CN101454345B - 人il-6受体的高亲和力抗体 - Google Patents
人il-6受体的高亲和力抗体 Download PDFInfo
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Abstract
本申请提供了人抗体或抗原结合片断,其与人IL-6受体(hIL-6R)结合的KD为约500pM或更小,封闭IL-6活性的IC50为200pM或更小。所述抗体或抗体片断与hIL-6R结合的亲和力比与猴IL-6R的结合高至少两倍。
Description
相关领域的说明
白细胞介素-6(IL-6)是由免疫细胞和非免疫细胞产生的多向性细胞因子,在免疫反应、急性期反应和造血作用的调控中起至关重要的作用。其与可溶的和细胞膜结合的IL-6R(α链)相结合,形成二元复合物,此复合物能够与细胞膜结合的gp130(β链)相互作用,诱导信号传导复合物的形成,其包含IL-6、IL-6R和gp130各两个。
US 5,670,373、5,795,965、5,817,790、6,410,691和EP 409 607B1中描述了hIL-6R的抗体。US 5,888,510和6,723,319中描述了治疗方法。
发明概述
第一方面,本发明提供了与人白细胞介素-6受体(hIL-6R)特异性结合的人抗体,优选重组人抗体。这些抗体的特征在于,与hIL-6R以高亲和力和低解离动力学结合,且能够中和IL-6的活性。抗体可为全长(例如,IgG1或IgG4抗体),或可能仅包含抗原结合部分(例如,Fab、F(ab’)2或scFv片断),可能被修饰以影响功能性,例如,消除残留的效应功能(Reddy等人,(2000)J.Immunol.164:1925-1933)。在优选实施方案中,本发明提供抗体或其抗原结合片断,与人IL-6受体(SEQ ID NO:1)结合的KD为约500pM或更小,KD用表面等离子体共振测量。在更具体的实施方案中,抗体或抗原结合片断的KD小于300pM,或小于200pM,或甚至小于100pM。在多种实施方案中,抗体或其抗原结合片断封闭hIL-6活性的IC50为250pM或更小,IC50用荧光素酶生物测定法测量。在更具体的实施方案中,抗体或其抗原结合片断显示IC50为150pM或更小。
在相关方面,本发明的抗体或抗原结合片断与hIL-6R结合,比其与猴IL-6R结合的亲和力高至少两倍。在更优选的实施方案中,抗体或抗原结合片断与hIL-6R蛋白(SEQ ID NO:1)结合,比其与猴IL-6R(食蟹猴(Macaca fascicularis)胞外域,如SEQ ID NO:251所示)结合的亲和力高约达三倍。
在一个实施方案中,本发明抗体或抗体的抗原结合部分包含重链可变区(HCVR),选自SEQ ID NO:3、227、19、231、35、51、67、83、99、115、131、147、239、241、163、179、235、195和211,或与这些基本上相似的序列。在更具体的实施方案中,抗体或其抗原结合片断还包含轻链可变区(LCVR),选自SEQ ID NO:11、229、27、233、43、59、75、91、107、123、139、155、171、187、237、203和219,或与这些基本上相似的序列。在具体实施方案中,抗体或其抗原结合片断包含HCVR/LCVR对,选自SEQ ID NO:3/11;227/229;19/27;231/233;35/43;51/59;67/75;83/91;99/107;115/123;131/139;147/155;239/155;241/155;163/171;179/187;235/237;195/203;和211/219,或与这些基本上相似的序列。
第二方面,本发明提供分离的核酸分子,其编码本发明的抗体或抗体的抗原结合片断。在一个实施方案中,本发明的核酸分子编码包含上述HCVR的抗体或其片段。在具体实施方案中,编码HCVR的核酸分子选自SEQ ID NO:2、226、18、230、34、50、66、82、98、114、130、146、238、240、162、178、234、194和210,或与这些基本上相同的序列。在相关方面,本发明提供分离的核酸分子,其编码上述的LCVR。在具体实施方案中,编码LCVR的核酸分子为这样的核苷酸序列,其选自SEQ IDNO:10、228、26、232、42、58、74、90、106、122、138、154、170、186、236、202和218,或与这些基本上相同的序列。
第三方面,本发明提供这样的抗体或抗原结合片断,其包含重链互补决定区3(CDR3)结构域和轻链CDR3结构域,其中
重链CDR3结构域包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19(SEQ IDNO:247),其中X1=Ala,X2=Lys,X3=Gly,X4=Arg,X5=Asp,X6=Ser或Ala,X7=Phe,X8=Asp;X9=Ile,X10=Pro或缺失,X11=Phe或缺失,X12=Val或缺失,X13=Tyr或缺失,X14=Tyr或缺失,X15=Tyr或缺失,X16=Gly或缺失,X17=Met或缺失,X18=Asp或缺失,X19=Val或缺失;和
轻链CDR3结构域包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8-X9(SEQ ID NO:250),其中X1=Gln,X2=Gln或His,X3=Ala,X4=Asn或Tyr,X5=Ser,X6=Phe,X7=Pro,X8=Pro,X9=Thr。
在更具体的实施方案中,抗体或抗原结合片断还包含
重链CDR1结构域,其包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8(SEQ ID NO:245),其中X1=Gly或Arg,X2=Phe,X3=Thr,X4=Phe,X5=Asp,X6=Asp,X7=Tyr,X8=Ala;
重链CDR2结构域,其包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8(SEQ ID NO:246),其中X1=Ile或Val,X2=Ser,X3=Trp,X4=Asn,Xs=Ser,X6=Gly,X7=Ser,X8=Ile;
轻链CDR1结构域,其包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8(SEQ ID NO:248),其中X1=Gln,X2=Gly,X3=Ile,X4=Ser,X5=Ser,X6=Trp;和
轻链CDR2结构域,其包含下式的氨基酸序列:X1-X2-X3(SEQ IDNO:249),其中X1=Gly或Ala,X2=Ala,X3=Ser。
第四方面,本发明提供抗体或抗原结合片断,其包含:
重链CDR3结构域,选自SEQ ID NO:25、153、9、185、41、57、73、89、105、121、137、169、201和217;和
轻链CDR3结构域,选自SEQ ID NO:33、161、17、193、49、65、81、97、113、129、145、177、209和225。
在更具体的实施方案中,抗体或抗原结合片断还包含:
重链CDR1结构域,选自SEQ ID NO:21、149、5、181、37、53、69、85、101、117、133、165、197和213;
重链CDR2结构域,选自SEQ ID NO:23、151、7、183、39、55、71、87、103、119、135、167、199和215;
轻链CDR1结构域,选自SEQ ID NO:29、157、13、189、45、61、77、93、109、125、141、173、205和221;和
轻链CDR2结构域,选自SEQ ID NO:31、159、15、191、47、63、79、95、111、127、143、175、207和223。
在具体实施方案中,抗体或抗原结合片断包含重链CDR序列SEQ IDNO:21、23、25和轻链CDR序列SEQ ID NO:29、31、33;重链CDR序列SEQ ID NO:149、151、153和轻链CDR序列SEQ ID NO:157、159、161;重链CDR序列SEQ ID NO:5、7、9和轻链SEQ ID NO:13、15、17;重链CDR序列SEQ ID NO:181、183、185和轻链CDR序列SEQ IDNO:189、191、193。
第五方面,本发明提供分离的核酸分子,其编码本发明的抗体或抗原结合片断,其中抗体或其片断包含:
重链CDR3结构域,其编码核苷酸序列选自SEQ ID NO:24、152、8、184、40、56、72、88、104、120、136、168、200和216;和
轻链CDR3结构域,其编码核苷酸序列选自SEQ ID NO:32、160、16、192、48、64、80、96、112、128、144、176、208和224;以及与这些基本相同的核酸序列。
在更具体的实施方案中,提供分离的核酸分子,其编码本发明的抗体或抗原结合片断,其中抗体或其片断包含:
重链CDR1,其编码核苷酸序列选自SEQ ID NO:20、148、4、180、36、52、68、84、100、116、132、164、196和212;
重链CDR2结构域,其编码核苷酸序列选自SEQ ID NO:22、150、6、182、38、54、70、86、102、118、134、166、198和214;
轻链CDR1结构域,其编码核苷酸序列选自SEQ ID NO:28、156、12、188、44、60、76、92、108、124、140、172、204和220;和
轻链CDR2结构域,其编码核苷酸序列选自SEQ ID NO:30、158、14、190、30、46、62、78、94、110、126、142、174、206和222;以及与这些基本上相同的核酸序列。
本发明包含具有修饰的糖基化模式的抗hIL-6R抗体或其抗原结合片断。在一些应用中,除去不期望的糖基化位点的修饰或在寡糖链上缺乏岩藻糖部分的抗体可用于,例如,增加抗体依赖性细胞介导的细胞毒作用(ADCC)(见Shield等人,(2002)JBC 277:26733)。在其它应用中,可进行半乳糖基化修饰以改变补体依赖性细胞毒性反应(CDC)。
在其它方面,本发明提供载有本发明核酸分子的重组表达载体、引入该载体的宿主细胞、以及通过培养本发明的宿主细胞制备本发明的抗体或抗原结合片断的方法。宿主细胞可以是原核或真核细胞,优选宿主细胞为大肠杆菌(Ecoli)细胞或哺乳动物细胞,如CHO细胞。
在其它方面,本发明提供药物组合物,其包含与hIL-6R特异性结合的人抗体或抗体的抗原结合片断和可药用的载体。
在其它方面,本发明提供利用本发明的抗体或其抗原结合部分抑制人IL-6活性的方法。在一个实施方案中,本发明包含这样的治疗方法,包括对患病的人类受试者给药本发明的抗体或其片段,其病症通过抑制IL-6活性得到治疗或改善。病症可为例如关节炎,包括慢性类风湿性关节炎;炎性肠病,包括克罗恩氏病和溃疡性结肠炎;系统性红斑狼疮和炎性疾病。
在其它方面,本发明提供如上定义的抗体或抗体的抗原结合片断在制备药物中的用途,用于减轻或抑制IL-6介导的人类疾病或病症。在相关方面,本发明提供如上定义的抗体或抗体的抗原结合片断,用于减轻或抑制IL-6介导的人类疾病或病症。
通过以下详细说明,本发明的其它目的和优点将显而易见。
发明详述
说明本发明方法之前,应理解本发明并不局限于所描述的特定方法和实验条件,因为这样的方法和条件可以变动。还应理解此处使用的术语仅用于说明具体实施方案的目的,而非限制性的,因为本发明的范围仅由随附的权利要求书限定。
除非另有定义,此处使用的所有技术和科学术语,其含义与本发明所属技术领域普通技术人员通常理解的相同。尽管在实施或检验本发明时,可使用与在此说明的相似或等同的任何方法和材料,现对优选的方法和材料予以说明。
此处使用的术语“人IL6R”(hIL-6R),意指与白细胞介素-6(IL-6)特异性结合的人细胞因子受体。hIL-6R的胞外域以SEQ ID NO:1表示。
此处使用的术语“抗体”,意指免疫球蛋白分子,其包含四条多肽链:两条重(H)链和两条轻(L)链,由二硫键互相连接。各重链包含重链可变区(此处缩写为HCVR或VH)和重链恒定区。重链恒定区包含三个结构域:CH1、CH2和CH3。各轻链包含轻链可变区(此处缩写为LCVR或VL)和轻链恒定区。轻链恒定区包含一个结构域(CL1)。VH和VL区可进一步细分为高变区,称为互补决定区(CDR),其间散布着更为保守的区域,称为框架区(FR)。各VH和VL包含三个CDR和四个FR,从氨基末端到羧基末端以如下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
此处使用的术语抗体的“抗原结合部分”(或只是“抗体部分”或“抗体片断”),指抗体的一个或多个片段,其保留了与抗原(例如,hIL-6R)特异性结合的能力。已显示抗体的抗原结合功能可由全长抗体的片段实现。术语抗体的“抗原结合部分”所涵盖的结合片段的例子包括:(i)Fab片断,包含VL、VH、CL1和CH1结构域的单价片段;(ii)F(ab’)2片断,二价片断,包含两个Fab片断,由铰链区的二硫键连接;(iii)Fd片断,包含VH和CH1结构域;(iv)Fv片断,包含抗体单臂的VL和VH结构域,(v)dAb片断(Ward等人,(1989)Nature241:544-546),包含VH结构域;和(vi)分离的互补决定区(CDR)。此外,尽管Fv片断的两个结构域VL和VH由独立的基因编码,但可用重组方法连接起来,通过合成接头使它们制备为单个连续链,其中VL和VH区配对形成单价分子(称为单链Fv(scFv);见例如,Bird等人,(1988)Science 242:423-426;和Huston等人,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。术语抗体的“抗原结合部分”也旨在涵盖这样的单链抗体。还涵盖其它形式的单链抗体,如双体抗体(见例如,Holliger等人,(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448)。
此处使用的“中和”或“封闭”抗体,意指与hIL-6R结合、导致抑制hIL-6的生物活性的抗体。通过测量一个或多个本领域已知的hIL-6生物活性的指标,如hIL-6诱导的细胞激活和hIL-6与hIL-6R的结合(见下文实施例),可评估对hIL-6生物活性的抑制。
“CDR”或互补决定区为高变区,其间散布着更为保守的区域,称为“框架区”(FR)。在本发明的抗hIL-6R抗体或片断的不同实施方案中,FR可以与人生殖系序列相同,或可以经天然或人工修饰。一组CDR可被定义为氨基酸共有序列;例如,在一个实施方案中,本发明的抗hIL-6R抗体或抗原结合片断可描述为包含这样的重链CDR3结构域,其包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19(SEQ ID NO:247),其中X1=Ala,X2=Lys,X3=Gly,X4=Arg,X5=Asp,X6=Ser或Ala,X7=Phe,X8=Asp;X9=Ile,X10=Pro或缺失,X11=Phe或缺失,X12=Val或缺失,X13=Tyr或缺失,X14=Tyr或缺失,X15=Tyr或缺失,X16=Gly或缺失,X17=Met或缺失,X18=Asp或缺失,X19=Val或缺失;和这样的轻链CDR3结构域,其包含下式的氨基酸序列:X1-X2-X3-X4-X5-X6-X7-X8-X9(SEQ IDNO:250),其中X1=Gln,X2=Gln或His,X3=Ala,X4=Asn或Tyr,X5=Ser,X6=Phe,X7=Pro,X8=Pro,X9=Thr。
此处使用的术语“表面等离子体共振”指一种光学现象,例如通过使用BIAcoreTM系统(Pharmacia Biosensor AB,法玛西亚生物传感器公司),检测生物传感器基质中蛋白质浓度的变化,可以实时分析蛋白质相互作用。
术语“表位”,为抗原决定簇,其与抗体分子可变区中称为对位的特异性抗原结合位点相互作用。单个抗原可有不止一个表位。表位可为构象表位或线性表位。构象表位由来自线性多肽链中不同部分的氨基酸在空间上并列产生。线性表位由多肽链中相邻的氨基酸残基产生。在某些情况下,表位可包括抗原上的糖类、磷酰基或磺酰基部分。
术语“基本同一性”或“基本上相同”,当指核酸或其片断时指的是,当其以适当的核苷酸插入或缺失与另一核酸(或其互补链)进行最佳比对时,核苷酸碱基中的核苷酸序列同一性至少约95%,更优选至少约96%、97%、98%或99%,使用任何众所周知的序列同一性算法测定,例如以下讨论的FASTA、BLAST或Gap。
当用于多肽时,术语“基本相似性”或“基本上相似”指当两个肽序列最佳比对时,例如用GAP或BESTFIT程序,使用缺省空位权重,享有至少95%的序列同一性,甚至更优选至少98%或99%的序列同一性。优选不相同的残基位置的差别是保守氨基酸取代。“保守氨基酸取代”是氨基酸残基被侧链(R基团)化学性质(例如,电荷或疏水性)相似的另一氨基酸残基所取代。通常,保守氨基酸取代不会实质上改变蛋白质的功能性质。在两个或多个氨基酸序列彼此的区别为保守取代的情况下,序列同一性百分比或相似性程度可由于取代的保守性而予以上调。做此调整的方法为本领域技术人员所熟知。见,例如,Pearson(1994)Methods Mol.Biol.24:307-331。侧链具有相似化学性质的氨基酸组的例子包括:1)脂肪族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂肪族羟基侧链:丝氨酸和苏氨酸;3)含酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳香族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸,和7)含硫侧链,为半胱氨酸和甲硫氨酸。优选的保守氨基酸取代组为:缬氨酸-亮氨酸-异亮氨酸,苯丙氨酸-酪氨酸,赖氨酸-精氨酸,丙氨酸-缬氨酸,谷氨酸-天冬氨酸,和天冬酰胺-谷氨酰胺。可选地,保守性替换为在Gonnet等人,(1992)Science256:144345中公开的PAM250对数似然矩阵中,具有正值的任何改变。“适度保守性”替换为在PAM250对数似然矩阵中具有非负值的任何改变。
多肽的序列相似性,也称为序列同一性,通常用序列分析软件测定。蛋白质分析软件使用对多种取代、缺失和其它修饰包括保守氨基酸取代赋值的相似性测量方法来匹配相似序列。例如,GCG软件包含程序如Gap和Bestfit,可用于以缺省参数测定密切相关的多肽之间的序列同源性或序列同一性,如来自不同物种生物的同源多肽,或野生型蛋白和其突变蛋白。见,例如,GCG版本6.1。还可用FASTA以缺省或推荐的参数比较多肽序列,GCG版本6.1.FASTA中的程序(例如,FASTA2和FASTA3)提供查询和搜索序列之间最佳重叠区域的比对和序列同一性百分比(Pearson(2000),同前)。当用本发明的序列与包含大量来自不同生物序列的数据库相比较时,另一优选算法是计算机程序BLAST,特别是blastp或tblastn,使用缺省参数。见,例如,Altschul等人,(1990)J.Mol.Biol.215:403 410和Altschul等人,(1997)Nucleic Acids Res.25:3389 402。
人抗体的制备
产生人抗体的方法包括例如VeloclmmuneTM(雷杰纳荣制药Regeneron Pharmaceuticals)、XenoMouseTM技术(Green等人,(1994)Nature Genetics 7:13-21;Abgenix公司)、“微小基因座(minilocus)”方法和噬菌体展示(见,例如,US 5,545,807,US 6,787,637)。VeloclmmuneTM技术(US 6,596,541)包含针对选定抗原产生高特异性全人抗体的方法。此技术包括建立转基因小鼠,其基因组包含人轻链和轻链可变区,与小鼠内源性恒定区基因座有效地相连,从而小鼠响应抗原刺激产生包含人可变区和小鼠恒定区的抗体。分离抗体重链和轻链可变区的编码DNA,与人重链和轻链恒定区的编码DNA有效地相连。而后DNA在能够表达全人抗体的细胞中表达。在具体实施方案中,细胞为CHO细胞。
抗体可在治疗上用于封闭配体-受体相互作用或抑制受体组分相互作用,而不是通过补体结合(补体依赖性细胞毒性反应)(CDC)和参与抗体依赖性细胞介导的细胞毒作用(ADCC)杀死细胞。抗体的恒定区对抗体结合补体和介导细胞依赖性细胞毒作用的能力十分重要。因此,可依据是否期望抗体介导细胞毒作用而选择抗体的同种型。
人免疫球蛋白可以以与铰链区异质性相关的两种形式存在。在一种形式中,免疫球蛋白分子包含稳定的四条链结构,约150-160kDa,其中二聚体通过链间的重链二硫键结合。在第二种形式中,二聚体不通过链间的二硫键连接,形成约75-80kDa的分子,其包含共价偶联的轻链和重链(半抗体)。即使在亲和纯化之后,也极其难以分离这些形式。第二种形式在多种完整IgG同种型中出现的频率是由于但不限于与抗体的铰链区同种型相关的结构差异。事实上,人IgG4铰链区的单个氨基酸取代可显著减少第二种形式的出现(Angal等人,(1993)Molecular Immunology 30:105),减少至使用人IgG1铰链时通常观察到的水平。本发明包含在铰链、CH2或CH3区具有一个或多个突变的抗体,其在例如制备中可期望提高期望抗体形式的产量。
本发明的抗体优选用VeloclmmuneTM技术制备。转基因小鼠内源免疫球蛋白的重链和轻链可变区被替换为相应的人可变区,用目的抗原攻击这样的转基因小鼠,从表达抗体的小鼠中回收淋巴细胞(如B细胞)。淋巴细胞可与骨髓瘤细胞系融合以制备永生的杂交瘤细胞系,筛选和选择这样的杂交瘤细胞系,以鉴定生产特异于目的抗原的抗体的杂交瘤细胞系。可分离重链和轻链可变区的编码DNA,与期望的同种型重链和轻链恒定区相连。可在细胞中,如CHO中制备这样的抗体蛋白。可选地,编码抗原特异性嵌合抗体或轻链和重链可变区的DNA可直接从抗原特异性淋巴细胞中分离。
在一个实施方案中,转基因小鼠包含多达18种有功能的人可变重链基因和12种有功能的人可变κ轻链基因。在另一实施方案中,转基因小鼠包含多达39种人可变重链基因和30种人可变κ轻链基因。在又一实施方案中,转基因小鼠包含多达80种人可变重链基因和40种人可变κ轻链基因。
一般而言,本发明的抗体具有非常高的亲和力,通过与固定在固相或处在液相中的抗原的结合测定,通常具有KD约10-9到约10-12M。
首先,分离具有人可变区和小鼠恒定区的高亲和力嵌合抗体。如下文所述,表征并选择具期望特征的抗体,特征包括对hIL-6R的结合亲和力、封闭hIL-6的能力、和/或对人类蛋白质的选择性。用期望的人恒定区替换小鼠恒定区,以产生本发明的全人抗体,例如野生型或修饰的IgG4或IgG1(例如,SEQ ID NO:242、243、244)。尽管选择的恒定区可根据具体用途有所不同,但高亲和力的抗原结合和靶特异性特征位于可变区中。
表位作图和相关技术
为筛选与特定表位结合的抗体,可使用常规交叉封闭测定法(cross-blocking assay),如在Antibodies:A Laboratory Manual 1988 ColdSpring Harbor Laboratory,Harlow和Lane编中描述的方法。其它方法包括丙氨酸扫描突变体、肽印迹(Reineke(2004)Methods Mol Biol 248:443-63)、或在下文实施例中描述的肽切割分析。此外,可使用诸如表位切除、表位提取和抗原化学修饰(Tomer(2000)Protein Science:9:487-496)等方法。
修饰辅助分型(Modification-Assisted Profiling)(MAP),也称为基于抗原结构的抗体分型(Antigen Structure-based antibody Profiling)(ASAP),是根据各抗体与经化学或酶促修饰的抗原表面(美国专利申请公开号2004/0101920)结合特点的相似性,将大量针对相同抗原的单克隆抗体(mAb)加以分类的方法。各种类可能反映独特的表位,与另一种类表示的表位明显不同或部分重叠。此技术能够快速过滤遗传上相同的抗体,从而可以集中表征遗传上不同的抗体。当用于杂交瘤筛选时,MAP可帮助鉴定具有期望特征的稀有杂交瘤克隆。可使用MAP将本发明的hIL-6R抗体分类为结合不同表位的抗体组。
可用于改变固定抗原的结构的物质有酶如蛋白水解酶和化学试剂。抗原蛋白可固定于生物传感器芯片表面或聚苯乙烯珠上。后者可用例如LuminexTM多重检测法(multiplex LuminexTM detection assay)(卢明内斯公司(Luminex Corp.),美国德州)测定。由于具有可处理多达100种不同类型小珠的多重分析容量,LuminexTM提供了几乎无限的具有多种修饰的抗原表面,使得抗体表位分型的分辨率高于生物传感器测定法。
治疗性给药和剂型
根据本发明的治疗实体与掺入制剂中以提供改善的转移、递送、耐受等性质的适合载体、赋形剂和其它试剂一同给药。许多适合的剂型可在所有药剂师均知的处方集中找到:《雷氏药学大全》(Remington’sPharmaceutical Sciences)(第15版,麦克出版公司(Mack PublishingCompany),伊斯顿,美国宾州,1975),特别是其中由Blaug,Seymour撰写的第87章。这些剂型包括,例如,粉剂、糊剂、膏剂、胶冻剂、腊类、油类、脂类、含脂(阳离子或阴离子)的囊泡(如LipofectinTM)、DNA缀合物、无水吸收糊剂、水包油乳剂和油包水乳剂、碳蜡(多种分子量的聚乙二醇)乳化剂、半固体凝胶剂、和含碳蜡的半固体混合物。只要制剂中的活性成份不由于配制失活,且制剂对于给药路径是生理相容和耐受的,任何上述混合物均可适合根据本发明的治疗和疗法。关于药剂师所熟知的赋形剂和载体的额外信息,也见Powell等人,PDA(1998)J Pharm SciTechnol.52:238-311和其中引述的文献。
实施例
下列实施例,意在为本领域普通技术人员提供如何制备和使用本发明的方法和组合物的完整公开和说明,而不是限制发明人所认为的本发明的范围。就使用的数字(例如,用量、温度等)而言,已尽力确保精确,但应说明有一定实验误差和偏差。除非另有说明,份为重量份,分子量为平均分子量,温度为摄氏度,压力等于或接近大气压。
实施例1.产生人IL-6受体的人抗体
可用本领域已知的任何方法免疫啮齿动物(见,例如,Harlow和Lane(1988),同前;Malik和Lillehoj,Antibody techniques:Academic Press,1994,美国加州)。在优选实施方案中,对包含编码人Ig重链可变区和κ轻链可变区的DNA基因座的小鼠,直接给药hIL-6R抗原和佐剂(VeloclmmuneTM,雷杰纳荣制药公司(Regeneron Pharmaceuticals,Inc.);US 6,596,541),以刺激免疫反应。这样的佐剂包括完全和不完全弗氏佐剂,MPL+TDM佐剂系统(西格玛公司(Sigma)),或RIBI(胞壁酰二肽)(见O’Hagan,Vaccine adjuvant,by Human Press,2000,美国新泽西州)。这样的佐剂通过将抗原隔离在局部药库可防止多肽的快速扩散,且可包含能刺激宿主免疫反应的因子。在一个实施方案中,用DNA质粒间接给药hIL-6R,DNA质粒包含hIL-6R基因,用宿主细胞的蛋白表达机器表达hIL-6R,在体内产生抗原多肽。两种方法中,免疫接种程序表都需要间隔数周数次给药。用标准的抗原特异性免疫测定监测抗体免疫反应。当动物的免疫反应达到最大时,收获表达抗体的B细胞,与小鼠骨髓瘤细胞融合以维持其存活力,形成杂交瘤细胞。为选择具期望功能的单克隆抗体,基于特异性、抗原结合亲和力和封闭hIL-6与hIL-6R结合的能力,来筛选杂交瘤细胞或被转染细胞的条件培养基(在下文中说明)。
实施例2.通过直接分离脾细胞产生抗-hIL6R抗体
VH和VL结构域的编码DNA可直接从单个抗原阳性的B细胞中分离。简短地说,处死hIL-6Rα免疫的转基因小鼠并收获脾细胞。通过裂解而后沉淀收获的脾细胞除去红血细胞。重悬的脾细胞首先与人IgG、FITC-抗-mFc和生物素-IL6Ra的混合物孵育1小时。染色的细胞用PBS洗涤两次,而后用人和大鼠IgG、APC-抗-mIgM和SA-PE的混合物染色1小时。染色的细胞用PBS洗涤一次,使用MoFlo(Cytomation公司)用流式细胞仪分析。分选各IgG阳性、IgM阴性和抗原阳性B细胞,置入96孔板的不同孔中。根据Wang等人(2000)(J Immunol Methods 244:217-225)描述的方法,对来自这些B细胞的抗体基因进行RT-PCR。简短地说,通过RT-PCR合成各单个B细胞的cDNA。而后将得到的各RT产物一分为二,移入两个96孔板上两个相应的孔中。使用特异于人IgG重链可变区前导序列的5’简并引物,和特异于小鼠重链恒定区的3’引物,先通过PCR扩增一组得到的RT产物,形成扩增子。然后使用特异于人IgG重链可变区序列框架1的5’简并引物集合和特异于小鼠重链恒定区的3’巢式引物,再次通过PCR扩增该扩增子。使用特异于人κ轻链可变区前导序列的5’简并引物和特异于小鼠κ轻链恒定区的3’引物,先通过PCR扩增一组得到的RT产物,形成扩增子。然后使用特异于人κ轻链可变区序列框架1的5’简并引物集合和特异于小鼠κ轻链恒定区的3’巢式引物,再次通过PCR扩增该扩增子。将重链和轻链PCR产物克隆进分别包含IgG1重链恒定区和κ轻链恒定区的Sap I线性化抗体载体中。重链质粒在重链表达盒两侧具有lox2272位点和lox511位点。此外,在重链质粒中紧接着lox2272的下游,有缺乏启动子和起始ATG的潮霉素抗性基因。潮霉素抗性基因还通过IRES序列与下游eGFP在转录上相连。轻链质粒在轻链表达盒两侧具有loxP位点和lox2272位点。此外,轻链质粒具有SV40启动子,在位于lox2272位点的ATG之前紧接着出现,从而使得整合进入适当的宿主细胞时,轻链质粒中邻近lox2272的SV40启动子和起始ATG以正确的读码框与重链质粒中的潮霉素抗性基因相邻,使得潮霉素抗性和eGFP基因能够转录和翻译。而后将具有重链可变区序列的纯化的重组质粒与具有来自相同B细胞的轻链可变区序列的质粒混合,连同表达Cre重组酶的质粒一起转染到改良的CHO宿主细胞系中。所述改良的CHO宿主细胞系从5’到3’包含loxP位点、eCFP、lox2272位点、DsRed和位于转录活性座位上的lox511位点。因此,所述宿主CHO细胞可通过流式细胞仪分离为蓝色阳性、红色阳性、和绿色阴性细胞。当表达重链和轻链基因的重组质粒与表达Cre重组酶的质粒一起转染时,由Cre重组酶介导的位点特异性重组导致抗体质粒整合在包含lox位点的染色体座位上,导致eCFP和DsRed基因的替换。重组体而后可通过流式细胞仪分离为蓝色阴性、红色阴性、绿色阳性细胞。从而,用具有重链可变区序列的重组质粒和具有来自相同B细胞的轻链可变区序列的质粒转染的CHO细胞,通过流式细胞仪分选,分离显示蓝色阴性、红色阴性和绿色阳性表型的正确重组体,由分离的克隆建立了表达抗体的稳定重组CHO细胞系。
实施例3.测定抗原结合亲和力
抗原与上述选定抗体结合的KD通过用实时生物传感器表面等离子体共振测定法(BIAcoreTM)测量其表面动力学而测定。更具体地,用 2000或 3000测量抗体对人IL-6R的亲和力。抗体被捕获在抗小鼠IgG表面上,与多种浓度的单体或二聚体形式的重组hIL-6R蛋白相接触。用BIAevaluationTM软件进行动力学分析,得到结合和解离速率常数。
也以杂交瘤条件培养基或纯化的蛋白形式,通过基于平板的竞争免疫测定法测定抗体对hIL-6R的结合亲和力。从已除去牛IgG的杂交瘤细胞条件培养基(英骏公司Invitrogen)中用G蛋白亲和层析纯化抗体蛋白。对于竞争ELISA,简短地说,将不同水平的定量抗体,与抗原蛋白hIL-6R-hFc范围为0到10μg/ml的系列稀释液预混合,室温孵育两小时,以达到抗体和抗原之间的伪结合平衡状态。然后将这些溶液移入96孔hIL-6R-hFc预包被板,使得混合物中的游离抗体与板上包被的hIL-6R-hFc结合。通常用1到2μg/ml hIL-6R-hFc蛋白的PBS溶液包被板,在4℃过夜,随后进行BSA非特异性封闭。洗去溶液中的过量抗体之后,用HRP-缀合的山羊抗小鼠IgG或IgA多克隆抗体试剂检测与板结合的抗体,用比色底物或化学发光底物进行显影。用PrismTM软件(Graph Pad公司)通过4参数拟合分析(4-parameter fit analysis)来分析信号对溶液中抗原浓度的相关性,报告为IC50。用稳态溶液相(steady state solution phase)KinexaTM仪器(Sapidyne公司)进行竞争免疫测定。
结果显示在表1中(对照:人IL-6R的人源化单克隆抗体(美国专利号5,817,790,SEQ ID NO:69和71)。抗体(HCVR和LCVR氨基酸序列):VQ8A9-6(3,11);VQ8F11-21(19,27);VV7G4-1(35,43);VV7G4-10(51,59)VV6C10-1(67,75);VV6C10-3(83,91);VV6C10-4(99,107);VV6F12-11(115,123);VV9A6-11(131,139);VV6A9-5(147,155),VV3D8-4(163,171);VV1G4-7(179,187);248982-13-1-E5(195,203);248982-13-2-A9(211,219)。单体和二聚体的KD由BIAcoreTM测定;溶液KD由KinexaTM测定;IC50由ELISA测定(n.d.=未测得)。
表1.抗原结合亲和力
抗体 | KD单体(nM) | KD二聚体(nM) | 溶液KD单体(nM) | ELISA IC50二聚体(nM) |
VQ8A9-6 | 0.222 | 0.101 | 0.120 | 0.004 |
VQ8F11-21 | 0.067 | 0.023 | 0.009 | 0.008 |
VV3D8-4 | 2.410 | 0.172 | 1.910 | 0.013 |
VV6A9-5 | 0.097 | 0.146 | 0.032 | 0.005 |
VV1G4-7 | 0.225 | 0.070 | 0.197 | 0.041 |
VV6C10-1 | 0.267 | 0.032 | 2.050 | 0.010 |
VV6F12-11 | n.d. | n.d | n.d | 0.033 |
VV7G4-10 | n.d. | n.d. | n.d. | 1.880 |
VV9A6-11 | n.d. | n.d. | n.d. | 0.347 |
VV6C10-3 | n.d. | n.d. | n.d. | 0.009 |
248982-13-1-E5 | 0.987 | 0.785 | n.d. | 0.3860 |
248982-13-2-A9 | 2.870 | n.d. | n.d. | 0.054 |
对照 | 1.790 | n.d. | 1.960 | n.d. |
实施例4.中和hIL-6活性
用hIL-6封闭免疫测定法、体外hIL-6依赖性细胞生长生物测定法和表面等离子体共振(BIAcoreTM)筛选本发明抗hIL-6R抗体的hIL-6封闭活性。免疫测定用于筛选实验抗体封闭hIL-6与hIL-6R结合的能力,体外生物测定法用于测定抗体中和hIL-6R介导的细胞信号传导的能力。
对于免疫测定,用hIL-6重组蛋白包被96孔板,其处于PBS缓冲液中,在4℃过夜。该板用于捕获抗体样品溶液中的游离hIL-6R-hFc,根据标准曲线定量所捕获的hIL-6R-hFc。样品溶液由定量的hIL-6R-hFc重组蛋白(100pM)和变量的抗体组成,抗体在杂交瘤条件培养基原液中或为纯化的抗体蛋白,以0到约50nM的范围系列稀释。抗体-抗原在室温孵育~2小时,使抗体-抗原结合达平衡状态。随后将平衡的样品溶液移入hIL-6包被的板,测量游离hIL-6R-hFc。经结合1小时后,洗涤板,用HRP缀合的山羊抗hFc多克隆抗体(杰克逊免疫研究公司(JacksonImmuno Research))检测结合的hIL-6R-hFc,用TMB底物(BD Pharmigen公司)显影。IC50测定为使板上结合的hIL-6配体可检测的IL-6R-hFc降低50%所需的抗体量。结果于表2第一列中显示。
另外,用表面等离子体共振测定实验抗体封闭hIL-6与hIL-6R受体结合的能力。用山羊抗人IgG多克隆抗体捕获纯化的抗原hIL-6R-hFc分子,山羊抗人IgG多克隆抗体通过胺偶联固定在CM-5表面上,密度为250RU。将hIL-6溶液(0.25ml,50nM)注射到受体表面上,记录结合的hIL-6(IL-6第一次注射)。用3M MgCl2及条件缓冲液(conditioning buffer)脉冲除去结合的hIL-6。将杂交瘤条件培养基中的抗-hIL6R抗体注射到所捕获的受体表面上,而后第二次注射hIL-6。用由于形成抗体和受体复合物导致的hIL-6结合降低的百分比作为评分来定义hIL-6封闭剂,与非封闭剂相区分(第二列,表2)。
表2.中和hIL-6结合
抗体 | hIL6R/hIL6结合抑制IC50(nM) | hIL6/hIL6R结合抑制(%) | XG-1细胞增殖抑制IC50(nM) | HepG2/Stat3荧光素酶活性IC50(nM) |
VQ8A9-6 | 0.39 | 68 | 0.40 | 0.097 |
VQ8F11-21 | 0.12 | 98 | 0.62 | 0.135 |
VV3D8-4 | 0.61 | 93 | >100 | n.d. |
VV6A9-5 | 0.35 | 100 | 1.1D | 0.188 |
VV1G4-7 | 1.10 | 34 | 1.80 | 0.578 |
VV6C10-1 | 4.60 | 61 | >8.90 | n.d. |
VV6F12-11 | 2.20 | n.d. | n.d. | n.d. |
VV7G4-10 | 13.00 | n.d. | n.d. | n.d. |
VV9A6-11 | 0.50 | n.d. | n.d. | n.d. |
VV6C10-3 | 0.06 | n.d. | n.d. | n.d. |
对照 | 2.20 | 91 | 1.50 | 0.854 |
用hIL-6依赖性骨髓瘤细胞系XG-1测量hIL-6R抗体体外封闭hIL-6活性的能力。用不含hIL-6的培养液洗涤用含hIL-6的培养液维持的XG-1细胞两次,在不含hIL-6的培养液中培养24小时以除去残留的hIL-6。而后离心沉淀饥饿的细胞,以4 x 105细胞/ml在培养液中重悬,用20,000细胞/孔在96孔组织培养板中铺板。纯化的抗体蛋白在培养液中系列稀释,以0到50nM的浓度范围加到铺板的细胞中。接着,将重组hIL-6加入孔中至终浓度为8pM。令细胞在37℃,增湿的5%CO2培养箱中生长~72小时。在生长期结束时,用CCK-8试剂盒(同仁化学研究所(Dojindo),日本)测定活细胞。IC50以上述方法测定,在表2第三列中报告。
也在hIL-6应答性人肝瘤细胞系HepG2中测量hIL-6R抗体体外封闭hIL-6活性的能力。用报道质粒转染HepG2细胞,报道质粒包含与荧光素酶基因相连的STAT3(信号转导及转录激活因子3)应答元件。用胰蛋白酶处理转染的细胞,离心,以约2.5×105细胞/ml在培养液中重悬,用20,000细胞/孔在96孔组织培养板中铺板。纯化的抗体蛋白在培养液中系列稀释,以0到100nM的浓度范围加到铺板的细胞中。接着,将重组hIL-6加入孔中至终浓度为50pM。在37℃,增湿的5%CO2培养箱中孵育细胞6小时后测量应答。用Steady-GloTM荧光素酶测定系统(普洛麦格公司(Promega))测量荧光素酶活性。IC50以上述方法测定,在表2第四列中报告。
实施例5.结合表位多样性
用人IL-6R的对照人源化抗体进行抗体结合的竞争免疫测定。简短地说,用20ng/孔hIL-6R重组蛋白包被96孔免疫吸附板,在4℃过夜。用BSA封闭非特异性结合后,通过在一半的板中以500ng/孔加入对照,结合对照抗体以饱和hIL-6R的结合位点,另一半板中只加入结合缓冲液。在室温结合3小时后,加入纯化的抗体至终浓度为50ng/ml,孔中存在或不存在已有的对照抗体。1小时额外结合之后,洗去游离抗体,用HRP缀合的山羊抗小鼠IgG或IgA多克隆抗体检测板上结合的抗体,用显色HRP底物对板进行显影,记录450nm的吸光度。由于对照抗体存在,抗hIL6R抗体结合减少的百分比在下表3中列出。用表面等离子体共振技术(表3)进行相似的实验。两种方法得到一致的结果。抗体VQ8F11、VV3D8、VV6A9、VV6C10-1结合的表位与对照抗体重叠;而由于抗原结合不被对照抗体封闭,抗体VQ8A9、VV1G4、VV6F12、VV7G4、VV9A6和VV6C10-3显示结合不同的表位。即使表位可能不重叠,由于第一抗体结合所造成的空间位阻也可能导致部分竞争。
表3.与对照抗体竞争抗原结合
抗体 | BIAcoreTM(%减少) | 免减测定(%减少) |
VQ8A9-6 | 26 | 3 |
VQ8F11-21 | 96 | 79 |
VV3D8-4 | 97 | 84 |
VV6A9-5 | 96 | 84 |
VV1G4-7 | 12 | 3 |
VV6C10-1 | 90 | 80 |
VV6F12-11 | n.d. | 3 |
VV7G4-10 | n.d. | 26 |
VV9A6-11 | n.d. | 18 |
VV6C10-3 | n.d. | 1 |
实施例6.物种交叉结合性质
用BIAcoreTM技术测试四种抗体对猴IL-6R重组蛋白的交叉反应性。简短地说,使用其上固定了山羊抗小鼠Fc多克隆抗体的生物传感器芯片呈现抗hIL-6R单克隆抗体,密度约75RU。重组人或猴单体IL-6R蛋白(食蟹猴(Macaca fascicularis),胞外域;SEQ ID NO:251)以浓度范围1.25-40nM,注射到抗体表面上。实时监测受体与抗体的结合和结合复合物的解离。得到结合速率常数(ka)和解离速率常数(kd),计算KD(表4)。
表4.对人IL-6R和猴IL-6R结合亲和力的比较
在四种实验抗体中,VQ8F11、VV6A9和VQ8A9与猴受体反应强烈,K0值分别达到与人受体结合的约1.5倍到约3倍。不被对照抗体封闭的VV1G4(表3),尽管与人受体以241pM的KD有力结合,但显示不与猴受体结合。
实施例7.恒定区对结合亲和力的影响
除了使用山羊抗人Fc多克隆抗体表面捕获hIgG抗体,依上述方法用BIAcoreTM测定具有小鼠IgG、人IgG1或人IgG4(野生型和修饰的)的四种抗体与单体hIL-6R的结合亲和力。单体hIL-6R以12.5、6.25、3.12和1.56nM的浓度注射。用荧光素酶测定法测定抗体中和hIL-6依赖性HepG2/STAT3信号传导的能力(IC50)。不同IgG同种型的IC50相似,说明同种型对于抗体对抗原的亲和力没有影响。
表5.IgG同种型的比较
Claims (12)
1.抗体或其抗原结合片段,其与人白细胞介素-6受体特异性结合,其中所述抗体或其抗原结合片段包含SEQ ID NO:21所示的重链CDR1结构域,SEQ ID NO:23所示的重链CDR2结构域,SEQ ID NO:25所示的重链CDR3结构域,SEQ ID NO:29所示的轻链CDR1结构域,SEQ IDNO:31所示的轻链CDR2结构域和SEQ ID NO:33所示的轻链CDR3结构域。
2.权利要求1的抗体或其抗原结合片段,包含具有SEQ ID NO:19的重链可变区。
3.权利要求1的抗体或其抗原结合片段,包含具有SEQ ID NO:27的轻链可变区。
4.权利要求1-3中任一项的抗体或其抗原结合片段,包含具有SEQ IDNO:19的重链可变区和具有SEQ ID NO:27的轻链可变区。
5.权利要求1-3中任一项的抗体或其抗原结合片段,其中所述抗原结合片段选自Fab、F(ab’)2和scFv。
6.分离的核酸分子,其编码前述权利要求任一项所述的抗体或其抗原结合片段。
7.包含权利要求6的核酸分子的表达载体。
8.分离的宿主细胞,其包含权利要求7的表达载体。
9.权利要求8的宿主细胞,其中所述宿主细胞是大肠杆菌(E.coli)细胞或CHO细胞。
10.制备抗白细胞介素-6受体抗体或其抗原结合片段的方法,包括培养权利要求8或9所述的宿主细胞,并回收所产生的抗体或抗体片段。
11.权利要求1至5任一项所述的抗体或其抗原结合片段在制备用于减轻或抑制IL-6介导的人类疾病或病症的药物中的用途。
12.权利要求11所述的用途,其中IL-6介导的疾病或病症选自类风湿性关节炎,炎性肠病和系统性红斑狼疮。
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US20050142635A1 (en) * | 1991-04-25 | 2005-06-30 | Chugai Seiyaku Kabushiki Kaisha | Reshaped human antibody to human interleukin-6 receptor |
CN1678744A (zh) * | 2002-08-30 | 2005-10-05 | 财团法人化学及血清疗法研究所 | 人的抗人白细胞介素-6抗体以及所述抗体的片段 |
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