CN106188304A - 人源化的抗‑d因子抗体 - Google Patents
人源化的抗‑d因子抗体 Download PDFInfo
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- CN106188304A CN106188304A CN201610570481.9A CN201610570481A CN106188304A CN 106188304 A CN106188304 A CN 106188304A CN 201610570481 A CN201610570481 A CN 201610570481A CN 106188304 A CN106188304 A CN 106188304A
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Abstract
本发明涉及人源化的抗‑人D因子单克隆抗体、它们的核酸和氨基酸序列、含有这些抗体的细胞和载体以及这些抗体在制备用于治疗与过度或不受控制的补体激活有关的疾病和病症的组合物和药物中的应用。这些抗体可用于疾病的诊断、预防和治疗。
Description
本申请是申请日为2007年10月31日、申请号为200780048936.X、名称为“人源化的抗-D因子抗体”的发明申请的分案。
发明背景
补体系统在免疫复合物的清除以及在对感染试剂、外来抗原、病毒-感染细胞和肿瘤细胞的免疫应答中起着重要作用。然而,补体还参与病理性的炎症以及自身免疫疾病。因此,对过度或不受控制的补体级联激活加以抑制可以对患有这样的疾病和病情的患者提供临床益处。
补体系统包括两个不同激活途径:经典途径和旁路途径(V.M.Holers,InClinical Immunology:Principles and Practice,R.R.Rich编辑,Mosby Press;1996,363-391)。经典途径为钙/镁-依赖的级联,其通常由抗原-抗体复合物的形成激活。旁路途径为镁-依赖的级联,其通过某些易感表面(例如酵母和细菌的细胞壁多糖以及某些生物聚合物材料)上C3的沉积和活化而被激活。补体途径的激活产生补体蛋白质的生物活性片段,例如C3a、C4a和C5a过敏毒素以及C5b-9膜攻击复合物(MAC),它们介导炎症活动,包括白细胞趋化反应,巨噬细胞、嗜中性粒细胞、血小板、肥大细胞和内皮细胞的活化,血管通透性,细胞溶解以及组织损伤。
D因子为旁路补体途径激活必不可缺的高特异性丝氨酸蛋白酶。其裂解结合C3b的B因子,产生C3b/Bb酶,其为旁路途径C3/C5蛋白转化酶的活性组分。D因子可能是用于抑制的合适靶,因为在人中其血浆浓度非常低(1.8μg/ml),并且已经证明其为旁路补体途径激活的限速酶(P.H.Lesavre和H.J.Muller-Eberhard.J.Exp.Med.,1978;148:1498-1510;J.E.Volanakis等,New Eng.J.Med.,1985;312:395-401)。
在动物模型和体外研究中已经显示,下调补体活性对治疗一些疾病指征有效,例如系统性红斑狼疮和肾小球肾炎(Y.Wang等,Proc.Natl.Acad.Sci.;1996,93:8563-8568)、风湿性关节炎(Y.Wang等,Proc.Natl.Acad.Sci.;1995,92:8955-8959)、心肺体外循环和血液透析(C.S.Rinder,J.Clin.Invest.,1995;96:1564-1572)、器官移植中的超急性排斥(T.J.Kroshus等,Transplantation,1995;60:1194-1202)、心肌梗死(J.W.Homeister等,J.Immunol.,1993;150:1055-1064;H.F.Weisman等,Science,1990;249:146-151)、再灌注损伤(E.A.Amsterdam等,Am.J.Physiol.,1995;268:H448-H457)、以及成人呼吸窘迫综合征(R.Rabinovici等,J.Immunol.,1992;149:1744-1750)。此外,其他炎性病症和自身免疫/免疫复合物疾病也与补体激活紧密相关(V.M.Holers,ibid.,B.P.Morgan.Eur.J.Clin.Invest.,1994:24:219-228),包括烫伤、严重哮喘、过敏性休克、肠炎、荨麻疹、血管性水肿、脉管炎、多发性硬化、重症肌无力、膜增殖性肾小球肾炎和干燥综合症(Sjogren's综合症)。
在补体-介导的病症领域需要抗体疗法,而本发明人源化的抗体提供了有效满足该需求的高亲和力抗体。
发明概述
一般地,本发明涉及包含小鼠抗体166-32的重链和轻链可变区序列的抗体,小鼠抗体166-32是能够抑制与D因子有关的生物活性的抗体。例如,在18μg/ml浓度时(相当于血液中人D因子摩尔浓度的约1.5倍;抗-D因子抗体与D因子的摩尔比约1.5:1),可以观察到该抗体显著抑制旁路补体的活性(参见,例如美国专利号6,956,107)。
本发明还涉及小鼠Mab 166-32的人源化抗体。本发明包括这些抗体的可变重链和轻链的氨基酸序列以及其相应的核酸序列。本发明的另一个实施方案包括这些抗体的CDR序列。
本发明的另一个实施方案包括包含本发明抗体的组合物。在另一个实施方案中,本发明提供了含有本发明抗体序列的细胞系和载体。在一个方面,本发明包括制备和使用本发明抗体和组合物的方法。
本发明的另一个实施方案是这些人源化抗体在制备治疗与过度或不受控制的补体激活有关的病症的药物或组合物中的应用。所述病症包括心肺体外循环期间的补体激活,由急性心肌梗塞、动脉瘤、中风、出血性休克、挤压伤、多器官衰竭、低血容量性休克(hypobolemic shock)、肠局部缺血或引起局部缺血的其他事件后的缺血-再灌注而引起的补体激活。还显示补体激活与炎性病症有关,如严重烧伤、内毒素血症、脓毒性休克、成人呼吸窘迫综合征、血液透析、过敏性休克、严重哮喘、血管性水肿、克罗恩氏病、镰刀形红细胞贫血病、链球菌感染后肾小球肾炎和胰腺炎。病症可以是不良药物反应、药物过敏、IL-2诱导的血管渗漏综合症或放射摄影造影剂过敏的结果。它还包括自身免疫性疾病如系统性红斑狼疮、重症肌无力、类风湿性关节炎、阿尔茨海默氏病和多发性硬化。补体激活还与移植排斥有关。此外,补体激活与眼病如年龄-相关的黄斑变性、糖尿病性视网膜病有关。
附图简述
图1A和1B描述了小鼠MAb 166-32可变重链(图1A)和可变轻链(图1B)的氨基酸序列。
图2A和2B描述了小鼠MAb 166-32可变重链(图2A)和可变轻链(图2B)的核酸序列。
图3描述了小鼠MAb 166-32重链的比对。
图4描述了小鼠MAb 166-32轻链的比对。
图5描述了每一个人源化抗体克隆#56、#111、#250和#416的可变重链和可变轻链的氨基酸序列。
图6描述了人源化抗体Fab克隆#56、#111、#250和#416的溶血实验结果。
图7描述了人源化抗体Fab克隆#56、#111、#250和#416对旁路补体激活的抑制。
图8A-B(可变重链(VH)共有框架)和图9A-B(可变轻链(VL)共有框架)描述了示例性的受者人共有框架序列,其可用于实施本发明并具有如下序列标识符:(图8A-B)人VH亚组I共有框架减去Kabat CDR(SEQ ID NO:28)、人VH亚组I共有框架减去延伸的高变区(SEQID NO:29-31)、人VH亚组II共有框架减去Kabat CDR(SEQ ID NO:32)、人VH亚组II共有框架减去延伸的高变区(SEQ ID NO:33-35)、人VH亚组III共有框架减去Kabat CDR(SEQ ID NO:36)、人VH亚组III共有框架减去延伸的高变区(SEQ ID NO:37-39)、人VH亚组VII共有框架减去Kabat CDR(SEQ ID NO:55)、人VH亚组VII共有框架减去延伸的高变区(SEQ ID NO:56-58)、人VH受体框架减去Kabat CDR(SEQ ID NO:40)、人VH受体框架减去延伸的高变区(SEQID NO:41-42)、人VH受体2框架减去Kabat CDR(SEQ ID NO:43)和人VH受体2框架减去延伸的高变区(SEQ ID NO:44-46)以及(图9A-B)人VLκ亚组I共有框架(SEQ ID NO:47)、人VLκ亚组II共有框架(SEQ ID NO:48)、人κ亚组III共有框架(SEQ ID NO:49)和人κ亚组IV共有框架(SEQ ID NO:50)。
发明详述
定义
本文全篇中所用的术语应解释为具有对本领域普通技术人员而言常规和典型的意义。然而,申请人希望给予下列术语如下特定定义。
短语“基本一致”相对于抗体链多肽序列而言可以被解释为抗体链与参考多肽序列有至少约70%、80%、90%或95%的序列一致性。对于核酸序列,该术语可以被解释为核苷酸序列与参考核酸序列有至少约85%、90%、95%或97%的序列一致性。
术语“一致性”或“同源性”应解释成是指,在比对序列并引入空隙(如果需要,以使整个序列达到最大的序列一致性百分比)之后,并且不考虑保守替代作为序列一致性的一部分时,候选序列中和与其比较的对应序列中的残基相同的氨基酸残基的百分数。N端或C端延伸或插入不应被理解成是减少了一致性或同源性。用于比对的方法和计算机程序是本领域所熟知的。用序列分析软件可以测定序列一致性。
术语“抗体”以其最广的意义使用,并且特定地包括:单克隆抗体(包括全长的单克隆抗体)、多克隆抗体和多特异性抗体(例如双特异性抗体)。抗体(Ab)和免疫球蛋白(Ig)是具有相同结构特征的糖蛋白。抗体对特定靶表现出结合特异性,而免疫球蛋白则包括抗体以及缺乏靶特异性的其它抗体样分子。天然抗体和天然免疫球蛋白通常是约150,000道尔顿的异四聚体糖蛋白,其由两个相同的轻链(L)和两个相同的重链(H)组成。每条重链的一端有可变区(VH),其后是多个恒定区。每条轻链的一端有可变区(VL),另一端是恒定区。
此处所用的“抗-人D因子抗体”指以抑制或基本上降低补体激活的方式特异性结合人D因子的抗体。
在抗体可变区语境中所用的术语“可变”指:在抗体之间可变区的某些部分在序列上有很大的不同,并且这些部分在每个特定抗体对其特定靶的结合和特异性中有作用。然而,可变性并非均匀地分布在抗体可变区中。它集中在轻链和重链可变区中称为互补决定区(CDR)(也称为高变区(HVR))的三个节段中。可变区中更高度共有的部分称为框架(FR)。天然重链和轻链的可变区各包含四个FR区,它们大多数采取β折叠构型,由三个CDR连接,该三个CDR连接形成环连接且在某些情况下形成β折叠的一部分。每条链中的多个CRD通过FR区连接在相邻近的位置,并且和另一条链的CDR一起形成抗体的靶结合部位(参见Kabat等)。除非另外指明,如此处所用的,免疫球蛋白氨基酸残基的编号是根据Kabat等(Sequences of Proteins of Immunological Interest,National Institute ofHealth,Bethesda,Md.1987)的免疫球蛋白氨基酸残基编号系统来进行的。
术语“高变区”、“HVR”或“HV”在此使用时指其序列高度可变的和/或形成结构限定环的抗体可变区的区域。通常,抗体包括6个高变区:3个在VH中(H1、H2、H3),3个在VL中(L1、L2、L3)。本发明使用并包括许多高变区描述。Kabat互补决定区(CDR)是基于序列可变性的且最常用(Kabat等,Sequences of Proteins of Immunological Interest,第五版,Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。而Chothia指结构环的位置(Chothia和Lesk J.Mol.Biol.196:901-917(1987))。AbM高变区代表Kabat CDR和Chothia结构环之间的折衷,并且为Oxford Molecμlar的AbM抗体模型软件所使用。“接触”高变区是基于可获得的复合晶体结构分析。来自每个这些高变区的残基记录如下。
Kabat编号
H1 H31-H35 H26-H35 H26-H32 H30-H35
Chothia编号
高变区可包括如下“延伸的高变区”:VL中的24-36或24-34(L1)、46-56或50-56(L2)和89-97(L3)以及VH中的26-35(H1)、50-65或49-65(H2)和93-102、94-102或95-102(H3)。每个这些定义的可变区残基根据上文的Kabat进行编号。
“框架”或“FR”残基为此处定义的除高变区残基或CDR残基以外的可变区残基。
术语“如Kabat编号的可变区残基”或“如Kabat编号的氨基酸位点”及其变体,指Kabat等,Sequences of Proteins of Immunological Interest,第五版,Public HealthService,National Institutes of Health,Bethesda,MD.(1991)中用于抗体编译的重链可变区或轻链可变区的编号系统。利用该编号系统,事实上线性的氨基酸序列相应于对可变区FR或CDR的截短或插入可包含更少的或额外的氨基酸。例如,重链可变区可包括H2的残基52后的单个氨基酸插入(根据Kabat为残基52a)以及重链FR残基82后插入的残基(例如根据Kabat为残基82a、82b和82c等等)。对于给定的抗体,可通过将该抗体序列的同源区域与“标准的”Kabat编号序列进行比对来确定其Kabat残基编号。
Kabat编号系统通常在提及可变区中的残基(大约轻链的残基1-107以及重链的残基1-113)时使用(例如,Kabat等,Sequences of Immunological Interest,第五版,PublicHealth Service,National Institutes of Health,Bethesda,Md.(1991))。“EU编号系统”或“EU索引”通常在提及免疫球蛋白重链恒定区中的残基时使用(例如,上文Kabat等中报道的EU索引;重链恒定区中的铰链区大约为重链的残基216-230(EU编号))。“如Kabat中的EU索引”指人IgG1EU抗体的残基编号。除非此处另有说明,抗体可变区中的残基编号的参照物指通过Kabat编号系统编号的残基。除非此处另有说明,抗体恒定区中的残基编号的参照物指通过EU编号系统编号的残基(例如,参见美国临时申请号60/640,323,EU编号的图)。
术语“抗体片段”指全长抗体的一部分,通常是靶结合区或可变区。抗体片段的例子包括Fab、Fab’、F(ab’)2和Fv片段。短语抗体的“功能性片段或类似物”为具有与全长抗体相同的定性生物学活性的化合物。例如,抗-人D因子抗体的功能性片段或类似物为可以以阻止或基本上降低补体激活的方式结合D因子的一种化合物。如此处所用的,对于抗体“功能性片段”是指Fv、F(ab)和F(ab’)2片段。“Fv”片段是含有全部靶识别和结合位点的最小抗体片段。该区域由紧密、非共价关联的一个重链可变区和一个轻链可变区的二聚物(VH-VL二聚物)组成。在该构型中,各可变区中的三个CDR相互作用,从而形成VH-VL二聚物表面上的靶结合位点。6个CDR共同赋予抗体靶结合特异性。然而,即使是单个可变区(或Fv的一半,只包含对靶有特异性的三个CDR)也能识别并结合抗原。“单链Fv”或“sFv”抗体片段包括抗体的VH和VL结构域,其中这些结构域存在于单个多肽链中。通常,Fv多肽进一步包括VH和VL结构域之间的多肽接头,其使sFv形成靶结合所需的结构。
Fab片段含有轻链的恒定区和重链的第一个恒定区(CH1)。Fab’片段和Fab片段不同,因为在重链CH1区的羧基端增加了几个残基(包括来自抗体铰链区的一个或多个半胱氨酸)。通过裂解F(ab’)2胃蛋白酶消化产物的铰链半胱氨酸处的二硫键,产生Fab’片段。抗体片段的其它化学偶联方式也是本领域普通技术人员已知的。
此处所用的术语“单克隆抗体”指从一群基本均一的抗体中获得的抗体,即该群体中包含的各个抗体是相同的,除了很少量可能存在的天然发生的突变外。单克隆抗体是高特异性的,针对单个靶位点。而且,与通常包括针对不同决定簇(表位)的不同抗体的常规(多克隆)抗体制剂不同,每个单克隆抗体针对靶上的单个决定簇。除了它们的特异性外,单克隆抗体的优点还在于它们是通过杂交瘤培养来合成的,不会被其它免疫球蛋白污染。修饰语“单克隆”表示抗体是从基本均一的抗体群中获得的特性,不应被解释成需要用任何特殊方法来制备抗体。例如,用于本发明的单克隆抗体可用本领域熟知的技术从噬菌体抗体文库中分离获得。用于本发明的单克隆抗体可用杂交瘤方法(由Kohler和Milstein,Nature,256:495(1975)首先提出)制得,或可用重组方法制得。
“人源化”形式的非人(如小鼠)抗体是嵌合的免疫球蛋白、免疫球蛋白链或其片段(如抗体的Fv、Fab、Fab’、F(ab’)2或其它靶结合亚序列),它们含有来自非人免疫球蛋白的最小序列。通常,人源化抗体包含了基本上所有的(至少一个、通常两个)可变区,其中所有或基本上所有的CDR区对应于非人免疫球蛋白的CDR区,所有或基本上所有FR区是人免疫球蛋白共有序列的FR区。人源化抗体还可以包括免疫球蛋白恒定区(Fc)的至少一部分,通常是所选的人免疫球蛋白模板的Fc部分。
用于人源化非-人抗体的方法为本领域所熟知。通常,人源化抗体具有引入的来自非-人来源的一个或多个氨基酸残基。这些非-人的氨基酸残基常常称为“引入”残基,其通常取自“引入”可变区。可基本上根据Winter和其同事的方法[Jones等,Nature,321:522-525(1986);Reichmann等,Nature,332:323-329(1988);Verhoeyen等,Science,239:1534-1536(1988)],通过用一个或多个啮齿类CDR取代人抗体的相应序列来进行人源化。因此,所述“人源化”抗体为嵌合抗体(美国专利号4,816,567),其中并不是完整的人可变区均被来自非-人物种的相应序列代替。实际上,人源化抗体通常为人抗体,其中一些CDR残基和可能一些FR残基由来自啮齿类抗体中类似位点的残基代替。
在一些情况下,当抗体将被用于治疗人时,选择用于制备人源化抗体的人可变区(轻链和重链)对于降低抗原性和/或HAMA应答(人抗小鼠抗体)很重要。HAMA应答的降低或消除通常为临床开发合适治疗剂的重要方面。参见例如.,Khaxzaeli等,J.Natl.CancerInst.(1988),80:937;Jaffers等,Transplantation(1986),41:572;Shawler等,J.Immunol.(1985),135:1530;Sears等,J.Biol.Response Mod.(1984),3:138;Miller等,Blood(1983),62:988;Hakimi等,J.Immunol.(1991),147:1352;Reichmann等,Nature(1988),332:323;Junghans等,Cancer Res.(1990),50:1495。如此处所述的,本发明提供了人源化抗体,使得HAMA应答得到降低或消除。可进一步利用本领域已知的常规方法获得这些抗体的变体,其中一些进一步如下文所述。根据所谓的“最佳拟合”方法,基于已知的人可变区序列的完整文库筛查啮齿类抗体可变区的序列。鉴定最接近于啮齿类V结构域序列的人V结构域序列,并且其内部的人框架区(FR)接受人源化抗体(Sims等,J.Immunol.151:2296(1993):Chothia等,J.Mol.Biol.,196:901(1987))。另一种方法利用源自特定轻链或重链亚组的所有人抗体的共有序列的特定框架区。相同的框架可用于若干不同的人源化抗体(Carter等,Proc.Natl.Acad.Sci.USA,89:4285(1992);Presta等,J.Immunol.151:2623(1993))。
例如,来自此处所述的抗体的氨基酸序列可用作起始(亲本)序列,用于使框架和/或高变序列多样化。所选的连接起始高变序列的框架序列在此指受者人框架。虽然该受者人框架可以是来自或源自人免疫球蛋白(其VL和/或VH区域),但该受者人框架可以来自或源自人的共有框架序列,因为这样的框架区已被证实在人患者中具有最低的或没有免疫原性。对于本发明目的而言,“受者人框架”为这样的框架,其包含源自人免疫球蛋白框架的VL或VH框架的氨基酸序列,或来自人共有框架的氨基酸序列。“源自”人免疫球蛋白框架或人共有序列框架的受者人框架可以包括其相同的氨基酸序列或可以包含之前存在的氨基酸序列改变。当存在之前存在的氨基酸改变时,优选存在不超过5个并且优选4个或更少、或3个或更少的之前存在的氨基酸改变。在一个实施方案中,VH受者人框架的序列与VH人免疫球蛋白框架序列或人共有框架序列相同。在一个实施方案中,VL受者人框架的序列与VL人免疫球蛋白框架序列或人共有框架序列相同。“人共有框架”为代表人免疫球蛋白VL或VH框架序列选择中最常出现的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列的选择来自可变区序列的亚组。通常,序列亚组为如Kabat等中的亚组。在一个实施方案中,对于VL,该亚组为Kabat等中的kappa I亚组。在一个实施方案中,对于VH,该亚组为Kabat等中的kappaIII亚组。
如果受者源自人免疫球蛋白,可以任选地如下选择人框架序列:通过比对供者框架序列与人框架序列集合中不同的人框架序列基于人框架序列与供者框架序列的同源性进行选择,并且选择最同源的框架序列作为受者。受者人框架区以来自或源自公共数据库中可获得的人抗体胚系序列。
在一个实施方案中,此处的人共有框架来自或源自VH亚组VII和/或VLκ亚组I共有框架序列。
在一个实施方案中,用于制备抗-D因子抗体的人框架模板可包括来自下述模板的框架序列,该模板包含VH链中的VI-4.1b+(VH7家族)与JH4d组合(图3)和/或VL链中的DPK4(VκI家族)与JK2组合(图4)。
因此,VH受者人框架可以包括一种、两种、三种或所有下列框架序列:包含QX1QLVQSGX2ELKKPGASVKVSCKAS(SEQ ID NO:27的氨基酸1-25)的FR1,其中X1为I或V,X2为P或S;包含WVX3QAPGQGLE(SEQ ID NO:27的氨基酸36-46)的FR2,其中X3为K或R;包含RFVFSLDTSVSTAYLQISSLKAEDTAX4YYCX5R(SEQ ID NO:27的氨基酸67-98)的FR3,其中X4为T或V,X5为E或A;包含WGQGTLVTVSS(SEQ ID NO:8的氨基酸105-115或SEQ ID NO:27的氨基酸105-115)的FR4。
VH共有框架的例子包括:
人VH亚组I共有框架减去Kabat CDR(SEQ ID NO:28);
人VH亚组I共有框架减去延伸的高变区(SEQ ID NO:29-31);
人VH亚组II共有框架减去Kabat CDR(SEQ ID NO:32);
人VH亚组II共有框架减去延伸的高变区(SEQ ID NO:33-35);
人VH亚组Ⅲ共有框架减去Kabat CDR(SEQⅢD NO:36);
人VH亚组Ⅲ共有框架减去延伸的高变区(SEQ ID NO:37-39);
人VH亚组VII共有框架减去Kabat CDR(SEQ ID NO:55);
人VH亚组VII共有框架减去延伸的高变区(SEQ ID NO:56-58);
人VH受者框架减去Kabat CDR(SEQ ID NO:40);
人VH受者框架减去延伸的高变区(SEQ ID NO:41-42);
人VH受者2框架减去Kabat CDR(SEQ ID NO:43);或
人VH受者2框架减去延伸的高变区(SEQ ID NO:44-45);
在一个实施方案中,VH受者人框架包括一个、两个、三个或所有下列框架序列:
包含QVQLVQSGPELKKPGASVKVSCKAS(SEQ ID NO:8的氨基酸1-25)的FR1,
包含WVRQAPGQGLE(SEQ ID NO:8的氨基酸36-46)的FR2,
包含RFVFSLDTSVSTAYLQISSLKAEDTAVYYCER(SEQ ID NO:8的氨基酸67-98)的FR3,
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCE(SEQ ID NO:8的氨基酸67-97),
RFVFSLDTSVSTAYLQISSLKAEDTAVYYC(SEQ ID NO:8的氨基酸67-96),
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCS(SEQ ID NO:51),或
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCSR(SEQ ID NO:52),
包含WGQGTLVTVSS(SEQ ID NO:8的氨基酸105-115或SEQ ID NO:27的氨基酸105-115)的FR4。
VL受者人框架可以包括一个、两个、三个或所有下列框架区序列:
包含DIQX6TQSPSSLSX7SVGDRVTITC(SEQ ID NO:26的氨基酸1-23)的FR1,其中X6为V或M,X7为M或A;
包含WYQQKPGKX8PKLLIX9(SEQ ID NO:26的氨基酸35-49)的FR2,其中X8为P或V,X9为S或Y;
包含GVPSRFSX10SGSGX11DFTLTISSLQPEDVATYYC(SEQ ID NO:26的氨基酸57-88)的FR3,其中X10为S或G,X11为A或T;
包含FGQGTKX12EIK(SEQ ID NO:54)的FR4,其中X12为V或L。
VL共有框架的例子包括:
人VLκ亚组I共有框架(SEQ ID NO:47);
人VLκ亚组II共有框架(SEQ ID NO:48);
人VLκ亚组III共有框架(SEQ ID NO:49);或
人VLκ亚组IV共有框架(SEQ ID NO:50)。
在一个实施方案中,VL受者人框架可以包括一个、两个、三个或所有下列框架序列:
包含DIQVTQSPSSLSASVGDRVTITC(SEQ ID NO:7的氨基酸1-23)的FR1,
包含WYQQKPGKVPKLLIS(SEQ ID NO:7的氨基酸35-49)的FR2,
包含GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC(SEQ ID NO:7的氨基酸57-88)的FR3,
包含FGQGTKLEIK(SEQ ID NO:7的氨基酸98-107)的FR4,或
FGQGTKVEIK(SEQ ID NO:53)。
虽然受者的序列可以与所选的人框架序列相同,无论该人框架序列来自人免疫球蛋白或是人共有框架,本发明预期受者序列可以包括相对于人免疫球蛋白序列或人共有框架序列而言之前存在的氨基酸取代。这些之前存在的取代优选为最少的;通常相对于人免疫球蛋白序列或共有框架序列仅4个、3个、2个或1个氨基酸不同。
将非-人抗体的高变区残基掺入VL和/或VH受体人框架中。例如,可以掺入对应于Kabat CDR残基、Chothia高变环残基、Abm残基和/或接触残基的残基。任选地,以下延伸的高变区残基可被掺入:24-34(L1)、50-56(L2)和89-97(L3),26-35(H1)、50-65或49-65(H2)和93-102、94-102或95-102(H3)。
在一个方面,本发明提供了包含至少一个、两个、三个、四个、五个或六个HVR的抗体,所述HVR选自(a)HVR-H1,其包含选自SEQ ID NO:13和SEQ ID NO:25的氨基酸序列;(b)HVR-H2,其包含SEQ ID NO:14的氨基酸序列;(c)HVR-H3,其包含选自SEQ ID NO:15和SEQID NO:20的氨基酸序列;(d)HVR-L1,其包含SEQ ID NO:16的氨基酸序列;(e)HVR-L2,其包含选自SEQ ID NO:17、SEQ ID NO:21和SEQ ID NO:24的氨基酸序列;和(f)HVR-L3,其包含选自SEQ ID NO:18、SEQ ID NO:22和SEQ ID NO:19的氨基酸序列。
在一个方面,本发明提供包含至少一个、两个、三个、四个、五个或六个HVR的抗-D因子抗体,所述HVR选自(a)HVR-H1,其包含与选自SEQ ID NO:13和SEQ ID NO:25的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列;(b)HVR-H2,其包含与SEQ ID NO:14的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列;(c)HVR-H3,其包含与选自SEQ ID NO:15和SEQ ID NO:20的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列;(d)HVR-L1,其包含与SEQ ID NO:16的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列;(e)HVR-L2,其包含与选自SEQ ID NO:17、SEQ ID NO:21和SEQ IDNO:24的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列;和(f)HVR-L3,其包含与选自SEQ ID NO:18、SEQ ID NO:22和SEQID NO:19的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列。在一些实施方案中,含有与参照序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列的HVR包含取代、插入或缺失,但包含那些氨基酸序列的抗体保留结合D因子的能力。在一些实施方案中,在选自SEQ ID NO:13、SEQ ID NO:25、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:20、SEQ IDNO:16、SEQ ID NO:17、SEQ ID NO:21、SEQ ID NO:23、SEQ ID NO:18、SEQ ID NO:22和SEQID NO:24的参照序列中总共有1至10个氨基酸被取代、插入或缺失。在一些实施方案中,本发明提供了包含至少一个、两个、三个、四个、五个或六个HVR的抗体,所述HVR选自(a)HVR-H1,其包含选自SEQ ID NO:13和SEQ ID NO:25的氨基酸序列;(b)HVR-H2,其包含SEQ IDNO:14的氨基酸序列;(c)HVR-H3,其包含选自SEQ ID NO:15和SEQ ID NO:20的氨基酸序列;(d)HVR-L1,其包含SEQ ID NO:16的氨基酸序列;(e)的HVR-L2,其包含选自SEQ ID NO:17、SEQ ID NO:21和SEQ ID NO:24的氨基酸序列;和(f)HVR-L3,其包含选自SEQ ID NO:18、SEQID NO:22和SEQ ID NO:19的氨基酸序列。
在一个方面,本发明提供了包含选自SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12的重链可变区的抗体。在一个方面,本发明提供了包含选自SEQ ID NO:5、SEQID NO:7、SEQ ID NO:9和SEQ ID NO:11的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:6的重链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:5的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:6的重链可变区和含有SEQ ID NO:5的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:8的重链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:7的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:8的重链可变区和含有SEQ ID NO:7的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:10的重链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:9的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:10的重链可变区和含有SEQ ID NO:9的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:12的重链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:11的轻链可变区的抗体。在一个方面,本发明提供了包含含有SEQ ID NO:12的重链可变区和含有SEQ ID NO:11的轻链可变区的抗体。
在一个方面,本发明提供了包含重链可变区的抗-D因子抗体,该重链可变区包含与选自SEQ ID NO:6、8、10和12的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列。在一些实施方案中,与参照序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列包含取代、插入或缺失,但包含该氨基酸序列的抗体保留结合D因子的能力。在一些实施方案中,在选自SEQ ID NO:6、8、10或12的序列中,总共有1至10个氨基酸被取代、插入或缺失。在一些实施方案中,所述取代、插入或缺失存在于HVR以外的区域(即在FR中)。在一些实施方案中,抗-D因子抗体包含含有选自SEQ ID NO:6、8、10或12的氨基酸序列的重链可变区。
在一些实施方案中,本发明提供了包含轻链可变区的抗-D因子抗体,该轻链可变区包含与选自SEQ ID NO:5、7、9和11的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列。在一些实施方案中,与参照序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列包含取代、插入或缺失,但包含那些氨基酸序列的抗体保留结合D因子的能力。在一些实施方案中,在选自SEQ ID NO:5、7、9和11的序列中,总共有1至10个氨基酸被取代、插入或缺失。在一些实施方案中,该取代、插入或缺失存在于HVR以外的区域(即在FR中)。在一些实施方案中,抗-D因子抗体包含具有选自SEQ ID NO:5、7、9和11的氨基酸序列的轻链可变区。
抗-D因子抗体可以包含任何合适的框架可变区序列,条件是该抗体保留结合D因子的能力。例如,在一些实施方案中,本发明的抗-D因子抗体包含的重链可变区框架序列是Vl.4.1b+和JH4d的组合(参见图3)。在一些实施方案中,本发明的抗-D因子抗体包含人亚组VII重链框架区共有序列。在一些实施方案中,本发明的抗-D因子抗体包含的重链可变区框架序列包含FR1,其包含SEQ ID NO:8的氨基酸1-25;FR2,其包含SEQ ID NO:8的氨基酸36-46;FR3,其包含SEQ ID NO:8的氨基酸67-98;和FR4,其包含SEQ ID NO:8的氨基酸105-115。在这些抗体的一个实施方案中,所述重链可变区序列包含位点40和/或88(Kabat编号)处的取代。这些抗体的一个实施方案中,位点40为半胱氨酸(C)或丙氨酸(A)和/或位点88为半胱氨酸(C)或丙氨酸(A)。在一些实施方案中,本发明的抗-D因子抗体包含的轻链可变区框架序列是DPK4和JK2的组合(参见图4)。在一些实施方案中,本发明的抗-D因子抗体包含人κI(κI)轻链框架共有序列。在一些实施方案中,本发明的抗-D因子抗体包含的轻链可变区框架序列包含FR1,其包含SEQ ID NO:7的氨基酸1-23;FR2,其包含SEQ ID NO:7的氨基酸35-49;FR3,其包含SEQ ID NO:7的氨基酸57-88;和FR4,其包含SEQ ID NO:7的氨基酸98-107。在这些抗体的一个实施方案中,所述轻链可变框架序列包含位点15、43和/或104(Kabat编号)处的一个或多个取代。这些抗体的一个实施方案中,位点15为半胱氨酸(C)或缬氨酸(V),位点43为半胱氨酸(C)或丙氨酸(A)和/或位点104为缬氨酸(V)或亮氨酸(L)。
进一步地,抗-D因子抗体可以包含任何合适的恒定区序列,条件是该抗体保留结合D因子的能力。例如,在一些实施方案中,本发明的抗-D因子抗体至少包含重链恒定区的一部分。在一个实施方案中,本发明的抗-D因子抗体包含α、δ、ε、γ或μ重链的一种或其组合的重链恒定区。取决于其重链恒定区(CH)的氨基酸序列,免疫球蛋白可分为不同的类别或同种型。存在五种类别的免疫球蛋白:IgA、IgD、IgE、IgG和IgM,分别具有命名为α、δ、ε、γ和μ的重链。基于在CH序列和功能方面的相对微小的差别,将γ和α类别进一步分成亚类,例如人表达下列亚类:IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。在一个实施方案中,本发明的抗-D因子抗体包含的重链恒定区在对效应子功能(例如结合亲和力)产生预期效果的氨基酸位点处包含取代。在一个实施方案中,本发明的抗-D因子抗体包含的重链恒定区在对效应子功能(例如结合亲和力)不产生预期效果的氨基酸位点处包含取代。在一个实施方案中,本发明的抗-D因子抗体包含IgG类型(例如IgG1、IgG2、IgG3或IgG4)的重链恒定区,并且进一步包含位点114(Kabat编号;相当于EU编号的118)、168(Kabat编号;相当于EU编号的172)、172(Kabat编号;相当于EU编号的176)和/或228(EU编号)处的取代。在一个实施方案中,本发明的抗-D因子抗体包含IgG(例如IgG1、IgG2、IgG3或IgG4)类型的重链恒定区,并且进一步包含位点114处的取代,其中位点114为半胱氨酸(C)或丙氨酸(A),位点168为半胱氨酸(C)或丙氨酸(A),位点172为半胱氨酸(C)或丙氨酸(A)和/或位点228为脯氨酸(P)、精氨酸(R)或丝氨酸(S)。
进一步地,例如在一些实施方案中,本发明的抗-D因子抗体包含轻链恒定区的至少一部分。在一个实施方案中,本发明的抗-D因子抗体包含κ或λ轻链的一种或其组合的轻链恒定区,因为基于轻链恒定区的氨基酸序列,来自任何脊椎动物物种的轻链可分类到两种明显不同类型(称为κ和λ)中的一种。在一个实施方案中,本发明的抗-D因子抗体包含的轻链恒定区在对效应子功能(例如结合亲和力)产生预期效果的氨基酸位点处包含取代。在一个实施方案中,本发明的抗-D因子抗体包含的轻链恒定区在对效应子功能(例如结合亲和力)不产生预期效果的氨基酸位点出包含取代。在一个实施方案中,本发明的抗-D因子抗体包含κ类型的轻链恒定区,并且进一步包含位点110、144、146和/或168(Kabat编号)处的取代。在一个实施方案中,本发明的抗-D因子抗体包含κ类型的轻链恒定区,并且进一步包含位点110处的取代,其中位点110为半胱氨酸(C)或缬氨酸(V);位点144的取代,其中位点144为半胱氨酸(C)或丙氨酸(A);位点146的取代,其中位点146为异亮氨酸(I)或缬氨酸(V);和/或位点168的取代,其中位点168为半胱氨酸(C)或丝氨酸(S)。
在一个方面,本发明提供了与小鼠抗166-32和/或人源化抗-D因子抗体克隆#56、#111、#250或#416和/或包含人源化抗-D因子抗体克隆#56、#111、#250或#416的可变区或HVR序列的抗体竞争的抗体。本发明还提供了与小鼠抗166-32和/或人源化抗-D因子抗体克隆#56、#111、#250或#416和/或包含人源化抗-D因子抗体克隆#56、#111、#250或#416的可变区或HVR序列的抗体结合相同表位的抗体。
在一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体对D因子的单价亲和力(例如该抗体作为Fab片段对D因子的亲和力)较低,例如比嵌合抗体的单价亲和力(例如该嵌合抗体作为Fab片段对D因子的亲和力)低至少1倍或2倍,该抗体包含SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区、或由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成,或基本上由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成。
在一个实施方案中,本发明提供抗-D因子抗体,其中该抗体对D因子的二价亲和力(例如该抗体作为IgG对D因子的亲和力)较低,例如比嵌合抗体的二价亲和力(例如该嵌合抗体作为IgG对D因子的亲和力)低至少1倍或2倍,该抗体包含SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区、或由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成,或基本上由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体对D因子的单价亲和力(例如该抗体作为Fab片段对D因子的亲和力)较高,例如比嵌合抗体的单价亲和力(例如该嵌合抗体作为Fab片段对D因子的亲和力)高至少1倍或2倍,该抗体包含SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区、或由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成或基本上由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体对D因子的二价亲和力(例如该抗体作为IgG对D因子的亲和力)较高,例如比嵌合抗体的二价亲和力(例如该嵌合抗体作为IgG对D因子的亲和力)高至少1倍或2倍,该抗体包含SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区、或由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成或基本上由SEQ ID NO:2的轻链可变区和SEQ ID NO:1的重链可变区组成。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为1.0nM(1.0×10-9M)或更高。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为0.5nM(0.5×10-9M)或更高。在另一个实施方案中,本发明提供抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为1.0pM(1.0×10-12M)或更高。在另一个实施方案中,本发明提供抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为0.5pM(0.5×10-12M)或更高。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为1.0nM(1.0×10-9M)或更高。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为0.5nM(0.5×10-9M)或更高。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为1.0pM(1.0×10-12M)或更高。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为0.5pM(0.5×10-12M)或更高。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)在0.5mM(0.5×10-6M)和0.5pM(0.5×10-12M)之间。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)在15nM(15×10-9M)和0.1nM(0.1×10-9M)之间。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)在5.5nM(5.5×10-9M)和1nM(1×10-9M)之间。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)在0.5pM(0.5×10-12M)和2mM(2×10-12M)之间。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)在0.5mM(0.5×10-6M)和0.5pM(0.5×10-12M)之间。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)在10nM(10×10-9M)和0.05nM(0.05×10-9M)之间。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)在5.5nM(5.5×10-9M)和1nM(1×10-9M)之间。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)在0.5pM(0.5×10-12M)和2pM(2×10-12M)之间。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约0.37nM(3.7×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约0.33nM(3.3×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约0.51nM(5.1×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约2.7nM(2.7×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约1.4nM(1.4×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约1.4pM(1.4×10-12M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为约1.1pM(1.1×10- 12M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约0.19nM(0.19×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为约0.08nM(0.08×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约12.3nM(12.3×10-9M)。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为约9.0nM(9.0×10-9M)。
在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约1.4pM(1.4×10-12M)+/-0.5。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为约1.1pM(1.1×10-12M)+/-0.6。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约0.19nM(0.19×10-9M)+/-0.1。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为约0.08nM(0.08×10-9M)+/-0.01。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)为约12.3nM(12.3×10-9M)+/-2。在另一个实施方案中,本发明提供了抗-D因子抗体,其中该抗体以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)为约9.0nM(9.0×10-9M)+/-1。
在另一个实施方案中,抗-D因子抗体可以具有约3.7nM(3.7×10-9M)+/-2的单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约3.3nM(3.3×10-9M)+/-2的单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约5.1nM(5.1×10-9M)+/-2的单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约2.7nM(2.7×10-9M)+/-2的单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约1.4nM(1.4×10-9M)+/-2的单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约1.4pM(1.4×10-12M)+/-2的单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约1.1pM(1.1×10-12M)+/-2的二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约0.19nM(0.19×10-9M)+/-2的以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约0.08nM(0.08×10-9M)+/-2的以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约12.3nM(12.3×10-9M)+/-2的以其单价形式对D因子的亲和力(例如,该抗体作为Fab片段对D因子的亲和力)。在另一个实施方案中,抗-D因子抗体可以具有约9.0nM(9.0×10-9M)+/-2的以其二价形式对D因子的亲和力(例如,该抗体作为IgG对D因子的亲和力)。
如本领域公认的,可利用任何各种测定法测定配体对其受体的结合亲和力,并且通过各种定量值表示。因此,在一个实施方案中,结合亲和力(binding affinity)可以表示为Kd值并且反映固有的结合亲和力(例如具有最小化的活动性(avidity)影响)。通常并且优选在体外测量结合亲和力,可以用无细胞的或细胞相关的装置。如此处更详细描述的,可通过人源化抗体的单价结合亲和力值(例如,以Fab形式)与对照/比较抗体(例如具有供者高变区序列的小鼠抗体)的单价结合亲和力值(例如,以Fab形式)的比例对结合亲和力的倍数差异进行定量,其中所述结合亲和力值在类似的测定条件下测定。因此在一个实施方案中,结合亲和力的倍数差异被确定为Fab形式的人源化抗体与所述对照/比较Fab抗体的Kd值的比例。例如,在一个实施方案中,如果本发明的抗体(A)具有比对照抗体(M)的亲和力低“3倍”的亲和力,则如果A的Kd值为3×,M的Kd值将为1×,并且A的Kd与M的Kd的比值将为3:1。反之,在一个实施方案中,如果本发明的抗体(C)具有比对照抗体(R)的亲和力高“3倍”的亲和力,则如果C的Kd值为1×,R的Kd值将为3×,并且C的Kd与R的Kd的比值将为1:3。本领域已知的任何多种测定法,包括此处所述的那些,可用于获得结合亲和力的测量值,包括例如Biacore、放射免疫测定法(RIA)与ELISA。
此外,本发明抗体的Kd值可以根据所用具体测定法的条件而不同。例如,在一个实施方案中,结合亲和力的测定可以在下述测定法中实现,其中固定Fab或抗体,并且测定配体(即D因子)的结合,或者固定Fab或抗体的配体(即D因子),并且测定Fab或抗体的结合。在一个实施方案中,结合亲和力的测定可以在下述测定法中实现,其中再生条件可以包括(1)pH为1.5,10mM甘氨酸或4M MgCl2和(2)pH在1.0和pH 7.5之间,包括pH 1.5、pH 5.0、pH 6.0和pH 7.2。在一个实施方案中,结合亲和力的测定可以用下述测定法实现,其中结合条件可以包括(1)PBS或HEPES缓冲盐水和(2)Tween-20,即0.1%Tween-20。在一个实施方案中,结合亲和力的测定可以在下述测定法中实现,其中配体(即D因子)的来源可以从市场上获得。在一个实施方案中,结合亲和力的测定可以在下述测定法中实现,其中(1)固定Fab或抗体并且测定配体(即D因子)的结合,(2)再生条件包括pH 7.2,4M MgCl2和(3)结合条件包括HEPES缓冲盐水,pH 7.2,含有0.1%Tween-20。在一个实施方案中,结合亲和力的测定可以在下述测定法中实现,其中(1)固定配体(即D因子)并且测定Fab或抗体的结合,(2)再生条件包括pH 1.5,10mM甘氨酸和(3)结合条件包括PBS缓冲液。
术语“细胞”、“细胞系”和“细胞培养物”包括子代。也应理解,由于有意或无意的突变,所有子代也许在DNA内容上不精确相同。在原始转化细胞中筛选出的具有相同功能或生物活性的不同子代也被包括在内。本发明所用的“宿主细胞”通常是原核或真核宿主。
术语“载体”指含有DNA序列的DNA构建物,该DNA序列与能使该DNA在合适宿主中表达的合适的调控序列操作性连接。所述调控序列包括实现转录的启动子、控制该转录的任选的操纵子序列、编码合适的mRNA核糖体结合位点的序列、以及控制转录和翻译终止的序列。载体可以是质粒、噬菌体颗粒、或简单地是潜在的基因组插入物。一旦转化到合适宿主中,该载体能不依赖于宿主基因组进行复制和起作用,或在一些情况下,其本身整合入基因组中。在本说明书中,“质粒”和“载体”有时可互换使用,因为质粒是目前最常用的载体形式。然而,本发明还包括具有等同功能的其它形式的载体,它们是本领域中已知的。
此处所用的词语“标记物”指直接或间接与分子或蛋白质例如抗体偶联的可被检测的化合物或组合物。标记物自身可以被检测到(例如放射性同位素标记物或荧光标记物),或者,如果是酶标记物,它们可催化底物化合物或组合物发生可检测的化学转变。
如此处所用的,“固相”指本发明抗体可粘附于其上的非水性基质。固相的例子在此包括:部分或完全由玻璃(例如可控多孔玻璃)、多糖(例如琼脂糖)、聚丙烯酰胺、聚苯乙烯、聚乙烯醇和硅氧烷形成的固相。在某些实施方案中,根据上下文,固相可包括测试板的孔;而在其它实例中是纯化柱(例如亲和层析柱)。
抗体的制备
宿主细胞的选择和转化
此处用于克隆或在载体中表达DNA的合适的宿主细胞为原核细胞、酵母细胞或更高等的真核细胞。用于此目的合适的原核生物包括革兰氏阴性和革兰氏阳性生物,例如肠细菌如大肠杆菌(E.coli)、肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯氏杆菌属(Klebsiella)、变形杆菌属(Proteus)、沙门氏菌属(Salmonella)、沙雷氏菌属(Serratia)和志贺氏菌属(Shigella),以及芽胞杆菌属(Bacilli)、假单胞菌属(Pseudomonas)和链霉菌属(Streptomyces)。一个优选的大肠杆菌克隆宿主为大肠杆菌294(ATCC 31,446),虽然其他菌株如大肠杆菌B、大肠杆菌X1776(ATCC 31,537)以及大肠杆菌W3110(ATCC 27,325)也合适。这些例子为示例性的而不是限制性的。
除原核生物之外,真核微生物如丝状真菌或酵母为抗体-编码载体的合适克隆或表达宿主。酿酒酵母(Saccharomyces cerevisiae)在较低级的真核宿主微生物当中为最常使用的。然而,许多其他属、种和菌株通常可获得并在本发明中有用,如非洲粟酒裂殖酵母(Schizosaccharomyces pombe);克卢费氏酵母(Kluyveromyces);假丝酵母(Candida);木霉(Trichoderma);粗糙链孢(Neurospora crassa);以及丝状真菌如脉孢菌(Neurospora)、青霉(Penicillium)、弯颈霉属(Tolypocladium)和曲霉属(Aspergillus)宿主,如构巢曲霉(A.nidulans)和黑曲霉(A.niger)。
用于糖基化抗体表达的合适的宿主细胞源自多细胞生物。原则上,任何高级真核细胞培养物都是可使用的,无论其来自脊椎动物或是无脊椎动物培养物。无脊椎动物细胞的例子包括植物和昆虫细胞,Luckow等,Bio/Technology 6,47-55(1988);Miller等,Genetic Engineering,Setlow等编辑,第8卷,277-279页(Plenam publishing 1986);Mseda等,Nature 315,592-594(1985)。各种杆状病毒株和变体和来自如草地夜蛾(caterpillar)、埃及伊蚊(mosquito)、黑尾果蝇(fruitfly)和家蚕宿主的相应的可感染昆虫宿主细胞已被鉴定。用于转染的各种病毒株(例如,苜蓿丫纹夜蛾(Autographacalifornica)NPV的L-1变体和家蚕NPV的Bm-5株)是公众可获得的,这些病毒可用作本发明中所述的病毒,尤其可用于转染草地夜蛾细胞。另外,也可用棉、玉米、土豆、大豆、矮牵牛、西红柿和烟草的植物细胞培养物作为宿主。
脊椎动物细胞在培养(组织培养)中的繁殖已经成为常规手段。参见Tissue Cμlture,Academic Press,Kruse和Patterson编辑(1973)。有用的哺乳动物宿主细胞系例子是:猴肾细胞;人胚肾细胞系;乳仓鼠肾细胞;中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub等,Proc.Natl.Acad.Sci.USA,77:4216(1980));小鼠足细胞;人宫颈癌细胞(HELA);犬肾细胞;;人肺细胞;人肝细胞;小鼠乳房肿瘤和NS0细胞。
为了生产抗体用上述载体转化宿主细胞,并将宿主细胞培养在常规的营养培养基中,培养基经适当修改以适合诱导启动子、选择转化子或扩增编码所需序列的基因。
用于产生本发明抗体变体的宿主细胞可以在各种培养基中培养。商业上可获得的培养基如Ham’s F10(Sigma)、最低必需培养基(MEM)(Sigma)、RPMI-1640(Sigma)、和Dulbecco改进Eagle培养基(DMEM,Sigma)适用于培养宿主细胞。此外,Ham等,Meth.Enz.,58:44(1979),Barnes等,Anal.Biochem.,102:255(1980),美国专利No.4,767,704;4,657,866;4,560,655;5,122,469;5,712,163或6,048,728中所述的任一培养基可用作(本发明)宿主细胞的培养基。所有这些培养基中可以按需添加入激素和/或其它生长因子(如胰岛素、转铁蛋白或表皮生长因子)、盐(如X氯化物,其中X是钠、钙、镁;和磷酸盐)、缓冲剂(如HEPES)、核苷酸(如腺苷和胸苷)、抗生素(如GENTAMYCINTM药)、微量元素(定义为最终浓度通常在微摩尔范围内的无机化合物)以及葡萄糖或等价能源。另外也可加入合适浓度的本领域技术人员已知的其它必需补充物。培养条件,如温度、pH等,与前述选择宿主细胞表达时所用条件一样,这对本领域普通技术人员来说是显而易见的。
抗体纯化
当采用重组技术时,抗体可产生在细胞内(周质空间内)或被直接分泌到培养基中。如果抗体突变体产生在细胞内,则第一步是除去宿主细胞或裂解片段的颗粒碎片,例如通过离心或超离心除去。Carter等,Bio/Technology 10:163-167(1992)描述了分泌入大肠杆菌周质空间的抗体的分离过程。简言之,在乙酸钠(pH3.5)、EDTA和苯甲基磺酰氟(PMSF)存在下融解细胞浆状物约30分钟。离心除去细胞碎片。若抗体突变体被分泌到培养基中,则通常首先用商业上购得的蛋白浓缩滤膜(例如Amicon或Millipore Pellicon超滤装置)浓缩该表达系统的上清液。在前述任何步骤中均可加入抑制蛋白水解的蛋白酶抑制剂(如PMSF),还可加入抗生素来防止外来污染物的生长。
例如,可用羟基磷灰石层析、凝胶电泳、透析和亲和层析来纯化从细胞中制得的抗体组合物,其中亲和层析是优选的纯化方法。蛋白A作为亲和配体的合适性取决于抗体突变体中免疫球蛋白Fc区的种类和同种型。蛋白A可用来纯化以人IgG1、IgG2或IgG4重链为基础的抗体(Lindmark等,J.Immunol.Meth.62:1-13(1983))。对于所有小鼠同种型和人IgG3,建议采用蛋白G(Guss等,EMBO J.5:1567-1575(1986))。亲和配体附着的基质通常是琼脂糖,但是也可采用其它基质。机械上稳定的基质,如控制孔径的玻璃或聚(苯乙烯二乙烯基)苯能达到比琼脂糖更快的流速,并使操作时间缩短。当抗体突变体包含CH3区时,可用Bakerbond ABXTM树脂(J.T.Baker,Phillipsburg,NJ)来纯化。根据待回收的抗体突变体,还可采用其它蛋白纯化方法,如在离子交换柱上分级分离、乙醇沉淀、反向HPLC、硅胶层析、肝素SEPHAROSETM层析、阴离子或阳离子交换树脂(如聚天冬氨酸柱)层析、聚焦层析、SDS-PAGE和硫酸铵沉淀。
在初步纯化后,可对包含目的抗体突变体和污染物的混合物进行低pH疏水作用层析,采用pH约2.5-4.5的洗脱缓冲液,最好是在低盐浓度(如约0-0.25M盐浓度)下进行。
药物制剂
将具有所需纯度的多肽与本领域中通常采用的任选的“药学上可接受”载体、赋形剂或稳定剂(所有这些均称为“赋形剂”)例如缓冲剂、稳定剂、防腐剂、等渗剂、非离子性洗涤剂、抗氧化剂和其它各种添加剂)(参见Remington’s Pharmaceutical Sciences,16版,Osol,A.编辑(1980)混合,制成多肽或抗体的药物制剂,以用于作为冻干制剂或水性溶液保藏。这些添加剂必须在所采用的剂量和浓度下对接受者没有毒性。
缓冲剂有助于将pH维持在大致为生理条件的范围内。缓冲剂的浓度最好在大约2mM至50mM内。适用于本发明的缓冲剂包括有机和无机酸及其盐,例如柠檬酸盐缓冲液(例如柠檬酸单钠-柠檬酸二钠混合物、柠檬酸-柠檬酸三钠混合物、柠檬酸-柠檬酸单钠混合物等)、琥珀酸盐缓冲液(例如琥珀酸-琥珀酸单钠混合物、琥珀酸-氢氧化钠混合物、琥珀酸-琥珀酸二钠混合物等)、酒石酸盐缓冲液(例如酒石酸-酒石酸钠混合物、酒石酸-酒石酸钾混合物、酒石酸-氢氧化钠混合物等)、延胡索酸盐缓冲液(例如延胡索酸-延胡索酸单钠混合物)、延胡索酸盐缓冲液(例如延胡索酸-延胡索酸钠混合物、延胡索酸-延胡索酸二钠混合物、延胡索酸单钠-延胡索酸二钠混合物等)、葡糖酸盐缓冲液(例如葡糖酸-葡糖酸钠混合物、葡糖酸-氢氧化钠混合物、葡糖酸-葡糖酸钾混合物等)、草酸盐缓冲液(例如草酸-草酸钠混合物、草酸-氢氧化钠混合物、草酸-草酸钾混合物等)、乳酸盐缓冲液(例如乳酸-乳酸钠混合物、乳酸-氢氧化钠混合物、乳酸-乳酸钾混合物等)、以及乙酸盐缓冲液(例如乙酸-乙酸钠混合物、乙酸-氢氧化钠混合物等)。另外,也可以是磷酸盐缓冲液、组氨酸缓冲液和三甲胺如(Tris)。
加入防腐剂以阻止微生物生长,加入量在0.2-1%(w/v)范围内。用于本发明的合适的防腐剂包括苯酚、苄醇、间甲酚、对羟苯甲酸甲酯、对羟苯甲酸丙酯、十八烷基二甲基苯基氯化铵、苯扎卤(例如氯、溴、碘)铵、氯化己烷双胺、对羟苯甲酸烷酯(如对羟苯甲酸甲酯或对羟苯甲酸丙酯)、邻苯二酚、间苯二酚、环己醇和3-戊醇。
等渗剂有时称为“稳定剂”,可以添加以确保本发明的液体组合物的等渗性,其包括多羟基糖醇,优选三羟或更多羟基的糖醇,例如甘油、丁四醇、阿糖醇、木糖醇、山梨糖醇和甘露糖醇。
稳定剂指广义的赋形剂,其功能从填充剂到溶解治疗剂或有助于防止变性或粘附在容器壁上的添加剂。典型的稳定剂可以是多羟基糖醇(如上所述);氨基酸,如精氨酸、赖氨酸、甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、丙氨酸、鸟氨酸、L-亮氨酸、2-苯基丙氨酸、谷氨酸、苏氨酸等;有机糖或糖醇,如乳糖、海藻糖、木苏糖、甘露糖、山梨糖醇、木糖醇、核糖醇、肌醇、半乳糖醇、甘油等,包括环多醇如环己六醇;聚乙二醇;氨基酸聚合物;含硫还原剂,如尿素、谷胱苷肽、硫辛酸、巯基乙酸钠、硫代甘油、α-单硫代甘油和硫代硫酸钠;低分子量多肽(即小于10个残基);蛋白质,如人血清白蛋白、牛血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,如聚乙烯吡咯烷酮单糖(单糖是例如木糖、甘露糖、果糖、葡萄糖);二糖如乳糖、麦芽糖、蔗糖和三糖如蜜三糖;多糖如葡聚糖。稳定剂的含量范围为每份重量活性蛋白中有0.1-10,000重量份。
添加非离子表面活性剂或洗涤剂(也称为“润湿剂”)有助于溶解治疗剂以及保护治疗剂避免受搅动引起的凝集,它还使得当制剂暴露于遭受应力的剪切表面时不会引起蛋白变性。合适的非离子表面活性剂包括聚山梨醇酯(20、80等)、polyoxamer(184,188等)、Pluronic.RTM.多元醇、聚氧乙烯山梨糖醇单醚(吐温.RTM.-20、吐温.RTM.-80等)。非离子性表面活性剂的含量约为0.05mg/ml至1.0mg/ml,较佳的约0.07mg/ml至约0.2mg/ml。
其它各种赋形剂包括填充剂(如淀粉)、螯合剂(如EDTA)、抗氧化剂(如抗坏血酸、甲硫氨酸、维生素E)和共溶剂。本发明的制剂还含有待治疗特定适应症所需的多种活性化合物,优选相互间没有不利影响的有互补活性的那些化合物。例如,理想地还可以提供免疫抑制剂。这些分子适于以组合形式存在,其量对期望的目的有效。在胶态药物递送系统(例如,脂质体、白蛋白微珠、微乳剂、纳颗粒和纳胶囊)或巨乳剂中,活性组分还可被包裹在例如通过团聚技术或界面聚合制得的微胶囊(例如羟甲基纤维素或明胶微囊和聚(甲基丙烯酸甲酯)微囊)中。这些技术公开在Remington’s Pharmaceutical Sciences,16版(1980),A.Osal编辑。
用于体内给药的制剂必须无菌。这很容易例如通过无菌滤膜过滤来实现。可以制得缓释制剂。缓释制剂的合适例子包括含有抗体突变体的固体疏水聚合物半渗透基质,其中所述基质是成形制品,如薄膜或微胶囊。缓释基质的例子包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟基乙酯)或聚(乙烯醇))、聚交酯(美国专利号3,773,919)、L-谷氨酸和L-谷氨酸乙酯的共聚物、不能降解的乙烯乙酸乙烯酯、可降解的乳酸-羟基乙酸共聚物如LUPRONDEPOTTM(由乳酸-羟基乙酸共聚物和乙酸亮丙瑞林组成的可注射的微珠)、和聚-D-(-)-3-羟基丁酸。尽管聚合物例如乙烯乙酸乙烯酯和乳酸-羟基乙酸能够在100天内持续释放分子,但是某些水凝胶释放蛋白的时间却较短。当包裹在胶囊内的抗体长时间停留在体内时,它们会由于暴露在37℃潮湿环境下而变性或凝聚,从而导致生物活性丧失,且免疫原性可能会改变。可以根据涉及的机理来设计合理策略加以稳定。例如,如果发现凝聚的机理是通过硫代-二硫键互换而形成了分子间S-S键,则可通过修饰巯基残基、从酸性溶液中冻干、控制含水量、采用合适的添加剂和开发特定的聚合物基质组合物来达到稳定化。
在治疗特定疾病或状况中,治疗性多肽、抗体或其片段的有效量将取决于疾病或状况的性质,并且能用标准临床技术来确定。在可能的时候,希望首先在体外测定本发明药物组合物的剂量-反应曲线,然后在人体内测试前在有用的动物模型系统中测定。
在一优选的实施方案中,通过皮下注射给予治疗性多肽、抗体或其片段的水溶液。每剂的范围在大约0.5μg至50μg/千克体重,或更优选从3μg至约30μg/千克体重。
皮下给药的剂量方案可以从一月一次到每日一次,这取决于许多临床因素,包括疾病类型、疾病严重程度以及患者对治疗剂的敏感程度。
人源化抗体的应用
本发明的人源化抗体可用于诊断实验,例如检测特定细胞、组织或血清中感兴趣靶的表达。对于诊断性应用,抗体突变体通常用可检测基团作标记。可采用许多标记物。定量测定荧光变化的技术如上所述。化学发光底物通过化学反应被电激发,然后可发出可测定(例如通过化学发光计)的光或提供能量给荧光接受器。酶标记物的例子包括萤光素酶(如萤火虫萤光素酶和细菌萤光素酶;美国专利号4,737,456)、荧光素、2,3-二氢酞嗪二酮、苹果酸脱氢酶、脲酶、过氧化物酶(如辣根过氧化物酶(HRPO))、碱性磷酸酶、β-半乳糖苷酶、葡糖淀粉酶、溶菌酶、糖氧化酶(例如,葡糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶)、杂环氧化酶(如尿酸酶和黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。O’Sμllivan等,Method for the Preparation of Enzyme-Antibody Conjμgates for use in EnzymeImmunoassay,Methods in Enzym.(Ed.J.Langone&H.Van Vunakis),Academic press,NewYork,73:147-166(1981)中将描述了将酶偶联于抗体的技术。
有时,标记可以与抗体变体间接偶联。本领域技术人员应该知道实现这一目的的各种方法。例如,抗体变体可以与生物素偶联,而上述三大类标记物则与亲和素偶联,或两者互换。生物素选择性地结合亲和素,从而通过这一间接方式将标记物和抗体变体偶联起来。或者,为了间接地偶联标记物和抗体变体,可使抗体变体与小的半抗原(如洋地黄毒苷(digloxin))偶联,而上述不同类型的标记物中的一种则与抗该半抗原的抗体变体(如抗洋地黄毒苷抗体)偶联。这样,就间接地将标记物和抗体变体偶联起来。
在本发明的另一个实施方案中,不标记抗体变体,该抗体变体的存在可用与之结合的标记的抗体来检测。
本发明的抗体可用于任何已知的实验方法,如竞争性结合实验,直接和间接夹心实验和免疫沉淀实验。Zola,Monoclonal Antibodies:A Manual of Techniques),147-158页(CRC Press,Inc.1987)。
竞争性结合实验依赖于标记的标准品与测试样品竞争结合有限量抗体变体的能力。测试样品中靶的量与结合抗体的标准品的量成反比。为了便于确定已结合的标准品的量,抗体通常在竞争前后为不溶性的。这样就能方便地将已结合抗体的标准品和测试样品从仍未结合的标准品和测试样品中分离出来。
夹心实验包括采用两种抗体,每种抗体能结合待检测蛋白的不同的免疫原性部分或表位。在夹心测定法中,待分析的测试样品与固定在固相载体上的第一抗体结合,然后,第二抗体与测试样品结合,从而形成了不溶性的三组分复合物。例如见美国专利号4,376,110。第二抗体本身可用可检测物质标记(直接夹心测定法),或可利用标记了可检测物质的抗免疫球蛋白抗体来测定(间接夹心测定法)。例如,一类夹心测定法是ELISA测定法,在该种情况下,可检测物是酶。
对于免疫组织化学,肿瘤样品可以是新鲜的或冷冻的,或可包埋在石蜡中并用防腐剂(例如福尔马林)来固定。
抗体也可用于体内诊断实验。通常,抗体用放射性核素(如.sup.111In、.sup.99Tc、.sup.14C、.sup.131I、.sup.3H、.sup.32P或.sup.35S)标记,这样通过免疫闪烁显影可确定肿瘤的位置。例如,本发明的高亲和力抗-lgE抗体可用于检测存在于例如哮喘患者肺中IgE的量。
本发明的多肽或抗体可以试剂盒形式提供,即,将预定剂量的试剂与进行诊断实验的说明书组合包装。当抗体变体用酶标记时,试剂盒将包括酶所需的底物和辅因子(如提供可检测的发色团或荧光团的底物前体)。另外,还可包括其它添加剂,如稳定剂、缓冲液(如封闭缓冲液或裂解缓冲液)等。各种试剂的相对量可以变化很大,使得提供的溶液中试剂浓度能使实验的灵敏度基本上达到最优。特别是,试剂可以干粉形式(通常是冻干的)提供,包括在溶解时能提供浓度合适的试剂溶液的赋形剂。
抗体的体内应用
预期本发明的多肽或抗体可用来治疗哺乳动物。例如在一个实施方案中,将抗体给予非人哺乳动物以获得临床前数据。示例性的待治疗非人哺乳动物包括非人的灵长类、狗、猫、啮齿类动物和其它能进行临床前研究的哺乳动物。所述哺乳动物可以是已经建立的待用抗体来治疗的疾病动物模型,或者可用来研究目的抗体毒性的动物模型。在每个实施方案中,可在哺乳动物中进行剂量逐步增加的研究。
抗体或多肽可通过任何合适的方法施用,包括肠胃外、皮下、腹膜内、肺内、和鼻内给药,如果需要局部免疫抑制治疗,可以在病变区内施用。胃肠外输注包括肌内、静脉内、动脉内、腹膜内、或皮下施用。另外,抗体突变体可通过脉冲注入的方式施用,特别是伴随减少抗体突变体的剂量。优选通过注射施用药物剂量,最优选是静脉内或皮下注射施用,这部分地取决于是瞬时施用还是不断地施用。
为了预防或治疗疾病,抗体或多肽的合适剂量取决于待治疗疾病的类型、疾病的严重程度和病程、给予抗体突变体是出于预防目的还是治疗目的、以往的治疗、患者的临床病史以及对抗体的反应、和治疗医师的判断。
根据疾病的类型和严重程度,无论是通过例如一次或多次分开施用还是连续输注,施用于患者的抗体初始候选剂量大约是0.1mg/kg至150mg/kg(例如0.1-20mg/kg)。根据上述因素,典型的每日剂量可以在大约1mg/kg至100mg/kg或以上的范围内。对于几天或更长时间内的重复施用,根据病征,应维持治疗直至疾病症状受到所需的抑制。然而,可采用其它剂量方案。这种治疗的进程很容易用常规技术和实验来监测。示例性的剂量方案公开在WO94/04188中。
抗体组合物可以以与良好的医学实践相一致的方式配制、按剂量给药或施用。在本文上下文中考虑的因素包括待治疗的特定的疾病、待治疗的特定的哺乳动物、患者个体的临床状况、病因、递送试剂的部位、施用方法、施用方案以及医生所知的其它因素。所施用的抗体的“治疗有效量”将由这些考虑因素决定,并且是预防、改进或治疗疾病或失调所需的最少量。抗体不需要但任选地可以与目前使用的一种或多种试剂配制在一起,以预防或治疗所讨论的疾病。所述其他试剂的有效量取决于制剂中抗体的量、疾病或治疗的类型、以及上述的其它因素。这些试剂的用量和施用途径通常和上文所用的相同,或者约为上文所用剂量的1-99%。
识别D因子作为其靶的本发明抗体可用于治疗补体介导的病症。这些病症与过度的或不受控制的补体激活有关。它们包括:心肺体外循环期间的补体激活;急性心肌梗塞、动脉瘤、中风、出血性休克、挤压伤、多器官衰竭、低血容量性休克、肠局部缺血后的局部缺血再灌注引起的补体激活。病症还可以包括的疾病或病情为炎症病情,如严重烧伤、内毒素血症、脓毒性休克、成人呼吸窘迫综合征、血液透析、过敏性休克、严重哮喘、血管性水肿、克罗恩氏病、镰刀形红细胞贫血病、链球菌感染后肾小球肾炎和胰腺炎。所述病症可以是不良药物反应、药物过敏、IL-2诱导的血管渗漏综合症或放射摄影造影剂过敏的结果。所述病症还包括自身免疫性疾病如全身性红斑狼疮、重症肌无力、类风湿性关节炎、阿尔茨海默氏病和多发性硬化。补体激活还与移植排斥有关。最近已表明补体激活和眼病如年龄相关的黄斑变性,糖尿病性视网膜病之间强烈相关。
实施例
提供下列实施例进行说明,而非进行限制。
实施例1:D因子小鼠MAb166-32的人源化。
将小鼠mAb166-32的重链可变区(VH)和轻链可变区(VL)序列与公共数据库中可利用的人抗体系序列比较。在如上述步骤1中确定模板时使用一些标准,包括全长、框架区内类似的CDR位点、整体同源性、CDR的大小等。所有这些标准一起提供结果用于选择最优的人模板,如166-32MAb重链和轻链序列与图3和4中描述的各个人模板序列之间的序列比对所示。
在这种情况下,用多个人框架模板设计所述抗体。选择用于VH链的人模板为VI-4.1b+(7-04.1基因座)(登录号#X62110)(VH7家族)与JH4d(参见图3)的组合。选择用于VL链的人模板为DPK4(VK I家族)与JK2的组合(参见图4)。
一旦选择了模板,通过DNA合成与重叠PCR构建Fab文库。文库由用各自选择的人模板合成的MAb 166-32CDR组成。编码部分VH与VL序列的重叠核苷酸在约63至约76个核苷酸范围内被合成,其具有18至21个核苷酸重叠。构建表达抗D因子抗原的人源化Fab文库的载体,并且转化入大肠杆菌DH10B中,随后在XL-1B细菌菌苔上铺板。
用规模(独立克隆的数目)和多样性(突变体的分布)来评估文库质量。具有轻链和重链双插入的单个克隆在测序的20个中为约14个。框架摆动突变体均匀分布。
PCR扩增VL和VH基因,利用包含框架区FR1的序列和与前导序列末端退火的突出端序列(GeneⅢ)的生物素化正向引物,以及来自保守恒定区(CK或CH1)的反向引物,在标准PCR条件下进行。通过琼脂糖凝胶电泳或通过商业的PCR纯化试剂盒纯化PCR产物以去除未反应的生物素化引物和非特异性PCR。
实施例2:文库筛选
用捕获过滤挖出法(Capture Filter Lift)进行初步筛选。实际的筛选规模比理论文库的规模大3倍。候选者进一步通过单点ELISA实验筛选。基于Fab浓度,利用D因子直接抗原滴定法进一步确定最好的结合剂。
捕获挖出筛选
用捕获过滤挖出法进行Fab结合D因子的初步筛选。高效价的噬菌体在37℃中植于平皿中并且孵育直至使用(约6-8小时)。山羊抗-人κ在10ml PBST中稀释至10μg/ml;根据标准的斑点挖取流程制备用于挖取斑点的硝酸纤维素滤膜,随后浸入振荡器上的10ml封闭缓冲液中2小时。滤膜用PBST漂洗3次。滤膜用于斑点菌苔并且在RT孵育大约15-24小时。随后从平皿移去滤膜并且用TBST漂洗3次。
D因子(50μg/ml)在PBST中稀释至0.1μg/ml并且每个滤膜添加4ml。滤膜在振荡器上溶液中RT孵育2小时,随后漂洗3次,每次5分钟。稀释的166-222-HRP(用PBST以1:10,000稀释)以每个滤膜4ml的体积添加并且在振荡器上温育1小时。滤膜漂洗4次。干燥滤膜并随后浸入TMB底物中,接着浸入水中以终止反应。鉴定阳性克隆。
实施例3:单点ELISA筛选
用单点ELISA实验进行第二次筛选。用山羊抗-人Fab包被Immμlon II平皿(1:12,000,50μl/孔),RT过夜。第二天用平皿洗涤剂洗涤平皿4次。以每孔l00μl的体积添加封闭缓冲液并且平皿在RT孵育1小时。随后洗涤平皿4次。
所要筛选的每种Fab以每孔50μl的体积添加(或者来自15ml周质制备物或上清)并且在RT温育1小时。洗涤平皿4次,随后添加0.01μg/ml的50μl/孔生物素化的D因子。在RT孵育平皿1小时后洗涤4次。添加链亲和素-HRP(PBST中1:10,000)并且在RT温育1小时。洗涤平皿5次,随后通过以50μl/孔添加TMB底物而显影。当其很好地显影(10-45分钟)时添加50μl体积的终止缓冲液并且在450nm读取平皿。
实施例4:人源化抗D因子克隆的测序
对与人D因子具有良好结合亲和力的16个人源化克隆测序(参见表1)。这当中,轻链中的位点2(100%人)和49(100%小鼠)和重链中的位点93(100%小鼠)为高度保守的,表明其对于维持抗体的结合能力很重要。
表1.来自人源化文库的人源化克隆的氨基酸序列分析
VK | 2 | 4 | 13 | 43 | 49 | 64 | 69 | VH | 2 | 9 | 38 | 93 | 97 |
鼠 | T | V | M | P | S | S | A | I | P | K | T | E | |
人 | I | M | A | V | Y | G | T | V | S | R | V | A | |
7 | I | M | M | V | S | S | T | I | P | K | V | E | |
30 | I | V | A | V | S | S | A | V | P | K | T | E | |
45 | I | V | M | V | S | G | A | I | S | R | V | E | |
46 | I | V | M | V | S | S | T | I | S | R | V | E | |
47 | I | V | A | V | S | S | T | I | S | R | V | E | |
48 | I | V | M | V | S | S | T | V | P | R | V | E | |
50 | I | V | M | V | S | G | A | V | P | R | T | E | |
51 | I | M | M | V | S | G | T | I | S | K | T | E | |
56 | I | V | A | V | S | G | T | V | P | K | T | E | |
57 | I | M | M | V | S | S | A | V | S | R | V | E | |
58 | I | V | M | P | S | G | A | V | P | R | V | E | |
59 | I | V | A | P | S | S | T | V | P | K | V | E | |
60 | I | V | M | P | S | G | T | V | P | R | V | E | |
63 | I | V | M | V | S | S | T | V | S | R | T | E | |
74 | I | V | M | V | S | S | T | I | S | R | V | E |
通过BIAcore分析和溶血抑制实验评估克隆#56。BIAcore分析表明克隆#56具有与嵌合的166-32Fab类似的对人D因子的亲和力(参见表4)。溶血抑制实验表明克隆#56比嵌合的166-32Fab更加有效力(参见图6)。克隆#56含有轻链框架中的两个小鼠残基以及重链中的四个小鼠残基(参见表1)。基于这些结果,进行进一步的优化。
表2.夹自人源化/CDR3优化文库的优化抗体的氨基酸序列分析
通过BIAcore分析表征克隆#111和#114(参见表4)。克隆#104、#111、#114和#130还通过溶血抑制实验来表征(参见图6)。这些克隆具有比嵌合的166-32更高的亲和力,并且如通过溶血抑制实验所示,对抑制旁路途径比嵌合的Fab更有效(图7)。克隆#111含有与克隆#56相同的两个轻链中的小鼠残基(位点4和49)。如克隆#56中发现的,其在重链位点97处也含有保守的小鼠残基。克隆#111的轻链和重链中均存在一个有益的突变。从两个独立的筛选文库(人源化文库和人源化/CDR3优化文库),发现最好克隆具有类似的共有序列残基。
为了进一步优化克隆#111的亲和力,通过将单突变同时引入CDR-H1和CDR-L2中来构建抗体文库。简言之,通过将编码单突变的寡核苷酸退火至克隆#111的模板,用定点诱变方法构建所述文库。对人D因子具有很高亲和力的总共24个克隆被测序。在这24个克隆当中,鉴定一些冗余有益突变。选择克隆#250、#315、#345和#416用于BIAcore分析(参见表4)。BIAcore数据表明这些克隆比原始克隆#111对人D因子的亲和力更高。克隆#250、#315、#348和#416也在溶血抑制实验中(参见图6)和旁路途径的抑制中(图7)测试。
实施例5:AP溶血实验
利用溶血抑制实验和BIAcore分析测定人源化克隆的生物学功能(参见以下实施例6)。根据下列流程进行溶血实验。从20ml盐水(0.9%NaCl)中1∶20稀释的兔红血细胞(RRBC)(0.5ml+9.5ml GVB/Mg-EGTA缓冲液)(大约1:2×104稀释),取20μl通过Coulter计数器计数。细胞浓度随后调整至约2-5×104细胞/ml。每个平皿接受约500×106/平皿RRBC或约1ml RRBC/平皿(500×106/2-5×104)。
细胞稀释于6ml GVB/Mg-EGTA缓冲液/平皿,在4℃以1360rpm×4分钟离心而混合并洗涤3次。RRBC小团沉淀物悬浮于3ml GVB/Mg-EGTA缓冲液/平皿中并且保存于冰上。
在使用之前融解来自-80℃冰箱的人血清。血清稀释于GVB/Mg-EGTA缓冲液中至20%的浓度,5ml/平皿(最终为10%)并且保存于冰上。
表3
样品在5-6℃振荡30秒且随后在37℃振荡40分钟。样品在振荡时冷却至5-6℃且随后在4℃,2,000rpm离心3分钟。转移大约80μl上清液至平底96孔平皿并且利用标准的平皿读数器读取590nm的OD值。如下计算抑制百分比:%抑制={[(S-SB)-(U-SB)]/(S-SB)}×100%。(U=样品1、2或3(分别为表3的第1、2或3列))。
实施例6:通过BiaCore动力学分析抗-人D因子Fab
固定:人D因子(Advanced Research Inc,0.1mg/ml)利用胺-偶联方法直接固定在CM5芯片上(BiaCore)。流程简要描述如下:(1)恒流(PBS)为5μl/min。(2)注入35μl EDC/NHS(1:1)。(3)注入pH 4.5的35μl乙酸盐缓冲液中的人D因子。(4)注入35μl乙醇胺阻断激活的组。(5)用5μl pH 1.5的10mM甘氨酸净化表面。配体(人D因子)固定水平为约1,000RU。利用α人D因子(huDi,40μl,31.5μg/ml)检验产生约900RU的相对应答。
动力学分析:所有抗-人D因子Fab稀释于PBS缓冲液中。每个样品用连续稀释的方式制备:12.5nM、25nM、50nM、75nM、100nM、125nM和150nM,以高采集率的40μl脉冲注入。通过施加5μl pH 1.5的10mM甘氨酸脉冲实现再生。通过在拟一阶动力学下利用BIAvaluation3.0版本将Fab结合痕迹拟合至1:1结合模型而获得动力学参数。结果在以下表4中呈现。通过全局拟合程序获得所有的数据。
表4BIAcore结果
Fab克隆
本领域技术人员将认识到或仅仅利用常规实验能够确定此处所述的本发明具体实施方案的许多等同方案。所述等同方案由下列权利要求所涵盖。
Claims (37)
1.包含SEQ ID NO:1的重链可变区序列的小鼠抗体。
2.包含SEQ ID NO:2的轻链可变区序列的小鼠抗体。
3.包含权利要求1的重链可变区序列和权利要求2的轻链可变区序列的小鼠抗体。
4.包含SEQ ID NO:13、14、15、16、17和18的抗体。
5.包含SEQ ID NO:1和SEQ ID NO:2的嵌合抗体。
6.人源化抗体的可变区,其包含选自SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10和SEQID NO:12的重链可变区氨基酸序列。
7.人源化抗体的可变区,其包含选自SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9和SEQID NO:11的轻链可变区氨基酸序列。
8.人源化抗-D因子抗体,其包含SEQ ID NO:5的可变区序列和SEQ ID NO:6的可变区序列。
9.人源化抗-D因子抗体,其包含SEQ ID NO:7的可变区序列和SEQ ID NO:8的可变区序列。
10.人源化抗-D因子抗体,其包含SEQ ID NO:9的可变区序列和SEQ ID NO:10的可变区序列。
11.人源化抗-D因子抗体,其包含SEQ ID NO:11的可变区序列和SEQ ID NO:12的可变区序列。
12.具有可变轻链的人源化抗-D因子抗体,该轻链包含具有SEQ ID NO:16的序列的CDR-L1;具有SEQ ID NO:17、21或23的序列的CDR-L2和具有SEQ ID NO:18、22或24的序列的CDR-L3。
13.具有可变重链的人源化的抗-D因子抗体,该重链包含具有SEQ ID NO:13或25的序列的CDR-H1;具有SEQ ID NO:14的序列的CDR-H2;和具有SEQ ID NO:15或20的序列的CDR-H3。
14.包含下列氨基酸序列的多肽:QX1QLVQSGX2E LKKPGASVKVSCKASGYTFT SYGMNWVX3QAPGQGLEWMGWINTYTGETTYADDFKGRFVF SLDTSVSTAY LQISSLKAED TAX4YYCX5REG GVNNWGQGTLVTVSS(SEQ ID NO:27),其中X1为I或V;X2为P或S;X3为K或R;X4为T或V;且X5为E或A。
15.包含下列氨基酸序列的多肽:DIQX6TQSPSSLSX7SVGDRVTITCITSTDIDDDMNWYQQKPGKX8PKLLIX9DGNTLRPGVPSRFSX10SGSGX11DFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKLEIK(SEQ IDNO:26),其中X6为V或M;X7为M或A;X8为P或V;X9为S或Y;X-10为S或G且X11为A或T。
16.包含SEQ ID NO:6、8、10或12的氨基酸序列的多肽。
17.包含SEQ ID NO:5、7、9或11的氨基酸序列的多肽。
18.包含权利要求14的多肽的人源化抗体。
19.权利要求18的人源化抗体,进一步包含权利要求15或33的多肽。
20.权利要求1-13、18-19、31或32的任一项的抗体片段。
21.包含SEQ ID NO:3的序列的分离的核酸。
22.包含SEQ ID NO:4的序列的分离的核酸。
23.分离的核酸,其编码权利要求1-13、18-19、31或32的任一项的抗体。
24.分离的核酸,其编码权利要求14至17的任一项的多肽。
25.包含权利要求23的核酸的载体。
26.包含权利要求24的核酸的载体。
27.包含权利要求25或26的载体的细胞系。
28.包含权利要求1-13、18或19的任一项的抗体的组合物。
29.权利要求28的组合物在治疗补体介导的病症中的应用。
30.权利要求29的应用,其中所述病症为眼病,如年龄相关的黄斑变性或糖尿病性视网膜病。
31.权利要求7的可变区,其中SEQ ID NO:7的位点104处的氨基酸为缬氨酸或亮氨酸。
32.权利要求9的人源化抗-D因子抗体,其包含SEQ ID NO:7的可变区序列和SEQ IDNO:8的可变区序列,其中SEQ ID NO:7的位点104处的氨基酸为缬氨酸或亮氨酸。
33.权利要求15的多肽,其中SEQ ID NO:26的位点104处的氨基酸为缬氨酸或亮氨酸。
34.权利要求17的多肽,其中SEQ ID NO:7的位点104处的氨基酸为缬氨酸或亮氨酸。
35.制备权利要求1-13、18-19、31或32的任一项的人源化抗-D因子抗体或其片段的方法。
36.与小鼠抗体166-32和/或人源化抗-D因子抗体克隆#56、#111、#250或#416和/或包含人源化抗-D因子抗体克隆#56、#111、#250或#416的可变区或HVR序列的抗体竞争的抗体。
37.与小鼠抗体166-32和/或人源化抗-D因子抗体克隆#56、#111、#250或#416和/或包含人源化抗-D因子抗体克隆#56、#111、#250或#416的可变区或HVR序列的抗体结合相同表位的抗体。
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