CN100390288C - 多价抗体及其应用 - Google Patents
多价抗体及其应用 Download PDFInfo
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- CN100390288C CN100390288C CNB018103723A CN01810372A CN100390288C CN 100390288 C CN100390288 C CN 100390288C CN B018103723 A CNB018103723 A CN B018103723A CN 01810372 A CN01810372 A CN 01810372A CN 100390288 C CN100390288 C CN 100390288C
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Abstract
本申请描述具有三个或更多个功能性抗原结合部位的基因工程抗体,和此类基因工程抗体的用途,例如治疗应用。
Description
发明背景
发明领域
本发明涉及具有三个或更多个功能性抗原结合部位的基因工程抗体,和此类基因工程抗体的用途,如治疗应用。
相关技术描述
天然存在抗体的结构
天然存在抗体(免疫球蛋白)包含靠二硫键连接在一起的两条重链和两条轻链,每一条轻链与每一条重链靠二硫键相连。每条重链在一末端有一个可变区(VH),其后是多个恒定区(三个或四个恒定区,CH1、CH2、CH3和CH4,取决于抗体种类)。每条轻链在一末端有一个可变区(VL),在另一末端有一个恒定区(CL);轻链的恒定区与重链的第一恒定区对齐,而轻链可变区与重链可变区对齐。见本文图1。据信,在轻链和重链可变区之间由具体的氨基酸残基形成一个界面,参见例如,Chothia等,J.Mol.Biol.186:651-663(1985);及Novotny和Haber,Proc.Natl.Acad.Sci.USA 82:4592-4596(1985)。
恒定区并不直接参与抗体与抗原的结合,但却参与各种效应器功能,如参与抗体在抗体依赖性细胞介导的细胞毒作用(ADCC)和补体依赖性细胞毒性(CDC)中的作用。每对轻链和重链的可变区直接参与抗体与抗原的结合。天然存在轻链和重链的可变区具有相同的一般结构;每一可变区包括由3个互补决定区(CDRs)连接的4个框架区(FRs),其序列多少有些保守。(见Kabat等,Sequences of proteins of Immunological Interest,National Institutes ofHealth,Bethesda,MD,(1991))。此4个FRs大多采取β-片层构象,而CDRs形成环连接,某些情况下形成β-片层结构的一部分。每条链的CDRs通过FRs而与另一条链的CDRs紧密相接,从而形成抗原结合部位。
图2A-E描述5种主要天然存在免疫球蛋白同种型的结构。IgG、IgD和IgE免疫球蛋白仅有2个抗原结合部位。另一方面,IgA和IgM能够形成具有更高价的多聚结构。
IgM是由浆细胞分泌的五聚体,其五个单体由连接它们羧基末端(Cμ4/Cμ4)结构域和Cμ3/Cμ3结构域的二硫键结合在一起。这五个单体亚单位是这样排列的:它们的Fc区位于五聚体的中央,10个抗原结合部位位于分子的外周。每个五聚体包含另外的称为J(连接)链的Fc-连接多肽,它通过二硫键连接到10个μ链中2个的羧基末端半胱氨酸残基上。该J链似乎对于单体聚合以形成由五聚体IgM而言是必需的;它恰好是在五聚体分泌之前才加上去的。一个IgM分子可以结合10个小的半抗原分子;然而,由于空间位阻,仅能同时结合5个较大的抗原分子。增加了价数的五聚体IgM,增加了其结合多维抗原如病毒颗粒和红细胞(RBCs)的能力。
IgA主要以单体存在,尽管有时可以见到其聚合体形式,如二聚体、三聚体、甚至四聚物。外分泌的IgA由二聚体或四聚物,一个J链多肽和一个称为分泌成分的多肽链构成。
抗体的临床应用
单克隆抗体具有广泛的用途,特别是衍生自啮齿类动物(包括鼠)的单克隆抗体,可是,在人临床应用中它们常常具有抗原性。例如,啮齿类动物单克隆抗体在临床应用中的主要局限性是治疗期间的抗球蛋白反应(Miller等,Blood 62:988-995(1983);and Schroff,R.W.等,Cancer Res.45:879-885(1985))。
本领域技术人员试图通过构建″嵌合″抗体来攻克这一难题,在所述嵌合抗体中,动物抗原结合可变区与人恒定区偶联(Cabilly等,美国专利4,816,567;Morrison等,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984);Boulianne等,Nature 312:643-646(1984);及Neuberger等,Nature 314:268-270(1985))。可以选择人恒定区同种型以适应嵌合抗体参与ADCC和CDC(参见例如Brüggemann等,J.Exp.Med.166:1351-1361(1987);Riechmann等,Nature 332:323-327(1988);Love等,Methods in Enzymology 178:515-527(1989);以及Bindon等,J.Exp.Med.168:127-142(1988))。在代表性的实施方案中,此类嵌合抗体含有约三分之一的啮齿类动物(或其它非人种)序列,因而能够在人类引发显著的抗球蛋白反应。例如,在使用鼠抗-CD3抗体OKT3的情况下,所引起的抗球蛋白反应主要是对抗可变区而不是恒定区(Jaffers等,Transplantation 41:572-578(1986))。
另一努力是为解决抗体的抗原结合功能和减少使用人抗体中的异源序列,Winterse及其同事(Jones等,Nature 321:522-525(1986);Riechmann等,Nature 332:323-327(1988);和Verhoeyen等,Science 239:1534-1536(1988))已经用啮齿类动物的CDRs或CDR序列替换了人抗体的相应片段。
该研究的治疗前景得到临床效果的支持:人源化抗体对2个非何杰金淋巴瘤患者的CAMPATH-1抗原特异,其中一个患者此前已出现了对亲本大鼠抗体的抗球蛋白反应(Riechmann等,Nature 332:323-327(1988);和Hale等,Lancet i:1394-1399(1988))。
有些情况下,用来自啮齿类动物抗体的CDRs代替人框架的人CDRs,足以带来高抗原结合亲和力(Jones等,Nature 321:522-525(1986);Verhoeyen等,Science 239:1534-1536(1988)),而在其它情况下,有必要另外替换一个(Riechmann等,Nature 332:323-327(1988))或数个(Queen等,Proc.Natl.Acad.Sci.USA 86:10029-10033(1989))框架残基。也参见Co等,Proc.Natl.Acad.Sci.USA 88:2869-2873(1991);美国专利5,821,337(Carter等);和美国专利5,530,101(Queen等)。有关人源化抗体的其它参考文献包括:Gorman等,Proc.Natl.Acad.Sci.USA 88:4181-4185(1991);Daugherty等,核酸Research19(9):2471-2476(1991);Brown等,Proc.Natl.Acad.Sci.USA 88:2663-2667(1991);以及Junghans等,Cancer Research 50:1495-1502(1990)。
为了避免产生对抗鼠抗体的人抗体(称为″HAMA反应″),人们可以用人抗体取代嵌合/人源化抗体,来治疗患者。数种技术可用于产生人抗体。
使用噬菌体展示技术可以筛选人抗体。噬菌体展示已被用于从未免疫供体中筛选人抗体(Marks等J.Mol.Biol.222:581-597(1991))。根据这一方法,PCR用于从人外周血淋巴细胞(PBLs)制备的mRNA中扩增可变区基因。使用使IgG和IgM重链的DNA以及κ和λ链的DNA得到扩增的引物。然后,这些基因随机地结合并以与M13噬菌体的基因III外被蛋白融合的单链Fv(scFv)形式进行表达。接着,通过几轮生长(rounds of growth)并且经过与抗原结合(如结合固相化抗原)的筛选而鉴定抗目的抗原的人抗体。见Griffiths等EM80J.12:725-734(1993)。
″合成的″噬菌体-抗体所有组成成分,也已从克隆的人VH-基因片段制得。使用5或8个随机残基的短H3环,首先构建所有组成成分(每一具有49个片段)(2X107克隆),并与固定轻链结合(Hoogenboom等J.Mol.Biol.227:381-388(1992))。经加入一段不同长度的H3环(达到12残基),建立单个文库,从此文库可以筛选出大于20个结合特性的范围(Winter等Ann.Rev.Immuno.12:433-55(1994))。通过随机化处理人抗体CDRs,已从单个抗体的框架建立了其它的合成文库(Garrard and Henner gene 128:103-109(1993))。由此类合成的噬菌体-抗体所有组成成分得来的抗体,也被认为是本文的″人″抗体。
使用噬菌体展示技术,可以改善低亲和力″初级″噬菌体-抗体的亲和力。一个方法是使用链改组策略,其中VH区域保持不变,然后与VL基因的原始文库和通过与固相化抗原结合选择出的更紧密结合物进行重组。通过固定新的VL区并与原始VH文库重组,重复进行此循环(Marks等Bio/technology 10:779-783(1992))。或者,利用错配PCR和由使用噬菌体展示选择出的更高亲和力的结合物,而在初级抗体中引入点突变。Gram等PNAS(USA)89:3576-3580(1992)。
人们也可通过免疫那些已经进行了遗传基因工程改造使之表达人抗体的小鼠来产生人抗体。
重度复合性免疫缺陷病(SCID)小鼠,由于其重组酶基因中的缺陷而缺乏产生自身免疫球蛋白的能力。通过转移人外周血淋巴细胞(PBLs),数个研究组已在这些小鼠中重建了功能性体液免疫系统。这些hu-PBL-SCID小鼠可用于抗原免疫时产生人抗体。Duchosal等Nature 355:258-262(1992)。使用另一方法,关闭小鼠体内的重链和轻链基因,然后把已用含有人重链和轻链基因的大DNA序列进行过工程改造的酵母人工染色体(YACs)引入小鼠中。此″异种小鼠(XenoMice)″能够在目的抗原免疫下产生人抗体。见美国专利5,434,340;美国专利5,591,699;美国专利5,569,825;美国专利5,545,806;和美国专利5,545,807。
也可以通过无限增殖产生目的抗体的人B淋巴细胞,来生产人单克隆抗体。在体外免疫人淋巴细胞,可以避免为产生活化的人B淋巴细胞而免疫人所带来的道德问题。
已经成功地对人PBLs(Borrebaeck等Proc.Natl.Acad.Sci.USA 85:3995-4000(1988))和人脾细胞(Boerner等J.Immunol.147,86-95(1991))进行了体外免疫。使用鼠-人异源杂交作为融合配对,已经在人杂交瘤技术领域取得了进展(Boerner等)。
抗体变体
为了增加抗体的抗原-结合价数,已对抗体进行了修饰。举例来说,Ghetie等使用两个异源双功能性交联剂,在一对IgG间用化学方法引入硫醚键,使肿瘤-反应性单克隆抗体(抗-CD19、抗-CD20、抗-CD21、抗-CD22和抗-HER2抗体)同型二聚体化。Ghetie等PNAS(USA)94:7509-7514(1997);和WO 99/02567.Wolff等Cancer Research 53:2560-2565(1993)使用异源双功能交联剂,也用化学方法联接了IgG单克隆抗体(CHiBR96),在裸鼠产生了具有提高了抗-肿瘤活性的单克隆抗体同型二聚体。
Shopes等,在人IgG1重链羧基末端附近(Ser444)用半胱氨酸替换丝氨酸残基。在Cys444残基间引入的分子间二硫键″尾-对-尾″联接一对免疫球蛋白,从而形成共价二聚体(H2L2)2。据称,抗-丹磺酰二聚体较单体人IgG1在对携带半抗原的红细胞的抗体依赖性补体介导的细胞溶解方面更为有效。Shopes,B.J.Immunol.148(9):2918-2922(1992);和WO 91/19515。该涉及引入半胱氨酸残基的方法,已被用于产生CAMPATH-1H抗体的同型二聚体。使用低密度靶细胞表达性抗原,同型二聚体CAMPATH-1H抗体显示出改善的细胞溶解作用,但是使用高密度细胞表达性抗原,未观察到细胞溶解作用改善。Greenwood等Ther.Immunol.1:247255(1994)。也参见,Caron等J.Exp.Med.176:1191-1195(1992),涉及在重链444位用丝氨酸取代半胱氨酸的基因工程抗CD33抗体使得在IgG的COOH末端形成链间二硫键。据说,同型二聚体性IgG与其亲本IgG具有相同的亲和力,但明显显示出改善内化和使放射性同位素保留在靶白血病细胞内的能力,而且在使用人效应细胞时,对补体介导的白血病细胞杀死和抗体依赖的细胞性细胞毒作用方面更为有效。
Coloma和Morrison Nature Biotech.15:159-163(1997)描述了四价双特异性抗体,所述抗体是经过将编码IgG3抗-丹磺酰抗体C末端(CH3-scFv)之后或铰链(铰链-scFv)之后的单链抗-丹磺酰抗体Fv(scFv)的DNA融合而进行基因工程改造的。也参见WO95/09917。Smith和Morrison通过把(1)IgM重链的Cys 414或(2)IgM重链的Cys 575,或者(1)和(2)插入IgG3重链基因,而改造了3个版本的mu-样IgG3。所有3个突变构建物,均由Sp2/0细胞表达并且装配成含有多达6个H2L2亚单位的聚合物。认为如此产生的IgG的′IgM-样′聚合物既具有IgG的Fcγ受体结合特性又具有IgM的更强补体活性。参见,Smith和Morrison Bio/technique 12:683-688(1994)。
Shuford及其同事从转染的骨髓瘤细胞系分离出了人IgG1抗-B族链球菌抗体低聚体。Shuford等Science 252:724-727(1991)。免疫化学分析和DNA测序表明,细胞系既产生正常κ轻链又产生37kD V-V-C变异轻链(L37)。共转染编码重链与L37的载体,导致低聚IgG的产生。
美国专利5,641,870(Rinderknecht等)描述了与轻链共分泌的含有串连重复重链片段(VH-CH1-VH-CH1)的二价线状F(ab′)2片段。
CH1的C-末端与VH的N-末端直接联接,而没有任何无关的联接蛋白序列。
有关抗体变体的其它出版物包括WO 00/06605;美国专利5,591,828;美国专利5,959,083;美国专利6,027,725;WO98/58965;WO94/13804;Tutt等J.Immunol.147:60-69(1991);WO99/37791;美国专利5,989,830;WO94/15642;EP 628,078B1;WO97/14719;Stevenson等Anti-Cancer DrugDesign 3:219-230(1989)。
ErbB受体酪氨酸激酶
ErbB受体酪氨酸激酶是细胞生长、分化和存活的重要介质。该受体家族包括至少四个不同的成员,包括表皮生长因子受体(EGFR或ErbB1)、HER2(ErbB2或p185neu)、HER3(ErbB3)和HER4(ErbB4或tyro2)。
EGFR,由erbB1基因编码,被推断为与导致人类恶性肿瘤有关。具体而言,已经观察到EGFR在乳腺癌、膀胱癌、肺癌、头颈部癌和胃癌以及神经胶质瘤的表达增加。EGFR受体表达增加常常与同一肿瘤细胞EGFR配体—转化生长因子α(TGF-α)产生增加有关,导致受体由自分泌刺激通路活化。Baselga和Mendelsohn Pharmac.Ther.64:127-154(1994)。在治疗此类恶性肿瘤中,已经评价了抗EGFR或其配体TGF-α和EGF的单克隆抗体,作为治疗剂的价值。参见例如,Baselga和Mendelsohn.,出处同上;Masui等Cancer Research 44:1002-1007(1984);及Wu等J.Clin.Invest.95:1897-1905(1995)。
ErbB家族的第二个成员,p185neu,最初被认定为化学处理过的大鼠的神经母细胞瘤的转化基因产物。neu原癌基因的活化形式,源自所编码蛋白跨膜区的点突变(缬氨酸变为谷氨酸)。观察到乳腺癌和卵巢癌中人neu同系物扩增,并且与预后差相关(Slamon等,Science,235:177-182(1987);Slamon等,Science,244:707-712(1989);和美国专利4,968,603)。迄今,尚未有关于人肿瘤的类似于neu原癌基因的点突变的报道。已观察到HER2过度表达(经常但不是一律归咎于基因扩增)与其他癌症有关,其中包括胃癌、子宫内膜癌、唾液腺癌、肺癌、肾癌、结肠癌、甲状腺癌、胰腺癌和膀胱癌。
抗大鼠p185neu和人HER2蛋白产物的抗体已有描述。Drebin及其同事已经生产了抗大鼠neu基因产物-P185neu的抗体。参见例如,Drebin等,Cell41:695-706(1985);Myers等,Meth.Enzym.198:277-290(1991);和WO94/22478。Drebin等Oncogene 2:273-277(1988)报道,与p185neu两个不同区反应的抗体混合物对植入裸鼠的neu-转化的NIH-3T3细胞产生协同抗-肿瘤效应。也参见1998年10月20日发布的美国专利5,824,311。
Hudziak等,Mol.Cell.BioL 9(3):1165-1172(1989)描述一系列抗HER2抗体的产生,其特征是使用人乳腺肿瘤细胞系SKBR3。SKBR3细胞暴露于抗体后72小时,对单层细胞进行结晶紫染色测定相对细胞增生。利用该分析测定,得到的结果是:称作4D5的抗体抑制细胞增生的最大抑制为56%。在此分析测定中,一系列抗体中的其他抗体较小程度减少细胞增生。进一步发现,抗体4D5使HER2-过度表达性乳腺肿瘤细胞系对TNF-α的细胞毒性作用敏感。也参见,1997年10月14日发布的美国专利5,677,171。在Hudziak等中讨论的抗-HER2抗体,在下述文献中做了进一步描述:Fendly等Cancer Research 50:1550-1558(1990);Kotts等In Vitro 26(3):59A(1990);Sarup等Growth Regulation 1:72-82(1991);Shepard等J.Clin.Immunol.11(3):117-127(1991);Kumar等Mol.Cell.Biol.11(2):979-986(1991);Lewis等Cancer Immunol.Immunother.37:255-263(1993);Pietras等Oncogene 9:1829-1838(1994);Vitetta等Cancer Research 54:5301-5309(1994);Sliwkowski等J.Biol.Chem.269(20):14661-14665(1994);Scott等J.Biol.Chem.266:14300-5(1991);D′souza等Proc.Natl.Acad.Sci.91:7202-7206(1994);Lewis等Cancer Research 56:1457-1465(1996);及Schaefer等Oncogene 15:1385-1394(1997)。
重组人源化IgG1版本的小鼠抗-HER2抗体4D5(rhuMAb HER2或;购自Genentech,Inc.,South San Francisco),对在前已经接受过抗癌治疗的患HER2-过度表达性转移性乳腺癌的患者具有临床疗效(Baselga等,J.Clin.Oncol.14:737-744(1996))。于1998年9月25日得到食品药品管理局的上市许可,用于治疗患有过度表达HER2蛋白的肿瘤的转移性乳腺癌患者。
其他具有不同特性的抗-HER2抗体,描述在下列文献中:Tagliabue等Int.J.Cancer 47:933-937(1991);McKenzie等Oncogene 4:543-548(1989);Maier等Cancer Res.51:5361-5369(1991);Bacus等MolecularCarcinogenesis 3:350-362(1990);Stancovski等PNAS(USA)88:8691-8695(1991);Bacus等Cancer Research 52:2580-2589(1992);Xu等Int.J.Cancer53:401-408(1993);WO94/00136;Kasprzyk等Cancer Research 52:2771-2776(1992);Hancock等Cancer Res.51:4575-4580(1991);Shawver等Cancer Res.54:1367-1373(1994);Arteaga等Cancer Res.54:3758-3765(1994);Harwerth等J.Biol.Chem.267:15160-15167(1992);美国专利5,783,186;Klapper等Oncogene 14:2099-2109(1997);WO 98/77797;以及美国专利5,783,186。同源筛选导致发现了另外2个ErbB受体家族成员;HER3(美国专利5,183,884和5,480,968,以及Kraus等PNAS(USA)86:9193-9197(1989))和HER4(欧洲专利申请599,274;Plowman等,Proc.Natl.Acad.Sci.USA,90:1746-1750(1993);和Plowman等,Nature,366:473-475(1993))。这两种受体均显示至少在某些乳腺癌细胞系中表达增加。
通常发现ErbB受体在细胞中呈各种结合形式,而异源二聚化被认为增加对各种ErbB配体的细胞应答的多样性(Earp等Breast Cancer Researchand Treatment 35:115-132(1995))。EGFR被6种不同的配体结合:表皮生长因子(EGF)、转化生长因子α(TGF-α)、双调节素(amphiregulin)、肝素结合性表皮生长因子(HB-EGF)、β细胞调节素(betacellulin)和表皮调节素(epiregulin)(Groenen等Growth factors 11:235-257(1994))。由单基因选择性(alternative)剪接产生的遗传调节蛋白(heregulin)蛋白家族是HER3和HER4的配体。遗传调节蛋白家族包括α、β和γ遗传调节蛋白(Holmes等,Science,256:1205-1210(1992);美国专利5,641,869;和Schaefer等Oncogene 15:1385-1394(1997));neu分化因子(NDFs),神经胶质生长因子(GGFs);乙酰胆碱受体诱导活性(ARIA);及感觉和运动神经元衍生因子(SMDF)。评述见Groenen等Growth factors 11:235-257(1994);Lemke,G.Molec.&Cell.Neurosci.7:247-262(1996)和Lee等Pharm.Rev.47:51-85(1995)。近日,鉴定了另外两种ErbB配体:神经调节蛋白-2(NRG-2)和神经调节蛋白-3,据报道,神经调节蛋白-2结合HER3或HER4(Chang等Nature 387509-512(1997);和Carraway等Nature 387:512-516(1997)),而神经调节蛋白-3结合HER4(Zhang等PNAS(USA)94(18):9562-7(1997))。HB-EGF、β细胞调节素和表皮调节素也与HER4结合。
尽管EGF和TGF-α不结合HER2,但是,EGF刺激EGFR和HER2形成异二聚体,后者激活EGFR并导致异二聚体中HER2的磷酸根转移。二聚作用和/或磷酸根转移似乎激活HER2酪氨酸激酶。见Earp等,出处同上。同样地,当HER3与HER2共表达时,形成一活性信号复合物,抗HER2的抗体能够干扰此复合物(Sliwkowski等,J.Biol.Chem.,269(20):14661-14665(1994))。此外,在与HER2共表达时,HER3与遗传调节蛋白(HRG)的亲和力升高到更高亲和力水平。有关HER2-HER3蛋白复合物,也参见,Levi等,Journal of Neuroscience 15:1329-1340(1995);Morrissey等,Proc.Natl.Acad.Sci.USA 92:1431-1435(1995);和Lewis等,Cancer Res.,56:1457-1465(1996)。HER4,象HER3一样,与HER2形成一活性信号复合物(Carraway and Cantle,Cell 78:5-8(1994))。
TNF受体超家族
有多种分子已被鉴定为细胞因子肿瘤坏死因子(″TNF″)家族的成员,如肿瘤坏死因子-α(″TNF-α″)、肿瘤坏死因子-β(″TNF-β″)、淋巴毒素-α(″LT-α″)、CD30配体、CD27配体、CD40配体、OX40配体、4-1BB配体、Apo-1配基(也称作Fas配体或CD95配体)、Apo-2配体(也称作TRAIL)、Apo-3配体(也称作TWEAK)、osteoprotegerin(OPG)、APRIL、RANK配体(也称作TRANCE)和TALL-1(也称作BlyS、BAFF或THANK)(参见例如,Gruss和Dower,Blood,85:3378-3404(1995);Pitti等,J.Biol.Chem.,271:12687-12690(1996);Wiley等,Immunity,3:673-682(1995);Browning等,Cell,72:847-856(1993);Armitage等Nature,357:80-82(1992);1997年1月16日公布的WO 97/01633;1997年7月17日公布的WO97/25428;Marsters等,Curr.Biol.,8:525-528(1998);Simonet等,Cell,89:309-319(1997);Chicheportiche等,Biol.Chem.,272:32401-32410(1997);Hahne等,J.Exp.Med.,188:1185-1190(1998);1998年7月2日公布的WO98/28426;1998年10月22日公布的WO 98/46751;1998年5月7日公布的WO/98/18921;Moore等,Science,285:260-263(1999);Shu等,J.LeukocyteBiol.,65:680(1999);Schneider等,J.Exp.Med.,189:1747-1756(1999);以及Mukhopadhyay等,J.Biol.Chem.,274:15978-15981(1999))。在这些分子中,已报道TNF-α、TNF-β、CD30配体、4-1BB配体、Apo-1配体、Apo-2配体(Apo2L/TRAIL)和Apo-3配体(TWEAK)参与细胞凋亡。据报道,TNF-α和TNF-β均诱导易感肿瘤细胞中的细胞凋亡(Schmid等,Proc.Natl.Acad.Sci.,83:1881(1986);Dealtry等,Eur.J.Immunol.,17:689(1987))。
也声称,TNF家族中的多种分子在免疫系统的功能或发育中发挥作用(Gruss等,Blood,85:3378(1995))。Zheng等已报道,TNF-α参与CD8-阳性T细胞刺激后的细胞凋亡(Zheng等,Nature,377:348-351(1995))。其他研究者报道,CD30配体可能参与胸腺自身反应T细胞的耗竭(Amakawa等,ColdSpring Harbor Laboratory Symposium on Programmed Cell Death,Abstr.No.10,(1995))。CD40配体激活B细胞的许多功能,包括增生、免疫球蛋白分泌和存活(Renshaw等,J.Exp.Med.,180:1889(1994))。已有报道称,另一新近鉴定的TNF家族细胞因子,TALL-1(BlyS),在一定条件下诱导B细胞增生和免疫球蛋白分泌(Moore等,出处同上;Schneider等,出处同上;Mackay等,J.Exp.Med.,190:1697(1999))。
小鼠Fas/Apo-1受体或配体基因(分别称作Ipr和gld,)的突变与某些自身免疫病有关,表明Apo-1配体可能在调节外周自身反应淋巴细胞的克隆耗竭中发挥作用(Krammer等,Curr.Op.Immunol.,6:279-289(1994);Nagata等,Science,267:1449-1456(1995))。也报道称,Apo-1配体诱导CD4-阳性T淋巴细胞和B淋巴细胞的刺激后细胞凋亡,并且可能参与活化淋巴细胞在其功能不再需要时的消除(Krammer等,出处同上;Nagata等,出处同上)。已有报道,激动剂与Apo-1受体特异结合的小鼠单克隆抗体,显示出与TNF-α堪比的或类似的杀细胞活性(Yonehara等,J.Exp.Med.,169:1747-1756(1989))。
据信,由此类TNF家族细胞因子介导的各种细胞应答的诱导是由其与特异细胞受体的结合而引发的。以前,鉴定了大约55-kDa(TNFR1)和75-kDa(TNFR2)的两种不同TNF受体(Hohman等,J.Biol.Chem.,264:14927-14934(1989);Brockhaus等,Proc.Natl.Acad.Sci.,87:3127-3131(1990);1991年3月20日公开的EP 417,563;Loetscher等,Cell,61:351(1990);Schall等,Cell,61:361(1990);Smith等,Science,248:1019-1023(1990);Lewis等,Proc.Natl.Acad.Sci.,88:2830-2834(1991);Goodwin等,Mol.Cell.Biol.,11:3020-3026(1991))。发现那些TNFR具有细胞表面受体的典型结构,包括胞外区、跨膜区和胞内区。发现两种受体的胞外部分也均作为天然可溶性TNF-结合蛋白(Nophar等,EMBO J.,9:3269(1990);和Kohno等,Proc.Natl.Acad.Sci.U.S.A.,87:8331(1990);Hale等,J.Cell.Biochem.Supplement 15F,1991,p.113(P424))。
1型和2型TNFRs(TNFR1 and TNFR2)的细胞外部分,包含重复的从NH2-末端开始指定为1至4的四个半胱氨酸-丰富区(CRDs)的氨基酸序列基序(Schall等,出处同上;Loetscher等,出处同上;Smith等,出处同上;Nophar等,出处同上;Kohno等,出处同上;Banner等,Cell,73:431-435(1993))。其他细胞表面蛋白存在CRDs的相似重复基序,所述细胞表面蛋白包括:p75神经生长因子受体(NGFR)(Johnson等,Cell,47:545(1986);Radeke等,Nature,325:593(1987))、B细胞抗原CD40(Stamenkovic等,EMBO J.,8:1403(1989))、T细胞抗原OX40(Mallet等,EMBO J.,9:1063(1990))以及Fas抗原(Yonehara等,出处同上,和Itoh等,Cell,66:233-243(1991))。在Shope痘病毒和粘液瘤痘病毒的可溶性TNFR(sTNFR)-样T2蛋白中,也发现了CRDs(Upton等,Virology,160:20-29(1987);Smith等,Biochem.Biophys.Res.Commun.,176:335(1991);Upton等,Virology,184:370(1991))。这些序列的最适排列表明,半胱氨酸残基的位置是相当保守的。有时,将这些受体共同称为TNF/NGF受体超家族的成员。
迄今鉴定了的TNF家族配体,除淋巴毒素-α外,是type 11跨膜蛋白,其C-末端是胞外的。相反,迄今鉴定了的TNF受体(TNFR)家族的大多数受体,是I型跨膜蛋白。然而,在TNF配体和受体家族中,家族成员间的同源性鉴定均发现主要是在胞外区(″ECD″)。数个TNF家族细胞因子,包括TNF-α、Apo-1配体和CD40配体,在细胞表面蛋白水解性裂解;每种情况下产生的蛋白质通常形成作为可溶性细胞因子发挥作用的同源三聚体分子。TNF受体家族蛋白也通常蛋白水解性裂解以释放出可以作为同族细胞因子抑制剂而发挥作用的可溶性受体ECDs。
最近,已鉴定了TNFR家族的其他成员。在von Bulow等,Science,278:138-141(1997)中,研究者描述了称作跨膜激活剂和CAML-交互剂(Interactor)或″TACI″的质膜受体。据报道,TACI受体包含TNFR家族特征的半胱氨酸-丰富基序。在体外分析测定中,转染Jurkat细胞表面的TACI与TACI-特异性抗体交联,导致NF-KB活化(也参见,1998年9月18日公布的WO 98/39361)。
Laabi等,EMBO J.,11:3897-3904(1992)报道,鉴定了称作″BCM″的新基因,发现其表达与B细胞最终成熟相一致。BCM正常cDNA的开放读框,预示具有单个跨膜结构域的184个氨基酸长的多肽。后来,这些研究者将此基因命名为″BCMA.″(Laabi等,Nucleic Acids Res.,22:1147-1154(1994))。据报道,代表原-B淋巴细胞阶段的人恶性B细胞系没有BCMA mRNA表达,因此,认为BCMA mRNA表达与淋巴细胞分化阶段有关(Gras等,Int.Immunology,7:1093-1106(1995))。在Madry等Int.Immunology,10:1693-1702(1998)中,描述了小鼠BCMA cDNA的克隆。据报道,小鼠BCMAcDNA编码185个氨基酸长的多肽,后者与人BCMA多肽具有62%一致性。小鼠与人BCMA蛋白序列对比揭示在N-末端区6个半胱氨酸的保守基序,提示BCMA蛋白属于TNFR超家族(Madry等,出处同上)。
在Marsters等,Curr.Biol.,6:750(1996)中,研究者描述了称为Apo-3的全长天然序列人多肽,其显示出与TNFR家族相似的在其胞外半胱氨酸丰富区的重复性,并且因为其含有胞质死亡结构域序列而与TNFR1和CD95相似(也参见Marsters等,Curr Biol.,6:1669(1996))。Apo-3也被其他研究者称作DR3、wsl-1、TRAMP和LARD(Chinnaiyan等,Science,274:990(1996);Kitson等,Nature,384:372(1996);Bodmer等,Immunity,6:79(1997);Screaton等,Proc.Natl.Acad.Sci.,94:4615-4619(1997))。
Pan等已公开了称作″DR4″的另一TNF受体家族成员(Pan等,Science,276:111-113(1997);也参见1998年7月30日公布的WO98/32856)。据报道,DR4包含能够参与细胞自杀的胞质死亡结构域。Pan等披露,据信DR4是已知Apo2L/TRAIL配体的受体。
在Sheridan等,Science,277:818-821(1997)和Pan等,Science,277:815-818(1997)中,描述了据信是Apo2L/TRAIL受体的另一分子(也参见,1998年11月19日公开的WO 98/51793;和1998年9月24日公开的WO98/41629)。称该分子为DR5(它也被称作Apo-2;TRAIL-R,TR6,Tango-63,hAP08,TRICK2或KILLER(Screaton等,Curr.Biol.,7:693-696(1997);Walczak等,EMBO J.,16:5386-5387(1997);Wu等,Nature Genetics,17:141-143(1997);1998年8月20日公开的WO 98/35986;1998年10月14日公开的EP870,827;1998年10月22日公开的WO 98/46643;1999年1月21日公开的WO 99/02653;1999年2月25日公开的WO 99/09165;和1999年3月11日公开的WO 99/11791)。据报道,DR5与DR4一样,含有能够传输细胞凋亡信号的胞质死亡结构域。在Hymowitz等,Molecular Cell,4:563-571(1999)中,描述了Apo2L/TRAIL和DR5之间形成的复合物的晶型结构。
最近鉴定了含有死亡结构域的另一受体,DR6(Pan等,FEBS Letters,431:351-356(1998))。除了含有4个推定的胞外半胱氨酸丰富结构域和胞质死亡结构域外,据信DR6含有推定的与胞质区脯氨酸-丰富基序重叠的亮氨酸拉链序列。脯氨酸-丰富基序类似于与src-同源性-3结构域相结合的序列,其见于许多细胞内信号转导分子中。
最近鉴定的另一组受体被称作″引诱受体(decoy receptor)″,据信,它们起抑制物而不是信号转导物的功能。该组受体包括:DcR1(也称作TRID、LIT或TRAIL-R3)(Pan等,Science,276:111-113(1997);Sheridan等,Science,277:818-821(1997);McFarlane等,J.Biol.Chem.,272:25417-25420(1997);Schneider等,FEBS Letters,416:329-334(1997);Degli-Esposti等,J.Exp.Med.,186:1165-1170(1997);和Mongkolsapaya等,J.Immunol.,160:3-6(1998))和DcR2(也称作TRUNDD或TRAIL-R4)(Marsters等,Curr.Biol.,7:1003-1006(1997);Pan等,FEBS Letters,424:41-45(1998);Degli Esposti等,Immunity,7:813-820(1997)),这两种细胞表面分子,以及OPG(Simonet等,出处同上;Emery等,infra)和DcR3(Pitti等,Nature,396:699-703(1998)),均是分泌的可溶性蛋白。
近来鉴定的TNFR家族的其他成员包括CAR1、HVEM、GITR、ZTNFR-5、NTR-1和TNFL1(Brojatsch等,Cell,87:845-855(1996);Montgomery等,Cell,87:427-436(1996);Marsters等,J.Biol.Chem.,272:14029-14032(1997);Nocentini等,Proc.Natl.Aca d.Sci.USA 94:6216-6221(1997);Emery等,J.Biol.Chem.,273:14363-14367(1998);1999年1月28日公开的WO 99/04001;1999年2月18日公开的WO 99/07738;1999年7月8日公开的WO 99/33980)。
如Tewari等最近评述的那样,TNFR1、TNFR2和CD40通过激活转录因子-NF-κB,来调节炎症原性(proinflammatory)和共刺激性(costimulatory)细胞因子、细胞因子受体和细胞粘附分子的表达(Tewari等,Curr.Op.Genet.Develop.,6:39-44(1996))。
NF-κB是二聚体型转录因子家族的原型,所述二聚体型转录因子的亚单位含有保守的Rel区(Verma等,Gene Develop.,9:2723-2735(1996);Baldwin,Ann.Rev.Immunol.,14:649-681(1996))。在其非活性形式中,NF-κB是与I-κB抑制物家族成员相复合的;对某些刺激应答时,I-κB失活,释放出的NF-κB易位到细胞核,结合到特异DNA序列上,从而激活基因转录。如前所述,迄今鉴定的TNFR成员包括或缺乏细胞内死亡结构域。一些缺乏死亡结构域的TNFR分子,如TNFR2、CD40、HVEM和GITR,能够调节NF-κB活性(参见,如,Lotz等,J.Leukocyte Biol.,60:1-7(1996))。
有关细胞因子TNF家族及其受体的综述,参见Ashkenazi and Dixit,Science,281:1305-1308(1998);Golstein,Curr.Biol.,7:750-753(1997);Grussand Dower,出处同上,和Nagata,Cell,88:355-365(1997)。
B细胞表面抗原
淋巴细胞是造血过程中由骨髓产生的多种白细胞中的一种。有两种主要的淋巴细胞群:B淋巴细胞(B细胞)和T淋巴细胞(T细胞)。本文特别关注的淋巴细胞是B细胞。
B细胞在骨髓内成熟,其细胞表面表达抗原-结合型抗体时离开骨髓。当初始B细胞首次遇到对所具有的膜结合抗体来说是特异的抗原时,细胞开始迅速分裂,其子代细胞分化为记忆B细胞和称为″浆细胞″的效应细胞。记忆B细胞具有较长的寿命并继续表达与原始母细胞具有相同特异性的膜结合抗体。浆细胞不产生膜结合抗体,但是,代之膜结合抗体的是,它产生可分泌形式的抗体。分泌的抗体是体液免疫的主要效应分子。
CD20抗原(也称作人B-淋巴细胞-限制性分化抗原,Bp35)是一个位于前-B和成熟B淋巴细胞上的分子量约35kD的疏水性跨膜蛋白(Valentine等J.Biol.Chem.264(19):11282-11287(1989);和Einfeld等EMBO J.7(3):711-717(1988))。该抗原也在大于90%的B细胞非何杰金氏淋巴瘤(NHL)中表达(Anderson等Blood 63(6):1424-1433(1984)),但是,在造血干细胞、前-B细胞、正常浆细胞或其他正常组织未见表达(Tedder等J.Immunol.135(2):973-979(1985))。CD20调节细胞周期启动和分化的活化过程中的早期步骤(Tedder等,出处同上),而且可能起钙离子通道的功能(Tedder等J.Cell.Biochem.14D:195(1990))。
如果CD20在B细胞淋巴瘤中表达,该抗原可作为″靶向″此类淋巴瘤的候选物。实质上,此靶向可如下产生:向患者施用对B细胞CD20表面抗原特异的抗体。这些抗-CD20抗体与正常和恶性B细胞上的CD20抗原(表面)特异结合;与CD20表面抗原结合的抗体可导致瘤性B细胞破坏和耗竭。另外,具有破坏肿瘤效力的化学药品或者放射性标记物可与抗-CD20抗体偶联,从而使得这些药品或制剂特异地向瘤性B细胞“释放”。不管采用什么方法,其主要目标是破坏肿瘤;具体方法可通过使用的特定抗-CD20抗体确定,因此,靶向CD20抗原的可利用方法可以是极为不同的。
CD19是在B淋巴细胞系细胞表面表达的另一抗原。象CD20一样,从干细胞阶段至即将分化为终末浆细胞之前的整个过程中,在细胞上均发现有CD19(Nadler,L.Lymphocyte Typing II 2:3-37和Appendix,Renling等编著(1986)by Springer Verlag)。然而,不象CD20,CD19抗体结合CD19引起CD19抗原内化。除了别的之外,CD19抗原通过HD237-CD19抗体(也称作″B4″抗体)进行鉴定(Kiesel等Leukaemia Research II,12:1119(1987))。CD19抗原存在于外周血4-8%的单核细胞上,而在从外周血、脾脏、淋巴结或扁桃体分离的B细胞上存在量则大于90%。在外周血T细胞、单核细胞或粒细胞上,未检测到CD19。事实上,非-T细胞型急性淋巴母细胞性白血病(ALL)、B细胞慢性淋巴细胞性白血病(CLL)和B细胞淋巴瘤,表达可由抗体B4测得的CD19(Nadler等J.Immunol.131:244(1983);and Nadler等inProgress in Hematology Vol.XII pp.187-206.Brown,E.ed.(1981)by Grune&Stratton,Inc)。
已鉴定了识别由B细胞系细胞表达的分化阶段-特异性抗原的其它抗体。在这些抗体中,抗CD21抗原的是B2抗体;抗CD22抗原的是B3抗体;和抗CD10抗原(也称作CALLA)的是J5抗体。参见1997年1月21日公布的美国专利5,595,721(Kaminski等)。
rituximab(抗体是遗传基因工程改造的抗CD20抗原的嵌合小鼠/人单克隆抗体。在1998年4月7日公布的美国专利5,736,137中,Rituximab被称作″C2B8″抗体(Anderson等)。指出,用于治疗复发性或顽固性低级或滤泡性CD20阳性B细胞非何杰金氏淋巴瘤患者。体外作用机制研究已经证明,结合人补体并通过CDC溶解淋巴样B细胞系(Reff等Blood 83(2):435-445(1994))。此外,在分析ADCC中,具有显著的活性。最近,业已证明在氚标记去氧胸腺嘧啶核苷掺入试验中具有抗-增殖作用并且直接诱导细胞凋亡,而其它抗-CD19和CD20抗体无此作用(Maloney等Blood 88(10):637a(1996))。也已经试验性地观察到和化学疗法之间的协同和毒性。更具体而言,使抗药人B细胞淋巴瘤细胞系对阿霉素、CDDP、VP-16、白喉毒素和篦麻毒蛋白的细胞毒作用敏感(Demidem等CancerChemotherapy&Radiopharmaceuticals 12(3):177-186(1997))。在体内进行的临床前研究证明,从外周血、淋巴结和骨髓耗竭猕猴的B细胞,推断是通过补体和细胞介导的过程进行的(Reff等Blood 83(2):435-445(1994))。
发明概述
本发明提供具有三个或更多个抗原结合部位的多价抗体(如四价抗体),其可通过编码抗体多肽链的核酸重组表达而方便地产生。在一实施方案中,多价抗体含有二聚化结构域和三个或更多个抗原结合部位。优选的二聚化结构域含有一个Fc区或一个铰链区(或由其组成)。在一实施方案中,本发明提供分离的在其氨基末端含有二聚化结构域和三个或更多个抗原结合部位的抗体。本发明进一步提供分离的含有一个Fc区和在Fc区氨基末端三个或更多个抗原结合部位的抗体。本文优选的多价抗体含有(或由其组成)3至约8个,优选4个抗原结合部位(如本文定义的那样,它们一般均是″功能性的″)。在一实施方案中,多价抗体含有5个或更多个(如多达约8个)抗原结合部位。本文的多价抗体优选不是天然序列IgA或IgM,并且缺乏Fc区或者仅有一个Fc区。
在优选的实施方案中,多价抗体含有至少一条多肽链(并优选2条多肽链),其中多肽链含有2个或更多个可变区。举例来说,多肽链可含有VD1-(X1)n-VD2-(X2)n-Fc,其中VD1是第一个可变区,VD2是第二个可变区,Fc是Fc区的一条多肽链,X1和X2代表氨基酸或多肽,n是0或1。譬如,多肽链可含有:VH-CH1-柔性接头-VH-CH1-Fc区链;VH-CH1-VH-CH1-Fc区链;VL-CL-柔性接头-VL-CL-Fc区链;或者VL-CL-VL-CL-Fc区链。多肽链含有Fd-柔性接头-Fd时,柔性接头可含有肽如gly-ser,gly-ser-gly-ser(SEQ ID NO:10),ala-ser,或者gly-gly-gly-ser(SEQ ID NO:11)。
本文多价抗体优选还含有至少2个(和优选4个)轻链可变区多肽。譬如,本文多价抗体可包括约2至约8个轻链可变区多肽。本文考虑到的轻链可变区多肽包括轻链可变区,和任选地,进一步包括CL区。
从治疗观点讲,本文多价抗体具有所需的特性。举例来说,多价抗体可以(1)通过与抗体相结合的细胞表达性抗原而较二价抗体更快内化(和/或发生分解代谢);(2)是一激动型抗体;和/或(3)诱导表达多价抗体能够与之结合的抗原的细胞死亡和/或细胞凋亡。可提供多价抗体的至少一个抗原结合特异性的″亲本抗体″,可以通过抗体与之结合的细胞表达性抗原而内化(和/或发生分解代谢);和/或可以是激动剂、细胞死亡-诱导性和/或细胞凋亡-诱导性抗体,本文描述的多价形式抗体可显示出在这些特性中一种或多种特性的改善。而且,亲本抗体可能缺少这些特性中的一种或多种,但是当构建前述多价抗体时则赋予它们这些特性。
本文多价抗体的三个或更多个抗原结合部位均可以结合相同的抗原;或者可与2种或更多种(如2至约3种)不同的抗原结合。
多价抗体可结合(1)肿瘤细胞表达的(或过度表达的)细胞表面蛋白,如表皮生长因子受体(EGFR)、HER2受体、HER3受体、HER4受体,或DcR3;(2)肿瘤坏死因子(TNF)受体超家族中的受体(如Apo2L受体,诸如DR4、DR5、DcR1或DcR2);和/或(3)B细胞表面抗原(如CD19、CD20、CD22或CD40)。在本发明一优选实施方案中,多价抗体的所有功能性抗原结合部位均与前面列出的相同抗原相结合(例如,四价抗体的所有4个抗原结合部位均与(1)、(2)或(3)结合)。
本发明也提供包括与细胞毒制剂相偶联的多价抗体的免疫偶联剂。本文的细胞毒制剂可以是一旦内化即具有杀细胞活性的物质。
本发明另外涉及包含VD1-(X1)n-VD2(X2)n-Fc的肽链,其中VD1是第一可变区,VD2是第二可变区,Fc是Fc区的一条多肽链,X1和X2代表氨基酸或多肽,而n是0或1。举例来说,多肽链可包含VH-CH1-柔性接头-VH-CH1-Fc区链;VH-CH1-VH-CH1-Fc区链;VL-CL-柔性接头-VL-CL-Fc区链;或VL-CL-VL-CL-Fc区链。在另一实施方案中,多肽链包含VH-CH1-柔性接头-VH-CH1-二聚化结构域;VH-CH1-VH-CH1-二聚化结构域;VL-CL-柔性接头-VL-CL-二聚化结构域;或VL-CL-VL-CL-二聚化结构域。譬如,多肽链可包含VH-CH1-柔性接头-VH-CH1-铰链区;VH-CH1-VH-CH1-铰链区。本发明另外提供包含一个或多个(优选2个)此类多肽链的抗体。该抗体优选进一步包含至少2个(并优选4个)轻链或重链可变区多肽,例如,其轻链可变区多肽含有VL-CL而重链可变区多肽含有VH-CH1。
本发明进一步提供包含三个或更多个重链或轻链可变区的多肽链,其中每一可变区能够与三个或更多个轻链或重链可变区多肽结合以形成三个或更多个抗原结合部位,每一抗原结合部位对抗相同的抗原。本发明也提供分离的包含多肽链的抗体。在一优选的实施方案中,多肽链包含三个或更多个重链可变区,抗体优选进一步包含三个或更多个能够与重链可变区结合的轻链可变区多肽以形成三个或更多个抗原结合部位。此类抗体的实例示于图23D(具有3个抗原结合部位)和图23E(具有4个抗原结合部位)。此外,本发明提供包含下列各式的多肽链:(a)VL-CL-柔性接头-VL-CL-柔性接头-VL-CL;(b)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;(c)(VL-CL)n,其中n是3或更大数;或(d)(VH-CH1)n,其中n是3或更大数。
本发明进一步提供:分离的编码多价抗体或多肽链的核酸;包含编码多聚抗体或多肽链的核酸的载体,任选地,与被用载体转化过的宿主细胞所识别的控制序列可操作地相连接;含有编码多聚抗体或多肽链的核酸(如用所述核酸转化)的宿主细胞;制备多价抗体或多肽链的方法,包括培养宿主细胞以便使得核酸被表达,和任选地,从宿主细胞培养物(如,从宿主细胞培养基)中回收多价抗体或多肽链。优选地,编码多价抗体(1)重链可变区和(2)轻链可变区的核酸由被(1)和(2)二者转化过的宿主细胞共表达。核酸(1)和(2)可存在于相同或不同的载体中。
考虑了本文公开的多价抗体的诊断和治疗用途。在一诊断应用中,本发明提供测定目的抗原的方法,包括将可疑含有抗原的样本暴露于多价抗体,并检测多价抗体与样本的结合。提供了体外和体内诊断方法。
在一治疗应用中,本发明提供治疗患有疾病或病症或具有患病倾向的哺乳动物的方法,包括向哺乳动物施用治疗有效量的本文公开的多价抗体或者含有所述多价抗体与可药用载体的组合物。本文所述被治疗的病症可以是癌症,在此情况下,该方法可进一步包括向哺乳动物施用治疗有效量的细胞毒制剂。本发明还涉及诱导癌细胞凋亡的方法,包括使细胞暴露于本文描述的多价抗体,其中多价抗体与肿瘤坏死因子(TNF)受体超家族中的受体结合。该方法可涉及通过使细胞暴露于结合B细胞表面抗原的多价抗体而杀死B细胞。而且,该方法可涉及杀死表达(或过度表达)ErbB受体的细胞,包括使细胞暴露于与ErbB受体结合的抗体的步骤。
附图简述
图1是天然IgG和其用(1)木瓜蛋白酶消化以产生2个Fab片段和一个Fc区或用(2)胃蛋白酶消化以产生一个F(ab′)2片段和多个小片段的图示。用CH1和CL区之间以及2个CH2区之间的线表示二硫键。V是可变区;C是恒定区;L代表轻链而H代表重链。
图2A-E描述5种主要天然存在免疫球蛋白同种型的结构;IgG(图2A)、IgD(图2B)、IgE(图2C)、IgA二聚体(图2D),和IgM五聚体(图2E)。
图3描述天然序列IgG Fc区的排列。显示天然序列人IgG Fc区序列,humIgG1(非-A和A同种异型)(分别是SEQ ID NO:1和2)、humIgG2(SEQ IDNO:3)、humIgG3(SEQ ID NO:4)和humIgG4(SEQ ID NO:5)。人IgG1序列是非-A同种异型,该序列与A同种异型的差异示于人IgG1序列之下(在356位和358位;EU编号系统)。也显示了天然序列小鼠IgG Fc区序列,murIgG1(SEQ ID NO:6)、murIgG2A(SEQ ID NO:7)、murIgG2B(SEQ ID NO:8)和murIgG3(SEQ ID NO:9)。
图4A-B图示描述本发明的四价抗体。图4A中,对4个抗原结合的Fab进行了编号(1和2代表四价抗体的各臂),X代表二聚化结构域。图4B中,四价抗体的二聚化结构域是Fc区。
图5显示用于表达实施例1中的四价抗-HER2抗体(OctHER2)的构建体。
图6A-C描述使用酶联免疫吸附试验(ELISA)进行测定,OctHER2(图6A)、由293细胞表达的二价IgG1 rhuMAb 4D5-8(图6B)和瓶装(由中国仓鼠卵巢(CHO)细胞表达)(图6C)与HER2胞外区(ECD)的结合。
图7描述超速离心测定OctHER2与HER2 ECD的结合。显示平均分子量(理论值或试验测定值)对OctHER2与HER2 ECD摩尔比。假定四价抗体具有四个全功能性结合部位,理论计算的平均分子量用圆圈表示;假定四价抗体具有三个全功能性结合部位,理论计算的平均分子量用正方形表示;三角代表试验测得的分子量。
图8A-D描述使用SKBR3(3+HER2过度表达)(图8A)、MDA 361(2+HER2过度表达)(图8B)、BT474(3+HER2过度表达)(图8C)和MCF7(0+HER2表达)(图8D)细胞系,与OctHER2相比的生长抑制活性。
图9描述针对MDA 231细胞(1+HER2过度表达)或SKBR3细胞(3+HER2过度表达),柔性接头对四价抗-HER2抗体的生长抑制活性的影响。
图10A-B比较OctHER2与(图10B)涉及MDA 453(2+HER2过度表达)和SKBR3(3+HER2过度表达)细胞系的内化/分解代谢(图10A)之速率。
图11A-I是显示OctHER2内化的电子显微镜照片。图11A-F显示125I-OctHER2在SKBR3细胞中的亚细胞定位。观察到与顶端细胞膜的绒毛有关的放射自显影银粒(图11A),紧紧靠近形成的有被小窝(图11B,箭头)、光滑的胞质囊泡(图11C和D)和核内体(图11E和F)。棒=0.25μM。图11G-I显示在0小时(图11G)和5小时(图11H和11I)时的内化。
图12A-E描述与非-癌对照细胞系-HUMEC(图12E)相比,由抗-DR5四价抗体(16E2章鱼)、抗-DR5二价IgG抗体(16E2 IgG)和Apo2L/TRAIL(Apo2L)诱导的下述癌细胞系的细胞凋亡:COLO 205(图12A)、SK-MES-1(图12B)、HCT116(图12C)和HOP 92(图12D)。
图13A-D是染色的组织学玻片以检测凋亡的细胞。取自用16E2章鱼或Apo2L/TRAIL治疗过的小鼠的肿瘤组织固定在10%福尔马林中,接着石蜡包埋并切片到玻片上,然后用苏木精和伊红染色,在400倍放大比例下观测。16E2章鱼于6和24小时的作用分别示于图13A和B;对照-处理的细胞示于图13C;Apo2L/TRAIL-处理的细胞示于图13D。
图14表示Apo2L/TRAIL(60mg/kg,5×/周)、3H3二价IgG(5mg/kg给药0、3、5和9天)、16E2二价IgG(16E2)(5mg/kg给药0、3、5和9天)和16E2章鱼(5mg/kg给药0、3、5和9天)对无胸腺裸鼠COLO 205肿瘤的体内活性。
图15表示证实小鼠实验中所用材料(Apo2L/TRAIL和16E2章鱼)的凋亡活性与Apo2L标准阳性对照相比的alamarBlue体外测定。小鼠实验中用作阴性对照的抗-IgE抗体(E25)被证实没有凋亡活性。
图16表示抗-DR5 3H3章鱼与各批量抗-DR5 16E2章鱼相比,结晶紫的细胞凋亡测定的结果。
图17A-B显示Apo2L/TRAIL(WO97/25428)、抗-DR5 3H3章鱼抗体、抗-DR5 16E2章鱼抗体和具有通过抗-FLAG抗体(WO97/25428)交叉连接的FLAG表位-标记的Apo2L/TRAIL,对SK-MES-1(图17A)和Jurkat(图17B)细胞,在存在5%小牛血清(FBS)时alamarBlue凋亡测定的结果。
图18A-C显示2天时,抗-DR5 16E2章鱼(较高的曲线)与Apo2L/TRAIL(较低的曲线)相比,对白血病、非-小细胞肺癌、结肠癌、中枢神经系统(CND)癌、黑色素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌人肿瘤细胞系生长的作用的剂量反应曲线。结果得自国立癌症研究所发展治疗项目(the National Cancer Institute Developmental Therapeutics Program)。所有样本均在5个浓度下检测,从1%贮存液开始(16E2章鱼贮存液浓度为0.2mg/ml)和4×0.5对数稀释。
图19A-C显示6天时,抗-DR5 16E2章鱼(较高的曲线)与Apo2L/TRAIL(较低的曲线)相比,对白血病、非-小细胞肺癌、结肠癌、中枢神经系统(CND)癌、黑色素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌人肿瘤细胞系生长的作用的剂量反应曲线。结果得自国立癌症研究所发展治疗项目。所有样本均在5个浓度下检测,从1%贮存液浓度开始(16E2章鱼贮存液浓度为0.2mg/ml)和4×0.5对数稀释。
图20A-B表示2天时,抗-DR5 16E2章鱼(图20A)与Apo2L/TRAIL(图20B)的生长抑制(GI50)、停滞(TGI)和毒性(LC50)的体外定量测定结果,该结果得自国立癌症研究所发展治疗项目。
图21A-B表示6天时,抗-DR5 16E2章鱼(图20A)与Apo2L/TRAIL(图20B)的生长抑制(GI50)、停滞(TGI)和毒性(LC50)的体外定量测定结果,该结果得自国立癌症研究所发展治疗项目。
图23A-E是描述全长章鱼/四价抗体(图23B)、章鱼F(ab)′2(图23C)、POPoct-3Fab(图23D)和POPoct-4Fab(图23E)与天然IgG(图23A)比较的卡通画。抗-CD20(C2B8)章鱼蛋白的代表性考马斯染色的Tris-甘氨酸凝胶,比较了在非-还原条件下完整抗体的大小(图23F)与在还原条件下重链的大小,在还原条件下二硫键被打开而造成重链与轻链分开(图23G)。
图24描述章鱼F(ab′)2主链的构建。任何VH/CH1区可通过BamHI、NheI和BspEI限制性内切酶位点而替换入F(ab′)2主链中。
图25描述POPoct-3重链的构建。
图26描述POPoct-4重链的构建。
图27描述多价抗-HER2抗体在使用BT474细胞进行的细胞增殖抑制测定中的活性。
图28A-B描述多价抗-HER2抗体在使用SKBR3细胞进行的细胞增殖抑制测定中的活性。这些图是n=4的细胞增殖抑制测定的代表性绘图。
图29A-B显示多价抗-HER2抗体在SKBR3细胞(图29A)和BT474细胞(图29B)中的内化能力。
图30A-B显示由多价抗-DR5抗体导致的COLO205细胞的凋亡。
图31A-B证明多价抗-DR5抗体通过caspase通路的信号传输。
图33显示由多价抗-CD20抗体、IF5抗-CD20抗体(Clark等PNAS(USA)82:1766-1770(1985))和交叉-连接IF5抗体的IgG(IF5+IgG X)导致的WIL2细胞凋亡。
图34描述由IF5抗-CD20抗体、交叉-连接IF5抗体的IgG和POPoct-3CD20的诱导的在WIL2S细胞中的同型细胞粘附。
图35反映DB、WIL2和Ramos B细胞淋巴瘤系上的RITUXAN或OctCD20的内化/分解代谢。
优选实施方案详述
I.定义
在本发明整个说明书和权利要求书中,免疫球蛋白重链中残基的编号是Kabat等在Sequence of Proteins of Immunological Interest,5th Ed.PublicHealth Service,National Institutes of Health,Bethesda,MD(1991)的EU指数的编号,所述文献特别在此引入作为参考。如在Kabat文献中那样,″EU指数″是指人IgG1 EU抗体的残基编号。
″ErbB受体″,是属于ErbB受体家族的受体蛋白酪氨酸激酶,包括EGFR、HER2、ErbB3和ErbB4受体以及TEGFR(美国专利5,708,156)和今后被识别的该家族的其他成员。ErbB受体通常包含:胞外区,它可与ErbB配体结合;亲脂性跨膜结构域;保守的胞内酪氨酸激酶结构域;和包含数个酪氨酸残基(它们可被磷酸化)的羧基末端信号结构域。ErbB受体可以是天然序列ErbB受体或其氨基酸序列变体。优选地,ErbB受体是天然序列人ErbB受体。
″ErbB配体″,是指与ErbB受体结合和/或激活ErbB受体的多肽。本文特别感兴趣的ErbB配体是天然序列人ErbB配体,例如:表皮生长因子(EGF)(Savage等,J.Bio/.Chem.247:7612-7621(1972));转化生长因子α(TGF-α)(Marquardt等,Science 223:1079-1082(1984));双调节素也称作schwanoma或角质形成细胞自分泌生长因子(Shoyab等Science 243:1074-1076(1989);Kimura等Nature 348:257-260(1990);和Cook等Mol.Cell.Biol.11:2547-2557(1991));β细胞调节素(Shing等,Science 259:1604-1607(1993);Sasada等Biochem.Biophys.Res.Commun.190:1173(1993));肝素结合表皮生长因子(HB-EGF)(Higashiyama等,Science 251:936-939(1991));表皮调节素(Toyoda等,J.Biol.Chem.270:7495-7500(1995);和Komurasaki等Oncogene 15:2841-2848(1997)),遗传调节蛋白(下述);神经调节蛋白-2(NRG-2)(Carraway等,Nature 387:512-516(1997));神经调节蛋白-3(NRG-3)(Zhang等,Proc.Natl.Acad.Sci.94:9562-9567(1997));或cripto(CR-1)(Kannan等J.Biol.Chem.272(6):3330-3335(1997))。结合EGFR的ErbB配体包括EGF、TGF-α、双调节素、β细胞调节素、HB-EGF和表皮调节素。结合HER3的ErbB配体包括遗传调节蛋白。能够结合HER4的ErbB配体包括β细胞调节素、表皮调节素、HB-EGF、NRG-2、NRG-3和遗传调节蛋白。
本文所用″遗传调节蛋白″(HRG),是指如美国专利5,641,869或Marchionni等,Nature,362:312-318(1993)公开的那样,含有由遗传调节蛋白基因产物编码的氨基酸序列的多肽及该多肽的生物活性变体。遗传调节蛋白的实例包括遗传调节蛋白-α、遗传调节蛋白-β1、遗传调节蛋白-β2和遗传调节蛋白-β3(Holmes等,Science,256:1205-1210(1992);和美国专利5,641,869);neu分化因子(NDF)(Peles等Cell 69:205-216(1992));乙酰胆碱受体-诱导活性(ARIA)(Falls等Cell 72:801-815(1993));神经胶质生长因子(GGFs)(Marchionni等,Nature,362:312-318(1993));感觉和运动神经元衍生因子(SMDF)(Ho等J.Biol.Chem.270:14523-14532(1995));γ-遗传调节蛋白(Schaefer等Oncogene 15:1385-1394(1997))。天然序列HRG多肽的生物活性片段/氨基酸序列变体的实例,是EGF-样结构域片段(如HRGβ1177-244)。
本文的″ErbB异源-低聚体″,是非共价结合的低聚体,包括至少2个不同的ErbB受体。当表达2个或更多个ErbB受体的细胞暴露于ErbB配体时,可形成该复合物,并且该复合物可通过免疫沉淀而被分离,并可通过SDS-PAGE予以测定,例如Sliwkowski等在J.Biol.Chem.,269(20):14661-14665(1994)中描述的方法。此类ErbB异源-低聚体的实例包括EGFR-HER2、HER2-HER3和HER3-HER4复合物。而且,ErbB异源-低聚体可包含2个和更多个与不同ErbB受体(如HER3、HER4或EGFR)结合的HER2受体。其它蛋白,如细胞因子受体亚单位(如gp130),可包括在异源-低聚体中。
在本文中可交换使用的术语″ErbB1″、″表皮生长因子受体″和″EGFR″,是指例如Carpenter等在Ann.Rev.Biochem.56:881-914(1987)公开的天然序列EGFR,包括其变体(如在Humphrey等PNAS(USA)87:4207-4211(1990)中所述的缺失突变EGFR)。erbB1是指编码EGFR蛋白产物的基因。与EGFR结合的抗体的实例包括:MAb 579(ATCC CRL HB 8506)、MAb 455(ATCCCRL HB8507)、MAb 225(ATCC CRL 8508)、MAb 528(ATCC CRL 8509)(参见美国专利4,943,533,Mendelsohn等)及其变体,如嵌合的(chimerized)225(C225)和重构的(reshaped)人225(H225)(参见WO 96/40210,ImcloneSystems Inc.)。
本文中可交换使用的术语″ErbB2″和″HER2″,是指例如Semba等在PNAS(USA)82:6497-6501(1985)和Yamamoto等在Nature 319:230-234(1986)(Genebank编号X03363)描述的天然序列人HER2蛋白及其变体。术语erbB2是指编码人HER2的基因,而neu则是指编码大鼠P185neu的基因。优选的HER2是天然序列人HER2。与HER2结合的抗体的实例包括:MAbs4D5(ATCC CRL 10463)、2C4(ATCC HB-12697)、7F3(ATCC HB-12216)和7C2(ATCC HB 12215)(参见美国专利5,772,997;WO98/77797;和美国专利5,840,525,这些文献特别在此引入作为参考)。人源化抗-HER2抗体,包括美国专利5,821,337中表3所述的huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8,该文献特别在此引入作为参考;人源化520C9(WO93/21319)。人抗-HER2抗体,描述在1998年6月30日公布的美国专利5,772,997和1997年1月3日公开的WO 97/00271中。
″ErbB3″和″HER3″,是指例如美国专利5,183,884和5,480,968以及Kraus等PNAS(USA)86:9193-9197(1989)中所描述的受体多肽,包括其变体。结合HER3的抗体的实例,描述在美国专利5,968,511(Akita和Sliwkowski)中,如8B8抗体(ATCC HB 12070)或其人源化变体。
本文中的术语″ErbB4″和″HER4″,是指例如在EP专利申请599,274;Plowman等,Proc.Natl.Acad.Sci.USA,90:1746-1750(1993);和Plowman等,Nature,366:473-475(1993)中所述的受体多肽,包括其变体,如WO 99/19488中公开的HER4同种型。
本文的″B细胞表面标志″,是在B细胞表面表达的可作为与之结合的抗体的靶向目标的抗原。例证性B细胞表面标志包括:CD10,CD19,CD20,CD21,CD22,CD23,CD24,CD37,CD40,CD53,CD72,CD73,CD74,CDw75,CDw76,CD77,CDw78,CD79a,CD79b,CD80,CD81,CD82,CD83,CDw84,CD85和CD86白细胞表面标志。特别感兴趣的B细胞表面标志,是与哺乳动物的其它非-B细胞组织相比优选在B细胞上表达的,并且既可在前体B细胞又可在成熟B细胞上表达。在一个实施方案中,标志是一个,象CD20或CD19,它发现于B细胞系从干细胞阶段直至最终分化成浆细胞之前一刻的整个分化过程中的B细胞上。本文优选的B细胞表面标志是CD19、CD20、CD22和CD40。
″CD20″抗原是在来自外周血或淋巴器官的大于90%的B细胞上发现的约35kDa的非-糖基化磷蛋白。CD20在前-B细胞发育早期表达并一直保持直到浆细胞分化。CD20既存在于正常B细胞也存在于恶性B细胞上。文献中对于CD20的其它命名包括″B淋巴细胞-限制性抗原″和″Bp35″。例如,CD20抗原描述在Clark等PNAS(USA)82:1766(1985)中。与CD20抗原结合的抗体的实例包括:目前称作″rituximab″(″RITUXANS″)的″C2B8″(美国专利5,736,137,特别在此引入作为参考);称作″Y2B8″的钇-[90]-标记的2B8小鼠抗体(美国专利5,736,137,特别在此引入作为参考);任选用131I标记以产生″131I-B1″抗体(BEXXARTM)的小鼠IgG2a″B1″(美国专利5,595,721,特别在此引入作为参考);小鼠单克隆抗体″1F5″(Press等Blood 69(2):584-591(1987));″嵌合2H7″抗体(美国专利5,677,180,特别在此引入作为参考);和可购自International Leukocyte Typing Workshop的单克隆抗体L27、G28-2、93-1B3、B-C1或NU-B2(Valentine等,In:Leukocyte Typing III(McMichael,Ed.,p.440,Oxford University Press(1987))。
″CD19″抗原,是指例如通过HD237CD19或B4抗体识别的约90kDa的抗原(Kiesel等Leukaemia Research II,12:1119(1987))。象CD20一样,CD19发现于B细胞系从干细胞阶段直至最终分化成浆细胞之前一刻的整个分化过程的细胞上。抗体与CD19的结合可引起CD19抗原的内化。与CD19抗原结合的抗体的实例包括:Hekman等在Cancer Immunol.Immunother.32:364-372(1991)和Vlasveld等在Cancer Immunol.Immunother.40:37-47(1995)中描述的抗-CD19抗体;以及Kiesel等在Leukaemia Research II,12:1119(1987)中描述的B4抗体。
″CD22″抗原的分子量约为140,000kD。CD22在早期前-B细胞和祖细胞的胞浆内表达,仅出现在成熟B细胞和大多数非何杰金淋巴瘤(NHL)细胞的表面,然后在浆细胞阶段之前的最终分化期间从细胞表面和胞浆中消失。抗-CD22抗体的一个实例是Juweid等在Cancer Research 55:5899-5907(1995)中描述的LL2抗体,包括其嵌合/人源化变体。
″CD40″抗原是细胞表面磷酸化糖蛋白,它在各种类型细胞上表达,所述细胞包括:B细胞、B细胞恶性肿瘤、滤泡树突细胞、基底上皮细胞和癌。CD40结合CD40配体(CD40L)。除了是B细胞表面抗原外,CD40也是TNF受体超家族的成员之一。结合CD40的抗体的实例,包括那些(1)阻断CD40/CD40L相互作用和具有抗-肿瘤特性的抗体(Armitage等,美国专利5,674,492);(2)通过CD40拮抗信号传输的抗体(deBoer等,美国专利5,677,165);(3)通过CD40释放刺激性信号但是并不增加CD40和CD40L之间相互作用的抗体,如G28-5(Ledbetter等,美国专利5,182,368);(4)增加CD40和CD40L之间相互作用的抗体,如CD40.4(5C3)(PharMingen,San Diego,California)和S2C6(于1999年5月25日以登记号PTA-110保藏于地处Manassass,Virginia的美国典型培养物保藏中心(ATCC))。
本文的″肿瘤坏死因子受体超家族″或″TNF受体超家族″,是指可与TNF家族的细胞因子结合的受体多肽。一般而言,这些受体是在其胞外区具有一个或多个半胱氨酸丰富的重复序列的I型跨膜受体。TNF受体超家族可进一步细分为(1)死亡受体;(2)引诱受体;和(3)缺少死亡结构域的信号传输受体。″死亡受体″在其胞浆或胞内区含有一″死亡结构域″,即,在细胞中起到传输导致细胞凋亡信号或诱导某些基因的作用的区或序列。″引诱受体″缺乏功能性死亡结构域,不能够传输导致细胞凋亡的信号。TNF基因家族中细胞因子的实例包括:肿瘤坏死因子-α(TNF-α)、肿瘤坏死因子-β(TNF-β或淋巴毒素)、CD30配体、CD27配体、CD40配体、OX-40配体、4-1BB配体、Apo-1配体(也称作Fas配体或CD95配体)、Apo-2配体(也称作TRAIL)、Apo-3配体(也称作TWEAK)、osteoprotegerin(OPG),APRIL、RANK配体(也称作TRANCE),和TALL-1(也称作BlyS、BAFF或THANK)。TNF受体超家族中受体的实例包括:1型肿瘤坏死因子受体(TNFR1)、2型肿瘤坏死因子受体(TNFR2)、p75神经生长因子受体(NGFR)、B细胞表面抗原CD40、T细胞抗原OX-40、Apo-1受体(也称作Fas或CD95)、Apo-3受体(也称作DR3、swl-1、TRAMP和LARD)、称作″跨膜激活剂和CAML-相互作用子(interactor)″或″TACI″的受体、BCMA蛋白、DR4、DR5(或者,也称作Apo-2;TRAIL-R2,TR6,Tango-63,hAPO8,TRICK2或KILLER)、DR6、DcR1(也称作TRID、LIT或TRAIL-R3)、DcR2(也称作TRAIL-R4或TRUNDD)、OPG、DcR3(也称作TR6或M68)、CAR1、HVEM(也称作ATAR或TR2)、GITR、ZTNFR-5、NTR-1、TNFL1、CD30、淋巴毒素β受体(LTBr)、4-1BB受体和TR9(EP988,371A1)。
术语″Apo-2配体″或″Apo2L″,是指1997年7月17日公开的WO97/25428中所述的Apo2L多肽,该专利文献特别在此引入作为参考。为了本申请的目的,这些术语也指1997年1月16日公开的WO97/01633和1998年6月9日公布的美国专利5,763,223中公开的称作TRAIL的多肽,所述文献特别在此引入作为参考。
″Apo2L受体″是Apo2L能与之特异结合的多肽。本文所用术语″Apo2L受体″,涵盖天然序列Apo2L受体及其变体。这些术语囊括来自哺乳动物包括人的各种Apo2L受体。Apo2L受体可以是从各种来源(如从人组织类型或从其它来源)中分离得到的,或者是通过重组或合成的方法制备的。″天然序列″Apo2L受体的实例包括:Apo-2多肽或DR5(WO98/51793,特别在此引入作为参考)、Pan等在Science 276:111-113(1997)描述的天然序列DR4;Sheridan等在Science 277:818-821(1997)中所述的天然序列引诱受体1或DcR1,和Marsters等Curr.Biol.7:1003-1006(1997)中所述的天然序列引诱受体2或DcR2;天然序列osteoprotegerin(参见,Simonet等,Cell 89:309-319(1997);和Emery等J.Interferon and Cytokine Research 18(5):A47Abstract 2.17(1998))。抗-DR5抗体的实例包括:3F11.39.7(ATCCHB-12456)、3H3.14.5(ATCC HB-12534)、3D5.1.10(HB12536)和3H1.18.10(HB-12535)、16E2和20E6(参见WO 98/51793,特别在此引入作为参考)。抗-DR4抗体的实例包括4E7.24.3(ATCC HB-12454)和4H6.17.8(ATCCHB12455)(参见WO 99/37684,特别在此引入作为参考)。
天然序列″DcR3″描述于WO99/14330,该文献特别在此引入作为参考。在该专利出版物中,描述了下列抗DcR3的mAbs:4C4.1.4(ATCC HB-12573);5C4.14.7(ATCC HB-12574);11 C5.2.8(ATCC HB-12572);8D3.1.5(ATCCHB-12571);和4B7.1.1(ATCC HB-12575)。
″天然序列″多肽包括与得自天然的多肽具有相同氨基酸序列的多肽。因此,天然序列多肽可具有天然存在的人多肽、鼠多肽或其它哺乳动物物种来源多肽的氨基酸序列。此天然序列多肽可从自然中分离,或者可通过重组或合成方法制备。术语″天然序列″多肽特别包括天然截短型或分泌型(例如,细胞外结构域序列)、天然变体型(例如,可替换式剪切型)和天然等位变体。
“多肽变体”是指与天然序列多肽具有至少约80%氨基酸序列同一性的生物活性多肽。此类变体多肽包括,例如,在多肽的N-和/或C-末端增加或删减一个或多个氨基酸残基的多肽。通常,变体多肽与天然序列多肽具有至少约80%的氨基酸序列同一性,更优选至少约90%的氨基酸序列同一性,甚至更优选至少约95%的氨基酸序列同一性。
″细胞凋亡″是指程序性细胞死亡。表明细胞凋亡发生的生理事件常包括:DNA片段化,细胞皱缩,内织网膨胀,细胞碎裂,和/或膜泡(称为凋亡小体)形成。可用各种方法检测与凋亡相关的细胞事件。例如,磷脂酰丝氨酸(PS)易位可通过膜联蛋白ν结合来测定;DNA片段化可通过DNA序列梯(laddering)来评估;与DNA片段化相伴的核/染色体浓缩可通过亚二倍体细胞中的任何增加来评估。
术语″抗体″是指最广义上的抗体,包括单克隆抗体(包括全长或完整单克隆抗体)、多克隆抗体、多价抗体、多特异性抗体(如双特异性抗体)和抗体片段(只要其显示所需生物学活性即可,并且见下述)。
除非另外指出,″多价抗体″的表述用于整个说明书中,其是指包含三个或更多个抗原结合部位的抗体。多价抗体优选基因工程改造为具有三个或更多个抗原结合部位并且通常不是天然序列IgM或IgA抗体。
″抗体片段″,仅包括完整抗体的一部分,一般包括完整抗体的抗原结合部位,因而保持结合抗原的能力。本说明书定义的抗体片段的实例包括:(i)Fab片段,具有VL、CL、VH和CH1区;(ii)Fab′片段,它是在CH1区的C-末端具有一个或多个半胱氨酸残基的Fab片段;(iii)具有VH和CH1区的Fd片段;(iv)具有VH和CH1区并且在CH1区的C-末端有一个或更多个半胱氨酸残基的Fd′片段;(v)具有单臂抗体的VL和VH区的Fv片段;(vi)由一个VH区构成的dAb片段(Ward等,Nature 341,544-546(1989));(vii)分离的CDR区;(viii)F(ab′)2片段,包括在铰链区由一个二硫桥连接的2个Fab′片段的二价片段;(ix)单链抗体分子(如单链Fv;scFv)(Bird等,Science 242:423-426(1988);和Huston等,PNAS(USA)85:5879-5883(1988));(x)具有2个抗原结合部位的″双抗体(diabodies)″,包含与同一多肽链中的轻链可变区(VL)相连接的重链可变区(VH)(参见如,EP 404,097;WO 93/11161;和Hollinger等,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993));(xi)包含一对串联Fd片段(VH-CH1-VH-CH1)的″线性抗体″,串连Fd片段与互补的轻链多肽一起形成一对抗原结合区(Zapata等Protein Eng.8(10):1057-1062(1995);和美国专利5,641,870)。
本文中术语“单克隆抗体”,是指来自基本上均质的抗体群的抗体,即除了可能少量存在的天然突变以外,该抗体群中的各个抗体均相同。单克隆抗体具有高度的特异性,是抗单个抗原的。而且,与通常包括的抗不同决定簇(表位)的不同抗体的多克隆抗体制剂相反,每种单克隆抗体针对抗原上的单个表位。修饰词“单克隆”,不解释为需通过任何特殊方法产生该抗体。例如,本发明所用的单克隆抗体可通过由Kohler等(Nature,256:495(1975))首先描述的杂交瘤法进行制备,或者可通过重组DNA法进行制备(例如见美国专利4816567)。“单克隆抗体”还可利用例如Clackson等(Nature,352:624-628(1991))和Marks等(分子生物学杂志,222:581-597(1991))所述技术从噬菌体抗体文库中分离。
本文中的单克隆抗体特别包括“嵌合”抗体,其重链和/或轻链的一部分与源自特殊物种或属于特殊抗体种类或亚类的抗体的相应序列相同或同源,但所述链的其余部分的序列与源自另一个物种或属于另一个抗体种类或亚类的抗体(以及此抗体的片段,只要它们显示所需的生物学活性)的相应序列相同或同源(美国专利4,816,567;和Morrison等,Proc.Natl.Acad.Sci.U.S.A.,81:6851-6855(1984))。
“人源化”型非人(例如小鼠)抗体是包含非人免疫球蛋白的最小序列的嵌合免疫球蛋白。在很大程度上,人源化抗体是人免疫球蛋白(受者抗体)中受者超变区残基被具有所需特异性、亲和力和性能的小鼠、大鼠、家兔或非人灵长类等非人源物种抗体(供体抗体)的超变区残基所取代。在一些实例中,人免疫球蛋白的框架区(FR)残基由相应的非人类残基所取代。而且,人源化抗体可包括在受者抗体或供者抗体中不存在的残基。这些修饰旨在进一步改善抗体的性能。通常,人源化抗体基本上包括至少一个(通常包括两个)可变区的全部,其中超变环的全部或基本上全部对应于非人免疫球蛋白的相应部分,而FR序列的全部或基本上全部是人免疫球蛋白序列。人源化抗体还任选包括免疫球蛋白恒定区(Fc)的一部分,通常为人免疫球蛋白的恒定区的至少一部分。详见Jones等,Nature 321:522-525(1986);Riechmann等,Nature 332:323-329(1988);和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
″人抗体″是具有与人产生的和/或使用本文公开的制备人抗体的任何技术已经制得的抗体相一致氨基酸序列的抗体。人抗体的定义特别排除含有非-人抗原-结合残基的人源化抗体。可以使用本领域已知的各种技术来制备人抗体。在一实施方案中,由表达人抗体的噬菌体展示文库筛选人抗体[Hoogenboom和Winter,J.Mol.Biol.,227:381(1991);Marks等,J.MoL Biol,222:581(1991)]。也可通过把人免疫球蛋白基因座引入转基因动物(例如鼠),来制备人抗体,所述转基因动物的内源性免疫球蛋白基因已被部分或完全失活。攻击鼠后,观察到人抗体产生,所产生的抗体在各个方面均与在人观察到的极为相似,包括基因重排、装配和抗体所有组成部分。这方面的进展参见例如,美国专利5545807、5545806、5569825、5625126、5633425、5661016,和下述科学出版物:Marks等,Bio/Technology 10:779-783(1992);Lonberg等,Nature 368:856-859(1994);Morrison,Nature 368:812-13(1994);Fishwild等,Nature Biotechnology 14:845-51(1996);Neuberger,NatureBiotechnology 14:826(1996);Lonberg和Huszar,Intern.Rev.Immunol.13:65-93(1995)。或者,可通过产生抗靶抗原的抗体的无限增殖人B淋巴细胞来制备人抗体(如B淋巴细胞可从个体中回收或者已在体外被免疫)。参见,如,Cole等,Monoclonal Antibody and Cancer Therapy,Alan R.Liss,p.77(1985);Boerner等,J.Immunol.,147(1):86-95(1991);美国专利5,750,373。
术语“可变”是指可变区某些部分的序列在抗体之间有很大差异,它们可在各个抗体对其特殊抗原的结合和特异性方面发挥作用。然而,该变异性不是均匀的分布于整个抗体的可变区。它集中于轻链和重链可变区中三个称作超变区的节段中。可变区中保守性较高的区域称为框架区(FR)。天然重链和轻链的可变区各包括4个FR,主要采取β折叠构象,由三个超变区相连接,所述三个超变区形成环状连接,而在某些情况下可形成部分β折叠结构。每条链的超变区通过FR紧密地靠近在一起,并且与其它链的超变区一起形成抗体的抗原结合位点(见Kabat等,NIH Publ.No.91-3242,第I卷,第647-669页(1991))。恒定区不直接参与抗体与抗原的结合,但是表现出各种效应器功能,例如参与抗体的抗体依赖性细胞毒性作用(ADCC)。
本文所用术语″超变区″,是指负责与抗原-结合的抗体的氨基酸残基。超变区通常包含来自″互补决定区″或″CDR″的氨基酸残基(如轻链可变区中的残基24-34(L1),50-56(L2)和89-97(L3)及重链可变区中的31-35(H1),50-65(H2)and 95-102(H3);Kabat等,Sequence of proteins of ImmunologicalInterest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))和/或来自″超变区环″的那些残基(如轻链可变区中的残基26-32(L1),50-52(L2)和91-96(L3)及重链可变区中的26-32(H1),53-55(H2)和96-101(H3);Chothia和Lesk J.Mol.Biol.196:901-917(1987))。″框架区″或″FR″残基是那些可变区的残基而不是本文定义的超变区残基。
根据其重链恒定区的氨基酸序列,可将完整抗体分为不同“类”。主要有5类完整抗体:IgA、IgD、IgE、IgG和IgM,其中一些还可进一步分成“亚类”(同种型),例如IgG1(包括非-A和A同种异型)、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类抗体的重链恒定区,分别称为α、δ、ε、γ和μ。不同类免疫球蛋白的亚单位结构和三维构象是众所周知的。
脊椎动物任何物种的抗体的“轻链”,可依据其恒定区氨基酸序列而归为完全不同的两型(称为k和λ)中的一型。
术语″Fc区″用于定义免疫球蛋白重链的C-末端区,它可通过木瓜蛋白酶消化完整抗体而制得。Fc区可以是天然序列Fc区或变体Fc区。尽管免疫球蛋白重链Fc区的边界可能不同,但是人IgG重链Fc区通常定义为从氨基酸残基约Cys 226位或从约Pro230位伸展到羧基-末端的Fc区。免疫球蛋白的Fc区一般包括2个恒定区即CH2区和CH3区,以及任选地包含CH4区。
本文的″Fc区链″,是指Fc区的一个或2个多肽链。
人IgG Fc区的″CH2区″(也称作″Cγ2″区),一般从约231位氨基酸残基延伸到约340位氨基酸残基。CH2区是独特的,因为它不与另一区紧密配对。而且,在完整天然IgG分子的2个CH2区之间插入2个N-连接的分支碳水化物链。已推测,碳水化合物可能替代区-区配对并帮助稳定CH2区。Burton,Molec.Immunol.22:161-206(1985)。本文的CH2区,可以是天然序列CH2区或变体CH2区。
″CH3区″,包含C-末端向Fc区中CH2区延伸的残基(即,从IgG的约341位氨基酸残基向约447位氨基酸残基延伸)。本文的CH3区,可以是天然序列CH3区或变体CH3区(如,CH3区具有在一条链引入的″突起(protroberance)″,而另一条链相应引入的″空穴″;参见美国专利5,821,333,特别在此引入作为参考)。此类变体CH3区可用于制备本文所述的多特异(如双特异)性抗体。
″铰链区″,一般定义为从人IgG1的约Glu216或约Cys226向约Pro230延伸(Burton,Molec.Immunol.22:161-206(1985))。通过把形成链间-重链S-S键的第一个和最后一个半胱氨酸残基放入到相同的位置,可将其它IgG同种型的铰链区与IgG1序列对齐。本文的铰链区可以是天然序列铰链区或变体铰链区。变体铰链区的两条多肽链的每一条多肽链一般保留至少1个半胱氨酸残基,以便变体铰链区的多肽链可在两条链间形成二硫键。本文优选的铰链区是天然序列人铰链区,如天然序列人IgG1铰链区。
″功能性Fc区″具有天然序列Fc区的至少一个″效应器功能″。″效应器功能″的实例包括:Clq结合;补体依赖性细胞毒性(CDC);Fc受体结合;抗体依赖性细胞-介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(如B细胞受体;BCR)的下调,等等。此类效应器功能一般需要Fc区被结合结构域(如抗体可变区)结合并且能使用各种本领域已知的评价此类抗体效应器功能的方法而被评定。
″天然序列Fc区″,包含与天然Fc区氨基酸序列相同的氨基酸序列。图3提供天然序列人和小鼠IgG Fc区的氨基酸序列。
″变体Fc区″,包含由于至少1个氨基酸修饰而与天然序列Fc区不同的氨基酸序列。优选地,与天然序列Fc区或亲本多肽的Fc区相比,变体Fc区具有至少1个氨基酸取代,如约1个至约10个氨基酸取代,优选地,天然序列Fc区或亲本多肽的Fc区中有约1至约5个氨基酸取代。本文的变体Fc区,将优选与天然序列Fc区和/或与亲本多肽的Fc区具有至少约80%序列同一性,最优选至少约90%序列同一性,更优选至少约95%序列同一性。
″抗体依赖性细胞-介导的细胞毒性″和″ADCC″,是在指细胞-介导的反应,在此反应中,表达Fc受体(FcRs)的非特异性细胞毒细胞(如,天然杀伤(NK)细胞、中性白细胞和巨噬细胞)识别结合在靶细胞上的抗体并且继而引起靶细胞的溶胞作用。介导ADCC的主要细胞,NK细胞,仅表达FcγRIII,而单核细胞则表达FcγRI、FcγRII和FcγRIII。FcR在造血细胞上的表达情况总结于Ravetch and Kinet,Annu.Rev.Immunol 9:457-92(1991)第464页的表3中。为评定相关分子的ADCC活性,可进行体外ADCC测定,如描述于美国专利5,500,362或5,821,337中的测定方法。用于此类测定的有用效应器细胞,包括外周血单核细胞(PBMC)和天然杀伤(NK)细胞。或者或另外,在体内如,用Clynes等PNAS(USA)95:652-656(1998)公开的动物模型,测定有关分子的ADCC活性,。
″人效应器细胞″是表达一种或多种FcR并发挥效应器功能的白细胞。优选地,细胞至少表达FcγRIII且发挥ADCC效应器功能。人介导ADCC的白细胞的实例包括:外周血单核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞和中性白细胞;以PBMC和NK细胞为优选。效应器细胞可从其天然来源中分离得到,如从血液或者本文所述的PBMC分离。
术语″Fc受体″和″FcR″,用于描述与抗体Fc区结合的受体。优选的FcR是天然序列人FcR。而且,优选的FcR是结合IgG抗体的FcR(一种γ受体),并包括FcγRJ,FcγRII,和FcγRIII亚类受体,包括等位基因变体和这些受体的不同剪切形式。FcγRII受体包括FcγRIIA(一种″激活性受体″)和FcγRIIB(一种″抑制性受体″),其具有类似的氨基酸序列,主要区别在于它们胞质结构域的不同。激活性受体FcγRIIA在其胞质结构域含有基于酪氨酸激活基序(ITAM)的免疫受体。抑制性受体FcγRIIB在其胞质结构域含有基于酪氨酸抑制基序的免疫受体(ITIM)。(综述于Daeron,Annu.Rev.Immunol.15:203-234(1997))。对FcR的综述,参见Ravetch和Kinet,Annu.Rev.Immunol9:457-92(1991);Capel等,Immunomethods 4:25-34(1994);以及de Haas等,J.Lab.Clin.Med.126:330-41(1995)。其它FcR,包括今后将被鉴定的那些FcR,均涵盖在本文术语″FcR″之内。该术语也包括新生(neonatal)受体,FcRn,该受体负责将母亲的IgG传递给胎儿(Guyer等,J.Immunol.117:587(1976);和Kim等,J.Immunol.24:249(1994))。
″补体依赖性细胞毒性″和″CDC″,是指补体存在下的靶细胞溶解。补体激活途径是由补体系统的第一个组分(Clq)与已与相关抗原复合的分子(如抗体)相结合而启动的。为了评定补体激活,可使用CDC测定,如Gazzano-Santoro等,J.Immunol.Methods 202:163(1996)中所描述的方法。
″亲和力成熟″抗体,是指该抗体的一个或多个CDR区中存在一个或多个改变,从而导致该抗体相对于其没有这些改变的亲本抗体而言,对所要结合的抗原的亲和力得到改善。优选的亲和力成熟抗体对其靶抗原具有纳摩尔甚至皮克摩尔的亲和力。使用本领域已知的任何方法,制备亲和力成熟抗体。Marks等Bio/technology 10:779-783(1992)描述通过VH和VL区改组(shuffling)的亲和力成熟。CDR和/或框架残基的随机诱变描述在下列文献中:Barbas等Proc Nat.Acad.Sci,USA 91:3809-3813(1994);Schier等Gene 169:147-155(1995);Yelton等J.Immunol.155:1994-2004(1995);Jackson等,J.Immunol.154(7):3310-9(1995);和Hawkins et al,J.Mol.Biol.226:889-896(1992)。
本文的″百分比(%)氨基酸序列同一性″,定义为候选序列的氨基酸残基与选择序列的氨基酸残基进行序列对比,并在必要时导入空隙以获取最大百分比的序列同一性,而不将任何保守取代视为序列同一性的部分时,候选序列与选择序列的氨基酸残基相同的百分数。可使用本领域各种方法进行序列对比以便测定氨基酸序列同一性百分比,例如,使用公众可得到的计算机软件如BLAST、BLAST-2、ALIGN、ALIGN-2或Megalign(DNASTAR)软件。本领域技术人员可以决定测量对比的适宜参数,包括对所比较的序列全长获得最大对比所需的任何算法。然而,为此目的,氨基酸序列同一性%值是使用下述序列对比计算机程序ALIGN-2而获得的。ALIGN-2序列对比计算机程序的作者是Genentech,Inc.,该程序和用户资料一起已经提交地处Washington D.C.,20559的美国版权局,其美国版权注册登记号为TXU510087。公众通过Genentech,Inc.,South San Francisco,California可以得到ALIGN-2程序。ALIGN2程序应当为在UNIX操作系统,优选在数码UNIX V4.0D使用而进行编制。ALIGN-2程序设定了所有序列对比参数并且不变。
为了本发明目的,给定氨基酸序列A相对于给定氨基酸序列B的氨基酸序列同一性%(或者这样说:给定氨基酸序列A具有或含有给定氨基酸序列B相同氨基酸序列的%)如下计算:
X/Y比值乘以100
其中X是用序列对比程序ALIGN-2比较A和B的氨基酸残基后计算出的相同氨基酸数,其中Y是B的氨基酸残基总数。可以理解,当氨基酸序列A与氨基酸序列B的长度不相等时,A相对于B的氨基酸序列同一性%将不等于B相对于A的氨基酸序列同一性%。
″多肽链″,是其中每一个结构域与其它结构域均通过肽键而不是通过非-共价相互作用或二硫键相连接的多肽。
本文的″柔性接头″,是指含有由肽键连接的2个或更多个氨基酸残基、并且为其连接的2个多肽(如2个Fd区)提供更大转动自由度的肽。此转动自由度使得由柔性接头连接的2个或更多个抗原结合部位接近其各自靶抗原(一个或多个)更加高效。适宜柔性接头的实例包括包含下列序列的肽序列:gly-ser,gly-ser-gly-ser(SEQ ID NO:10)、ala-ser和gly-gly-gly-ser(SEQ IDNO:11)。优选地,柔性接头含有2至约10氨基酸残基,最优选4个或更少残基。
″二聚化结构域″,是通过至少2个氨基酸残基(一般为半胱氨酸残基)或至少2个肽或多肽(其可具有相同或不同的氨基酸序列)相缔合而形成的。肽或多肽相互之间可通过共价和/或非-共价缔合而相互作用。本文二聚化结构域的实例包括:Fc区;铰链区;CH3区;CH4区;CH1-CL对;具有基因工程改造的″隆凸″和/或″突起″的″界面″(描述于美国专利5,821,333中,特别在此引入作为参考);亮氨酸拉链(如jun/fos亮氨酸拉链,参见Kostelney等,J.Immunol.,148:1547-1553(1992);或酵母GCN4亮氨酸拉链);异亮氨酸拉链;受体二聚体对(如,白介素-8受体(IL-8R);和整联蛋白异二聚体如LFA-1和GPIIIb/IIIa),或者它们的二聚化区;二聚配体多肽(如神经生长因子(NGF),神经营养蛋白-3(NT-3),白介素-8(IL-8),血管内皮生长因子(VEGF),和脑衍生的神经营养因子(BDNF);参见Arakawa等J.Biol.Chem.269(45):27833-27839(1994)和Radziejewski等Biochem.32(48):1350(1993)),或者它们的二聚化区;一对能够形成二硫键的半胱氨酸残基;一对肽或多肽,每一包含至少一个半胱氨酸残基(如从约1、2或3至约10个半胱氨酸残基),这样使得在肽或多肽之间可以形成二硫键(此后指″合成的铰链″);和抗体可变区。本文最优选的二聚化结构域是Fc区或铰链区。
″天然存在氨基酸残基″(即,由遗传密码编码的氨基酸残基)可选自:丙氨酸(Ala);精氨酸(Arg);天冬酰胺(Asn);门冬氨酸(Asp);半胱氨酸(Cys);谷氨酰(Gln);谷氨酸(Glu);甘氨酸(Gly);组氨酸(His);异亮氨酸(Ile):亮氨酸(Leu);赖氨酸(Lys);蛋氨酸(Met);苯丙氨酸(Phe);脯氨酸(Pro);丝氨酸(Ser);苏氨酸(Thr);色氨酸(Trp);酪氨酸(Tyr);和缬氨酸(Val)。″非-天然存在氨基酸残基″,是指在多肽链中能够与相邻氨基酸残基共价连接但不是上述列举的天然存在氨基酸残基的残基。非-天然存在氨基酸残基的实例包括:正亮氨酸、鸟氨酸、正缬氨酸、高丝氨酸和其它例如描述于Ellman等Meth.Enzym.202:301-336(1991)中的氨基酸残基类似物。为了产生这些非-天然存在氨基酸残基,可以使用Noren等Science 244:182(1989)和Ellman等(出处同上)的方法。简言之,这些方法涉及用非-天然存在氨基酸残基化学性激活抑制型tRNA,继之在体外转录和翻译RNA。
″分离的″多肽,是指已从其天然环境组分中鉴定和分离和/或收获的多肽。肽的天然环境中的污染成分是那些将干扰使用多肽进行诊断和治疗的物质,可包括酶、激素和其它蛋白性或非-蛋白性溶质。在优选的实施方案中,多肽被纯化为:(1)使用Lowry方法测定为大于95重量%、最优选大于99重量%的多肽,(2)用转杯式蛋白测序仪,达到足以获得N-末端或内部氨基酸序列至少15个残基的程度,或者(3)使用考马斯蓝或优选银染色,达到在非-还原或还原条件下SDS-PAGE电泳同质性的程度。分离的多肽包括在重组细胞内的原位多肽,因为多肽天然环境中的至少一个组分是不存在的。然而,通常用至少一个纯化步骤来制备分离的多肽。
抗体的″功能性抗原结合部位″,是能够结合靶抗原的部位。抗原结合部位的抗原结合亲和力,并不必需具有与抗原结合部位所衍自的亲本抗体同样的强度,但是结合抗原的能力必须是使用任何一种已知评价抗原结合抗体的各种方法可以测定的。而且,本文多价抗体每一抗原结合部位的抗原结合亲和力,不必具有相同的定量。对于本文的多聚抗体,功能性抗原结合部位的数量可用下述实施例2中所描述的超速离心法进行评定。根据此方法,假定有不同数量功能性结合部位的情况下,计算靶抗原与多聚抗体缔合的不同比率和复合物的平均分子量。为了计算功能性结合部位的数量,将这些理论值与得到的实际试验值进行比较。
″受体的配体激活″,是指由与受体(或含有目标受体的受体复合物)结合的配体所介导的信号转导(例如,对于酪氨酸激酶受体来说,是由酪氨酸激酶受体的胞内激酶结构域磷酸化受体或底物多肽中的酪氨酸残基而引起)。在ErbB受体时,通常将会涉及ErbB配体与ErbB异源-低聚体的结合,这将激活异源-低聚体中一个或多个ErbB受体的激酶结构域,并因而导致一个或更多个ErbB受体中酪氨酸残基的磷酸化和/或其它底物多肽(一条或多条多肽)中酪氨酸残基的磷酸化。
″阻断″受体的配体激活的抗体,是降低或阻止上面定义的配体激活的抗体。此阻断可以任何方法发生,如通过干扰:配体与受体的结合、受体复合物形成、受体复合物中酪氨酸激酶受体的酪氨酸激酶活性,和/或受体内或受体附近酪氨酸激酶残基(一个或多个)的磷酸化。阻断ErbB受体的配体激活的抗体的实例,包括单克隆抗体2C4和7F3(它阻断HER2/HER3和HER2/HER4异源-低聚体的HRG激活;和EGFR/HER2异源-低聚体的EGF、TGF-β或双调节素激活);和L26、L96及L288抗体(Klapper等Oncogene 14:2099-2109(1997)),它阻断EGF和NDF与表达EGFR、HER2、HER3和HER4的T47D细胞之结合。
具有指定抗体的″生物特性″的抗体,是具有能够将抗体同那些与相同抗原结合的其它抗体区别开来的一种或多种生物特性的抗体。
本文所用的″生长抑制剂″,是指抑制体内或体外细胞生长的化合物或组合物。因此,细胞因子抑制剂是显著降低S期细胞百分比的化合物或组合物。生长抑制剂的实例包括阻断细胞周期进程的制剂(在S期之外的环节),譬如,诱导G1期和M-期停滞的制剂。传统的M-期阻断剂包括长春花碱(长春新碱和长春碱)、紫杉酚和拓扑酶II抑制剂如阿霉素、表阿霉素、柔红霉素、依托泊苷和博莱霉素。那些使G1期停滞的制剂也使S-期停滞,例如,DNA烷化剂如他莫昔芬、泼尼松、达卡巴嗪、氮芥、顺铂、氨甲蝶呤、5-氟尿嘧啶和阿糖胞嘧啶-C。进一步的信息可在下列文献中找到:TheMolecular Basis of Cancer,Mendelsohn和Israel,eds.,Chapter 1,entitled″Cellcycle regulation,oncogens,and antineoplastic drugs″by Murakami等(WBSaunders:Philadelphia,1995),特别是第13页。
″生长抑制性″抗-HER2抗体的实例,是那些与HER2结合并抑制过度表达HER2的癌细胞生长的抗体。优选的生长抑制性抗-HER2抗体在抗体浓度约0.5~30μg/ml时抑制培养物中SKBR3乳腺肿瘤细胞生长大于20%、优选大于50%(如从约50%至约100%),该生长抑制是在SKBR3细胞暴露于抗体6天后测定的。(见1997年10月14日公布的美国专利5,677,171)。
″诱导细胞死亡″的抗体,是引起活细胞变得无法生存的抗体。细胞通常是表达抗体要与之结合的抗原的细胞,尤其是过度表达抗原的细胞。优选地,细胞是癌细胞,如乳腺癌、卵巢癌、胃癌、子宫内膜癌、唾液腺癌、肺癌、肾癌、结肠癌、甲状腺癌、胰腺癌或者膀胱癌细胞。在体外,细胞可以是SKBR3、BT474、Calu 3、MDA-MB-453、MDA-MB-361或SKOV3细胞。体外的细胞死亡可在不存在补体和免疫效应器细胞的情况下测定,以区别于抗体依赖性细胞-介导的细胞毒性(ADCC)或补体依赖性细胞毒性(CDC)引起的细胞死亡。因此,细胞死亡试验可使用热灭活血清(即不含有补体)并在不含免疫效应器细胞时进行。为了测定抗体是否能够诱导细胞死亡,可评定相对于未处理细胞的胞膜完整性是否丧失,细胞完整性可通过碘化丙啶(propidium iodide)(PI)、台盼蓝(见Moore etal.Cytotechnology 17:1-11(1995))或7AAD的摄取进行测定。
″诱导细胞凋亡″的抗体,是诱导程序性细胞死亡的抗体,程序性细胞死亡是通过测定膜联蛋白V结合、DNA片段化、细胞皱缩、内质网膨胀、细胞碎裂和/或膜泡(称为凋亡小体)形成而确定的。细胞是表达抗体要与之结合的抗原的细胞,并且可以是过度表达抗原的细胞。细胞可以是肿瘤细胞,如乳腺癌、卵巢癌、胃癌、子宫内膜癌、唾液腺癌、肺癌、肾、结肠癌、甲状腺癌、胰腺癌或膀胱癌细胞。体外,细胞可以是SKBR3、BT474、Calu3细胞、MDA-MB-453、MDA-MB-361或SKOV3细胞。可用各种方法检测与凋亡相关的细胞事件。例如,磷脂酰丝氨酸(PS)易位可通过膜联蛋白结合来测定;DNA片段化可通过本文实施例中所公开的DNA序列梯来评估;与DNA片段化相伴的核/染色体浓缩可通过亚二倍体细胞中的任何增加来评估。优选地,诱导细胞凋亡的抗体是,在使用表达抗体要与之结合的抗原的细胞的膜联蛋白结合试验中,该抗体对膜联蛋白结合的诱导是未处理细胞的约2~50倍,优选约5~50倍,最优选约10~50倍。
诱导细胞凋亡的抗体的实例包括:抗-HER2单克隆抗体7F3(ATCCHB-12216)和7C2(ATCC HB 12215),包括其人源化和/或亲和力成熟变体;抗-DR5抗体3F11.39.7(ATCC HB-12456);3H3.14.5(ATCC HB-12534);3D5.1.10(ATCC HB-12536);和3H3.14.5(ATCC HB-12534),包括其人源化和/或亲和力成熟变体;人抗-DR5受体抗体16E2和20E6,包括其亲和力成熟变体(WO98/51793,特别在此引入作为参考);抗-DR4抗体4E7.24.3(ATCC HB-12454);4H6.17.8(ATCC HB-12455);1H5.25.9(ATCC HB-12695);4G7.18.8(ATCC PTA-99);和5G11.17.1(ATCC HB-12694),包括其人源化和/或亲和力成熟变体。
为了筛选与被感兴趣抗体结合的抗原上的表位相结合的抗体,可进行如在Antibody,A Laboratory Manual,Cold Spring Harbor Laboratory,EdHarlow and David Lane(1988)中描述的常规交叉-阻断试验。
″激动型抗体″是与受体结合并激活受体的抗体。通常,激动型抗体的受体激活能力至少与受体的天然激动型配体性质上相似(并且可以是基本上性质相似)。激动型抗体的实例,是与TNF受体超家族中受体结合并诱导表达TNF受体的细胞凋亡。测定细胞凋亡诱导作用的试验描述在WO98/51793和WO99/37684中,该两篇文献特别在此引入作为参考。
″病症″是指将受益于抗体治疗的任何状况。其包括慢性和急性病症或疾病,包括哺乳动物易于患上正被讨论病症的那些病理学状况。在本文中,受治病症的非-限定性实例包括良性和恶性肿瘤;白血病和淋巴系统恶性肿瘤;神经元、神经胶质细胞、星形胶质细胞、下丘脑和其他腺体、巨噬细胞、上皮、基质和囊胚腔的病症;以及炎性、血管生成和免疫学的病症。
术语″治疗有效量″,是指药物有效治疗哺乳动物疾病或病症的量。在癌症的情况下,药物的治疗有效量是减少癌细胞数量;缩小肿瘤;抑制(即,减缓到一定程度并优选停止)癌细胞侵润入周边器官;抑制(即,减缓到一定程度并优选停止)肿瘤转移;抑制肿瘤生长至一定程度;和/或缓解与病症有关的一种或更多种症状至一定程度。到此程度,药物可以阻止现存的癌细胞生长和/或杀死癌细胞,药物可以是细胞抑制剂和/或细胞毒素。对于癌症治疗,体内效力可以是例如,通过评定疾病进展时间(TTP)和/或测定反应速度(RR)来测量。
″治疗″是指治疗性治疗和预防性措施。需要治疗的那些对象,包括已经患有病症的那些个体,也包括要预防发生病症的那些个体。
术语″癌″,是指或描述哺乳动物的以无控性细胞生长为特征的生理状况。癌的实例包括但不限于,癌、淋巴瘤、胚细胞瘤、肉瘤和白血病。此类癌的更具体的实例包括:鳞状细胞癌、小细胞肺癌、非-小细胞肺癌、肺的腺癌、肺的鳞癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、肝癌、前列腺肾癌、外阴癌、甲状腺癌、肝癌和各种类型的头颈癌。
本文的″自身免疫性疾病″,是由对抗个体自身组织应答而引起的非-恶性疾病或病症。自身免疫性疾病或病症的实例包括但不限于:炎症性反应,如包括牛皮癣和皮炎(如特应性皮炎)的炎症性皮肤疾病;系统性硬皮病和硬化症;与炎性肠道疾病有关的反应(如克罗恩氏病和溃疡性结肠炎);呼吸窘迫综合征(包括成年呼吸窘迫综合征;ARDS);皮炎;脑膜炎;脑炎;眼色素层炎;结肠炎;肾小球肾炎;变应性状况如湿疹和哮喘以及涉及T细胞浸润和慢性炎症性反应的其它状况;动脉粥样硬化;白细胞粘附缺陷;类风湿性关节炎;系统性红斑狼疮(SLE);糖尿病(如I型糖尿病或胰岛素依赖型糖尿病);多发性硬化症;雷诺氏综合征;自身免疫性甲状腺炎;变应性脑脊膜炎;Sjorgen′s综合征;青少年糖尿病;和由细胞因子和T淋巴细胞介导的与急性和迟发型超敏反应有关的免疫反应,通常见于结核、类肉瘤病、多肌炎、肉芽肿病和结节性脉管炎;恶性贫血(阿狄森氏病);涉及白细胞渗出的疾病;中枢神经系统(CNS)炎症性病症;多器官损伤综合征;溶血性贫血(包括但不限于冷沉淀球蛋白血症或Coombs试验阳性贫血);重症肌无力;抗原-抗体复合物介导的疾病;抗-肾小球基膜疾病;抗磷脂综合征;变应性神经炎;格雷夫斯病;Lambert-Eaton肌无力综合征;大疱性天疱疮;天疱疮;自身免疫性多内分泌腺病;莱特尔氏病;强直-人综合征(stiff-man syndrome);贝切特氏病;巨细胞性动脉炎;免疫复合物性肾炎;IgA肾病;IgM多神经病;特发性血小板减少性紫癜(ITP)或自身免疫性血小板减少症等。
″外来抗原″,是指对于接触之的哺乳动物而言不是内原性或天然的分子。外来抗原可引发免疫应答,如在哺乳动物介导的体液和/或T细胞应答。通常,外来抗原将诱导对抗所述抗原的抗体产生。本文考虑到的外来抗原的实例包括:免疫原性治疗剂,例如蛋白如抗体,特别是含有非-人氨基酸残基的抗体(如啮齿类动物、嵌合/人源化抗体和灵长化(primatized)抗体);毒素(任选地与靶向分子如抗体偶合,其中靶向分子也可以是免疫原性的);基因治疗病毒载体,如逆转录病毒和腺病毒;移植物;传染性物质(如细菌和病毒);同种抗原(即在某些成员中存在而在同一物种的其他成员中却不存在的抗原),例如在血型、人淋巴细胞抗原(HLA)、血小板抗原、在移植器官上表达的抗原、血液成分、妊娠(Rh)以及血友病因子(如因子VIII和因子IX)方面的差异。
″阻断对外来抗原的免疫应答″,是指减少或阻止因暴露于外来抗原而产生的至少一种免疫-介导的应答。例如,人们可以减轻对抗外来抗原的体液应答,即,通过阻止或减少哺乳动物中抗该抗原的抗体产生。或者,或另外,抑制独特型抗体;″减缓″包被有同种抗体的细胞的清除;和/或通过耗竭抗原-呈递细胞而影响同种抗原呈递。
本文所用术语″移植物″,是指得自供体的用于移植入接受者的生物学材料。移植物包括各种材料,例如,分离的细胞,如胰岛细胞;组织,如新生儿的羊膜、骨髓、造血前体细胞,和眼组织如角膜组织;以及器官,如皮肤、心脏、肝脏、脾脏、胰腺、甲状腺叶、肺、肾、管状器官(如,肠、血管或者食管)等。管状器官可用于替换食管、血管或胆管的损伤部分。皮肤移植物不仅可用于烧伤,而且可用作损伤肠道或者封闭一些缺损如膈疝的敷料。移植物得自于任何哺乳动物,包括人,无论是来自尸体还是活的供体。优选地,移植物是骨髓或者器官如心脏,并且移植物的供体与宿主的HLAII类抗原相适配。
本文所用术语″哺乳动物宿主″,是指任何相容的移植物接受者。″相容的″是指将接受捐赠移植物的哺乳动物宿主。优选,宿主是人。如果移植物的供体和宿主均是人,那么优选他们HLA II类抗原相适配,以便改善组织相容性。
本文所用术语″供体″,是指移植物所取自的死的或活的哺乳动物。供体优选是人。人供体优选是体检正常并且具有相同主要ABO血型的血统-相关的志愿者供体,因为交叉主要血型可能影响同种移植物的存活。然而,将例如O型血供体的肾脏移植给A、B或者AB接受者是可能的。
术语″移植″及其变异(variations),是指移植物插入宿主,无论移植术是同系移植(其中供体和接受者在遗传上是完全相同的)、同种异体移植(其中供体和接受者是不同的基因来源但是属于相同的物种),还是异种移植(其中供体和接受者来源于不同的物种)。因此,在一代表性方案中,宿主是人而移植物是来自于相同或不同遗传起源的人的同种移植物。在另一方案中,移植物来自于不同于要移植入的种群的物种,譬如狒狒心脏移植入人接受者宿主体内,并包括种系发生上具有极大差异的物种的动物,例如,将猪心脏瓣膜或动物β胰岛细胞或者神经元细胞移植入人宿主体内。
″脱敏待移植哺乳动物″,是指在将移植物施用到哺乳动物之前减少或者消除对移植物的过敏性敏感度或者反应性。这可通过任何机制而达到:例如减少脱敏哺乳动物的抗-供体抗体,例如其中抗-供体抗体是抗人淋巴细胞抗原(HLA)的。
本文所用术语″细胞毒制剂″,是指抑制或阻止细胞功能和/或引起细胞破坏的物质。该术语意在包括:放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、p32和Lu的放射性同位素),化疗剂,毒素如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体。
“化疗剂”是在肿瘤治疗中使用的化学化合物。化疗剂实例包括烷化剂,如噻替哌(thiotepa);环磷酰胺(cyclosphamide)(CYTOXANTM);烷基磺酸酯如白消安(busulfan),英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶(aziridine)如苯并多巴(benaodopa),卡波醌(carboquone),美妥替哌(meturedopa)和尿烷亚胺(uredopa);氮丙啶和methylamelamine包括六甲蜜胺(altretamine),三亚胺嗪(triethylenemelamine),三亚乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基蜜胺(trimethylolomelamine);acetogenins(特别是bullatacin和bullatacinone);喜树碱(包括合成的类似物拓扑替康(topotecan));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);cryptophycins(特别是cryptophycin 1和cryptophycin 8);海兔毒素(dolastatin);duocarmycin(包括合成类似物,KW-2189和CBI-TMI);eleutherobin;pancratistatin;sarcodictyin;spongistatin;氮芥(nitrogen mustards)如苯丁酸氮芥,萘氮芥,胆磷酰胺(cholophosphamide),雌氮芥(estramustine),异环磷酰胺(ifosfamide),氮芥(mechlorethamine),盐酸氧氮芥;左旋苯丙氨酸氮芥(melphalan),新氮芥(novembichin),胆甾醇苯乙酸氮芥,松龙苯芥(prednimustine),曲磷胺(trofosfamide),尿嘧啶氮芥;亚硝基脲(nitrosureas)如亚硝基脲氮芥(carmustine),氯脲菌素(chlorozotocin),福莫司汀(fotemustine),洛莫司汀(lomustine),尼莫司汀(nimustine),雷莫司汀(ranimustine);抗生素如enediyne抗生素(如加利车霉素,尤其是加利车霉素γ1和加利车霉素θ1,参见例如Agnew Chem Intl.Ed.Engl.33:183-186(1994);dynemicin,包括dynemicinA;esperamicin;以及新制癌菌素生色团(chromophore)和相关的色蛋白enediyne抗生素生色团),阿克拉霉素,放线菌素,authramycin,重氮丝氨酸,博来霉素,放线菌素C(cactinomycin),carabicin,洋红霉素(carminomycin),嗜癌素(carzinophilin),色霉素,放线菌素D,柔红菌素(daunorubicin),地托比星(detorubicin),6-重氮-5-氧-L-正亮氨酸,阿霉素(doxorubicin)(包括吗啉代-阿霉素,氰基吗啉代-阿霉素,2-吡咯啉基-阿霉素和脱氧阿霉素),表阿霉素(epirubicin),依索比星(esorubicin),伊达比星(idarubicin),发波霉素(marcellomycin),丝裂霉素,霉酚酸,诺加霉素(nogalamycin),橄榄霉素(olivomycin),培洛霉素(peplomycin),potfiromycin,嘌呤霉素,三铁阿霉素(quelamycin),罗多比星(rodorubicin),链黑菌素;链脲霉素(streptozocin),杀结核菌素,乌苯美司(ubenimex),净司他丁(zinostatin),佐柔比星(zorubicin);抗代谢药如氨甲蝶呤,5-氟尿嘧啶(5-FU);叶酸类似物,如二甲叶酸(denopterin),氨甲蝶呤,蝶罗呤,三甲曲沙(trimetrexate);嘌呤类似物氟达拉滨(fludarabine),6-巯基嘌呤,硫咪嘌呤,硫鸟嘌呤;嘧啶类似物,如安西他滨(ancitabine),阿扎胞苷(azacitidine),6-氮尿苷,卡莫氟(carmofur),阿糖胞苷,双脱氧尿苷,去氟氧尿苷(doxifluridine),依诺他滨(enocitabine),氟尿苷,5-FU;雄激素类,如二甲睾酮(calusterone),丙酸甲雄烷酮(dromostanolong propionate),环硫雄醇(epitiostanol),美雄氨(mepitiostane),睾内酯(testolactone);抗肾上腺类,如氨鲁米特(aminoglutethimide),米托坦(mitotane),曲洛司坦(trilostane);叶酸补充剂如frolinic acid;醋葡内酯;醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);bestrabucil;比生群(biasntrene);依达曲沙(edatraxate);defofamine;秋水仙胺;地吖醌(diaziquone);elfornithine;依利醋铵(elliptiniumacetate);epothilone;依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidamine);美登木素生物碱(maytan sinoids)(包括美登素和柄型菌素)米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);硝呋旦(nitracrine);喷司他丁(pentostatin);phenamet;吡柔比星(pirarubicin);鬼臼树酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼(procarbazine);;雷佐生(razoxane);rhizoxin;西索菲兰(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸;三亚胺醌;2,2′,2″-三氯三乙胺(trichlorrotriethylamine);单端孢霉烯族毒素类(尤其是T-2毒素,verracurinA,杆孢菌素A,蛇形菌素(anguidine));乌拉坦(urethan);长春碱酰胺;达卡巴嗪(dacarbazine);甘露醇氮芥;二溴甘露醇(mitobronitol);二溴卫矛醇;哌泊溴烷(pipobroman);gacytosine;阿拉伯糖苷(“Ara-C”);环磷酰胺;三胺硫磷(thiotepa);taxoids,如紫杉醇(,Bristol-Myers Squibb Oncology,Princeton,NJ)和紫杉萜(,Rhone-Poulenc Rorer,Antony,France);苯丁酸氮芥;吉西他滨(gemcitabine);6-硫代鸟嘌呤;巯基嘌呤;氨甲蝶呤;铂类似物如顺铂和卡铂;长春花碱;铂;依托泊甙(etoposide)(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞宾(vinorelbine);新霉酰胺(navelbine);novantrone;替尼泊甙(teniposide);柔红霉素;氨基蝶呤;xeloda;伊拜膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);维甲酸;esperamicins;卡培他滨(capecitabine);以及上述任何物质的可药用盐、酸或衍生物。此定义还包括能调节或抑制激素对肿瘤的作用的抗激素制剂,如抗雌激素制剂,包括他莫昔芬(tamoxifen),雷洛昔芬(raloxifene),芳香酶抑制剂4(5)-咪唑,4-羟基他莫昔芬,曲沃昔芬(trioxifene),keoxifene,LY117018,奥那司酮(onapristone),和托瑞米芬(Fareston);和抗雄激素制剂,如氟他氨(flutamide),尼鲁米特(nilutamide),比卡鲁胺(bicalutamide),亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);和上述任何物质的可药用盐、酸或衍生物。
术语″细胞因子″,是由一个细胞群释放出的作为细胞内递质作用于另一细胞的蛋白质的通用词。此类细胞因子的实例是淋巴因子、单核因子和传统的多肽激素。包括在细胞因子中的有:生长激素,如人生长激素、N-甲硫氨酰人生长激素和牛生长激素;甲状旁腺素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素,如卵泡刺激素(FSH)、促甲状腺激素(TSH和黄体生成素(LH);肝生长因子;成纤维细胞生长因子;催乳激素;胎盘催乳激素(placenta lactogen);肿瘤坏死因子-α和肿瘤坏死因子-β;苗勒氏-抑制物质;鼠促性腺素-有关的肽;抑制素;活化素;血管内皮生长因子;整合素;血小板生成素(TPO);神经生长因子,如NGF-α;血小板-生长因子;转化生长因子(TGFs),如TGF-α和TGF-β;胰岛素-样生长因子-I和胰岛素-样生长因子-II;促红细胞生成素(EPO);骨诱导因子(osteoinductive factors);干扰素,如干扰素-α、干扰素-β和-γ集落刺激因子(CSFs)如巨噬细胞-CSF(M-CSF);粒细胞巨噬细胞-CSF(GM-CSF);和粒细胞-CSF(G-CSF);白介素(ILs)如IL-1,IL-1α,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-10,IL-11,IL-12;肿瘤坏死因子,如TNF-α或TNF-β;以及其他多肽因子,包括LIF和kit配体(KL)。本文所用术语细胞因子,包括来自天然来源或来自重组细胞培养物的蛋白和天然序列细胞因子的生物活性等效物。
本申请所用术语″前体药物″,是指药物活性物质的前体或衍生物形式,其相对于亲本药物对肿瘤细胞的细胞毒作用较小且可酶促活化或被转换成更具活性的亲本形式。例见Wilman,“癌症化疗中的前体药物”BiochemicalSociety Transaction,14,pp.375-382,615th Meeting Belfast(1986)和Stella等,“前体药物:一种药物定向运送的化学方法”定向药物运送,Borchardt等(编),pp.247-267,Humana press(1985)。本发明的前体药物包括但不限于:含有磷酸盐的前体药物、含有硫代磷酸盐的前体药物、含有硫酸盐的前体药物、含有肽的前体药物、D-氨基酸修饰的前体药物、糖基化的前体药物、含有β-内酰胺的前体药物、任选取代的含有苯氧乙酰胺的前体药物或任选取代的含有苯基乙酰胺的前体药物、5-氟胞嘧啶和可转化为更具细胞毒活性的游离药物的其它5-氟尿嘧啶前体药物。可衍生为本发明所用前体药物形式的细胞毒药物包括,但不限于上述化疗剂。
″血管生成因子″是刺激血管发育的生长因子。在本文中,优选的血管生成因子是血管内皮生长因子(VEGF)。
本文中所用″标记″一词,是指直接或间接地与多肽偶联的可检测的化合物或组合物。标记可以是其本身可被测得(例如放射性同位素标记或荧光标记),或者如果是酶标记时,可以是可测得的催化底物化合物或组合物发生的化学变化。
″分离的″核酸分子,是从至少一个污染核酸分子中鉴定和分离出来的核酸分子,而天然来源的多肽核酸通常与所述污染核酸分子缔合在一起。一分离的核酸分子不是在自然界中发现的形式或按其天然存在的形式。因而,分离的核酸分子区别于天然细胞中存在的核酸分子。但是,分离的核酸分子,含有包含在通常表达多肽的细胞中的核酸分子,例如,所述核酸分子所在的染色体位置与在天然细胞中所处位置不同。
术语″控制序列″,是指在特定宿主生物中表达可操作连接的编码序列所必要的DNA序列。适宜于原核生物的控制序列是例如包括启动子,任选地启动子序列,和核糖体结合位点。已知真核细胞是使用例如启动子、多腺苷酸化信号和增强子。
当置入核酸使与另一核酸序列功能性关联时,核酸是″可操作地连接″。例如,如果一个肽是作为参与多肽分泌的前蛋白而被表达的话,则把DNA前序列(presequence)或分泌性前导序列可操作性地连接于这个多肽的DNA;如果启动子或增强子影响序列的转录,则把该启动子或增强子可操作地连于该编码序列;或者如果核糖体结合位点所处位置是为了促进序列的翻译,则把该核糖体结合位点可操作地连于该编码序列。通常,″可操作地连接″是指连接的DNA序列是邻接的,和在分泌性前导序列的情况下,是邻接的并且是在阅读相的。然而,增强子并非必须是邻接的。通过在适宜限制性酶切位点的连接反应完成连接。如果不存在这样的酶切位点,则根据常规实践使用合成的寡核苷酸衔接子或接头。
在本文中,″细胞″、″细胞系″和″细胞培养物″的表述互换使用,并且所有命名均包括后代细胞。因此,单词″转化物(transformants)″和″转化的细胞″包括原始主体细胞和由其传代的培养物,而不考虑传递的数量。也应理解,由于有意或无意的突变,所有后代细胞在DNA内容上可能并不精确地完全相同。与所筛选的最初转化的细胞具有相同功能或生物学活性的突变的后代细胞包括在本发明中。不同的命名旨在使发明内容更清楚。
II.实现本发明的方法
A.多价抗体
本发明涉及制造多价抗体的方法。本申请下一部分将描述生产多价抗体的可变区所起源的″亲本″或″起始″抗体的各种技术。
本文感兴趣的具体多价抗体,是包含至少3个(并优选4个或更多,如4或5至约8个)抗原结合部位的抗体。通常,所有抗原结合部位均是如前所定义的″功能性的″。优选地,多价抗体在自然界不存在,而且不是天然序列IgM或IgA抗体。本文多价抗体优选不在体外通过把一对抗体进行化学交联而产生(如Ghetie等(1997),出处同上或Wolff等(1993),出处同上所描述的方法)。本申请也提供不需要在亲本抗体中引入半胱氨酸残基(一个或多个)以便通过在一对Fc区之间的二硫键来形成多价抗体的多价抗体(如Shopes等(1992),出处同上或Caron等(1992),出处同上所描述的方法)。
在一实施方案中,多价抗体包含含有至少2个重链(或轻链)可变区的第一条多肽链和含有至少2个重链(或轻链)可变区的第二条多肽链。优选地,第一条多肽链含有2个重链可变区而第二条多肽链也含有2个重链可变区,它们可以与相应的轻链可变区(每条多肽链至少2个)结合从而产生4个(或更多个)抗原结合部位。
在本发明一优选的实施方案中,多价抗体包含一个二聚化结构域,它将(1)2个(或更多个)抗原结合部位与(2)1个、2个(或更多个)抗原结合部位相结合。本文考虑到了各种二聚化结构域,但是优选的二聚化结构域是Fc区或铰链区。当多价抗体包含Fc区(如天然序列或变体Fc区)时,Fc区优选是前述定义的″功能性的″,因而它能够起到一个或更多个抗体效应器功能,如ADCC或CDC。优选地,多价抗体仅含有一个Fc区或缺乏Fc区。
当多价抗体包含一个Fc区时,优选地,为Fc区氨基末端(而不是Coloma和Morrison,(1997)出处同上所述的Fc区羧基末端)提供三个或更多个抗原结合部位。这可以通过提供用式VD1-X1-VD2-X2-Fc表示的第一条多肽链来实现:,其中(1)VD1是第一个重链或轻链可变区(优选是重链可变区),(2)VD2是第二个重链或轻链可变区(优选是重链可变区),(3)Fc含有Fc区的一条链,和(4)X1与X2代表任选插入的氨基酸或多肽。X1与X2优选包含或者由CH1区(其VD1或VD2是重链可变区)或CL区(其VD1或VD2是轻链可变区)组成。任选地,X1进一步包含一个柔性接头,它一般由C-末端至VD1(或C-末端至CH1或CL,如果存在的话)。柔性接头可含有肽如gly-ser、gly-ser-gly-ser(SEQ ID NO:10)、ala-ser或gly-gly-gly-ser(SEQ ID NO:11)。
本文感兴趣的多价抗体包含三个或更多个(如4或5至约8个)Fab多肽,每一多肽均能够结合抗原。Fab片段优选提供对应Fc区的氨基末端(此时多价抗体具有Fc区)。举例来说,2个或更多个Fd片段可以与Fc区一条链的氨基末端相融合。如此基因工程产生的多肽链可以:与(1)通过2个或更多个Fd片段与Fc区另一条链的氨基末端相融合形成的另一条多肽链结合,以及与(2)互补性VL区(如4个或更多个VL区,其中每一区任选地与CL区融合)相结合。任选地,抗体包含2个或更多个Fd片段之间的柔性接头。
多价抗体可以,例如,包含一对具有式(1)VH-CH1-柔性接头-VH-CH1-Fc链,或式(2)VH-CH1-VH-CH1-Fc链(即,式中2个Fd片段之间没有柔性接头)的多肽链。
本文多价抗体的三个或更多个功能性抗原结合部位,优选每一个均是通过重链和轻链可变区形成的。因此,其中2个或更多个重链可变区融合在一起(正如前面所指出的那样,任选与插入氨基酸残基(一个或多个)融合),含有2个或更多个互补轻链可变区的多肽与重链可变区结合(例如,在相同宿主细胞中通过共-表达融合蛋白和轻链可变区多肽(一个或多个))。优选地,抗体包含4个或5个或者更多个(如多达约8个)轻链可变区多肽,其中每一个任选地含有CL区。
在本文的一个实施方案中,具有三个或更多个(如3至约10个,但优选3个或4个)抗原结合部位的抗体可以包含含有三个或更多个(如3至约10个,但优选3个或4个)重链或轻链可变区的多肽链,其中每一可变区以形成抗原结合部位的方式与三个或更多个(如3至约10个,但优选3个或4个)轻链或重链可变区多肽相结合或者联合。由此,当多肽链含有三个或更多个重链可变区时,它与三个或更多个相应的轻链可变区多肽(如与VL-CL多肽)相结合或者联合。或者,当多肽链含有三个或更多个轻链可变区时,它与三个或更多个相应的重链可变区多肽(如与VH-CH1多肽)相结合或联合。优选地,三个或更多个抗原结合部位中的每一个均抗相同的抗原。与此类抗体结合的抗原的实例包括:(1)肿瘤坏死因子(TNF)受体超家族中的受体(该受体可以是′三聚体受体′,这样抗体仅需要包括所需的3个抗原结合部位)如DR4和DR5;(2)B细胞表面抗原如CD20;(3)以HER2受体为例的ErbB受体;或者(4)由肿瘤细胞表达的细胞表面蛋白。举例来说,多肽链可包括3个(或4个)能够与3个(或4个)轻链可变区多肽(优选VL-CL多肽)结合以产生抗相同抗原的3个(或4个)抗原结合部位的重链可变区。此类抗体例示于图23D(具有3个抗原结合部位)和图23E(具有4个抗原结合部位)中。多价抗体也可包含含有下列各式的多肽链:(a)VL-CL-柔性接头-VL-CL-柔性接头-VL-CL;在该实施方案中,多肽可含有由柔性接头连接的3至约8个VL-CL多肽;(b)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;在该实施方案中,多肽可含有由柔性接头连接的3至约8个VH-CH1多肽;(c)(VL-CL)n,其中n是三个或更多个(如3至约8个,但优选3个或4个);或(d)(VH-CH1)n,其中n是三个或更多个(如3至约8个,但优选3个或4个)。优选地,多肽链含有下式:(a)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;(b)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;或者(c)(VH-CH1)n,其中n是3或4。
本文多价抗体具有特别用于体内治疗和诊断所需的特性。举例来说,多价抗体可由表达抗体要与之结合的抗原的细胞内化并且发生较二价抗体更快的分解代谢。因此,本发明提供含有与细胞毒制剂(如一旦内化则具有杀细胞活性的细胞毒制剂)偶联的多价抗体的免疫偶联物。本文描述了生产免疫偶联物的各种细胞毒制剂,但是优选的细胞毒制剂是放射性同位素、美登素或加利车霉素。
多价抗体,和/或多价抗体的至少一个抗原结合特异性所源自的亲本抗体,可具有某些特性。举例来说,多价抗体和/或亲本抗体可以(1)是激动型抗体(如,其中抗体所结合的抗原是TNF受体家族的受体或B细胞表面抗原);(2)诱导细胞凋亡(譬如,其中抗体所结合的抗原是ErbB受体或TNF受体超家族的受体);(3)结合肿瘤细胞上所表达的细胞表面蛋白(如B细胞表面抗原或者ErbB受体);(4)结合由肿瘤细胞过度表达的细胞表面蛋白(如表皮生长因子受体(EGFR)、HER2受体、ErbB3受体、ErbB4受体或DcR3受体);和/或(5)是生长抑制性抗体。
本文的多价抗体可以仅对一个抗原,或一个以上抗原(如2至约3个抗原)具有特异性。在一实施方案中,多价抗体的三个或更多个功能性抗原结合部位可以结合相同的抗原(优选结合抗原上相同的表位,在这种情况下,多价抗体被认为是″单特异性的″)。本申请也提供″多特异″抗体。这样,三个或更多个功能性抗原结合部位可结合2个或更多个(如2至约3个)不同的抗原或者表位。
本申请显示,可以基因工程改造抗受体抗原的多价抗体,该抗体令人惊奇地具有在定量上与天然配体相似的激动性和/或细胞凋亡-诱导能力。这里的″定量上相似″,是指在测定激动性和/或细胞凋亡-诱导活性的试验中,多价抗体具有天然配体活性的约10倍、优选约5倍以内的激动性和/或细胞凋亡诱导活性。在该实施方案中,具有激动性和/或细胞凋亡诱导活性的抗体可以是一个对TNF受体超家族受体(诸如Apo2L受体,如DR4、DR5、DcR1和DcR2(优选DR4或DR5))具有特异性的抗体,在此情况下,如在下面实施例3中所述的那样,抗体在细胞凋亡试验中的活性是在该试验中Apo2L活性的约10倍以内,如约5倍以内。
在本发明一实施方案中,本文的多价抗体可以结合B细胞表面抗原。优选的B细胞表面抗原包括CD19、CD20、CD22和CD40,最优选CD20。
考虑了本文多价抗体的各种应用并在下面做进一步详述。多价抗体拥有一个或更多个功能性Fc区时,预期它具有介导效应器功能(如ADCC和CDC)并且较缺乏Fc区的多价抗体具有更长的半衰期。此类多价抗体可用于期望杀死细胞,如肿瘤或者癌细胞的情形。需要本文缺少Fc区的多价抗体的其他形式的情况有:在期望短的半衰期时(如治疗心血管或者炎症性疾病或病症,或者抗体是与细胞毒制剂相偶联的情况);当期望抗体被内化时(如用含有抗体和细胞毒制剂的免疫偶联物治疗);用于改善对实体肿瘤的穿透时;当期望多价抗体在非-哺乳类宿主细胞(如原核宿主细胞如大肠杆菌宿主细胞)表达时;用于非肿瘤疾病或病症治疗时;和/或为了避免向患者施用一些具有效应器功能(一种或多种)抗体所观察到的′首次剂量影响时。此类形式的抗体可包含包括二聚化结构域的多价抗体,其中二聚化结构域含有与亮氨酸拉链区相融合的抗体铰链区(亮氨酸拉链区促进形成二聚化结构域的多肽的联合,但可随后在施用于患者之前通过蛋白水解而去除)(见图23C);具有3个抗原结合部位的多价抗体,如图23D所示;或者具有4个抗原结合部位的多价抗体,如图23E所示的那些。
B.抗原结合特异性
本文多价抗体直接针对或者特异地结合于一个或更多个靶抗原。优选地,被多价抗体结合的至少一个抗原是生物学上重要的多肽,而且向患有疾病或病症的哺乳动物施用该抗体可以在哺乳动物产生有益治疗效果。然而,对抗非多肽抗原的抗体(如肿瘤-相关糖脂抗原;参见美国专利5,091,178)也在考虑之中。
当抗原是多肽时,它可以是跨膜分子(如受体)或配体(如生长因子)。例证性抗原包括:分子如肾素;生长激素,包括人生长激素和牛生长激素;生长激素释放因子;甲状旁腺素;促甲状腺激素;脂蛋白;α-1-抗胰蛋白酶;胰岛素A-链;胰岛素B-链;胰岛素原;卵泡刺激激素;降钙素;黄体化激素;胰高血糖素;凝血因子,如因子VIIIC、因子IX、组织因子(TF),和冯·威利布兰德因子(von Willebrands factor);抗-凝血因子,如蛋白C;心房利钠因子;肺表面活性物质;纤溶酶原激活物质,如尿激酶或人尿或组织-型纤溶酶原激活物质(t-PA);铃蟾肽;凝血酶;造血生长因子;肿瘤坏死因子-α和肿瘤坏死因子-β;脑啡肽酶;RANTES(regulated on activation normally T-cellexpressed and secreted);人巨噬细胞炎性蛋白(MIP-1-α);血清白蛋白,如人血清白蛋白;Muellerian-抑制性物质;松弛素A-链;松弛素B-链;松弛素原;小鼠促性腺激素相关肽;微生物蛋白,如β-内酰胺酶;DNA酶;IgE;细胞毒性T-淋巴细胞相关抗原(CTLA),如CTLA-4;抑制素(inhibin);活化素(activin);血管内皮生长因子(VEGF);激素或生长因子的受体;蛋白A或D;类风湿因子;神经营养因子,如骨-衍生的神经营养因子(BDNF)、亲神经素-3、-4、-5或-6(NT-3,NT-4,NT-5,或NT-6),或者神经生长因子如NGF-β;血小板-衍生的生长因子(PDGF);成纤维细胞生长因子如aFGF和bFGF;表皮生长因子(EGF);转化生长因子(TGF),如TGF-α和TGF-β,包括TGF-β1、TGF-β2、TGF-β3、TGF-β4或TGF-R5;胰岛素-样生长因子-I和-II(IGF-I和IGF-II);去(des)(1-3)-IGF-I(脑IGF-I),胰岛素-样生长因子结合蛋白;CD蛋白,如CD3、CD4、CD8、CD19、CD20和CD25(IL-2受体的Tac亚单位);促红细胞生成素;骨诱导因子;免疫毒素;骨形态形成蛋白(BMP);干扰素,如干扰素-α、-β,和γ;集落刺激因子(CSFs),如M-CSF、GM-CSF和G-CSF;白介素(ILs),如IL-1至IL-10;超氧化物歧化酶;T-细胞受体;表面膜蛋白;衰变加速因子;病毒性抗原,诸如AIDS包膜的一部分;转运蛋白;归巢受体;地址素;调节蛋白;整联蛋白,如CD11a、CD11b、CD11c、CD18和ICAM、VLA-4或VCAM;肿瘤相关抗原,如HER2、HER3或HER4受体;以及任何上述所列多肽的片段。
本发明包含的抗体的优选分子靶,包括白细胞表面标志或CD蛋白,如CD1a-c、CD2、CD2R、CD3、CD4、CD5、CD6、CD7、CD8、CD9、CD10、CD11a、CD11b、CD11c、CDw12、CD13、CD14、CD15、CD15s、CD16、CD16b、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、C41、CD42a-d、CD43、CD44、CD44R、CD45、CD45A、CD45B、CD45O、CD46-CD48、CD49a-f、CD50、CD51、CD52、CD53-CD59、CDw60、CD61、CD62E、CD62L、CD62P、CD63、CD64、CDw65、CD66a-e、CD68-CD74、CDw75、CDw76、CD77、CDw78、CD79a-b、CD80-CD83、CDw84、CD85-CD89、CDw90、CD91、CDw92、CD93-CD98、CD99、CD99R、CD100、CDw101、CD102-CD106、CD107a-b、CDw108、CDw109、CD115、CDw116、CD117、CD119、CD120a-b、CD121a-b、CD122、CDw124、CD126-CD129和CD130;ErbB受体家族的成员,如EGF受体、HER2受体、HER3受体或HER4受体;前列腺特异抗原;细胞粘附分子,如IIb/IIIa、LFA-1、Macl、p150.95、VLA-4、ICAM-1、VCAM、α4/β7整联蛋白,以及αv/β3整联蛋白,后者包括其α或β亚单位(如抗-CD11a、抗-CD18或抗-CD11b抗体);生长因子,如VEGF;组织因子(TF);α干扰素(αIFN);白介素,如IL-8;IgE;血型抗原;flk2/flt3受体;肥胖(OB)受体;c-mp1受体;CTLA-4;蛋白C等。
可溶性抗原或其片段,任选与其他分子偶联,可用作产生抗体的免疫原。对于跨膜分子,如受体、这些跨膜分子的片段(如受体的胞外区)可用作免疫原。或者,表达跨膜分子的细胞可用作免疫原。此类细胞可得自天然来源(如癌细胞系)或者是经重组技术转化的用于表达跨膜分子的细胞。其它抗原及其制备抗体有用的形式对于本领域技术人员而言是显而易见的。
本文多价抗体的优选靶抗原包括:(1)ErbB受体,包括EGFR、HER2、HER3和HER4;(2)TNF受体超家族的受体,例如Apo2L受体,如DR4、DR5、DcR1和DcR2;(3)B细胞表面抗原,尤其是CD19、CD20、CD22和CD40;(4)肿瘤细胞表达的抗原;(5)肿瘤细胞过度表达的抗原(如ErbB受体;DcR3受体);(6)多价(如二聚体或三聚体)配体(如TNF受体超家族的受体;VEGF受体等)激活的受体。在一个实施方案中,多价抗体的三个或更多个(如4至约8个)抗原结合部位可以均直接针对上述抗原之一上的相同抗原决定簇或者表位。
本申请也提供多特异性抗体,即,对至少两个不同表位或抗原决定簇具有结合特异性的抗体。多特异性抗体(如双特异性抗体;BsAbs)作为靶向剂在体外和体内免疫诊断和治疗以及诊断性免疫测定的广泛临床应用中具有显著的潜在可能性。
双特异性抗体在探查细胞表面分子的功能性特性和确定不同Fc受体介导细胞毒作用的能力方面非常有用(Fanger等,Crit.Rev.Immunol.12:101-124(1992))。Nolan等,Biochem.Biophys.Acta.1040:1-11(1990)描述了BsAbs的其它诊断应用。更具体而言,可以构建BsAbs以便固相化酶免疫测定所用的酶。为了达到此目的,可将BsAb的一个臂设计成与酶上的特异表位相结合从而使得该结合不引起酶抑制,BsAb的另一个臂与固定基质结合从而确保在所需位点具有高密度的酶。此类诊断性BsAbs的实例包括:Hammering等在J.Exp.Med.128:1461-1473(1968)中描述的兔抗-1gG/抗-铁蛋白BsAb,其用于定位表面抗原。也已开发出对辣根过氧化酶(HRP)以及激素具有结合特异性的BsAbs。BsAbs的另一潜在免疫化学应用涉及其在两-点免疫测定中的应用。例如,生产了与分析物(analyte)蛋白上的两个分离表位相结合的两个BsAbs-其一BsAb结合不溶性基质复合物,另一结合指示酶(参见Nolan等,出处同上)。
多特异性抗体也可用于各种疾病如癌症的体外或体内免疫诊断(Songsivilai等,Clin.Exp.Immunol.79:315(1990))。为了便于BsAb的诊断应用,BsAb的一个臂可以结合肿瘤相关抗原,而另一个臂可结合可检测标志,如与放射性核素紧密结合的螯合剂。使用该方法,Le Doussal等使得BsAb适用于结肠直肠癌和甲状腺癌的放免检测,其具有与癌胚抗原(CEA)结合的一条臂和与二乙三胺五乙酸(DPTA)结合的另一条臂。参见Le Doussal等,Int.J.Cancer Suppl.7:58-62(1992)和Le Doussal等,J.Nucl.Med.34:1662-1671(1993)。Stickney等类似地描述了使用放免检测法检测表达CEA的结肠直肠癌策略。这些研究描述了结合CEA和羟乙基硫脲-苄基-EDTA(EOTUBE)的BsAb。参见Stickney等,Cancer Res.51:6650-6655(1991)。
通过提供与靶(如病原体或肿瘤细胞)结合的一个臂和与细胞毒性触发分子(如T-细胞受体或Fcγ受体)结合的另一个臂,多特异性抗体也可用于重新传入的细胞毒性的人体治疗。相应地,多特异性抗体可用于引导患者的对肿瘤细胞或感染物质特异的细胞免疫反应机制。利用该策略,已经证明结合FcγRIII(即CD16)的双特异性抗体可以在体外介导通过自然杀伤(NK)细胞/大颗粒淋巴细胞(LGL)的肿瘤细胞杀伤,并且对于阻止体内的肿瘤生长是有效的。Segal等,Chem.Immunol.47:179(1989)和Segal等,Biologic Therapy ofCancer 2(4)DeVita等编著J.B.Lippincott,Philadelphia(1992)p.1。类似地,已经开发出用于治疗过度表达HER2抗原的卵巢癌和乳腺癌的具有一个臂与FcγRIII结合而另一个臂与HER2受体结合的双特异性抗体(Hseih-Ma等Cancer Research 52:6832-6839(1992)和Weiner等Cancer Research 53:94-100(1993))。双特异性抗体也介导经T细胞的杀伤。正常地,双特异性抗体将T细胞上的CD3复合物连接到肿瘤-相关抗原上。由连接到抗-p185HER2的抗CD3构成的完全人源化F(ab′)2BsAb,已经用于引导T细胞以杀死过度表达HER2受体的肿瘤细胞。Shalaby等,J.Exp.Med.175(1):217(1992)。已在数个早期临床试验中检测了双特异性抗体,获得了令人鼓舞的结果。在一个试验中,给患有肺癌、卵巢癌或乳腺癌的12个患者输注抗-CD3/抗-肿瘤(MOC31)双特异性抗体引导活化T-淋巴细胞进行治疗。DeLeij等Bispecific Antibodies and Targeted Cellular Cytotoxicity,Romet-Lemonne,Fanger和Segal Eds.,Lienhart(1991)p.249。被引导过来的细胞诱导对肿瘤细胞可观的局部溶胞作用、中度炎症反应,但是没有毒副作用或者抗-鼠抗体反应。在对一个B细胞恶性肿瘤患者使用抗-CD3/抗-CD19双特异性抗体所进行的极为初步的试验中,也取得了显著减少外周肿瘤细胞数量的效果。Clark等Bispecific Antibodies and Targeted Cellular Cytotoxicity,Romet-Lemonne,Fanger和Segal Eds.,Lienhart(1991)p.243。有关多特异性抗体的治疗应用,也参见Kroesen等,Cancer Immunol.Immunother 37:400407(1993),Kroesen等,Br.J.Cancer 70:652-661(1994)以及Weiner等,J.Immunol.152:2385(1994)。
多特异性抗体也用作纤维蛋白溶解剂或者疫苗佐剂。另外,这些抗体也用于治疗感染性疾病(如使效应器细胞靶向病毒(如HIV或流感病毒)或者原虫如鼠弓形虫感染的细胞),用于将免疫毒素递送到肿瘤细胞,或者使免疫复合物靶向细胞表面受体(参见Fanger等,出处同上)。
本文考虑到了各种多特异性抗体。举例来说,多特异性抗体可以结合目的抗原上的2个或更多个不同表位。或者,多价抗体对下列抗原具有特异性:(1)靶细胞表达的抗原(如,靶细胞是肿瘤细胞时),和(2)白细胞上的触发分子,如T-细胞受体分子(如CD2或CD3),或者IgG的Fc受体(FcγR),如FcγRI(CD64)、FcγRII(CD32)和FcγRIII(CD16),以便将细胞防御机制集中到表达抗原的细胞上。多特异性抗体也可用于将细胞毒制剂局限于表达靶抗原的细胞处。这些抗体拥有靶抗原-结合臂和结合细胞毒制剂(如皂草素、干扰素-α、长春花生物碱、蓖麻毒蛋白A链、氨甲蝶呤或者放射性同位素半抗原)的臂。
WO 96/16673描述了双特异抗-HER2/抗-FcγRIII抗体而美国专利5,837,234公开了双特异抗-HER2/抗-FcγRI抗体。双特异抗-HER2/Fcα抗体见于WO98/02463。美国专利5,821,337教导了双特异抗-HER2/抗-CD3抗体。
C.制备亲本抗体
为了产生多价抗体,可使用制备抗体的各种方法学,如下面所描述的那些,来制备对抗抗原的具有可变区的″亲本″或″起始″抗体。起始或亲本抗体的可变区序列可用于设计本文的多价抗体。
(i)多克隆抗体
优选通过多次皮下(sc)或腹膜内(ip)注射相关抗原和佐剂而在哺乳动物中产生多克隆抗体。使用双功能试剂或衍生制剂,例如,硫代琥珀酰亚胺马来酰亚胺苯甲酰酯(maleimidobenzoyl sulfosuccinimide)(通过半胱氨酸残基偶联)、N-羟基琥珀酰亚胺(通过赖氨酸残基偶联)、戊二醛、琥珀酸酐、SOCL2或者R1N=C=NR,其中R和R1是不同的烷基,将相关抗原与对要进行免疫的种属来说具有免疫原性的蛋白进行偶联是有用的,所述免疫原性蛋白的实例包括但不限于:匙孔血蓝蛋白、血清白蛋白、牛甲状腺球蛋白和大豆胰蛋白酶抑制剂。
用所述抗原、免疫原性偶联物或衍生物免疫动物,方法是,将100μg或5μg蛋白或偶联物(分别对抗兔或鼠)与3倍体积的弗氏完全佐剂混合,在多位点皮内注射该溶液。1个月后,多位点皮下注射起始量的1/5-1/10的弗氏完全佐剂中的肽或偶联物来加强免疫。7-14天后,对动物采血,测定血清中的抗体效价。对动物加强免疫直到效价达到平台期为止。优选给动物加强注射相同抗原的偶联物,但也可以是偶联至不同蛋白和/或通过不同的交联剂偶联的偶联物。偶联物还可以是重组细胞培养物中产生的融合蛋白。此外,可用明矾等聚集剂增强免疫应答。
(ii)单克隆抗体
单克隆抗体来自基本均一的抗体群,即该群体中的每个抗体除了可能的很小量天然突变外都相同。因此,修饰词“单克隆”指所述抗体不是不同抗体混合物的特性。
例如,单克隆抗体可用由Kohler等,Nature256:495(1975)首次描述的杂交瘤技术制备,或用重组DNA方法制备(美国专利4,816,567)。
在杂交瘤方法中,如上述免疫小鼠或其它适合的宿主动物如仓鼠,以激发那些产生或能产生与用于免疫之蛋白特异性结合的抗体的淋巴细胞。另外,可体外免疫淋巴细胞。然后用适当融合剂,如聚乙二醇,使淋巴细胞与骨髓瘤细胞融合,形成杂交瘤细胞(Goding,单克隆抗体:原理及应用,pp.59-103(Academic Press,1986))。
将如此制备的杂交瘤细胞接种至适当培养基中并进行培养,优选该培养基含有一或多种能抑制未融合的亲本骨髓瘤细胞生长或存活的物质。例如,如果亲本骨髓瘤细胞缺乏次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGPRT或HPRT),杂交瘤培养基通常将包含次黄嘌呤、氨基蝶呤和胸腺嘧啶核苷(HAT培养基),这些物质阻止HGPRT-缺陷型细胞的生长。
优选骨髓瘤细胞是那些能有效融合、支持所选抗体生成细胞以稳定的高水平产生抗体,并对诸如HAT培养基等类似培养基敏感的细胞。其中,优选的骨髓瘤细胞系是小鼠骨髓瘤系,如由Salk Institute Cell DistreibutionCenter,San Diego,California USA提供的MOPC-21和MPC-11小鼠肿瘤细胞和由美国典型培养物保藏中心,Rockville,Maryland USA提供的SP-2或X63-Ag8-653细胞。也有报道称人骨髓瘤以及小鼠-人异源骨髓瘤(heteromyeloma)细胞系可用于产生人单克隆抗体(Kozbor,免疫学杂志133:3001(1984);Brodeur等,单克隆抗体制备技术及应用,pp.51-63(MarcelDekker,Inc.,New York,1987))
可在含有生长的杂交瘤细胞培养基中测定抗所述抗原的单克隆抗体的产生。杂交瘤细胞所产生的单克隆抗体的结合特异性通过免疫沉淀或通过体外结合试验,如放射免疫测定(RIA)或酶联免疫吸附试验(ELISA)来测定。
单克隆抗体的结合亲和力可通过如Muson等,Anal.Biochem.,107:220(1980)所述Scatchard测定来测定。
一旦鉴定出能产生具有所需特异性、亲和力、和/或活性的抗体的杂交瘤细胞后,将这些克隆通过有限稀释法进一步克隆并用标准方法进行培养(Goding,单克隆抗体:原理及应用,pp.59-103(Academic Press,1986))。适于此目的的培养基包括如D-MEM或RPMI-1640培养基。另外,杂交瘤细胞可作为腹水中肿瘤的形式在动物体内生长。
由亚克隆分泌的单克隆抗体可用常规抗体纯化方法如蛋白-A-琼脂糖凝胶、羟基磷灰石层析、凝胶电泳、透析或亲和层析从培养基、腹水或血清中分离。
编码单克隆抗体的DNA可用常规方法很容易的分离和测序(如利用能与编码小鼠抗体重链和轻链的基因特异结合的寡核苷酸探针)。杂交瘤细胞是这类DNA的优选来源。DNA分离后,可将其插入表达载体中,然后用此表达载体转染宿主细胞,如大肠杆菌细胞、猕猴COS细胞、中国仓鼠卵巢(CHO)细胞或不产生抗体蛋白的骨髓瘤细胞,以便在重组宿主细胞中合成单克隆抗体。编码抗体的DNA在细菌中的重组表达的综述见Skerra等,Curr.Opinion in Immunol.,5:256-262(1993)和Pluckthun,Immunol.Revs.,130:151-188(1992)。
在另一实施方案中,可从用McCafferty等,Nature,348:552-554(1990)所述技术产生的抗体噬菌体文库中分离抗体或抗体片段。Clackson等,Nature,352:624-628(1991)和Marks等,分子生物学杂志222:581-597(1991)分别描述了用噬菌体文库分离鼠和人的抗体。后来的文献描述了通过链改组制备高亲和力(nM范围)的人型抗体(Marks等,生物/技术10:779-783(1992)),以及用于构建极大规模噬菌体文库的组合感染和体内重组方法(Waterhouse等,核酸研究21:2265-2266(1993))。因此,这些技术都可取代传统单克隆抗体杂交瘤技术来分离克隆抗体。
DNA也可通过用人类重链和轻链的恒定区编码序列取代小鼠同源序列来修饰(美国专利4,816,567;Morrison等,Proc.Natl.Acad.Sci.U.S.A.81:6851(1984)),或通过将非免疫球蛋白多肽的全部或部分编码序列与免疫球蛋白编码序列共价结合来修饰。
通常用所述非免疫球蛋白多肽取代抗体恒定区,或取代抗体上一个抗原结合点的可变区,形成二价嵌合抗体,其中一个抗原结合位点特异于一种抗原而另一个抗原结合位点特异于另一种抗原。
(iii)人抗体
改造Kohler和Milstein首次描述的杂交瘤方法,使用人B淋巴细胞作为融合配对,制得人单克隆抗体。产生目的抗体的人B淋巴细胞,可以例如在征得同意后从人个体中分离出来。举例来说,个体可以是在患有某种疾病如系统性红斑狼疮(Shoenfeld等J.Clin.Invest.70:205(1982))、免疫-介导的血小板减少性紫癜(ITP)(Nugent等Blood 70(1):16-22(1987))或癌症时出现产生对抗自身抗原的抗体。或者或另外,在体外使淋巴细胞免疫。举例来说,人们可以将分离的人外周血淋巴细胞在体外暴露于lysomotrophicagent(如L-亮氨酸-O-甲酯、L-谷氨酸二甲酯或L-亮氨酰-L-亮氨酸-O-甲酯)(美国专利5,567,610,Borrebaeck等);和/或在体外用佐剂如8-巯基鸟苷和细胞因子处理T-细胞耗竭的人外周血淋巴细胞(美国专利5,229,275,Goroff等)。
然后,一般使从个体收获的或者在体外致免疫的B淋巴细胞无限增殖以便产生人单克隆抗体。使B淋巴细胞无限增殖的技术包括但不限于:(a)将人B淋巴细胞与人、小鼠骨髓瘤或者小鼠-人异源骨髓瘤细胞融合;(b)病毒转化(如用Epstein-Barr病毒转化;参见例如Nugent等,出处同上);(c)与成淋巴细胞细胞系融合;或者(d)与淋巴瘤细胞融合。
使用适宜的融合试剂如聚乙二醇,将淋巴细胞与骨髓瘤细胞融合,从而形成杂交瘤细胞[Goding,单克隆抗体:Principles and Practice,AcademicPress,(1986)59-103页]。可在适宜培养基中接种杂交瘤细胞并使之生长,所述培养基优选含有一种或多种抑制未融合的亲本杂交瘤细胞生长或生存的物质。例如,亲本细胞缺乏次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGPRT或HPRT),杂交瘤的培养基通常包括次黄嘌呤、氨甲蝶呤和胸苷(HAT培养基),这些物质抑制HGPRT-缺陷型细胞生长。适宜的人骨髓瘤和小鼠-人异源骨髓瘤细胞系已有描述(Kozbor,J.Immunol.,133:3001(1984);Brodeur等,Monoclonal Antibody Production Techniques and Applications,pp.51-63(Marcel Dekker,Inc.,New York,1987))。可在含有生长的杂交瘤细胞培养基中测定抗所述抗原的单克隆抗体的产生。杂交瘤细胞所产生的单克隆抗体的结合特异性通过免疫沉淀或通过体外结合试验,如放射免疫测定(RIA)或酶联免疫吸附试验(ELISA)来测定。
鉴定出能产生具有所需特异性、亲和力、和/或活性的抗体的杂交瘤细胞后,将这些克隆通过有限稀释法进一步克隆并用标准方法进行培养(Goding,单克隆抗体:原理及应用,pp.59-103(Academic Press,1986))。适于此目的的培养基包括如D-MEM或RPMI-1640培养基。使用常规免疫球蛋白纯化方法,例如蛋白质A-层析法、凝胶电泳、渗析或亲和层析,可以从培养基或腹水中分离或纯化由亚克隆分泌的单克隆抗体。
也可利用能够产生人抗体的非-人宿主例如小鼠来产生人抗体。如上所述,通过免疫,转基因鼠现在已能产生人类抗体的所有成分,而不产生内源免疫球蛋白。例如,已有报道称,嵌合及种系(germ-line)突变小鼠中抗体重链连接区(JH)基因的纯合缺失导致内源性抗体的产生被完全抑制。将人类种系免疫球蛋白基因阵列(array)转移到这类种系突变小鼠中将导致因抗原攻击而诱导人类的抗体产生。见Jakobovits等,Proc.Natl.Acad.Sci.,USA,90:2551(1993);Jakobovits等,Nature,362:255-258(1993);Bruggermann等,Year in Immuno.7:33(1993);和美国专利5591669,5589369和5545807。也可利用SCID-hu小鼠制备人抗体(Duchosal等Nature 355:258-262(1992))。
在另一实施方案中,可从人抗体噬菌体展示文库中选择人抗体。抗体或其片段的文库的制备是本领域众所周知的,任何已知方法均可用于构建可被引入宿主细胞的转化载体家族。按照已知方法,可以制备噬菌体中抗体轻链和重链的文库(Huse等,Science,246:1275(1989))或者噬菌体或噬菌粒中的融合蛋白的文库,参见例如,Vaughan等,Nature Biotechnology 14:309-314(1996);Barbas等,Proc.Natl.Acad.Sci.,USA,88:7978-7982(1991);Marks等,J.Mol.Biol.,222:581-597(1991);Hoogenboom和Winter,J.Mol.Biol.,227:381-388(1992);Barbas等,Proc.Natl.Acad.Sci.,USA,89:4457-4461(1992);Griffiths等,EMBO Journal,13:3245-3260(1994);de Kruif等,J.Mol.Biol.,248:97-105(1995);WO 98/05344;WO 98/15833;WO97/47314;WO 97/44491;WO 97/35196;WO 95/34648;美国专利5712089;美国专利5,702,892;美国专利5,427,908;美国专利5,403,484;美国专利5,432,018;美国专利5,270,170;WO 92/06176;WO 99/06587;美国专利5,514,548;WO97/08320;和美国专利5,702,892。使用选择与靶抗原结合的噬菌体-抗体的本领域已知方法,淘选对抗噬菌体文库的目的抗原。
(iv)人源化抗体
本领域已有关于人源化非人类抗体的制备方法的描述。优选地,人源化抗体中已导入一或多个源自非人类的氨基酸残基。这些非人类氨基酸残基常称为“引进的”残基,它们通常来自“引进的”可变区。人源化过程基本如Winter及其同事(Jones等,Nature,321:522-525(1986);Riechmann等,Nature,332:323-327(1988);Verhoeyen等,Science,239:1534-1536(1988))所述,用高变区序列取代人类抗体的相应序列来进行。因此,这样的“人源化”抗体是嵌合抗体(美国专利4,816,567),其中完整人类可变区的很少一部分被非人类物种的相应序列取代。实践中,人源化抗体通常是人的抗体,其中一些高变区残基且可能有部分FR残基被啮齿类抗体中类似位点的残基取代。
对用于制备人源化抗体的人类可变区(包括重链和轻链)的选择,对降低抗原性非常重要。根据所谓“最适应”方法,对抗已知人类可变区序列的整个文库筛选啮齿类抗体可变区序列。将与啮齿类的序列最相似的人类序列作为人源化抗体的人框架区(FR)(Sims等,免疫学杂志,151:2296(1993);Chothia等,分子生物学杂志,196:901(1987))。另一种方法是用人类轻链或重链特定亚型的所有抗体的共有序列作为特定框架区。相同的框架可用于几种不同的人源化抗体(Carter等,Proc.Natl.Acad.Sci.U.S.A.,89:4285(1992);Presta等,免疫学杂志,151:2623(1993))。
更重要的是,将抗体人源化后保留了对抗原的高亲和力和其它有利的生物特性。为达到此目的,在一种优选方法中,通过用亲本序列和人源化序列的三维模型测定亲本序列和各种概念性人源化产物来制备人源化抗体。免疫球蛋白三维模型已有商品,是本领域技术人员所熟悉的。还有用于描述和展示所选免疫球蛋白序列可能的三维构象的计算机程序。通过观察这些展示结果可分析残基在候选免疫球蛋白序列的功能中可能发挥的作用,即分析能影响候选免疫球蛋白与其抗原结合的能力的残基,通过这种方法,可从受者和引进序列中选出FR残基并组合,从而得到所需抗体性质,如对靶抗原的亲和力增加。总之,高变区残基直接并且最主要涉及对抗原的结合。
(v)抗体片段
已开发了生成抗体片段的多种技术。传统上,这些片段通过对完整抗体的蛋白水解性消化获得(见Morimoto等,生物化学和生物物理学方法杂志(Journal of Biochemical and Biophysical Methods)24:107-117(1992))和Brennan等,Science,229:81(1985))。但现在可直接通过重组宿主细胞产生这些片段。例如,可从上述抗体噬菌体库分离抗体片段。另外,可从大肠杆菌直接回收Fab’-SH片段,并经化学连接形成F(ab’)2片段(Carter等,生物/技术10:163-167(1992))。依据另一种方法,可直接从重组宿主细胞培养中分离F(ab’)2片段。其它产生抗体片段的技术对本领域技术人员是显而易见的。在其它实施方案中,所选抗体是单链Fv片段(scFv)。见WO 93/16185;美国专利5,571,894;和美国专利5,587,458。抗体片段也可以是“线性化抗体”,如美国专利5,641,870所述。这类线性化抗体片段可以是单特异性或双特异性的。
(vi)抗体变体序列
本申请考虑了本文所述抗体的氨基酸序列修饰。例如,可能需要改进抗体的结合亲和力和/或其它生物学特点。抗体的氨基酸序列变体可通过在抗体核酸中引入适当的核苷酸变化或者通过肽合成制备。这类修饰包括例如抗体的氨基酸序列内残基的缺失、和/或插入和/或取代。可进行缺失、插入和取代的任何组合以获得最终的构建体,只要最终的构建体具有所需的特性即可。所述氨基酸变化还可改变抗体的翻译后加工过程,例如改变糖基化位点的数目或位置。可以对亲本抗体和/或多价抗体进行此类改变,和/或在制备多价抗体氨基酸序列时在序列中引入这些改变。
一种鉴别抗体中处于诱变优选位置的特定残基或区域的有效方法是Cunningham和Wells,Science 244:1081-1085(1989)所述的“丙氨酸扫描诱变”。这里,鉴定一个残基或一组靶残基(例如,带电荷的残基如精氨酸、天冬氨酸、组氨酸、赖氨酸和谷氨酸)并用中性或带负电荷的氨基酸取代(最优选丙氨酸或多聚丙氨酸)取代,以便影响氨基酸与抗原的相互作用。那些证实对取代具有功能敏感性的氨基酸位置通过在取代位点引入进一步的或其他的变体而改进。故,尽管引入氨基酸序列变异的位点是预先决定的,但突变性质本身不必是预定的。例如,为测定在指定位点处突变的作用,在所述靶密码子或区域实行丙氨酸扫描或随机诱变,并筛选所表达的具有所需活性的抗体变体。
氨基酸序列插入包括氨基-和/或羧基-端的融合(其长度从一个残基至包括100个或更多残基的多肽),以及序列内单个或多个氨基酸残基的插入。末端插入的例子包括带有N-末端甲硫氨酰残基的抗体或与细胞毒性多肽融合的抗体。抗体分子的其它插入变体包括使抗体的N-或C-末端与能增加该抗体的血清半衰期的酶(如ADEPT)或多肽融合。
另一类变体是氨基酸取代变体。这些变体使抗体分子中至少一个氨基酸残基被不同残基取代。最有兴趣进行取代诱变的位点包括高变区,也可以考虑FR的改变。保守取代见表1的“优选取代”栏。如果这些取代引起生物学活性的改变,则可引入表1中“取代举例”栏的更实质性改变,或进一步参考下文的氨基酸分类并筛选产物。
表1
原始残基 | 取代举例 | 优先取代 |
Ala(A) | val;leu;ile | val |
Arg(R) | lys;gln;asn | lys |
Asn(N) | gln;his;asp;lys;arg | gln |
Asp(D) | glu;asn | glu |
Cys(C) | ser;ala | ser |
Gln(Q) | asn;glu | asn |
Glu(E) | asp;gln | asp |
Gly(G) | ala | ala |
His(H) | Asn;gln;lys;arg | arg |
Ile(I) | Leu;val;met;ala;phe;正亮氨酸 | leu |
Leu(L) | 正亮氨酸;ile;val;met;ala;phe | ile |
Lys(K) | arg;gln;asn | arg |
Met(M) | leu;phe;ile | leu |
Phe(F) | leu;val;ile;ala;tyr | tyr |
Pro(P) | ala | ala |
Ser(S) | thr | thr |
Thr(T) | ser | ser |
Trp(W) | tyr;phe | tyr |
Tyr(Y) | trp;phe;thr;ser | phe |
Val(V) | ile;leu;met;phe ala;正亮氨酸 | leu |
对所述抗体的生物学特性的实质性修改可通过选择性取代来完成,所述取代的效应在维持(a)取代区多肽骨架的结构,例如片层结构或螺旋构象,(b)该分子靶位点的电荷或疏水性,(c)侧链的大小这几方面有显著差异。天然残基根据共有的侧链特性可分为:
(1)疏水性:正亮氨酸,蛋氨酸,丙氨酸,缬氨酸,亮氨酸异亮氨酸
(2)中性亲水:半胱氨酸,丝氨酸,苏氨酸
(3)酸性:天冬氨酸,谷氨酸
(4)碱性:天冬酰胺,谷氨酰胺,组氨酸,赖氨酸,精氨酸
(5)影响侧链定向的残基:甘氨酸,脯氨酸
(6)芳香族:色氨酸,酪氨酸,苯丙氨酸。
非保守取代将限定上述某一类的成员被另一类取代。
不参与维持抗体的正确构象的任何半胱氨酸残基也可被取代,通常被丝氨酸取代,以提高该分子的氧化稳定性,并阻止异常交联。相反,可在该抗体中添加半胱氨酸连接以提高其稳定性。
取代变体的特别优选类型包括取代亲本抗体(如人源化或人抗体)高变区的一或多个残基。通常,所选用于进一步开发的变体相对于其亲本抗体应具有改进的生物学活性。产生这种取代变体的一个方便方法是利用了噬菌体展示的亲和力成熟。简单地说,使高变区的几个位点(如6-7个位点)突变以便在每一位点产生所有可能的氨基酸取代。这样产生的抗体变体以单价形式从丝状噬菌体颗粒展示,其为与每个颗粒内包装的M13基因III产物的融合体。然后筛选噬菌体展示的变体是否具有本文所述生物学活性(如结合亲和力)。为了鉴定备选的高变区修饰位点,可通过丙氨酸扫描诱变来鉴定对抗原结合作出主要贡献的高变区残基。或者或另外,测定抗原-抗体复合物的晶体结构以确定抗原与抗体之间的接触点也较有利。这些接触残基及其邻近残基是根据本文所述技术进行取代的候选位点。一旦产生这样的变体,如本文所述对它们全部进行筛选,选出在一或多个相关实验中具有优势特性的抗体以便进一步开发。
所述抗体的另一种氨基酸变体改变了该抗体原来的糖基化基序。所谓改变就是去掉该抗体中的一或多个碳水化合物部分,和/或添加一或多个原本不存在于该抗体中的糖基化位点。
抗体的糖基化通常为N-连接或O-连接。N-连接指将碳水化合物部分与天冬酰胺残基的侧链相连。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸以外的任何氨基酸)是使碳水化合物部分与天冬酰胺侧链酶促相连的识别序列。因此,多肽中存在上述任一种三肽序列都可产生潜在的糖基化位点。O-连接糖基化指将N-乙酰半乳糖胺、半乳糖、或木糖附着于羟基氨基酸,主要是丝氨酸、苏氨酸,但也可用5-羟脯氨酸和5-羟赖氨酸。
在抗体中添加糖基化位点可通过改变氨基酸序列,使其包含一或多个上述三肽序列而方便地实现(在添加N-连接糖基化位点的情况下)。这种改变也可通过在原始抗体的序列中添加或取代一或多个丝氨酸或苏氨酸残基来实现(在添加O-连接的情况下)。
编码抗体的氨基酸序列变体的核酸分子由本领域已知的各种方法制备。这些方法包括但不限于从天然来源分离(在天然氨基酸序列变体的情况下),或通过对抗体之早期制备的变体或非变体形式进行寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来制备。
也可预期修饰本发明抗体的效应物功能,例如使该抗体的抗体依赖性细胞介导的细胞毒作用(ADCC)和/或补体依赖的细胞毒作用(CDC)增强。这可以通过在抗体Fc区引入一或多个氨基酸修饰而实现,从而产生变体Fc区。该Fc区变体可包含含有在一个或多个氨基酸位置上有氨基酸修饰(如取代)的人Fc区序列(例如IgG1、IgG2、IgG3或IgG4Fc区)。
在一实施方案中,存在人效应器细胞时,变体Fc区较天然序列Fc区介导更有效的抗体依赖性细胞-介导的细胞毒性(ADCC)或者对Fcγ受体(FcγR)结合具有更好亲和性。此类Fc区变体可含有在Fc区氨基酸256、290、298、312、326、330、333、334、360、378或430位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
具有减少与FcγR结合特性的Fc区变体,可含有在Fc区的氨基酸238、239、248、249、252、254、265、268、269、270、272、278、289、292、293、294、295、296、298、301、303、322、324、327、329、333、335、338、340、373、376、382、388、389、414、416、419、434、435、437、438或439位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
例如,Fc区变体可显示出减少与FcγRI的结合,并且其可含有在Fc区的氨基酸238、265、269、270、327或329位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
Fc区变体可显示出与FcγRII的结合减少,其可含有在Fc区的氨基酸238、265、269、270、292、294、295、298、303、324、327、329、333、335、338、373、376、414、416、419、435、438或439位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
有关Fc区变体可显示出与FcγRIII的结合减少,其含有在Fc区的氨基酸238、239、248、249、252、254、265、268、269、270、272、278、289、293、294,、295、296、301、303、322、327、329、338、340、373、376、382、388、389、416、434、435或437位的一个或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
在另一实施方案中,Fc区变体显示出与FcγR的结合改善并含有在Fc区的氨基酸255、256、258、267、268、272、276、280、283、285、286、290、298、301、305、307、309、312、315、320、322、326、330、331、333、334、337、340、360、378、398或430位任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
例如,Fc区变体可显示出与FcγRIII结合增加,而且任选地,可进一步显示出与FcγRII结合下降。一例证性此类变体含有Fc区在298和/或333位的氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
Fc区变体可显示出与FcγRII结合增加,并含有在Fc区氨基酸255、256、258、267、268、272、276、280、283、285、286、290、301、305、307、309、312、315、320、322、326、330、331、337、340、378、398或430位任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数编号。
此类具有与FcγRII结合增加特性的Fc区变体,可任选地进一步显示与FcγRIII的结合下降,并可例如含有在Fc区氨基酸268、272、298、301、322或340位的一个或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数。
或者或另外,变体Fc区具有改变的新生Fc受体(FcRn)结合亲和力。此类变体Fc区可含有在Fc区氨基酸238、252、253、254、255、256、265、272、286、288、303、305、307、309、311、312、317、340、356、360、362、376、378、380、382、386、388、400、413、415、424、433、434、435、436、439或447位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数。具有与FcRn结合减少特性的Fc区变体,可含有在Fc区氨基酸252、253、254、255、288、309、386、388、400、415、433、435、436、439或447位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数。或者,上述提到的Fc区变体可显示出与FcRn的结合增加,其含有在Fc区氨基酸238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434位的任一或更多个氨基酸修饰,其中Fc区残基编号是Kabat中的EU指数。
具有改变Clq结合(即提高或者减少)和/或补体依赖性细胞毒性(CDC)特性的Fc区变体描述于WO99/51642。此类变体可含有在Fc区氨基酸270、322、326、327、329、331、333或334位的一个或更多个氨基酸取代。有关Fc区变体,也参见Duncan和Winter Nature 322:738-40(1988);美国专利5,648,260;美国专利5,624,821;以及WO94/29351。
为了延长该抗体的血清半衰期,可在该抗体(尤其抗体片段)中掺入一个补救受体结合表位,如美国专利5,739,277所述。本文中术语“补救受体结合表位”是指IgG分子(例如IgG1,IgG2、IgG3、或IgG4)Fc区中负责延长该IgG分子的体内血清半衰期的表位。
(vii)免疫偶联物
本发明还涉及免疫偶联物,其中含有与细胞毒剂偶联的抗体,所述细胞毒剂如化疗药物、毒素(例如小分子毒素或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体)或放射性同位素(即放射偶联物)等。
可有效用于制备这类免疫偶联物的化疗药物已如上述。
本文还涉及抗体与一或多种小分子毒素,如加利车霉素、美登素(美国专利5,208,020)、单端孢霉烯(trichothene)、CC1065的偶联物。
在本发明的一个优选实施方案中,使抗体与一或多个美登素分子偶联(如每个抗体分子与约1-10个美登素分子偶联)。美登素可转化成May-SS-Me,然后还原成May-SH3,并与修饰过的抗体反应(Chari等,癌症研究52:127-131(1992))产生美登木素生物碱-抗体偶联物。
另外,抗体可以与一或多个加利车霉素分子结合。加利车霉素家族的抗生素能在亚pM浓度水平产生双链DNA断裂。可使用的加利车霉素结构类似物包括,但不限于γ1 I、α2 I、α3 I、N-乙酰基-γ1 I、PSAG以及θI 1(Hinman等,癌症研究53:3336-3342(1993)和Lode等,癌症研究58:2925-2928(1998)),这些文献特别在此引入作为参考。
可以应用的酶活性毒素及其片段包括:白喉毒素A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单孢菌)、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒素A链、α-帚曲毒素、油桐(Aleutites fordii)蛋白、石竹素蛋白、美洲商陆(Phytolaca Americana)蛋白(PAPI,PAPII,PAP-S)、苦瓜(momordica charantia)抑制因子、麻疯树毒蛋白、巴豆毒蛋白、肥皂草(sapaonaria officinalis)抑制剂,白树毒素、米托菌素(mitogellin)、局限曲菌素、酚霉素、依诺霉素和单端孢菌毒素(tricothecenes)。参见例如1993年10月28日公开的WO93/21232。
本发明还涉及一种免疫偶联物,其由抗体与具有核酸分解活性的化合物(如核糖核酸酶或DNA内切核酸酶如脱氧核糖核酸酶;DNase)偶联。
多种放射性同位素可用于制备放射性偶联的抗体,实例包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32以及Lu的放射性同位素。
抗体与细胞毒制剂的偶联物可通过多种双功能蛋白偶联剂来连接,所述双功能蛋白偶联剂如:N-琥珀酰亚氨基-3-(2-吡啶基二巯基)丙酸酯(SPDP),琥珀酰亚氨基-4-(N-马来酰亚氨甲基)环己烷-1-羧酸酯,亚氨基硫醇(iminothiolane)(IT),亚氨酸酯的双功能衍生物(如盐酸二甲基己二酸亚氨酯(dimethyladipimidate HCl),活性酯类(如二琥珀酰亚胺基辛二酸酯),醛类(如戊二醛(glutareldehyde)),双-叠氮化合物(如双(对-叠氮基苯甲酰基)己二胺),双-重氮衍生物(如双-(对-重氮苯甲酰基)-乙二胺),二异氰酸酯(如亚甲代苯基2,6-二异氰酸酯),和双-活性氟化合物(如1,5-二氟-2,4-二硝基苯)。例如,蓖麻毒蛋白免疫毒素可如Vitetta等,科学238:1098(1987)所述制备。C14标记的1-异硫氰酸苯甲基-3-甲基二乙烯三氨五乙酸(MX-DTPA)是将放射性核苷酸偶联至抗体的偶联剂之一。见WO94/11026。这种接头可能是有利于细胞毒药物在细胞内释放的“可断开的接头”。例如,可使用酸不稳定型接头,肽酶敏感型接头,二甲基接头或含二硫键的接头(Chari等,癌症研究52:127-131(1992))。
或者,可通过例如重组技术或肽合成来获得含有抗体与细胞毒制剂的融合蛋白。
在另一实施方案中,抗体可与肿瘤预靶向中应用的“受体”(如链霉抗生物素蛋白)偶联,将该抗体-受体偶联物给予患者,之后用清除剂除去循环中未结合的偶联物,再给予已偶联了细胞毒制剂(如放射性核苷酸)的“配体”(如抗生物素蛋白)。
(viii)抗体依赖性酶介导的前体药物治疗(ADEPT)
本发明的抗体还可与前体药物活化酶相结合,然后用于ADEPT,所述活化酶可以将前体药物(如肽基化疗剂,见WO81/01145)转化为活性抗癌药物。见WO88/07378和美国专利4,975,278。
这些用于ADEPT的偶联物中的酶组分包括能作用于前体药物使其转化为活性更强的细胞毒形式的任何酶。
本发明的方法中用到的酶包括,但不限于,能将含磷酸基的前体药物转化为游离药物的碱性磷酸酶;可将含硫酸基的前体药物转化为游离药物的芳香基硫酸酯酶;将无毒的5-氟胞嘧啶转化为抗癌药物,5-氟尿嘧啶的胞嘧啶脱氨酶;能将含肽的前体药物转化为游离药物的蛋白酶,如沙雷氏菌属蛋白酶、嗜热菌蛋白酶、枯草杆菌蛋白酶、羧肽酶和组织蛋白酶(如组织蛋白酶B和L)等;可转化含D-氨基酸取代基的前体药物的D-丙氨酰羧肽酶;能将糖基化前体药物转化为游离药物的碳水化合物裂解酶类如β-半乳糖苷酶和神经氨酸酶;能将β-内酰胺衍生的药物转化为游离药物的β-内酰胺酶;能在药物中的氨基氮处分别用苯氧乙酰基或苯乙酰基转化而使药物游离的青霉素酰胺酶如青霉素V酰胺酶或青霉素G酰胺酶。或者,可用本领域称为“抗体酶”的具有酶活性的抗体,将本发明的前体药物转化为游离的活性药物(见Massey,Nature 328:457-458(1987))。可如本文所述制备抗体-抗体酶偶联物以便将抗体酶运送至肿瘤细胞群。
本发明的酶可通过本领域已知的技术,如上述异源双功能交联试剂的使用而与抗体共价结合。或者,可以通过本领域已知的DNA重组技术(如Neuberger等,Nature,312:604-608(1984))构建含至少本发明抗体的抗原结合区的融合蛋白,所述抗体与本发明酶的至少一个功能活性部分连接。
(ix)其它抗体修饰
本文还涉及对抗体的其它修饰。例如,可以使抗体与一种非蛋白多聚物,如聚乙二醇、聚丙二醇、聚氧化烯(polyoxyalkylene)、或聚乙二醇与聚丙二醇的共聚物交联。还可将抗体包裹于微囊中(可通过凝聚技术或界面聚合作用制备,如分别制成羟甲基纤维素或明胶微囊和聚-(甲基丙烯酸甲酯(methylmethacylate)微囊))、胶体药物传递系统(如脂质体、白蛋白微球、微乳胶、纳米颗粒和纳米胶囊)中或巨乳胶(macroemulsions)中。这些技术见Remingtons’s Pharmaceutical Sciences,16版,Oslo,A.,Ed.(1980)。
本文公开的抗-ErbB2抗体还可配成免疫脂质体。含抗体的脂质体可通过本领域已知方法制备,如Epstein等,Proc.Natl.Acad.Sci.U.S.A.82:3688(1985);Hwang等,Proc.Natl.Acad.Sci.U.S.A.77:4030(1980);美国专利4,485,045和4,544,545及1997年10月23日公开的WO97/38731。在美国专利5,013,566中公开了循环时间已增加了的脂质体。
特别有用的脂质体可利用包含磷脂酰胆碱、胆固醇和PEG衍生的磷脂酰乙醇胺(PEG-PE)的脂质组合物经反相蒸发法产生。脂质体通过确定孔径大小的滤膜挤压可获得具有所需直径的脂质体。本发明抗体的Fab’片段可如Martin等,生物学化学杂志,257:286-288(1982)所述,经二硫化物交换反应与脂质体偶联。可任选在所述脂质体中包含一种化疗药物。见Gabizon等,J.National Cancer Inst,81(19)1484(1989)。
D.载体、宿主细胞和重组方法
本发明还提供了分离的编码本文公开的抗体的核酸、含所述核酸的载体和宿主细胞,以及制备所述抗体的重组技术。
为了对抗体进行重组制备,分离其编码核酸并插入到可复制载体中,来进一步克隆(DNA扩增)或表达。利用传统方法(例如利用能与编码单克隆抗体重链或轻链的基因特异性结合的探针),可容易地分离并测序编码所述抗体的DNA。许多载体可应用。载体组分通常包括但不限于一个或多个下述组分:信号序列,复制起始点,一个或多个标记基因,增强子元件,启动子和转录终止序列。
(i)信号序列组分
本发明的多价抗体不仅可直接重组制备,而且还可制备成与异源多肽的融合多肽,优选所述异源多肽为信号序列或在成熟蛋白或多肽的N末端上具有特异性裂解位点的其它多肽。优选的异源信号序列是被宿主细胞识别并加工(即通过信号肽酶裂解)的信号序列。对于不能识别并加工天然多价抗体信号序列的原核宿主细胞,用选自例如碱性磷酸酶、青霉素酶、Ipp或热稳定肠毒素II前导区的原核信号序列取代所述信号序列。对于酵母分泌,可用例如酵母转化酶前导区、α因子前导区(包括糖酵母属和克鲁维酵母属的α因子前导区)、酸性磷酸酶前导区、白色念珠菌葡萄糖淀粉酶前导区或WO90/13646中所述信号序列等取代上述天然信号序列。在哺乳动物细胞表达时,可使用哺乳动物信号序列以及如单纯疱疹gD信号序列等病毒分泌前导区。
将这些前导区DNA在阅读框架内与编码多价抗体的DNA连接。
(ii)复制起始点组分
表达载体和克隆载体中均含有能使载体在一或多种所选宿主细胞中进行复制的核酸序列。通常,在克隆载体中,此序列是能使载体独立于宿主染色体DNA而进行复制的序列,它包括复制起始点或自主复制序列。在多种细菌、酵母和病毒中,这样的序列众所周知。来自质粒pBR322的复制起始点适合于大多数革兰氏阴性细菌,2μ质粒起始点适合于酵母,而各种病毒(SV40、多瘤病毒、腺病毒、VSV或BPV)复制起始点可用于哺乳动物细胞中的克隆载体。通常,哺乳动物表达载体不需要复制组分的复制起始点(只有SV40起始点常用,因为它含有早期启动子)。
(iii)筛选基因组分
表达载体和克隆载体可包含筛选基因(也称为可筛选标记)。典型的筛选基因编码蛋白,该蛋白(a)提供对抗生素或其它毒素,如氨苄青霉素、新霉素、氨甲喋呤或四环素等的抗性,(b)弥补营养缺陷,或(c)提供从复合培养基中不能得到的关键营养物质,例如编码芽孢杆菌属D-丙氨酸消旋酶的基因。
筛选方案的一个实例是利用药物阻滞宿主细胞的生长。那些被异源基因成功转化的细胞产生能赋予药物抗性的蛋白,从而在筛选过程中存活。这样的显性筛选实例使用新霉素、霉酚酸和潮霉素药物。
另一种适于哺乳动物细胞的可筛选标记实例是那些能对可摄入多价抗体核酸的感受态细胞进行鉴定的标记,例如DHFR、胸苷激酶、金属硫蛋白I和II(优选灵长类金属硫蛋白基因)、腺苷脱氨酶、鸟氨酸脱羧酶等等。
例如,首先通过在含氨甲喋呤(Mtx)(DHFR的竞争性拮抗剂)的培养基中培养所有转化体,鉴定被DHFR筛选基因转化的细胞。当使用野生型DHFR时,适当的宿主细胞是DHFR活性缺陷的中国仓鼠卵巢(CHO)细胞系。
或者,通过在含抗可筛选标记的氨基糖苷抗生素(例如卡那霉素、新霉素或G418)等筛选药物的培养基中培养细胞,可筛选用编码多价抗体、野生型DHFR蛋白和另一个可筛选标记(如氨基糖苷3’-磷酸转移酶(APH))的DNA序列转化或共转化的宿主细胞。见美国专利4965199。
适用于酵母的适当筛选基因是存在于酵母质粒YRp7中的trp1基因(Stinchcomb等,Nature,282:39(1979))。trp1基因为不能在色氨酸中生长的酵母突变株(例如ATCC 44076或PEP4-1)提供了筛选标记。Jones,Genetics,85:12(1977)。酵母宿主细胞基因组中trp损伤的存在,为通过在无色氨酸的条件下的培养对转化进行检测提供了有效的环境。同样,Leu2缺陷的酵母株(ATCC 20622或38626)被含有Leu2基因的已知质粒弥补。
另外,可将源自1.6μm环状质粒pKD1的载体用于转化克鲁维酵母属的酵母。另有关于用乳酸克鲁维酵母大规模制备重组牛凝乳酶的表达系统的报道。Van den Berg.Bio/Technology,8:135(1990)。用于通过克鲁维酵母工业菌株分泌成熟的重组人血清白蛋白的稳定型多拷贝表达载体也被发现。Fleer等,Bio/Technology 9:968-975(1991)。
(iv)启动子组分
表达载体和克隆载体通常含有可被宿主生物识别并与多价抗体核酸可操作相连的启动子。适合于在原核宿主中应用的启动子包括phoA启动子,β-内酰胺酶和乳糖启动子系统,碱性磷酸酶,色氨酸(trp)启动子系统和杂合启动子如tac启动子。然而,其它已知的细菌启动子也是适合的。用于细菌系统的启动子还含有Shine-Dalgarno(S.D.)序列,它与编码多价抗体的DNA可操作连接。
用于真核生物的启动子序列是已知的。几乎所有的真核基因在转录起始位点上游约25-30个碱基处具有一个富含AT的区域。在许多基因的转录起始点上游70-80个碱基处发现的另一个序列是CNCAAT区,其中N可以是任何核苷酸。在大多数真核基因的3’末端是AATAAA序列,它是用于在编码序列3’末端添加poly A尾的信号。所有这些序列均被适当地插入到真核表达载体。
适于在酵母宿主中应用的启动序列实例包括3-磷酸甘油酸激酶或其它糖酵解酶的启动子,例如烯醇化酶、甘油醛-3-磷酸脱氢酶、己糖激酶、丙酮酸脱羧酶、磷酸果糖激酶、葡糖-6-磷酸异构酶、3-磷酸甘油酸变位酶、丙酮酸激酶、磷酸丙糖异构酶、磷酸葡糖异构酶和葡糖激酶。
其它的酵母启动子,即那些能通过生长条件控制转录的诱导型启动子,是下述基因的启动子区,即乙醇脱氢酶2、异细胞色素C、酸性磷酸酶、与氮代谢相关的降解酶、金属硫蛋白、甘油醛-3-磷酸脱氢酶和负责麦芽糖和半乳糖利用的酶。在EP73657中进一步叙述了用于酵母表达系统的适当载体和启动子。酵母增强子与酵母启动子一起使用更有利。
在哺乳动物宿主细胞中,由载体转录多价抗体可受下述启动子调控,所述启动子来自病毒基因组(如多瘤病毒、鸡痘病毒、腺病毒(如腺病毒2)、牛乳头瘤病毒、禽肉瘤病毒、巨细胞病毒、逆转录病毒、乙型肝炎病毒,最优选猴病毒40(SV40))启动子,或来自肌动蛋白启动子或免疫球蛋白启动子等异源哺乳动物启动子,或来自热休克启动子,只要这些启动子与宿主细胞系统相容。
SV40病毒的早期和晚期启动子可方便地以SV40限制性片段的形式获得,它还包括SV40病毒的复制起始点。人巨细胞病毒的即刻早期启动子方便地以Hind III E限制性片段的形式获得。在美国专利4419446中公开了在哺乳动物宿主中用牛乳头瘤病毒作为载体的表达系统。在美国专利4601978中叙述了对这个系统改进。另见Reyes等,Nature 297:598-601(1982)中关于在单纯疱疹病毒胸苷激酶启动子控制下在小鼠细胞中表达人β干扰素cDNA。或者,劳氏肉瘤病毒长末端重复序列可作为启动子使用。
(v)增强子元件组分
在载体中插入增强子序列通常可增加编码本发明多价抗体的DNA在高等真核生物中的转录。已经知道很多哺乳动物基因(珠蛋白,弹性蛋白酶、白蛋白、α胎蛋白和胰岛素)的增强子序列。然而人们通常使用真核细胞病毒的增强子。实例包括在其复制起始点晚期侧的SV40增强子(bp100-270),巨细胞病毒早期启动子增强子,在其复制起始点晚期侧的多瘤增强子,和腺病毒增强子。另见Yaniv,Nature 297:17-18(1982)中所述的用于活化真核启动子的增强元件。所述增强子可以剪接入多价抗体编码序列的5’或3’端,但优选位于启动子的5’端。
(vi)转录终止组分
用于真核宿主细胞(酵母、真菌、昆虫、植物、动物、人或来自其它多细胞生物的有核细胞)的表达载体,还包括对转录终止和稳定mRNA结构所必须的序列。这些序列通常来自真核或病毒DNA或cDNA的5’(偶尔为3’)非翻译区。这些区域包含核苷酸片段,其转录为编码多价抗体的mRNA的非翻译区中的聚腺苷酸化片段。一种有效的转录终止组分是牛生长激素聚腺苷酸区。见WO94/11026及其所公开的表达载体。
(vii)宿主细胞的筛选和转化
用于克隆或表达本发明载体中DNA的合适的宿主细胞是上述原核细胞、酵母或高等真核细胞。用于此目的的适合的原核细胞包括革兰氏阴性或革兰氏阳性细菌等真细菌,如肠杆菌科(Enterobacteriaceae)的埃希菌属(例如大肠杆菌)、肠杆菌属、欧文菌属、克雷白菌属、变形菌杆属、沙门菌属(例如鼠伤寒沙门菌)、沙雷菌属(粘质沙雷菌)和志贺菌属等,以及芽孢杆菌属的枯草芽孢杆菌和地衣芽孢杆菌(例如1989年4月12日出版的DD266710中所述地衣芽孢杆菌41P)等,假单胞菌属的铜绿菌假单胞菌,及链霉菌。优选大肠杆菌克隆宿主是大肠杆菌294(ATCC31446),尽管大肠杆菌B、大肠杆菌X177(ATCC31537)和大肠杆菌W3110(ATCC27325)等其它菌株也适合。这些实例是用于说明而不是限制于此。
除了原核生物,丝状真菌或酵母等真核微生物也是适于使编码多价抗体的载体克隆或表达的宿主。酿酒酵母,或常用的面包酵母,在低等真核宿主微生物中最为常用。然而,多种其它属、种和株也是可公开得到的并可用于本发明,例如粟酒裂殖酵母;克鲁维酵母属,例如乳酸克鲁维酵母(K.lactis)、脆壁克鲁维酵母(K.fragilis)(ATCC 12424)、保加利亚克鲁维酵母(K.bulgaricus)(ATCC16045)、威克曼氏克鲁维酵母(K.wickeramll)(ATCC24178)、K.waltii(ATCC 56500)、果蝇克鲁维酵母(K.drosophilarum)(ATCC36906)、耐热克鲁维酵母(K.thermotolerans)和马克斯克鲁维酵母(K.marxianus)等;yarrowia(EP402226);巴斯德毕赤酵母(pichia pastoris)(EP183070);念珠菌属;Trichoderma reesia(EP244234);粗糙链孢霉;许旺氏酵母属(schwanniomyces)如西方许旺氏酵母(schwanniomyces occidentalis)等;和丝状真菌,例如链孢霉属、青霉属、Tolypocladium以及曲霉属如构巢曲霉和黑曲霉等。
用于表达糖基化多价抗体的适合宿主细胞来自多细胞生物。无脊椎动物细胞的实例包括植物和昆虫细胞。已经从下述宿主中鉴定了大量的杆状病毒株和变体以及相应的容许型昆虫宿主细胞,所述宿主包括草地夜蛾(毛虫)、埃及伊蚊(蚊子)、白纹伊蚊(蚊子)、Drosophila melanogaster(果蝇)和家蚕蛾等。用于转染的各种病毒株可以公开地获得,例如加利福尼亚Y级夜蛾(autographa california)NPV的L-1变体和家蚕蛾NPV的Bm-5株,并且这些病毒可以在此用作为根据本发明的病毒,尤其是用于草地夜蛾细胞的转化。
棉花、玉米、土豆、大豆、牵牛花、西红柿和烟草的植物细胞培养物也可以用作宿主。
然而,关注最多的是脊椎动物细胞,而且在培养(组织培养)中繁殖脊椎动物细胞已经成为常规方法。有效哺乳动物宿主细胞的实例是用SV40转化的猴肾CV1细胞系(COS-7,ATCC CRL 1651);人胚肾细胞系(293细胞或亚克隆培养成悬浮培养液的293细胞,Graham等,普通病毒杂志(J.Gen Virol.)36:59(1977));幼仓鼠肾细胞(BHK,ATCC CCL 10);中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub等,Proc.Natl.Acad.Sci.U.S.A.77:4216(1980));小鼠足细胞(TM4,Mather,Biol.Reprod.23:243-251(1980));猴肾细胞(CV1ATCC CCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL 2);犬肾细胞(MDCKATCC CCL 34);布法罗(buffalo)大鼠肝细胞(BRL 3A,ATCC CRL 1442);人肺细胞(W138,ATCC CCL 75);人肝细胞(Hep G2,HB 8065);小鼠乳腺肿瘤(MMT 060562,ATCC CCL 51);TRI细胞(Mather等,纽约科学院年鉴(Annals N.Y.Acad.Sci.)383:44-68(1982));MRC 5细胞;FS4细胞;和人肝细胞癌细胞系(Hep G2);以及骨髓瘤或淋巴瘤细胞(如Y0、J558L、P3和NSO细胞)(参见美国专利5807715)。
宿主细胞用上述用于多价抗体制备的表达或克隆载体转化,并在改进型传统营养培养基上培养,所述培养基经改进已适于诱导启动子、筛选转化体或扩增编码所需序列的基因。
(viii)培养宿主细胞
用于制备本发明多价抗体的宿主细胞可在各种培养基中培养。市售培养基如Ham’s F10(Sigma)、最小基本培养基((MEM)(Sigma)、RPMI-1640(Sigma)和Dulbecco氏改良型Eagle氏培养基((DMEM),Sigma)均适合于培养所述宿主细胞。另外,在Ham等,酶学方法58:44(1979);Barnes等,Anal.Biochem.102:255(1980);美国专利4767704、4657866、4927762、4560655或5122469;WO 90/03430;WO 87/00195;或美国专利Re.30985中所述任何培养基可作为所述宿主细胞的培养基。任何所述培养基可在需要时补充激素和/或其它生长因子(例如胰岛素、转铁蛋白或表皮生长因子)、盐(如氯化钠,钙,镁,和磷酸盐)、缓冲液(例如HEPES),核苷酸(例如腺苷和胸苷)、抗生素(例如GENTAMYCINTM)、痕量元素(定义为通常以微摩尔级终浓度出现的无机化合物)、葡萄糖或一种等价能源。还包括任何其它必须补充物,其相应浓度为本领域已知。培养条件如温度、pH等是现有技术中应用于表达型宿主细胞的那些,本领域技术人员对此很熟悉。
(ix)纯化
当使用重组技术时,多价抗体可以在细胞内周质空间中产生,或直接分泌到培养基中。如果所述多价抗体在细胞内产生,第一步通过离心或超滤除去颗粒状碎片,即宿主细胞或其裂解片段。Carter等,Bio/Technology 10:163-167(1992)中叙述了用于分离分泌到大肠杆菌周质空间中的抗体的方法。简言之,在醋酸钠(pH3.5)、EDTA和苯甲基磺酰氟(PMSF)存在的条件下融解细胞团超过约30分钟。通过离心可以将细胞碎片除去。在多价抗体分泌到培养基的情况中,通常首先用市售的蛋白浓缩滤膜(例如Amicon或Millipore Pellicon超滤单位)浓缩此类表达系统的上清。在任何上述步骤中可以包括抑制蛋白裂解的PMSF等蛋白酶抑制剂,并且可以包括抑制外来污染物生长的抗生素。
从所述细胞中制备的多价抗体组合物可利用例如羟基磷灰石层析、凝胶电泳、透析和亲和层析等方法纯化,优选亲和层析。蛋白A作为亲和配体的适合性取决于该多价抗体上任何免疫球蛋白Fc区的种类和同种型。蛋白A可用于纯化基于人γ1、γ2或γ4重链的抗体(Lindmark等,免疫学方法杂志,62:1-13(1983))。蛋白G被建议用于所有的小鼠同种型和人γ3(Guss等,EMBO J.5:1567-1575(1986))。与亲和配体结合的基质最常用琼脂糖,但也可利用其它基质。具有机械稳定性的基质如控制孔径的玻璃或聚(苯乙烯二乙烯)苯等,比琼脂糖允许更快的流速且耗时更短。在所述多价抗体包括CH3结构域的情况中,Bakerbond ABXTM树脂(J.T.Baker,PhilliPBSurg,NJ)有利于纯化。根据待回收的抗体,还可以应用其它蛋白纯化技术,例如在离子交换柱上的分级分离、乙醇沉淀、反向HPLC、硅层析、在阳离子或阴离子交换树脂层析(例如聚天冬氨酸柱)上进行的肝素SEPHAROSETM层析、聚焦层析、SDS-PAGE和硫酸铵沉淀。
E.药物制剂
根据本发明使用的多价抗体的药用制剂通过将具有所需纯度的多价抗体与任选的可药用载体、赋形剂或稳定剂(雷氏药学(Remington’sPharmaceutical Sciences)第16版,Osol,A.编(1980))混合而制备,然后以冻干剂或含水剂的形式保存。可药用载体、赋形剂、稳定剂在所用剂量及浓度下对受者无毒性,并包括缓冲剂例如磷酸盐,柠檬酸盐及其它有机酸;抗氧化剂包括抗坏血酸和蛋氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化己烷双胺;氯化苄烷铵(benzalkonium chloride),苯索氯铵;酚、丁醇或苯甲醇;烷基对羟基苯甲酸酯如甲基或丙基对羟基苯甲酸酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;间甲酚);低分子量多肽(少于10个残基);蛋白质如血清白蛋白,明胶或免疫球蛋白;亲水聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸,谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖,二糖及其它碳水化合物包括葡萄糖、甘露糖、或糊精;螯合剂如EDTA;糖类如蔗糖、甘露醇、海藻糖或山梨醇;成盐反离子如钠;金属复合物(例如锌-蛋白复合物);和/或非离子表面活性剂如吐温TM,PLURONICSTM或聚乙二醇(PEG)。
所述制剂还可根据所治疗的具体情况而包含一种以上活性成分,优选具有互补活性但相互无负面影响的那些。在下述标题为“多价抗体体内应用”的G部分,给出了活性化合物结合实例。这些分子以对所需目有效的总量在组合中适当地存在。
活性成分也可容纳在通过凝聚技术或界面聚合作用制备的微胶囊中,如分别在胶体性质的药物运送系统(如脂质体,白蛋白小球体,微乳剂,纳米颗粒及纳米胶囊)或大乳剂(macroemulsions)的羟甲基纤维素或明胶微胶囊和聚(异丁烯酸甲酯)微胶囊。这些技术见雷氏药学,第16版Osol,A.编(1980)。
用于体内给药的制剂必须是无菌的。这可以通过除菌滤膜过滤而轻易实现。
也可制备控释制剂。控释制剂的适当实例包括含有抗体的固态疏水聚合物的半通透性基质,所述基质为具有一定形状的制品,如膜或微胶囊。控释制剂实例包括聚酯、水凝胶(如聚(2-羟基乙基-异丁烯酸酯)或聚(乙烯醇)、聚交酯(美国专利3,773,919)、L-谷氨酸与γ乙基-L-谷氨酸酯的共聚物、不可降解的乙烯乙酸乙酯、可降解的乳酸-羟基乙酸共聚物如LUPRONDEPOTTM(由乳酸-羟基乙酸共聚物和亮氨酰脯氨酸(leuprolide)乙酸酯组成的可注射的微球体),以及聚D-(-)-3-羟丁酸。尽管聚合物如乙烯-乙酸乙烯酯和乳酸-羟基乙酸能持续释放分子100天以上,但是某些水凝胶释放蛋白的时间却较短。当胶囊化的抗体长时间停留在体内时,它们会由于暴露在37℃水分下而变性或凝聚,从而导致生物活性损失,且免疫原性可能会改变。可以根据涉及的机理来设计稳定化的合理策略。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、自酸性溶液中冻干、控制湿度程度、采用合适的添加剂和开发特殊的聚合物基质组合物来达到稳定化。
F.多价抗体的非-治疗应用
本发明多价抗体可用作亲和纯化试剂。在这个过程中,可利用本领域已知技术将多价抗体固定在Sephadex树脂或滤纸等固相上。使固相化的多价抗体与要纯化的包含抗原(或其片段)的样品接触,之后用适当溶剂洗涤支持相,使得基本除去样品中除了与固相化多价抗体结合的抗原之外的所有其它物质。最后,用另一种适当溶液(例如甘氨酸缓冲液,pH 5.0)洗涤支持相,使抗原从多价抗体中释放。
多价抗体也可用于诊断检测,例如检测相关抗原在特异性细胞、组织或血清中的表达。
对于诊断性应用,通常用可检测的组分标记抗体。多种标记物可用,它们总体上分为下述几类:
(a)放射性同位素,例如35S、14C、125I、3H和131I。利用例如在免疫学最新方案(Current Protocols in Immunology),卷1和2,Coligen等编,Wiley-interscience,纽约,New York Pubs.(1991)中所述方法,用放射性同位素对所述抗体进行标记,并且可以利用闪烁计数器检测放射活性。
(b)可以应用荧光标记,例如稀土元素螯合物(铕螯合物)或荧光素及其衍生物,例如罗丹明及其衍生物、丹磺酰、丽丝胺、藻红蛋白和得克萨斯红。可以利用例如在Current Protocols in Immunology(出处同上)中所述技术,将所述荧光标记物与所述抗体连接。利用荧光计定量荧光。
(c)可以应用各种酶-底物标记,在美国专利号4275149中提供了对其中一些的综述。所述酶通常催化生色底物的化学变化,可以利用各种技术测定这些变化。例如,所述酶可以催化底物的颜色变化,其可以被分光光度计所检测。或者,所述酶可以改变底物的荧光或化学发光。用于定量荧光改变的技术见上面的叙述。化学发光底物通过化学反应激发电子,然后发出可以被检测(例如,用化学发光仪)或给荧光受体提供能量的光。酶标记的实例包括萤光素酶(例如萤火虫萤光素酶或细菌萤光素酶,美国专利号4737456)、萤光素、2,3-二氢二氮杂萘二酮、苹果酸酯脱氢酶、脲酶、辣根过氧化物酶(HRPO)等过氧化物酶、碱性磷酸酶、β半乳糖苷酶、葡萄糖淀粉酶、溶菌酶、糖氧化酶(例如葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶)、杂环氧化酶(例如尿酸酶和黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。在O’Sullivan等,制备酶免疫测定所用酶-抗体偶联物的方法,酶学方法,(J.Langone和H.Van Vunakis编),Academic press,纽约,73:147-166(1981)中叙述了将酶与抗体偶联的技术。
酶-底物组合的实例包括:
(i)辣根过氧化物酶(HRPO)以氢过氧化物酶为其底物,由氢过氧化物酶氧化染料前体(例如邻苯二胺(OPD)或3,3’,5,5’-四甲基联苯胺氢氯化物(TMB));
(ii)碱性磷酸酶(AP),以对硝基苯磷酸盐为生色底物;和
(iii)β-D-半乳糖苷酶(β-D-Gal),有生色底物(例如对硝基苯-β-D-半乳糖苷酶)或发荧光底物4-甲基伞形基(umbelliferyl)-β-D-半乳糖苷酶。
本领域技术人员可以应用其它多种酶-底物组合。其综述见美国专利号4275149和4318980。
有时,标记物与多价抗体间接连接。技术人员知道用于此的各种技术。例如,可使多价抗体与生物素偶联,并使上述三类标记物之任一与抗生物素蛋白结合,反之亦然。生物素与抗生物素蛋白选择性结合,使标记物能以这种方式间接与多价抗体相偶联。或者,为使标记物与多价抗体间接连接,将多价抗体与小分子半抗原(例如地高辛)偶联,并将上述不同类型标记物之一与抗半抗原多价抗体(例如抗地高辛抗体)偶联。如此可实现标记物与多价抗体的间接偶联。
在本发明另一实施方案中,多价抗体不需要标记,其存在可利用与该多价抗体结合的标记抗体检测。
本发明多价抗体可用于任何已知的试验方法,如竞争结合试验、直接和间接夹心试验以及免疫沉淀试验。Zola,单克隆抗体:技术指南,147-158页(CRC Press,Inc.1987)。
所述多价抗体还可以用于体内诊断试验。通常用放射性核素(例如111In、99Tc、14C、131I、125I、3H、32P或35S)标记所述抗体,以便该抗原或其表达细胞可利用免疫闪烁成像术定位。
G.多价抗体的体内应用
已经考虑到将本发明多价抗体用于治疗患有疾病或病征或者有患病倾向的能够从施用多价抗体中受益的哺乳动物如患者。
当抗体与ErbB受体如HER2结合时,被治疗病征的实例包括良性或恶性肿瘤;白血病和淋巴的恶性疾病;其它疾病,如神经细胞、神经胶质细胞、星形胶质细胞、下丘脑、腺体、巨噬细胞、上皮、基质、囊胚腔、炎症性、血管生成性和免疫性的疾病。通常,用将与ErbB受体结合的抗体治疗的疾病或病症是癌症。
本文中,所治癌症的实例包括但不限于:癌(carcinoma)、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴的恶性病。这些癌的更具体实例包括:鳞状细胞癌、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌)、腹膜癌、肝细胞癌、胃癌(包括胃肠癌)、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、肝癌(liver cancer)、前列腺癌、外阴癌、甲状腺癌,肝癌(hepatic carcinoma)以及头颈癌。
所述癌症通常含有表达被抗体结合的抗原的细胞,从而使所述抗体能与癌结合。在一个实施方案中,癌以过度表达抗原(例如ErbB受体)为特征。为检测由癌过度表达的抗原,可使用各种诊断/预测测定手段。在一实施方案中,抗原是HER2时,通过IHC(例如利用(Dako))检测抗原过度表达。在HER2 IHC检测中,可对肿瘤活检的石蜡包埋组织切片进行IHC检测,记录HER2蛋白染色强度的标准如下:
分值0没有观察到染色,或在少于10%的肿瘤细胞中观察到膜染色。
分值1+在多于10%的肿瘤细胞中检测到微弱/勉强看得见的膜染色。所述细胞仅有膜的一部分被染色。
分值2+在多于10%的肿瘤细胞中观察到从弱到中等强度的完全膜染色。
分值3+在多于10%的肿瘤细胞中观察到从中度到强的完全膜染色。
那些HER2过度表达评估分值为0或1+的肿瘤并不以过度表达HER2为特征,而那些分值为2+或3+的肿瘤以过度表达HER2为特征。
或者(或另外),可在甲醛固定且石蜡包埋的肿瘤组织上进行例如INFORMTM(购自Ventana,Arizona)或PATHVISIONTM(Vysis,Illinois)等FISH检测,以测定肿瘤中抗原过度表达的程度(如果有的话)。
在一个实施方案中,所述癌症是表达(并且可能过度表达)选自EGFR、ErbB3和ErbB4之一ErbB受体的癌。可表达/过度表达EGFR、ErbB3和ErbB4的癌的实例包括鳞状细胞癌,肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌),腹膜癌,肝细胞癌,胃癌(包括胃肠癌),胰腺癌,成胶质细胞瘤,宫颈癌,卵巢癌,肝癌(liver cancer),膀胱癌,肝细胞瘤,乳腺癌,结肠癌,结直肠癌,子宫内膜或子宫癌,唾液腺癌,肾癌,肝癌(liver cancer)前列腺癌,外阴癌,甲状腺癌,肝癌(hepatic carcinoma)以及头颈癌和成胶质细胞瘤。
本文中所治疗的癌可以是以ErbB受体(例如EGFR)的过度活化为特点的癌。此过度活化的原因可能是ErbB受体或ErbB配体的过度表达或产量增加。在本发明的一个实施方案中,进行诊断性或预后性检测,以确定患者的癌是否是以ErbB受体过度活化为特点。例如,可检测所述癌症中ErbB基因的扩增和/或ErbB受体的过度表达。可测定这种扩增/过度表达的各种试验为本领域现有,包括IHC、FISH和上述脱落抗原试验。或者(或另外),可根据已知方法检测肿瘤中的或与肿瘤相关的TGF-α等ErbB配体的水平。这些试验可检测待检样品中的蛋白或其编码核酸。在一个实施方案中,利用免疫组化法(IHC)可检测肿瘤中ErbB配体的水平;见例如Scher等,临床癌症研究1:545-550(1995)。或者(或另外),可通过例如FISH、southern印迹或PCR技术等评估待检样品中编码ErbB配体的核酸的水平。
而且,ErbB受体或ErbB配体的过度表达或扩增可利用体内诊断试验评估,如施用能与待检分子结合并带有可检测标记(如放射性同位素)的分子(如抗体),并从外部对患者进行扫描以定位该标记。
当抗体与B细胞表面抗原结合时,抗体可用于治疗B细胞淋巴瘤(包括低程度/滤泡性非-何杰金氏淋巴瘤(NHL);小淋巴细胞(SL)NHL;中等程度/滤泡性NHL;中等程度弥散性NHL;高程度免疫母细胞性NHL;高程度成淋巴细胞性NHL;高程度小非-分裂细胞(non-cleaved cell)NHL;bulky疾病NHL;外膜(mantle)细胞淋巴瘤;AIDS-相关淋巴瘤;以及Waldenstrom′s巨球蛋白血症;慢性淋巴细胞性白血病(CLL);急性淋巴细胞性白血病(ALL);毛细胞白血病;和慢性髓母细胞性白血病;以及移植后淋巴增生病症(PTLD)。
抗体,如抗-B细胞表面抗原抗体,也可用于治疗自身免疫性疾病。自身免疫性疾病或病症的实例包括但不限于:炎症性反应如炎症性皮肤疾病,包括牛皮癣和皮炎(如特异性皮炎);系统性硬皮病和硬化症;与炎性肠道疾病有关的反应(如克罗恩氏病和溃疡性结肠炎);呼吸窘迫综合征(包括成年呼吸窘迫综合征;ARDS);皮炎;脑膜炎;脑炎;眼色素层炎;结肠炎;肾小球肾炎;变应性状况,如湿疹和哮喘以及涉及T细胞浸润与慢性炎症性反应的其它病症;动脉粥样硬化;免疫粘附缺陷;类风湿性关节炎;系统性红斑狼疮(SLE);糖尿病(如I型糖尿病或胰岛素依赖型糖尿病);多发性硬化;雷诺氏综合征;自身免疫性甲状腺炎;变应性脑脊膜炎;Sjorgen′s综合征;青少年糖尿病;和由细胞因子和T淋巴细胞介导的与急性和迟发型超敏反应有关的免疫反应,通常见于肺结核、类肉瘤病、多肌炎、肉芽肿病和结节性脉管炎;恶性贫血(阿狄森氏病);涉及白细胞渗出的疾病;中枢神经系统(CNS)炎症性病症;多器官损伤综合征;溶血性贫血(包括但不限于冷沉淀球蛋白血症或Coombs试验阳性贫血);重症肌无力;抗原-抗体复合物介导的疾病;抗-肾小球基膜疾病;抗磷脂综合征;变应性神经炎;格雷夫斯病;Lambert-Eaton肌无力综合征;大疱性天疱疮;天疱疮;自身免疫性多内分泌腺病;莱特尔氏病;强直-人综合征;贝切特氏病;巨细胞性动脉炎;免疫复合物性肾炎;IgA肾病;IgM多神经病;特发性血小板减少性紫癜(ITP)或自身免疫性血小板减少症等。
抗B细胞表面抗原的抗体也可用于阻断对外来抗原的免疫应答。本文的″外来抗原″,是指对于接触之的哺乳动物而言不是内源性或天然的分子。外来抗原可引发免疫应答,如在哺乳动物中体液和/或T细胞介导的应答。通常,外来抗原将诱导抗所述抗原的抗体产生。本文考虑到的外来抗原的实例包括:免疫原性治疗剂,例如蛋白如抗体,特别是含有非-人氨基酸残基的抗体(如啮齿类动物、嵌合人源化抗体和灵长化抗体);毒素(任选地与靶向分子如抗体偶合,其中靶向分子也可以是免疫原性的);基因治疗病毒载体,如逆转录病毒和腺病毒;移植物;传染性物质(如细菌和病毒);同种抗原(即在某些成员中存在而在同一物种的其他成员中却不存在的抗原),例如在血型、人淋巴细胞抗原(HLA)、血小板抗原、在移植器官上表达的抗原、血液成分、妊娠(Rh)以及血友病因子(如因子VIII和因子IX)方面的差异。
抗-B细胞表面抗原的抗体也用于使待移植的哺乳动物脱敏。
抗TNF受体超家族的受体的抗体,可用于激活或刺激癌细胞的凋亡。
在某些实施方案中,将包括与细胞毒制剂偶联的多价抗体的免疫偶联物施用于患者。优选所述免疫偶联物和/或与它结合的抗原被细胞内化(internalize),导致在杀伤与它结合的癌细胞时增加免疫偶联物的治疗效果。在优选的实施方案中,细胞毒制剂在癌细胞中靶向或干扰核酸。此细胞毒制剂的实例包括本文公开的化疗剂(如美登素、加利车霉素)、放射性同位素、或者核糖核酸酶或DNA内切核酸酶。如上所述,多价抗体也可用于ADEPT。
本申请考虑到了将多价抗体(或其免疫偶联物)与一种或多种其它治疗剂尤其是肿瘤治疗剂联合使用。举例来说,多价抗体可以与另一多价抗体(或另外多个多价抗体)、单价抗体或二价抗体、化疗剂(包括化疗剂的混合物)、其它细胞毒制剂、抗-血管生成剂、细胞因子和/或生长抑制剂共同给药。当多价抗体诱导细胞凋亡时,则特别期望多价抗体与一种或更多种也诱导细胞凋亡的其它治疗剂联合。举例来说,抗B细胞表面抗原的前-凋亡抗体(如二价或多价抗体)(如RITUXAN、ZEVALIN或BEXXAR抗-CD20抗体)可以与下列抗体联合:(1)前-凋亡抗体(如抗TNF受体超家族受体的二价或多价抗体,如抗-DR4或抗-DR5抗体),或(2)细胞因子TNF家族的细胞因子(如Apo2L)。同样地,抗-ErbB抗体(如抗-HER2抗体)可以与(1)和/或(2)联合。或者,或另外,患者可接受联合的放射治疗(如外源光束照射或用放射活性标记试剂如抗体治疗)。上述这种联合治疗包括联合给药(此时两种或多种试剂包含在同一制剂或者独立制剂中)和分隔给药,在后一情况下,多价抗体可在施用辅助治疗之前和/或之后施用。
可用任何适当的方法施用多价抗体(和辅助治疗剂),方法包括非肠道、皮下、腹膜内、肺内和鼻内给药,如果需要局部治疗的话,则可创面内给药。非肠道输注包括肌内、静脉内、动脉内、腹膜内或皮下给药。另外,多价抗体适宜经脉冲输注给药,特别是使用递减剂量的多价抗体时。部分取决于药物是短暂还是长期(慢性)施用,优选经注射给药,最优选静脉或皮下注射给药。
除了向患者施用抗体蛋白外,本申请考虑了通过基因治疗而给予抗体。编码抗体的核酸的这种给药方式包含在术语“施用治疗有效量的抗体”中。见例如1996年3月14日公布的WO96/07321,其中涉及利用基因治疗来产生细胞内抗体。
有两种主要途径使所述核酸(任选包含在载体中)进入患者的细胞中:体内和回体(ex vivo)。在体内运输中,直接向患者注射所述核酸,通常在需要所述抗体的部位注射。在回体治疗中,取出患者的细胞,将核酸导入这些离体的细胞中,然后将改良的细胞直接回输给患者或将其包被在多孔膜中移植至患者体内(见例如美国专利4892538和5283187)。有许多技术可用于将核酸引入活细胞中。根据所述核酸是在体外转移入培养细胞中,还是在体内转移入目的宿主细胞中,所应用的技术不同。适于在体外将核酸转移入哺乳动物细胞中的技术包括使用脂质体、电穿孔、显微注射、细胞融合、DEAE-葡聚糖、磷酸钙沉淀法等。基因的回体传递常用的载体是逆转录病毒。目前优选的体内核酸转移技术包括用病毒载体(例如腺病毒、单纯疱疹病毒I型或腺伴随病毒)和基于脂质的系统(用于脂质介导的基因转移的有用的脂质是例如DOTMA、DOPE和DC-Chol)进行转染。在一些情况中,需要提供核酸来源,及靶向靶细胞的药剂,例如对细胞表面膜蛋白或靶细胞具有特异性的抗体、靶细胞上受体的配体等等。在使用脂质体的情况中,与内吞作用相关的表面膜蛋白结合的蛋白可用于靶向和/或促进摄取,例如对特殊细胞类型具有定向性的衣壳蛋白或其片段,在循环中进行内化的蛋白的抗体,靶向细胞内部位并延长细胞内半衰期的蛋白。受体介导的胞吞作用的技术参见Wu等,生物学化学杂志262:4429-4432(1987);Wagner等,Proc.Natl.Acad.Sci.U.S.A.87:3410-3414(1990)。关于目前已知的基因标记和基因治疗方案的综述见Anderson等,Nature 256:808-813(1992)。另见WO93/25673,该文献在此引入作为参考。
为了预防或治疗疾病,多价抗体的适当剂量取决于所治疾病的类型(如上所述)、疾病的严重程度和进程、多价抗体给药的目的是预防还是治疗、先前的治疗、患者的临床病史和对多价抗体的应答、以及主治医生的判断。抗体可一次或分多次向患者给药。
取决于疾病的类型或严重程度,无论是例如一次或多次分别给药,还是连续输注给药,向患者施用的起始候选剂量是约1μg/kg-15mg/kg(例如0.1-20mg/kg)抗体。取决于上述因素,典型的日给药剂量范围是从1μg/kg到100mg/kg或更多。重复给药数天或更长时间时,视具体情况而将治疗持续至出现对疾病症状的所需抑制为止。但其它剂量方案也有效。此治疗的进展可通过传统的技术和检测容易地监控。
按照与良好医疗实践一致的方式制备、分配剂量和施用多价抗体组合物。本文中要考虑的因素包括:接受治疗的具体病症、接受治疗的具体哺乳动物、个体患者的临床状况、病征发生的原因、药剂释放的部位、给药方法、给药时程表和医疗实践者所熟知的其它因素。要施用的多价抗体的″治疗有效量″受此考虑控制,并且是预防、缓解或者治疗疾病或病症所必要的最小剂量。多价抗体并不必需,但任选地,与一种或更多种用于预防或治疗相关病征的试剂配制在一起。此其它试剂的有效量,取决于制剂中多价抗体的含量、病症或治疗的类型以及上述讨论的其它因素。这些试剂一般使用其此前所用相同剂量并按照此前相同给药途径施用或者使用此前所用剂量的约1~99%.。
H.制品
在本发明的另一个实施方案中,提供了含用于治疗上述病症的物质的制品。所述制品包括一个容器和位于该容器表面的或与该容器相关的标签或包装插页。适当的容器有瓶子,小瓶,注射器等。容器可由各种材料如玻璃或塑料制成。该容器可内含一种能有效治疗目标疾病的组合物,并具有无菌存取口(例如该容器可以是静脉溶液袋或带有能通过皮下注射针穿刺的塞子的小瓶)。组合物中至少一种活性药剂是多价抗体。所述标签或包装插页说明所述组合物可用于治疗指定的疾病(例如癌)。而且,所述制品可包括:(a)其中装有组合物的第一个容器,所述组合物含有多价抗体;和(b)其中装有组合物的第二个容器,所述组合物含有其它细胞毒制剂。本发明的此实施方案中的制品可进一步包括包装插页,其说明第一和第二抗体组合物可用于治疗癌症。或者(或另外),所述制品可进一步包括第二个(或第三个)容器,其中含可药用的缓冲液,例如用于注射的抑细菌水(BWFI),磷酸盐缓冲液,Ringer’s溶液和葡萄糖溶液。还可进一步包括具有商业需要以及符合用户需要的其它材料,如其它缓冲液、稀释剂,滤器,针头和注射器。
I.材料保藏
下述杂交瘤细胞已保藏在美国典型培养物保藏中心,10801 UniversityBoulevard,Manassas,VA 20110-2209,美国(ATCC):
抗体命名 ATCC编号 保藏日
7C2(抗-HER2) ATCC HB-12215 1996年10月17日
7F3(抗-HER2) ATCC HB-12216 1996年10月17日
4D5(抗-HER2) ATCC CRL 10463 1990年5月24日
2C4(抗-HER2) ATCC HB-12697 1999年4月8日
3F11.39.7(抗-DR5) HB-12456 1998年1月13日
3H3.14.5(抗-DR5) HB-12534 1998年6月2日
3D5.1.10(抗-DR5) HB-12536 1998年6月2日
3H1.18.10(抗-DR5) HB-12535 1998年6月2日
4E7.24.3(抗-DR4) HB-12454 1998年1月13日
4H6.17.8(抗-DR4) HB-12455 1998年1月13日
下述实施例只是为了描述的目的而提供,并非旨在以任何方式限定本发明的保护范围。本说明书中引证的所有专利和参考文献,以其全部在此引入作为参考。
实施例1
构建多价抗体
本文图5描述了用于产生四价抗-HER2抗体,称为″章鱼抗体″(OctHER2)的构建体。此章鱼抗体的骨架是重组、人源化单克隆抗体4D5变体8(rhuMAb 4D5-8)(美国专利5,821,337,Carter等,特别在此引入作为参考)。将rhuMAb 4D5-8的重链亚克隆入pRK5载体中(1989年3月15日公布的EP 307,247)。通过诱变除去重链的VH-CH1区,并插入3个唯一的限制性酶切位点(BamHl;Nhel;BspEl)。将这些位点引入为扩增来源于不同抗体的VH-CH1区而设计的PCR引物。产生的片段亚克隆入载体而产生章鱼重链。pRK5载体中的章鱼重链与适宜轻链在转染的哺乳动物细胞中共表达,产生完全的章鱼抗体(图4)。
对包含插在串联Fd区之间的柔性接头的章鱼构建体也进行了基因工程改造。通过诱变,编码″gly-ser″(柔性接头1)或″gly-ser-gly-ser″(SEQ ID NO:10)(柔性接头2)的DNA插在编码重链VH-CH1区的DNA之间。
实施例2
评价抗-HER2章鱼抗体
OctHER2在瞬时转染的293细胞表达(Graham等J.Gen.Virol.36:5972(1977))并过蛋白A琼脂糖凝胶柱进行纯化。完全抗体约245kDa,亲本抗体分子量为150kDa。章鱼重链是75kDa(没有糖),而轻链是30kDa。
抗原结合
使用HER2ELISA测定法,测定OctHER2与抗原、HER2胞外区(HER2ECD)的结合(Sias等J.Immunol.Methods 132:73-80(1990))。用HER2胞外区(ECD)包被96孔板(WO90/14357),用不同稀释度的抗-HER2抗体进行温育。洗涤除去未结合的抗体后,接着加入偶联过氧化物酶的第二抗体以检测与ECD结合的抗-HER2抗体。然后,加入适宜的底物,目测检验各孔并在板阅读器上于562nm处定量测定。
图6A-C显示OctHER2、293细胞表达的二价人IgG1抗-HER2抗体rhuMAb 4D5-8、或二价抗-HER2抗体(商购于Genentech,Inc.,South San Francisco,USA)的ELISA结果。用ELISA测定时,OctHER2结合HER2ECD类似于。293细胞表达的rhuMAb 4D5-8同样结合于瓶装的(由中国仓鼠卵巢(CHO)细胞产生),表明293细胞基本上并不改变抗体的抗原结合能力。
超速离心测定用于检测OctHER2是否能够结合具有4个抗原结合部位的靶。用章鱼抗体滴定测量不同量的HER2胞外区(ECD)(WO90/14357),假定章鱼抗体要么具有4个全功能性结合部位,要么具有3个全功能性结合部位,基于这些比例,计算复合物的平均分子量。这些理论值(圆圈,假定OctHER2具有4个功能性结合部位;正方形,假定OctHER2具有3个功能性结合部位)与得到的实际实验值(三角)进行比较。描述于图7的实验值更接近代表4个结合部位的曲线,然而,观察到的漂移表明4个位点可能并不都具有相同的亲和力。
生物功能
抗增生测定:在测定HER2过度表达肿瘤细胞系的生长抑制的功能性测定中,对OctHER2与进行比较。使用Lewis等CancerImmuno.Immunother.37:255-263(1993)所描述的生长抑制测定法。简要讲,系列稀释的OctHER2和加入到培养板细胞的培养基中,使之继续生长5天。此后,移出培养基,用结晶紫染色细胞并用分光光度测定法定量测定。结晶紫是使细胞着色的比色染料,从而使得能够测定处理后的细胞生长情况。
在3+HER2过度表达细胞中(对此类细胞极为有效),OctHER2些微较好抑制SKBR3细胞(图8A)生长,但不如对BT474细胞有效(图8B)。有趣的是,OctHER2较更有效抑制2+过度表达细胞系,MDA 361(图8B)。
内化测定:为了评定章鱼抗体在免疫毒素治疗中的应用,测定了章鱼抗体的内化能力。为了抗体装备(arming)或免疫毒素治疗,细胞毒制剂与抗体偶联或融合,并且由此产生的免疫毒素特异地结合其细胞靶标;由此结合的细胞内化该抗体,并分解代谢或者降解该抗体,释放出杀细胞毒素。
在本文进行的内化测定中,抗体是放射性碘标记的,而且抗体与细胞温育不同时间。接下来,测定上清夜中完好无损未结合抗体的量,结合到细胞表面的量,内化的量,以及最后,分解代谢和降解的量。
用3+过度表达细胞系(SKBR3)和2+过度表达细胞系(MDA453)(实线表示2+HER2过度表达,虚线表示3+过度表达)进行的内化测定的结果示于图10A-B。这些结果表明,OctHER2在两个细胞系的内化和分解代谢均令人惊奇地较快2倍。对于装备的抗体而言,章鱼抗体显示的快速内化和分解代谢性能是理想的。与未结合型相比,在2+过度表达细胞中只有极少量游离的章鱼抗体。这些结果再一次揭示:章鱼抗体将是偶联向肿瘤释放的细胞毒制剂的出色候选物。
电子显微镜放射自显影:为了证实章鱼抗体在适合的小囊泡中被内化和降解,而不是仅仅非特异地被内化和降解,故而使用了电子显微镜(EM)放射自显影。按照在内化测定中相同的方式,将章鱼抗体碘化并与细胞温育。描绘于图11A-C的结果证实,章鱼抗体正在内化进入合适的小囊泡(早期内体,图11B;和溶酶体,图11C)。另外,在这些测定中观察到的OctHER2和内化百分比与在内化测定中的测量结果相匹配。
实施例3
抗-DR5章鱼抗体评价
DR5是与3价Apo2L/TRAIL(Apo2L)结合的TNF受体超家族的一个成员。在Apo2L受体结合Apo2L并集簇之后,受体胞质区的死亡结构域诱导caspases以触发细胞凋亡。构建两个版本的抗-DR5章鱼构建体:一个来自16E2,是克隆自单链人Fv噬菌体文库的抗-DR5(见WO98/51793,特别在此引入作为参考);第二个抗-DR5章鱼抗体由Mab 3H3.14.5(″3H3″抗体;ATCC HB-12534,WO99/64461)制备,Mab 3H3.14.5是当交联时诱导细胞凋亡的小鼠抗-DR5Mab。既然抗-死亡受体单克隆抗体需要交联以触发细胞凋亡,那么它们就是章鱼抗体构建体的候选物。通过用来自16E2或3H3的VL和VH区替代上述OctHER2构建体的可变区,来制备抗-DR5章鱼抗体。
在细胞凋亡测定中,使用结晶紫或者alamarBlue染色法测定抗-DR5章鱼抗体。简言之,将系列稀释的章鱼抗体或Apo2L加入到培养板细胞的培养基中,继续生长24小时。到时间后,要么移出细胞进行结晶紫染色,要么将alamarBlue加入到培养基中并与细胞短暂温育。结晶紫染色细胞,而alamarBlue检测培养基中的代谢活性,因此,这些染料能够测量处理后细胞的存活情况。用两种比色染料(结晶紫和alamarBlue)染色后,用分光光度测定法定量测定。
如图12A-E所示,16E2章鱼,在肺(SK-MES-1;HOP 92)和结肠(HCT116;COLO 205)肿瘤细胞系,令人惊奇地诱导细胞凋亡,效力堪比Apo2L。然而在正常对照细胞系(HUMEC)不诱导细胞凋亡。由16E2章鱼诱导的细胞凋亡是caspase-依赖性的。
在无胸腺裸鼠,抗-DR5 16E2章鱼在体内也有效诱导细胞凋亡并且使结肠肿瘤(人COL0205)缩小。如图13A-D所示,用苏木精和伊红染色的肿瘤组织的组织学切片,其来自用16E2章鱼或者诱导细胞类似水平凋亡的Apo2L处理的小鼠。
如图14所示,16E2章鱼-处理的小鼠也显示显著减小肿瘤体积,类似于用Apo2L和2个二价抗-DR5 mAbs(16E2和3H3)测定的结果。没有接受任何抗-DR5抗体或Apo2L(载体)的小鼠,由于无控生长而显示出肿瘤体积的显著增加。
图15显示,小鼠试验中所用材料的细胞凋亡活性在体外细胞凋亡测定中得以证实。在alamarBlue细胞凋亡测定中,试验所用抗-DR5 16E2章鱼和Apo2L与Apo2L标准阳性对照及抗-IgE MAb(E25)阴性对照进行了比较。
图16证明:另一抗-DR5章鱼,3H3章鱼,能够诱导类似于16E2章鱼的细胞凋亡。另外,图16显示,章鱼抗体的细胞凋亡活性不是批量依赖性的,因为在不同日期制备的数种16E2章鱼抗体保持相似的功能。
图17A和B表明,对于肺肿瘤细胞系,SK-MES-1(图17A)和T细胞肿瘤系,Jurkat(图17B),16E2和3H3章鱼抗体的细胞凋亡活性均优于Apo2L。抗-DR5章鱼抗体在将DR5集簇于肿瘤细胞表面方面较Apo2L更为有效。
对16E2章鱼在2-天和6-天时针对国立癌症研究所(NCI)的一系列人肿瘤细胞系做了筛选测定,以与Apo2L进行比较。图18A-C描述2-天时的剂量反应曲线,表明16E2章鱼和Apo2L对数种人白血病、非-小细胞肺癌、结肠癌、中枢神经系统(CND)癌、黑色素瘤、卵巢癌、肾癌、前列腺癌和乳腺癌肿瘤细胞系生长的作用,而图19A-C显示6天筛选时的剂量反应曲线。16E2章鱼和Apo2L对抗大多数肿瘤细胞系方面,观察到可比拟的结果,再一次证明抗-DR5章鱼功能类似于Apo2L。对肺和结肠癌细胞系的相似抑制证实了前面细胞凋亡测定中16E2章鱼和Apo2L对这些癌细胞系的体内体外研究结果。16E2章鱼杀死某些肿瘤细胞系(例如,CNS癌细胞系、SF-295(图19B)以及2个肾癌细胞系,ACHN和RXF393)的能力是没有预想到的(图19C)。
NCI肿瘤系列筛选结果,定量描述于图20A和B(2天结果)以及图21A和B(6-天结果),其总结了16E2章鱼与Apo2L对受治肿瘤细胞系生长的抑制(GI50)、停滞(TGI)和毒性(LC50)方面的作用。这些结果再一次提示,16E2章鱼可有效对抗多于前述观察到的种类的癌症。
实施例4
抗-CD20章鱼抗体评价
在提高嵌合抗-CD20抗体C2B8;美国专利5,736,137,特别在此引入作为参考)效力的努力中,研究的一个方法是抗体触发肿瘤细胞凋亡的能力。按照Koopman等Blood 84:1415-1420(1994)所述方法进行细胞凋亡测定。在制备抗-CD20章鱼抗体中,使用C2B8 VL和VH区制备章鱼抗-CD20抗体(OctCD20)。按照前述实施例描述的方法,在293细胞表达OctCD20抗体并通过蛋白A琼脂糖凝胶层析法进行纯化。
如图22所示,单独不能触发大多数非-何杰金淋巴瘤B细胞系Wil-2的细胞凋亡,除非它与抗-人IgG相交联。然而,OctCD20能够在Wil-2细胞诱导非交联依赖性的细胞凋亡。但是,使用OctCD20观察到的细胞凋亡水平低于交联的所诱导的细胞凋亡水平,提示OctCD20的细胞凋亡活性或许通过使用柔性接头而可以提高。
实施例5
更多多价抗体的构建
对实施例2(抗-HER2)、实施例3(抗-DR5)和实施例4(抗-CD20)的带有抗体铰链区二聚化结构域(本文设计的″章鱼F(ab′)2″)的各种章鱼抗体进行了抗体基因工程改造。用编码亮氨酸-拉链基序序列代替重链cDNA的Fc区,将抗-HER2章鱼F(ab′)2构建体进行基因工程改造,其中亮氨酸拉链基序表达为蛋白时,发生二聚化以有效连接于章鱼Fab臂(图23C)。章鱼F(ab′)2可保持亮氨酸拉链基序,或者基序能够例如按照所期望的那样经蛋白水解而去除。如图24所述,PCR用于扩增双份VH/CH1区和用于在章鱼重链cDNA末端插入限制性酶切位点(NotI)以使得在框架内亚克隆入含有亮氨酸-拉链基序的载体(VG15)。又一次利用PCR而将另一限制性酶切位点(XhoI)增加到重链终止密码子下游,以使得能够亚克隆入用于在哺乳动物细胞表达的pRK载体中。使用唯一的限制性酶切位点BamHI、NheI和BspEI,抗-DR5 Mab16E2和抗-CD20Mab C2B8的VH/CH1区取代进入Oct F(ab)′2重链骨架。
通过将Fab区串连重复地连接在一起以形成线性Fab多聚体,由此而建立″POPoctopus″抗体。″POPoct-3″含有3个连接的Fab区(图23D),而″POPoct-4″含有4个Fab重复单元(图23E)。象抗-HER2(rhuMab 4D5)和抗-DR5(16E2)POPoct-4构建体那样,产生了抗-HER2(rhuMab 4D5)、抗-DR5(16E2)和抗-CD20(C2B8)POPoct-3构建体。将POPoct-3抗体基因工程改造成含有和不含有柔性接头1。
图25描述POPoct-3重链cDNA的构建体。PCR用于扩增加有5′-BspE1位点和3′-Notl位点的VH/CH1区。消化该序列并且用BamHI/BspEI一起消化章鱼重链,连接进入pRK载体以产生含有3个VH/CH1区序列的章鱼重链。BspEl位点编码丝氨酸和甘氨酸残基。
为了基因工程改造POPoct-4抗体(图26),定点寡核苷酸诱变(site-directed oligomutagenesis)用于引入沉寂突变,导致消除章鱼重链cDNA上双份VH/CH区之间的Nhel限制性酶切位点。再次使用寡核苷酸诱变而在紧接第二个VH/CH1序列的下游处加入Nhel限制性酶切位点。该cDNA与POPoct-3构建体一起用BamHI/NheI限制性核酸内切酶消化,并与pRK载体连接在一起以产生含有4个VH/CH1区序列的重链cDNA。
用适当的轻链cDNA将不同的章鱼重链瞬时转染入293哺乳动物细胞以表达含有3个Fab区(POPoct-3Fab)或4个Fab区的抗体(全长型章鱼;章鱼F(ab)′2;POPoct-4Fab)。尽管天然IgG Mab和全长型章鱼抗体经蛋白A琼脂糖凝胶纯化,但是章鱼F(ab)′2和POPoct-3以及POPoct-4是经蛋白G琼脂糖凝胶柱纯化的。
章鱼F(ab)′2约200kDa(图23F,泳道4),小于240kDa的全长型章鱼抗体(图23F,泳道3),但大于150kDa天然IgG Mab(图23F,泳道1和2)。POPoct-3约140kDa(图23F,泳道5),略小于天然IgG Mab,而190kDa的POPoct-4则略大于天然IgG Mab。章鱼F(ab)′2的重链(图23G,泳道4)大小与55kDa的天然IgG Mab重链(图23G,泳道1和2)大致相同。POPoct-3重链(图23G,泳道5)大小类似于全长型章鱼重链(图23G,泳道3),而POPoct-4具有约97kDa的最大重链。
实施例6
抗-HER2多价抗体评价
抗增生测定:OctHER F(ab)′2、POPoct-3HER2、OctHER2、OctHER2 flex1和rhuMAb 4D5以等克分子浓度加入到3+HER2过度表达的肿瘤细胞系BT474中,并通过结晶紫染色测定来评价它们抑制细胞生长的能力。测定结果示于图27。尽管所有抗体诱导BT474细胞的某些程度的细胞增殖抑制,但是,POPoct-3HER2和rhuMAb 4D5显示出最有效的抑制而且抑制生长程度相等,而随着浓度降低,OctHER2F(ab)′2迅速丧失效力。OctHER2 flex1显示出轻微但一致的(consistent)超出OctHER2(n=6)的改善作用,提示改进的柔性可能导致Fab更易进入HER2靶。
在结晶紫细胞增殖抑制测定中,也评价了等克分子浓度OctHER2、OctHER2 flex-1、POPoct-3HER2、POPoct-3HER2 flex-1和rhuMAb 4D5对另一3+HER2过度表达细胞系-SKBR3的作用。该测定结果描述于图28。对于此细胞系,所有受测章鱼构建体同等程度抑制细胞生长,并优于rhuMab 4D5(n=4)。由于OctHER2或POPoct-3的Fab臂之间的柔性接头带来的效力改善作用对于该细胞系并不明显。
内化测定:在内化测定中,比较POPoct-3HER2与OctHER和对两种3+HER2过度表达肿瘤细胞系-SKBR3和BT474的作用,以评定它们在免疫毒素治疗中应用的候选资格。尽管结构上与全长OctHER2抗体不同,但是两个细胞系对POPoct-3HER2的内化和分解代谢与OctHER2相同(图29A和B),并且速度是的两倍。
实施例7
抗-DR5多价抗体评价
细胞凋亡测定:在该实施例中,评价了多价版本的抗-DR5 16E2Mab。等克分子浓度的Oct1 DR5、OctDR5 flex-1、OctDR5F(ab)′2、POPoct-3DR5、POPoct-3DR5flex-1和POPoct-4DR5加入到结肠肿瘤细胞系COLO205中,并在结晶紫细胞凋亡测定中与16E2 MAb进行比较测定(n=4)。结果示于图30A和B。所有章鱼抗体较16E2 MAb诱导更多的细胞凋亡,效力等级由最强到最弱依次是:OctDR5flex-1>OctDR5=POPoct-4DR5=POPoct-3flex-1DR5=POPoct-3DR5>OctDR5F(ab)′2>16E2 Mab。与OctDR5相比,OctDR5flex-1具有提高的效力,尤其是在低浓度时(图30A),表明Fab臂之间的柔性改善了效力。POPoct-3flex-1DR5诱导等同于OctHER的细胞凋亡(图30A)并显示出与POPoct16-3和POPoct16-4相似的效力(图30B)。
细胞信号传导:Apo2L结合于死亡受体并通过caspase信号传导通路触发细胞的细胞凋亡。如图31A和31B所示,抗-DR5章鱼抗体通过与Apo2L相同的信号通路诱导细胞凋亡。对肺肿瘤细胞系SK-MES-1,Oct16E2触发类似于APO2L水平的细胞凋亡(图31A,虚线),但在加入ZVAD(caspase 3和9的抑制剂)之后,由Apo2L和Oct16E2触发的细胞凋亡均被抑制(图31B,实线)。用DISC(死亡诱导信号复合物)测定,得到了抗-DR5章鱼抗体通过与Apo2L相同的通路传导信号的进一步证据(图31B)。BJAB细胞,一种表达DR5的B-细胞淋巴瘤系,在两种不同抗-DR5章鱼抗体-Oct16E2和Oct3H3的两种不同浓度下温育不同时间。纯化抗体-DR5复合物后,进行Western印迹测定以鉴定与复合物共纯化的分子。如与Apo2L一样,信号传导分子caspase 8和与DR5相关的FADD在受体后与Oct16E2和Oct3H3结合(图31B)。
实施例8
抗-CD20章鱼抗体评价
细胞凋亡测定:如图22所示,并不有效触发B-cell淋巴瘤细胞系WIL-2的体外细胞凋亡,除非首先与抗-IgG抗体交联。OctCD20能够诱导WIL-2细胞非交联依赖性的细胞凋亡,水平高于单用时,但是略微低于抗-IgG-交联的。当与抗IgG抗体交联时,OctCD20较交联的诱导更多的WIL-2细胞发生细胞凋亡(图32)。既然对体内效力的可能解释为抗体与补体或者FcγR携带细胞交联,那么该观察提示OctCD20在体内将更为有效。
在WIL-2细胞的细胞凋亡测定中,检测了不同浓度的OctCD20F(ab)′2、POPoct-3CD20和POPoct-3CD20flex-1,最适剂量显示于图33的最大反应曲线中。将章鱼抗体与抗-CD20抗体1F5进行比较(Clark等出处同上),后者功能与相似,因为它除非与抗-IgG抗体交联才诱导细胞凋亡。受测章鱼抗体较交联1F5抗CD20诱导类似(OctCD20F(ab)′2)或者较高(POPoct-3CD20,POPoct-3CD20flex-1)水平的细胞凋亡。另外,章鱼抗体在相当低浓度时较交联的抗-CD20有效。
当把交联的抗-CD20抗体加入到B细胞淋巴瘤系WIL-2S中,观察到细胞的同型粘附。细胞集聚是细胞已经通过CD20激活的一个指征。章鱼抗-CD20抗体诱导与此相同的非交联剂依赖性同型粘附现象,并且如图34所示,POPoct-3CD20的浓度较交联的IF5抗-CD20低许多。
使用从患有慢性淋巴细胞性白血病(CLL)患者采集的血液,进一步评定了由各种抗-CD20抗体引发的细胞凋亡诱导。使用葡聚糖沉降法分离PBL′s,洗涤,并接种在不含血清的淋巴细胞培养基中,用不含样本、1F5(20μg/ml)、1F5+交联小鼠抗-IgG(100μg/ml)、约0.5或1.0μg/ml OctCD20F(ab′)2和0.5μg/ml POPoct-3CD20处理过夜。
使用膜联蛋白和PI染色进行细胞凋亡测定。凋亡细胞百分比是:
未处理的 | 38.5% |
1F5 | 37.1% |
与抗-1gG连接的1F5X | 25.1% |
POPoct-3CD20(0.5μg) | 50.2% |
OctCD20F(ab′)<sub>2</sub>(0.5μg) | 37.7% |
OctCD20F(ab′)<sub>2</sub>(1.0μg) | 48.6% |
数据表明,多价抗-CD20抗体(尤其是POPoct-3CD20)以剂量依赖性方式提高细胞凋亡。
序列表
<110>杰南技术公司(GENENTECH,INC.)
<120>多价抗体及其应用
<130>P1780R1PCT
<140>PCT/US01/08928
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1
Claims (91)
1.一种重组抗体,含有二聚化结构域和三个或更多个抗原结合部位,所述抗原结合部位结合在所述二聚化结构域的氨基末端。
2.权利要求1的重组抗体,其中所述二聚化结构域包含Fc区。
3.权利要求2的抗体,含有4个抗原结合部位。
4.权利要求2的抗体,含有5个或更多个抗原结合部位。
5.权利要求2的抗体,包含一条多肽链,其中该多肽链含有2个或更多个可变区。
6.权利要求5的抗体,其中所述多肽链含有VD1-(X1)n-VD2-(X2)n-Fc,其中VD1是第一可变区,VD2是第二可变区,Fc是Fc区的其中一条多肽链,X1和X2代表氨基酸或多肽,n是0或1。
7.权利要求6的抗体,包含2个或更多个多肽链,每一条多肽链含有VD1-(X1)n-VD2-(X2)n-Fc。
8.权利要求2的抗体,包含至少一条具有式(a)VH-CH1-柔性接头-VH-CH1-Fc区链;或式(b)VH-CH1-VH-CH1-Fc区链的多肽链。
9.权利要求2的抗体,包含至少2个轻链可变区多肽。
10.权利要求9的抗体,其中轻链可变区多肽进一步含有CL区。
11.权利要求2的抗体,包含多肽链,其中该多肽链含有Fd-柔性接头-Fd。
12.权利要求11的抗体,其中柔性接头含有选自下组的肽:gly-ser、gly-ser-gly-ser(SEQ ID NO:10)、ala-ser和gly-gly-gly-ser(SEQ ID NO:11)。
13.权利要求2的抗体,其与二价抗体相比,被表达相应抗原的细胞内化的速度更快,其中所述相应抗原是能与所述抗体结合的抗原。
14.权利要求2的抗体,其是激动型抗体。
15.权利要求2的抗体,其诱导细胞凋亡。
16.权利要求2的抗体,其中所述三个或更多个抗原结合部位均结合相同抗原。
17.权利要求2的抗体,其中所述三个或更多个抗原结合部位结合2种或更多种不同的抗原。
18.权利要求2的抗体,其结合由肿瘤细胞表达的细胞表面蛋白。
19.权利要求18的抗体,其中细胞表面蛋白选自:表皮生长因子受体(EGFR)、HER2受体、HER3受体、HER4受体和DcR3受体。
20.权利要求18的抗体,其中细胞表面蛋白是HER2受体。
21.权利要求2的抗体,其结合由肿瘤细胞过度表达的细胞表面蛋白。
22.权利要求2的抗体,其结合肿瘤坏死因子(TNF)受体超家族中的一种受体。
23.权利要求22的抗体,其中所述TNF受体是Apo2L受体。
24.权利要求23的抗体,其中所述Apo2L受体选自DR4、DR5、DcR1和DcR2。
25.权利要求24的抗体,其中所述Apo2L受体是DR4或DR5。
26.权利要求22的抗体,其是激动型抗体。
27.权利要求22的抗体,其诱导细胞凋亡。
28.权利要求2的抗体,其结合B细胞表面抗原。
29.权利要求28的抗体,其中B细胞表面抗原选自CD19、CD20、CD22和CD40。
30.权利要求28的抗体,其中B细胞表面抗原是CD20。
31.一种免疫偶联物,包含与细胞毒制剂偶联的权利要求1的抗体。
32.权利要求31的免疫偶联物,其中细胞毒制剂一旦内化则具有杀细胞活性。
33.权利要求31的免疫偶联物,其中细胞毒制剂选自放射性同位素、美登木素生物碱和加利车霉素。
34.权利要求1的重组抗体,该抗体能够结合肿瘤坏死因子(TNF)受体超家族中的一种受体。
35.权利要求34的抗体,其不是天然序列IgM或IgA抗体。
36.权利要求34的抗体,其仅有一个Fc区或者缺乏Fc区。
37.权利要求34的抗体,其包含多肽链,其中该多肽链含有2个或更多个可变区。
38.权利要求34的抗体,其包含4个抗原结合部位,每一抗原结合部位均能结合所述TNF受体。
39.权利要求34的抗体,其中TNF受体是Apo2L受体。
40.权利要求39的抗体,其中Apo2L受体选自DR4、DR5、DcR1和DcR2。
41.权利要求39的抗体,其中Apo2L受体是DR4或DR5。
42.权利要求34的抗体,其是激动型抗体。
43.权利要求34的抗体,其诱导细胞凋亡。
44.权利要求1的重组抗体,该抗体能够结合ErbB受体。
45.权利要求44的抗体,其不是天然序列IgM或IgA抗体。
46.权利要求44的抗体,其仅有一个Fc区或者缺乏Fc区。
47.权利要求44的抗体,其包含多肽链,其中该多肽链含有2个或更多个可变区。
48.权利要求44的抗体,其含有4个抗原结合部位,每一抗原结合部位均能结合所述ErbB受体。
49.权利要求44的抗体,其中ErbB受体选自表皮生长因子受体(EGFR)、HER2受体、HER3受体和HER4受体。
50.权利要求44的抗体,其中ErbB受体是HER2受体。
51.权利要求1的重组抗体,该抗体能够结合B细胞表面抗原。
52.权利要求51的抗体,其不是天然序列IgM或IgA抗体。
53.权利要求51的抗体,其仅有一个Fc区或者缺乏Fc区。
54.权利要求51的抗体,其包含多肽链,其中该多肽链含有2个或更多个可变区。
55.权利要求51的抗体,其含有4个抗原结合部位,每一抗原结合部位均能结合所述B细胞表面抗原。
56.权利要求51的抗体,其中B细胞表面抗原选自CD19、CD20、CD22和CD40。
57.权利要求1的重组抗体,该抗体能够结合由癌细胞过度表达的抗原。
58.权利要求1的重组抗体,包含含有下式的多肽链:(a)VH-CH1-柔性接头-VH-CH1-二聚化结构域;或(b)VH-CH1-VH-CH1-二聚化结构域。
59.权利要求58的抗体,进一步含有2个或更多个轻链可变区多肽。
60.权利要求59的抗体,其中轻链可变区多肽含有VL-CL。
61.权利要求1的抗体,其中二聚化结构域选自铰链区、Fc区、CH3区和CH4区。
62.权利要求61的抗体,其中二聚化结构域是铰链区。
63.权利要求62的抗体,其中二聚化结构域进一步含有亮氨酸拉链。
64.权利要求62的抗体,包含含有下式的多肽链:(a)VH-CH1-柔性接头-VH-CH1-铰链区;或(b)VH-CH1-VH-CH1-铰链区。
65.权利要求1的重组抗体,包含多肽链,所述多肽链含有三个或更多个重链或轻链可变区,其中每一可变区能够与三条或更多条轻链或重链可变区多肽结合以形成三个或更多个抗原结合部位,每一抗原结合部位针对相同抗原。
66.权利要求65的抗体,其中所述多肽链含有3个重链可变区,所述可变区能够与3条轻链可变区多肽结合从而形成3个针对相同抗原的抗原结合部位。
67.权利要求65的抗体,其中所述多肽链含有4个重链可变区,所述可变区能够与4条轻链可变区多肽结合以形成4个针对相同抗原的抗原结合部位。
68.权利要求65的抗体,其中所述抗原是肿瘤坏死因子(TNF)受体超家族中的一种受体。
69.权利要求65的抗体,其中所述抗原是B细胞表面抗原。
70.权利要求65的抗体,其中所述抗原是ErbB受体。
71.权利要求65的抗体,其中所述抗原是由肿瘤细胞表达的细胞表面蛋白。
72.权利要求1的重组抗体,包含多肽链,所述多肽链含有下式:(a)VL-CL-柔性接头-VL-CL-柔性接头-VL-CL;(b)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;(c)(VL-CL)n,其中n是3或更大;或者(d)(VH-CH1)n,其中n是3或更大。
73.权利要求66的抗体,其中所述多肽链含有式:(a)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;(b)VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1-柔性接头-VH-CH1;或(c)(VH-CH1)n,其中n是3或4。
74.权利要求65的重组抗体,进一步含有三条或更多条轻链或重链可变区多肽。
75.权利要求74的重组抗体,包含三条或更多条轻链可变区多肽,每一条多肽含有VL-CL。
76.权利要求75的重组抗体,包含4条轻链可变区多肽,每一条多肽含有VL-CL。
77.权利要求1的重组抗体,包含多肽链,所述多肽链含有(a)VL-CL-柔性接头-VL-CL-二聚化结构域;(b)VL-CL-VL-CL-二聚化结构域。
78.一种免疫偶联物,包含与细胞毒制剂偶联的权利要求65的抗体。
79.一种分离的核酸,编码权利要求1-30和34-77之一所述抗体。
80.含有权利要求79的核酸的载体。
81.含有权利要求79的核酸的宿主细胞。
82.一种产生抗体或多肽链的方法,包括培养权利要求81所述的宿主细胞以使所述核酸得以表达。
83.权利要求82的方法,进一步包括从宿主细胞培养物中回收抗体或多肽链。
84.权利要求83的方法,其中所述抗体或多肽链是从宿主细胞培养基质中回收的。
85.权利要求1-30和34-77之一所述的抗体在制备用于治疗哺乳动物病症的药物中的用途。
86.权利要求85的用途,其中所述病症是癌症。
87.权利要求1-30和34-77之一的抗体和细胞毒制剂在制备用于治疗哺乳动物病症的药物中的用途。
88.权利要求34所述的抗体在制备用于诱导癌细胞凋亡的药物中的用途。
89.权利要求51所述的抗体在制备用于杀死B细胞的药物中的用途。
90.权利要求44所述的抗体在制备用于杀死表达ErbB受体的细胞的药物中的用途。
91.权利要求90的用途,其中所述细胞是过度表达ErbB受体的癌细胞。
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