗体MR16-1(中外制药)4mg/mouse,之后每7日腹腔给药4次0.5mg/mouse。对照组给予phophate-bufferedsaline(PBS;SIGMA-ALDRICH Inc.)(每组10只)。移入脾细胞后,测定小鼠的体重每周三次,用体重来评价GVHD的发病。
结果
结果示于图1。观察对照组中2相性的体重减少。即,在移入脾细胞后第9~14天发现体重减少,然后在第16天暂时恢复,之后在第19~21天体重再次减少,第33日大致恢复。另一方面,MR16-1给予组中未观察到第9~14天的体重减少。即,认为抗IL-6受体抗体抑制GVHD的发病。
Claims (3)
1.抗白细胞介素6受体抗体在制备移植物抗宿主病治疗剂中的用途。
2.如权利要求1所述的用途,其中,抗白细胞介素6受体抗体为人IL-6受体抗体。
3.如权利要求1或2所述的用途,其中,抗白细胞介素6受体抗体为嵌合抗体、人源化抗体或人抗体。
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EP2196220A4 (en) | 2011-12-21 |
TWI468173B (zh) | 2015-01-11 |
EP2196220B1 (en) | 2014-12-03 |
MX2010003139A (es) | 2010-04-07 |
RU2010117171A (ru) | 2011-11-10 |
BR122019021238B1 (pt) | 2021-02-23 |
CA2701155C (en) | 2016-11-22 |
US8529895B2 (en) | 2013-09-10 |
BRPI0817482A2 (pt) | 2015-09-29 |
TW200932262A (en) | 2009-08-01 |
JP5264752B2 (ja) | 2013-08-14 |
KR101601986B1 (ko) | 2016-03-17 |
RU2490025C2 (ru) | 2013-08-20 |
BR122019021238B8 (pt) | 2021-07-27 |
BRPI0817482B8 (pt) | 2021-05-25 |
BRPI0817482B1 (pt) | 2020-01-14 |
AU2008308163B2 (en) | 2013-03-21 |
WO2009044774A1 (ja) | 2009-04-09 |
EP2196220A1 (en) | 2010-06-16 |
JPWO2009044774A1 (ja) | 2011-02-10 |
CN101815532A (zh) | 2010-08-25 |
US20100255007A1 (en) | 2010-10-07 |
HK1145288A1 (en) | 2011-04-15 |
AU2008308163A1 (en) | 2009-04-09 |
KR20100075591A (ko) | 2010-07-02 |
CA2701155A1 (en) | 2009-04-09 |
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