CN102245207A - 人源化抗il-6抗体 - Google Patents
人源化抗il-6抗体 Download PDFInfo
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- CN102245207A CN102245207A CN2009801500721A CN200980150072A CN102245207A CN 102245207 A CN102245207 A CN 102245207A CN 2009801500721 A CN2009801500721 A CN 2009801500721A CN 200980150072 A CN200980150072 A CN 200980150072A CN 102245207 A CN102245207 A CN 102245207A
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Abstract
本发明涉及新型嵌合的、人源化的或CDR嫁接的抗IL-6抗体,包括分离的编码至少一种此类抗IL-6抗体的核酸、载体、宿主细胞、转基因动物或植物、及生成和使用它们的方法,包括治疗性组合物、方法和装置。
Description
相关申请信息
本申请是以Femta Pharmaceuticals,Inc.(一家美国公司)(除美国外的所有国家的指定的申请人),及Gerhard Frey(一位德国公民)、Hwai Wen Chang(一位美国公民)、和Jay Short(一位美国公民)(只有美国的指定的申请人)的名义作为PCT国际专利申请于2009年11月13日提交的,而且要求2008年11月13日提交的美国临时专利申请流水号61/114,295的优先权。
发明领域
本发明涉及对至少一种白介素-6(IL-6,也称作干扰素β2)蛋白或其片段特异性的抗体,包括具体部分或变体,以及编码此类抗IL-6抗体的核酸、互补核酸、载体、宿主细胞、及生成和使用它们的方法,包括治疗性组合物、施用和装置。
发明背景
白介素-6(IL-6)是一种由多种不同细胞类型生成的促炎性细胞因子。在体内,受到刺激的单核细胞、成纤维细胞、和内皮细胞代表IL-6的主要来源。其它细胞诸如巨噬细胞、T和B淋巴细胞、粒细胞、角质形成细胞、肥大细胞、成骨细胞、软骨细胞、神经胶质细胞、和平滑肌细胞也在刺激后生成IL-6。数种肿瘤细胞也生成IL-6,而且已经暗示IL-6是前列腺癌进展的预后因子。IL-6生成能被IL-6自身调节,而且取决于细胞类型,IL-6能刺激或抑制它自己的合成。
IL-6能结合在丝裂原活化的B细胞、T细胞、外周单核细胞、和某些肿瘤上表达的IL-6受体。IL-6受体具有至少两种不同成分,而且由称作gp80,负责IL-6结合的α链和信号转导所需要的、称作gp130的β链构成。包括IL-6、LIF、制瘤素M、IL-11、CNTF、和CT-1的细胞因子家族都在结合它们的关联受体后经由gp130发信号。另外,IL-6细胞因子家族的所有成员都能诱导急性期蛋白质的肝表达。
IL-6有至少两种主要生物学功能:介导急性期蛋白质和起分化和活化因子的作用。已知急性期蛋白质调节免疫应答,介导炎症,及在组织重塑中发挥作用。作为一种分化和活化因子,IL-6诱导B细胞分化和分泌抗体,它诱导T细胞分化成细胞毒性T细胞,活化细胞信号传导因子,及促进造血。IL-6突出地涉及多种至关重要的身体功能和过程。因此,依靠抗体在体内操控IL-6的生物学活性能增强、遏制、或阻止包括骨代谢、致瘤性转化、及免疫和炎症应答的生理过程。
需要提供高亲和力的中和性的嵌合的或人的针对IL-6的抗体或其片段,用于预防、治疗、改善、或诊断涉及IL-6的状况。
发明概述
本发明提供了分离的具有至少一个自高亲和力BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939抗IL-6抗体来源的抗原结合区的人源化抗IL-6抗体,以及涉及它的抗IL-6抗体组合物、编码或互补核酸、载体、宿主细胞、组合物、配制剂、装置、转基因动物、转基因植物,及生成和使用它们的方法,如本文中描述的和赋予的,联合本领域已知的。本发明的抗体以高亲和力特异性中和人IL-6。
本发明提供了至少一种分离的人源化抗IL-6抗体,如本文中描述的。依照本发明的抗体包括BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939中的任一项,或者包括任何如下的蛋白或多肽分子,该蛋白或多肽分子包含至少一个自BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939之一来源的抗体重链或轻链互补决定区(CDR)或其配体结合部分,还可包含可掺入本发明抗体中的重链或轻链恒定区、框架区、或其任何部分。在一个实施方案中,本发明致力于包含轻链和重链的抗IL-6抗体,所述链中的每条链包含自每一项均对人IL-6具有特异性的BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939中一项或多项来源的至少部分人恒定区和至少部分可变区(v),所述抗体以高亲和力结合人IL-6的抑制性和/或中和性表位。本发明还包括此类抗体的片段或衍生物,诸如抗体链的一个或多个部分,诸如抗体恒定、连接、多变或可变区,或轻链恒定、连接或可变区。
该抗体可包含自抗IL-6抗体(如该术语在本文中所定义的)来源的至少一种互补决定区(CDR)(例如重链或轻链可变区的CDR1、CDR2或CDR3)的至少一个具体部分,和/或至少一个恒定区或可变框架区,或其任何部分。该抗体氨基酸序列可进一步任选包含至少一处具体替代、插入或删除,如本文中描述的或如本领域已知的。
本发明优选的抗体包括BA399,BA436,BA802,BA808,BA840,BA848,BA890,BA939,BA399-01,BA399-02,BA399-03,BA399-04,BA399-05,BA399-06,BA399-07,BA399-08,BA399-09和BA399-10,以及它们的片段和区域。
在一个实施方案中,本公开文本提供了分离的与人IL-6结合的抗体或抗体片段,其包含具有氨基酸序列SEQ ID NO:3,7,11,15,19,23,27,31,134,140,141,144,147,149,152,153或156的重链可变区;具有氨基酸序列SEQ IDNO:1,5,9,13,17,21,25,29,68,71,72,75,76,80或88的轻链可变区;和自一种或多种人抗体来源的恒定区。在一个方面,本公开文本提供了分离的与人IL-6结合的抗体或抗体片段,其包含自BA399,BA436,BA802,BA808,BA840,BA848,BA890和BA939中一项或多项的可变区来源的重链和轻链互补决定区(CDR),和自一种或多种人抗体来源的恒定区。在另一个方面,本公开文本提供了依照权利要求1的抗体或片段,其中所述抗体或片段在体内竞争性抑制抗IL-6小鼠抗体对人IL-6的结合。
本发明优选的抗体是那些结合人IL-6且阻断受体结合的,其包括Brackenhoff et al.(supra)披露的表位。通过竞争性抑制来测定单克隆抗体特异性和亲和力的优选方法可见于Harlow,et al,Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1988,在此通过述及而收入本申请。至少一种本发明抗体结合至少一种对人IL-6蛋白特异性的具体表位、亚基、片段、部分或其任意组合,例如Brackenhoff et al.(supra)记载的。该表位可包含至少一种抗体结合区,该表位优选由人IL-6蛋白的至少一部分,诸如但不限于其至少一种功能性、细胞外、可溶性、亲水性、外部或胞质结构域或其任何部分的至少1-5个氨基酸构成。
在一个方面,本发明提供了至少一种分离的哺乳动物抗IL-6抗体,其包含至少一种来自BA399,BA436,BA802,BA808,BA840,BA848,BA890,BA939,BA399-01,BA399-02,BA399-03,BA399-04,BA399-05,BA399-06,BA399-07,BA399-08,BA399-09和BA399-10之一的可变区,及编码它们的核酸序列。
在另一个方面,本发明提供了至少一种分离的哺乳动物抗IL-6抗体,其包含(i)自BA399,BA436,BA802,BA808,BA840,BA848,BA890,BA939,BA399-01,BA399-02,BA399-03,BA399-04,BA399-05,BA399-06,BA399-07,BA399-08,BA399-09和BA399-10之一来源的所有重链互补决定区(CDR)氨基酸序列,及编码它们的核酸序列;或(ii)来自BA399,BA436,BA802,BA808,BA840,BA848,BA890,BA939,BA399-01,BA399-02,BA399-03,BA399-04,BA399-05,BA399-06,BA399-07,BA399-08,BA399-09和BA399-10之一的所有轻链CDR氨基酸序列,及编码它们的核酸序列。
在一个方面,本发明提供了至少一种分离的哺乳动物抗IL-6抗体,其包含至少一种具有自BA399,BA436,BA802,BA808,BA840,BA848,BA890,BA939,BA399-01,BA399-02,BA399-03,BA399-04,BA399-05,BA399-06,BA399-07,BA399-08,BA399-09和BA399-10来源的氨基酸序列的重链或轻链CDR,及编码它们的核酸序列。
在另一个方面,本发明提供了至少一种分离的哺乳动物嵌合、人源化或CDR嫁接的抗IL-6抗体,其包含至少一种人CDR,其中所述抗体特异性结合至少一种包含人IL-6表位的至少1-3个氨基酸的表位。
至少一种抗体可任选进一步以至少10-9M、优选至少10-10M的亲和力(Kd)结合IL-6,和/或实质性中和至少一种IL-6蛋白的至少一种活性。在一个优选的实施方案中,该抗体以至少5x10-10M、优选5x10-11、更优选5x10-12的亲和力(Kd)结合IL-6且中和人IL-6。
在一个方面,本发明提供了分离的核酸分子,其包含编码上述包含至少一种具体序列、其结构域、部分或变体的特定抗IL-6抗体的多核苷酸、或与该多核苷酸互补、或与该多核苷酸杂交。本发明进一步提供了包含所述抗IL-6抗体核酸分子的重组载体,含有此类核酸和/或重组载体的宿主细胞,以及生成和/或使用此类抗体核酸、载体和/或宿主细胞的方法。如此,本发明包含分离的编码至少一种分离的哺乳动物抗IL-6抗体的核酸;分离的包含该分离的核酸的核酸载体;和/或包含该分离的核酸的原核或真核宿主细胞。该宿主细胞可任选是选自COS-1,COS-7,HEK293,BHK21,CHO,BSC-1,Hep G2,653,SP2/0,293,HeLa,PER.骨髓瘤,或淋巴瘤细胞,或其任何衍生物、永生化或转化细胞的至少一项。本发明还提供了用于生成至少一种抗IL-6抗体的方法,其包括在体外、在体内或原位在使得IL-6抗体以可检测或可回收的量表达的条件下翻译抗体编码核酸。
本发明还提供了至少一种用于在宿主细胞中表达至少一种上述抗IL-6抗体的方法,其包括在其中至少一种抗IL-6抗体以可检测和/或可回收的量表达的条件下培养本文所述宿主细胞。
本发明还提供了至少一种组合物,其包含(a)分离的本文所述抗IL-6抗体编码核酸和/或抗体;和(b)合适的载体或稀释剂。该载体或稀释剂可任选是药学可接受的已知载体或稀释剂。该组合物可任选进一步包含至少一种别的化合物、蛋白质或组合物。
本发明进一步提供了至少一种抗IL-6抗体方法或组合物,用于施用治疗有效量以在细胞、组织、器官、动物或患者中调控或治疗至少一种IL-6相关状况,和/或在相关状况之前、之后、或期间,如本领域已知的和/或如本文中描述的。如此,本发明提供了用于在细胞、组织、器官或动物中诊断或治疗IL-6相关状况的方法,其包括使包含有效量的至少一种分离的本发明抗IL-6抗体的组合物接触或施用于细胞、组织、器官或动物。该方法可任选进一步包括对细胞、组织、器官或动物使用有效量0.001-50mg/kg的本发明抗IL-6抗体。该方法可任选进一步包括通过至少一种选自胃肠外、皮下、肌肉内、静脉内、关节内、支气管内、腹内、囊内、软骨内、腔内、体腔内、小脑内(intracelebellar)、脑室内、结肠内、颈内、胃内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜内、前列腺内、肺内、直肠内、肾内、视网膜内、脊柱内、滑膜内、胸内、子宫内、膀胱内、推注、阴道、直肠、含服、舌下、鼻内、或经皮的模式来使用接触或施用。该方法可任选进一步包括在该抗体接触或施用之前、并行、或之后施用至少一种包含有效量的至少一种选自下述至少一项的化合物或蛋白质的组合物:可检测标记物或受体,TNF拮抗剂,抗风湿药,肌肉松弛药,麻醉药,非类固醇抗炎药(NSAID),镇痛药,麻醉剂,镇静药,局部麻醉剂,神经肌肉阻断剂,抗微生物剂,抗银屑病药,皮质类固醇,促蛋白合成类固醇,红细胞生成素,免疫剂,免疫球蛋白,免疫抑制药,生长激素,激素替代药物,放射学药物,抗抑郁药,安定药,兴奋剂,哮喘药物,β激动剂,吸入的类固醇,肾上腺素或其类似物,细胞毒性或其它抗癌剂,抗代谢药诸如甲氨蝶呤,抗增殖剂,细胞因子,细胞因子拮抗剂,和抗TNFα或IL-12/IL-23单克隆抗体。
本发明进一步提供了在细胞、组织、器官、动物或患者中和/或在相关状况之前、之后、或期间诊断至少一种IL-6相关状况的至少一种抗IL-6抗体方法,如本领域已知的和/或如本文中描述的。
本发明还提供了为诊断而投递至少一种依照本发明的抗IL-6抗体的至少一种组合物、装置和/或方法。
还提供了包含至少一种分离的人源化抗IL-6抗体和至少一种药学可接受载体或稀释剂的组合物。该组合物可进一步包含有效量的至少一种选自下述至少一项的化合物或蛋白质:可检测标记物或受体,细胞毒性或其它抗癌剂,抗代谢药诸如甲氨蝶呤,抗增殖剂,细胞因子或细胞因子拮抗剂,TNF拮抗剂,抗风湿药,肌肉松弛药,麻醉药,非类固醇抗炎药(NTHE),镇痛药,麻醉剂,镇静药,局部麻醉剂,神经肌肉阻断剂,抗微生物剂,抗银屑病药,皮质类固醇,促蛋白合成类固醇,红细胞生成素,免疫剂,免疫球蛋白,免疫抑制药,生长激素,激素替代药物,放射学药物,抗抑郁药,安定药,兴奋剂,哮喘药物,β激动剂,吸入的类固醇,肾上腺素或类似物。
还提供了包含至少一种本发明的分离的哺乳动物抗IL-6抗体的医疗装置,其中所述装置适合于通过至少一种选自胃肠外、皮下、肌肉内、静脉内、关节内、支气管内、腹内、囊内、软骨内、腔内、体腔内、小脑内(intracelebellar)、脑室内、结肠内、颈内、胃内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜内、前列腺内、肺内、直肠内、肾内、视网膜内、脊柱内、滑膜内、胸内、子宫内、膀胱内、推注、阴道、直肠、含服、舌下、鼻内、或经皮的模式来接触或施用所述至少一种抗IL-6抗体。
在另一个方面,本公开文本提供了试剂盒,其包含第一容器中冻干形式的至少一种本公开文本的抗IL-6抗体或片段,和任选的装有无菌水、无菌缓冲水、或水性稀释剂的第二容器,所述水性稀释剂中含有至少一种选自下组的防腐剂:酚,间甲酚,对甲酚,邻甲酚,氯甲酚,苯甲醇,亚硝酸苯汞,苯氧乙醇,甲醛,氯丁醇,氯化镁,对羟基苯甲酸烃基酯,苯扎氯铵,苄索氯铵,脱氢乙酸钠和硫柳汞,或其混合物。在一个方面,在该试剂盒中,第一容器中抗IL-6抗体或具体部分或变体的浓度用第二容器中的内容物重建至约0.1mg/ml至约500mg/ml的浓度。在另一个方面,第二容器进一步包含等张剂。在另一个方面,第二容器进一步包含生理可接受缓冲液。在一个方面,本公开文本提供了治疗至少一种抗IL-6介导的状况的方法,其包括对有所需要的患者施用试剂盒中提供的并在施用之前重建的配制剂。
还提供了用于人类药物或诊断用途的制品,其包含包装材料和装有至少一种本发明的分离的哺乳动物抗IL-6抗体的溶液或冻干形式的容器。该制品可任选包含容器,装有作为胃肠外、皮下、肌肉内、静脉内、关节内、支气管内、腹内、囊内、软骨内、腔内、体腔内、小脑内(intracelebellar)、脑室内、结肠内、颈内、胃内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜内、前列腺内、肺内、直肠内、肾内、视网膜内、脊柱内、滑膜内、胸内、子宫内、膀胱内、推注、阴道、直肠、含服、舌下、鼻内、或经皮投递装置或系统的成分。
本发明进一步提供了本文所述任何发明。
附图简述
图1分别显示了抗IL-6抗体BA399轻链(SEQ ID NO:1,2)和重链(SEQ IDNO:3,4)可变区的氨基酸序列和核酸序列。
图2分别显示了抗IL-6抗体BA436轻链(SEQ ID NO:5,6)和重链(SEQ IDNO:7,8)可变区的氨基酸序列和核酸序列。
图3分别显示了抗IL-6抗体BA802轻链(SEQ ID NO:9,10)和重链(SEQ IDNO:11,12)可变区的氨基酸序列和核酸序列。
图4分别显示了抗IL-6抗体BA808轻链(SEQ ID NO:13,14)和重链(SEQID NO:15,16)可变区的氨基酸序列和核酸序列。
图5分别显示了抗IL-6抗体BA840轻链(SEQ ID NO:17,18)和重链(SEQID NO:19,20)可变区的氨基酸序列和核酸序列。
图6分别显示了抗IL-6抗体BA848轻链(SEQ ID NO:21,22)和重链(SEQID NO:23,24)可变区的氨基酸序列和核酸序列。
图7分别显示了抗IL-6抗体BA890轻链(SEQ ID NO:25,26)和重链(SEQID NO:27,28)可变区的氨基酸序列和核酸序列。
图8分别显示了抗IL-6抗体BA939轻链(SEQ ID NO:29,30)和重链(SEQID NO:31,32)可变区的氨基酸序列和核酸序列。
图9分别显示了抗IL-6抗体BA001轻链(SEQ ID NO:33,34)和重链(SEQID NO:35,36)可变区的氨基酸序列和核酸序列。
图10显示了BA001和本发明抗IL-6抗体的竞争ELISA分析。
图11显示了BA001和本发明抗IL-6抗体的BiaCore和ELISA分析。
图12显示了BA399 CPS轻链可变区的核酸序列抗IL-6抗体BA399 LC01DNA至LC06 DNA(分别为SEQ ID NO:2,37,38,39,40和41)。
图13显示了BA399 CPS轻链可变区的核酸序列抗IL-6抗体BA399 LC07DNA至LC12 DNA(分别为SEQ ID NO:42,43,44,45,46和47)。
图14显示了BA399 CPS轻链可变区的核酸序列抗IL-6抗体BA399 LC13DNA至LC18 DNA(分别为SEQ ID NO:48,49,50,51,52和53)。
图15显示了BA399 CPS轻链可变区的核酸序列抗IL-6抗体BA399 LC19DNA至LC24 DNA(分别为SEQ ID NO:54,55,56,57,58和59)。
图16显示了BA399 CPS轻链可变区的核酸序列抗IL-6抗体BA399 LC25DNA至LC30 DNA(分别为SEQ ID NO:60,61,62,63,64和65)。
图17显示了BA399 CPS轻链可变区的核酸序列抗IL-6抗体BA399 LC31DNA和LC32 DNA(分别为SEQ ID NO:66和67);及轻链可变区的氨基酸序列抗IL-6抗体BA399 LC01 PRO至LC08 PRO(分别为SEQ ID NO:1,68,69,70,71,72,73和74)。
图18显示了BA399 CPS轻链可变区的氨基酸序列抗IL-6抗体BA399LC09 PRO至LC20 PRO(分别为SEQ ID NO:75,76,77,78,79,80,81,82,83,84,85和86)。
图19显示了BA399 CPS轻链可变区的氨基酸序列抗IL-6抗体BA399LC21 PRO至LC32 PRO(分别为SEQ ID NO:87,88,89,90,91,92,93,94,95,96,97和98)。
图20显示了BA BA399 CPS重链可变区的核酸序列抗IL-6抗体BA399HC01 DNA至HC06 DNA(分别为SEQ ID NO:4,99,100,101,102和103)。
图21显示了BA399 CPS重链可变区的核酸序列抗IL-6抗体BA399 HC07DNA至HC12 DNA(分别为SEQ ID NO:104,105,106,107,108和109)。
图22显示了BA399 CPS重链可变区的核酸序列抗IL-6抗体BA399 HC13DNA至HC18 DNA(分别为SEQ ID NO:110.111,112,113,114和115)。
图23显示了BA399 CPS重链可变区的核酸序列抗IL-6抗体BA399 HC19DNA至HC24 DNA(分别为SEQ ID NO:116,117,118,119,120和121)。
图24显示了BA399 CPS重链可变区的核酸序列抗IL-6抗体BA399 HC25DNA至HC30 DNA(分别为SEQ ID NO:122,123,124,125,126和127)。
图25显示了BA399 CPS重链可变区的核酸序列抗IL-6抗体BA399 HC31DNA和HC3 2DNA(分别为SEQ ID NO:128和129);及重链可变区的氨基酸序列抗IL-6抗体BA399 HC01 PRO至HC06 PRO(分别为SEQ ID NO:3,130,131,132,133和134)。
图26显示了BA399 CPS重链可变区的氨基酸序列抗IL-6抗体BA399HC07 PRO至HC15 PRO(分别为SEQ ID NO:135,136,137,138,139,140,141,142和143)。
图27显示了BA399 CPS重链可变区的氨基酸序列抗IL-6抗体BA399HC16 PRO至HC25 PRO(分别为SEQ ID NO:144,145,146,147,148,149,150,151,152和153)。
图28显示了BA399 CPS重链可变区的氨基酸序列抗IL-6抗体BA399HC26 PRO至HC32 PRO(分别为SEQ ID NO:154,155,156,157,158,159和160)。
图29显示了来自通过综合位置进化(comprehensive positional evolution,CPE)进行的BA399亲和力成熟的前10名命中的相对比活性。每种克隆的相对比活性是相对抗IL-6抗体BA399的比活性(其显示为黑色水平线)标准化的。
图30显示了来自通过组合蛋白质合成(combinatorial protein synthesis,CPS)进行的抗IL-6抗体BA399轻链可变区亲和力成熟的399CPS LC01至399CPS LC32(分别为SEQ ID NO:1,68,69,70...98)的氨基酸序列比较。完整序列和相应SEQ ID NO显示于图17-19。
图31显示了来自通过组合蛋白质合成(CPS)进行的抗IL-6抗体BA399重链可变区亲和力成熟的399CPS HC01至399CPS HC32(分别为SEQ ID NO:3,130,131,132...160)的氨基酸序列比较。完整序列和相应SEQ ID NO显示于图25-28。
图32显示了来自通过组合蛋白质合成(CPS)进行的BA399亲和力成熟的前10名命中的标准化比活性。每种克隆的相对比活性是相对抗IL-6抗体BA399的比活性(其显示为水平黑色线)标准化的。
图33显示了来自抗IL-6单抗克隆BA003(CNTO136)和通过抗IL-6抗体BA399亲和力成熟生成的BAP001克隆1至BAP001克隆10的Sapidyne动力学排除分析的解离常数(Kd)表。
图34显示了来自通过抗IL-6抗体BA399亲和力成熟生成的抗IL-6抗体克隆BA399-2,BA399-5,BA399-9和BA399-10的BiaCore分析的结合数据表。
图35显示了THP-1细胞中渐增的抗IL-6单抗浓度对IL-6/sIL6R诱导的Stat3磷酸化的抑制。所述数据是基于总Stat3的Western印迹标准化的。
图36在(A)中显示了受IL-6/sIL-6R刺激的THP-1细胞中多种抗IL6单抗包括003,BA399,BA399-2和BA399-9对Stat3磷酸化的抑制,其中使用100ng/mLIL-6。每种条件的总Stat3 Western印迹显示于(B)。
图37在(A)中显示了受IL-6/sIL-6R刺激的THP-1细胞中多种抗IL6单抗包括003,BA399,BA399-2和BA399-5对Stat3磷酸化的抑制,使用10ng/mL IL-6。每种条件的总Stat3 Western印迹显示于(B)。
图38在(A)中显示了受IL-6/sIL-6R刺激的THP-1细胞中多种抗IL6单抗包括BA003,BA399,BA399-2和BA399-9对Stat3磷酸化的抑制,使用10ng/mLIL-6。每种条件的总Stat3 Western印迹显示于(B)。
图39显示了抗IL-6单抗CNTO136,BA399,BA399-2,BA399-9的连续稀释液在24小时时对用人IL-6,sIL-6R和IL-1b刺激的HepG2细胞的血清淀粉状蛋白A蛋白生成的抑制。
图40显示了抗IL-6单抗CNTO136,BA399,BA399-2,BA399-9的连续稀释液在48小时时对用人IL-6,sIL-6R和IL-1b刺激的HepG2细胞的血清淀粉状蛋白A蛋白生成的抑制。
图41显示了生物素化抗IL-6单抗001对猴IL-6的交叉反应性,及非生物素化人源化抗IL-6单抗BA001,BA003,BA399,BA399-2和BA399-9阻断生物素化BA001对猴IL-6的结合的能力。人IgG用作非特异性抗体。
图42显示了抗IL-6单抗BA001,BA399,BA436,BA802,BA808,BA840,BA848和BA890在48小时时对IL-6诱导的DS-1细胞增殖的抑制。
图43显示了抗IL-6单抗BA001,BA399,BA436,BA802,BA808,BA840,BA848和BA890在96小时时对IL-6诱导的DS-1细胞增殖的抑制。
图44显示了来自BA399抗IL-6单抗之CPS亲和力成熟的前10名克隆中利用的轻链和重链组合。轻链和重链的相应氨基酸序列和SEQ ID NO分别可见于图17-19和图25-28。
发明详述
引用
本文中引用的所有出版物或专利通过述及而完整收入本文,因为它们显示了本发明之时的现有技术和/或提供了本发明的说明和实现。出版物指任何科学或专利出版物,或者以任何介质形式可得的任何其它信息,包括所有记录的、电子的或印刷的形式。下述参考文献通过述及而完整收入本文:Ausubel,et al.,ed.,Current Protocols in Molecular Biology,John Wiley & Sons,Inc.,NY,N.Y.(1987-2001);Sambrook,et al.,Molecular Cloning:A LaboratoryManual,2.sup.nd Edition,Cold Spring Harbor,N.Y.(1989);Harlow and Lane,Antibodies,a Laboratory Manual,Cold Spring Harbor,N.Y.(1989);Colligan,etal.,eds.,Current Protocols in Immunology,John Wiley & Sons,Inc.,NY(1994-2001);Colligan et al.,Current Protocols in Protein Science,John Wiley &Sons,NY,N.Y.,(1997-2001)。
氨基酸代码
常常缩写构成本发明抗IL-6抗体的氨基酸。氨基酸名称可以通过以它的单字母代码、它的三字母代码、名称、或三核苷酸密码子指明氨基酸来指明,正如本领域普遍理解的(参见Alberts,B.,et al.,Molecular Biology of The Cell,Third Ed.,Garland Publishing,Inc.,New York,1994)。
定义
如本文中使用的,“抗白介素-6抗体”、“抗IL-6抗体”、“抗IL-6抗体部分”、或“抗IL-6抗体片段”和/或“抗IL-6抗体变体”等等包括任何含有如下分子的蛋白质或肽,该分子包含至少部分免疫球蛋白分子,该免疫球蛋白分子含有至少一种自BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939人源化单克隆抗体中至少一项来源的重链或轻链互补决定区(CDR)或其配体结合部分,联合可掺入本发明抗体中的非鼠起源的、优选人起源的重链或轻链可变区、重链或轻链恒定区、框架区、或其任何部分。或者,术语“抗IL-6抗体”应共同地或个别地指人源化单克隆抗体BA399,BA436,BA802,BA808,BA840,BA848,BA890和BA939。此类抗体能够在体外、原位和/或在体内调控、降低、拮抗、减低、减轻、阻断、抑制、消除和/或干扰至少一种IL-6活性或结合,或者IL-6受体活性或结合。作为一个非限制性例子,本发明的合适的抗IL-6抗体、具体部分或变体能以高亲和力结合受到至少BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939单克隆抗体中至少一项识别的抑制性和/或中和性人IL-6表位。合适的抗IL-6抗体、规定部分、或变体还能任选影响至少一种IL-6活性或功能,诸如但不限于RNA、DNA或蛋白质合成,IL-6释放,IL-6受体信号传导,膜IL-6切割,IL-6活性,IL-6生成和/或合成。
术语“抗体”进一步意图涵盖抗体、其消化片段、具体部分和变体,包括抗体模拟物或者包含模拟抗体或其规定片段或部分之结构和/或功能的抗体部分,包括单链抗体及其片段,每一项含有至少一种自抗IL-6来源的CDR。功能性片段包括与哺乳动物IL-6结合的抗原结合片段。例如,本发明涵盖能够与IL-6或其部分结合的抗体片段,包括但不限于Fab(例如通过木瓜蛋白酶消化)、Fab′(例如通过胃蛋白酶消化和部分还原)和F(ab′)2(例如通过胃蛋白酶消化)、facb(例如通过纤溶酶消化)、pFc′(例如通过胃蛋白酶或纤溶酶消化)、Fd(例如通过胃蛋白酶消化、部分还原和再聚集)、Fv或scFv(例如通过分子生物学技术)片段(参见例如Colligan,Immunology,supra)。
抗体片段可通过酶促切割、合成或重组技术来生成,如本领域已知的和/或如本文中描述的。抗体还可多种截短形式生成,使用在天然终止位点的上游引入了一个或多个终止密码子的抗体基因。例如,编码F(ab′)2重链部分的组合基因可设计成包括编码CH1域和/或重链铰链区的DNA序列。抗体的多种部分可通过常规技术通过化学方法连接到一起,或者可使用遗传工程技术作为连续蛋白质制备。
如本文中使用的,“嵌合”抗体或“人源化”抗体或“CDR嫁接的”包括本文所述抗IL-6抗体或自其来源的任何CDR与一种或多种自非鼠、优选人抗体来源的蛋白质或肽组合的任何组合。依照本发明,嵌合或人源化抗体包括那些其中CDR衍生自一种或多种本文所述抗IL-6抗体且抗体的至少一部分或剩余部分衍生自一种或多种人抗体的。如此,抗体的人部分可包括在人中基本上没有免疫原性的框架、CL、CH域(例如CH1、CH2、CH3)、铰链(VL、VH))区。抗体中自人抗体来源的区域不需要与人抗体具有100%同一性。在一个优选的实施方案中,保留尽可能多的人氨基酸残基以使免疫原性可忽略,但是在必要时可修饰人残基以在使抗体人源化最大化的同时支持由CDR形成的抗原结合位点。此类变化或变异任选且优选相对于未修饰抗体保持或降低在人或其它物种中的免疫原性。指出了人源化抗体可由能够表达功能性重排的人免疫球蛋白(例如重链和/或轻链)基因的非人动物或原核或真核细胞来生成。另外,当抗体是单链抗体时,它可包含在天然人抗体没有找到的接头肽。例如,Fv可包含接头肽,诸如两个至约八个甘氨酸或其它氨基酸残基,其连接重链可变区和轻链可变区。此类接头肽被认为是人起源的。
抗体人源化可通过例如合成组合文库来实施,其包含非人目标单克隆抗体的六个CDR,符合读码框地融合至个别人框架集合。可利用含有代表所有已知重链和轻链人种系基因的基因的人框架文库。然后可对所得组合文库筛选对感兴趣抗原的结合。这种办法可容许在维持亲本抗体的结合活性方面选择完全人的框架的最有利组合。然后可通过多种技术来进一步优化人源化抗体。
抗体人源化可用于使小鼠或其它非人抗体进化成“完全人的”抗体。所得抗体只含有人序列,没有小鼠或非人抗体序列,同时维持与起始抗体相似的结合亲和力和特异性。
术语“综合位置进化”(CPETM)用于描述一种可用于组合综合诱变、改组和合成技术以增强单一或多重抗体特性和结合特征的抗体进化技术平台。CPE平台容许为蛋白质内每个位置处所有63种潜在密码子变化对蛋白质内每种个别密码子变化的体内效果综合绘图。这种综合诱变技术通过测试沿抗体可变域序列的每个位置处的氨基酸变化来快速生成抗体变体。
术语“组合蛋白质合成”(CPSTM)用于描述通过将其最好特性组合入一种新的高性能抗体,可用于优化期望抗体特征的组合蛋白质合成技术。CPSTM可用于CPETM之后,而且能容许随后生成和体内选择改良个别密码子的所有排列,以鉴定蛋白质或抗体内最佳密码子变化组合或套组。这些技术的组合能显著扩大可供筛选的抗体变体集合,而且他显著提高找到具有单一或多重增强特征(诸如结合亲和力、特异性、热稳定性、表达水平、效应器功能、糖基化、和溶解度)的抗体的概率。
对于全长抗体分子,可以自杂交瘤细胞系的基因组DNA或mRNA获得免疫球蛋白基因。在哺乳动物载体系统中克隆抗体重链和轻链。用双链序列分析证明装配。可以在其它人或哺乳动物宿主细胞系中表达抗体构建物。然后可通过所表达的感兴趣抗体的瞬时转染测定法和Western印迹分析来验证构建物。可使用快速测定方法来分离和筛选具有最高生产力的稳定细胞系。
术语“亲和力成熟”指对抗原的免疫应答的平均亲和力的升高。在自然界中,它可发生于重复暴露于抗原之后。一种特别优选类型的替代变体涉及替代亲本抗体(例如人抗体)的一个或多个高变区残基。一般地,为进一步开发而选择的所得变体会具有相对于生成它们的亲本抗体改良的生物学特性。一种用于生成此类替代变体的便利方式涉及亲和力成熟,其使用本文中描述的技术或本领域技术人员知道的其它技术,例如噬菌体展示(Schier R.,J.Mol.Biol.,263:551-67,1996)。然后对变体筛选它们的生物学活性(例如结合亲和力),如本文中描述的,例如Biacore分析。为了鉴定可用于修饰的良好候选物的高变区残基,可实施丙氨酸扫描诱变来鉴定对抗原结合有显著贡献的高变区残基。在一种或多种有关测定法中具有卓越特性的抗体可进行进一步开发。
“有效量”为抗IL6抗体或片段在施用它的活的生物体中在一定时间段里有效治疗或预防病症,例如在期望剂量给药间隔期间提供治疗效果的量。
术语“治疗”包括:(1)阻止或延迟在可罹患或易患状态、病症或状况但尚未经历或展示该状态、病症或状况的临床或亚临床症状的动物中正在形成的状态、病症或状况的临床症状出现;(2)抑制所述状态、病症或状况(即阻滞、减轻或延迟疾病或其复发(在维持治疗的情况中),至少一种其临床或亚临床症状的形成);和/或(3)解除所述状况(即引起所述状态、病症或状况或者至少一种其临床或亚临床症状消退)。对待治疗的患者的好处或是统计学显著的或是至少患者或医师可觉察的。
如本文中联合测量得到的数量使用的,术语“约”指与测量目的和所使用的测量设备的精度相称的,进行测量并仔细练习的熟练技术人员会预期的,该测量得到的数量的正常变差。除非另外指明,“约”指所提供值的+/-10%的变差。
本发明的抗体
依照本发明,抗IL-6抗体包含下述任一项:BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939抗体或者如下的抗体,其中可变区或CDR衍生自BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939抗体中任一项且抗体框架和恒定区衍生自一种或多种人抗体。自抗体来源的可变区或CDR优选与BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939抗体中任一项的可变区或CDR具有约90%至约100%同一性,虽然涵盖任何和所有修饰(包括替代、插入和删除),只要嵌合抗体维持结合和抑制IL-6的能力。嵌合、人源化或CDR嫁接的抗体中自人抗体来源的区域不需要与人抗体具有100%同一性。在一个优选的实施方案中,保留尽可能多的人氨基酸残基以使免疫原性可忽略,但是在必要时及如本文下文中教导的依照本发明可替代人残基,特别是框架区的残基。本文中公开的此类修饰是在使抗体人源化最大化的同时支持由CDR形成的抗原结合位点所必需的。
依照本发明,抗IL-6抗体可变区(轻链和重链)的核酸序列和推导氨基酸序列列于图1-8。BA001轻链和重链可变区的序列列于图9。来自BA399亲和力成熟的轻链和重链可变区的核酸和氨基酸序列示于图12-28。轻链和重链可变区的序列分别比较于图30和31。重链和轻链可变区各自含有三个CDR,它们组合形成抗原结合位点。三个CDR被四个FR区包围,后者的主要功能是支持CDR。重链和轻链可变区序列内的CDR序列可通过计算机辅助比对(Kabat et al.(1987)in Sequences of Proteins of Immunological Interest,4th ed.,United States Department of Health and Human Services,U.S.Government Printing Office,Washington,D.C.)或通过可变区的分子建模,例如利用ENCAD程序(Levitt(1983)J.Mol.Biol.168:595)来鉴定。
在一个优选的实施方案中,CDR衍生自BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939中任一项。重链CDR和轻链CDR的确定完全在本领域技术范围内。参见例如http://www.bioinf.org.uk/abs/。
抗IL-6抗体的CDR的序列可通过插入、替代和删除来修饰,其程度为CDR嫁接的抗体维持结合和抑制人IL-6的能力。通过实施本文下文描述的功能测定法,普通技术人员能确定对这种活性的维持。
或者,可以将BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939中任一项的整个重链可变区和轻链可变区与人恒定和框架区组合以形成本发明的嵌合抗体。在一个方面,来自亲和力成熟的抗IL6单抗BA399前十名克隆所利用的可变轻链和重链氨基酸序列公开于图44。克隆BA399-01包含轻链BA399CPS-LC06(SEQ ID NO:72)和重链BA399CPS-HC-06(SEQID NO:134)。克隆BA399-02包含轻链BA399CPS-LC02(SEQ ID NO:68)和重链BA399CPS-25(SEQ ID NO:153)。克隆BA399-03包含轻链BA399CPS-LC05(SEQ ID NO:71)和重链BA399CPS-HC21(SEQ ID NO:149)。克隆BA399-04包含轻链BA399CPS-LC06(SEQ ID NO:72)和重链BA399CPS-HC13(SEQ ID NO:141)。克隆BA399-05包含轻链BA399CPS-LC10(SEQ ID NO:76)和重链BA399CPS-HC16(SEQ ID NO:144)。克隆BA399-06包含轻链BA399CPS-LC22(SEQ ID NO:88)和重链BA399CPS-HC24(SEQ ID NO:152)。克隆BA399-07包含轻链BA399CPS-LC14(SEQ ID NO:80)和重链BA399CPS-HC19(SEQ ID NO:147)。克隆BA399-08包含轻链BA399CPS-LC10(SEQ ID NO:76)和重链BA399CPS-HC12(SEQ ID NO:140)。克隆BA399-09包含轻链BA399CPS-LC09(SEQ ID NO:75)和重链BA399CPS-HC24(SEQ ID NO:152)。克隆BA399-10包含轻链BA399CPS-LC09(SEQ ID NO:75)和重链BA399CPS-HC28(SEQ ID NO:156)。
通过已知方法,编码本发明人源化抗体、片段和区之恒定(C)区的人基因可衍生自人胎肝文库。人C区基因可衍生自任何人细胞,包括那些表达和生成人免疫球蛋白的。人CH区可衍生自任何已知类或同种型的人H链,包括γ,μ,α,δ,ε,及它们的亚型,诸如G1,G2,G3和G4。由于H链同种型负责抗体的多种效应器功能,因此CH区的选择会由期望效应器功能来指导,诸如补体固定或抗体依赖性细胞的细胞毒性(ADCC)中的活性。优选地,CH区衍生自伽马1(IgG1)。
人CL区可衍生自人L链同种型,卡帕或拉姆达,优选卡帕。
通过标准克隆技术,自人细胞获得编码人免疫球蛋白C区的基因(Sambrook,et al.,Molecular Cloning:A Laboratory Manual,2nd Edition,ColdSpring Harbor Press,Cold Spring Harbor,N.Y.(1989)和Ausubel et al.,eds.Current Protocols in Molecular Biology(1987-1993))。人C区基因易于自含有代表两类L链、五类H链及其亚类的基因的已知克隆获得。嵌合抗体片段,诸如F(ab1)2和Fab,可通过设计恰当截短的嵌合H链基因来制备。例如,编码F(ab1)2片段H链部分的嵌合基因会包括编码H链CH1域和铰链区的DNA序列,接着是翻译终止密码子以产生截短分子。
一般地,在一个例子中,本发明的人源化抗体、片段和区如下生成,即克隆编码抗IL-6特异性抗体H和L链抗原结合区的DNA区段,并分别将这些DNA区段连接至包括CH和CL区的DNA区段,以生成全长嵌合免疫球蛋白编码基因。
抗体可变区的序列可通过插入、替代和删除来修饰,其程度为嵌合抗体维持结合和抑制人IL-6的能力。通过实施本文下文描述的功能测定法,普通技术人员能确定对这种活性的维持。可变区可以与SEQ ID NO:1-32的可变区具有例如约50%至约100%同源性。在一个优选的实施方案中,抗体可变区与SEQ ID NO:1-32和37-160的可变区具有约80%至约100%同源性。在一个更优选的实施方案中,所述可变区与SEQ ID NO:1-32和37-160的可变区具有约90%至约100%同源性。
在一个具体的方面,本公开文本的优选抗IL-6单抗包含与SEQ ID NO:1具有95%,96%,97%,98%或99%氨基酸序列同源性的可变轻链区,而且进一步包含与SEQ ID NO:3具有95%,96%,97%,98%或99%氨基酸序列同源性的可变重链区。
在一个具体的方面,本公开文本的优选抗IL-6单抗包含选自SEQ ID NO:68-98之一的可变轻链区。在一个进一步的具体的方面,本公开文本的优选抗IL-6单抗包含选自SEQ ID NO:68,71,72,75,76,80和88之一的可变轻链区。
在另一个具体的方面,本公开文本的优选抗IL-6单抗包含选自SEQ IDNO:130-160之一的可变重链区。在一个进一步的具体的方面,本公开文本的优选抗IL-6单抗包含选自SEQ ID NO:134,140,141,144,147,149,152,153和156之一的可变重链区。
可使用用于改造或人源化非人抗体或人抗体的方法,而且它们是本领域公知的。一般地,人源化或工程化抗体具有一个或多个来自非人来源(例如但不限于小鼠、大鼠、家兔、非人灵长类动物或其它哺乳动物)的氨基酸残基。这些人氨基酸残基常常称作“输入”残基,它们通常取自已知人序列的“输入”可变、恒定或其它域。已知人Ig序列披露于例如
www.ncbi.nlm.nih.gov/entrez/query.fcgi;www.atcc.org/phage/hdb.html;
www.sciquest.com/;www.abcam.com/;
www.antibodyresource.com/onlinecomp.html;
www.public.iastate.edu/.about.pedro/research_tools.html;
www.mgen.uni-heidelberg.de/SD/IT/IT.html;
www.whfreeman.com/immunology/CH05/kuby05.htm;
www.library.thinkquest.org/12429/Immune/Antibody.html;
www.hhmi.org/grants/lectures/1996/vlab/;
www.path.cam.ac.uk/.about.mrc7/mikeimages.html;www.antibodyresource.com/;
mcb.harvard.edu/BioLinks/Immunology.html.www.immunologylink.com/;
pathbox.wustl.edu/.about.hcenter/index.html;www.biotech.ufl.edu/.about.hcl/;
www.pebio.com/pa/340913/340913.html;www.nal.usda.gov/awic/pubs/antibody/;
www.m.ehime-u.ac.jp/.about.yasuhito/Elisa.html;www.biodesign.com/table.asp;
www.icnet.uk/axp/facs/davies/links.html;
www.biotech.ufl.edu/.about.fccl/protocol.html;www.isac-net.org/sites_geo.html;
aximt1.imt.uni-marburg.de/.about.rek/AEPStart.html;
baserv.uci.kun.nl/.about.jraats/links1.html;
www.recab.uni-hd.de/immuno.bme.nwvu.edu/;
www.mrc-cpe.cam.ac.uk/imt-doc/public/INTRO.html;
www.ibt.unam.mx/vir/V_mice.html;imgt.cnusc.fr:8104/;
www.biochem.ucl.ac.uk/.about.martin/abs/index.html;antibody.bath.ac.uk/;
abgen.cvm.tamu.edu/lab/wwwabgen.html;
www.unizh.ch/.about.honegger/AHOseminar/Slide01.html;
www.cryst.bbk.ac.uk/.about.ubcg07s/;
www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.htm;
www.path.cam.ac.uk/.about.mrc7/humanisation/TAHHP.html;
www.ibt.unam.mx/vir/structure/stat_aim.html;
www.biosci.missouri.edu/smithgp/index.html;
www.cryst.bioc.cam.ac.uk/.about.fmolina/Web-pages/Pept/spottech.html;
www.jerini.de/fr_products.htm;www.patents.ibm.con/ibm.html.
Kabat et al.Sequences of Proteins of Immunological Interest,U.S.Dept.Health(1983),均通过述及而完整收入本文。
此类输入序列可用于降低免疫原性或者降低、增强或改变结合、亲和力、结合速率、解离速率、亲合力、特异性、半衰期、或任何其它合适特征,如本领域已知的。一般地,保留部分或所有非人或人CDR序列,同时用人或其它氨基酸替换可变和恒定区的非人序列。抗体还可任选在人源化的同时保留对抗原的高亲和力和其它有利生物学特性。为了实现这个目标,人源化抗体可任选通过如下过程来制备,即使用亲本和人源化序列的三维模型分析亲本序列和各种概念性人源化产物。三维免疫球蛋白模型是公众可得的,而且是本领域技术人员熟悉的。图示和展示选定候选免疫球蛋白序列的可能的三维构象结构的计算机程序是可得的。检查这些展示图允许分析残基在候选免疫球蛋白序列发挥功能中的可能作用,即分析影响候选免疫球蛋白结合其抗原的能力的残基。这样,可以选择和组合来自共有和输入序列的FR残基,使得期望抗体特征(诸如提高的对靶抗原的亲和力)得以实现。一般地,CDR残基直接且最实质性地涉及影响抗原结合。本发明抗体的人源化或改造可使用任何已知方法来实施,诸如但不限于那些记载于下述文献的:Winter(Jones etal.,Nature 321:522(1986);Riechmann et al.,Nature 332:323(1988);Verhoeyenet al.,Science 239:1534(1988)),Sims et al.,J.Immunol.151:2296(1993);Chothia and Lesk,J.Mol.Biol.196:901(1987),Carter et al.,Proc.Natl.Acad.Sci.U.S.A.89:4285(1992);Presta et al.,J.Immunol.151:2623(1993),美国专利Nos.5,723,323,5,976,862,5,824,514,5,817,483,5,814,476,5,763,192,5,723,323,5,766,886,5,714,352,6,204,023,6,180,370,5,693,762,5,530,101,5,585,089,5,225,539;4,816,567,PCT/:US98/16280,US96/18978,US91/09630,US91/05939,US94/01234,GB89/01334,GB91/01134,GB92/01755;WO90/14443,WO90/14424,WO90/14430,EP 229246,均通过述及而完整收入本文,包括其中引用的参考文献。
本发明人源化抗体的人恒定区可以是任何类(IgG,IgA,IgM,IgE,IgD,等)或同种型的,而且可包含卡帕或拉姆达轻链。在一个实施方案中,人恒定区包含IgG重链或规定片段,例如至少一种同种型,IgG1,IgG2,IgG3或IgG4。在另一个实施方案中,抗人IL-6人抗体包含IgG1重链和IgG1 K轻链。分离的本发明抗IL-6抗体同样包含由任何合适多核苷酸编码的本文中公开的抗体氨基酸序列。优选地,抗体或抗原结合片段结合人IL-6,并由此部分或实质性中和所述蛋白质的至少一种生物学活性。抗体或其具体部分或变体部分或优选实质性中和至少一种IL-6蛋白或片段的至少一种生物学活性,并由此抑制经由IL-6结合IL-6受体或经由其它IL-6依赖性或介导的机制介导的活性。如本文中使用的,术语“中和性抗体”指能根据测定法将IL-6依赖性活性抑制约20-120%,优选至少约10,20,30,40,50,55,60,65,70,75,80,85,90,91,92,93,94,95,96,97,98,99,100%或更多的抗体。抗IL-6抗体抑制IL-6依赖性活性的能力优选通过至少一种合适的IL-6蛋白或受体测定法来评估,如本文中描述的和/或如本领域已知的。
至少一种本发明抗体结合至少一种对至少一种IL-6蛋白、亚基、片段、部分或其任何组合特异性的规定表位。至少一种表位可包含至少一种抗体结合区,其包含至少一个蛋白质部分,该表位优选由蛋白质的至少一种胞外、可溶性、亲水性、外部或胞质部分构成。一般地,本发明的人抗体或抗原结合片段会包含如下的抗原结合区,其包含自本文所述抗IL-6抗体来源的至少一种人互补决定区(CDR1,CDR2和CDR3)或至少一种重链可变区的变体和至少一种人互补决定区(CDR4,CDR5和CDR6)或至少一种轻链可变区的变体。在一个具体的实施方案中,抗体或抗原结合片段可具有如下的抗原结合区,其包含至少一种具有相应CDR 1,2和/或3之氨基酸序列的重链CDR(即CDR1,CDR2和/或CDR3)的至少一部分。在另一个具体的实施方案中,抗体或抗原结合部分或变体可具有如下的抗原结合区,其包含至少一种具有相应CDR 4,5和/或6之氨基酸序列的轻链CDR(即CDR4,CDR5和/或CDR6)的至少一部分。在一个优选的实施方案中,抗体或抗原结合片段的三个重链CDR和三个轻链CDR具有BA399,BA436,BA802,BA808,BA840,BA848,BA890或BA939中至少一项的相应CDR的氨基酸序列。此类抗体可如下来制备,即使用常规技术将抗体的各个部分(例如CDR、框架)化学连接到一起,使用重组DNA技术的常规技术来制备和表达(一种或多种)编码抗体的核酸分子,或使用任何其它合适方法和使用任何可能的冗余密码子(其会导致本发明的多肽表达)。
可采用轻链和重链的组合可变域人源化文库的液相合成。例如,人源化轻链(LC)可变域文库的装配含有人轻链框架(FW)和非人互补决定区(CDR)。文库通过例如使用逐步液相连接FW和CDR DNA片段来装配。文库通过使用逐步液相连接FW1-CDR1-FW2-CDR2-FW3-CDR3次序的FW和CDR DNA片段来装配,其通过本领域技术人员知道的技术来进行。例如,通过一篇或多篇下述参考文献的技术,均通过述及而收入本文:Lo,B.K.,2003,Antibodyhumanization by CDR grafting.Antibody Engineering,Methods and protocols.Edit by Benny K.C.Lo,Methods in Molecular Biology,248,135-159;Kashmiriet al.,2003,Developing a minimally immunogenic humanized antibody by SDRgrafting.Antibody Engineering,Methods and protocols.Edit by Benny K.C.Lo,Methods in Molecular Biology,248,361-376;Bassette,P.H.,et al.,2003,Construction of Designed Protein Libraries Using Gene Assembly Mutagenesis.Directed Evolution Library Creation,Methods and protocols.Edit.Arnold andGeorgiou,Methods in Molecular Biology,231,29-37;Chames,P.,et al.,2001,Selections on Biotinylated antigens.Antibody Engineering,Edit by R.Kontermann and S.Dubel,Springer Lab Manual,149-166;O’Brien S.,and Jones,T.,2001,Humanising antibodies by CDR grafting.Antibody Engineering,Edit byR.Kontermann and S.Dubel,Springer Lab Manual,567-590。
结合人IL-6和包含规定重链或轻链可变区或CDR区的抗体可使用合适方法来制备,诸如噬菌体展示(Katsube,Y.,et al.,Int J.Mol.Med,1(5):863-868(1998))或采用转基因动物的方法,如本领域已知的和/或如本文中描述的。例如,抗体、具体部分或变体可使用编码核酸或其部分在合适宿主细胞中表达。
如所述的,本发明还涉及在序列中包含与本文所述氨基酸序列实质性相同的氨基酸的抗体、抗原结合片段、免疫球蛋白链和CDR。此类抗IL-6抗体可包括一处或多处氨基酸替代、删除或添加,或是来自天然突变或是来自人操作,如本文中描述的。优选地,此类抗体或抗原结合片段和包含此类链或CDR的抗体能以高亲和力(例如小于或等于约10-9M的KD)结合人IL-6。与本文所述序列实质性相同的氨基酸序列包括包含保守氨基酸替代以及氨基酸删除和/或插入的序列。保守氨基酸替代指第一种氨基酸用与第一种氨基酸具有相似的化学和/或物理特性(例如电荷、结构、极性、疏水性/亲水性)的第二种氨基酸替换。保守替代包括下述各组内一种氨基酸用另一种氨基酸替换:赖氨酸(K),精氨酸(R)和组氨酸(H);天冬氨酸(D)和谷氨酸(E);天冬酰胺(N),谷氨酰胺(Q),丝氨酸(S),苏氨酸(T),酪氨酸(Y),K,R,H,D和E;丙氨酸(A),缬氨酸(V),亮氨酸(L),异亮氨酸(I),脯氨酸(P),苯丙氨酸(F),色氨酸(W),甲硫氨酸(M),半胱氨酸(C)和甘氨酸(G);F,W和Y;C,S和T。
当然,熟练技术人员会进行的氨基酸替代的数目取决于多种因素,包括上文描述的那些。一般而言,任何给定抗IL-6抗体、片段或变体的氨基酸替代、插入或删除的数目不会超过40,30,20,19,18,17,16,15,14,13,12,11,10,9,8,7,6,5,4,3,2,1,诸如1-30或其中的任何范围或值,如本文中规定的。
本发明的抗IL-6抗体中对功能至关重要的氨基酸可通过本领域已知的方法来鉴定,诸如定点诱变或丙氨酸扫描诱变(例如Ausubel,supra,Chapters 8,15;Cunningham and Wells,Science 244:1081-1085(1989))。后一种规程在分子中的每一个残基处引入单一丙氨酸突变。然后对所得突变体分子测试生物学活性,诸如但不限于至少一种IL-6中和活性。对抗体结合至关重要的位点还可通过结构分析来鉴定,诸如结晶、核磁共振或光亲和标记(Smith,et al.,J.Mol.Biol.224:899-904(1992)和de Vos,et al.,Science 255:306-312(1992))。
本发明的抗IL-6抗体可包括但不限于选自来源于SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159或160中至少一项的CDR的5个至所有连续氨基酸的至少一部分、序列或组合。
抗IL-6抗体可任选进一步包含自SEQ ID NO:1,3,5,...31中至少一项来源的CDR的连续氨基酸至少70-100%的多肽。在一个具体的方面,抗IL-6抗体包含与SEQ ID NO:1具有95-99%序列同源性的多肽;优选包含SEQ ID NO:68-98之一的CDR。在另一个具体的方面,抗IL-6抗体包含与SEQ ID NO:3具有95-99%序列同源性的多肽;优选包含SEQ ID NO:130-160之一的CDR。
在一个实施方案中,免疫球蛋白链或其部分(例如可变区、CDR)的氨基酸序列与SEQ ID NO:1,3,5,...31中至少一项的氨基酸序列具有约70-100%同一性(例如70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100或者其中的任何范围或数值)。例如,轻链可变区的氨基酸序列可以与SEQ ID NO:1,5,9,13,17,21,25,29的序列比较。优选地,使用本领域已知的合适计算机算法确定70-100%氨基酸同一性(即90,91,92,93,94,95,96,97,98,99,100或者其中的任何范围或数值)。在一个具体的方面,抗IL-6抗体包含与SEQ ID NO:1具有95-99%序列同源性的多肽;优选包含SEQ ID NO:68-98之一的可变区。在另一个具体的方面,抗IL-6抗体包含与SEQ ID NO:3具有95-99%序列同源性的多肽;优选包含SEQ ID NO:130-160之一的可变区。
例示性重链和轻链可变区序列提供于SEQ ID NO:1,3,5,...31,68-98或130-160。本发明的抗体或其规定变体可包含任意数目来自本发明抗体的连续氨基酸残基,其中该数目选自下述整数组:抗IL-6抗体中连续残基数目的10-100%。任选地,这种连续氨基酸子序列的长度为至少约10,20,30,40,50,60,70,80,90,100,110,120,130,140,150,160,170,180,190,200,210,220,230,240,250或更多个氨基酸,或者其中的任何范围或数值。另外,此类子序列的数目可以是选自下组的任何整数:1至20,诸如至少2,3,4或5。
如技术人员会领会的,本发明包括本发明的至少一种生物学活性抗体。生物学活性抗体具有如下的比活性,其为天然(非合成)、内源或相关和已知抗体的比活性的至少20%,30%或40%,和优选至少50%,60%或70%,和最优选至少80%,90%或95%-100%。测量酶活性和底物特异性的测定和定量方法是本领域技术人员公知的。
在另一个方面,本发明涉及本文所述人抗体和抗原结合片段,其通过共价附着有机模块来修饰。此类修饰可生成具有改良药动学特性(例如延长的体内血清半衰期)的抗体或抗原结合。有机模块可以是线性或分支的亲水性聚合物基团、脂肪酸基团、或脂肪酸酯基团。在具体的实施方案中,亲水性聚合物基团可具有约800至约120,000道尔顿的分子量,而且可以是聚烷二醇(例如聚乙二醇(PEG)、聚丙二醇(PPG))、碳水化合物聚合物、氨基酸聚合物或聚乙烯吡咯烷酮,而且脂肪酸或脂肪酸酯基团可包含约8个至约40个碳原子。
经修饰的本发明抗体和抗原结合片段可包含一个或多个直接或间接共价键合至抗体的有机模块。每一个键合至本发明抗体或抗原结合片段的有机模块可独立为亲水性聚合物基团、脂肪酸基团或脂肪酸酯基团。如本文中使用的,术语“脂肪酸”涵盖单羧酸和二羧酸。如本文中使用的,术语“亲水性聚合物基团”指在水中比辛烷更易溶的有机聚合物。例如,聚赖氨酸在水中比辛烷更易溶。如此,本发明涵盖通过共价附着聚赖氨酸而修饰的抗体。适合于修饰本发明抗体的亲水性聚合物可以是线性或分支的,而且包括例如聚烷二醇(例如PEG、单甲氧基-聚乙二醇(mPEG)、PPG等等)、碳水化合物(例如右旋糖苷、纤维素、寡糖、多糖等等)、亲水性氨基酸的聚合物(例如聚赖氨酸、聚精氨酸、聚天冬氨酸等等)、聚烷氧化物(例如聚氧化乙烯、聚氧化丙烯等等)和聚乙烯吡咯烷酮。优选地,修饰本发明抗体的亲水性聚合物作为分开的分子实体具有约800至约150,000道尔顿的分子量。例如,可使用PEG5000和PEG20,000,其中下标是聚合物以道尔顿计的平均分子量。亲水性聚合物基团可用一个至约六个烃基、脂肪酸或脂肪酸酯基团取代。经脂肪酸或脂肪酸酯基团取代的亲水性聚合物可通过采用合适方法来制备。例如,包含胺基团的聚合物可偶联至脂肪酸或脂肪酸酯的羧酸根,而脂肪酸或脂肪酸酯上活化的羧酸根(例如用N,N-羰二咪唑活化的)可偶联至聚合物上的羟基。
适合于修饰本发明抗体的脂肪酸和脂肪酸酯可以是饱和的,或者可以含有一个或多个不饱和单元。适合于修饰本发明抗体的脂肪酸包括例如正十二烷酸根(C12,月桂酸根)、正十四烷酸根(C14,肉豆蔻酸根)、正十八烷酸根(C18,硬脂酸根)、正二十烷酸根(C20,花生酸根)、正二十二烷酸根(C22,山萮)、正三十烷酸根(C30)、正四十烷酸根(C40)、顺-δ9-十八烷酸根(C18,油酸根)、全顺-δ5,8,11,14-二十碳四烯酸根(C20,花生四烯酸根)、辛二酸、十四烷二酸、十八烷二酸、二十二烷二酸、等等。合适的脂肪酸酯包括包含线性或分支的低级烃基的二羟酸的单酯。低级烃基可包含1个至约12个,优选1个至约6个碳原子。
经修饰的人抗体和抗原结合片段可使用合适方法来制备,诸如通过与一种或多种修饰剂反应。如本文中使用的,术语“修饰剂”指包含活化基团的合适有机基团(例如亲水性聚合物、脂肪酸、脂肪酸酯)。“活化基团”为如下的化学模块或官能团,其在适宜条件下能与第二化学基团反应,由此在修饰剂与第二化学基团之间形成共价键。例如,胺反应性活化基团包括亲电子基团,诸如甲苯磺酸根、甲磺酸根(mesylate)、卤素(氯、溴、氟、碘)、N-羟基琥珀酰亚氨基酯(NHS)、等等。能与硫醇反应的活化基团包括例如马来酰亚胺、碘乙酰基、丙烯酰基、吡啶基二硫化物、5-硫醇-2-硝基苯甲酸硫醇(TNB-thiol)、等等。醛官能团可偶联至含胺或酰肼的分子,而叠氮化物基团能与三价磷基团反应以形成氨基磷酸酯或磷酰亚胺(phosphorimide)连接。将活化基团引入分子的合适方法是本领域已知的(参见例如Hernanson,G.T.,Bioconjugate Techniques,Academic Press:San Diego,Calif.(1996))。活化基团可直接地或经由接头基团(例如二价C1-C12基团,其中一个或多个碳原子可以用杂原子诸如氧、氮或硫置换)键合至有机基团(例如亲水性聚合物、脂肪酸、脂肪酸酯)。合适的接头模块包括例如四乙二醇,--(CH2)3--,--NH--(CH2)6--NH--,--(CH2)2--NH--和--CH2--O--CH2--CH2--O--CH2--CH2--O--CH--NH--。包含接头模块的修饰剂可例如通过在1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)存在下使单Boc-烃基二胺(例如单Boc-乙二胺、单Boc-二氨基己烷)与脂肪酸反应以在游离胺和脂肪酸羧酸根之间形成酰胺键来生成。可通过用三氟乙酸(TFA)处理来自产物清除Boc保护基团以暴露伯胺,其可以偶联至另一羧酸根,如描述的,或者可以与马来酸酐反应,并且所得产物环化以生成脂肪酸的活化的马来酰亚氨子基衍生物(参见例如Thompson,et al.,WO 92/16221,通过述及将完整教导收入本文)。
经修饰的本发明抗体可通过使人抗体或抗原结合片段与修饰剂反应来生成。例如,可以通过采用胺反应性修饰剂,例如PEG的NHS酯,以非位点特异性方式将有机模块键合至抗体。经修饰的人抗体或抗原结合片段还可如下来制备,即还原抗体或抗原结合片段的二硫键(例如链内二硫键)。然后使还原的抗体或抗原结合片段与硫醇反应性修饰剂反应以生成经修饰的本发明抗体。包含键合至本发明抗体特定位点的有机模块的经修饰人抗体和抗原结合片段可使用合适方法来制备,诸如反相蛋白水解(Fisch et al.,Bioconjugate Chem.,3:147-153(1992);Werlen et al.,Bioconjugate Chem.,5:411-417(1994);Kumaran et al.,Protein Sci.6(10):2233-2241(1997);Itoh etal.,Bioorg.Chem.,24(1):59-68(1996);Capellas et al.,Biotechnol.Bioeng.,56(4):456-463(1997))及Hermanson,G.T.,Bioconjugate Techniques,AcademicPress:San Diego,Calif.(1996)中记载的方法。
本发明的抗体能以广泛的亲和力(KD)结合人IL-6。在一个优选的实施方案中,至少一种本发明人单抗任选能以高亲和力结合人IL-6。例如,单抗能以等于或小于约10-7M的KD结合人IL-6,诸如但不限于0.1-9.9(或其中的任何范围或数值)X 10-7,10-8,10-9,10-10,10-11,10-12,10-13或者其中的任何范围或数值。
抗体对抗原的亲和力或亲合力可使用任何合适方法以实验来测定(参见例如Berzofsky,et al.,″Antibody-Antigen Interactions,″In FundamentalImmunology,Paul,W.E.,Ed.,Raven Press:New York,N.Y.(1984);Kuby,JanisImmunology,W.H.Freeman and Company:New York,N.Y.(1992);及本文所述方法)。特定抗体-抗原相互作用的测量亲和力若在不同条件(例如盐浓度、pH)下测量则可变化。如此,亲和力和其它抗原结合参数(例如KD、Ka、Kd)的测量优选用抗体和抗原的标准化溶液和标准化缓冲液诸如本文所述缓冲液来进行。
在本发明的方法和组合物中有用的抗IL-6抗体特征在于对IL-6的高亲和力结合及任选和优选具有低毒性。特别地,各成分诸如可变区、恒定区和框架个别地和/或共同地任选和优选拥有低免疫原性的本发明抗体、规定片段或变体在本发明中有用。可用于本发明的抗体任选特征在于它们治疗患者的能力,在延长的时段里有可测量的症状缓解和低和/或可接受的毒性。低或可接受的免疫原性和/或高亲和力,以及其它合适特性可促进所实现的治疗结果。“低免疫原性”在本文中定义为在少于约75%、或优选少于约50%的所处理患者中引起显著的HAHA、HACA或HAMA应答和/或在所处理患者中引起低滴度(少于约300、优选少于约100,用双重抗原酶免疫测定法测量)(Elliottet al.,Lancet 344:1125-1127(1994),通过述及完整收入本文)。
还可使用双特异性、异特异性、异源偶联或类似抗体,它们是对至少两种不同抗原具有结合特异性的单克隆人源化抗体。在本案中,结合特异性之一是对于至少一种IL-6蛋白,另一是对于任何其它抗原。用于生成双特异性抗体的方法是本领域已知的。传统上,双特异性抗体的重组生成基于两对免疫球蛋白重链-轻链的共表达,其中两种重链具有不同特异性(Milstein andCuello,Nature 305:537(1983))。由于免疫球蛋白重链和轻链的随机配合,这些杂交瘤(四源杂交瘤)生成10种不同抗体分子的潜在混合物,其中只有一种具有正确的双特异性结构。通常通过亲和层析步骤来进行的对正确分子的纯化相当麻烦,而且产物产率低。相似规程披露于例如WO 93/08829,美国专利No.6,210,668,6,193,967,6,132,992,6,106,833,6,060,285,6,037,453,6,010,902,5,989,530,5,959,084,5,959,083,5,932,448,5,833,985,5,821,333,5,807,706,5,643,759,5,601,819,5,582,996,5,496,549,4,676,980,WO 91/00360,WO 92/00373,EP 03089,Traunecker et al.,EMBO J.10:3655(1991),Suresh etal.,Methods in Enzymology 121:210(1986),均通过述及完整收入本文。
核酸分子
使用本文中提供的信息,诸如编码SEQ ID NO:1,3,5,...31,68-98或130-160中至少一项的连续氨基酸的至少70-100%的核苷酸序列或其规定片段、变体或共有序列,或包含至少一种这些序列的保藏载体,编码至少一种抗IL-6抗体的本发明核酸分子可使用本文中描述的或本领域已知的方法来获得。
本发明的核酸分子可以是RNA的形式,诸如mRNA、hnRNA、tRNA或任何其它形式,或者是DNA的形式,包括但不限于通过克隆获得的或合成生成的cDNA和基因组DNA,或者它们的任意组合。DNA可以是三链的、双链的或单链的,或者它们的任意组合。DNA或RNA的至少一条链的任何部分可以是编码链,也称作有义链,或者它可以是非编码链,也称作反义链。
分离的本发明核酸分子可包括如下的核酸分子,其包含可读框(ORF),任选有一个或多个内含子,例如但不限于至少一种重链(例如SEQ ID NO:4,8,12,16,20,24,28,32或99-129)或轻链(例如SEQ ID NO:2,6,10,14,18,22,26,30或37-67)的至少一种CDR,像CDR1、CDR2和/或CDR3的至少一个具体部分;如下的核酸分子,其包含抗IL-6抗体或可变区(例如SEQ ID NO:2,4,6...32,37-67或99-129)的编码序列;和如下的核酸分子,其包含与上文所述那些实质性不同但由于遗传密码的简并性仍编码本文描述的和/或本领域已知的至少一种抗IL-6抗体的核苷酸序列。当然,遗传密码是本领域公知的。如此,生成编码特定本发明抗IL-6抗体的此类简并核酸变体对本领域技术人员是常规的。参见例如Ausubel,et al.,supra,而且本发明包括此类核酸变体。分离的本发明核酸分子的非限制性例子包括SEQ ID NO:2,4,6...32,37-67或99-129;对应于分别编码HC CDR1、HC CDR2、HC CDR3、LC CDR1、LC CDR2、LC CDR3、HC可变区和LC可变区的核酸的非限制性例子。
如本文中指出的,包含编码抗IL-6抗体的核酸的本发明核酸分子可包括但不限于那些自身编码抗体片段的氨基酸序列的,完整抗体或其部分的编码序列,抗体、片段或部分的编码序列,以及别的序列,诸如至少一种信号前导或融合肽的编码序列,有或无前述别的编码序列,诸如至少一种内含子,连同别的非编码序列,包括但不限于非编码的5′和3′序列,诸如在转录、mRNA加工(包括剪接和聚腺苷酸化信号(例如mRNA的核糖体结合和稳定性)中发挥作用,转录但不翻译的序列;别的编码序列,其编码别的氨基酸,诸如那些提供别的功能性的。如此,编码抗体的序列可融合至标志物序列,诸如编码促进包含抗体片段或部分的融合多肽纯化的肽的序列。
与本文所述多核苷酸选择性杂交的多核苷酸
本发明提供了分离的在选择性杂交条件下与本文公开的多核苷酸杂交的核酸。如此,这个实施方案的多核苷酸可用于分离、检测、和/或定量包含此类多核苷酸的核酸。例如,本发明的多核苷酸可用于鉴定、分离、或扩增保藏文库中的部分或全长克隆。在一些实施方案中,多核苷酸是自人或哺乳动物核酸文库分离的或与来自人或哺乳动物核酸文库的cDNA互补的基因组或cDNA序列。
优选地,cDNA文库包含至少80%全长序列,优选至少85%或90%全长序列,和更优选至少95%全长序列。cDNA文库可标准化以提高罕见序列的呈现。低或中等严格杂交条件通常但非唯一用于相对于互补序列具有降低的序列同一性的序列。中等和高严格条件可任选用于具有较高同一性的序列。低严格条件容许具有约70%序列同一性的序列选择性杂交,而且可用于鉴定直系同源或旁系同源序列。
任选地,本发明的多核苷酸会编码由本文所述多核苷酸编码的抗体的至少一部分。本发明的多核苷酸涵盖可用于与编码本发明抗体的多核苷酸选择性杂交的核酸序列。参见例如Ausubel,supra;Colligan,supra,均通过述及而完整收入本文。
核酸的构建
分离的本发明核酸可以使用(a)重组方法,(b)合成技术,(c)纯化技术,或它们的组合来生成,如本领域公知的。
核酸可方便地包含本发明多核苷酸之外的序列。例如,包含一种或多种内切核酸酶限制性位点的多克隆位点可插入核酸中以帮助多核苷酸的分离。还有,可插入可翻译序列以帮助本发明的翻译多核苷酸的分离。例如,六组氨酸标志物序列提供一种方便的手段来纯化本发明的蛋白质。本发明的核酸-排除编码序列-任选是载体、衔接头、或接头,用于克隆和/或表达本发明的多核苷酸。
别的序列可添加至此类克隆和/或表达序列以优化它们在克隆和/或表达中的功能,帮助多核苷酸的分离,或提高多核苷酸进入细胞的导入。克隆载体、表达载体、衔接头、和接头的使用是本领域公知的(参见例如Ausubel,supra;Sambrook,supra)。
用于构建核酸的重组方法
分离的本发明核酸组合物,诸如RNA、cDNA、基因组DNA、或其任意组合,可使用任何数目的本领域技术人员知道的克隆方法自生物学来源获得。在一些实施方案中,在严格条件下与本发明的多核苷酸选择性杂交的寡核苷酸探针用于鉴定cDNA或基因组DNA文库中的期望序列。RNA的分离及cDNA和基因组文库的构建是本领域普通技术人员公知的(参见例如Ausubel,supra;Sambrook,supra)。
核酸筛选和分离方法
可使用基于本发明多核苷酸序列诸如本文中公开的那些的探针筛选cDNA或基因组文库。探针可用于与基因组DNA或cDNA序列杂交以分离相同或不同生物体中的同源序列。本领域技术人员会领会,测定法中可使用各种程度的杂交严格性;而且杂交或清洗培养基任一可以是严格。随着杂交条件变得更加严格,双链体形成的发生要求探针和靶之间的互补性程度更高。严格性的程度可以通过温度、离子强度、pH和部分变性溶剂诸如甲酰胺的存在中一项或多项来控制。例如,经由例如在0%至50%的范围内操控甲酰胺的浓度,通过改变反应物溶液的极性来方便地改变杂交严格性。可检测结合所需要的互补性(序列同一性)程度会根据杂交培养基和/或清洗培养基的严格性而变化。互补性程度最佳地会是100%、或70-100%、或其中的任何范围或数值。然而,应当理解,探针和引物中微小的序列变异可通过降低杂交和/或清洗培养基的严格性来补偿。
扩增RNA或DNA的方法是本领域公知的,而且基于本文中呈现的教导和指导,无需过度实验,可依照本发明来使用。
已知的DNA或RNA扩增方法包括但不限于聚合酶链式反应(PCR)及相关扩增过程(参见例如Mullis等人的美国专利No.4,683,195,4,683,202,4,800,159,4,965,188;Tabor等人的4,795,699和4,921,794;Innis的5,142,033;Wilson等人的5,122,464;Innis的5,091,310;Gyllensten等人的5,066,584;Gelfand等人的4,889,818;Silver等人的4,994,370;Biswas的4,766,067;Ringold的4,656,134)和RNA介导的扩增,其使用靶序列的反义RNA作为双链DNA合成的模板(Malek等人的美国专利No.5,130,238,商品名NASBA),通过述及将这些参考文献的完整内容收入本文(参见例如Ausubel,supra;Sambrook,supra)。
例如,聚合酶链式反应(PCR)技术可用于直接自基因组DNA或cDNA文库扩增本发明多核苷酸及相关基因的序列。PCR和其它体外扩增方法还可用于例如克隆编码待表达蛋白质的核酸序列,生成待用作探针用于检测样品中期望mRNA的存在、用于核酸测序、或用于其它目的的核酸。足以指导技术人员进行体外扩增方法的技术的例子见于Berger,supra,Sambrook,supra,Ausubel,supra,以及Mullis,et al.,美国专利No.4,683,202(1987);Innis,et al.,PCR Protocols A Guide to Methods and Applications,Eds.,Academic Press Inc.,San Diego,Calif.(1990)。用于基因组PCR扩增的商品化试剂盒是本领域已知的。参见例如Advantage-GC基因组PCR试剂盒(Clontech)。另外,例如T4基因32蛋白(Boehringer Mannheim)可用于提高长PCR产物的产量。
用于构建核酸的合成
分离的本发明核酸还可通过已知方法通过直接化学合成来制备(参见例如Ausubel,et al.,supra)。化学合成一般生成单链寡核苷酸,其可以通过与互补序列杂交或通过使用单链作为模板用DNA聚合酶聚合而转变成双链DNA。本领域技术人员会认识到虽然DNA的化学合成可能限于约100或更多个碱基的序列,但是更长的序列可通过较短序列的连接来获得。
重组表达盒
本发明进一步提供了包含本发明核酸的重组表达盒。本发明的核酸序列,例如编码本发明抗体的cDNA或基因组序列,可用于构建重组表达盒,其可以导入至少一种期望宿主细胞中。重组表达盒通常会包含本发明的多核苷酸,其与转录启动调节序列可操作连接,它们会指导预定宿主细胞中多核苷酸的转录。异源和非异源(即内源)启动子均可用于指导本发明核酸的表达。
在一些实施方案中,充当启动子、增强子、或其它元件的分离核酸可引入以以非异源形式的本发明多核苷酸的适宜位置(上游、下游或在内含子中)以上调或下调本发明多核苷酸的表达。例如,可通过突变、删除和/或替代在体内或在体外改变内源启动子。
载体和宿主细胞
本发明还涉及包括分离的本发明核酸分子的载体,经重组载体遗传工程改造的宿主细胞,和通过重组技术生产至少一种抗IL-6抗体,如本领域公知的。参见例如Sambrook,et al.,supra;Ausubel,et al.,supra,均通过述及而完整收入本文。
多核苷酸可任选连接至含有选择标志的载体,以在宿主中扩增。一般地,在沉淀物(诸如磷酸钙沉淀物中或在与带电荷的脂质的复合物中导入质粒载体。如果载体是病毒,可使用适宜的包装细胞系在体外包装病毒,然后再导入宿主细胞。
DNA插入物应当可操作连接适宜的启动子。表达构建物会进一步含有转录区中供转录起始、终止用的位点,供翻译的核糖体结合位点。由构建物表达的成熟转录物的编码部分会优选包括开始处的翻译起始和恰当位于待翻译mRNA结束处的终止密码子(例如UAA、UGA或UAG),其中UAA和UAG是哺乳动物或真核细胞表达所优选的。
表达载体会优选但任选包括至少一种选择标志。此类标志包括例如但不限于用于真核细胞培养的甲氨蝶呤(MTX)、二氢叶酸还原酶(DHFR,美国专利No.4,399,216;4,634,665;4,656,134;4,956,288;5,149,636;5,179,017)、氨苄青霉素、新霉素(G418)、霉酚酸、或谷氨酰胺合成酶(GS,美国专利No.5,122,464;5,770,359;5,827,739)抗性,及用于大肠杆菌和其它细菌或原核生物培养的四环素或氨苄青霉素抗性基因(在此通过述及而完整收录上述专利)。对于上述宿主细胞适宜的培养基和条件是本领域已知的。合适的载体对于熟练技术人员会是显而易见的。将载体构建物导入宿主细胞中可通过磷酸钙转染、DEAE-右旋糖苷介导的转染、阳离子脂质介导的转染、电穿孔、转导、感染或其它已知方法来实现。此类方法在本领域有记载,诸如Sambrook,supra,1-4和16-18章;Ausubel,supra,1,9,13,15,16章。
至少一种本发明抗体可以以修饰形式表达,诸如融合蛋白,而且可以不仅包括分泌信号,而且还包括别的异源功能区。例如,可将额外氨基酸(特别是带电荷的氨基酸)的一个区域添加至抗体的N端以提高在纯化期间、或后续操作和贮存期间,在宿主细胞中的稳定性和持久性。还有,可将肽模块添加至本发明的抗体以促进纯化。此类区可在抗体或至少一种其片段的最终制备之前消除。此类方法在许多标准实验室手册中有记载,诸如Sambrook,supra,17.29-17.42和18.1-18.74章;Ausubel,supra,16,17和18章。
本领域普通技术人员知道多种表达系统可供表达编码本发明蛋白质的核酸。
或者,本发明的核酸可以通过含有编码本发明抗体的内源DNA的宿主细胞中的开启(通过操作)而在宿主细胞中表达。此类方法是本领域公知的,例如记载于美国专利No.5,580,734,5,641,670,5,733,746和5,733,761,通过述及而完整收入本文。
可用于生产抗体、其具体部分或变体的细胞培养物的例示是哺乳动物细胞。哺乳动物细胞系统常常会是细胞单层的形式,尽管也可使用哺乳动物细胞悬浮液或生物反应器。本领域已经开发了多种能够表达完整糖基化蛋白质的合适宿主细胞系,而且包括COS-1(例如ATCC CRL 1650)、COS-7(例如ATCC CRL-1651)、HEK293、BHK21(例如ATCC CRL-10)、CHO(例如ATCCCRL 1610)和BSC-1(例如ATCC CRL-26)细胞系、Cos-7细胞、CHO细胞、hep G2细胞、P3X63Ag8.653、SP2/0-Ag14、293细胞、HeLa细胞等等,它们易于自例如美国典型培养物保藏中心(American Type Culture Collection,Manassas,Va.)(www.atcc.org)获得。优选的宿主细胞包括淋巴样起源的细胞,诸如骨髓瘤和淋巴瘤细胞。特别优选的宿主细胞是P3X63Ag8.653细胞(ATCC编号CRL-1580)和SP2/0-Ag14细胞(ATCC编号CRL-1851)。在一个特别优选的实施方案,重组细胞是P3X63Ab8.653或SP2/0-Ag14细胞。
用于这些细胞的表达载体可包括一种或多种下述表达控制序列,诸如但不限于复制起点;启动子(例如晚期或早期SV40启动子、CMV启动子(美国专利No.5,168,062;5,385,839)、HSV tk启动子、pgk(磷酸甘油酸激酶)启动子、EF-1α启动子(美国专利No.5,266,491)、至少一种人免疫球蛋白启动子;增强子、和/或加工信息位点,诸如核糖体结合位点、RNA剪接位点、聚腺苷酸化位点(例如SV40大T抗原poly A添加位点)、和转录终止子序列。参见例如Ausubel et al.,supra;Sambrook,et al.,supra。对于生成本发明的核酸或蛋白质有用的其它细胞是已知的和/或可得的,例如美国典型培养物保藏中心细胞系和杂交瘤目录(www.atcc.org)或其它已知的或商业性的来源。
当采用真核宿主细胞时,通常将聚腺苷酸化或转录终止序列掺入载体中。终止子序列的一个例子是来自牛生长激素基因的聚腺苷酸化序列。还可包括精确转录物剪接所需序列。剪接序列的一个例子是来自SV40的VP1内含子(Sprague,et al.,J.Virol.45:773-781(1983))。另外,可将在宿主细胞中控制复制所需基因序列掺入载体,如本领域已知的。
抗体的生成
至少一种本发明抗IL-6抗体可任选通过细胞系、混合细胞系、永生化细胞或永生化细胞的克隆群来生成,如本领域公知的。参见例如Ausubel,et al.,ed.,Current Protocols in Molecular Biology,John Wiley & Sons,Inc.,NY,N.Y.(1987-2001);Sambrook,et al.,Molecular Cloning:A Laboratory Manual,2.sup.nd Edition,Cold Spring Harbor,N.Y.(1989);Harlow and Lane,antibodies,a Laboratory Manual,Cold Spring Harbor,N.Y.(1989).Colligan,et al.,eds.,Current Protocols in Immunology,John Wiley & Sons,Inc.,NY(1994-2001);Colligan et al.,Current Protocols in Protein Science,John Wiley & Sons,NY,N.Y.,(1997-2001),均通过述及而完整收入本文。
在一种办法中,通过融合合适的永生化细胞系(例如骨髓瘤细胞系,诸如但不限于Sp2/0、Sp2/0-AG14、NSO、NS1、NS2、AE-1、L.5、>243、P3X63Ag8.653、Sp2 SA3、Sp2 MAI、Sp2 SS1、Sp2 SA5、U937、MLA 144、ACT IV、MOLT4、DA-1、JURKAT、WEHI、K-562、COS、RAJI、NIH 3T3、HL-60、MLA 144、NAMAIWA、NEURO 2A)等等,或异源骨髓瘤、其融合产物,或自其来源的任何细胞或融合细胞,或本领域已知的任何其它合适细胞系(参见例如www.atcc.org,www.lifetech.com.,等等)与抗体生成细胞(诸如但不限于分离的或克隆的脾、外周血、淋巴、扁桃体、或含有其它免疫或B细胞的细胞、或表达重链或轻链恒定或可变或框架或CDR序列(或是作为内源或异源核酸,或是作为重组或内源、病毒、细菌、藻类、原核、两栖类、昆虫、爬虫类、鱼类、哺乳类、啮齿类、马、羊、山羊、绵羊、灵长类、真核、基因组DNA、cDNA、rDNA、线粒体DNA或RNA、叶绿体DNA或RNA、hnRNA、mRNA、tRNA、单链、双链或三链、杂交的、等等或它们的任意组合)的任何其它细胞来生成杂交瘤。参见例如Ausubel,supra和Colligan,Immunology,supra,chapter 2,通过述及而完整收入本文。
任何其它合适的宿主细胞也可用于表达编码本发明抗体、其规定片段或变体的异源或内源核酸。融合细胞(杂交瘤)或重组细胞可使用选择性培养条件或其它合适的已知方法来分离,并通过有限稀释或细胞分选或其它已知方法来克隆。生成具有期望特异性的抗体的细胞可通过合适的测定法(例如ELISA)来选择。
本发明的抗体还可如下制备,即使用至少一种抗IL-6抗体编码核酸来提供在它们的乳中生成此类抗体的转基因动物或哺乳动物,诸如山羊、牛、马、绵羊、等等。参见例如但不限于美国专利No.5,827,690;5,849,992;4,873,316;5,849,992;5,994,616,5,565,362;5,304,489等等,均通过述及而完整收入本文。
本发明的抗体另外可如下来制备,即使用至少一种抗IL-6抗体编码核酸来提供在植物部分中或在自其培养的细胞中生成此类抗体、具体部分或变体的转基因植物和培养的植物细胞(例如但不限于烟草和玉米)。作为一个非限制性例子,表达重组蛋白的转基因烟草叶已经成功用于提供大量的重组蛋白,例如使用诱导型启动子。参见例如Cramer et al.,Curr.Top.Microbol.Immunol.240:95-118(1999)及其中引用的参考文献。还有,转基因玉米已经用于在商业性生产水平表达哺乳动物蛋白质,生物学活性等同于在其它重组系统生成的或自天然来源纯化的那些。参见例如Hood et al.,Adv.Exp.Med.Biol.464:127-147(1999)及其中引用的参考文献。抗体还已经自转基因植物种子大量生成,包括抗体片段,诸如单链抗体(scFv′s),包括烟草种子和马铃薯块茎。参见例如Conrad et al.,Plant Mol.Biol.38:101-109(1998)及其中引用的参考文献。如此,本发明的抗体还可依照已知方法使用转基因植物来生成。还可参见例如Fischer et al.,Biotechnol.Appl.Biochem.30:99-108(October,1999);Ma et al.,Trends Biotechnol.13:522-7(1995);Ma et al.,Plant Physiol.109:341-6(1995);Whitelam et al.,Biochem Soc.Trans.22:940-944(1994);及其中引用的参考文献。通过述及将每一篇上述参考文献完整收入本文。
抗体的纯化
抗IL-6抗体可通过公知方法自重组细胞培养物回收和纯化,包括但不限于蛋白A纯化、蛋白G纯化、硫酸铵或乙醇沉淀、酸提取、阴离子或阳离子交换层析、磷酸纤维素层析、疏水相互作用层析、亲和层析、羟磷灰石层析和凝集素层析。高效液相层析(″HPLC″)也可用于纯化。参见例如Colligan,Current Protocols in Immunology,或Current Protocols in Protein Science,JohnWiley & Sons,NY,N.Y.,(1997-2001),例如1,4,6,8,9和10章,均通过述及完整收入本文。
本发明的抗体包括天然纯化的产物、化学合成规程的产物、和通过重组技术自真核宿主(包括例如酵母、高等植物、昆虫和哺乳动物细胞)生成的产物。根据重组生产规程中采用的宿主,本发明的抗体可以是糖基化的,或者可以是未糖基化的,优选糖基化的。此类方法在许多标准实验室手册中有记载,诸如Sambrook,supra,Sections 17.37-17.42;Ausubel,supra,10,12,13,16,18和20章;Colligan,Protein Science,supra,12-14章,均通过述及完整收入本文。
纯化的抗体可通过例如ELISA、ELISPOT、流式细胞术、免疫细胞学、分析、Sapidyne KinExATM动力学排阻测定法、SDS-PAGE和Western印迹,或通过HPLC分析以及通过多种其它功能测定法来表征,如本文中公开的。
哺乳动物细胞中IL-6抗体的克隆和表达
一种典型的哺乳动物表达载体含有至少一种介导mRNA转录启动的启动子元件、抗体编码序列、及转录物的转录终止和聚腺苷酸化所需信号。别的元件包括增强子、Kozak序列及侧翼为RNA剪接供体和受体位点的间插序列。高效的转录可用来自SV40的早期和晚期启动子、来自逆转录病毒例如RSV、HTLVI、HIVI的长末端重复(LTRS)、和巨细胞病毒(CMV)的早期启动子来实现。然而,也可使用细胞元件(例如人肌动蛋白启动子)。对在本发明的实践中使用合适的表达载体包括例如载体,诸如pIRES1neo、pRetro-Off、pRetro-On、PLXSN、或pLNCX(Clonetech Labs,Palo Alto,Calif.)、pcDNA3.1(+/-)、pcDNA/Zeo(+/-)或pcDNA3.1/Hygro(+/-)(Invitrogen)、PSVL和PMSG(Pharmacia,Uppsala,Sweden)、pRSVcat(ATCC 37152)、pSV2dhfr(ATCC37146)和pBC12MI(ATCC 67109)。可使用的哺乳动物宿主细胞包括人Hela293、H9和Jurkat细胞,小鼠NIH3T3和C127细胞,Cos 1、Cos 7和CV 1,鹌鹑QC1-3细胞,小鼠L细胞和中国仓鼠卵巢(CHO)细胞。
或者,基因可在如下的稳定细胞系中表达,其含有整合入染色体中的基因。与选择标志诸如dhfr、gpt、新霉素、或潮霉素的共转染容许鉴定和分离受到转染的细胞。
所转染的基因还可扩增以大量表达所编码的抗体。DHFR(二氢叶酸还原酶)标志可用于开发携带感兴趣基因的数百个或甚至数千个拷贝的细胞系。另一种有用的选择标志是谷氨酰胺合酶(GS)(Murphy,et al.,Biochem.J.227:277-279(1991);Bebbington,et al.,Bio/Technology 10:169-175(1992))。使用这些标志,在选择性培养基中培养哺乳动物细胞,并选择具有最高抗性的细胞。这些细胞系含有扩增的基因,其整合入染色体中。中国仓鼠卵巢(CHO)和NSO细胞常常用于抗体生产。
CHO细胞中的克隆和表达
用T4 DNA连接酶连接分离的可变和恒定区编码DNA和去磷酸化载体。然后转化大肠杆菌HB101或XL-1 Blue细胞,并使用例如限制酶分析来鉴定含有插入质粒pC4中的片段的细菌。
将缺乏活性DHFR基因的中国仓鼠卵巢(CHO)细胞用于转染。使用Lipofectin与0.5μg质粒pSV2-neo一起转染5μg表达质粒pC4。质粒pSV2neo含有一种显性选择标志,即来自Tn5的neo基因,其编码赋予对一组包括G418在内的抗生素的抗性的酶。在补充有1μg/ml G418的α负MEM中接种细胞。2天后,将细胞用胰蛋白酶处理,并在杂交瘤克隆板(Greiner,Germany)中在补充有10,25或50ng/ml甲氨蝶呤加1μg/ml G418的α负MEM中接种。约10-14天后,将单克隆用胰蛋白酶处理,然后在6孔皮氏皿或10ml烧瓶中接种,使用不同浓度的甲氨蝶呤(50nM,100nM,200nM,400nM,800nM)。然后将在最高浓度的甲氨蝶呤中生长的克隆转移至新的6孔板,其中装有甚至更高浓度的甲氨蝶呤(1mM,2mM,5mM,10mM,20mM)。重复相同规程,直至获得在浓度100-200mM生长的克隆。分析期望基因产物的表达,例如通过SDS-PAGE和Western印迹,ELISA,或者通过反相HPLC分析。
抗IL-6抗体组合物
本发明还提供了至少一种抗IL-6抗体组合物,其包含至少一种、至少两种、至少三种、至少四种、至少五种、至少六种或更多种其抗IL-6抗体,如本文中描述的和/或如本领域已知的,以非天然存在的组合物、混合物或形式提供。此类组合物包含非天然存在的组合物,其包含选自下组的抗IL-6抗体氨基酸序列的至少一种或两种全长、C和/或N端删除的变体、结构域、片段、或规定变体:本文所述抗体的CDR区的70-100%连续氨基酸,或其具体片段、结构域或变体。优选的抗IL-6抗体组合物包括至少一种或两种全长、片段、结构域或变体,像至少一种含有本文所述抗IL-6抗体序列一部分的CDR或LBR。别的优选的组合物包含40-99%的至少一种本文所述抗IL-6抗体的CDR区的70-100%。所述组合物百分比以液体的或干的溶液、混合物、悬浮液、乳状液或胶体的重量、体积、浓度、容积摩尔数、或质量摩尔数计,如本领域已知的或如本文中描述的。
本发明的抗IL-6抗体组合物可进一步包含至少一种任何合适和有效量的如下组合物或药物组合物,其包含至少一种抗IL-6抗体,对需要此类调控、处理或治疗的细胞、组织、器官、动物或患者(施用),任选进一步包含至少一种选自至少一种TNF拮抗剂(例如但不限于TNF抗体或片段、可溶性TNF受体或片段、其融合蛋白、或小分子TNF拮抗剂)、抗风湿药(例如甲氨蝶呤(methotrexate)、金诺芬(auranofin)、金硫代葡萄糖(aurothioglucose)、硫唑嘌呤(azathioprine)、依那西普(etanercept)、硫代苹果酸金钠(gold sodiumthiomalate)、硫酸羟氯喹(hydroxychloroquine sulfate)、来氟米特(leflunomide)、柳氮磺吡啶(sulfasalazine))肌肉松弛药、麻醉药、非类固醇抗炎药(NSAID)、镇痛药、麻醉剂、镇静药、局部麻醉剂、神经肌肉阻断剂、抗微生物剂(例如氨基糖苷(aminoglycoside)、抗真菌药、抗寄生物药、抗病毒药、碳青霉烯、头孢菌素、氟喹诺酮(flurorquinolone)、大环内酯、青霉素、磺胺、四环素、其它抗微生物剂)、抗银屑病药、皮质类固醇、促蛋白合成类固醇、糖尿病相关药剂、矿物、营养物、甲状腺药剂、维生素、钙相关激素、止泻药、镇咳药、止吐药、抗溃疡药、轻泻药、抗凝血药、红细胞生成素(例如epoetinα)、非格司亭(例如G-CSF,Neupogen)、沙莫司亭(GM-CSF,Leukine)、免疫、免疫球蛋白、免疫抑制药(例如巴利昔单抗(basiliximab)、环孢霉素(cyclosporine)、达克珠单抗(daclizumab))、生长激素、激素替代药物、雌激素受体调控剂、扩瞳药、睫状肌麻痹剂、烷化剂、抗代谢药、有丝分裂抑制剂、放射学药物、抗抑郁药、抗躁狂剂、安定药、抗焦虑药、催眠药、拟交感神经药、兴奋剂、多奈哌齐、他克林、哮喘药物、β激动剂、吸入的类固醇、白三烯抑制剂、甲基黄嘌呤、色甘酸钠、肾上腺素或类似物、domase α(Pulmozyme)、细胞因子或细胞因子拮抗剂。此类细胞因子的非限制性例子包括但不限于任何IL-1至IL-34。合适的剂量是本领域公知的。参见例如Wellset al.,eds.,Pharmacotherapy Handbook,2.sup.nd Edition,Appleton and Lange,Stamford,Conn.(2000);PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia2000,Deluxe Edition,Tarascon Publishing,Loma Linda,Calif.(2000),通过述及将每一篇参考文献完整收入本文。
此类抗癌药或抗感染药还可包括与至少一种本发明抗体联合、结合、共配制或共施用的毒素分子。毒素可任选起选择性杀死病态细胞或组织的作用。病态细胞可以是癌症或其它细胞。此类毒素可以是但不限于纯化的或重组的毒素或毒素片段,其包含至少一种毒素功能性细胞毒性域,例如选自至少一种蓖麻毒蛋白、白喉毒素、毒液毒素、或细菌毒素。术语毒素还包括内毒素和外毒素二者,其由任何天然存在的、突变的或重组的细菌或病毒生成,其可以在人类和其它哺乳动物中引起任何病理状况,包括毒素休克,其可导致死亡。此类毒素可包括但不限于肠毒性大肠杆菌热不稳定肠毒素(LT)、热稳定肠毒素(ST)、志贺杆菌细胞毒素、气单胞菌肠毒素、中毒性休克综合征毒素-1(TSST-1)、葡萄球菌肠毒素A(SEA),B(SEB)或C(SEC)、链球菌肠毒素等等。此类细菌包括但不限于下述各项物种的菌株:肠毒性大肠杆菌(ETEC)、肠出血性大肠杆菌(例如血清型0157:H7的菌株)、葡萄球菌属物种(例如金黄色葡萄球菌(Staphylococcus aureus)、酿脓葡萄球菌(Staphylococcus pyogenes))、志贺杆菌属物种(例如痢疾志贺杆菌(Shigelladysenteriae)、弗氏志贺杆菌(Shigella flexneri)、鲍氏志贺杆菌(Shigella boydii)、和索氏志贺杆菌(Shigella sonnei))、沙门氏菌属物种(例如伤寒沙门氏菌(Salmonella typhi)、猪霍乱沙门氏菌(Salmonella cholera-suis)、肠炎沙门氏菌(Salmonella enteritidis))、梭菌属物种(例如产气荚膜梭菌(Clostridiumperfringens)、难辨梭菌(Clostridium dificile)、肉毒梭菌(Clostridiumbotulinum))、弯曲杆菌属物种(例如空肠弯曲杆菌(Camphlobacter jejuni)、胚胎弯曲杆菌(Camphlobacter fetus))、螺杆菌属物种(例如幽门螺杆菌(Heliobacter pylori))、气单胞菌属物种(例如温和气单胞菌(Aeromonassobria)、嗜水气单胞菌(Aeromonas hydrophila)、豚鼠气单胞菌(Aeromonascaviae))、类志贺邻单胞菌(Pleisomonas shigelloides)、小肠结肠炎耶尔森氏菌(Yersina enterocolitica)、弧菌属物种(例如霍乱弧菌(Vibrios cholerae)、副溶血弧菌(Vibrios parahemolyticus))、克雷伯氏菌属(Klebsiella)物种、铜绿假单胞菌(Pseudomonas aeruginosa)、和链球菌属(Streptococci)。参见例如Stein,ed.,INTERNAL MEDICINE,3rd ed.,pp 1-13,Little,Brown and Co.,Boston,(1990);Evans et al.,eds.,Bacterial Infections of Humans:Epidemiology and Control,2d.Ed.,pp 239-254,Plenum Medical Book Co.,New York(1991);Mandell et al,Principles and Practice of Infectious Diseases,3d.Ed.,Churchill Livingstone,N.Y.(1990);Berkow et al,eds.,The Merck Manual,16th edition,Merck and Co.,Rahway,N.J.,1992;Wood et al,FEMS Microbiology Immunology,76:121-134(1991);Marrack et al,Science,248:705-711(1990),通过述及将这些参考文献的内容完整收入本文。
本发明抗IL-6抗体化合物、组合物或组合可进一步包含至少一种任何合适辅助剂,诸如但不限于稀释剂、粘合剂、稳定剂、缓冲剂、盐、亲脂性溶剂、防腐剂、佐剂等等。药学可接受辅助剂是优选的。此类无菌溶液的非限制性例子和制备方法是本领域公知的,诸如但不限于Gennaro,Ed.,Remington′s Pharmaceutical Sciences,18th Edition,Mack Publishing Co.(Easton,Pa.)1990。药学可接受载体可常规选择,其适合抗IL-6抗体、片段或变体组合物的施用模式、溶解性和/或稳定性,如本领域公知的或如本文中描述的。
在本发明的组合物中有用的药物赋形剂和添加剂包括但不限于蛋白质、肽、氨基酸、脂质、和碳水化合物(例如糖,包括单糖、二糖、三糖、四糖、和寡糖;衍生糖,诸如(醛)糖醇、醛糖酸、酯化的糖等等;和多糖或糖聚合物),其可以单一或组合存在,包含单独的或以重量或体积计1-99.99%组合的。例示性的蛋白质赋形剂包括血清清蛋白诸如人血清清蛋白(HSA)、重组人清蛋白(rHA)、明胶、酪蛋白、等等。也能以缓冲能力发挥功能的代表性的氨基酸/抗体成分包括丙氨酸、甘氨酸、精氨酸、甜菜碱、组氨酸、谷氨酸、天冬氨酸、半胱氨酸、赖氨酸、亮氨酸、异亮氨酸。缬氨酸、甲硫氨酸、苯丙氨酸、天冬氨酰苯丙氨酸甲酯等等。一种优选的氨基酸是甘氨酸。
适合用于本发明的碳水化合物赋形剂包括例如单糖,诸如果糖、麦芽糖、半乳糖、葡萄糖、D-甘露糖、山梨糖、等等;二糖,诸如乳糖、蔗糖、海藻糖、纤维二糖、等等;多糖,诸如棉子糖、松三糖(melezitose)、糊精-麦芽糖复合物(maltodextrin)、葡聚糖/右旋糖苷(dextran)、淀粉、等等;和(醛)糖醇,诸如甘露醇、木糖醇、麦芽醇(maltitol)、拉克替醇(lactitol)、木糖醇(xylitol)山梨醇(sorbitol)(glucitol)、肌醇等等。在本发明中使用的优选碳水化合物赋形剂是甘露醇、海藻糖、和棉子糖。
抗IL-6抗体组合物还可包括缓冲剂或pH调节剂;通常,缓冲剂是自有机酸或碱制备的盐。代表性的缓冲剂包括有机酸盐,诸如柠檬酸、抗坏血酸、葡糖酸、碳酸、酒石酸、琥珀酸、乙酸、或酞酸的盐;Tris、盐酸氨丁三醇(tromethamine hydrochloride)、或磷酸盐缓冲剂。本发明组合物中使用的优选缓冲剂是有机酸盐,诸如柠檬酸盐。
另外,本发明的抗IL-6抗体组合物可包括聚合赋形剂/添加剂,诸如聚乙烯吡咯烷酮、Ficolls(一种聚合糖)、dextrates(例如环糊精,诸如2-羟基丙基-β-环糊精)、聚乙二醇、芳香剂、抗微生物剂、甜味剂、抗氧化剂、抗静电剂、表面活性剂(例如聚山梨酯诸如“TWEEN 20”和“TWEEN 80”)、脂质(例如磷脂、脂肪酸)、类固醇(例如胆固醇)、和螯合剂(例如EDTA)。
这些和别的适合于在依照本发明的抗IL-6抗体、部分或变体组合物中使用的已知药物赋形剂和/或添加剂是本领域已知的,例如″Remington:TheScience & Practice of Pharmacy″,19.sup.th ed.,Williams & Williams,(1995)和″Physician′s Desk Reference″,52nd ed.,Medical Economics,Montvale,N.J.(1998)中所列,通过述及将它们的公开内容完整收入本文。优选的载体或赋形剂材料是碳水化合物(例如糖和(醛)糖醇)和缓冲剂(例如柠檬酸盐)或聚合剂。
配制剂
如上所述,本发明提供了稳定的配制剂(其优选磷酸盐缓冲液及盐水或选择的盐),以及防腐的溶液和配制剂(其含有防腐剂)以及适合于药学或兽医用途的多次使用防腐配制剂,其在药学可接受配制剂中包含至少一种抗IL-6抗体。防腐配制剂在水性稀释剂中含有至少一种防腐剂或任选选自下组:至少一种酚,间甲酚,对甲酚,邻甲酚,氯甲酚,苯甲醇,亚硝酸苯汞,苯氧乙醇,甲醛,氯丁醇,氯化镁(例如六水合物),对羟基苯甲酸烃基酯(甲酯、乙酯、丙酯、丁酯等等),苯扎氯铵,苄索氯铵,脱氢乙酸钠和硫柳汞,或其混合物。可使用本领域已知的任何合适浓度或混合物,诸如0.001-5%,或其中的任何范围或数值,诸如但不限于0.001,0.003,0.005,0.009,0.01,0.02,0.03,0.05,0.09,0.1,0.2,0.3,0.4.,0.5,0.6,0.7,0.8,0.9,1.0,1.1,1.2,1.3,1.4,1.5,1.6,1.7,1.8,1.9,2.0,2.1,2.2,2.3,2.4,2.5,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4,3.5,3.6,3.7,3.8,3.9,4.0,4.3,4.5,4.6,4.7,4.8,4.9,或其中的任何范围或数值。非限制性例子包括无防腐剂,0.1-2%间甲酚(例如0.2,0.3.0.4,0.5,0.9,1.0%),0.1-3%苯甲醇(例如0.5,0.9,1.1.,1.5,1.9,2.0,2.5%),0.001-0.5%硫柳汞(例如0.005,0.01),0.001-2.0%酚(例如0.05,0.25,0.28,0.5,0.9,1.0%),0.0005-1.0%对羟基苯甲酸烃基酯(例如0.00075,0.0009,0.001,0.002,0.005,0.0075,0.009,0.01,0.02,0.05,0.075,0.09,0.1,0.2,0.3,0.5,0.75,0.9,1.0%),等等。
如上所述,本发明提供了制品,其包含包装材料和至少一个管形瓶,其中装有至少一种抗IL-6抗体及指定缓冲剂和/或防腐剂的溶液(任选在水性稀释剂中),其中所述包装材料包含标签,其指明此类溶液可保存1,2,3,4,5,6,9,12,18,20,24,30,36,40,48,54,60,66,72小时或更久的时段。本发明进一步包含如下的制品,其包含包装材料、装有冻干的至少一种抗IL-6抗体的第一管形瓶、和装有指定缓冲剂或防腐剂的水性稀释剂的第二管形瓶,其中所述包装材料包含标签,其指示患者在水性稀释剂中重建至少一种抗IL-6抗体以形成能保存24小时或更久的时段的溶液。
依照本发明使用的至少一种抗IL-6抗体可以通过重组手段来生产,包括来自哺乳动物细胞或转基因制备物,或者可以自其它生物学来源纯化,如本文中描述的或如本领域已知的。
本发明的产品中至少一种抗IL-6抗体的范围包括重建后产生的量,如果在湿的/干的系统中的话,约1.0ug/ml至约1000mg/ml的浓度,尽管更低或更高的浓度是可操作的且取决于预定的投递媒介,例如溶液配制剂会不同于透皮贴剂、肺、经粘膜、或渗透或微量泵方法。
优选地,水性稀释剂任选进一步包含药学可接受防腐剂。优选的防腐剂包括那些选自下组的:酚,间甲酚,对甲酚,邻甲酚,氯甲酚,苯甲醇,对羟基苯甲酸烃基酯(甲酯、乙酯、丙酯、丁酯等等),苯扎氯铵,苄索氯铵,脱氢乙酸钠和硫柳汞,或其混合物。配制剂中使用的防腐剂的浓度为足以产生抗微生物效果的浓度。此类浓度取决于所选择的防腐剂,而且是熟练技术人员易于确定的。
其它赋形剂,例如等张剂、缓冲剂、抗氧化剂、防腐剂增效剂,可任选和优选添加至稀释剂。通常以已知浓度使用等张剂,诸如甘油。优选添加生理学耐受的缓冲剂以提供改良的pH控制。配制剂可覆盖较宽范围的pH,诸如约pH4至约pH10,和约pH5至约pH9的优选范围,和约6.0至约8.0的最优选范围。优选地,本发明的配制剂具有介于约6.8和约7.8之间的pH。优选的缓冲剂包括磷酸盐缓冲剂,最优选磷酸钠,特别是磷酸盐缓冲盐水(PBS)。
其它添加剂,诸如药学可接受增溶剂,像Tween 20(聚氧乙烯(20)山梨聚糖单月桂酸酯)、Tween 40(聚氧乙烯(20)山梨聚糖单棕榈酸酯)、Tween 80(聚氧乙烯(20)山梨聚糖单油酸酯)、Pluronic F68(聚氧乙烯聚氧丙烯嵌段共聚物)、和PEG(聚乙二醇)或非离子型表面活性剂诸如聚山梨酯20或80或Poloxamer 184或188、Pluronic.RTM.polyls、其它嵌段共聚物、和螯合剂诸如EDTA和EGTA可任选添加至配制剂或组合物以降低聚集。如果使用泵或塑料容器来施用配制剂的话,这些添加剂是特别有用的。药学可接受表面活性剂的存在降低蛋白质聚集的倾向。
本发明的配制剂可通过如下过程来制备,其包括在水性稀释剂中混合至少一种抗IL-6抗体和选自下组的防腐剂:酚,间甲酚,对甲酚,邻甲酚,氯甲酚,苯甲醇,对羟基苯甲酸烃基酯(甲酯、乙酯、丙酯、丁酯等等),苯扎氯铵,苄索氯铵,脱氢乙酸钠和硫柳汞,或其混合物。在水性稀释剂中混合至少一种抗IL-6抗体和防腐剂是使用常规溶解和混合规程来进行的。为了制备稳定的配制剂,例如,以足以提供期望浓度的蛋白质和防腐剂的数量将缓冲溶液中实测量的至少一种抗IL-6抗体与缓冲溶液中期望的防腐剂组合。本领域普通技术人员会领会这种过程的变化。例如,成分的添加次序、是否使用另外的添加剂、制备配制剂的温度和pH都是可以为所使用的浓度和施用手段进行优化的因素。
要求保护的配制剂可作为清澈的溶液或作为双管形瓶(包括一管冻干的至少一种抗IL-6抗体,其用装有水、水性稀释剂中的防腐剂和/或赋形剂优选磷酸盐缓冲液和/或盐水和选择的盐的第二管形瓶重建)提供给患者。单一溶液管形瓶或需要重建的双管形瓶均能多次再使用,而且能满足单个或多个周期的患者处理,并因此能提供比当前可得的要更加方便的治疗方案。
本发明要求保护的制品对于立即至24小时或更久的时段的施用是有用的。因而,本发明要求保护的制品给患者提供显著优势。本发明的配制剂可任选安全地贮存于约2℃至约40℃的温度,并在较长的时间段保留蛋白质的生物学活性,如此容许包装标签指明溶液可以在6,12,18,24,36,48,72或96小时或更久的时段上保存和/或使用。如果使用防腐的稀释剂的话,此类标签可包括长达1-12个月、半年、1年半、和/或两年的使用。
本发明的至少一种抗IL-6抗体的溶液可通过如下过程来制备,其包括在水性稀释剂中混合至少一种抗体。混合是使用常规溶解和混合规程来进行的。为了制备合适的稀释剂,例如,以足以提供期望浓度的蛋白质和任选防腐剂或缓冲剂的量组合水或缓冲液中实测量的至少一种抗体。本领域普通技术人员会领会这种过程的变化。例如,成分的添加次序、是否使用另外的添加剂、制备配制剂的温度和pH都是可以为所使用的浓度和施用手段进行优化的因素。
要求保护的产品可作为清澈的溶液或作为双管形瓶(包括一管冻干的至少一种抗IL-6抗体,其用装有水性稀释剂的第二管形瓶重建)提供给患者。单一溶液管形瓶或需要重建的双管形瓶均能多次再使用,而且能满足单个或多个周期的患者的治疗,并因此能提供比当前可使用的要更加方便的治疗方案。
通过给药房、诊所、或其它此类机构和单位提供清澈的溶液或作为双管形瓶(包括一管冻干的至少一种抗IL-6抗体,其用装有水性稀释剂的第二管形瓶重建),要求保护的产品可间接提供给患者。这种情况中的清澈的溶液的体积可多达1升或甚至更大,提供一个大储库,自其可一次或多次取得至少一种抗体溶液的较小部分以转移入较小的管形瓶中,并由药房或诊所提供给它们的客户和/或患者。
包含这些单一管形瓶系统的公认装置包括那些用于投递溶液的笔式喷射器装置,诸如BD Pens,BD Autojector.RTM.,Humaject.RTM.,NovoPen.RTM.,B-D.RTM.Pen,AutoPen.RTM.,和OptiPen.RTM.,GenotropinPen.RTM.,Genotronorm Pen.RTM.,Humatro Pen.RTM.,Reco-Pen.RTM.,RoferonPen.RTM.,Biojector.RTM.,iject.RTM.,J-tip Needle-Free Injector.RTM.,Intraject.RTM.,Medi-Ject.RTM.,例如由Becton Dickensen(Franklin Lakes,N.J.,www.bectondickenson.com),Disetronic(Burgdorf,Switzerland,www.disetronic.com;Bioject,Portland,Oreg.(www.bioject.com);NationalMedical Products,Weston Medical(Peterborough,UK,www.weston-medical.com),Medi-Ject Corp(Minneapolis,Minn.,www.mediject.com)生产或开发的。包含双管形瓶系统的公认装置包括那些用于重建弹药筒中的冻干药物,用于投递重建的溶液的笔式喷射器系统,诸如HumatroPen.RTM。
当前要求包含的产品包括包装材料。在管理机构要求的信息之外,包装材料提供可使用该产品的状况。对于两个管形瓶的湿的/干的产品,本发明的包装材料给患者提供在水性稀释剂中重建至少一种抗IL-6抗体以形成溶液及在2-24小时或更久的时段里使用该溶液的指导。对于单一管形瓶,溶液产品,标签指明此类溶液可以在2-24小时或更久的时段里使用。当前要求保护的产品对于人类药学产品用途是有用的。
本发明的配制剂可通过如下过程来制备,其包括混合至少一种抗IL-6抗体和选择的缓冲剂,优选含有盐水或选择的盐的磷酸盐缓冲剂。在水性稀释剂中混合至少一种抗体和缓冲剂是使用常规溶解和混合规程来进行的。为了制备合适的配制剂,例如,以足以提供期望浓度的蛋白质和缓冲剂的量将水或缓冲液中实测量的至少一种抗体与水中期望的缓冲剂组合。本领域普通技术人员会领会这种过程的变化。例如,成分的添加次序、是否使用另外的添加剂、制备配制剂的温度和pH都是可以为所使用的浓度和施用手段进行优化的因素。
要求保护的稳定或防腐的配制剂可作为清澈的溶液或作为双管形瓶(包括一管冻干的至少一种抗IL-6抗体,其用装有水性稀释剂中的防腐剂或缓冲剂和赋形剂的第二管形瓶重建)提供给患者。单一溶液管形瓶或需要重建的双管形瓶均能多次再使用,而且能满足单个或多个周期的患者的治疗,并因此能提供比当前可利用的要更加方便的治疗方案。
本文中描述的稳定或防腐的配制剂或溶液中的至少一种抗IL-6抗体可依照本发明经多种投递方法施用于患者,包括SC或IM注射;经皮、肺、经粘膜、植入物、渗透泵、弹药筒、微量泵、或熟练技术人员领会的其它手段,如本领域公知的。
治疗应用
在本发明的一个实施方案中,包含本公开内容的抗IL-6抗体的药物组合物便于将人源化抗体施用于生物体,优选动物,优选哺乳动物。具体的哺乳动物包括牛、犬、马、猫、绵羊、和猪动物、非人灵长类动物、和人。人是特别优选的。
由于其多效活性,IL-6涉及多种疾病的病理。因此,针对IL-6的高亲和力的中和性嵌合或人抗体会希望用于IL-6相关疾病,诸如癌症、恶病质、SLE、类风湿性关节炎、骨质疏松、脑外伤、脑水肿、抑郁症、和CHF。在一个优选的方面,本公开内容的抗IL-6抗体可用于治疗类风湿性关节炎。抗IL-6抗体或这些单抗的任何衍生物(包括嵌合或人源化的)或片段可用于减轻骨痛,抑制肿瘤诸如黑素瘤、肾癌、前列腺癌、乳腺癌、肺癌、结肠癌和多发性骨髓瘤、淋巴增生性病症和IL-6所涉及的其它疾病的生长。这些抗体可作为单一药剂或与其它治疗剂组合使用。另外,这些单抗可用作化学敏化剂,由此它能提高细胞毒剂的治疗功效。这些抗体可用作放射敏化剂,由此它能提高辐射的功效。它们还可以与其它肿瘤免疫调控剂诸如IL-2、IL-12和/或IFNα组合使用。另外,抗IL-6抗体可以与其它单克隆抗体诸如抗TNF-α、IL-12/IL-23、IL-2、GpIIb/IIIa受体、CD52、CD20、RSV蛋白、HER2/neu受体、等等;以及与得到商业批准的抗体包括Rituxan、Herceptin、Mylotarg、Campath、Zevalin、Bexxar、Erbitux、Avastin和Vectibix组合使用。
如此,本发明还提供了用于在细胞、组织、器官、动物、或患者中调控或治疗至少一种IL-6相关疾病的方法,如本领域已知的或如本文中描述的,其使用本发明的至少一种抗IL-6抗体。
已知IL-6在多发性骨髓瘤(MM)中经由涉及抑制恶性细胞凋亡的自分泌或旁分泌机制增强恶性浆细胞的增殖、分化和存活。MM是一种无法治愈的恶性浆细胞病症,其中假定阻断IL-6是一种有效疗法(Anderson et al.,MultipleMyeloma:New Insights and Therapeutic Approaches.Hematology:147-165,2000)。IL-6还在基底细胞癌中具有致瘤效果,其中通过遏制凋亡和积极促进二者,经IL-6转染的细胞显示出升高的肿瘤生长速率(Jee et al.,Overexpression of interleukin-6 in human basal cell carcinoma cell linesincreases anti-apoptotic activity and tumorigenic potency.Oncogene,Vol.20,No.2pp.198-208,2001)。通过诱导mdr1基因表达(mdr1和金属硫蛋白途径),IL-6还能促进乳腺癌细胞对化疗的抗性(Conze et al,Autocrine Production ofInterleukin 6 Causes Multidrug Resistance in Breast Cancer Cells.Cancer Res 61:8851-8858,2001)。
IL-6介导肿瘤细胞存活和疾病进展的能力得到了抗IL-6单抗在体外和在体内二者对肿瘤生长的抑制效果的证实。有报告说在体外阻断IL-6能抑制人脑瘤(成胶质细胞瘤)的生长(Goswami et al.,interleukin-6-mediated autocrinegrowth promotion in human glioblastoma multiforme cell line U87MG.JNeurochem 71:1837-1845,1998)。使用相同的办法,显示了注射鼠CLB8抗IL-6抗体延长携带人肿瘤的小鼠的存活(Mauray et al.,Epstein-Barrvirus-dependent lymphoproliferative disease:critical role of IL-6.Eur J Immunol;30(7):2065-73,2000)。还有报告说mCLB8抗IL-6抗体在裸鼠中逆转人肾癌肿瘤的生长并降低血清钙浓度(Weisglass et al.,The role of interleukin-6 in theinduction of hypercalcemia in renal cell carcinoma transplanted into nude mice.Endocrinology 138(5):1879-8.,1995)。CLB-8抗体还在小鼠中逆转已建立的人激素不应性前列腺肿瘤异种移植物(Smith et al.2001)。抗IL-6单克隆抗体在裸鼠中诱导人前列腺癌异种移植物的消退(Smith and Keller,Prostate;48(1):47-53)。
IL-6还可以是恶性肿瘤的预后因子和标志物。在肾细胞癌(RCC)中,有报告说高IL-6水平与肿瘤转移和最终与较差的预后和较短的存活有关(Jean-Yves Blay et al.1992)。此外,在RCC中,升高的血清IL-6与较差的对IL-2疗法的响应有关(Fumagalli et al.1999,Pretreatment serum markers andlymphocyte response to interleukin-2 therapy.Br J Cancer 80(3-4):407-11),而且与IL-2相关毒性的程度有关(Capuron et al.2001,Association between immuneactivation and early depressive symptoms in cancer patients treated withinterleukin-2-based therapy.Psychoneuroendocrinology;26(8):797-808)。
升高的IL-6水平还与乳腺癌中较差的预后和转移性疾病的存在有关(Kurebayashi 2000 and Benoy 2002.Regulation of interleukin-6 secretion frombreast cancer cells and its clinical implications.Breast Cancer;7(2):124-9.Seruminterleukin 6,plasma VEGF,serum VEGF,and VEGF platelet load in breastcancer patients.Clin Breast Cancer;2(4):311-5)。
IL-6被假设是癌症相关发病诸如虚弱/恶病质和骨再吸收中的病因因素。发现肿瘤诱导的恶病质(Cahlin et al.2000)和骨再吸收(后续高钙血症)(Sandhu et al.1999)在IL-6敲除小鼠中降低。已经将脑瘤继发的癌症相关抑郁和脑水肿与高IL-6水平联系起来(Musselman et al.2001)。本发明的抗IL-6抗体还能在裸鼠中抑制人黑素瘤和人前列腺癌诱导的恶病质。
本发明包括用于在细胞、组织、器官、生物体或患者中调控或治疗至少一种恶性疾病的方法,所述恶性疾病包括但不限于以下至少一种:多发性骨髓瘤,白血病,急性白血病,急性成淋巴细胞性白血病(ALL),B细胞、T细胞或FAB ALL,急性髓样白血病(AML),慢性髓样白血病(CML),慢性淋巴细胞性白血病(CLL),毛细胞白血病,脊髓发育不良综合征(MDS),淋巴瘤,何杰金(Hodgkin)氏病,恶性淋巴瘤,非何杰金氏淋巴瘤,伯基特(Burkitt)氏淋巴瘤,多发性骨髓瘤,卡波西(Kaposi)氏肉瘤,结肠直肠癌,肾细胞癌,胰腺癌,前列腺癌,鼻咽癌,恶性组织细胞增生症,瘤周围综合征/恶性高钙血症,实体瘤,腺癌,肉瘤,恶性黑素瘤,血管瘤,转移性疾病,癌症相关骨再吸收,癌症相关骨痛;对癌症转移的遏制;癌症恶病质的改善;和对炎性疾病诸如系膜增生性肾小球肾炎等等的治疗。通过在施用此类IL-6抗体之前、并行或之后施用,此类方法可任选与放射疗法、抗血管发生剂、化疗剂、法尼基转移酶抑制剂等等组合使用。
本发明还提供了用于在细胞、组织、器官、生物体、动物、或患者中调控或治疗至少一种IL-6介导的免疫相关疾病的方法,所述免疫相关疾病包括但不限于以下至少一种:类风湿性关节炎,幼年型类风湿性关节炎,系统发作幼年型类风湿性关节炎,银屑病关节炎,强直性脊柱炎,胃溃疡,血清阴性关节病,骨关节炎(asteoarthritis),炎性肠病,溃疡性结肠炎,系统性红斑狼疮,抗磷脂综合征,虹膜睫状体炎/葡萄膜炎/视神经炎,特发性肺纤维化,系统性血管炎/韦格纳(Wegener)氏肉芽肿病,结节病,睾丸炎/输精管切除逆转术,变应性/特应性疾病,哮喘,变应性鼻炎,湿疹,变应性接触性皮炎,变应性结膜炎,超敏感性肺炎,移植物,器官移植物排斥,移植物抗宿主病,全身炎症反应综合征,脓毒病综合征,革兰氏阳性脓毒病,革兰氏阴性脓毒病,培养物阴性脓毒病,真菌性脓毒病,中性白细胞减少性发热,尿脓毒病,脑膜炎球菌血症,外伤/出血,烧伤,电离辐射暴露,急性胰腺炎,成人呼吸窘迫综合征,类风湿性关节炎,酒精诱发的肝炎,慢性炎性病理,结节病,克罗恩(Crohn)氏病理,镰状细胞贫血,糖尿病,肾病,特应性疾病,超敏感性反应,变应性鼻炎,枯草热,常年性鼻炎,结膜炎,子宫内膜异位症,哮喘,荨麻疹,系统性过敏反应,皮炎,恶性贫血,溶血性疾病,血小板减少,任何器官或组织的移植物排斥,肾移植物排斥,心移植物排斥,肝移植物排斥,胰移植物排斥,肺移植物排斥,骨髓移植物(BMT)排斥,皮肤同种异体移植物排斥,软骨移植物排斥,骨移植物排斥,小肠移植物排斥,胎儿胸腺植入物排斥,甲状旁腺移植物排斥,任何器官或组织的异种移植物排斥,同种异体移植物排斥,抗受体超敏感性反应,格雷夫斯(Graves)氏病,雷诺(Raynoud)氏病,B型胰岛素抗性糖尿病,哮喘,重症肌无力,抗体介导的细胞毒性,III型超敏感性反应,系统性红斑狼疮,POEMS综合征(多神经病,器官巨大症,内分泌病,单克隆丙种球蛋白病,和皮肤变化综合征),多神经病,器官巨大症,内分泌病,单克隆丙种球蛋白病,和皮肤变化综合征,抗磷脂综合征,天疱疮,硬皮病,混合性结缔组织病,特发性阿狄森(Addison)氏病,糖尿病,慢性活动性肝炎,原发性胆汁性肝硬化,白癜风,血管炎,MI心切开术后综合征,IV型超敏感性,接触性皮炎,超敏感性肺炎,同种异体移植物排斥,细胞内生物体所致肉芽肿,药物敏感性,代谢的/特发性的,威尔逊(Wilson)氏病,血色病,α-1-抗胰蛋白酶缺乏,糖尿病,桥本(Hashimoto)氏甲状腺炎,骨质疏松症,下丘脑-垂体-肾上腺轴评估,原发性胆汁性肝硬化,甲状腺炎,脑脊髓炎,恶病质,囊性纤维化病,新生儿慢性肺病,慢性阻塞性肺病(COPD),家族性噬红细胞性淋巴组织细胞增生症,皮肤病学状况,银屑病,脱发,肾病综合征,肾炎,肾小球肾炎,急性肾衰竭,血液透析,尿毒症,毒性反应,先兆子痫,okt3疗法,抗cd3疗法,细胞因子疗法,化学疗法,放射疗法(例如包括但不限于虚弱、贫血、恶病质、等等),慢性水杨酸盐/酯中毒,睡眠呼吸暂停,肥胖症,心力衰竭,窦炎,炎性肠病,等等。参见例如the Merck Manual,12th-17th Editions,Merck & Company,Rahway,N.J.(1972,1977,1982,1987,1992,1999),Pharmacotherapy Handbook,Wells et al.,eds.,Second Edition,Appleton and Lange,Stamford,Conn.(1998,2000),均提供述及而完整收录。
本发明还提供了用于在细胞、组织、器官、动物或患者中调控或治疗至少一种传染病的方法,所述传染病包括但不限于以下至少一种:急性或慢性细菌感染,急性和慢性寄生或传染过程,包括细菌、病毒和真菌感染,HIV感染/HIV神经病,脑膜炎,肝炎(甲型、乙型或丙型、等等),脓毒性关节炎,腹膜炎,肺炎,会咽炎,大肠杆菌0157:h7,溶血性尿毒症性综合征/血栓溶解性血小板减少性紫癜,疟疾、登革出血热,利什曼病,麻风病,中毒性休克综合征,链球菌肌炎,气性坏疽,结核分支杆菌(mycobacteriumtuberculosis)感染,细胞内鸟分支杆菌(mycobacterium avium intracellulare)感染,卡式肺囊虫(pneumocystis carinii)肺炎,骨盆炎性疾病,睾丸炎/附睾炎,军团杆菌属(legionella)感染,莱姆病,甲型流感,EB病毒感染,病毒(vital)相关噬血细胞综合征,致命性脑炎/无菌性脑膜炎,等等;
任何此类方法可任选包括对需要此类调控、处理或治疗的细胞、组织、器官、动物或患者施用有效量的包含至少一种抗IL-6抗体的至少一种组合物或药物组合物。用抗IL-6疗法治疗的适应症披露于下列参考文献,在此通过述及将它们收入本申请:Van Snick,″Interleukin-6:An Overview,″Ann.Rev.Immunol.,8:253-278(1990);Campbell et al.,″Essential Role forInterferon-gamma.And Interleukin-6 in Autoimmune Insulin-DependentDiabetes in NOD/Wehi Mice,″J.Clin.Invest,87:739-742(1991);Heinrich et al.,″Interleukin-6 Monoclonal Antibody Therapy for a Patient with Plasma CellLeukemia,″Blood,78(5):1198-1204(1991);Starnes et al.,″Anti-IL-6Monoclonal Antibodies Protect Against Lethal Escherichia coli Infection andLethal Tumor Necrosis Factor-alpha.Challenge in Mice,″J.Immunol.,145(12):4185-4191(1990);Strassman et al.,″Evidence for the Involvement ofinterleukin 6 in Experimental Cancer Cachexia,″J.Clin.Invest.,89:1681-1684(1992)。
本发明的任何方法可包括对需要此类调控、处理或治疗的细胞、组织、器官、动物或患者施用有效量的包含至少一种抗IL-6抗体的组合物或药物组合物。此类方法可任选进一步包括用于治疗此类免疫疾病或恶性疾病的共施用或组合疗法,其中施用所述至少一种抗IL-6抗体、其具体部分或变体进一步包括在之前、并行、和/或之后施用选自下述的至少一种:至少一种TNF拮抗剂(例如但不限于TNF抗体或片段、可溶性TNF受体或片段、其融合蛋白、或小分子TNF拮抗剂)、IL-18抗体或片段、小分子IL-18拮抗剂或IL-18受体结合蛋白、IL-1抗体(包括IL-1α和IL-1β二者)或片段、可溶性IL-1受体拮抗剂、抗风湿药(例如甲氨蝶呤、金诺芬、金硫代葡萄糖、硫唑嘌呤、依那西普、硫代苹果酸金钠、硫酸羟氯喹、来氟米特、柳氮磺吡啶、放射疗法、抗血管发生剂、化疗剂、沙利度胺、肌肉松弛药、麻醉药、非类固醇抗炎药(NSAID)、镇痛药、麻醉剂、镇静药、局部麻醉剂、神经肌肉阻断剂、抗微生物剂(例如氨基糖苷、抗真菌药、抗寄生物药、抗病毒药、碳青霉烯、头孢菌素、氟喹诺酮、大环内酯、青霉素、磺胺、四环素、其它抗微生物剂)、抗银屑病药、皮质类固醇、促蛋白合成类固醇、糖尿病相关药剂、矿物、营养物、甲状腺药剂、维生素、钙相关激素、红细胞生成素(例如epoetin α)、非格司亭(例如G-CSF,Neupogen)、沙莫司亭(GM-CSF,Leukine)、免疫、免疫球蛋白、免疫抑制药(例如巴利昔单抗、环孢霉素、达克珠单抗)、生长激素、激素替代药物、雌激素受体调控剂、扩瞳药、睫状肌麻痹剂、烷化剂、抗代谢药、有丝分裂抑制剂、放射学药物、抗抑郁药、抗躁狂剂、安定药、抗焦虑药、催眠药、拟交感神经药、兴奋剂、多奈哌齐、他克林、哮喘药物、β激动剂、吸入的类固醇、白三烯抑制剂、甲基黄嘌呤、色甘酸钠、肾上腺素或类似物、domase α(Pulmozyme)、细胞因子或细胞因子拮抗剂。合适的剂量是本领域公知的。参见例如Wells et al.,eds.,Pharmacotherapy Handbook,2nd Edition,Appleton and Lange,Stamford,Conn.(2000);PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000,Deluxe Edition,Tarascon Publishing,Loma Linda,Calif.(2000),均通过述及而完整收入本文。
适合于本发明的组合物、组合疗法、共施用、装置和/或方法(进一步包含本发明的至少一种抗体、其具体部分和变体)的TNF拮抗剂包括但不限于抗TNF抗体、其抗原结合片段、和特异性结合TNF的受体分子;阻止和/或抑制TNF合成、TNF释放或其对靶细胞的作用的化合物,诸如沙利度胺(thalidomide)、替尼达普(tenidap)、磷酸二酯酶抑制剂(例如己酮可可碱(pentoxifylline)和咯利普兰(rolipram))、A2b腺苷受体激动剂和A2b腺苷受体增强剂;阻止和/或抑制TNF受体信号传导的化合物,诸如丝裂原活化蛋白(MAP)激酶抑制剂;阻断和/或抑制膜TNF切割的化合物,诸如金属蛋白酶抑制剂;阻断和/或抑制TNF活性的化合物,诸如血管紧张素转化酶(ACE)抑制剂(例如卡托普利(captopril));和阻断和/或抑制TNF生成和/或合成的化合物,诸如MAP激酶抑制剂。
治疗处理
本发明的任何方法可包含用于治疗IL-6介导的病症的方法,包括对需要此类调控、处理或治疗的细胞、组织、器官、动物或患者施用有效量的包含至少一种抗IL-6抗体的组合物或药物组合物。此类方法可任选进一步包括用于治疗此类免疫疾病的共施用或组合疗法,其中施用所述至少一种抗IL-6抗体、其具体部分或变体进一步包括在之前、并行、和/或之后施用至少一种上文所述药剂。
通常,病理状况的处理通过施用有效量或有效剂量的至少一种抗IL-6抗体组合物来实现,总共,平均,范围为至少约0.01至500mg至少一种抗IL-6抗体每kg患者每剂,和优选至少约0.1至100mg抗体/kg患者每单次或多次施用,这取决于组合物中所含的比活性。或者,有效血清浓度可包含0.1-5000ug/ml血清浓度每单次或多次施用。合适的剂量是医学从业人员已知的,而且当然会取决于具体的疾病状态、所施用的组合物的比活性、和接受治疗的具体的患者。在一些情况中,为了实现期望的治疗量,可能需要提供重复施用,即重复各次施用特定监控或计量的剂量,其中重复各次施用直至实现期望的日剂量或效果。
优选的剂量可任选包括0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99和/或100-500mg/kg/施用,或其任何范围、数值或分数,或每单次或多次施用以实现0.1,0.5,0.9,1.0,1.1,1.2,1.5,1.9,2.0,2.5,2.9,3.0,3.5,3.9,4.0,4.5,4.9,5.0,5.5,5.9,6.0,6.5,6.9,7.0,7.5,7.9,8.0,8.5,8.9,9.0,9.5,9.9,10,10.5,10.9,11,11.5,11.9,20,12.5,12.9,13.0,13.5,13.9,14.0,14.5,4.9,5.0,5.5.,5.9,6.0,6.5,6.9,7.0,7.5,7.9,8.0,8.5,8.9,9.0,9.5,9.9,10,10.5,10.9,11,11.5,11.9,12,12.5,12.9,13.0,13.5,13.9,14,14.5,15,15.5,15.9,1.6,16.5,16.9,17,17.5,17.9,18,18.5,18.9,19,19.5,19.9,20,20.5,20.9,21,22,23,24,25,26,27,28,29,30,35,40,45,50,55,60,65,70,75,80,85,90,96,100,200,300,400,500,600,700,800,900,1000,1500,2000,2500,3000,3500,4000,4500和/或5000μg/ml的血清浓度,或其任何范围、数值或分数的血清浓度。
或者,施用的剂量可随已知的因素而变化,诸如具体药剂的药效学特征、及其施用模式和路径;接受者的年龄、健康状况、和体重;症状的性质和程度、并行治疗的种类、治疗的频率、和期望的效果。通常,活性组分的剂量可以是约0.1至100mg每kg体重。通常,0.1至50,优选0.1至10mg每kg体重每次施用或以持续释放形式给药以有效获得期望的结果。
作为一个非限制性例子,人类或动物的治疗可作为一次性或周期性剂量(periodic dosage)的至少一种本发明抗体来提供,所述剂量为0.1至100mg/kg,诸如0.5,0.9,1.0,1.1,1.5,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,40,45,50,60,70,80,90或100mg/kg每天,持续至少1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39或40天,或者或另外至少1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51或52周,或者/另外至少1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19或20年,或其任意组合,使用单一、输注、或重复剂量。
适合于内部施用的剂量形式(组合物)一般含有约0.1mg至约500mg活性组分每单位或容器。在这些药物组合物中,活性组分通常会以基于组合物的总重以重量计约0.5-99.999%的量存在。
胃肠外配制剂和施用
为了胃肠外施用,抗体可配制成溶液、悬浮液、乳状液或冻干粉末,其与药学可接受的胃肠外媒介联合或分开提供。此类媒介的例子是水、盐水、林格(Ringer)氏溶液、右旋糖/葡萄糖溶液、和1-10%人血清清蛋白。脂质体和非水性媒介,诸如不挥发性油也可使用。媒介或冻干粉末可含有维持等张性(例如氯化钠、甘露醇)和化学稳定性(例如缓冲剂和防腐剂)的添加剂。配制剂通过已知的或合适的技术来灭菌。
合适的药物载体记载于最新版的Remington′s Pharmaceutical Sciences,A.Osol,它是本领域的一份标准参考教科书。
用于胃肠外施用的配制剂可含有无菌水或盐水、聚烷撑二醇诸如聚乙二醇、植物起源的油、氢化萘等等作为常规赋形剂。用于注射的水性或油性悬浮液可通过依照已知方法使用适宜的乳化剂或增湿剂和悬浮剂来制备。用于注射的药剂可以是无毒、非口服施用的稀释剂,诸如水性溶液或溶剂中的无菌可注射溶液或悬浮液。作为可使用的媒介或溶剂,水、林格(Ringer)氏溶液、等张盐水、等是容许的;作为普通溶剂或悬浮溶剂,可使用无菌不挥发性油。为了这些目的,可使用任何种类的不挥发性油和脂肪酸,包括天然或合成或半合成脂肪油或脂肪酸;天然或合成或半合成甘油单或二或三酯。胃肠外施用是本领域已知,而且包括但不限于方便的注射手段、气体加压无针头注射装置如美国专利No.5,851,198中记载的、和激光射孔器装置如美国专利No.5,839,446中记载的,通过述及完整收入本文。
备选投递
本发明进一步涉及通过胃肠外、皮下、肌肉内、静脉内、关节内、支气管内、腹内、囊内、软骨内、腔内、体腔内、小脑内(intracelebellar)、脑室内、结肠内、颈内、胃内、肝内、心肌内、骨内、骨盆内、心包内、腹膜内、胸膜内、前列腺内、肺内、直肠内、肾内、视网膜内、脊柱内、滑膜内、胸内、子宫内、膀胱内、推注、阴道、直肠、含服、舌下、鼻内、或经皮手段来施用至少一种抗IL-6抗体。可制备至少一种抗IL-6抗体组合物供用于胃肠外(皮下、肌肉内或静脉内)或任何其它施用,特别是液体溶液或悬浮液的形式;用于阴道或直肠施用,特别是半固体的形式,诸如但不限于乳膏剂和栓剂;用于含服或舌下施用,诸如但不限于片剂或胶囊剂的形式;或鼻内,诸如但不限于粉剂、滴鼻剂或气雾剂或某些药剂的形式;或经皮,诸如但不限于凝胶剂、软膏剂、洗剂、悬浮液或贴剂投递系统,其具有化学增效剂,诸如诸如二甲亚砜来改变皮肤结构或提高透皮贴剂中的药物浓度(Junginger,et al.In″Drug Permeation Enhancement″;Hsieh,D.S.,Eds.,pp.59-90,MarcelDekker,Inc.New York 1994,通过述及完整收入本文),或具有氧化剂,其能够将含有蛋白质和肽的配制剂应用到皮肤上(WO 98/53847),或应用电场来创建瞬时运输途径,诸如电穿孔,或提高带电荷的药物穿过皮肤的移动性,诸如离子电渗,或应用超声波,诸如超声促渗(美国专利No.4,309,989和4,767,402)(通过述及将上述出版物和专利完整收入本文)。
肺/鼻施用
为了肺施用,以有效到达肺或窦的下气道的粒度投递优选至少一种抗IL-6抗体。依照本发明,至少一种抗IL-6抗体可通过本领域已知用于通过吸入来施用治疗剂的多种吸入或鼻腔装置中的任一种来投递。这些能够在患者的窦腔或肺泡中沉积气雾化配制剂的装置包括计量吸入器、雾化器、干粉生成器、喷雾器、等等。本领域还知道其它适合于指导抗体的肺或鼻施用的装置。所有此类装置可使用适合于施用的配制剂,用于在气雾剂中分配抗体。此类气雾剂可包含溶液(水性的和非水性的二者)或固体颗粒。计量吸入器像Ventolin.RTM.计量吸入器通常使用推进气体且需要在吸气期间开启(参见例如WO 94/16970,WO 98/35888)。干粉吸入器像Turbuhaler.TM.(Astra)、Rotahaler.RTM.(Glaxo)、Diskus.RTM.(Glaxo)、Spiros.TM.吸入器(Dura)、由Inhale Therapeutics销售的装置、和Spinhaler.RTM.粉剂吸入器(Fisons)使用混合粉剂的呼吸开启(美国专利No.4,668,218 Astra,EP 237507 Astra,WO97/25086 Glaxo,WO 94/08552 Dura,美国专利No.5,458,135 Inhale,WO94/06498 Fisons,通过述及而完整收入本文)。雾化器像AERx.TM.Aradigm、Ultravent.RTM.雾化器(Mallinckrodt)、和Acorn II.RTM.雾化器(MarquestMedical Products)(美国专利No.5,404,871 Aradigm,WO 97/22376)(通过述及将上述参考文献完整收入本文)自溶液生成气雾剂,而计量吸入器、干粉吸入器等生成小颗粒气雾剂。商品化吸入装置的这些具体例子意图代表适合于实施本发明的具体装置,并非意图限制本发明的范围。优选地,包含至少一种抗IL-6抗体的组合物通过干粉吸入器或喷雾器来投递。用于施用至少一种本发明抗体的吸入装置有数项期望特征。例如,有利的是,通过吸入装置进行的投递是可靠,可再现,和精确的。为了较好地呼吸,吸入装置能任选运送小的干的颗粒,例如小于约10μm,优选约1-5μm的颗粒。
IL-6抗体组合物作为喷雾的施用
包括IL-6抗体组合物蛋白质的喷雾可以通过在压力下迫使至少一种抗IL-6抗体的悬浮液或溶液穿过喷嘴来生成。可选择喷嘴的尺寸和构造、应用的压力、和液体进料速率来实现期望的输出和粒度。电子喷雾可通过例如与毛细或喷嘴进料联合的电场来生成。有利地是,通过喷雾器投递的至少一种抗IL-6抗体组合物蛋白质具有小于约10μm,优选约1μm至约5μm,和最优选约2μm至约3μm范围中的粒度。
适合于与喷雾器一起使用的至少一种抗IL-6抗体组合物蛋白质的配制剂通常包括水性溶液中的抗体组合物蛋白质,其浓度为每ml溶液或mg/gm约0.1mg至约100mg至少一种抗IL-6抗体组合物蛋白质,或该范围内的任何范围或数值,例如但不限于0.1,0.2.,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,40,45,50,60,70,80,90或100mg/ml或mg/gm。配制剂可包括诸如赋形剂、缓冲剂、等张剂、防腐剂、表面活性剂、和优选的锌等药剂。配制剂还可包括赋形剂或用于稳定抗体组合物蛋白质的药剂,诸如缓冲剂、还原剂、填充蛋白、或碳水化合物。在配制抗体组合物蛋白质中有用的填充蛋白包括清蛋白、鱼精蛋白、等等。在配制抗体组合物蛋白质中有用的典型碳水化合物包括蔗糖、甘露醇、乳糖、海藻糖、葡萄糖、等等。抗体组合物蛋白质配制剂还可包括表面活性剂,其能降低或阻止表面诱导的抗体组合物蛋白质聚集,其是由形成气雾剂时溶液的雾化引起的。可采用多种常规表面活性剂,诸如聚氧乙烯脂肪酸酯和醇,和聚氧乙烯山梨醇脂肪酸酯。量的范围一般会介于0.001和14%之间,以配制剂的重量计。为了本发明的目的尤其优选的表面活性剂是聚氧乙烯山梨聚糖单油酸酯、聚山梨酯80、聚山梨酯20、等等。本领域已知用于配制蛋白质诸如IL-6抗体、或具体部分、或变体的的别的药剂也可包括在配制剂中。
IL-6抗体组合物通过雾化器的施用
抗体组合物蛋白质可通过雾化器,诸如喷射雾化器或超声雾化器来施用。通常,在喷射雾化器中,使用加压气体源来产生高速气体喷射穿过喷口。随着气体离开喷嘴膨胀,产生低压区,其吸引抗体组合物蛋白质的溶液穿过连接液体储库的毛细管。随着它离开管,来自毛细管的液体流被剪切成不稳定的细丝和小滴,产生气雾剂。可采用一定范围的构造、流速、和挡板类型以实现来自给定的喷射雾化器的期望的性能特征。在超声雾化器中,使用高频电能来产生震动、机械能,通常采用压电换能器。这种能被传递给抗体组合物蛋白质的配制剂,或是直接地或是经由耦合液,产生包括抗体组合物蛋白质的气雾剂。有利的是,通过雾化器投递的抗体组合物蛋白质的颗粒具有小于约10μm,优选约1μm至约5μm,和最优选约2μm至约3μm范围的粒度。
适合于与雾化器(喷射的或超声的任一)一起使用的至少一种抗IL-6抗体的配制剂通常包括约0.1mg至约100mg的至少一种抗IL-6抗体蛋白质每ml溶液的浓度。配制剂可包括诸如赋形剂、缓冲剂、等张剂、防腐剂、表面活性剂、和优选的锌等药剂。配制剂还可包括赋形剂或用于稳定至少一种抗IL-6抗体组合物蛋白质的药剂,诸如缓冲剂、还原剂、填充蛋白、或碳水化合物。在配制至少一种抗IL-6抗体组合物蛋白质中有用的填充蛋白包括清蛋白、鱼精蛋白、等等。在配制至少一种抗IL-6抗体中有用的典型碳水化合物包括蔗糖、甘露醇、乳糖、海藻糖、葡萄糖、等等。至少一种抗IL-6抗体配制剂还可包括表面活性剂,其能降低或阻止表面诱导的至少一种抗IL-6抗体聚集,其是由形成气雾剂时溶液的雾化引起的。可采用多种常规表面活性剂,诸如聚氧乙烯脂肪酸酯和醇,和聚氧乙烯山梨醛(sorbital)脂肪酸酯。量的范围一般会介于0.001和4%之间,以配制剂的重量计。为了本发明的目的尤其优选的表面活性剂是聚氧乙烯山梨聚糖单油酸酯、聚山梨酯80、聚山梨酯20、等等。本领域已知用于配制蛋白质诸如抗体蛋白质的别的药剂也可包括在配制剂中。
通过计量吸入器施用IL-6抗体组合物
在计量吸入器(MDI)中,推进剂、至少一种抗IL-6抗体、和任何赋形剂或其它添加剂作为包括液化压缩气体的混合物装在罐中。计量阀的开启作为气雾剂释放管芯混合物,优选含有大小范围小于约10μm、优选约1μm至约5μm、和最优选约2μm至约3μm的颗粒。期望的气雾剂粒度可通过采用以本领域技术人员知道的多种技术生成的抗体组合物蛋白质配制剂来获得,包括喷射-研磨、喷雾干燥、临界点冷凝、等等。优选的计量吸入器包括那些由3M或Glaxo制造及采用含氟烃推进剂的。
与计量吸入器装置一起使用的至少一种抗IL-6抗体配制剂一般会包括含有至少一种抗IL-6抗体的磨碎的粉末,作为非水性介质中的悬浮液,例如在表面活性剂的帮助下悬浮在推进剂中。推进剂可以是用于此目的的任何方便材料,诸如含氯氟烃(chlorofluorocarbon)、含氯氟烃(hydrochlorofluorocarbon)、含氟烃(hydrofluorocarbon)、或烃,包括三氯氟甲烷、二氯二氟甲烷、二四氟乙烷和1,1,1,2-四氟乙烷、HFA-134a(含氟烷-134a)、HFA-227(含氟烷-227)、等等。优选地,推进剂是含氟烃。可选择表面活性剂来稳定作为推进剂中悬浮液的至少一种抗IL-6抗体,以通过抗化学降解等等来保护活性剂。合适的表面活性剂包括山梨聚糖三油酸酯、大豆卵磷脂、油酸、等等。在一些情况中,优选溶液气雾剂,其使用诸如乙醇等溶剂。本领域已知用于配制蛋白质的别的试剂也可包括在配制剂中。
本领域普通技术人员会认识到,本发明的方法可通过经本文中未描述的装置肺部施用至少一种抗IL-6抗体组合物来实现。
口服配制剂和施用
用于口服施用的配制剂依赖于共施用佐剂(例如间苯二酚/雷琐辛和非离子型表面活性剂诸如聚氧乙烯油基醚和正十六烷基聚乙烯醚)来人为提高肠壁的通透性,以及共施用酶抑制剂(例如胰脏胰蛋白酶抑制剂、二异丙基氟磷酸酯(DFF)和特斯乐(trasylol))来抑制酶促降解。用于口服施用的固体型剂量形式的活性组分化合物可混合至少一种添加剂,包括蔗糖、乳糖、纤维素、甘露醇、海藻糖、棉子糖、麦芽糖醇、右旋糖苷/葡聚糖、淀粉、琼脂、精氨酸盐、甲壳质、壳聚糖、果胶、黄蓍胶、阿拉伯胶、明胶、胶原、酪蛋白、清蛋白、合成或半合成聚合物、和甘油酯。这些剂量形式还可含有其它类型的添加剂,例如无活性的稀释剂、润滑剂诸如硬脂酸镁、对羟基苯甲酸酯、防腐剂诸如山梨酸、抗坏血酸、α-生育酚、抗氧化剂诸如半胱氨酸、崩解剂、粘合剂、增稠剂、缓冲剂、甜味剂、芳香剂、增香剂等。
片剂和丸剂可进一步加工成包有肠溶衣的制剂。用于口服施用的液体制剂包括容许医疗用途的乳状液、糖浆剂、酏剂、悬浮液和溶液制剂。这些制剂可含有所述领域常规使用的无活性稀释剂,例如水。脂质体也有记载作为胰岛素和肝素的药物投递系统(美国专利No.4,239,754)。最近,混合氨基酸的人造聚合物(类蛋白质)的微球体已经用于投递药剂(美国专利No.4,925,673)。另外,本领域已知美国专利No,5,879,681和美国专利No.5,5,871,753中记载的载体化合物用于口服投递生物学活性剂。
粘膜配制剂和施用
对于穿过粘膜表面的吸收,施用至少一种抗IL-6抗体的组合物和方法包括乳剂,其包含多数亚微米颗粒、粘膜附着性大分子、生物活性肽、和水性连续相,通过实现乳剂颗粒的粘膜附着来促进穿过粘膜表面的吸收(美国专利No.5,514,670)。适合于应用本发明乳剂的粘膜表面可包括角膜、结膜、口腔、舌下、鼻、阴道、肺、胃、肠、和直肠施用路径。用于阴道或直肠施用的配制剂(例如栓剂)可含有例如聚烷撑二醇、凡士林、可可脂、等等作为赋形剂。用于鼻内施用的配制剂可以是固体且含有例如乳糖作为赋形剂,或者可以是水性或油性溶液滴鼻剂。对于含服施用,赋形剂包括糖、硬脂酸钙、硬脂酸镁、pregelinatined淀粉、等等(美国专利No.5,849,695)。
经皮配制剂和施用
对于经皮施用,将至少一种抗IL-6抗体封装在投递装置中,诸如脂质体或聚合纳米颗粒、微粒、微胶囊、或微球体(共同称作微粒,除非另有说明)。许多合适装置是已知的,包括合成聚合物,诸如聚羟基酸诸如聚乳酸、聚乙醇酸及其共聚物,聚正酯,聚酐,和聚磷腈,及天然聚合物诸如胶原,多聚氨基酸、清蛋白和其它蛋白质,藻酸盐和其它多糖,及其组合(美国专利No.5,814,599)制成的微粒。
延长的施用和配制剂
有时可能希望自单次施用在延长的时间段里将本发明的化合物投递至受试者,例如1周至1年的时段。可使用多种缓慢释放、贮库(depot)或植入物剂量形式。例如,剂量形式可含有化合物的药学可接受的无毒的盐,其在体液中具有低度的溶解度,例如(a)与多元酸诸如磷酸、硫酸、柠檬酸、酒石酸、鞣酸/单宁酸、扑酸/巴莫酸、海藻酸、多聚谷氨酸、萘单或二磺酸、多聚半乳糖醛酸、等等的酸加成盐;(b)与多价金属阳离子诸如锌、钙、铋、钡、镁、铝、铜、钴、镍、镉等等或者与自例如N,N′-二苄基-乙二胺或乙二胺形成的有机阳离子的盐;或(c)(a)和(b)的组合,例如锌鞣酸/单宁酸盐。另外,本发明的化合物或(优选地)相对不溶的盐诸如刚刚描述的那些可在适合于注射的带例如芝麻油的凝胶,例如单硬脂酸铝凝胶中配制。特别优选的盐是锌盐、鞣酸/单宁酸锌盐、扑酸/巴莫酸盐、等等。另一类注射用缓慢释放贮库配制剂会含有为在缓慢降解的无毒无抗原性聚合物诸如聚乳酸/聚乙醇酸聚合物(例如如美国专利No.3,773,919中记载的)中封装而分散的化合物或盐。化合物或(优选地)相对不溶的盐诸如上文所述那些还可在胆固醇基质硅橡胶弹丸剂中配制,特别是用于动物。别的缓慢释放、贮库或植入物配制剂,例如气体或液体脂质体是文献中已知的(美国专利No.5,770,222和″Sustainedand Controlled Release Drug Delivery Systems″,J.R.Robinson ed.,MarcelDekker,Inc.,N.Y.,1978)。
缩写:
BSA--牛血清清蛋白
EIA--酶免疫测定法
FBS--胎牛血清
H2O2--过氧化氢
HRP--辣根过氧化物酶
Ig--免疫球蛋白
IL-6--白介素-6
IP--腹膜内
IV--静脉内
Mab--单克隆抗体
OD--光密度
OPD--邻苯二胺二盐酸盐
PEG--聚乙二醇
PSA--青霉素、链霉素、两性霉素
RT--室温
SQ--皮下
v/v--体积/体积(体积比)
w/v--重量/体积(重量体积比)
实施例1:亲和和定量ELISA。
用IL-6进行的亲和ELISA
将Nunc-Immuno MaxiSorp 96孔板用100μl 2μg/ml,0.2μg/ml,0.02μg/ml或0.002μg/ml IL-6在包被溶液中包被;覆盖板密封器并于4℃温育过夜。将板倒空并将残余液体在纸巾上扣出。添加200μl清洗溶液(含0.05% Tween-20的PBS)并以200RPM于室温摇动5分钟。将板倒空并将残余液体在纸巾上扣出。添加200μl封闭溶液(含2% Carnation牛奶的PBS)并以200RPM于室温摇动1小时。将板倒空并将残余液体在纸巾上扣出。将100μl稀释样品用于ELISA。将样品以200RPM于室温摇动1小时;将板倒空并将残余液体在纸巾上扣出。添加200μl清洗溶液(含0.05% Tween-20的PBS),以200RPM于室温摇动5分钟;将板倒空并将残余液体在纸巾上扣出。这个过程重复三次。为001样品添加100μl在封闭溶液(含2% Carnation牛奶的PBS)中1∶2500稀释的偶联有HRP的抗人IgG。为对照抗体添加100μl在封闭溶液(含2% Carnation牛奶的PBS)中1∶2500稀释的偶联有HRP的抗家兔IgG。将内容物以200RPM于室温摇动1小时,将板倒空并将残余液体在纸巾上扣出。添加200μl清洗溶液(含0.05% Tween-20的PBS),以200RPM于室温摇动5分钟;将板倒空并将残余液体在纸巾上扣出。这个过程重复三次。添加100μl TMB底物溶液,并于室温温育。用1 N HCl终止反应,并于450nm读板。
用生物素化IL-6进行的亲和ELISA
将Nunc-Immuno MaxiSorp 96孔板用100μl 10μg/ml亲和纯化的Fc特异性山羊抗人IgG在包被溶液中包被。给板覆盖板密封器并于4℃温育过夜。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。添加200μl封闭溶液(含2% Carnation牛奶的PBS)。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。为ELISA使用100μl稀释样品。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。重复三次。添加100μl在PBS中稀释的2μg/ml,0.2μg/ml,0.02μg/ml或0.002μg/ml生物素化IL-6。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。重复三次。添加100μl在封闭溶液(含2% Carnation牛奶的PBS)中1∶2000稀释的偶联有HRP的抗生物素抗体。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加100μl TMB底物溶液。于室温温育。用1 N HCl终止反应。于450nm读板。
定量ELISA
此ELISA用于测定细胞培养物上清液中的抗体表达水平。将Nunc-Immuno MaxiSorp 96孔板(Nalge Nunc)用100μl 10μg/ml亲和纯化的Fc特异性山羊抗人IgG在包被溶液中包被。覆盖板密封器并于4℃温育过夜。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。添加200μl封闭溶液(含2% Carnation牛奶的PBS)。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。为ELISA使用100μl稀释样品。为标准品使用20ng/ml人IgG及此后1∶2稀释液。为测定,将来自转染的上清液(50ng-200ng/ml)自原样稀释至1∶10。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。重复三次。添加100μl在封闭溶液(含2% Carnation牛奶的PBS)中1∶2500或1∶5000稀释的偶联有HRP的山羊抗人IgG。以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加100μl TMB底物溶液(Sigma)。于室温温育。用1 N HCl终止反应。于450nm读板。
比活性
每一种抗IL-6单抗的比ELISA活性以亲和ELISA的值除以定量ELISA的值来计算。图29显示了来自亲和力成熟的前10名CPE命中的标准化比活性。图32显示了前10名CPS命中的标准化比活性。克隆的比ELISA活性除以克隆BA399的比活性。BA399的标准化比活性为1(水平黑色线)。
001的功能ELISA
此ELISA用于比较细胞培养物上清液中抗体的亲和力。将NuncImmuno-MaxiSorp 96孔板用100uL 2μg/ml 001 IL-6抗原包被并于4℃温育过夜。将板倒空,清洗(含0.05% Tween-20的PBS)并用含2% Carnation脱脂奶的PBS于室温封闭1小时。使用20ng/ml抗001对照抗体及此后1∶2稀释液作为标准品。将双份100uL来自转染的上清液自原样稀释至1∶50供测定用(50ng-200ng/ml)并添加至板,于室温1小时。将板倒空并清洗3次。向每个孔添加100μl在封闭溶液(含2% Carnation牛奶的PBS)中1∶5000稀释的偶联有HRP的山羊抗人IgG,以200RPM于室温摇动1小时。将板倒空并清洗。添加100μl TMB底物溶液(Sigma)并于室温温育;每2-5分钟检查。用1 N HCl终止反应。于450nm读板。
实施例2:竞争ELISA以确认BA001和本发明抗IL-6抗体之间的表位交叠。
将Nunc-Immuno MaxiSorp 96孔板用100μl 0.2μg/ml IL-6在包被溶液中包被(为实验准备足够的孔)。覆盖板密封器并于4℃温育过夜。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。将板以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。添加200μl封闭溶液(含2% Carnation牛奶的PBS)。将板以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加100ul在PBS中稀释的0.05μg/ml生物素化001及0μg/ml,0.005μg/ml,0.05μg/ml,0.5μg/ml,5μg/ml纯化的001抗体(为每一种纯化的001抗体量准备两个实验)。还添加100μl在PBS中稀释的0.05μg/ml生物素化001及0μg/ml,0.005μg/ml,0.05μg/ml,0.5μg/ml,5μg/ml非抗IL6抗体(任何抗小鼠IgG或其它阴性对照抗体)(为每一种纯化的001抗体量准备两个实验)。将板以200RPM于室温摇动1小时。倒空板并在纸巾上扣出残余液体。添加200μl清洗溶液(含0.05% Tween-20的PBS)。将板以200RPM于室温摇动5分钟。倒空板并在纸巾上扣出残余液体。重复三次。添加100μl在封闭溶液(含2% Carnation牛奶的PBS)中1∶2000稀释的偶联有HRP的抗生物素抗体。将板以200RPM于室温摇动1小时。倒空板和在纸巾上扣出残余液体。添加100μl TMB底物溶液。于室温温育。用1 N HCl终止反应。于450nm读板。结果列于图10。如显示的,所有本发明抗IL-6抗体降低BA001对人IL6的结合。这指示新型人源化抗体与BA001结合相同区域。
实施例3:CHO-S细胞转染。
转染前1周,将CHO-S细胞(Invitrogen)转移至补充有血清的Dulbecco氏改良Eagle培养基(D-MEM)(Invitrogen)中的单层培养。转染前1天,以96孔形式为每一份转染样品在100uL补充有血清的D-MEM中分配0.4x105个细胞。为每一份转染样品制备DNA-Lipofectamine复合物。在25uL Opti-MEM血清减少培养基中稀释0.25ug DNA并温和混合,并于室温温育5分钟。在25uLOpti-MEM血清减少培养基中稀释0.5uL Lipofectamine 2000(Invitrogen)。温和混合并于室温温育5分钟。组合稀释的DNA与稀释的Lipofectamine。温和混合并于室温温育20分钟。向每一个装有细胞和培养基的孔添加50uLDNA-Lipofectamine复合物。通过摇动板来温和混合。将细胞于37℃在5% CO2温箱中温育过夜。吸出每一个孔中的培养基。向每一个孔添加100uL补充有血清的D-MEM。为ELISA测定法收集上清液,并为β-半乳糖苷酶测定法收集细胞溶胞物。
实施例4:自细胞培养物上清液纯化抗体。
以标准方式制备下述缓冲液。结合缓冲液:10mM Na2HPO4/NaH2PO4,pH7.0。洗脱缓冲液:12.5mM柠檬酸,pH2.7(使用柠檬酸三钠)。中和缓冲液:0.5M Na2HPO4/NaH2PO4,pH8.0。20%乙醇和水。所有缓冲液在使用前过滤(0.45μm)。上清液使用配有HiTrapTM蛋白G Sepharose HP(1mL体积)柱的FPLCTM系统来纯化。为了样品加载,将加载管用乙醇(20mL,5mL/min),然后用结合缓冲液(20mL,5mL/min)漂洗。将蛋白G柱装上系统并用结合缓冲液(10mL,1mL/mn)漂洗。以1mL/min或更慢(用于过夜加载)加载样品。加载后,将柱拆下并将加载管用水(20mL,5mL/min),然后用20%乙醇(20mL,5mL/min)漂洗。为了抗体纯化,用结合缓冲液清洗AKTA系统(A泵和所有管道)。通过向每一个管体积50μl中和缓冲液,为级分收集准备收集管。将蛋白G柱装上系统。流速设为1mL/min,并运行直至基线稳定。将柱阀换至位置3。用结合缓冲液(最少10mL)清洗柱直至达到基线。关闭泵并用水,然后用洗脱缓冲液清洗。流速设为1mL/min,并运行直至基线稳定。将柱阀换至位置3并启动级分收集器(0.5mL级分)。收集级分直至达到基线,此时关闭系统。将洗脱图谱拷贝至剪贴板,拷贝成WORD文件。用水,然后用结合缓冲液清洗泵。用结合缓冲液(10mL)清洗蛋白G柱。用20%乙醇清洗泵。用20%乙醇(20mL)清洗柱,贮藏于冷室。
实施例5:Sapidyne分析。
使用Sapidyne KinExATM动力学排阻测定法自动化免疫测定系统(Sapidyne Instruments,Inc.,Boise,ID)依照制造商的方案来测定各种抗体的平衡和速率常数。动力学排阻测定法(Kinetic Exclusion Assay)(KinExA)是一种对未修饰的分子在溶液相中测量真实平衡结合亲和力和动力学的方法。参见例如Darling et al.,Kinetic Exclusion Assay Technology:Characterization ofMolecular Interactions,ASSAY and Drug Dev.Technol.2(6):2004,通过述及而收入本文。简言之,KinExATM系统包含毛细流动/观察室(内径=1.6mm),配有微孔筛,各种溶液在负压下穿过它。比筛的平均孔径(53mm)要大的均一颗粒用抗原预包被并在填充床中保留在筛之上。然后使处于或接近平衡的抗原和抗体的各溶液混合物穿过填充床。每一种混合物中只有那些结合位点未被占据的抗体可供结合固相上包被的抗原。对如此被捕捉的一抗的定量可通过将颗粒简短暴露于荧光标记的抗物种二抗,接着测量清除过量的未结合的试剂后来自颗粒的所得荧光来实现。
将抗体在无菌1X PBS,pH7.4,0.02%叠氮钠,10mg/mL BSA中重建。抗原是IL-6(21,000kDa),在四个分开的管形瓶中,为0.5mg,1mg,0.5mg和0.5mg,用无菌1X PBS,pH7.4,0.02%叠氮钠稀释至375ug/mL,1mg/mL,500ug/mL和500ug/mL。标记物Cy5偶联的AffiniPure山羊抗人IgG(H+L),Cy5,1.5μg/mL购自Jackson ImmunoResearch(West Grove,PA)。将标记物在无菌1XPBS,pH7.4,0.02%叠氮钠中重建,并稀释至0.500mg/mL。运行缓冲液是1XPBS,pH7.4,0.02%叠氮钠。样品缓冲液是1X PBS,pH7.4,0.02%叠氮钠,1mg/mL牛血清清蛋白(BSA)。PMMA珠(Part# 440197/Lot3257)由SapidyneInstruments,Inc.(Boise,ID)提供并以下述方式用捕捉试剂包被。将干的珠等分成200mg部分并在1mL包被溶液(含30ug/mL BAP001的运行缓冲液)中摇动2小时。然后将珠在封闭溶液(含10mg/mL BSA的运行缓冲液)中摇动1小时并贮藏于4℃。
为了平衡分析,使用经IL-6包被的PMMA珠自受体(抗IL-6抗体)和配体(抗原;IL-6)的平衡样品捕捉一部分游离受体。为了每一个数据点,将一个经配体包被的珠的新鲜柱引入流动室。使平衡样品快速穿过柱以使与固定化配体的接触时间最小化。这确保与固定化配体的接触时间不破坏样品平衡。如此固定化配体起探针的作用来捕捉溶液中的游离受体。用荧光标记的抗人二抗来检测被捕捉的抗体。洗掉未结合的试剂,留下与平衡样品中的游离受体成比例的信号。荧光转变成与平衡样品中的游离受体(抗体)量成正比的电压。以高和低受体浓度二者运行实验,然后一起用于n-曲线分析以获得最佳结果。为了动力学分析的直接方法,动力学实验使用与平衡实验相同的固定化配体(经IL-6包被的PMMA)作为捕捉试剂。在平衡前测量样品中的游离受体(抗体)量,随着样品朝向平衡移动,产生监测游离受体(抗体)随时间而降低的数据点。图33显示了与BA003(CNTO136)相比,来自前10名命中抗IL6抗体BAP001-克隆1至BAP001-克隆10的Sapidyne分析数据表。
实施例6:BA001和人源化衍生物的Biacore(表面等离振子共振)亲和力测量。
使用BIAcore 3000,GE Healthcare来测定结合曲线和动力学参数。将一种抗人Fc(1.8mg/ml)在NaOAc缓冲液(10mM,pH4.8)中稀释至浓度50ug/ml并偶联至CM-5传感器芯片的羧甲基化右旋糖苷基质,使用制造商的胺偶联化学如BIAcore系统手册中所述进行。使用目标为10000RU的表面制备向导,首先用NHS/EDC活化传感器表面上的羧基,接着添加抗人Fc。通过注射1M乙醇胺来封闭剩余的活化的基团。个别地偶联每一个流动室。采用这些条件,准备了含有7554-9571RU抗人Fc的四个流动室表面。在预备实验中,确定了三次注射(15ul,30ul/min)100mM H3PO4/0.05% CHAPS会有效清除结合的免疫球蛋白并保留固定化抗人Fc的结合能力。
在BIAcore 3000上于25℃以流速30ul/min实施实验。将抗体候选在HBS(10mM HEPES含0.15M NaCl,3.4mM EDTA和0.05%表面活性剂P20,pH7.4)中溶解为5ug/ml。将分析物IL-6在HBS中溶解为0.25,0.125,0.062,0.031和0.015ug/ml。使3*30ul 5ug/ml抗体BA001流过其各自流动室,接着以30ul/min注射240ul每一种IL-6浓度(结合期)及不间断的1200秒缓冲液流(解离期)。通过三次序贯注射,每次15ul 100mM H3PO4/0.05% CHAPS来再生芯片的表面。HBS注射充当参照(空白传感图),用于扣除容积(bulk)折射率,以进行分析。在BIAevaluation 4.1中使用1∶1模型,为解离(kd,[s-1])和结合(ka,[M-1s-1])进行局部拟合和整体拟合二者,并计算(kd/ka)解离常数(KD,[M])。
使用3.0版BIAeveluation进行分析。通过将实验曲线拟合至自相互作用机制的模型推导的速率方程,自传感图数据推导动力学常数。使用1∶1结合模型的整体分析及局部RUmax拟合,确定了ka、kd、和KD。
使用下述方程:
亲和力成熟之前的人源化抗IL6单抗的Biacore数据列于图11。对抗IL-6单抗BA399实施BA399亲和力成熟之后,通过Biacore分析测试选定克隆。图34分别显示了克隆BA399-2,BA399-5,BA-399-9和BA399-10的Biacore数据。
实施例7:THP-1细胞中对Stat3磷酸化的抑制。
Stat3转录因子是许多细胞因子和生长因子受体的一种重要细胞信号传导分子(Heim.The Jak-STAT pathway:cytokine signaling from the receptor tothe nucleus.J.Recept.Signal Transduct.Res.1999.19(1-4):75-120)。Stat3在许多人肿瘤中组成性活化,而且拥有致瘤潜力(Bromberg et al.,Stat3 as anoncogene.Cell 1999 98(3):295-303)和抗凋亡活性。Stat3通过Tyr705处的磷酸化被活化,这诱导二聚化、核转运和DNA结合(Ihle,Cytokine receptor signaling.Nature 1995,377(6550):591-4)。经由MAPK或mTOR途径,转录活化似乎受Ser727处的磷酸化调节(Yokogami et al.,Serine phosphorylation and maximalactivation of Stat3 during CNTF signaling is mediated by rapamycin targetmTOR.2000 Curr Biol.10(1):47-50)。
在THP-1细胞中测量对Stat3磷酸化的抑制。依照标准方案使用THP-1(ATCC)细胞。为了每一种测试条件,血清饥饿2x106个细胞。阳性对照由用人IL-6(100,50,10ng/ml)及sIL-6R(200ng/ml)刺激的THP-1细胞刺激。阴性对照只由培养基组成。测试样品包括10mg/ml任一种CNTO 136,#399,BA399克隆#2或BA399克隆#9;每一种带人IL-6(100,50,10ng/ml)及带sIL-6R(200ng/ml)。将IL-6、sIL-6R和抗体于37℃温育15分钟。然后将反应混合物添加至THP-1细胞。于37℃温育15分钟后,将细胞用冷的PBS清洗并立即测定。Stat3的磷酸化水平是使用Cell Signaling Phosphot-Stat3三明治式ELISA试剂盒依照制造商的方案(例如Phospho-Stat3(Tyr705)三明治式ELISA试剂盒#7300,Cell Signaling Technology,Inc)来测量的。总Stat3的表达水平是通过针对人Stat 3(aa 50-240)的Santa Cruz家兔多克隆抗体(Santa CruzBiotechnology,Inc)来测量的。THP-1磷酸化数据示于图35-38。在每一幅图中,数据是基于总Stat3的Western印迹而标准化的。
如图35所示,与阳性对照相比,每一种抗IL-6单抗BA003(CNTO 136),BA399,BA399-2和BA399-9都引起IL6/sILR刺激的THP-1细胞中Stat-3磷酸化的浓度依赖性降低。
图36显示了当在多种条件下用100ng/mL IL6和sIL-6R刺激THP-1细胞时磷酸化的相对水平(A)。通过Western印迹测得的总Stat3水平示于(B)。与阳性对照相比,每一种抗IL-6单抗BA003(CNTO 136),BA399,BA399-2和BA399-9都引起IL6/sILR刺激的THP-1细胞中Stat-3磷酸化的显著降低。
图37显示了当在多种条件下用10ng/mL IL6和sIL-6R刺激THP-1细胞时磷酸化的相对水平(A)。通过Western印迹测得的总Stat3水平示于(B)。与阳性对照相比,每一种抗IL-6单抗BA003(CNTO 136),BA399,BA399-2和BA399-5都引起IL6/sILR刺激的THP-1细胞中Stat-3磷酸化的显著降低。
图38显示了当在多种条件下用10ng/mL IL6和sIL-6R刺激THP-1细胞时磷酸化的相对水平(A)。通过Western印迹测得的总Stat3水平示于(B)。与阳性对照相比,每一种抗IL-6单抗BA003(CNTO 136),BA399,BA399-2和BA399-9都引起IL6/sILR刺激的THP-1细胞中Stat-3磷酸化的显著降低。
实施例8:对HepG2细胞的血清淀粉状蛋白A蛋白生成的抑制。
血清淀粉状蛋白(serum amyloid)A(SAA)是一种急性期蛋白质,其生成是由IL-6诱导的。细胞因子诸如IL-6、IL-1和TNF被认为是SAA蛋白质合成的介导物。它们刺激肝细胞生成并释放SAA入血流中。高水平的SAA见于具有急性和慢性炎症的患者。继发性淀粉样变可因延长的或反复的炎性状况(其中SAA保持升高)而形成。这种渐进性致命状况特征在于器官功能的丧失。炎性病症诸如类风湿性关节炎、幼年型关节炎、强直性脊柱炎、家族性地中海热、渐进性硬化以及慢性感染诸如结核病和骨髓炎倾向于形成淀粉样变(Reinhoff et al.,Molecular and cellular biology of serum amyloid A.1990 Mol.Bio.Med.7:287-298)。
如下测试抗IL6单抗阻断受IL-6/sIL6R及IL-1b刺激的Hep G2细胞中血清淀粉状蛋白A蛋白质生成的能力。以24孔形式接种HepG2细胞,2.25x105个细胞/孔。每一种条件使用双份孔。阳性对照由人IL-6(100ng/ml)+sIL-6R(200ng/ml)+IL-1b(25ng/ml)组成。一种阴性对照仅由培养基组成。另一种阴性对照由人IL-6(100ng/ml)+sIL-6R(200ng/ml)组成。制备每一种抗IL6单抗CNTO 136,BA399,BA399-2,BA399-9(10-5,10-4,10-3,10-2,10-1,1mg/ml)的连续稀释液及人IL-6(100ng/ml)及sIL-6R(200ng/ml)和IL-1b(25ng/ml)。将IL-6、sIL-6R和单抗于室温温育30分钟。将IL-1b添加至IL6/抗体混合物。将整个反应混合物添加至HepG2细胞。血清淀粉状蛋白A(SAA)表达水平在添加反应混合物后24小时和48小时时使用Invitrogen人SAA免疫测定试剂盒依照制造商的方案来测量。数据示于图39和40。
图39显示了24小时时抗IL-6单抗对受人IL-6/ sIL-6R和IL-1b刺激的HepG2细胞的血清淀粉状蛋白A蛋白质生成的抑制。每一种抗IL6单抗003(CNTO 136),BA399,BA399-2和BA399-5都以剂量依赖性方式抑制SAA生成。人IgG是阴性对照。
图40显示了48小时时抗IL-6单抗对受人IL-6/ sIL-6R和IL-1b刺激的HepG2细胞的血清淀粉状蛋白A蛋白质生成的抑制。每一种抗IL6单抗003(CNTO 136),BA399,BA399-2和BA399-5都以剂量依赖性方式抑制SAA生成。人IgG是阴性对照。
实施例9:与猴IL-6的交叉反应性。
用抗猴IL-6抗体包被ELISA板。添加300pg/mL猴IL-6。阳性对照由生物素化抗猴IL-6组成。阴性对照仅由缓冲液组成。使用测试样品0.1mg/mL生物素化001及5mg/ml 001,003,BA399,BA399-2和BA399-9中每一项连同非特异性人IgG。用链霉亲合素-HRP实施ELISA。数据示于图41。生物素化抗IL6单抗展现出一些与猴IL-6的交叉反应性,这部分地被每一种抗IL6人源化单抗阻断,但是不被非特异性人IgG部分阻断。
实施例10:对IL-6诱导的DS-1细胞增殖的抑制。
DS-1是自一名具有肠淋巴管扩张和淋巴瘤的免疫缺陷患者来源的一种B细胞系。细胞增殖响应人IL-6而升高,但是不响应鼠IL-6。尽管有组成性IL-6生成,DS-1的体外生长依赖于外源IL-6(Bock et al.,Characterization of a newIL-6 dependent human B-lymphoma cell line in a long term culture.Cytokine5(5):480-489(1993))。
简言之,为每一种测试条件在96孔形式中接种800个细胞。使用10U/mL人IL-6和0,0.005,0.05和0.5μg/mL CNTO136,BA399和多种抗IL-6单抗。在添加抗体后0,2和4天使用Promega CellTiter-测定法(Promega Corp.,Madison,WI)测定细胞增殖。48小时和96小时时对IL-6诱导的DS-1细胞增殖的抑制分别示于图42和43。数种抗IL-6单抗在48和96小时时都以剂量依赖性方式降低DS-1细胞增殖,包括BA001,BA399,BA436,BA802,BA808和BA840。
清楚的是,本发明可以以上文描述和实施例中的具体记载以外的方式来实施。
根据上文教导,本发明的众多更改和变化是可能的,并因此在所附权利要求的范围内。
Claims (38)
1.一种分离的与人IL-6结合的抗体或抗体片段,其包含具有氨基酸序列SEQ ID NO:3,7,11,15,19,23,27,31,134,140,141,144,147,149,152,153或156的重链可变区;具有氨基酸序列SEQ ID NO:1,5,9,13,17,21,25,29,68,71,72,75,76,80或88的轻链可变区;和自一种或多种人抗体来源的恒定区。
2.一种分离的与人IL-6结合的抗体或抗体片段,其包含自BA399,BA436,BA802,BA808,BA840,BA848,BA890和BA939中一项或多项的可变区来源的重链和轻链互补决定区(CDR),和自一种或多种人抗体来源的恒定区。
3.依照权利要求1的抗体或片段,其中所述抗体或片段在体内竞争性抑制抗IL-6小鼠抗体对人IL-6的结合。
4.依照权利要求1的抗IL-6抗体或具体部分或变体,其中所述抗体或具体部分或变体以至少10-9M的亲和力(Kd)结合IL-6。
5.依照权利要求1的IL-6抗体或具体部分或变体,其中所述抗体或具体部分或变体以至少10-11M的亲和力(Kd)结合IL-6。
6.依照权利要求1的IL-6抗体或具体部分或变体,其中所述抗体或具体部分或变体以至少10-12M的亲和力(Kd)结合IL-6。
7.依照权利要求1的IL-6抗体或具体部分或变体,其中所述抗体或具体部分或变体实质性中和至少一种IL-6的至少一种活性。
8.依照权利要求7的IL-6抗体或具体部分或变体,其中所述活性是选自下组的至少一项:抑制IL-6介导的MCP-1生成,抑制THP-1人单核细胞白血病细胞中的IL-6信号传导,抑制IL-6诱导的来自HepG2细胞的血清淀粉状蛋白A生成,和抑制rhIL-6诱导的细胞增殖。
9.一种药物组合物,其包含依照权利要求1的分离的IL-6抗体或具体部分或变体和载体或稀释剂。
10.依照权利要求9的组合物,其进一步包含至少一种选自下述至少一项的化合物或蛋白质:TNF拮抗剂,抗风湿药,肌肉松弛药,麻醉药,非类固醇抗炎药(SNAID),镇痛药,麻醉剂,镇静药,局部麻醉剂,神经肌肉阻断剂,抗微生物剂,抗银屑病药,皮质类固醇,促蛋白合成类固醇,糖尿病相关药剂,矿物,营养物,甲状腺药剂,维生素,钙相关激素,止泻药,镇咳药,止吐药,抗溃疡药,轻泻药,抗凝血药,红细胞生成素,非格司亭,沙莫司亭,免疫剂,免疫球蛋白,免疫抑制药,生长激素,激素替代药物,雌激素受体调控剂,扩瞳药,睫状肌麻痹剂,烷化剂,抗代谢药,有丝分裂抑制剂,放射学药物,抗抑郁药,抗躁狂剂,安定药,抗焦虑药,催眠药,拟交感神经药,兴奋剂,多奈哌齐,他克林,哮喘药物,β激动剂,吸入的类固醇,白三烯抑制剂,甲基黄嘌呤,色甘酸钠,肾上腺素或类似物,dornase α,细胞因子,细胞因子拮抗剂,和抗TNFα或IL-12/IL-23单克隆抗体。
11.一种用于在细胞、组织、器官或动物中治疗免疫病症或疾病的方法,其包括:使至少一个选定免疫调控有效量的至少一种依照权利要求1的抗IL-6抗体或具体部分或变体接触或施用于所述细胞、组织、器官或动物。
12.依照权利要求11的方法,其中所述免疫状况是选自下组的至少一项:类风湿性关节炎/血清阴性关节病,骨关节炎,炎性肠病,系统性红斑狼疮,虹膜睫状体炎/葡萄膜炎/视神经炎,特发性肺纤维化,系统性血管炎/韦格纳(Wegener)氏肉芽肿病,结节病,睾丸炎/输精管切除逆转术,变应性/特应性疾病,哮喘,变应性鼻炎,湿疹,变应性接触性皮炎,变应性结膜炎,超敏感性肺炎,移植物,器官移植物排斥,移植物抗宿主病,全身炎症反应综合征,脓毒病综合征,革兰氏阳性脓毒病,革兰氏阴性脓毒病,培养物阴性脓毒病,真菌性脓毒病,中性白细胞减少性发热,尿脓毒病,脑膜炎球菌血症,外伤/出血,烧伤,电离辐射暴露,急性胰腺炎,成人呼吸窘迫综合征,系统性红斑狼疮和类风湿性关节炎,酒精诱发的肝炎,慢性炎性病理,结节病,克罗恩(Crohn)氏病理,镰状细胞贫血,糖尿病,肾病,特应性疾病,超敏感性反应,变应性鼻炎,枯草热,常年性鼻炎,结膜炎,哮喘,荨麻疹,系统性过敏反应,皮炎,恶性贫血,溶血性疾病,血小板减少,任何器官或组织的移植物排斥,肾移植物排斥,心移植物排斥,肝移植物排斥,胰移植物排斥,肺移植物排斥,骨髓移植物(BMT)排斥,皮肤同种异体移植物排斥,软骨移植物排斥,骨移植物排斥,小肠移植物排斥,胎儿胸腺植入物排斥,甲状旁腺移植物排斥,任何器官或组织的异种移植物排斥,同种异体移植物排斥,抗受体超敏感性反应,格雷夫斯(Graves)氏病,雷诺(Raynoud)氏病,B型胰岛素抗性糖尿病,哮喘,重症肌无力,抗体介导的细胞毒性,III型超敏感性反应,系统性红斑狼疮,天疱疮,硬皮病,混合性结缔组织病,特发性阿狄森(Addison)氏病,糖尿病,慢性活动性肝炎,原发性胆汁性肝硬化,白癜风,血管炎,MI心切开术后综合征,IV型超敏感性,接触性皮炎,超敏感性肺炎,同种异体移植物排斥,细胞内生物体所致肉芽肿,药物敏感性,代谢的/特发性的,威尔逊(Wilson)氏病,血色病,α-1-抗胰蛋白酶缺乏,糖尿病,桥本(Hashimoto)甲状腺炎,骨质疏松症,下丘脑-垂体-肾上腺轴评估,原发性胆汁性肝硬化,甲状腺炎,脑脊髓炎,恶病质,囊性纤维化病,家族性噬红细胞性淋巴组织细胞增生症,皮肤病学的,银屑病,脱发,肾病综合征,肾炎,血液透析,尿毒症,毒性反应,okt3疗法,抗cd3疗法,细胞因子疗法,化学疗法,放射疗法(例如包括但不限于虚弱、贫血、恶病质、等等),慢性水杨酸盐/酯中毒。
13.依照权利要求12的方法,其中所述有效量是0.0001-50mg/kg所述细胞、组织、器官或动物。
14.依照权利要求13的方法,其中所述有效量是0.001-50mg/kg所述细胞、组织、器官或动物。
15.一种用于在细胞、组织、器官或动物中调控癌性病症或状况的方法,其包括使药学有效量的至少一种依照权利要求1的抗IL-6抗体或具体部分或变体接触或施用于所述细胞、组织、器官或动物。
16.依照权利要求15的方法,其中所述癌性病症或状况是选自下组的至少一项:白血病,急性白血病,急性成淋巴细胞性白血病(ALL),B细胞、T细胞或FAB ALL,急性髓样白血病(AML),慢性髓细胞性白血病(CML),慢性淋巴细胞性白血病(CLL),毛细胞白血病,脊髓发育不良综合征(MDS),淋巴瘤,何杰金(Hodgkin)氏病,恶性淋巴瘤,非何杰金氏淋巴瘤,伯基特(Burkitt)氏淋巴瘤,多发性骨髓瘤,卡波西(Kaposi)氏肉瘤,结肠直肠癌,胰腺癌,肾细胞癌,前列腺细胞癌,鼻咽癌,恶性组织细胞增生症,恶性高钙血症/瘤周围综合征,实体瘤,腺癌,肉瘤,和恶性黑素瘤。
17.依照权利要求15的方法,其中所述有效量是0.01-100mg/kg所述细胞、组织、器官或动物。
18.权利要求11的方法,其中所述接触或所述施用是通过至少一种选自静脉内、肌肉内、推注、皮下、呼吸、吸入、阴道、直肠、含服、舌下、鼻内、或经皮的模式。
19.依照权利要求11的方法,其进一步包括在所述(1)接触或施用之前、并行或之后施用至少一种包含治疗有效量的至少一种选自下述至少一项的化合物或蛋白质的组合物:TNF拮抗剂,抗风湿药,肌肉松弛药,麻醉药,非类固醇抗炎药(NSAID),镇痛药,麻醉剂,镇静药,局部麻醉剂,神经肌肉阻断剂,抗微生物剂,抗银屑病药,皮质类固醇,促蛋白合成类固醇,糖尿病相关药剂,矿物,营养物,甲状腺药剂,维生素,钙相关激素,止泻药,镇咳药,止吐药,抗溃疡药,轻泻药,抗凝血药,红细胞生成素,非格司亭,沙莫司亭,免疫剂,免疫球蛋白,免疫抑制药,生长激素,激素替代药物,雌激素受体调控剂,扩瞳药,睫状肌麻痹剂,烷化剂,抗代谢药,有丝分裂抑制剂,放射学药物,抗抑郁药,抗躁狂剂,安定药,抗焦虑药,催眠药,拟交感神经药,兴奋剂,多奈哌齐,他克林,哮喘药物,β激动剂,吸入的类固醇,白三烯抑制剂,甲基黄嘌呤,色甘酸钠,肾上腺素或类似物,domase α,细胞因子,细胞因子拮抗剂,和抗TNFα或IL-12/IL-23单克隆抗体。
20.一种包含至少一种依照权利要求1的抗IL-6抗体或具体部分或变体的医疗装置,其中所述装置适合于通过至少一种选自静脉内、肌肉内、推注、皮下、呼吸、吸入、阴道、直肠、含服、舌下、鼻内、或经皮的模式来接触或施用所述至少一种IL-6抗体或具体部分或变体。
21.一种分离的完全人的抗体或其具体部分或变体,其中所述抗体或具体部分或变体与依照权利要求1的抗IL-6抗体或片段结合相同表位或抗原区。
22.一种药物组合物,其包含至少一种依照权利要求1的抗IL-6抗体或片段和选自无菌水、无菌缓冲水或水性稀释剂的至少一种载体,所述水性稀释剂中包含至少一种选自下组的防腐剂:酚,间甲酚,对甲酚,邻甲酚,氯甲酚,苯甲醇,亚硝酸苯汞,苯氧乙醇,甲醛,氯丁醇,氯化镁,对羟基苯甲酸烃基酯,苯扎氯铵,苄索氯铵,脱氢乙酸钠和硫柳汞,或其混合物。
23.权利要求22的组合物,其中抗IL-6抗体或具体部分或变体的浓度是约0.1mg/ml至约100mg/ml。
24.权利要求22的组合物,其进一步包含等张剂。
25.权利要求22的组合物,其进一步包含生理学可接受缓冲液。
26.一种试剂盒,其包含第一容器中冻干形式的至少一种依照权利要求1的抗IL-6抗体或片段,和任选的装有无菌水、无菌缓冲水、或水性稀释剂的第二容器,所述水性稀释剂中包含至少一种选自下组的防腐剂:酚,间甲酚,对甲酚,邻甲酚,氯甲酚,苯甲醇,亚硝酸苯汞,苯氧乙醇,甲醛,氯丁醇,氯化镁,对羟基苯甲酸烃基酯,苯扎氯铵,苄索氯铵,脱氢乙酸钠和硫柳汞,或其混合物。
27.权利要求26的试剂盒,其中抗IL-6抗体或具体部分或变体的浓度重建至约0.1mg/ml至约500mg/ml的浓度。
28.权利要求26的试剂盒,其进一步包含等张剂。
29.权利要求26的试剂盒,其进一步包含生理学可接受缓冲液。
30.一种治疗至少一种抗IL-6介导的状况的方法,其包括用权利要求26的第二容器的内容物重建权利要求26的第一容器的内容物,并对有所需要的患者施用重建后的第一容器内容物。
31.一种用于人类药物用途的制品,其包含包装材料和装有至少一种依照权利要求1的IL-6抗体或具体部分或变体的溶液或冻干形式的容器。
32.权利要求31的制品,其中所述容器是药物施用中可多次使用的具有塞子的玻璃或塑料容器。
33.一种用于生产依照权利要求1的抗IL-6抗体或片段的方法,其包括自经编码所述抗体或片段的核苷酸序列转化的宿主细胞或转基因动物或转基因植物或植物细胞表达所述抗体或片段并自其回收此类抗体或片段。
34.依照权利要求33的方法,其中所述宿主细胞是哺乳动物细胞、植物细胞或酵母细胞。
35.依照权利要求33的方法,其中所述转基因动物是哺乳动物。
36.依照权利要求33的方法,其中所述转基因哺乳动物选自山羊、牛、绵羊、马、和非人灵长类动物。
37.一种能够表达至少一种依照权利要求1的抗体的转基因动物或植物。
38.至少一种通过依照权利要求33的方法生成的抗IL-6抗体或具体部分或变体。
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CN105037548A (zh) * | 2014-04-21 | 2015-11-11 | 上海市免疫学研究所 | 抗人白介素-6受体β链单克隆抗体、其制备方法和用途 |
CN105037548B (zh) * | 2014-04-21 | 2018-08-03 | 上海市免疫学研究所 | 抗人白介素-6受体β链单克隆抗体、其制备方法和用途 |
WO2019109947A1 (zh) * | 2017-12-05 | 2019-06-13 | 南京金斯瑞生物科技有限公司 | 抗人il6单克隆抗体及其制备方法和用途 |
CN111304246A (zh) * | 2019-12-17 | 2020-06-19 | 百奥赛图江苏基因生物技术有限公司 | 一种人源化细胞因子动物模型、制备方法及应用 |
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JP2015172048A (ja) | 2015-10-01 |
CA2742786A1 (en) | 2010-05-20 |
EP2349331A4 (en) | 2012-12-12 |
BRPI0921665A2 (pt) | 2019-04-16 |
JP2012508762A (ja) | 2012-04-12 |
US8173398B2 (en) | 2012-05-08 |
AU2009313958A1 (en) | 2010-05-20 |
AU2009313958B2 (en) | 2015-09-10 |
US20120006716A1 (en) | 2012-01-12 |
JP5789192B2 (ja) | 2015-10-07 |
WO2010056948A3 (en) | 2010-07-22 |
KR20110094307A (ko) | 2011-08-23 |
WO2010056948A2 (en) | 2010-05-20 |
US20100138945A1 (en) | 2010-06-03 |
CN102245207B (zh) | 2015-11-25 |
RU2532826C2 (ru) | 2014-11-10 |
EP2349331A2 (en) | 2011-08-03 |
RU2011123870A (ru) | 2012-12-20 |
US8062866B2 (en) | 2011-11-22 |
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