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CN103656638A - 白细胞介素-1α 抗体及使用方法 - Google Patents

白细胞介素-1α 抗体及使用方法 Download PDF

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CN103656638A
CN103656638A CN201310556893.3A CN201310556893A CN103656638A CN 103656638 A CN103656638 A CN 103656638A CN 201310556893 A CN201310556893 A CN 201310556893A CN 103656638 A CN103656638 A CN 103656638A
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J·西马德
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Abstract

本发明涉及一种白细胞介素-1α抗体及使用方法。完全人单克隆抗体，其包含（i）抗原结合可变区，所述抗原结合可变区表现出对IL-1α的非常高的结合亲和力；和（ii）恒定区，所述恒定区对于通过C1q结合而活化补体系统和与几种不同的Fc受体结合都有效。

Description

白细胞介素-1α 抗体及使用方法
本申请是申请日为2009年6月1日，申请号为200980125033.6，发明名称为“白细胞介素-1α抗体及使用方法”（此为修改后的发明名称，原发明名称为IL-1α抗体及使用方法）的申请的分案申请。 
相关申请的交叉引用 
本申请要求分别于2008年5月30日、2008年12月10日和2009年5月14日提交的美国临时专利申请系列第61/057,586号、第61/121,391号和第61/178,350号的优先权。 
关于联邦政府赞助的研究的声明 
不适用。 
发明领域
本发明总的来说涉及免疫学、炎症、癌症、血管病症和医学领域。更具体地，本发明涉及特异性结合白细胞介素-1α（IL-1α）的抗体（Ab）以及使用这种抗体治疗、预防或检测与异常的IL-1α表达相关的病理的方法。 
背景 
IL-1α是促炎细胞因子，它在大量不同活性中发挥重要作用，所述大量不同活性包括炎症、免疫应答、肿瘤转移和血细胞生成。针对IL-1α的IgG自身抗体天然地存在于普通人群中并被认为有益于诸如动脉粥样硬化等疾病。 
概述 
本发明基于完全人单克隆抗体（mAb）的开发，所述完全人单克隆抗体包含（i）抗原结合可变区，所述抗原结合可变区表现出对人IL-1α的非常高的结合亲和力，和（ii）恒定区，所述恒定区对于通过C1q结合而活化补体系统以及对于与几种不同的Fc受体结合都有效。本文描述的IL-1α特异性的mAb通过用人IgG1mAb的恒定区取代人IgG4mAb的恒定区而制得，所述人IgG4mAb具有对人IL-1α特异性的可变区。 
因此，本发明的特征是与人IL-1α特异性结合的纯化的人IgG1mAb，所述mAb包含与轻链共价连接的重链。所述重链可包含SEQIDNO:9的氨基酸序列并且所述轻链可包含SEQIDNO:11的氨基酸序列。 
一组分离的核酸也在本发明之中，这组分离的核酸包含编码与IL-1α特异性结合的人IgG1mAb的重链的第一核酸，以及编码与人IL-1α特异性结合的人IgG1mAb的轻链的第二核酸。所述第一核酸可以编码SEQID NO:9的氨基酸序列且所述第二核酸可以编码SEQIDNO:11的氨基酸序列。所述第一核酸可包含SEQIDNO:10核苷酸序列且所述第二核酸可包含SEQIDNO:12的核苷酸序列。 
在一些实施方案中，上述组的分离的核酸可被包含在至少一种表达载体内。 
在一些实施方案中，上述组的分离的核酸可被包含在分离的宿主细胞中。 
在另一方面，本发明的特征是一种表达载体，该表达载体包含编码SEQIDNO:9或SEQIDNO:11的氨基酸序列的核酸。 
本发明的另一个特征是包含一组分离的核酸的分离的宿主细胞（例如，哺乳动物细胞，诸如CHO细胞），这组分离的核酸包含编码与IL-1α特异性结合的人IgG1mAb的重链的第一核酸，以及编码与人IL-1α特异性结合的人IgG1mAb的轻链的第二核酸。所述重链可包含SEQIDNO:9的氨基酸序列并且轻链可包含SEQIDNO:11的氨基酸序列。 
本发明的特征还是杀伤表达人IL-1α的细胞的方法。该方法可包括使所述细胞接触与人IL-1α特异性结合的纯化的人IgG1mAb的步骤。 
在一些实施方案中，所述人IgG1单克隆抗体可包含重链和轻链，所述重链可包含SEQIDNO:9的氨基酸序列并且所述轻链可包含SEQID NO:11的氨基酸序列。 
抑制人细胞穿过基膜基质迁移的方法也在本发明之中。该方法可包括将与人IL-1α特异性结合的纯化的mAb添加到包括基膜基质和人细胞的混合物中的步骤。 
在一些实施方案中，所述纯化的单克隆抗体可以是包含与轻链共价连接的重链的人IgG1单克隆抗体。 
在一些实施方案中，所述重链可包含SEQIDNO:9的氨基酸序列并且轻链可包含SEQIDNO:11的氨基酸序列。 
还在本发明中的是抑制IL-1α诱导的在人内皮细胞表面上的ICAM-1和/或E-选择素的表达增加的方法。该方法可以包括将与人IL-1α特异性结合的纯化的mAb添加到包含内皮细胞和IL-1α的混合物中的步骤。 
在一些实施方案中，所述纯化的单克隆抗体可以是包含与轻链共价连接的重链的人IgG1单克隆抗体。 
在一些实施方案中，所述重链可包含SEQIDNO:9的氨基酸序列并且轻链可包含SEQIDNO:11的氨基酸序列。 
另外，本发明包括在人受治疗者中示踪炎症的方法，所述人受治疗者之前经受了下列步骤：首次从受治疗者获得外周血单核细胞的第一样品；用与人IL-1α特异性结合的纯化的mAb接触所述第一样品；以及确定所述第一样品中与所述单克隆Ab结合的细胞的百分比。该方法可包括下列步骤：（a）再次从该受治疗者获得外周血单核细胞的第二样品；（b）使所述第二样品接触与人IL-1α特异性结合的纯化的mAb；（c）确定所述第二样品中与所述单克隆Ab结合的细胞的百分比；以及（d）将所述第一样品中结合所述mAb的细胞的百分比与所述第二样品中结合所述单克隆Ab的细胞的百分比相比较。 
在上述的方法中，纯化的mAb可以是包含与轻链共价连接的重链的人IgG1mAb，例如，其中所述重链包含SEQIDNO:9的氨基酸序列且所述轻链包含SEQIDNO:11的氨基酸序列。 
本发明中的另一种方法的特征是下列步骤：（a）使用滤器富集从人受治疗者获得的生物样品，所述滤器根据分子量将分子分为包含与IL-1α复合的完整IgG的第一级分和包含小于100Kda的分子的第二级分；以及（b）对所述第一级分中的IL-1α的量进行定量。 
本发明中的又一种方法的特征是下列步骤：（a）使用滤器富集从人受治疗者获得的血浆样品，所述滤器根据分子量将分子分为包含与IL-1α复合的完整IgG的第一级分和包含小于100Kda的分子的第二级分；（b）在允许所述第一级分中的IgG与固定在基质上的抗人IgGAb特异性结合的条件下，将所述第一级分添加到含有固定的抗人IgGAb的所述基质中；（c）洗涤所述基质以去除所述第一级分中未与所述固定的抗人IgGAb特异性结合的材料；（d）在允许特异性结合人IL-1α的Ab与结合于所述基质的任何人IL-1α特异性结合的条件下，使在步骤（c）中洗涤的基质接触与人IL-1α特异性结合的Ab；（e）洗涤所述基质以去除与未结合于基质的人IL-1α特异性结合的任何抗体；以及（f）对与步骤（e）之后仍结合于所述基质的人IL-1α特异性结合的抗体的量进行定量。 
除非另外定义，否则本文使用的所有技术术语具有如本发明所属领域的普通技术人员所通常理解的相同含义。通常理解的生物术语的定义可见于：Rieger等人，GlossaryofGenetics:ClassicalandMolecular（遗传学词汇：经典遗传学和分子遗传学），第5版，Springer-Verlag:NewYork,1991；和Lewin,GenesV（基因V），OxfordUniversityPress:NewYork,1994。 
如本文所使用的术语“特异性结合”，当涉及多肽（包括Ab）或受体时，指的是决定在异质蛋白群体和其它生物群体中的蛋白或多肽或受体的存在的结合反应。因此，在指定的条件下（例如，就Ab而言在免疫测定条件下），指明的配体或Ab与其特定的“靶”结合且不以显著的量与样品中存在的其它蛋白结合或与机体中该配体或Ab可能发生接触的其它蛋白结合。通常，与第二分子“特异性结合”的第一分子对所述第二分子具有 大于约105（例如，106、107、108、109、1010、1011和1012或更多）升/摩尔的平衡亲和力常数。 
当涉及蛋白分子例如Ab时，“纯化的”意思是与天然地伴随这种分子的组分分离的。通常，当Ab或蛋白是按重量计至少约10%（例如，9%、10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、98%、99%、99.9%和100%）、不含非抗体蛋白或与其天然缔合的其它天然存在的有机分子时，Ab或蛋白是纯化的。纯度可通过任何适当的方法测定，例如柱层析、聚丙烯酰胺凝胶电泳或HPLC分析。化学合成的蛋白或在其天然存在的细胞类型之外的细胞类型中产生的其它重组蛋白是“纯化的”。 
虽然类似于或等同于本文描述的那些方法和材料的方法和材料可用于本发明的实践或测试中，但是在下文描述了合适的方法和材料。本文提及的所有出版物通过引用整体并入。在矛盾的情况下，以包括定义的本说明书为标准。另外，下文讨论的具体实施方案仅是示例性的并且不旨在是限制性的。 
详述 
本发明涵盖与完全人mAb相关的组合物和方法，所述完全人mAb包含：（i）抗原结合可变区，所述抗原结合可变区表现出对IL-1α的非常高的结合亲和力；和（ii）恒定区，所述恒定区对于通过C1q结合而活化补体系统以及对于与几种不同的Fc受体结合都有效。下文描述的优选的实施方案显示这些组合物和方法的改编。尽管如此，由这些实施方案的描述，基于下文提供的描述可做出和/或实践本发明的其它方面。 
本文描述了包含常规免疫学技术和分子生物技术的方法。免疫学方法（例如，用于检测和定位抗原-抗体复合物的测定、免疫沉淀、免疫印迹及类似方法）通常是本领域已知的并在下述方法学专著中描述，诸如：Current ProtocolsinImmunology（现代免疫学实验技术），Coligan等人，编辑,John Wiley&Sons，NewYork。在下述专著中详细描述了分子生物学技术，诸如：MolecularCloning:ALaboratoryManual（分子克隆：实验室手册），第 二版，第1-3卷，Sambrook等人编辑，ColdSpringHarborLaboratoryPress，ColdSpringHarbor,N.Y.,2001；和CurrentProtocolsinMolecularBiology（现代分子生物学实验技术），Ausubel等人编辑，GreenePublishingand Wiley-Interscience,NewYork。在HandbookofTherapeuticAbs（治疗性抗体手册），Dubel,S.编辑，Wiley-VCH,2007中描述了抗体方法。细胞培养技术通常是本领域已知的并在下述方法学专著中详述：诸如RIanFreshney、Wiley-Liss、Hoboken，N.J.的CultureofAnimalCells:AManualofBasic Technique（动物细胞的培养：基础技术手册），第四版,2000；和MaureenA Harrison和IanFRae的GeneralTechniquesofCellCulture（细胞培养的一般技术），CambridgeUniversityPress,Cambridge,UK,1994。蛋白纯化的方法在GuidetoProteinPurification:MethodsinEnzymology（蛋白纯化指南：酶学中的方法），第182卷，DeutscherMP编辑，AcademicPress,SanDiego,Calif.,1990中讨论。 
在一个方面，本发明的特征为完全人mAb，其包含（i）抗原结合可变区，所述抗原结合可变区表现出对人IL-1α的非常高的结合亲和力，和（ii）恒定区，所述恒定区对于通过C1q的结合而活化补体系统以及对于与几种不同的Fc受体的结合都有效。人Ab优选地是IgG1。Ab的Ka优选地是至少1×109M-1或更高（例如，高于9×1010M-1、8×1010M-1、7×1010M-1、6×1010M-1、5×1010M-1、4×1010M-1、3×1010M-1、2×1010M-1或1×1010M-1）。 
因为人类中天然地存在表达对人IL-1α特异的Ig的B淋巴细胞，所以用于培育mAb的一种目前优选的方法是首先从受治疗者中分离这种B淋巴细胞，并之后将该B淋巴细胞永生化以便它能在培养中连续复制。可用一种或多种人IL-1α抗原免疫缺乏大量天然存在的表达对人IL-1α特异的Ig的B淋巴细胞的受治疗者以增加这种B淋巴细胞的数量。通过使人Ab分泌细胞（例如，人浆细胞）永生化来制备人mAb。参见，例如，美国专利第4,634,664号。 
在示例性的方法中，对一个或多个（例如：5、10、25、50、100、1000或更多个）人受治疗者（即，之前未施用人IL-1α疫苗的受治疗者）筛选 他们的血液中这种人IL-1α特异性的Ab的存在。表达期望的Ab的那些受治疗者之后可被用作B淋巴细胞供体。在一个可能的方法中，从拥有表达人IL-1α特异性的Ab的B淋巴细胞的人供体中获得外周血。之后从血液样品中分离这种B淋巴细胞，例如，通过细胞分选（例如，荧光激活的细胞分选“FACS”或磁珠细胞分选）以选择表达人IL-1α特异性的Ig的B淋巴细胞。之后可以根据已知的技术通过病毒转化（例如，使用EBV）或通过与诸如人骨髓瘤的另一种永生化细胞融合而将这些细胞永生化。之后可以通过有限稀释法分离该群体内表达对人IL-1α特异的Ig的B淋巴细胞（例如，选择微量滴定板孔中对人IL-1α特异的Ig呈阳性的细胞并传代培养，并重复上述步骤直至能够分离期望的克隆株系）。参见，例如Goding，MonoclonalAbs:PrinciplesandPractice（单克隆抗体：原理和实践），第59-103页，AcademicPress,1986。这些表达对人IL-1α具有至少纳摩尔或皮摩尔结合亲和力的Ig的克隆细胞系是优选的。可以通过常规的Ig纯化程序诸如盐析（saltcut）、尺寸排阻、离子交换分离和亲和层析从培养基或体液中（诸如腹水）纯化这些克隆细胞系分泌的mAb。 
虽然永生化的B淋巴细胞可用于体外培养以直接产生mAb，在某些情形下使用异源表达系统来产生mAb可能是期望的。参见，例如，在美国专利申请第11/754,899号中描述的方法。例如，可以将编码对人IL-1α特异的mAb的基因克隆并引入表达载体中（例如，基于质粒的表达载体）以在异源的宿主细胞（例如：CHO细胞、COS细胞、骨髓瘤细胞和大肠杆菌细胞）中表达。因为Ig包括H2L2构型的重链（H）和轻链（L），所以可在不同的载体中分别分离和表达编码重链和轻链各自的基因。 
虽然通常不优选，但是嵌合的mAb（例如，“人源化的”mAb）可用于本发明，嵌合的mAb是具有来源于不同动物物种的不同部分的抗原结合分子（例如，小鼠Ig的可变区与人Ig的恒定区融合）。这样的嵌合的Ab可以通过本领域已知的方法制备。E.G.,Morrison等人，Proc.Nat'l.Acad.Sci.USA,81:6851,1984；Neuberger等人，Nature,312:604,1984；Takeda等人，Nature,314:452,1984。类似地，可以用本领域已知的方法将Ab人源化。例如，具有期望的结合特异性的单克隆Ab可以是商业上人源化的 或如在美国专利第5,693,762号、第5,530,101号或第5,585,089号中描述的。 
可通过下列已知方法使本文描述的mAb亲和力成熟以增强或者另外改变它们的结合特异性：诸如VH和VL结构域改组（Marks等人Bio/Technology10:779-783，1992）、高变区（HVR）和/或框架残基的随机诱变（Barbas等人，ProcNat.Acad.Sci.USA91：3809-3813,1994；Schier等人，Gene169:147-155,1995；Yelton等人，J.Immunol.155:1994-2004,1995；Jackson等人，J.Immunol.154(7):3310-9,1995；和Hawkins等人，J.Mol.Biol.226:889-896,1992）。Ab的氨基酸序列变体可通过将合适的改变引入至编码该Ab的核苷酸序列中来制备。另外，可改变对编码mAb的核酸序列的修饰（例如，不改变mAb的氨基酸序列）以增强在某种表达系统中mAb的产生（例如，给定的表达系统的内含子消除和/或密码子优化）。本文描述的mAb也可通过与另一种蛋白（例如，另一种mAb）或非蛋白分子结合而被修饰。例如，mAb可与水溶性聚合物结合，诸如：聚乙二醇或碳纳米管（参见，例如Kam等人，Proc.Natl.Acad.Sci.USA102:11600-11605,2005）。参见，美国专利申请第11/754,899号。 
优选地，为保证可以将高效价的人IL-1α-特异性mAb以最小的副作用施用给受治疗者，本发明的mAb组合物按重量计至少为0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、20%、25%、30%、35%、40%、45%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%、99.9%或更高百分比的纯度（不包含任何赋形剂）。本发明的mAb组合物可仅包含单一类型的mAb（例如，从单一克隆的B淋巴细胞系中产生的mAb）或可包含两种或更多种（例如，2、3、4、5、6、7、8、9、10或更多）不同类型的mAb的混合物。除人IL-1αmAb之外，本发明的Ab组合物也可包含与除人IL-1α之外的抗原特异性结合的其它mAb。 
为修饰或增强它们的功能，人IL-1αmAb可与另一种分子诸如细胞毒素或可检测的标记结合。人IL-1α特异性mAb可与一种或多种细胞毒素结合以更有效地杀伤表达IL-1α的细胞。本发明中使用的细胞毒素可以是能 够与人IL-1α特异性的mAb结合的任何细胞毒性剂（例如，接触细胞后能杀伤细胞的分子）。细胞毒素的实例包括但不限于：放射性核素（如35S、 14C、32P、125I、131I、90Y、89Zr、201T1、186Re、188Re、57Cu、213Bi和211At）、结合的放射性核素和化疗剂。细胞毒素的其他实例包括但不限于：抗代谢物（如5-氟尿嘧啶（5-FU）、甲氨蝶呤（MTX）、氟达拉滨等）；抗微管剂（如长春新碱、长春碱、秋水仙碱、紫杉烷类（诸如紫杉醇和多西他赛）等）；烷化剂（如环磷酰胺、美法仑、亚硝脲氮芥（BCNU）等）；铂剂（如顺铂（也称为cDDP）、卡铂、奥沙利铂、JM-216、CI-973等）；蒽环类（如，多柔比星、柔红霉素等）；抗生素剂（如丝裂霉素-C）；拓扑异构酶抑制剂（如依托泊苷、替尼泊苷和喜树碱）；或其他细胞毒性剂诸如篦麻毒素、白喉毒素（DT）、假单胞菌外毒素（PE）A、PE40、相思豆毒蛋白、皂草毒蛋白、商陆病毒蛋白、溴化乙锭、糖皮质激素、炭疽毒素及其它。参见，例如美国专利申请第5,932,188号。 
人IL-1α特异性的mAb也可以与可检测的标记结合。本发明中有用的可检测标记包括：生物素或抗生蛋白链菌素、磁珠、荧光染料（例如异硫氰酸荧光素、德克萨斯红、罗丹明、绿色荧光蛋白及类似物）、放射性标记（如3H、125I、35S、14C、32P、111In、97Ru、67Ga、68Ga或72As）、不透射线物质诸如用于放射成像的金属、用于磁共振成像的顺磁剂、酶（如辣根过氧物酶、碱性磷酸酶和通常在ELISA中使用的其它酶）以及显色标记诸如胶体金或有色玻璃珠或塑料（如，聚苯乙烯、聚丙烯、胶乳等）珠。检测这种标记的方法是本领域技术人员熟知的。因此，例如，放射性标记可使用摄影胶片或闪烁计数器检测。也可使用荧光标志物并可以通过使用光探测器检测发射照度来检测。酶标记通常通过将底物提供给酶并检测由酶对底物的作用而产生的反应产物来检测，且显色标记通过简单地将有色的标记显像而检测。 
本发明也涵盖编码对人IL-1α特异的完全人mAb的核酸分子。虽然同一核酸分子可编码人IL-1α特异性的mAb的重链和轻链二者，但是也可使用两种不同的核酸分子，一种编码重链且另一种编码轻链。本文呈现了对人IL-1α特异的三种IgG1mAb的氨基酸序列。参见SEQIDNO:1、3、5、 7、9和11。本文也描述了编码这些氨基酸序列的示例性核酸分子。参见SEQIDNO:2、4、6、8、10和12。也可使用编码本发明中的两种描述的IgG1mAb或其它mAb的氨基酸序列的任何其它合适的核酸。 
为产生mAb，可以将本发明的核酸分子以如下方向并入表达载体中：其中该核酸分子与诸如转录控制序列和翻译控制序列等表达控制序列可操作地连接。表达载体的实例包括来源于质粒的载体和来源于病毒诸如腺病毒、腺相关病毒和反转录病毒的载体。编码轻链和重链的核酸分子可并入单一载体或不同载体中。本发明的载体还可包括调节序列诸如启动子和/或增强子（参见美国专利第5,168,062号、美国专利第4,510,245号和美国专利第4,968,615号）、选择性标记或编码亲和标签的序列（以有利于纯化）或可检测标记。 
为产生mAb，可以将本发明的载体引入至合适的宿主细胞中，例如诸如细菌等原核细胞或优选真核细胞，诸如哺乳动物宿主细胞、植物宿主细胞或酵母宿主细胞。用于将异源的多核苷酸引入至宿主细胞中的方法的实例包括使用病毒载体、电穿孔、多核苷酸在脂质体中的包封、右旋糖酐介导的转染、磷酸钙沉淀、聚凝胺介导的转染、原生质体融合、农杆菌介导的转化、基因枪转化和将DNA直接微注射入细胞核中。哺乳动物细胞系目前优选地用于从载体中表达mAb。哺乳动物宿主细胞的实例包括中国仓鼠卵巢（CHO）细胞（如，DG44CHO细胞系）、HeLa细胞、幼仓鼠肾（BHK）细胞、非洲绿猴肾细胞（COS）、人肝细胞癌细胞（如HepG2）、NS0细胞、SP2细胞、HEK-293T细胞、293Freestyle细胞和NIH-3T3细胞。本发明的mAb还可在转基因动物或转基因植物中表达。参见，例如美国专利第5,827,690号；第5,756,687号；第5,750,172号；第5,741,957号；第6,046,037号和第5,959,177号。 
本发明提供通过使细胞与人IL-1α特异性的mAb接触并检测与所述细胞结合的mAb来检测样品中表达人IL-1α的细胞的方法。本发明还提供通过使细胞与人IL-1α特异性的mAb接触来杀伤表达人IL-1α的细胞的方法。这种杀伤可通过补体介导的杀伤、Ab依赖性细胞介导的细胞毒性或Ab介导的细胞毒素的递送实现。本文描述的Ab还显示可用于其它方法。例如， MABp1已降低IL-1α诱导的ICAM1和E-选择素在内皮细胞上的表达。MABp1还显示用于检测和定量生物样品中的IL-1α的免疫测定。 
实施例
实施例1-抗-hIL-1αIgG1和κ链的克隆 
使用美国专利第5,959,085号提供的氨基酸序列信息对可变区重链（V-HC）序列和可变区轻链（V-LC）序列进行基因合成。PCR扩增V-HC以引入ATG起始密码子上游的HindIII/Cla1位点和3'末端的Nhe1位点。PCR扩增人种系IgG1恒定区（包括外显子和内含子）以将编码前两个氨基酸Ala-Ser的两个5'三联体修饰为Nhe1位点，并在3'末端引入BamHI位点。人种系IgG1恒定区氨基酸序列除K171Q和V261L互换之外，与Swiss-Prot条目P01857一致。使用Nhe1位点连接V-HC序列和恒定区IgG1-HC序列，并使用HindIII位点和BamHI位点将其克隆至pcDNA3中。>hIL-1a-IgG1-HC 
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAQTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIALEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK（SEQIDNO:1）>hIL-1a-IgG1-HC 
atggagttcgggctgagttgggtgttcctggtggctctgctgcggggcgtgcagtgccaggtgcagctggtggagagtgggggtggcgtggtgcagcctggccggtctctgcgcctgtcttgcactgcctccggttttaccttttctatgtttggtgtgcactgggtgcgccaggctcccggcaagggactggaatgggtggccgccgtgagttacgacgggtcc aacaaatattacgctgagagcgtgaaaggcagattcaccatcagcagagataattccaagaatattctgttcctgcagatggacagtctgagactggaggacactgctgtgtactactgcgctcgtggacgccctaaggtggtcatccccgcccccctggcacattggggccagggaactctggtgaccttttctagcgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtccacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtagtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcccagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccctggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccttaagtccgggaaaataa（SEQIDNO:2） 
PCR扩增V-LC以引入ATG起始密码子上游的HindIII/Cla1位点和3'末端的BsiWI位点。PCR扩增人恒定区κ-LC序列，以引入编码额外的Arg和第一个氨基酸Thr的5'BsiWI位点和位于3'末端的BamHI位点。人恒定区κ-LC氨基酸序列与Swiss-Prot条目P01834一致。使用BsiWI位点连接V-HC序列和恒定区κ-LC序列，并使用HindIII位点和BamHI位点将其克隆至pcDNA3中。 
>hIL-1a-K-LC 
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[SEQIDNO:3] >hIL-1a-K-LC 
atggacatgcgcgtgcccgcccagctgctggggctgctgctgctgtggttccctggatctaggtgcgacattcagatgacccagtcccccagctcagtgtcagcctccgtgggcgacagagtgacaatcacctgccgcgcctctcagggaatctctagttggctggcctggtaccagcagaagcctggaaaggcccccaagctgctgatctatgaagcctccaacctggagaccggcgtgccctctcgcttcagcggctcaggctcaggcagtgattttactctgaccatcagctccctgcagccagaggatttcgctacttactactgccagcagacctcttccttcctgctgtccttcgggggaggcacaaaggtggagcaccgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagttcaccggtgacaaagagcttcaacaggggagagtgttag[SEQIDNO:4] 
实施例2-NATHMAB-hIL-1aIgG1和κ链的产生 
对编码NATHMAB-hIL-1a/IgG1重链的完整序列进行基因合成。V-HC序列与在美国专利第5,959,085号中描述的氨基酸序列一致。人恒定区IgG1-HC序列与Swiss-Prot条目P01857一致。对核苷酸序列进行密码子优化以在CHO细胞中表达。将Kozac序列（gccacc）添加至起始ATG的上游。 
>NATHMAB-hIL-1A-IGG1-HC 
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[SEQIDNO:5] 
>NATHMAB-hIL-1A-IGG1-HC 
gccaccatggagtttggtctgtcctgggtgttcttggtggctctgctgaggggggtgcagtgccaggtccagctggtggagtctggtgggggagtggtgcagcctgggagatctctgcggctgtcttgcactgcctctggtttcactttctctatgtttggtgtgcattgggtcaggcaagcaccaggcaaaggactcgagtgggtcgcagctgtgagctatgacgggtctaacaaatattacgctgagtctgtcaagggtaggtttaccatcagccgggataattccaaaaatatcctgttcctgcaaatggactctctgaggctggaagatactgcagtctactattgtgcaagggggaggccaaaggtggtgatccccgctcccctcgctcactggggacagggaaccctggtgactttcagctctgctagcaccaagggccctagcgtgttcccattggctccttcctccaaatctacttctggaggcaccgccgccctgggatgtctcgtgaaagattattttcctgagcccgtcaccgtgagctggaacagcggcgccctgactagcggcgtgcacacctttcccgcagtgctgcaatctagcgggctgtactccctgagctctgtcgtgaccgtgccctccagcagcctcggaactcagacctacatctgcaatgtcaatcataaaccctctaataccaaagtcgataagaaggtcgaacctaaatcttgcgataaaacccatacctgccccccttgcccagcacccgaactgctgggcggtccctctgtgtttctgttcccccccaaacccaaagataccctgatgatctctaggacccccgaggtcacttgtgtcgtggtggatgtgtcccacgaagatccagaagtcaaattcaactggtatgtggacggggtcgaagtgcacaacgcaaagaccaagcctagggaggaacagtataatagcacatatagggtggtcagcgtcctgaccgtcctgcatcaggactggctgaatggcaaagaatataagtgtaaagtgtccaacaaggccctgccagccccaatcgaaaagacaatctctaaagccaaggggcaaccccgggaacctcaggtctatacactgccaccctctcgggatgaactgaccaagaatcaggtgagcctgacatgtcttgtgaagggtttttatccctccgacattgccgtggagtgggagagcaatggacaaccagaaaataactacaaaaccacaccccctgtgctggactccgatggttccttcttcctctactctaagctgacagtggataagtctaggtggcagcaggggaatgtgttctcctgctctgtgatgcacgaggcactgcacaatcattatacacaaaagtctctgtctctgtctccaggaaagtaa[SEQIDNO:6] 
对编码NATHMAB-hIL-1a/κ轻链的完整序列进行基因合成。V-LC序列与在美国专利第5,959,085号中描述的氨基酸序列一致。人恒定区κ-LC序列与Swiss-Prot条目P01834一致。对核苷酸序列进行密码子优化以在CHO细胞中表达。将Kozac序列（gccacc）添加至ATG的上游。 
>NATHMAB-hIL-1A-K-LC 
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISS LQPEDFATYYCQQTSSFLLSFGGGTKVEHTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[SEQIDNO:7] 
NATHMAB-hIL-1A-K-LC 
gccaccatggacatgcgcgttcctgcccagctcctcggactgctgctgctttggttcccaggctcccggtgtgatattcagatgacacagtctccctcctccgtatctgcatccgtgggcgacagggtcacaatcacttgtagggccagccaggggatctctagttggctcgcatggtaccaacaaaagccaggtaaggctccgaaactgctcatttacgaagctagtaacctcgaaacaggcgtgccaagccggtttagcggctccggttccggttctgacttcaccctcactatttcctccctgcaacctgaggattttgccacatattactgtcagcaaacttcttcttttctgctctcctttggtgggggaactaaggtggagcacacagtggccgcccccagcgtctttatcttccccccaagcgatgaacagctgaagtcagggaccgccagcgtggtctgcctgctcaataatttttaccctcgcgaggctaaggtccaatggaaagtggataacgccctccagagcggtaactctcaggagtctgtcacagagcaagacagcaaggatagcacctattccctctccagcaccctgacactgtctaaggccgactacgagaaacacaaagtgtacgcttgtgaggtgactcaccagggactgagtagccctgtgacaaaatctttcaataggggagaatgctga[SEQIDNO:8] 
实施例3-NATHMAB-IL-1-a（IgG1/κ亚型）的表达 
使用瞬时转染法表达和纯化NATHMAB-IL-1α。细胞培养上清液或蛋白G亲和纯化的Ab进一步经受如下文所描述的分析。在含有10%FCS的DMEM中培养人胚胎肾（HEK）293T细胞，并根据厂家的方案使用jetPEI试剂（Polyplus）瞬时转染。在转染之前24h将细胞接种在10cm皿中（每个10cm皿3×106个细胞）以在转染时间点达到约50%的密度。使用每皿5μg的pcDNA3-抗-hIL-1α-IgG1-HC和2倍摩尔过量的pcDNA3-抗-hIL-1α-κ进行转染。在回收之后，将培养基换为含有2%FCS的DMEM（每皿10ml）并收集Ab持续5至6天。收集上清液，过滤，将pH调至7.5-8，并储存在4℃直到进一步的使用。 
将部分上清液（250ml）与蛋白G琼脂糖（GEHealthcare）在旋转轮上在4℃下孵育3小时。之后，将蛋白G琼脂糖加样于重力流柱中并用PBS洗涤。使用在100μl Tris（pH8）中的100mM甘氨酸/150mMNaCl将Ab 洗脱在1ml的级分中，随后用含有10%甘油的PBS透析。使用BCA蛋白检测试剂盒（Pierce）测量各级分的总蛋白浓度。通过SDS-PAGE确认重链和轻链的正确大小和组装的天然Ab的正确大小。 
使用125I-hIL-1α在放射免疫测定（RIA）中测试含有NATHMAB-hIL-1α纯化的Ab的上清液和生产者HEK293T细胞的TritonX-100细胞裂解物的抗原结合。通过对蛋白G的吸收来测定结合。洗脱物中所有样品都以最高的活性与125I-hIL-1α结合。使用0.012%的浓度（在RIA中的半数最高活性）的纯化的NATHMAB-hIL-1α与125I-hIL-1α的结合测量亲和系数。在这些条件下NATHMAB-hIL-1α的Ka是3.03×1010M-1。反演计算揭示了在纯化的洗脱物中约30μg/ml的活性抗-hIL-1α-IgG的估计浓度。 
使用鼠EL4-6.1亚系在生物测定中测试NATHMAB-hIL1α的中和活性，所述鼠EL4-6.1亚系当用鼠IL-1α或人IL-1α处理时产生高水平的IL-2（Zubler等人，J.Immunol.134:3662-3668,1985）。将标示浓度的NATHMAB-hIL-1α（洗脱物）与多种浓度的重组hIL-1α（eBioscience）以100μl/孔的终体积在96-孔培养板（平底的）中在37℃下孵育30分钟。每点以一式三份且在培养基中（DMEM，5%FCS）实施。将100μl在含有0.2μg/ml离子霉素（ionomycin）的培养基中的EL4-6.1细胞（5×105细胞/ml）的悬浮液添加至各孔中。在37℃下5%CO2培养箱中孵育24小时之后，收获无细胞的上清液并使用商购获得的ELISA（R&DSystems）测定其IL-2浓度。结果显示NATHMAB-IL-1α有效地中和hIL-1α诱导的EL-4细胞的IL-2分泌。 
为测试膜结合的hIL-1α的中和，使用如上文所描述的相同的基于EL-4细胞的测定，但具有下述修改。用不同数量的活化的人单核细胞孵育不同浓度的NATHMAB-hIL-1α（洗脱物）。对于单核细胞制备，使用Ficoll-Paque离心从暗黄覆盖层中分离PBMC。允许单核细胞在塑料皿上RPMI中于37℃附着1.5小时。洗掉未附着的淋巴细胞以产生几乎纯的单核细胞培养物。将单核细胞在37℃下在5%CO2培养箱中在含有Gln、Pyr和10%FCS的RPMI中与LPS（1μg/ml）一起培养24小时。用PBS/2mMEDTA使细胞脱离，小心地从板上将细胞刮下，并转移至Falcon管中。用PBS洗涤细 胞两次，将细胞重悬在PBS/1%PFA中并在20℃固定10分钟。用甘氨酸缓冲液（150mM甘氨酸，75mMNaCl，pH7.4）然后用培养基洗涤细胞并计数。结果显示NATHMAB-hIL-1α有效地中和由膜结合的hIL-1α诱导的EL-4细胞的IL-2分泌。在类似于上文所描述的实验中，测试了NATHMAB-hIL-lα对鼠IL-1α的中和。用重组的人（h）IL-1α或鼠（m）IL-1α（eBioscience）孵育标示量的NATHMAB-hIL-1α上清液。含有Ab的上清液中和人IL-1α，而不中和鼠IL-1α。 
实施例4-Ab介导的癌细胞的杀伤 
在37℃下和5%CO2中将用标准FicollPaque制剂从暗黄覆盖层中分离的人外周血单核细胞（PBMC）在RPMI-1640CM或者含有rhIL-2（30ng/ml，ebioscience）的RPMI-1640-CM中孵育过夜，并将其用作效应细胞（E）。将THP1细胞用作靶（T）。在96-孔板中以每点一式三份进行测定。在用不同浓度的MABp1孵育1×104个靶15分钟之后，按25:1和50:1的ET比将效应细胞加入至1×104个靶中并孵育另外4小时。将75μl的测定体积转移至新的96-孔板中，并根据厂家的方案使用LDH细胞毒性检测试剂盒（Roche）测定细胞毒性。%特异性裂解=（平均的实验释放-无抗体的平均自发释放）×100/（平均的由靶最大释放-平均的由靶自发释放）。A.使用未处理的PBMC作为效应细胞。B.使用rhIL-2-处理的PBMC作为效应细胞。在两种情形下，增加MABp1的浓度（从1.25μg/ml至20μg/ml）在两种ET比之下都导致靶细胞杀伤增加（达约90%）。 
实施例5-人抗-IL1α特异性mAb序列 
如上文所述合成并表达编码对人IL1α特异的另一种人抗-hIL-1αIgG1/κ轻链的完整序列（MABp1）。在编码重链和轻链的核酸中，将Kozac序列（gccacc）添加至起始ATG的上游。 
重链 
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTF SMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[SEQIDNO:9] 
gccaccatggagtttggtctgtcctgggtgttcttggtggctctgctgaggggggtgcagtgccaggtccagctggtggagtctggtgggggagtggtgcagcctgggagatctctgcggctgtcttgcactgcctctggtttcactttctctatgtttggtgtgcattgggtcaggcaagcaccaggcaaaggactcgagtgggtcgcagctgtgagctatgacgggtctaacaaatattacgctgagtctgtcaagggtaggtttaccatcagccgggataattccaaaaatatcctgttcctgcaaatggactctctgaggctggaagatactgcagtctactattgtgcaagggggaggccaaaggtggtgatccccgctcccctcgctcactggggacagggaaccctggtgactttcagctctgctagcaccaagggccctagcgtgttcccattggctccttcctccaaatctacttctggaggcaccgccgccctgggatgtctcgtgaaagattattttcctgagcccgtcaccgtgagctggaacagcggcgccctgactagcggcgtgcacacctttcccgcagtgctgcaatctagcgggctgtactccctgagctctgtcgtgaccgtgccctccagcagcctcggaactcagacctacatctgcaatgtcaatcataaaccctctaataccaaagtcgataagagggtcgaacctaaatcttgcgataaaacccatacctgccccccttgcccagcacccgaactgctgggcggtccctctgtgtttctgttcccccccaaacccaaagataccctgatgatctctaggacccccgaggtcacttgtgtcgtggtggatgtgtcccacgaagatccagaagtcaaattcaactggtatgtggacggggtcgaagtgcacaacgcaaagaccaagcctagggaggaacagtataatagcacatatagggtggtcagcgtcctgaccgtcctgcatcaggactggctgaatggcaaagaatataagtgtaaagtgtccaacaaggccctgccagccccaatcgaaaagacaatctctaaagccaaggggcaaccccgggaacctcaggtctatacactgccaccctctcgggaggaaatgaccaagaatcaggtgagcctgacatgtcttgtgaagggtttttatccctccgacattgccgtggagtgggagagcaatggacaaccagaaaataactacaaaaccacaccccctgtgctggactccgatggttccttcttcctctactctaagctgacagtggataagtctaggtggcagcaggggaatgtgttctcctgctctgtgatgcacgaggcactgcacaatcattatacacaaaagtctctgtctctgtctccaggaaagtaa[SEQIDNO:10] 
轻链 
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[SEQIDNO:11] 
gccaccatggacatgcgcgttcctgcccagctcctcggactgctgctgctttggttcccaggctcccggtgtgatattcagatgacacagtctccctcctccgtatctgcatccgtgggcgacagggtcacaatcacttgtagggccagccaggggatctctagttggctcgcatggtaccaacaaaagccaggtaaggctccgaaactgctcatttacgaagctagtaacctcgaaacaggcgtgccaagccggtttagcggctccggttccggttctgacttcaccctcactatttcctccctgcaacctgaggattttgccacatattactgtcagcaaacttcttcttttctgctctcctttggtggaggaactaaggtggagcacaagcggacagttgctgctcctagcgtctttatcttccctccaagcgatgaacagctgaagtcagggaccgccagcgtggtctgcctgctcaataatttttaccctcgcgaggctaaggtccaatggaaagtggataacgccctccagagcggtaactctcaggagtctgtcacagagcaagacagcaaggatagcacctattccctctccagcaccctgacactgtctaaggccgactacgagaaacacaaagtgtacgcttgtgaggtgactcaccagggactgagtagccctgtgacaaaatctttcaataggggagaatgctga[SEQIDNO:12] 
实施例6-MABp1结合亲和力 
在BIAcore2000仪器（GEHealthSciences）上使用表面等离子共振（SPR）检测纯化的MABp1的结合亲和力。使用人Ab捕获试剂盒和胺偶联试剂盒（GEHealthSciences）将小鼠抗人IgG（Fc）单克隆Ab共价地固定在CM5传感器芯片的流动池上。通常达到8000–14000RU的固定水平。在小鼠抗-人IgG（Fc）捕获Ab固定之后，用HBS-EP运行缓冲液（GE HealthSciences）运行三次起始循环并用MABp1运行二次起始循环以稳定CM5表面并去除任何未共价结合的Ab。为了分析，将MABp1Ab稀释到HBS-EP运行缓冲液中至1μg/mL的终浓度并将其以700RU固定到CM5传感器芯片的一个流动池上。在100nM至0.05nM的检测范围内将无载体的人IL-1A细胞因子（eBioscience，#34-8019）系列稀释在HBS-EP运 行缓冲液中。流速为30μl/min。持续15分钟记录每个细胞因子稀释物的解离数据。在每次循环之后，用30μl/min的流速单次注射3MMgCl2持续25秒以再生CM5表面。使用BiaEvaluation软件和Langmuir结合模型拟合数据。测得MABp1的KD为小于2.0×10-10M。 
实施例7–MABp1抑制肿瘤细胞对基膜基质的侵袭 
将基质胶（BD）（一种基膜基质）在4℃下融化过夜并在无血清的冷细胞培养基中稀释（从5mg/ml至1mg/ml）。将100μl稀释的基质胶置于24-孔transwell（Costar）的上室中并将transwell在37℃下孵育至少4至5小时以凝胶化。用胰蛋白酶/EDTA从组织培养瓶中收获肿瘤细胞（MDA-MB-231和THP-1）、用培养基洗涤并以1×106细胞/ml的密度重悬在含有1%FBS的培养基中。用温的无血清培养基轻轻地洗涤凝胶化的基质胶，并将100μl细胞悬浮液添加至每孔中。用600μl培养基填充transwell的下室，并将板在37℃下孵育12至24小时。用棉拭子轻轻地将未侵袭基质胶的细胞从每个transwell的顶部擦去。之后将transwell从24-孔板中移出并在用70%乙醇或甲醇固定侵袭的细胞之后用结晶紫染色。在光学显微镜下对侵袭的细胞计数。在MABp1存在下，侵袭基质胶的细胞的百分比被显著地抑制。 
实施例8–MABp1阻断内皮细胞中ICAM1表达的增加 
将人脐静脉内皮细胞（HUVEC）（BDBiosciences）以在1mL补充了低血清生长补充物的M-200培养基（Invitrogen）中以5×105个/孔接种至24-孔板中。允许细胞沉降3-4小时。吸出培养基并将新鲜的1mLM-200添加到每孔中。以4.26μg/mL直接添加MABp1至细胞中，在室温下共孵育15分钟，并之后添加重组人IL-1α（rhIL1A，eBioscience）至40pg/mL的终浓度。阳性对照孔仅接受IL-1α的添加。使用不存在IL-1α或不存在MABp1的HUVEC细胞作为阴性对照。在37℃、5%CO2下孵育17-20小时之后，通过使用CellStripper试剂（CellgroMediatech）无酶处理20分钟 使细胞从板上浮起，并之后使用标准的流式细胞术方案立即测定CD54（ICAM-1）的表达。染色缓冲液包含补充了2%热灭活的胎牛血清的DulbeccoPBS。参照厂家的说明书，在室温下于黑暗中使用PE-结合的小鼠抗人CD54（ICAM-1）mAb（eBioscience，HA58克隆）或PE-结合的小鼠IgG1k同种型对照（eBiocience，#12-4714）以100微升染色体积将HUVEC细胞染色20分钟。随后用染色缓冲液进行两次洗涤并之后在FACSCalibur流式细胞仪（BDBiosciences）上获得样品。在几次独立的实验（n=5）中，HUVEC细胞表面上的由rhIL1A诱导的ICAM-1粘附分子的上调被MABp1中和至未被刺激的HUVEC细胞所显示的基线水平。 
实施例9–MABp1阻断内皮细胞中E-选择素的表达的增加 
类似于MABp1对ICAM-1诱导的作用，还观察到了MABp1-介导的HUVEC细胞上CD62E（E-选择素）诱导的中和。这个作用在当HUVEC细胞不是被可溶性的rhIL-1a刺激而是被通过糖基磷脂酰肌醇锚定在DG44CHO细胞（GPI-IL1A细胞）表面的膜IL-1a刺激时是最明显的。在本实验中，将在6-孔板中的HUVEC细胞的汇合培养物与5×106GPI-IL1ADG44细胞在单独的M-200培养基中共培养过夜、或在10μg/mL MABp1的存在下共培养过夜、或在10μg/mL D5同种型对照Ab的存在下共培养过夜。在17-20小时之后，用DulbeccoPBS彻底洗涤HUVEC单层并之后用CellStripper试剂（CellgroMediatech）无酶处理20分钟使HUVEC单层浮起，并且之后使用标准的流式细胞术方案立即测定CD62E（E-选择素）的表达。染色缓冲液包含补充了2%热灭活的胎牛血清的DulbeccoPBS。参照厂家的说明书，在室温下于黑暗中使用PE-结合的小鼠抗人CD62EmAb（eBioscience，P2H3克隆）或PE-结合的小鼠IgG1k同种型对照（eBiocience，P3克隆）在100微升的染色体积中将HUVEC细胞染色20分钟。随后用染色缓冲液进行两次洗涤并之后在FACSCalibur流式细胞仪（BDBiosciences）上获得样品。由膜GPI-IL-1a诱导的HUVEC细胞表面上的E选择素的表达上调被MABp1中和至由未被刺激的HUVEC细胞所显示的基线水平。 
实施例10–MABp1效价（rhIL1A的中和）的MRC-5生物测定 
来源于人胎儿肺成纤维细胞的MRC-5细胞系获自ATCC保藏中心（CCL-171）。通过测量IL-1A诱导的IL-6从MRC-5细胞中的释放测定MABp1的IL-1中和效价。将在100微升DMEM完全培养基中的MRC-5细胞按5×103每孔接种在96-孔板中。37℃下在加湿的5%CO2培养箱中培养细胞过夜。随后将汇合的MRC-5细胞与单独的20pg/mL的重组人IL-1A（rhIL1A，eBioscience）培养另外24小时或者在递增浓度的MABp1存在下与20pg/mL的重组人IL-1A（rhIL1A，eBioscience）培养另外24小时。阴性对照细胞不用rhIL1A刺激。24小时之后，收集上清液并用来自eBioscience的IL-6ELISA试剂盒测定IL-6释放。IC50或抑制最大IL-6释放的50%所需的MABp1浓度在0.001μg/mL–0.01μg/mL的范围中。 
实施例11–MABp1鉴定IL-1a+细胞 
将一百微升肝素钠抗凝的全血等分到聚苯乙烯FACS管中。将样品与1mg人IgG（蛋白A纯化的）加上2ml阻断Fc受体的热灭活的胎牛血清一起在室温下孵育15分钟。之后添加一抗至下列样品中：1mgAlexa-488标记的MABp1、1mgFITC-标记的单克隆抗膜人IL1AAb（FAB200F,R&D Systems）、或者1mg鼠同种型对照（IC002F,R&DSystems）。将一抗与样品在室温下黑暗中孵育30分钟。之后在室温下将样品红细胞裂解（BDBiosciencesPharmLyse溶液）15分钟，以300×g离心5分钟，并吸出。用1mL含有2%热灭活的胎牛血清的Hank's平衡盐溶液（HBSS）将样品团粒洗涤三次。将样品重悬在0.3mLHBSS+2%FBS中并在FACSCalibur流式细胞仪上获得数据并使用CellQuest软件分析数据。使用MABp1的人PBMC的流式细胞术分析显示仅0.2%的PBMC是IL-1α阳性的。 
实施例12–用于检测和示踪感染及炎症的MABp1 
使用MABp1的人PBMC的流式细胞术分析（如在实施例11中的） 显示与正常对照相比在具有亚临床感染的受治疗者中IL-1α+阳性的PBMC的百分比增加了3.6倍。类似地，在具有发炎的智齿的受治疗者中，IL-1α+阳性的PBMC的百分比也增加。在智齿去除之后14至45天，观察到IL-1α+PBMC的数量大量降低。 
实施例13–用于检测和/或定量IL-1α的免疫测定 
通常，人受治疗者的血浆中存在非常低水平的IL-1α。由于这些水平常常超出常规免疫测定的检测阈，所以开发了具有提高的灵敏度的ELISA。在该ELISA中，可以在允许Ab与样品中的IL-1α结合的条件下，将外源的抗-IL-1αAb（如，MABp1）添加至被测试的生物样品（如人血浆）中。因为观察到在人血浆样品中几乎所有的IL-1α都已经与内源抗-IL-1αAb结合存在，所以后一步骤通常可以省略。之后将具有IL-1α-Ab复合物的样品施加到具有约100kDa的分子量截留的滤器（Amicon离心装置）中，来将IL-1α-Ab复合物与样品中小于分子量截留的分子分离。在一个实验中，这引起50倍的浓缩。之后将处理的样品（及其稀释物）加至用抗-人IgG捕获Ab（2μg/ml小鼠抗人IgG，Fc-特异性的，SouthernBiotech产品编号9042-01）包被的微量滴定板的孔中。在允许结合样品中的IL-1α-Ab复合物的时间之后，洗涤各孔以去除未结合的材料。之后将标记的抗-人IL-1α二抗加至孔中（0.2μg/ml生物素结合的单克隆小鼠抗-人IL-1AAb，CRM6克隆，eBioscience目录号13-7017）。在允许结合孔中的IL-1α的时间之后，洗涤板，并将各孔中的标记的抗-人IL-1α的量定量作为被测试的样品中的IL-1α的浓度的指示。 
其它实施方案 
应理解虽然已经结合本发明的详述描述了本发明，但是上述描述旨在阐述且不限制由所附的权利要求书的范围所限定的本发明的范围。其它方面、优点及修改都在下述的权利要求书的范围内。 
Figure IDA0000411871400000011
Figure IDA0000411871400000021
Figure IDA0000411871400000031
Figure IDA0000411871400000041
Figure IDA0000411871400000051
Figure IDA0000411871400000061
Figure IDA0000411871400000071
Figure IDA0000411871400000081
Figure IDA0000411871400000091
Figure IDA0000411871400000101
Figure IDA0000411871400000111
Figure IDA0000411871400000121
Figure IDA0000411871400000131
Figure IDA0000411871400000141
Figure IDA0000411871400000151
Figure IDA0000411871400000161
Figure IDA0000411871400000171
Figure IDA0000411871400000181
Figure IDA0000411871400000201

Claims (5)

1.一种组合物，包含与人IL-1α特异性结合的纯化的人IgG1mAb和药学上可接受的赋形剂，其中所述mAb是不包含所述赋形剂，以重量计至少50%纯的。
2.如权利要求1所述的组合物，其中所述mAb是不包含所述赋形剂，以重量计至少90%纯的。
3.如权利要求1所述的组合物，其中所述mAb包含与轻链共价连接的至少一条重链，其中所述重链包含SEQIDNO:9的氨基酸序列并且所述轻链包含SEQIDNO:11的氨基酸序列。
4.如权利要求1所述的组合物，其中所述mAb与细胞毒素结合。
5.如权利要求1所述的组合物，其中所述mAb与可检测标记结合。
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