CN1164194A - 用于治疗il-6产生所致疾病的药物组合物 - Google Patents
用于治疗il-6产生所致疾病的药物组合物 Download PDFInfo
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- CN1164194A CN1164194A CN95196357A CN95196357A CN1164194A CN 1164194 A CN1164194 A CN 1164194A CN 95196357 A CN95196357 A CN 95196357A CN 95196357 A CN95196357 A CN 95196357A CN 1164194 A CN1164194 A CN 1164194A
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Abstract
用于预防或治疗因IL-6产生所致疾病的药物组合物,该组合物中含有白介素-6受体抗体(IL-6R抗体)。IL-6R抗体可采用除人类以外其它动物的抗体如小鼠,大鼠等抗体,也可采用介于这些抗体和人类抗体之间的嵌合抗体,还可采用重建的人类抗体等。药物组合物可用来预防或治疗因白介素-6产生所致的疾病,例如浆细胞增多症,抗IgG1血症,贫血及肾炎等。
Description
本发明涉及用于预防或治疗因白介素-6(IL-6)产生所致疾病的药物组合物,该组合物包括对抗白介素-6受体(IL-6R)的抗体(抗-IL-6R抗体)。
背景技术
IL-6为一种多功能细胞因子,目前认为在免疫,血液及急性期反应的各个阶段都有该因子参与(Taga,T.et al.,Critical Reviews inImmunol.11:265-280,1992),该因子在许多疾病的发病中也起着重要的作用,例如伴随浆细胞增多的疾病如类风湿(Hirano,T.et al.,Eur.J.Immunology 18:1797-1801,1988;Houssiau,F.A.et al.,Arth Rheum.31:784-788,1988),Castleman氏病(Yoshizaki,K.et al.,Blood 74:1360-1367,1989;Brant,S.J.et al.,J.Clin.Invest.86:592-599,1990),肾小球膜细胞增殖性肾炎(Ohta,K.et al.,Clin.Nephrol.(Germany)38:185-189,1992;Fukatsu,A.et al.,Lab.Invest,65:61-66,1991;Horri,Y.et al.,J.Immunol. 143:3949-3955,1989),伴随肿瘤生长的恶病质(Strassmann,G.et al.,J.Clin.Invest.89:1681-1684,1992)等,另外还可做为生长因子引起多发性骨髓瘤。
在H-2Ld hIL-6转基因小鼠(IL-6Tgm)中,由于其通过基因工程的方法使人类IL-6(hIL-6)表达过多,已经观察到IgG浆细胞增多,肾小球膜细胞增殖性肾炎,贫血,血小板减少,出现自身抗体等现象或疾病(Miyai,T,et al.,a presentation at the 21st Meeting ofJapan Immunology Society“Hematological changes in H-2LdhIL-6transgenic mice with age,”1991),上述这些表明IL-6与多种疾病的发生有关。然而现在还不知道抗白介素-6受体的抗体对白介素产生而引起的疾病是否有效。
本发明披露
依照本发明,本发明提供了用来预防或治疗由IL-6所致疾病的药物组合物。
为了解决上述的问题,本发明提供一种用来预防或治疗由IL-6产生所致疾病的药物组合物,该组合物含有抗白介素-6受体抗体。
附图的简要说明
图1所示为每组动物体重增加的变化。
图2所示为每组尿蛋白阳性率的变化。除组1和组3,其它组尿蛋白阳性率为零。
图3所示为每组血红蛋白浓度的变化。
图4所示为每组血红细胞数的变化。
图5所示为每组血小板的变化。
图6所示为每组白细胞的变化。
图7所示为每组血清中IgG1浓度的变化。
图8所示为组1到组5人IL-6浓度的变化。
图9为在组1和组2通过荧光抗体技术使用对照抗体IgG和Gr-1抗体对细胞进行分类的结果。
图10为在组6和组7通过荧光抗体技术使用对照抗体IgG和Gr-1抗体对细胞进行分类的结果。
图11为每组动物在实验结束时脾脏的重量。
图12为每组动物体重的变化。
图13为在实验的第11天,小鼠血中甘油三酯的浓度。
图14为在实验的第15天,小鼠的血糖浓度。
图15为在实验的第11天,小鼠血中钙离子的浓度。
图16所示为肿瘤对照组小鼠的生存率。
图17为实验开始后的第10天和12天小鼠的体重。
图18为实验开始后的第10天和第12天,小鼠血中的钙离子浓度。
详细的说明
白介素-6产生所致疾病包括有浆细胞增多性疾病如类风湿病及Castleman氏病;高免疫球蛋白血;贫血;肾炎如小球系膜增殖性肾炎;恶病质等。
用于本发明中的白介素-6受体抗体,只要能阻止IL-6的信号传导并抑制IL-6的生物活性就可以是任何一种来源或类型的抗体(单克隆,多克隆)。但最好是由哺乳类动物产生的单克隆抗体。抗体通过抑制IL-6与IL-6R的结合,阻断IL-6的信号传导并抑制其生物活性。
产生单克隆细胞的动物种类可为哺乳类动物的任何一种,可以是人类抗体或者是除人以外的一种动物的抗体。从容易制备这个角度考虑,除人以外的单克隆抗体,还是以兔或鼠类产生的单克隆抗体较好。鼠类产生的单克隆抗体较好,包括小鼠,大鼠,豚鼠等,但不局限于此。
这样的白介素-6受体抗体包括例如MR16-1抗体(Tamura,T.et al.,Proc.Natl.Acad.Sci.U.S.A.90:11924-11928),PM-1抗体(Hirata,Y.et al.,J.Immunol.143:2900-2906,1989)等。
单克隆抗体的制备基本上可通过下述的本领域已知方法来进行。采用常规的方法免疫动物,即使用IL-6R做为免疫抗原,然后通过常规的细胞融合方法将所得的免疫细胞与已知的母细胞融合,通过常规的筛选方法筛选产生抗体的细胞。
更具体地讲,单克隆抗体是通过下述的方法来制备的。如免疫抗原可通过欧洲专利申请EP325474中所述的采用人IL-6R基因序列来得到。先将人IL-6R基因序列***一个已知的表达载体内,以转化适合的宿主细胞,之后纯化宿主细胞或培养液上清产生的所要的IL-6R蛋白质,用该纯化的IL-6R蛋白质做为免疫抗原。
另外,也可采用与上述人IL-6R基因序列相同的方法,使用日本未审查专利公开3(1991)-155795中所述的小鼠IL-6R基因序列来得到上述的来源于小鼠的免疫抗原。
做为IL-6R,除了细胞膜上表达的外,还可有从细胞膜解吸的IL-6R(sIL-6R)也可做为抗原。sIL-6R主要是由与细胞膜结合的IL-6R的细胞外部分组成,其与和细胞膜结合的IL-6R不同之处:sIL-6R缺乏贯穿膜的区或者贯穿膜的区及细胞内区都缺乏。
免疫抗原免疫的哺乳类动物种类没有特别限制,但是如考虑到其与用做细胞融合的母细胞的相容性,优选使用小鼠,大鼠,豚鼠及兔等哺乳类动物。
可根据本领域技术人员已知的方法用免疫抗原免疫动物。例如,常用的方法是经腹腔或皮下给哺乳类动物注射免疫抗原。更具体地讲,将免疫抗原用PBS(磷酸缓冲盐溶液),生理盐水稀释或混悬至一定的体积,然后如需要再与适量的佐剂如弗氏完全估剂混合并乳化,此后优选每4-21天给哺乳类动物注射该乳剂几次。此外,在用免疫抗原免疫动物时可使用适当的载体。
在如上所述免疫动物且测定血清中抗体浓度已达到所希望的浓度后,从哺乳类动物取出免疫细胞并进行融合。具体提到的取出的免疫细胞以脾细胞较好。
本发明中,用于与免疫细胞融合的配对母细胞优选骨髓瘤细胞,其包括许多种已知的细胞系,如P3(p3x63Ag8.653)(J.Immunol 123:1548,1978),p3-U1(Current Topicsi Micro-biology and Immunology81:1-7,1978),NS-1(Eur.J.Immunol.6:511-519,1976),MPC-11(Cell 8:405-415,1976),SP2/0(Nature 276:269-270,1978),FO(J.Immunol.Meth.35:1-21,1980),S194(J.Exp.Med,148:313-323,1978)及R210(Nature 277:131-133,1979)等。
骨髓瘤细胞与所述免疫细胞的融合可按照Milstein等人所述的方法来进行(Milstein et al.,Methods Enzymol.73:3-46,1981)。
更具体地讲,上述细胞融合可在普通的营养液中加入细胞融合促进剂来进行。为了增加细胞融合的效率可使用聚乙烯乙二醇及Sendai病毒等做为细胞融合促进剂,还可按需要直接加入二甲基亚砜等作为佐剂。
免疫细胞与骨髓瘤细胞的比值优选多于骨髓瘤细胞的1-10倍免疫细胞。用于上述细胞融合的液体细胞培养液可使用RPMI1640液体培养液及MEM液体培养液,这些培养液非常适合骨髓瘤细胞系的生长,也可使用普通的培养肉汤进行细胞培养,另外还可使用血清添加剂如小牛血清(FCS)等。
制备所需的融合细胞(杂交瘤)需在上述的营养肉汤中按上述的比例加入免疫细胞及骨髓瘤细胞并充分混合,另外还需要向培养液中加入事先预热至37℃的PEG溶液。PEG溶液中PEG的平均分子量应在1000至6000这个范围,而PEG的浓度为30至60%(w/v)。在按顺序加免适宜培养介质后,进行离心以去除上清及细胞融合剂等,这些物质均对杂交瘤生长不利。
可通过常规的筛选培养液培养来筛选上述的杂交瘤,该筛选培养液如HAT液体培养液(含有次黄嘌呤,氨基喋呤及胸腺嘧啶的液体培养液)。将在HAT培养液中进行的细胞培养持续进行足够的时间,以使除杂交瘤以外的细胞(非隔合细胞)死亡,通常这样的细胞培养需要数天乃至数周。随后采用常规的有限稀释方法筛选并克隆产生所需抗体的杂交瘤。
可通过常规的液体培养液传代培养所得的产生单克隆抗体的杂交瘤,并可在液氮中长期保存该杂交瘤。
为了获得杂交瘤产生的单克隆抗体,可采用下述方法,如按照常规方法培养杂交瘤,然后取培养液上清,或者将杂交瘤植入并生长在一种合适的哺乳类动物体内,通过腹水等获取抗体。前一种方法可获取高纯度抗体,而后一种方法则可获取大量抗体。
另外,上述方法所得的单克隆抗体可采用常规的方法进行纯化,如盐析,凝胶过滤,及亲和层析等。
可采用常规的免疫方法如放射免疫分析,酶免疫分析(EIA,ELISA),荧光抗体方法(免疫荧光分析)等来确定所得单克隆抗体识别抗原的高亲和力及高度特异性的能力。
本发明中所使用的单克隆抗体并不局限于杂交瘤产生的单克隆抗体,也可是为减小对人的异种免疫原性而经人工改造过的单克隆抗体。例如使用含有小鼠单克隆抗体可变区及人抗体不变区的嵌合抗体。可通过已知的方法(主要是基因工程的方法)来制备嵌合抗体。
另外,本发明也可使用重构的人类抗体。在该抗体中可由除人类抗体外的其它哺乳动物抗体如小鼠抗体的互补决定簇区域替换人类抗体的互补决定簇区域。可采用已知的基因工程的通用方法来制备该种类型抗体。使用该方法可获取用于本发明中的重构人类抗体。
如必要,可替换抗体可变区域中框架区域(FR)的氨基酸,这样可使重建过的人类抗体的互补决定簇区域形成一合适的抗原结合位点(Sato et al.,Cancer Res.53:1-6,1993)。这种重构人类抗体举例有如人类化PM-1(hPM-1)抗体(见国际专利申请WO 9219759)。
编码如Fab或Fv,单链Fv(ScFv)(其中Fv的H链和L链已通过连结剂连结起来)的抗体片段的基因,可在合适的宿主细胞内构建并表达,只要该片段可结合抗原并抑制IL-6的活性(参见Bird et al.,TIBTECH 9:132-137,1991;Huston et al.,Proc.Natl.Acad.Sci.U.S.A.85:5879-5883,1988)。进一步讲,上述抗体的重构V区可用于制备Sc H链和L链的Fv来制备ScFv。
只要能阻断IL-6信号传导,有效治疗由IL-6产生所致疾病,本发明中用于预防或治疗由IL-6产生所致疾病的药物组合物包括活性成分为抗IL-6受体的抗体。
用于预防或治疗由IL-6产生所致疾病的药物组合物优选经非肠道途径给药,例如经静脉,肌内,腹膜内或皮下注射等途径给药,即可全身也可局部用药。此外,药物组合物可与至少一种药物载体或稀释液混合为药物组合物或药盒形式。
虽然本发明中药物组合物的剂量可根据病情,病人年龄或给药方式而有所不同,但还是需要选用合适的剂量。例如,每个病人可在1至1000mg的范围内有最多分4种不同的剂量供选用。也可按照1至10mg/kg/周的剂量进行给药。但是本发明中用于治疗或预防的药物组合物并不局限于上述的剂量。
本发明中药物组合物可采用常规的方法来配制。例如,非肠道制剂的制备可用一种溶剂如生理盐水,缓冲溶液等溶解纯化的IL-6R抗体,再向其中加入抗吸附剂如吐温80,明胶,人血清白蛋白(HSA)等,或制剂也可是通过使用前溶解再重组的冻干形式,用于冻干的赋形剂有糖醇如甘露糖醇,葡萄糖等,或者是糖类。
实施例
本发明将通过下述的实施例做更详细地说明,但本发明并不局限于下述的实施例。
参考实施例1.B6Ld-IL-6转基因小鼠的构建
按照Yamarnura等人所述的方法(Yamamura et al.,J.Biochem.96:357,1984)通过显微注射将带有连结有H-2Ld启动子的人IL-6cDNA的一个3.3Kbp Sphl-XhoI片段(Ld-IL-6)(Suematsu et al.,Proc.Natl.Acad,Sci,U.S.A.86:7547,1989)注入(57BL/6)(B6)小鼠(Nihon Clea)受精卵的***内。
将受精卵移植入一个经过假孕治疗的雌性ICR小鼠的输卵管。以后新生小鼠有关hIL-6cDNA的整合可采用32P标记的含有人IL-6cDNATaq I-BanII片段的探针与EcoRI内切酶消化的DNA尾部进行Southern印迹分析来筛选。整合试验阳性的小鼠可与B6小鼠繁殖建立具有同种基因型的小鼠系。
参考实施例2.大鼠抗IL-6R抗体的制备
可采用Saito等人所述的方法(J.Immunol.147:168-173,1991)制备产生小鼠可溶性IL-6R的CHO细胞。细胞在αMEM培养液中培养,该培养液含有5%小牛血清(FBS),培养条件为37℃,及含5% CO2有一定湿度的空气。收集所得的培养液并用来制备小鼠sIL-6R。培养液中小鼠sIL-6R的浓度可使用单克隆抗小鼠IL-6R抗体RS15(Saito et al.,J.Immunol.147:168-173,1991)及兔多克隆抗小鼠IL-6R抗体采用三明治ELISA方法来测定。
使用吸附有单克隆抗小鼠IL-6R抗体(RS12)的亲和柱由小鼠sIL-6R制剂纯化小鼠sIL-6R。溶于完全弗氏佐剂的50微克纯化的小鼠sIL-6R经皮下注入Wistar大鼠,此后,从第二周开始每周皮下注射一次溶于不完全弗尔佐剂的小鼠IL-6R,共注射四次以对动物增强免疫。第-次增强免疫注射一周后,对大鼠静脉注射溶于100μl磷酸缓冲盐溶液(PBS)的50μg小鼠sIL-6R。
三天后,从大鼠体内取出脾脏,然后用大鼠脾细胞与小鼠p3ul骨髓瘤细胞以10∶1的比例进行融合。在96孔板(Falcon 3075)的孔内用100μl含有10%FBS的RPMI1640培养液在37℃的温度下过夜培养细胞,然后加入含有次黄嘌呤/氨基喋呤/胸腺嘧啶(HAT)的培养液100μl。以后每天以HAT培养液更换一半的培养液,共4天。
7天后,通过小鼠sIL-6R结合分析的方法(ELISA)筛选出产生抗小鼠sIL-6R的杂交瘤。简言之,将100μl的杂交瘤培养液上清孵育在一个事先涂有1μg/ml的兔多克隆抗大鼠IgG抗体的板上。冲洗该孵育的板,然后再与100μg/ml的小鼠SIL-6R一起孵育。冲洗后,再加入2μg/ml的兔多克隆抗小鼠IL-6R抗体,冲洗该板,然后再与结合有碱性磷酸酶的山羊多克隆抗兔IgG抗体(Tago)一起孵育60分钟。
冲洗后,最后再将该板与碱性磷酸酶的底物(sIGMA 104;p-硝基苯磷酸盐)一起孵育,并使用板读数器(Toso)在405nm处读数。采用有限稀释的方法克隆2次识别小鼠sIL-6R的杂交瘤。如用腹水制备单克隆抗体,可先给BALB/c nu/nu小鼠注射2次0.5ml的降植烷,3天后将已建立起来的4×106个杂交瘤细胞注入腹腔。10到20天后,收集腹水,并采用G蛋白柱子(Oncogene Science)纯化单克隆抗体MR16-1。
由MR16-1产生的抗体对IL-6的中和作用可采用3H胸腺嘧啶对MH60.BSF2细胞的***情况来测定(Matsuda et al.,Eur.J.Immunol.18:951-956,1988)。将MH60.BSF2细胞以1×104个细胞/200μl/孔的数量等分加入96孔板,然后向孔内加入小鼠IL-6(10pg/ml)和MR16-1或RS12抗体,随后在37℃及5% CO2的条件下孵育细胞44小时。然后将3H胸腺嘧啶(1mCi/孔)加入板的每个孔中,4小时后测定3H的***情况。
实施例1
取31只经B6IL-6转基因小鼠(B6 IL-6Tgm)繁殖具有人IL-6cDNA的转基因小鼠,B6IL-6转基因小鼠的制备见参考实施例1,另外取正常的不携带人IL-6cDNA的同窝小鼠11只(均为4周龄,雄性)。将B6IL-6Tgm分为5组(组1-组5),每组6只动物,只有组1有7只动物。组6有5只正常的同窝小鼠,组7有6只。
给药计划如下:
组1(B6IL-6Tgm):给4周龄小鼠(实验第1天)静脉注射大鼠IgG1抗体(KH5)(对照抗体),剂量为2mg/0.2ml,5周龄后(实验的第8天),每周皮下注射2次100μg的KH5抗体(每3到4天注射1次)。
组2(B6IL-6Tgm):给4周龄小鼠静脉注射MR16-1抗体,剂量为2mg/0.2ml,5周龄以后,每周皮下注射2次100μg的MR16-1。
组3(B6IL-6Tgm):给4周龄小鼠静脉注射0.2ml的磷酸缓冲盐溶液,5周龄以后,每周皮下注射2次100μg的MR16-1。
组4(B6IL-6Tgm):给4周龄小鼠静脉注射2mg/0.2ml的MR16-1,5周龄以后每隔1周皮下注射400μg的MR16-1。
组5(B6IL-6Tgm):给4周龄小鼠静脉注射2mg/0.2ml的MR16-1,5周龄以后每隔周皮下注射1mg的MR16-1。
组6(正常的B6同窝小鼠):给4周龄小鼠静脉注射2mg/0.2ml的对照抗体KH5,5周龄以后每周皮下注射2次100μg的KH5。
组7(正常的B6同窝小鼠):给4周龄小鼠静脉注射2mg/0.2ml的MR16-1,5周龄以后每周皮下注射2次100μg的MR16-1。
所采用的实验方法如下:
测量体重并测定尿蛋白:每周测量体重并以尿蛋白试纸(Combistics Sankyo)测定尿蛋白。3个加号尿蛋白(100至300mg/dl)或更高的尿蛋白记为阳性。
血样的采用:从实验开始(4周龄)每隔1周从眶后静脉窦取血1次,实验结束时(18周龄)从下腔静脉采集全部血液。
血细胞计数:采用微型细胞计数仪(Sysmex F-800),测定血红蛋白含量(HGB),白细胞数(WBC),红细胞数(RBC),及血小板数(PLT)。实验结束时,在一些组(组1,2,6及7)制备血液涂片,并测定白细胞分类百分比。
血中IgG1浓度的测定:使用一种骨髓瘤蛋白为标准通过小鼠IgG1特异性的ELISA方法进行测定。
血IL-6浓度的测定:通过一种hIL-6特异的ELISA方法进行测定。
血抗大鼠IgG抗体(IgG类型)滴度的测定:由于所给的抗体对小鼠来说是一种异类抗体,对所给予抗体产生的抗体可使用大鼠IgG做为抗原通过ELISA方法来测定。结果以给予大鼠抗体的成年动物的标准IL-6Tgm血清为单位来表示。
血中化学参数的测定:实验结束时,使用自动分析仪(COBASFARA II,Roche)测定组1,2,3,6和7小鼠血清的总蛋白(TP),白蛋白(Alb),葡萄糖(Glu),甘油三脂(TG),肌酐(CGE),血尿素氮(BUN),钙(Ca),碱性磷酸酶(ALP),谷草转氨酶(GOT),及谷丙转氨酶(GPT)。
骨髓及脾细胞的FACS分析:实验结束时,从组1,2,6及7中取1只动物采集骨髓及脾细胞标本,并通过FACS can(BecktonDickensian)进行细胞表面抗原分析。所用抗体相应地为Gr-1(骨髓细胞),CD4,CD8,及B220(脾细胞)抗体(Pharmingen)。
尸检:实验结束时,进行尸检,测量脾脏重量并用眼检查主要脏器。
体重:每组体重的变化见图1。在组1和组3,体重增加。其它组中未见有体重不同的变化。
尿蛋白:在组1中从13周龄开始出现尿蛋白阳性动物(图2),7只动物中的4只在尸检时已经死亡(2只在16周龄时死亡,2只在17周龄时死亡)。然而在其它组未见有死亡动物。在组3,6只动物中也有2只在实验结束时尿蛋白呈阳性,而在其它组未见有尿蛋白呈阳性的动物。
血液学所见:在组1可见血红蛋白浓度减少(图3)及红细胞数减少(图4),并随着年令增大程度加重。血小板数(图5)呈现一过渡升高但随后很快减少。在组3虽然较组1稍迟些也可见相似的倾向。在组2,4和5,既没有观察到血红蛋白浓度及红细胞数的减少,也未见到血小板数增加及随后的减少。有关血涂片血细胞计数的分类,组1可见中性细胞及单核细胞增加及淋巴细胞部分相应的减少,但在组2则为正常值(表1)。组6和组7之间也未见有显著性差异。
表1
组 | 幼稚中性细胞 成熟中性细胞 嗜酸细胞 嗜碱细胞 单核细胞 淋巴细胞 其它 | |
1 | 均值SD* | 2.00 31.33 1.33 0.00 9.33 56.00 0.002.00 3.79 0.58 0.00 4.93 9.54 0.00 |
2 | 均值SD*t-检验 | 0.33 13.83 2.33 0.00 2.00 81.00 0.500.52 4.17 1.03 0.00 2.28 4.82 0.550.0676 0.0000 0.0557 - 0.0129 0.006 0.0676 |
6 | 均值SD* | 0.30 14.10 2.80 0.00 1.30 81.40 0.100.45 4.60 0.91 0.00 1.04 4.08 0.22 |
7 | 均值SD*t-检验 | 0.42 10.67 2.42 0.08 0.58 85.75 0.080.38 2.32 0.97 0.20 0.49 1.92 0.200.6484 0.1406 0.5101 0.3816 0.1644 0.0427 0.8992 |
*SD:标准差
血中IgG1浓度:在组1实验开始后,血IgG1浓度立即明显上升,最后达到正常小鼠浓度的100倍(图7)。在组3IgG1浓度的上升较组1稍晚。反过来,在组2,4和5未见IgG1浓度上升,在整个实验中其浓度几乎保持不变。另外,对于正常小鼠未见给予抗体后有关的变化。
血hIl-6浓度:血hIL-6浓度的变化与IgG1变化的方式相同(图8),即在组1和组3有增加,而其它组在整个实验过程中几乎无变化。
血抗大鼠IgG抗体的滴度:可在组1,3和6检测到抗大鼠IgG抗体(表2)。组1和组3的所有动物呈高滴度,而在组65只动物中只有2只呈现滴度升高。另外,其它组未见有明显的升高。
小鼠抗大鼠抗体(单位/毫升)表2
组别 年龄(周)4 6 8 10 12 14 16 18 |
1 0.15 0.78 1.69 7.41 100< 100< 100< 100<2 0.22 0.34 0.45 0.38 0.43 0.50 0.39 0.303 0.14 0.61 0.69 0.67 2.27 4.74 14.25 41.244 N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.575 N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.286 N.D. N.D. N.D. N.D. N.D. N.D. N.D. 3.557 N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.20 |
N.D.:未检测
血中化学参数的测定:在组1和组3可见TP升高, Alb减低,在组1和组3还可见到TG和Alp减低,在组1甚至血糖也减低。在组2未见这些改变。
表3
组别 总蛋白 白蛋白 葡萄糖 甘油三脂 肌酐 尿素氮 钙 碱性磷酸 谷草转氨 谷丙转氨(g/dl) (g/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) 酶(U/l) 酶(IU/L) 酶(U/l) |
1 均值 14 2.41 77.4 20.7 0.4 34.8 8.6 27.67 33.33 6标准差 1.33 0.3 14.5 8.33 0.2 23.7 0.35 5.69 5.86 1.732 均值 5.68 3.31 199 62.3 0.51 28.3 8.67 156.5 37.5 5.6标准差 0.3 0.2 29.5 10.9 0.22 4.08 0.58 14.31 8.22 1.143 均值 12.6 2.92 253 41 0.61 26.4 9.82 54.17 27.33 6.83标准差 2.85 0.64 60.2 16.3 0.17 6.25 0.83 42.62 5.65 1.726 均值 5.9 3.84 289 105 0.87 27.9 8.9 181 33.2 9.6标准差 0.65 0.46 98.9 28.8 0.22 6.32 0.74 21.24 8.9 5.817 均值 5.86 3.63 300 94 0.75 26.8 8.98 196.83 34.5 6.5标准差 0.53 0.34 25.5 20 0.2 5.26 0.82 21.68 4.89 3.08 |
FACS分析:对组1,2,6,7中的骨髓细胞(BM)及脾细胞(sp)的分析表明在组1BM细胞中Gr-1阳性的颗粒细胞祖细胞明显增加(图9和图10),但在组2中则与正常的同窝小鼠的数值相类似。组6和组7之间无明显不同。有关sp CD4-,CD8-,和B220-阳性细胞的比值除组1由于浆细胞的增加CD8-和B220阳性细胞减少外(表4),在其它组未见有不同。
表4脾细胞表面抗原的分析组别 CD4+ CD8+ B220+1 13.2% 5.4% 23.1%2 18.5% 14.3% 50.0%3 19.9% 15.0% 53.1%4 13.9% 10.6% 57.3%
尸检所见:在组1和组3可见全身***及脾脏明显肿大(图11),另外还可见肾脏退色。另外还可见部分肝脏肿大。而在其它组未见上述改变,除在组2,4和5与正常的同窝小鼠比较可见脾脏稍有肿大,未见有其它的明显改变。
下面对上述实验结果进行说明。在服用对照抗体的IL-6Tgm组(组1),可见到IgG1浆细胞增多,贫血,血小板增多,血小板减少,肾衰及血化学指标异常等若干表现。然而上述这些表现均可被MR16-1抑制。
已知IL-6可使B细胞最终分化为浆细胞(Muraguchi,A.et al.,J.Exp.Med.167:332-344,1988),在IL-6Igm组,IL-6的生成可致血IgG1浓度增加,血清中TP浓度增加及Alb浓度减少。这些表现表明已经出现IgG1浆细胞增多。
尽管在组1和组3由于疾病进展而总的情况恶化,但由疾病引起的全身淋巴组织如***及脾脏的明显肿大会导致体重增加。MR16-1不仅可完全抑制上述这些情况,而且可抑制血IL-6浓度的升高。这样证实在IL-6Tgm组中与年龄相关的血IL-6浓度升高与浆细胞增殖有直接的关系。所以认为增殖的浆细胞本身可促进IL-6产生,而IL-6又可进一步促进浆细胞的生长,其结果为IL-6大量产生。
有关IL-6对血细胞的作用,已知IL-6可引起血小板增加(Ishibashi,T.et al.,Proc.Natl.Acad.Sci.U.S.A.86:5953-5957,1989;Ishibashi,T.et al.,Blood 74:1241-1244,1989)并引起巨细胞贫血(Hawley,R.G.et al.,J.Exp.Med.176:1149-1163,1992)。除上所述,在IL-6Tgm组与年龄相关的血小板减少与多克隆B细胞激活所致的自身免疫有关(Miyai,Tatsuya et al.,ibid)。
MR16-1可完全抑制IL-6对血细胞所产生的直接和间接作用,但并不影响正常同窝小鼠的血细胞计数。所以可以肯定抗IL-6受体抗体根本不会影响血细胞。在IL-6Tgm组可见到被认为是颗粒细胞祖细胞的Gr-1阳性细胞的比值及外周血中性细胞的比值升高。虽然已知IL-6可增加中性粒细胞,但其详细的机制尚不清楚。本研究发现产生这一现象的作用发生在骨髓祖细胞的水平。本研究还发现MR16-1可完全抑制IL-6的作用,但并不影响骨髓及外周血的中性粒细胞水平。
在IL-6Tgm组还可观察到MR16-1可抑制肾炎的发生。已经有报道认为IL-6与系膜细胞自主生长因子所致的小球系膜细胞增殖型肾炎的发生有密切关系。虽然在IL-6Tgm组中所发生的肾炎已确定为小球系膜细胞增殖型肾炎,但也不能排除因IL-6增加免疫***是否在发病中也起-定的作用(Katsume,Asao et al.,a presentation at the21st Meeting of Japan Immunology Society,“Characterization ofSCID×(SCID×H-2LdhIL-6 transgenic mice),”1991)。总之,由于可抑制尿蛋白的出现,降低死亡数,抗IL-6受体抗体可有效地抑制因IL-6产生所致的肾炎发生这一点是很明确的。
在IL-6Tgm组可见有关恶病质的指标如血Glu和Tg浓度有明显下降。在本实验中由于组1 Glu和Tg减少,而在组2这些指标几乎回到正常动物的正常水平,所以认为给予MR16-1可有效缓解恶病质。
由于MR16-1为一种大鼠IgG1,对于小鼠来讲属于异种蛋白,所以很容易想到对于所服用抗体所产生的抗体将使得所服用的抗体失去效果。
在本实验第一次致敏时,为了通过暴露大剂量抗原引发免疫耐受,每组第1次给予抗体时静脉注射抗体2mg/鼠。在给予MR16-1的组中(组1,4,及5),经过上述免疫耐受法处理过的组无论给药间隔及给药剂量如何未检测出抗大鼠IgG抗体,而且可以完全抑制疾病的发生。虽然给予对照抗体的组3抗大鼠IgG抗体升高,最终组3还是表现出与组1相同的表现,只是疾病的发生稍晚于组1。
这样就说明引起免疫耐受的治疗是有效的,但是在以同样方式给予对照抗体的组1所有动物及组6 2/5的动物仍可检测出抗大鼠IgG抗体。由于在IL-6Tgm组中浆细胞增多引起多克隆B细胞激活,所以不能认为在组1和组3中检测出的抗大鼠IgG抗体为所给予抗体的特异性抗体。但是仍可以推断在组2,4和5由于第1次致敏时给予大量的抗原,加之由于给予大量MR16-1特异性抗体所产生的抑制作用可引发完全的免疫耐受反应。
本实验可以明确抗IL-6受体抗体可在不影响正常抗体水平的情况下非常有效地治疗由IL-6产生所致的各种疾病。
实施例2
研究了有关小鼠IL-6受体抗体对结肠26所致恶病质模型的作用。所用小鼠为6周龄雄性BALB/C小鼠,在实验的第1天给小鼠侧腹部皮下植入一段2mm的结肠26。在实验第1天植入结肠26前立即给动物静脉注射剂量为2mg/小鼠的小鼠IL-6受体抗体MR16-1(见参考实例2),以后在7,11,14和18天皮下注射剂量为0.5mg/小鼠的抗体(n=7)。前面的实验已经证实使用该方法并不容易产生抗异种蛋白的中和抗体。对肿瘤对照组的动物中按同样的方式给予大鼠IgG1对照抗体(KH5)(n=7)。另外对非肿瘤对照组的动物给予PBS(n=7)。实验开始后,每天测量体重,并在实验的11和15天测定血中的化学参数及血钙浓度。
10天后与非肿瘤组比较,肿瘤组体重有明显下降,而在给予了MR16-1的组中(图12),可以部分抑制体重的下降。图13和图14分别给出了11天时血甘油三脂的浓度及15天时血糖的浓度。与非肿瘤对照组比较,这些指标在肿瘤对照组有明显减少,而在给予MR16-1的组中可观察到对上述的血糖降低有抑制倾向,而对上述甘油三脂的降低则有明显的抑制作用。
与非肿瘤对照组比较,肿瘤对照组在实验的第11天血钙离子浓度明显上升,而在给予MR16-1的组中则对此有明显的抑制作用(图15)。
采用与上述类似的方法(n=10)进行的旨在确定生存时间效果的实验中,结果在给予MR16-1的组中可观察到有延长生存时间的作用(图16)。
实施例3
该实验研究了IL-6受体抗体对由OCC-1引起的伴有高血钙的恶病质模型的作用。所用小鼠为6周龄雄性裸鼠。实验第1天,在小鼠腹部外侧皮下植入鳞癌细胞系OOC-1。实验第1天植入肿瘤细胞系前经静脉给予剂量为2mg/小鼠的小鼠IL-6受体抗体MR16-1(见参考实施例2),此后在第7和10天皮下注射剂量为100μg/小鼠的上述抗体(n=6)。前面的实验已经证实使用该方法并不容易产生抗异种蛋白即大鼠抗体的中和抗体。对肿瘤对照组按同样的方法给予大鼠IgG1对照抗体(KH5)。另外一组动物给予PBS做为非肿瘤对照组(n=7)。实验开始后在第10天和12天测定体重及血钙浓度。
在肿瘤组体重有所下降,而在给予MR16-1的组则与非肿瘤对照组体重的变化类似,表明有抑制体重下降的作用(图17)。
与非肿瘤对照组相比,肿瘤对照组的血钙浓度明显升高,而在给予MR16-1的组则血钙升高被强烈的抑制(图18)。
Claims (14)
1.用于预防或治疗由IL-6产生所致疾病的药物组合物,其含有白介素-6受体的抗体。
2.根据权利要求1的用于预防或治疗的药物组合物,其中上述的由白介素-6产生所致的疾病为浆细胞增多症。
3.根据权利要求1的用于治疗或预防因白介素-6产生所致疾病的药物组合物,其中的疾病为高免疫球蛋白血症。
4.根据权利要求1的用于预防或治疗因白介素-6产生所致疾病的药物组合物,其中所述疾病为贫血。
5.根据权利要求1的用于预防或治疗因IL-6产生所致疾病的药物组合物,其中所述疾病为肾炎。
6.根据权利要求1的用于预防或治疗因白介素-6产生所致疾病的药物组合物,其中所述疾病为恶病质。
7.根据权利要求2的用于治疗或预防浆细胞增多症的药物组合物,其中浆细胞增多是由类风湿引起的。
8.根据权利要求2的用于预防或治疗浆细胞增多症的药物组合物,其中浆细胞增多是由Castleman氏病所引起。
9.根据权利要求5的预防或治疗肾类的药物组合物,其中肾炎为小球系膜细胞增殖型肾炎。
10.根据权利要求1至9中的任何一个权利要求的用于预防或治疗的药物组合物,其中的抗体为单克隆抗体。
11.按照权利要求10的用于预防或治疗的药物组合物,其中抗体为PM-1抗体。
12.按照权利要求10的用于预防或治疗的药物组合物,其中抗体为嵌合抗体。
13.按照权利要求10的用于预防或治疗的药物组合物,其中抗体为重建的人类抗体。
14.按照权利要求3的用于预防或治疗的药物组合物,其中抗体为重建的人类PM-1抗体。
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CN2007100843445A Division CN101011574B (zh) | 1994-10-21 | 1995-10-20 | Il-6受体的抗体在制备药物组合物中的用途 |
CN201010173242A Division CN101829325A (zh) | 1994-10-21 | 1995-10-20 | Il-6受体的抗体在制备药物组合物中的用途 |
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CNB951963570A Expired - Fee Related CN1306963C (zh) | 1994-10-21 | 1995-10-20 | 用于治疗il-6产生所致疾病的药物组合物 |
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