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CN1461310B - 结合人白介素-18的抗体及制备和使用方法 - Google Patents

结合人白介素-18的抗体及制备和使用方法 Download PDF

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Publication number
CN1461310B
CN1461310B CN018077358A CN01807735A CN1461310B CN 1461310 B CN1461310 B CN 1461310B CN 018077358 A CN018077358 A CN 018077358A CN 01807735 A CN01807735 A CN 01807735A CN 1461310 B CN1461310 B CN 1461310B
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Prior art keywords
antibody
antigen
binding portion
human
place
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CN1461310A (zh
Inventor
T·哈于尔
R·W·迪克松
M·罗古斯卡
M·怀特
B·拉布科夫斯基
J·萨菲尔德
A·R·敦坎
S·M·布洛克勒胡尔斯特
J·曼科维奇
C·P·索尔罗克
J·E·汤普森
S·N·伦纳德
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AbbVie Inc
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Abbott GmbH and Co KG
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Abstract

本发明提供结合人白介素-18(hIL-18)的抗体、尤其是结合人IL-18表位的抗体。所述抗体可以是例如完整的人抗体、重组抗体或单克隆抗体。优选抗体对hIL-18具有高亲和力并且在体外和体内均中和hIL-18活性。本发明的抗体可以全长抗体或其抗原结合部分。本发明也提供本发明抗体的制备方法和应用方法。本发明的抗体或抗体部分可用来检测hIL-18和可用来抑制hIL-18活性，例如抑制罹患其中hIL-18活性是有害的疾病的病人体内的hIL-18活性。

Description

结合人白介素-18的抗体及制备和使用方法
相关申请 
本申请要求于2000年2月10日申请的、题目是“结合人白介素-18的抗体及制备和使用方法”的美国临时专利申请顺序号60/181,608的非临时专利申请的优先权，该专利申请的内容通过引用结合到本文中。另外，整个本申请引用的包括参考文献、授予的专利和公布的专利申请的所有引用参考文献的内容均通过引用结合到本文中。 
发明背景 
白介素-18(IL-18)最早于1989年被描述为干扰素-γ诱导因子(IGIF)，它是除了能够诱导干扰素γ外还具有各种功能的促炎细胞因子。这些生物学特性包括激活NF-κb、Fas配体表达、诱导CC趋化因子和CXC趋化因子以及增加产生感受态人免疫缺陷病毒。 
由于IL-18能够诱导T细胞和巨噬细胞内产生干扰素γ，因此它在Th1型免疫应答中起重要作用且参与先天性免疫和获得性免疫。IL-18在结构和功能上与IL-1家族有关。有关IL-18结构、功能和生物活性的综述，参见例如Dinarello，C.等(1998)J.Leukoc.Biol. 63：658-654；Dinarello，C.A.(1999)Methods 19：121-132和Dinarello，C.A.(1999)J.Allergy Clin.Immunol.103：11-24。 
特别需要调节各种各样的人免疫应答中的IL-18。具体来说，与IL-18结合并中和IL-18的抗体是特别理想的。此外，由于存在小鼠抗体给予人体的相关问题，例如血清半寿期短、不能触发某些人类效应子功能并且在人体内诱发针对小鼠抗体不需要的免疫应答(“人抗小鼠抗体”(HAMA)反应)，因此小鼠IL-18抗体的体内应用受到限 制。 
一般而言，尝试克服与将完全小鼠抗体用于人类相关的问题，已经涉及对所述抗体进行基因工程改造以使其更“人样化(human-like)”。例如，已经制备出这样的嵌合抗体：其中所述抗体链的可变区来源于小鼠，而所述抗体链的恒定区来源于人(Junghans等(1990)Cancer Res.50：1495-1502；Brown等(1991)Proc.Natl.Acad.Sci.88：2663-2667；Kettleborough等(1991)Protein Engineering.4：773-783)。然而，因为这些嵌合人源化抗体仍保留某些小鼠序列，所以它们仍可能诱发不需要的免疫反应、人抗嵌合抗体(HAMA)反应，当长期给予时情况尤其如此。 
针对小鼠抗体或其衍生物(例如嵌合抗体或人源化抗体)的优选IL-18抑制剂将完全是人抗IL-18抗体，由于这样的药物不会诱发HAMA反应，因此即使长期应用也不会诱发HAMA反应。然而，这样的抗体本领域尚未见介绍，因此仍然需要这样的抗体。 
发明概述 
本发明涉及结合人IL-18的诸如抗体的化合物以及制备和应用这类化合物或抗体的方法。 
一方面，本发明涉及能够结合人IL-18氨基酸序列或其部分的化合物，其中所述氨基酸包含SEQ ID NO：70或SEQ ID NO：71提供的人IL-18的N末端部分或C末端部分。在一个实施方案中，所述化合物是一种小分子、肽、多肽、抗体或抗体片段，例如完全人抗体或片段。 
另一方面，本发明涉及能够与人IL-18结合的人单克隆抗体或其抗原结合部分。在其它实施方案，根据表面等离子体共振(surface plasmon resonance)测定，所述抗体或其片段与人IL-18解离的koff速率常数为0.1s-1或以下、1x 10E-2 s-1或以下、1x 10E-3 s-1或以下、1x 10E-4 s-1或以下、1x 10E-5 s-1或以下、1x 10E-6 s-1或以下； 或者抑制人IL-18活性的IC50为1x 10E-6或以下、1x 10E-7或以下、1x 10E-8或以下、1x 10E-9或以下、1x 10E-10或以下、或1x 10E-11或以下。 
另一方面，本发明涉及这样的分离抗体或其抗原结合部分：它结合包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQ ID NO：33)或二者任何一个的一部分的人IL-18表位。所述抗体最好是中和抗体。所述抗体最好是人抗体。在各种实施方案中，所述抗体是重组抗体(例如单链抗体(scFv))或单克隆抗体。 
在其它实施方案中，所述分离抗体或其抗原结合部分与人IL-18表位或二者任何一个的一部分结合，其中根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为0.1s-1或以下；或者其抑制人IL-18活性的IC50为1x 10-6M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-2s-1或以下；或者抑制人IL-18活性的IC50为1x 10-7M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分可以与人IL-18解离，其koff速率常数为1x 10-3s-1或以下；或者可以抑制人IL-18活性，其IC50为1x 10-8M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-4s-1或以下；或者抑制人IL-18活性的IC50为1x 10-9M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-5s-1或以下；或者抑制人IL-18活性的IC50为1x 10-10M或以下。或者，根据表面等离子体共振测定，所述抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x 10-6s-1或以下；或者抑制人IL-18活性的IC50为1x 10-11M或以下。 
本发明的另一方面涉及含有能够结合IL-18表位的至少一个可变区CDR结构域的分离的人抗体或其抗原结合部分。在相关实施方案中，所述分离抗体或其抗原结合部分的可变区含有如表6或表9所 示的重链和/或轻链CDR1结构域、CDR2结构域或CDR3结构域，所述结构域可以在表7-8和表10-11中所示的任一Kabat位置上或邻近所述位置具有例如一个或多个氨基酸取代或插入。在一个优选实施方案中，所述分离抗体或其抗原结合部分含有一个含氨基酸序列SEQ ID NO：29的轻链可变区(LCVR)和一个含氨基酸序列SEQ ID NO：26的重链可变区(HCVR)。在另一个优选实施方案中，所述分离抗体或其抗原结合部分含有一个具有氨基酸序列SEQ ID NO：29的轻链可变区(LCVR)和一个具有氨基酸序列SEQ ID NO：27的重链可变区(HCVR)。 
本发明的另一方面涉及包含本发明的抗体或其抗原结合部分和药学上可接受的载体的药用组合物。在一个实施方案中，所述药用组合物还包含至少一种另外的治疗其中IL-18活性是有害的疾病的治疗药物。 
本发明的另一方面涉及制备结合人白介素-18(IL-18)的抗体的方法。本发明提供的方法包括将抗体库(antibody repertoire)暴露于包含含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQ ID NO：33)或二者任何一个的一部分的人IL-18表位的抗原；并且从所述抗体库选择结合包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQID NO：33)或者二者任何一个的一部分的人IL-18表位的抗体。 
在一个实施方案中，所述抗体库是动物体内的体内抗体库，所述方法包括用包含以下组分的抗原免疫所述动物：包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQID NO：33)的人IL-18表位、人IL-18的N末端部分或C末端部分(SEQID NO：70-71)或这些表位中任一表位的一部分。在另一个实施方案中，所述抗体库是重组抗体文库，所述方法包括用含有以下组分的抗原筛选所述文库：具有氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)、VIRNLNDQVLFIDQ(SEQ ID NO：33)的人IL-18表位、SEQ ID NO： 31-32和SEQ ID NO：34-60表示的肽或任一前述组分的一部分。所述文库最好是人抗体文库。 
另一方面，本发明提供编码任一上述方面的抗体(例如重链和/或轻链可变区)或其部分的分离核酸。在相关实施方案中，所述编码抗IL-18抗体或其部分的分离核酸位于重组表达载体中，例如在宿主细胞中表达。 
因此，另一方面，本发明涉及采用已经导入所述重组表达载体中的前述宿主细胞合成结合人IL-18的抗体的方法，所述方法包括在培养基中培养所述宿主细胞直到所述细胞合成结合人IL-18的抗体。 
本发明的另一方面涉及抑制人IL-18活性的方法，所述方法包括将人IL-18与本发明的抗体或其抗原结合部分接触，使得人IL-18活性被抑制。 
本发明的再一方面涉及抑制罹患其中人IL-18活性是有害的疾病的病人体内的人IL-18活性的方法，所述方法包括给予所述病人本发明的抗体或其抗原结合部分，使得所述病人体内的人IL-18活性被抑制。在一个实施方案中，可以例如在给予另外的药物之前、同时或之后，给予所述抗IL-18抗体，所述另外的药物例如抗IL-12抗体或其抗原结合片段、氨甲蝶呤、抗TNF抗体或其抗原结合片段、皮质类固醇、环孢菌素、雷帕霉素、FK506或非甾体消炎药。 
附图简述 
图1显示与IL-1β(左)和IL1RA(右)相比的IL-18(中间)的结构模型。 
图2显示与IL-18受体复合的IL-18的结构模型，其中IL-18的包含氨基酸PLFEDMTDSDCRDNA(SEQ ID NO：1)的肽表位以深灰色表示。该肽表位被抗IL-18抗体2E1结合。 
图3显示与IL-18受体复合的IL-18的结构模型，其中IL-18的包含氨基酸VIRNLNDQVLFIDQ(SEQ ID NO：33)的肽表位以深灰色 表示。该肽表位被抗IL-18抗体LT28结合。 
图4显示与IL-18受体复合的全长IL-18的结构模型。球形浅灰色和深灰色表位代表IL-18的N末端和C末端接触表位(分别为SEQID NO：70和71)。 
图5显示三种不同的抗IL-18抗体中和IL-18的生物效应的效价与抑制KG1细胞内IFN-γ诱导作用的关系。抗体125H(方框)和2E1IgG抗体(圆形)或2E1单链抗体(三角形)的IC50值分别为2.1E-10、9.0E-10和3.3E-9。 
发明详述 
本发明涉及选择能够对IL-18介导的信号转导产生中和作用的抗体的肽表位、制备抗这些表位的抗体以及这些抗体的应用，包括用来治疗涉及IL-18的疾病。选择表位的策略必须构建IL-18蛋白及其相应的受体的同源性模型。然后组合应用目测和计算估计选择用于合成和抗体产生的代表性肽区段。本文所示的氨基酸序列运用标准单字母缩写代码。 
IL-18表位的选择
运用程序Modeler(Sali，A.等，通过MODELLER评价比较性蛋白质建模(Evaluation of comparative protein modeling by MODELLER)。Proteins：Struct.，Funct.，Genet.(1995)，23(3)，第318-26页。CODEN：PSFGEY；ISSN：0887-3585)产生用于IL-18和IL-18受体两者的同源性模型。IL-1β(Priestle，J.等，人白介素-1β的三维结构精确到2.0.ANG.分辨率(The three-dimensional structure of human interleukin-1.beta.refined to 2.0.ANG.resolution)。Prog.Clin.Biol.Res.(1990)，349(Cytokines Lipocortins Inflammation Differ.)，第297-307页)和IL-1RA(Schreuder，H.等，白介素-1受体拮抗剂的精细晶体结构：二硫键和顺式脯氨酸的存在(Refined crystal structure of the interleukin-1 receptor antagonist：presence of a disulfide link and a cis-proline)。Eur.J.Biochem.(1995))，227(3)，第838-47页)的X射线晶体结构是可得到的并且用作IL-18模型构建的参考坐标。应用IL-1受体结构(Viger，G.等，与白介素-1β复合的I型白介素-1受体的晶体结构(Crystal structure of thetype-1 interleukin-1-receptor complexed with interleukin-1.beta)。Nature(London)(1997)，386(6621)，第190-194页)对IL-18受体建模。 
下文进一步描述IL-18和IL-18受体的结构模型建立。 
IL-18模型建立
与所述两种蛋白质(即IL-1β和IL-18)的总体序列同源性低，然而，令人信服的证据是IL-18是IL-1家族成员(参见Dinarello，C.A.IL-18：一种TH1诱导型促炎细胞因子及IL-1家族新成员(IL-18：aTH1-inducing，proinflammatory cytokine and new member of the IL-1family)。J.Allergy Clin.Immunol.(1999))，103(1，Pt.1)，第11-24页)，并且总体蛋白质折叠非常相似。和IL-1β一样，IL-18最初以前体形式分泌出来。前体IL-1β(pro-IL-1β)和前体IL-18(pro-IL-18)两者均被IL-1β转化酶(ICE)激活(Fantuzzi，G.和Dinarello，C.A.白介素-18和白介素-1β：ICE(caspase-1)的两种细胞因子底物(Interleukin-18 andInterleukin-1β：two cytokine substrates for ICE(caspase-1))。J.Clin.Immunol.(1999))，19(1)，第1-11页)。还知道IL-1受体和IL-18受体相似(Dinarello，C.A.等，白介素-18的综述：不止是一种干扰素γ诱导因子(Overview of interleukin-18：more than an interferon-γinducingfactor)。J.Leukocyte Biol.(1998)，63(6)，658-664)。IL-1β能够与IL-18受体结合。虽然这两种蛋白质间的总体序列同源性和IL-18的序列同源性相同，但是作为最终论证，IL-1β和IL-1RA显示出相同的折叠。对这三种蛋白质(即IL-18、IL-1β和IL1-RA)间的序列比对运用程序InsightII人工进行。该序列比对可以参见表1： 
表1：IL-18与IL-1β和IL-1RA的序列比对 
Figure DEST_PATH_GWB00000013830100091
  H96   A，R，E，Q，S，Y，V，H，P，W，or C
  H97   A，R，E，Q，S，Y，V，H，P，W，or C
  H98   A，R，E，Q，S，Y，V，H，P，W，or C
  H99   A，R，E，Q，S，Y，V，H，P，W，or C
  H100   A，R，E，Q，S，Y，V，H，P，W，or C
  H100a   A，R，E，Q，S，Y，V，H，P，W，or C
  H101   A，R，E，Q，S，Y，V，H，P，W，or C
  H102   A，R，E，Q，S，Y，V，H，P，W，or C
[0155] 表11.引入LT28的轻链氨基酸取代 
如上所述引入取代。然后对得自每个诱变反应的多个代表性克隆测序，并将代表来自亲代LT28单链抗体序列改变的那些克隆在细菌中表达，然后将其纯化，供如下所述的进一步测试用。 
实施例3 
人抗体与IL-18的结合活性
采用BIAcore系统(Pharmacia Biosensor，Piscataway，NJ)，通过表面等离子体共振(SPR)，测定配体(固定在生物传感器基体上的生物素化重组人IL-18(rhIL-18))和分析物(抗体溶液)之间的实时结合相互作用。所述系统利用SPR的光学性能检测葡聚糖生物传感器基体中的蛋白质浓度改变。使蛋白质以已知浓度与所述葡聚糖基体共价结合。将抗体通过所述葡聚糖基体注入，在注入抗体和固定配体间的特异性结合导致基体蛋白质浓度增加和SPR信号产生变化。SPR信号变化以共振单位(RU)记录，并相对于时间沿sensorgram的y轴显示。 
为了有利于将生物素化rhIL-18固定在生物传感器基体上，首先用100mM N-羟基琥珀酰亚胺(NHS)和400mM N-乙基-N’-(3-二乙基氨基丙基)碳二亚胺盐酸盐(EDC)，使链霉抗生物素蛋白通过游离氨基与所述基体共价连接。接下来，穿过所述活化基体注入链霉抗生物素蛋白。穿过所述活化生物传感器注入35μl在乙酸钠、pH 4.5中稀释的链霉抗生物素蛋白(25μg/ml)，所述蛋白上的游离胺直接与所述活化羧基结合。未反应的基体EDC-酯通过注射1M乙醇胺而去活化。另外，链霉抗生物素蛋白偶联的生物传感器芯片是可商业性获得的(Pharmacia BR-1000-16，Pharmacia Biosensor，Piscataway，NJ)。 
生物素化rhIL-18如下制备：首先将5.0mg生物素(D-生物素基-ε-氨基己酸N-羟基琥珀酰亚胺酯；Boehringer Mannheim Cat.No.1008960)溶于500μl二甲亚砜中，制备10mg/ml溶液。每毫升rhIL-18加入10μl生物素(2.65mg/ml)，生物素与rhIL-18的摩尔比为2∶1。将反应物温和地混合，然后于室温下避光孵育2小时。将PD-10柱子Sephadex G-25M(Pharmacia Catalog No.17-0851-01)用25ml冷PBS平衡，然后每个柱子上样2ml rhIL-18-生物素。用10x1ml冷PBS洗脱所述柱子。收集流分，然后在OD280读数(1.0 OD＝1.25mg/ml)。合并合适流分，然后于-80℃贮藏待用。 
将需通过链霉抗生物素蛋白固定在所述基体上的生物素化rhIL-18在补充0.05％(BIAcore)表面活性剂P20(Pharmacia BR-1000-54，Pharmacia Biosensor，Piscataway，NJ)的PBS运行缓冲液(Gibco Cat.No.14190-144，Gibco BRL，Grand Island，NY)中稀释。为了测定rhIL-18特异性抗体结合固定化rhIL-18的能力，如下进行结合测定。等份生物素化rhIL-18(25nM；10μl等份样品)以流速5μl/min注射通过链霉抗生物素蛋白偶联的葡聚糖基体。注入所述蛋白之前和不久以后，PBS缓冲液单独流过每个流式测定池。在基线和完成生物素化rhIL-18注入后约30秒之间信号的净差值代表结合值。测定直接与固定生物素化rhIL-18结合的rhIL-18特异性抗体。将抗体(20μg/ml)在PBS运行缓冲液中稀释，将25μl等份样品以流速5μl/min注射通过所述固定化蛋白质基体。注入抗体之前和不久以后，PBS缓冲液单独流过每个流式测定池。在基线信号和完成抗体注入后的信号的净差值代表所述特定样品的结合值。在注入下一个样品前，生物传感器基体用100mM HCl再生。为了测定解离速率(Koff)常数、缔合速率(Kon)常数、缔合速率(Ka)常数和解离速率(Kd)常数，运用BIAcore动力学评价软件(version 2.1)。 
与亲代抗体2E1和LT28(和小鼠对照)相比，改进候选抗IL-18抗体与生物素化rhIL-18结合的代表性结果示于下表12中。为了比较，也包括基于细胞的中和测定的IC50值，这些均在实施例4中有描述。所有克隆均作为单链Fv抗体制备，用以采用Biacore分析进行测试，基于细胞的测定如下所述。列出的亲代克隆包含未突变的亲代重链和轻链，而单链突变体含有一条亲代链和一条突变链，其中所述突变链以重(H)链或轻(L)链显示，其后氨基酸取代的Kabat位置和性质。 
表12.来源于2E1和LT28的抗IL-18抗体的结合 
Figure G01807735819950825D000441
*某些数值为与亲代相比改进的倍数。 
                    实施例4 
            抗IL-18抗体的中和活性
为了检查本发明的抗人IL-18抗体的中和活性，使用本领域公知的测定来监测IL-18活性。 
概括地讲，所述测定利用按照标准技术培养的KG1细胞(ATCC#CCL-246，髓性白血病骨髓细胞)(例如使用RPMI 1640培养基Gibco#21870-076；(补充10％胎牛血清(BioWhittaker#14-501F)；2mM L谷氨酰胺(Gibco#25030-081)；50单位/ml青霉素，50μg/ml链霉素(Gibco#15070-063)和075％碳酸氢钠)。 
为了测试对IL-18的中和作用，用20ng/ml hTNF-α(Lot#19130132)刺激的3x10E5 KG-1细胞与50μl抗IL-18抗体(4x Conc.)和50μl IL-18(4xConc.＝8ng/ml)一起孵育并且于37℃孵育1小时或16-20小时。为了测定随诱导的hIFN-γ产生而发生中和作用的IL-18含量，采用市售Elisa Kit(R&D#DIF00/Endogen#EH-IFNG)，按照生产商的说明，进行ELISA，然后根据标准曲线计算hIFN-γ的产量(pg/ml)。 
总之，4种突变抗体，即2E1衍生的L34S、H53R、H53Y和H58Q比亲代2E1抗体显示更强的IL-18中和效力(参见表12)。采用KG-1测定IC50值改进2-5倍，并且采用BIAcore分析测得相似的改进结合结果。 
也制备出各种突变组合的克隆，并对其进行测试，该数据概述于表12中。最佳组合克隆L34S-H53R在基于KG-1细胞的测定和采用BIAcore分析两者显示比亲代抗体2E1有10倍改进。将所得抗体命名为2E1RS。 
根据采用KG-1测定确定，2E1的几个其它突变克隆显示效能增强，即IL-18中和作用增强。突变体L95Y比亲代2E1抗体IC50值增加5-8倍。几个其它突变体提高2-3倍，它们是2E1突变体H96A、 H96Q、H96S、H98S、L90C、L90W、L93C、L94P、L94P、L94Q、L94R、L94W、L95R、L95aA、L95aH、L95aP、L95aR、L95aW、L95bE、L95bW、L95bY、L97C和L97E。 
也比较了2E1以ScFv抗体或IgG抗体形式的结合(参见图5)。 
再者，衍生自LT28亲代的两个突变体与所述亲代抗体相比，其IL-18中和活性改善。 
这些结果证明完全人IL-18中和抗体可以采用本发明的方法和组合物获得。 
                   等同实施方案 
本领域技术人员知道，或者采用常规实验能够确定与本文所述的本发明的具体实施方案等同的许多实施方案。下文的权利要求将包括这样的等同实施方案。 
Figure IYZ000004607658000031
Figure IYZ000004607658000041
Figure IYZ000004607658000051
Figure IYZ000004607658000091
Figure IYZ000004607658000101
Figure IYZ000004607658000111
Figure IYZ000004607658000121
Figure IYZ000004607658000131
Figure IYZ000004607658000141
Figure IYZ000004607658000161
Figure IYZ000004607658000171
Figure IYZ000004607658000191
Figure IYZ000004607658000221
Figure IYZ000004607658000231
Figure IYZ000004607658000241
Figure IYZ000004607658000251

Claims (18)

1.一种分离的抗体或其抗原结合部分，其中所述抗体或其抗原结合部分包含重链可变区和轻链可变区，
所述重链可变区包含：
由SEQ ID NO：9所示的氨基酸序列组成的重链CDR1结构域；
由SEQ ID NO：10所示的氨基酸序列组成的重链CDR2结构域；
由SEQ ID NO：11所示的氨基酸序列组成的重链CDR3结构域；
所述轻链可变区包含：
由SEQ ID NO：12所示的氨基酸序列组成的轻链CDR1结构域；
由SEQ ID NO：13所示的氨基酸序列组成的轻链CDR2结构域；
由SEQ ID NO：14所示的氨基酸序列组成的轻链CDR3结构域；以及
其中所述抗体或其抗原结合部分任选地具有选自下述的一组置换：在Kabat位置L34处的S；在Kabat位置H53处的R；在Kabat位置H53处的Y；在Kabat位置H58处的Q；在Kabat位置L34处的S和在Kabat位置H53处的R；在Kabat位置L34处的S和在Kabat位置H58处的Q；在Kabat位置L34处的S和在Kabat位置H53处的Y；在Kabat位置H53处的R和在Kabat位置H58处的Q；在Kabat位置H53处的Y和在Kabat位置H58处的Q；在Kabat位置L34处的S、在Kabat位置H53处的R和Kabat位置H58处的Q；在Kabat位置L34处的S、在Kabat位置H53处的Y和在Kabat位置H58处的Q；在Kabat位置L90处的C；在Kabat位置L93处的C；在Kabat位置L94处的P；在Kabat位置L94处的Q；在Kabat位置L94处的R；在Kabat位置L95处的R；在Kabat位置L95处的Y；在Kabat位置L95b处的E；或在Kabat位置L95b处的W。
2.权利要求1的抗体或其抗原结合部分，其中所述抗体是中和抗体。
3.权利要求1的抗体或其抗原结合部分，所述抗体是重组抗体。
4.权利要求1的抗体或其抗原结合部分，所述抗体是单克隆抗体。
5.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-2s-1或1x10-2s-1以下；或者它抑制人IL-18活性的IC50为1x10-7M或1x10-7M以下。
6.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-3s-1或1x10-3s-1以下；或者它抑制人IL-18活性的IC50为1x10-8M或1x10-8M以下。
7.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-4s-1或1x10-4s-1以下；或者它抑制人IL-18活性的IC50为1x10-9M或1x10-9M以下。
8.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-5s-1或1x10-5s-1以下；或者它抑制人IL-18活性的IC50为1x10-10M或1x10-10M以下。
9.权利要求1的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-6s-1或1x10-6s-1以下；或者它抑制人IL-18活性的IC50为1x10-11M或1x10-11M以下。
10.一种分离的抗体或其抗原结合部分，其中所述抗体或其抗原结合部分包含重链可变区和轻链可变区，
所述重链可变区包含：
由SEQ ID NO：20所示的氨基酸序列组成的重链CDR1结构域；
由SEQ ID NO：21所示的氨基酸序列组成的重链CDR2结构域；
由SEQ ID NO：22所示的氨基酸序列组成的重链CDR3结构域；
所述轻链可变区包含：
由SEQ ID NO：23所示的氨基酸序列组成的轻链CDR1结构域；
由SEQ ID NO：24所示的氨基酸序列组成的轻链CDR2结构域；
由SEQ ID NO：25所示的氨基酸序列组成的轻链CDR3结构域；
其中所述抗体或其抗原结合部分任选地具有选自下述的一种置换：在Kabat位置H54处的Q或在Kabat位置H58处的W。
11.权利要求10的抗体或其抗原结合部分，其中所述抗体是中和抗体。
12.权利要求10的抗体或其抗原结合部分，所述抗体是重组抗体。
13.权利要求10的抗体或其抗原结合部分，所述抗体是单克隆抗体。
14.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-2s-1或1x10-2s-1以下；或者它抑制人IL-18活性的IC50为1x10-7M或1x10-7M以下。
15.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-3s-1或1x10-3s-1以下；或者它抑制人IL-18活性的IC50为1x10-8M或1x10-8M以下。
16.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-4s-1或1x10-4s-1以下；或者它抑制人IL-18活性的IC50为1x10-9M或1x10-9M以下。
17.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-5s-1或1x10-5s-1以下；或者它抑制人IL-18活性的IC50为1x10-10M或1x10-10M以下。
18.权利要求10的分离抗体或其抗原结合部分，其中根据表面胞质团共振测定，所述分离抗体或其抗原结合部分与人IL-18解离的koff速率常数为1x10-6s-1或1x10-6s-2以下；或者它抑制人IL-18活性的IC50为1x10-11M或1x10-11M以下。
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