CN106084053B - 针对组织因子的人抗体药物缀合物 - Google Patents
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Abstract
针对组织因子的抗体药物缀合物。亦公开了包含抗体和抗体药物缀合物的药物组合物,以及使用抗体和抗体药物缀合物的治疗和诊断方法。
Description
本申请是分案申请,其母案的中国申请号是:2011800399355,国际申请号是PCT/EP2011/059917,申请日是2011-06-15。
发明领域
本发明涉及抗体药物缀合物(ADC),其中抗体结合组织因子上的表位。这样的ADC对治疗癌症、炎症和血管疾病尤其有用。
发明背景
组织因子(TF),亦称为促凝血酶原激酶、因子III或CD142,是一种从酶原凝血酶原起始凝血酶形成所必需的存在于内皮下组织、血小板和白细胞的蛋白。凝血酶形成最终导致血液凝固。组织因子能够使得细胞起始血液凝固级联,且其作为凝血因子VII (FVII)(一种丝氨酸蛋白酶)的高亲和力受体起作用。所产生的复合物通过特定受限的蛋白水解提供负责起始凝血蛋白酶级联的催化事件。与作为非功能性前体循环的这些蛋白酶级联的其他辅因子不同,当该因子在细胞表面上表达时,其是全功能的强力抑制剂。
组织因子是丝氨酸蛋白酶因子VIIa (FVIIa)的细胞表面受体。FVIIa与组织因子的结合开始细胞内信号转导过程,所述信号转导功能在血管生成中起作用。然而血管生成是生长和发育以及伤口愈合中的正常过程,其亦是肿瘤从休眠状态转变为恶性状态的基本步骤:当癌细胞获得产生参与血管生成的蛋白(所谓的血管生成生长因子)的能力时,这些蛋白由肿瘤释放进入周围组织,并刺激新血管从现有的健康血管向肿瘤生长到肿瘤中。一旦新血管进入肿瘤,它可迅速扩大其大小并侵袭局部组织和器官。通过新血管,癌细胞可进一步逃脱到循环中并在其他器官暂住以形成新肿瘤(转移)。
此外,TF在炎症中起作用。TF的作用被假定为由血液凝固所介导(A. J. Chu:“Tissue factor mediates inflammation(组织因子介导炎症)” 载于Archives ofbiochemistry and biophysics, 2005, 第440卷, 第2号, 第123-132页)。因此,例如通过单克隆抗-TF抗体抑制TF在中断凝血-炎症循环中重要,其不仅有助于抗炎而且促进血管疾病。
在许多类型的癌症中观察到TF表达且其与更侵略性的疾病相关。此外,人TF亦以可溶性可变剪接形式(asHTF)存在。最近发现asHTF促进肿瘤生长(Hobbs 等, 2007Thrombosis Res. 120(2) S13-S21)。
虽然已取得许多进展,但是仍需治疗严重疾病的改进方法,例如基于治疗性抗体的癌症、炎症和血管疾病的改进治疗。
因此,本发明的目的在于提供高度特异和有效的抗-TF抗体药物缀合物,尤其提供用于治疗癌症的用途。
发明概述
本发明涉及新的抗-TF抗体药物缀合物,其对治疗癌症、炎症和血管疾病有用。本发明的抗-TF抗体药物缀合物在杀死表达组织因子(TF)的细胞时是高度有效的。此外,抗-TF抗体药物缀合物的益处在于具有有限的或无凝血抑制。
附图简述
图1:本发明的抗体序列的比对。
SEQ ID NO在序列右边的括号中列出。
根据Kabat的CDR1、CDR2和CDR3如下所示:斜体并加粗的序列代表CDR1区,下划线的序列代表CDR2区,加粗的序列代表CDR3区。
图2:IgG4序列 (SEQ ID NO: 81-82)
SEQ ID NO: 81:人IgG4的野生型CH区的氨基酸序列。斜体的序列代表CH1区,高亮的序列代表铰链区,普通的序列代表CH2区和下划线序列代表CH3区。
SEQ ID NO: 82:人IgG4的无铰链CH区的氨基酸序列。
图3:抗-TF HuMab与TF的细胞外结构域的结合。结合是通过ELISA测定的。EC50值是3次实验的平均值。
图4:抗-TF HuMab与MDA-MD-231细胞上的膜结合的TF的结合。结合是通过FACS分析测定的,将抗体分成a)、b)和c)中所示的3组,亦参见WO 10/066803,其中抗体被分为交叉封闭组。
图5:FVIIa结合被抗-TF HuMab抑制,是通过FACS分析测量的。显示的数据是在增加浓度的抗-TF HuMab存在下FVIIa结合的平均荧光强度(MFI)。在抗-TF HuMab不存在下100 nM FVIIa的MFI是149,942。显示一个代表性的实验。
图6:通过抗-κ-ETA’-缀合的抗-TF HuMab剂量依赖性地诱导细胞杀死。
图7:抗-TF HuMab和ADC与TF细胞外结构域的重组蛋白的结合,由ELISA测定。显示一个代表性的实验。
图8:通过抗-TF ADC体外剂量依赖性地诱导细胞杀死。对于各细胞系:A431 (a)、HPAF-II (b)和NCI-H441 (c),均显示一个代表性的实验。显示的数据是用抗-TF ADC处理的细胞的一式两份孔的百分比存活± S.E.M.。
图9:抗-TF ADC在治疗性处理SCID小鼠中的A431和HPAF-II异种移植物时的体内功效。将建立A431 (A)或HPAF-II (B)肿瘤的小鼠用抗-TF ADC处理。显示的数据是平均肿瘤体积± S.E.M./组(n = 7只小鼠/组)。
图10:ADC与未缀合的IgG1的SDS-PAGE分析以测试稳定性。在研究开始时(t=0)(a-d)或在5℃和< -65℃储存3个月后(e-h),通过SDS-PAGE分析样品。(a, c)泳道1, 9:分子量(MW)标志物,泳道2:IgG1内部对照,泳道3:HuMab-TF-098,泳道4:HuMab-TF -098-vcMMAE,泳道5:HuMab-TF-098-mcMMAF,泳道6:HuMab-TF-011,泳道7:HuMab-TF-011-vcMMAE,泳道8:HuMab-TF-mcMMAF。(b, d)泳道1, 9, 10:MW标志物,泳道2:IgG1内部对照,泳道3:HuMab-TF-111,泳道4:HuMab-TF-111-vcMMAE,泳道5:HuMab-TF-111-mcMMAF,泳道6:IgG1-b12,泳道7:IgG1-b12-vcMMAE,泳道8:IgG1-b12-mcMMAF。(e, g)泳道1, 11:MW标志物,泳道2:IgG1内部对照,泳道3:在< -65℃ 3个月后的HuMab-TF-098-vcMMAE,泳道4:在5℃ 3个月后的HuMab-TF-098-vcMMAE,泳道5:在< -65℃ 3个月后的HuMab-TF-098-mcMMAF,泳道6:在5℃ 3个月后的HuMab-TF-098-mcMMAF,泳道7:在< -65℃ 3个月后的HuMab-TF-011-vcMMAE,泳道8:在5℃ 3个月后的HuMab-TF-011-vcMMAE,泳道9:在< -65℃ 3个月后的HuMab-TF-011-mcMMAF,泳道10:在5℃ 3个月后的HuMab-TF-011-mcMMAF。(f, h)泳道1,11, 12:MW标志物,泳道2:IgG1内部对照,泳道3:在< -65℃ 3个月后的HuMab-TF-111-vcMMAE,泳道4:在5℃ 3个月后的HuMab-TF-111-vcMMAE,泳道5:在< -65℃ 3个月后的HuMab-TF-111-mcMMAF,泳道6:在5℃ 3个月后的HuMab-TF-111-mcMMAF,泳道7:在< -65℃3个月后的IgG1-b12-vcMMAE,泳道8:在5℃ 3个月后的IgG1-b12-vcMMAE,泳道9:在< -65℃3个月后的IgG1-b12-mcMMAF,泳道10:在5℃ 3个月后的IgG1-b12-mcMMAF。
对于非还原条件,显示不同的重链(H)-轻链(L)组合的大小:148 kDa (HHLL)、125kDa (HHL)、99 kDa (HH)、67 kDa (HL)、51 kDa (H)和25 kDa (L)。
图11:HuMab-TF-098-vcMMAE (a)、HuMab-TF-098-mcMMAF (b)、HuMab-TF-011-vcMMAE (c)、HuMab-TF-011-mcMMAF (d)、HuMab-TF-111-vcMMAE (e)、HuMab-TF-111-mcMMAF (f)、IgG1-b12-vcMMAE (g)和IgG1-b12-mcMMAF (h)在研究开始时和在5℃或< -65℃储存3个月后的高效尺寸排阻层析(HP-SEC)图。
图12:ADC和未缀合的IgG1与TF-ECDHis的结合测定以测试稳定性。在研究开始时(t=0)或者在5℃和< -65℃储存3个月后,对样品进行结合分析。
图13:抗-TF ADC在治疗性处理SCID小鼠中的HPAF-II异种移植物时的体内剂量反应。将建立HPAF-II肿瘤的小鼠用抗-TF vcMMAE ADC处理。显示的数据是平均肿瘤体积±S.E.M./组(n = 8只小鼠/组)。
发明详述
定义
术语“组织因子”、“TF”、“CD142”、“组织因子抗原”、“TF抗原”和“CD142抗原”本文可交换地使用,除非另外规定,否则该术语包括人组织因子的任何变体、同种型和物种同源物,人组织因子由细胞天然表达或者在用组织因子基因转染的细胞上表达。组织因子可为实施例1中使用的序列Genbank登录号NP_001984。
术语“免疫球蛋白”指,一类由两对多肽链组成的结构上相关的糖蛋白,一对轻(L)低分子量链和一对重(H)链,所有四条链由二硫键相互连接。免疫球蛋白的结构已被很好地表征。参见例如Fundamental Immunology 第7章 (Paul, W., 主编, 第二版 RavenPress, N.Y. (1989))。简言之,各重链通常由重链可变区(本文缩写为VH或VH)和重链恒定区(CH或CH)组成。重链恒定区通常由三个结构域CH1、CH2和CH3组成。各轻链通常由轻链可变区(本文缩写为VL或VL)和轻链恒定区(CL或CL)组成。轻链恒定区通常由一个结构域(CL)组成。VH和VL区可进一步细分为散布于更保守的称为框架区(FR)的区的高变化性的区(或高变区,其在序列和/或结构上限定的环形式中可为高变的),亦称为互补决定区(CDR)。各VH和VL通常由3个CDR和4个FR组成,从氨基端至羧基端以下述次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4 (亦参见Chothia和Lesk J. Mol. Biol. 196, 901-917 (1987))。通常,该区中的氨基酸残基的编号由以下所述的方法进行:Kabat等, Sequences of Proteins ofImmunological Interest, 第5版 Public Health Service, National Institutes ofHealth, Bethesda, MD. (1991) (短语例如Kabat中或根据Kabat的可变结构域残基编号本文指,重链可变结构域或轻链可变结构域的该编号系统)。使用该编号系统,肽的真实线性氨基酸序列可包含较少的或另外的对应于可变结构域的FR或CDR缩短或插入其中的氨基酸。例如,重链可变区可包含VH CDR2的残基52后的单氨基酸插入物(根据Kabat的残基52a)和重链FR残基82后的插入残基(例如根据Kabat的残基82a、82b和82c等)。通过在抗体序列与“标准”Kabat编号序列有同源性的区上比对,可确定给定抗体的残基的Kabat编号。
本发明的上下文中的术语“抗体”(Ab)指,免疫球蛋白分子、免疫球蛋白分子的片段或者它们之一的衍生物,其在典型的生理条件下具有与抗原特异性结合的能力,具有显著时间段的半寿期(例如至少约30分钟、至少约45分钟、至少约1小时、至少约2小时、至少约4小时、至少约8小时、至少约12小时、约24小时以上、约48小时以上、约3、4、5、6、7天以上等)或任何其他相关的功能上限定的时期(例如足够诱导、促进、增强和/或调节与抗体结合抗原相关的生理反应的时间和/或足够抗体募集效应子活性的时间)。免疫球蛋白分子的重链和轻链的可变区包含与抗原相互作用的结合结构域。抗体(Ab)的恒定区可介导免疫球蛋白与宿主组织或因子(包括免疫系统的多种细胞(例如效应细胞))和补体系统的成分例如C1q(补体激活的经典途径中的第一成分)的结合。如上文所示,除非另外说明或被上下文明显抵触,否则术语抗体在本文中包括保留与抗原特异性结合的能力的抗体片段。已显示,抗体的抗原结合功能可由全长抗体的片段进行。术语“抗体”内所涵盖的结合片段的实例包括:(i) Fab’或Fab片段、由VL、VH、CL和CH1结构域组成的单价片段或WO2007059782 (Genmab A/S)中所述的单价抗体;(ii) F(ab')2片段,包含在铰链区由二硫键连接的两个Fab片段的二价片段;(iii) 基本上由VH和CH1结构域组成的Fd片段;(iv) 基本上由抗体单臂的VL和VH结构域组成的Fv片段;(v) dAb片段(Ward等, Nature 341, 544-546 (1989)), 其基本上由VH结构域组成并亦称为结构域抗体(Holt 等; Trends Biotechnol. 2003年11月;21(11):484-90);(vi) 骆驼科(camelid)抗体或纳米抗体(nanobody)(Revets等; Expert OpinBiol Ther. 2005年1月;5(1):111-24)和(vii) 分离的互补决定区(CDR)。此外,虽然Fv片段的两个结构域(VL和VH)由单独的基因所编码,但是使用重组方法,可通过能够使它们成为单蛋白链的合成接头将它们连接,其中VL和VH区成对以形成单价分子(称为单链抗体或单链Fv (scFv),参见例如Bird 等, Science 242, 423-426 (1988)和Huston 等, PNAS USA85, 5879-5883 (1988))。除非上下文另外指出或明确表示,否则这样的单链抗体涵盖在术语抗体内。虽然这样的片段一般包含在抗体的涵义内,但是它们共同并各独立地为本发明的独特特征,显示不同的生物学性质和效用。本文另外讨论本发明上下文的这些和其他有用的抗体片段。还应该理解,除非另外说明,否则术语抗体亦包括多克隆抗体、单克隆抗体(mAb)、抗体样多肽,例如由任何已知的技术(例如酶促切割、肽合成和重组技术)所提供的嵌合抗体和人源化抗体以及保留与抗原特异性结合的能力的抗体片段(抗原结合片段)。产生的抗体可具有任何同种型。
在本发明的上下文中,术语“ADC”指抗体药物缀合物,其在本发明的上下文中指与本申请中所述的另一部分偶联的抗-TF抗体。
“抗-TF抗体”是上文所述的抗体,其与抗原组织因子或组织因子抗原特异性结合。
本文使用的术语“人抗体”旨在包括,具有来源于人种系免疫球蛋白序列的可变区和恒定区的抗体。本发明的人抗体可包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如通过体外随机或位点特异性诱变或者通过体内体细胞突变所导入的突变)。然而,本文使用的术语“人抗体”不旨在包括其中来源于另一哺乳动物物种(例如小鼠)的种系的CDR序列被移植到人框架序列上的抗体。
在一个优选实施方案中,抗体药物缀合物的抗体或本发明的抗体药物缀合物是分离的。本文使用的“分离的抗体”或“分离的抗体药物缀合物”旨在指,实质上无具有不同抗原特异性的其他抗体的抗体或抗体药物缀合物(例如,与组织因子特异性结合的分离的抗体实质上无与非组织因子抗原特异性结合的抗体)。本文使用的分离的抗体药物缀合物旨在指,亦实质上无“游离毒素”的抗体药物缀合物,其中“游离毒素”旨在意指不与抗体缀合的毒素。当如实施例16所述测定时,所使用的与毒素相关的术语“实质上无”可尤其意指,存在少于5% (例如少于4%,或少于3%,或少于2%,或少于1.5%,或少于1%,或少于0.5%)的未缀合药物。然而,与人组织因子的表位、同种型或变体特异性结合的分离的抗体或分离的抗体药物缀合物可,对其他相关的抗原(例如来自其他物种(例如组织因子物种同源物))具有交叉反应性。此外,分离的抗体或抗体药物缀合物可实质上无其他细胞物质和/或化学品。在本发明的一个实施方案中,在一个明确的组合物中组合两个或更多个具有不同抗原结合特异性的“分离的”单克隆抗体或抗体药物缀合物。
当本文在两个或更多个抗体的上下文中使用时,术语“与…竞争”或“与…交叉竞争”表示,两个或更多个抗体竞争结合TF,例如在WO 10/066803的实施例12所述的测定中竞争TF结合。对于一些抗体对,当一个抗体包被在板上和另一个用于竞争时,才观察到如WO10/066803的实施例12的测定中的竞争,反之不亦然。本文使用的术语“与…竞争”亦旨在涵盖抗体的这种组合。
本文使用的术语“单克隆抗体”或“单克隆抗体组合物”指单分子组成的抗体分子的制备物。单克隆抗体或其组合物可为本发明的药物缀合的抗体。单克隆抗体组合物对特定表位显示单一结合特异性和亲和力。因此,术语“人单克隆抗体”指,具有来源于人种系免疫球蛋白序列的可变区和恒定区的显示单一结合特异性的抗体。人单克隆抗体可由杂交瘤产生,杂交瘤包括与无限增殖化细胞融合的获自转基因或转染色体非人动物(例如具有包含人重链转基因和轻链转基因的基因组的转基因小鼠)的B细胞。
在抗体与预定的抗原结合的上下文中,当使用抗原作为配体和抗体作为分析物通过例如表面等离振子共振(SPR)技术在BIAcore 3000仪器中测定时,本文使用的术语“结合”或“特异性结合”通常是,具有对应于约10-7M以下(例如约10-8M以下、例如约10-9M以下、约10-10M以下或约10-11M或甚至更小)的KD的亲和力的结合,且以对应于比与除预定的抗原或密切相关的抗原外的非特异性抗原(例如BSA、酪蛋白)结合的亲和力至少低10倍(例如至少低100倍、例如至少低1,000倍、例如至少低10,000倍、例如至少低100,000倍)的KD的亲和力与预定的抗原结合。亲和力为较低的量取决于抗体的KD,使得当抗体的KD非常低时(即抗体是高度特异的),那么抗原的亲和力低于非特异性抗原的亲和力的量可为至少10,000倍。
本文使用的术语“kd” (sec-1)指,特定抗体-抗原相互作用的解离速率常数。所述值亦被称为koff值。
本文使用的术语“ka”(M-1 x sec-1)指,特定抗体-抗原相互作用的缔合速率常数。
本文使用的术语“KD” (M)指,特定抗体-抗原相互作用的解离平衡常数。
本文使用的术语“KA” (M-1)指,特定抗体-抗原相互作用的缔合平衡常数并由ka除以kd获得。
当在TF抗体的上下文中使用时,本文使用的术语“内化”包括,抗体从细胞表面内化到表达TF的细胞中的任何机制。抗体的内化可在测量内化的抗体-毒素缀合物或复合物的作用的间接或直接测定中评价(例如实施例15的抗-κ-ETA’测定或实施例18的内化和细胞杀死测定)。通常,直接测定用于测量抗体药物缀合物的内化,例如本文实施例18所述的测定,而间接测定可用于测量然后与第二缀合抗体预孵育的抗体的内化,例如本文实施例15所述的测定。
在一个实施方案中,本发明亦提供包含实施例抗体的VL区、VH区或者一个或多个CDR的功能变体的抗体。在抗-TF抗体的上下文中所使用的VL、VH或CDR的功能变体仍允许抗体保留母抗体亲和力/亲合力和/或特异性/选择性的至少实质比例(至少约50%、60%、70%、80%、90%、95%以上),并在一些情况下与母抗体相比这样的抗-TF抗体可与较大的亲和力、选择性和/或特异性相关。
这样的功能变体通常对母抗体保持显著的序列同一性。考虑需要被引入用于两条序列的最优比对的空位数量和各空位长度,两条序列之间的百分比同一性是序列所共有的相同位置的数量的函数(即%同源性=相同位置的#/位置的总# x 100)。两条序列之间的序列比较和百分比同一性测定可使用如下文非限制性实施例中所述的数学算法实现。
两条核苷酸序列之间的百分比同一性可使用GCG软件包(http://www.gcg.com上可得)中的GAP程序(使用NWSgapdna.CMP矩阵和空位权重为40、50、60、70或80以及长度权重为1、2、3、4、5或6)测定。两条核苷酸或氨基酸序列之间的百分比同一性亦可使用已结合到ALIGN程序(版本2.0)中的E. Meyers和W. Miller, Comput. Appl. Biosci 4, 11-17(1988)的算法(使用PAM120权重残基表、空位长度罚分为12和空位罚分为4)测定。另外,两条氨基酸序列之间的百分比同一性可使用已结合到GCG软件包(http://www.gcg.com上可得)的GAP程序中的Needleman和Wunsch, J. Mol. Biol. 48, 444-453 (1970))算法(使用Blossum 62矩阵或PAM250矩阵和空位权重为16、14、12、10、8、6或4以及长度权重为1、2、3、4、5或6)测定。
CDR变体的序列可通过大部分保守取代与母抗体序列的CDR序列不同;例如变体中至少约35%、约50%以上、约60%以上、约70%以上、约75%以上、约80%以上、约85%以上、约90%以上、约95%以上(例如约65-99%,例如约96%、97%或98%)的取代是保守氨基酸残基置换。
CDR变体的序列可通过大部分保守取代与母抗体序列的CDR序列不同;例如变体中至少10 (例如9、8、7、6、5、4、3、2或1)个取代是保守氨基酸残基置换。
在本发明的上下文中,保守取代可通过下述3个表中的一个或多个所显示的氨基酸种类内的取代所定义。
保守取代的氨基酸残基种类
酸性残基 | Asp (D)和Glu (E) |
碱性残基 | Lys (K)、Arg (R)和His (H) |
亲水不带电荷的残基 | Ser (S)、Thr (T)、Asn (N)和Gln (Q) |
脂肪族不带电荷的残基 | Gly (G)、Ala (A)、Val (V)、Leu (L)和Ile (I) |
非极性不带电荷的残基 | Cys (C)、Met (M)和Pro (P) |
芳香族残基 | Phe (F)、Tyr (Y)和Trp (W) |
备选的保守氨基酸残基取代种类
1 | A | S | T |
2 | D | E | |
3 | N | Q | |
4 | R | K | |
5 | I | L | M |
6 | F | Y | W |
氨基酸残基的备选的物理和功能分类
包含醇基的残基 | S和T |
脂肪族残基 | I、L、V和M |
环烯基相关的残基 | F、H、W和Y |
疏水残基 | A、C、F、G、H、I、L、M、R、T、V、W和Y |
带负电荷的残基 | D和E |
极性残基 | C、D、E、H、K、N、Q、R、S和T |
带正电荷的残基 | H、K和R |
小的残基 | A、C、D、G、N、P、S、T和V |
非常小的残基 | A、G和S |
涉及转角形成的残基 | A、C、D、E、G、H、K、N、Q、R、S、P和T |
柔性残基 | Q、T、K、S、G、P、D、E和R |
更多的保守取代分组包括:缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸和天冬酰胺-谷氨酰胺。
另外的氨基酸分组亦可使用例如Creighton (1984) Proteins: Structure andMolecular Properties (第二版 1993), W.H. Freeman and Company中所述的原理制定。
在本发明的一个实施方案中,与实施例抗体的CDR相比,根据亲水/亲水性质和残基重量/大小的保守在变体CDR中亦是实质上保留的 (例如,序列的重量种类、亲水得分或两者是至少约50%、至少约60%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%以上(例如约65-99%)保留的)。例如,保守残基取代亦可或备选基于基于强或弱的本领域已知的基于重量的保守基团的置换。
相似残基的保留亦可或备选通过相似性得分测量,如使用BLAST程序(例如通过NCBI可得的BLAST 2.2.8,使用标准设置:BLOSUM62、开放空位=11和延伸空位=1)测定的。合适的变体通常对母肽显示至少约45% (例如至少约55%、至少约65%、至少约75%、至少约85%、至少约90%、至少约95%以上(例如约70-99%))的相似性。
本文使用的“同种型”指由重链恒定区基因编码的免疫球蛋白种类(例如IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM)。
术语“表位”意指能够与抗体特异性结合的蛋白决定簇。表位通常由分子的表面基团例如氨基酸或糖侧链组成,并通常具有特定的三维结构特性以及特定的电荷特性。构象和非构象表位的区别在于,在变性溶剂的存在下与前者而不是后者的结合丢失。表位可包含直接参与结合的氨基酸残基(亦称为表位的免疫显性成分)和不直接参与结合的其他氨基酸残基,例如被特异性抗原结合肽所有效阻断的氨基酸残基(换言之,该氨基酸残基在特异性抗原结合肽的足迹内)。
本文使用的人抗体“来源于”特定种系序列,条件是抗体获自使用人免疫球蛋白序列的系统,例如通过免疫携带人免疫球蛋白基因的转基因小鼠或通过筛查人免疫球蛋白基因文库,和其中所选择的人抗体在氨基酸序列中与该种系免疫球蛋白基因所编码的氨基酸序列至少90% (例如至少95%、例如至少96%、例如至少97%、例如至少98%或例如至少99%)相同。通常,在重链CDR3外,与由该种系免疫球蛋白基因所编码的氨基酸序列相比,来源于特定人种系序列的人抗体将显示不超过20个氨基酸不同,例如不超过10个氨基酸不同,例如不超过9、8、7、6或5 (例如不超过4、3、2或1)个氨基酸不同。
当与抗-TF抗体药物缀合物接触时,与不与抗-TF抗体药物缀合物接触的相同细胞的生长相比,本文使用的术语“抑制生长”(例如指细胞,例如肿瘤细胞)旨在包括细胞生长中的任何可测量的减少,例如细胞培养物的生长抑制了至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、99%或100%。细胞生长中的这种减少可通过由抗-TF抗体和药物单独或组合所发挥的多种机制发生,例如抗体依赖性细胞介导的吞噬作用(ADCP),抗体依赖性细胞介导的细胞毒性(ADCC),补体介导的细胞毒性(CDC),和/或凋亡,或例如可由auristatin与微管蛋白相互作用所诱导的G2/M细胞周期停滞和凋亡。
术语“稳定化IgG4抗体”指被修饰以降低半分子交换的IgG4抗体(参见WO 2008/145142 (Genmab A/S)或van der Neut Kolfschoten M 等, (2007) Science 14;317(5844)和其中的参考文献)。
本文使用的术语“效应细胞”指参与免疫反应的效应阶段而不是免疫反应的认知和激活阶段的免疫细胞。例示性的免疫细胞包括骨髓或淋巴来源的细胞,例如淋巴细胞(例如B细胞和包括溶细胞性T细胞(CTL)在内的T细胞)、杀伤细胞、天然杀伤细胞、巨噬细胞、单核细胞、嗜酸性粒细胞、多形核细胞例如嗜中性粒细胞、粒细胞、肥大细胞和嗜碱性粒细胞。一些效应细胞表达特异性Fc受体(FcR)并执行特异性免疫功能。在一些实施方案中,效应细胞能够诱导ADCC,例如天然杀伤细胞能够诱导ADCC。例如,表达FcR的单核细胞、巨噬细胞参与靶细胞的特异性杀死并将抗原呈递至免疫系统的其他成分或与呈递抗原的细胞结合。在一些实施方案中,效应细胞可吞噬靶抗原或靶细胞。效应细胞上的特定FcR的表达可由激素因子例如细胞因子调节。例如已发现FcγRI的表达是通过干扰素γ (IFN-γ)和/或粒细胞集落刺激因子(G-CSF)上调的。该增强的表达增加携带FcγRI的细胞针对靶细胞的细胞毒活性。效应细胞可吞噬或裂解靶抗原或靶细胞。
本文使用的术语“载体”旨在指,能够运送已与其连接的另一核酸的核酸分子。一种类型的载体是“质粒”,其指另外的DNA区段可被连接到其中的环状双链DNA环。另一种类型的载体是病毒载体,其中另外的DNA区段可被连接到病毒基因组中。特定的载体能够在其被导入的宿主细胞中自主复制(例如具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其他载体(例如非附加型哺乳动物载体)可在导入到宿主细胞中时整合到宿主细胞的基因组中,并藉此与宿主基因组一起复制。此外,特定载体能够指导与其有效连接的基因的表达。这样的载体本文被称为“重组表达载体”(或简言之“表达载体”)。大体上,在重组DNA技术中实用的表达载体经常呈质粒的形式。在本说明书中,可交换使用“质粒”和“载体”,因为质粒是最常用的载体形式。然而,本发明旨在包括起等价功能的这样的其他形式的表达载体,例如病毒载体(例如复制缺陷型逆转录病毒、腺病毒和腺相关病毒)。
本文使用的术语“重组宿主细胞”(或简言之“宿主细胞”)旨在指,表达载体已被导入其中的细胞。应该理解,这样的术语旨在不仅指特定的受试者细胞,而且指这样的细胞的后代。因为由于突变或环境影响,可在随后的代中发生特定改变,所以这样的后代可事实上不与母细胞相同,但仍包括在本文使用的术语“宿主细胞”的范围内。重组宿主细胞包括,例如转染瘤,例如CHO细胞、HEK293细胞、NS/0细胞和淋巴细胞。
本文使用的术语“转染瘤”包括表达抗体的重组真核宿主细胞,例如CHO细胞、NS/0细胞、HEK293细胞、植物细胞或包括酵母细胞在内的真菌。
术语“转基因非人动物”指,具有包含一条或多条人重链和/或轻链转基因或转染色体的基因组(整合或非整合到动物的天然基因组DNA中)并能够表达全人抗体的非人动物。例如,转基因小鼠可具有人轻链转基因,以及人重链转基因或人重链转染色体之一,使得当用TF抗原和/或表达TF的细胞免疫时小鼠产生人抗-TF抗体。人重链转基因可整合到小鼠的染色体DNA中,如转基因小鼠的例子,例如HuMAb小鼠,例如HCo7、HCo17、HCo20或HCo12小鼠,或者人重链转基因可在染色体外维持,如WO02/43478中所述的转染色体KM小鼠的例子。这样的转基因和转染色体小鼠(本文共同称为“转基因小鼠”)通过经受V-D-J重组和同种型转换能够对给定抗原产生多种同种型的人单克隆抗体(例如IgG、IgA、IgM、IgD和/或IgE)。通过导入编码这种特异性抗体的基因(例如通过将基因与动物牛奶中表达的基因有效连接),转基因非人动物亦可用于产生针对特异性抗原的抗体。
“治疗”指给予有效量的本发明的治疗活性化合物,目的在于缓和、减轻、阻止或根除(治愈)症状或疾病状况。
“有效量”或“治疗有效量”指,在必需剂量和持续必要的时间段有效实现所需的治疗结果的量。根据因素例如个体的疾病状况、年龄、性别和体重以及抗-TF抗体药物缀合物引起个体的所需反应的能力,抗-TF抗体药物缀合物的治疗有效量可变化。治疗有效量亦是其中抗体或抗体部分的任何毒性或有害作用被治疗有益作用所超过的量。
“抗-独特型”(Id)抗体是识别通常与抗体的抗原结合位点相关的独特决定簇的抗体。
本发明的另外方面和实施方案
本发明提供抗-TF抗体药物缀合物。
在一个方面,本发明提供包含抗体的抗体药物缀合物,该抗体与组织因子结合并包含:
(i) 包含具有SEQ ID NO: 6所示的氨基酸序列的CDR1区、具有SEQ ID NO: 7所示的氨基酸序列的CDR2区和具有SEQ ID NO: 8所示的氨基酸序列的CDR3区的VH区,和包含具有SEQ ID NO: 46所示的氨基酸序列的CDR1区、具有SEQ ID NO: 47所示的氨基酸序列的CDR2区和具有SEQ ID NO: 48所示的氨基酸序列的CDR3区的VL区,或
(ii) 包含具有SEQ ID NO: 34所示的氨基酸序列的CDR1区、具有SEQ ID NO: 35所示的氨基酸序列的CDR2区和具有SEQ ID NO: 36所示的氨基酸序列的CDR3区的VH区,和包含具有SEQ ID NO: 74所示的氨基酸序列的CDR1区、具有SEQ ID NO: 75所示的氨基酸序列的CDR2区和具有SEQ ID NO: 76所示的氨基酸序列的CDR3区的VL区,或
(iii) 包含具有SEQ ID NO: 38所示的氨基酸序列的CDR1区、具有SEQ ID NO: 39所示的氨基酸序列的CDR2区和具有SEQ ID NO: 40所示的氨基酸序列的CDR3区的VH区,和包含具有SEQ ID NO: 78所示的氨基酸序列的CDR1区、具有SEQ ID NO: 79所示的氨基酸序列的CDR2区和具有SEQ ID NO: 80所示的氨基酸序列的CDR3区的VL区,或
(iv) 包含具有SEQ ID NO: 2所示的氨基酸序列的CDR1区、具有SEQ ID NO: 3所示的氨基酸序列的CDR2区和具有SEQ ID NO: 4所示的氨基酸序列的CDR3区的VH区,和包含具有SEQ ID NO: 42所示的氨基酸序列的CDR1区、具有SEQ ID NO: 43所示的氨基酸序列的CDR2区和具有SEQ ID NO: 44所示的氨基酸序列的CDR3区的VL区,或
(v) 所述抗体中任一个的变体,其中所述变体在所述序列中优选具有至多1、2或3个氨基酸修饰,更优选氨基酸取代,例如保守氨基酸取代,
其中该抗体经由接头与auristatin或者其功能肽类似物或衍生物缀合。
在一个实施方案中,抗体包含:
(i) 包含SEQ ID NO: 5的氨基酸序列的VH区和包含SEQ ID NO: 45的氨基酸序列的VL区,或
(ii) 包含SEQ ID NO: 33的氨基酸序列的VH区和包含SEQ ID NO: 73的氨基酸序列的VL区,或
(iii) 包含SEQ ID NO: 37的氨基酸序列的VH区和包含SEQ ID NO: 77的氨基酸序列的VL区,或
(iv) 包含SEQ ID NO: 1的氨基酸序列的VH区和包含SEQ ID NO: 41的氨基酸序列的VL区。
在一个实施方案中,抗体是全长抗体。
在一个实施方案中,抗体是全人单克隆IgG1抗体,例如IgG1,κ。在另一实施方案中,抗体是全人单克隆稳定化IgG4抗体。
在一个实施方案中,auristatin是单甲基auristatin E (MMAE):
其中波浪线表示接头的连接位点。
在一个实施方案中,auristatin是单甲基auristatin F (MMAF):
其中波浪线表示接头的连接位点。
在一个实施方案中,接头与通过(部分)还原抗-TF抗体所获得的抗-TF抗体的巯基残基连接。
在一个实施方案中,接头-auristatin是MC-vc-PAB-MMAF (亦指定为vcMMAF)或MC-vc-PAB-MMAE (亦指定为vcMMAE):
Ab-MC-vc-PAB-MMAF (vcMMAF)
Ab-MC-vc-PAB-MMAE (vcMMAE)
其中p表示1-8的数字,例如p可为3-5,S代表抗-TF抗体的巯基残基,和Ab指定抗-TF抗体。在一个实施方案中,接头-auristatin是vcMMAE。
在一个实施方案中,接头-缀合物是mcMMAF (其中mc/MC是马来酰亚胺基己酰基的缩写):
Ab-MC-MMAF (mcMMAF)
其中p表示1-8的数字,例如p可为3-5,S代表抗-TF抗体的巯基残基,和Ab指定抗-TF抗体。
在一个实施方案中,抗体阻断FVIIa与组织因子的结合,例如如实施例14所述测定。
在一个实施方案中,抗体抑制FVIIa与组织因子的结合,当如实施例14所述测定时,优选其中最大抑制值IC50为0.01-3.0 μg/mL,或例如0.1-2.0 μg/mL,或例如0.2-1.2 μg/mL。
在一个实施方案中,抗体与以下的抗体竞争组织因子结合:
包含含有SEQ ID NO: 33的序列的VH区和含有SEQ ID NO: 73的序列的VL区的抗体,
或
包含含有SEQ ID NO: 1的序列的VH区和含有SEQ ID NO: 41的序列的VL区的抗体,
或
包含含有SEQ ID NO: 5的序列的VH区和含有SEQ ID NO: 45的序列的VL区的抗体,
或
包含含有SEQ ID NO: 9的序列的VH区和含有SEQ ID NO: 49的序列的VL区的抗体,
或
包含含有SEQ ID NO: 13的序列的VH区和含有SEQ ID NO: 53的序列的VL区的抗体,
或
包含含有SEQ ID NO: 17的序列的VH区和含有SEQ ID NO: 57的序列的VL区的抗体,
或
包含含有SEQ ID NO: 21的序列的VH区和含有SEQ ID NO: 61的序列的VL区的抗体,
或
包含含有SEQ ID NO: 25的序列的VH区和含有SEQ ID NO: 65的序列的VL区的抗体,
或
包含含有SEQ ID NO: 29的序列的VH区和含有SEQ ID NO: 69的序列的VL区的抗体,
或
包含含有SEQ ID NO: 37的序列的VH区和含有SEQ ID NO: 77的序列的VL区的抗体。
在一个实施方案中,抗体包含:
a) 包含SEQ ID NO: 34、35和36的CDR1、2和3序列的VH区和包含SEQ ID NO: 74、75和76的CDR1、2和3序列的VL区,或
b) 包含SEQ ID NO: 2、3和4的CDR1、2和3序列的VH区和包含SEQ ID NO: 42、43和44的CDR1、2和3序列的VL区,或
c) 包含SEQ ID NO: 6、7和8的CDR1、2和3序列的VH区和包含SEQ ID NO: 46、47和48的CDR1、2和3序列的VL区,或
d) 包含SEQ ID NO: 10、11和12的CDR1、2和3序列的VH区和包含SEQ ID NO: 50、51和52的CDR1、2和3序列的VL区,或
e) 包含SEQ ID NO: 14、15和16的CDR1、2和3序列的VH区和包含SEQ ID NO: 54、55和56的CDR1、2和3序列的VL区,或
f) 包含SEQ ID NO: 18、19和20的CDR1、2和3序列的VH区和包含SEQ ID NO: 58、59和60的CDR1、2和3序列的VL区,或
g) 包含SEQ ID NO: 22、23和24的CDR1、2和3序列的VH区和包含SEQ ID NO: 62、63和64的CDR1、2和3序列的VL区,或
h) 包含SEQ ID NO: 26、27和28的CDR1、2和3序列的VH区和包含SEQ ID NO: 66、67和68的CDR1、2和3序列的VL区,或
i) 包含SEQ ID NO: 30、31和32的CDR1、2和3序列的VH区和包含SEQ ID NO: 70、71和72的CDR1、2和3序列的VL区,或
j) 包含SEQ ID NO: 38、39和40的CDR1、2和3序列的VH区和包含SEQ ID NO: 78、79和80的CDR1、2和3序列的VL区,或
k) 所述抗体中任一个的变体,其中所述变体在所述序列中优选具有至多1、2或3个氨基酸修饰,更优选氨基酸取代,例如保守氨基酸取代。
在一个实施方案中,抗体包含具有以下的VH:
a) 与选自SEQ ID NO: 33、1、5、9、13、17、21、25、37和29的VH区序列有至少80%同一性,例如至少90%、至少95%或至少98%或100%同一性,或者
b) 与选自SEQ ID NO: 33、1、5、9、13、17、21、25、37和29的VH区序列相比,至多20(例如15或10或5、4、3、2或1)个氨基酸修饰,更优选氨基酸取代,例如保守氨基酸取代。
在一个实施方案中,抗体包含具有以下的VL:
a) 与选自SEQ ID NO: 73、41、45、49、53、57、61、65、77和69的VL区序列有至少80%同一性,例如至少90%、至少95%或至少98%或100%同一性,或者
b) 与选自SEQ ID NO: 73、41、45、49、53、57、61、65、77和69的VH区序列相比,至多20 (例如15或10或5、4、3、2或1)个氨基酸修饰,更优选氨基酸取代,例如保守氨基酸取代。
在一个实施方案中,抗体包含:
a) 包含SEQ ID NO: 33的序列的VH区和包含SEQ ID NO: 73的序列的VL区,或
b) 包含SEQ ID NO: 1的序列的VH区和包含SEQ ID NO: 41的序列的VL区,或
c) 包含SEQ ID NO: 5的序列的VH区和包含SEQ ID NO: 45的序列的VL区,或
d) 包含SEQ ID NO: 9的序列的VH区和包含SEQ ID NO: 49的序列的VL区,或
e) 包含SEQ ID NO: 13的序列的VH区和包含SEQ ID NO: 53的序列的VL区,或
f) 包含SEQ ID NO: 17的序列的VH区和包含SEQ ID NO: 57的序列的VL区,或
g) 包含SEQ ID NO: 21的序列的VH区和包含SEQ ID NO: 61的序列的VL区,或
h) 包含SEQ ID NO: 25的序列的VH区和包含SEQ ID NO: 65的序列的VL区,或
i) 包含SEQ ID NO: 29的序列的VH区和包含SEQ ID NO: 69的序列的VL区,或
j) 包含SEQ ID NO: 37的序列的VH区和包含SEQ ID NO: 77的序列的VL区。
在一个实施方案中,抗体与组织因子的细胞外结构域结合,当如实施例12的测定中所述测定时,具有的表观亲和力(EC50)为3.0 nM以下,例如0.50 nM以下,例如0.35 nM以下,例如0.20 nM以下,例如0.1 nM以下。
在一个实施方案中,抗体与表达组织因子的哺乳动物细胞(例如用编码组织因子的构建体转染的A431细胞)结合,当如实施例13的测定中所述测定时,优选具有的表观亲和力(EC50)为10 nM以下,例如8 nM以下,例如5 nM以下,例如2 nM以下,例如1 nM以下,例如0.5 nM以下,例如0.3 nM以下。
在另一或备选方面,抗体与选自以下的治疗部分缀合:紫杉醇;细胞松弛素B;短杆菌肽D;溴化乙锭;依米丁;丝裂霉素;依托泊苷;替尼泊苷(tenoposide);长春新碱;长春碱;秋水仙碱;多柔比星;柔红霉素;二羟基炭疽菌素二酮;微管蛋白抑制剂,例如美坦辛或者其类似物或衍生物;米托蒽醌;光神霉素;放线菌素D;1-去氢睾酮;糖皮质激素;普鲁卡因;丁卡因;利多卡因;普萘洛尔;嘌呤霉素;加利车霉素或者其类似物或衍生物;抗代谢物例如氨甲喋呤、6巯基嘌呤、6硫鸟嘌呤、阿糖胞苷、氟达拉滨(fludarabin)、5氟尿嘧啶、氨烯咪胺、羟基脲、门冬酰胺酶、吉西他滨或克拉屈滨;烷化剂例如氮芥、塞替派(thioepa)、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲霉素、达卡巴嗪(DTIC)、丙卡巴肼、丝裂霉素C、顺铂、卡铂、多卡米星A、多卡米星SA、雷查霉素(CC-1065)或者其类似物或衍生物;吡咯并[2,1-c][1,4]苯二氮䓬类(PDB)或其类似物;抗生素例如更生霉素、博来霉素、柔红霉素、多柔比星、伊达比星、光神霉素、丝裂霉素、米托蒽醌、普卡霉素、安曲霉素(AMC);白喉毒素和相关的分子例如白喉A链及其活性片段和杂合分子、蓖麻毒蛋白毒素例如蓖麻毒蛋白A或去糖基化蓖麻毒蛋白A链毒素、霍乱毒素、志贺样毒素例如SLT I、SLT II、SLT IIV、LT毒素、C3毒素、志贺毒素、百日咳毒素、破伤风毒素、大豆Bowman-Birk蛋白酶抑制剂、假单胞菌外毒素、alorin、皂草素、塑莲根毒素、gelanin、相思豆毒蛋白A链、塑莲根毒素A链、α-sarcin、油桐(Aleurites fordii)蛋白、石竹素蛋白、美洲商陆(Phytolacca americana)蛋白例如PAPI、PAPII和PAP S、苦瓜(momordica charantia)抑制剂、麻疯树毒蛋白、巴豆毒蛋白、肥皂草(sapaonaria officinalis)抑制剂、白树毒素、mitogellin、局限曲菌素、酚霉素和依诺霉素毒素;核糖核酸酶(RNase);DNase I;葡萄球菌肠毒素A;美洲商陆抗病毒蛋白;白喉毒素;和假单胞杆菌内毒素。在另外的备选实施方案中,抗体与选自以下的细胞毒部分缀合:多拉司他汀、美坦辛、加利车霉素、多卡米星、雷查霉素(CC-1065)或者其任一种的类似物、衍生物或前药。
在另外的备选实施方案中,抗体与选自以下的细胞因子缀合:IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNα、IFNβ、IFNγ、GM-CSF、CD40L、Flt3配体、干细胞因子、安西司亭(ancestim)和TNFα。
在另外的备选实施方案中,抗体与放射性同位素缀合。
在一个实施方案中,抗体能够在A431、BxPC3或MDA-MB-23中通过内化与毒素偶联的抗体诱导细胞毒性,如实施例15所述的。
在一个实施方案中,抗体在A431细胞中通过如实施例15所述的内化诱导细胞毒性,其中EC50值为9 x 10-5-4 x 10-4 μg/mL。
在一个实施方案中,当如实施例16所述测定时,抗体药物缀合物的制备物得到少于2% (例如少于1.5%,或少于1%,或少于0.5%)的未缀合药物。
在一个实施方案中,当如实施例16所述测定时,抗体药物缀合物的制备物得到少于10% (例如少于8%,或少于7%,或少于6%,或少于5.5%)的聚集物。
在一个实施方案中,当如实施例16所述测定时,抗体药物缀合物的制备物得到少于1% (例如少于0.5%,或少于0.25%,或少于0.2%)的内毒素。
在一个实施方案中,当如实施例16所述测定时,抗体药物缀合物的制备物得到的抗体药物缀合物的浓度为1-100 mg/mL的范围,例如2-50 mg/mL的范围,或5-25 mg/mL的范围,或5-15 mg/mL的范围,或7.5-15 mg/mL的范围,或8-12 mg/mL的范围,或9-11 mg/mL的范围。
在一个实施方案中,当如实施例17所述测定时,抗体药物缀合物与组织因子的细胞外结构域结合,其中表观亲和力(EC50)为600 ng/mL以下,例如550 ng/mL以下,或500 ng/mL以下,例如其中EC50值范围为200-600 ng/mL,例如EC50值范围为300-600 ng/mL,或EC50值范围为350-550 ng/mL,或EC50值范围为400-500 ng/mL。
在一个实施方案中,抗体药物缀合物在A431细胞中通过如实施例18所述的内化诱导细胞毒性,其中EC50值为1-100 ng/mL。
在一个实施方案中,抗体药物缀合物在HPAF-II细胞中通过如实施例18所述的内化诱导细胞毒性,其中EC50值为0.5-20 ng/mL。
在一个实施方案中,抗体药物缀合物在NCI-H441细胞中通过如实施例18所述的内化诱导细胞毒性,其中EC50值为0.5-500 ng/mL,例如0.5-20 ng/mL。
在一个实施方案中,抗体药物缀合物在例如肿瘤细胞中通过如实施例18所述的内化诱导细胞毒性,该肿瘤细胞表达超过200,000个组织因子分子/细胞,例如200,000-1,000,000个组织因子分子/细胞,例如200,000-500,000个组织因子分子/细胞。EC50值在一个实施方案中可为0.1-100 ng/mL。
在一个实施方案中,抗体药物缀合物在例如肿瘤细胞中通过如实施例18所述的内化诱导细胞毒性,该肿瘤细胞表达超过20,000个组织因子分子/细胞,例如20,000-200,000个组织因子分子/细胞。EC50值在一个实施方案中可为0.5-500 ng/mL,例如0.5-20 ng/mL。
在一个实施方案中,抗体药物缀合物抑制肿瘤生长,如实施例19所述的。
在一个实施方案中,当如实施例19所述测定肿瘤生长时,抗体药物缀合物抑制细胞系的肿瘤生长,该细胞系表达超过1000个分子组织因子/细胞,例如超过10,000个组织因子分子/细胞,例如超过100,000个组织因子分子/细胞,或例如1000-20,000个组织因子分子/细胞,或20,000-200,000个组织因子分子/细胞,或200,000-500,000个组织因子分子/细胞,或200,000-1,000,000个组织因子分子/细胞。
在一个实施方案中,抗体药物缀合物在-65℃至少3个月是稳定的,其中当如实施例20所述测定时,稳定的指至少95%的抗体药物缀合物以单体分子存在。
在一个实施方案中,抗体药物缀合物在5℃至少3个月是稳定的,其中当如实施例20所述测定时,稳定的指至少95%的抗体药物缀合物以单体分子存在。
在另一方面,本发明提供包含上文实施方案中任一个所定义的抗体药物缀合物的药物组合物。在一个实施方案中,药物组合物另外包含药学上可接受的载体。
在另一方面,本发明提供上文实施方案中任一个所定义的抗体药物缀合物,其用作药物。
在另一方面,本发明提供上文实施方案中任一个所定义的抗体药物缀合物,其用于治疗病症。
在另一方面,本发明提供上文实施方案中任一个所定义的抗体药物缀合物,其用于治疗炎症。
在另一方面,本发明提供上文实施方案中任一个所定义的抗体药物缀合物,其用于治疗癌症。
在一个实施方案中,癌症选自中枢神经系统的肿瘤、头颈癌、肺癌例如NSCLC、乳腺癌具体地三阴乳腺癌、食道癌、胃癌(gastric or stomach cancer)、肝胆癌、胰腺癌、结直肠癌、膀胱癌、肾癌、前列腺癌、子宫内膜癌、卵巢癌、恶性黑色素瘤、肉瘤、未知原发来源的肿瘤、骨髓癌、急性成淋巴细胞白血病、慢性成淋巴细胞白血病和非霍奇金淋巴瘤、皮肤癌、神经胶质瘤、脑癌、子宫癌、急性髓性白血病和直肠癌。
在一个实施方案中,癌症是胰腺癌。
在一个实施方案中,癌症是结直肠癌。
在一个实施方案中,癌症是卵巢癌。
在一个实施方案中,癌症是乳腺癌。
在一个实施方案中,癌症是前列腺癌。
在一个实施方案中,癌症是膀胱癌。
在一个实施方案中,癌症是对用微管蛋白抑制剂治疗敏感的癌症。
在另一方面,本发明提供上文实施方案中任一个的抗体药物缀合物,其中药物是用于与一种或多种另外的治疗剂例如化学治疗剂联合治疗癌症。
在另一方面,本发明提供上文实施方案中任一个的抗体药物缀合物用于制备用于治疗癌症的药物的用途。在一个实施方案中,癌症可选自上文所述的癌症中的任一个。
在另一方面,本发明提供一种用于诱导表达组织因子的肿瘤细胞的细胞死亡或抑制其生长和/或增殖的方法,其包括向有需要的个体给予有效量的任何上文实施方案中任一个的抗体药物缀合物。
在另一方面,本发明提供一种治疗任何上文癌症疾病的方法,所述方法是通过向有需要的个体给予有效量的任何上文实施方案中任一个的抗体药物缀合物。在一个实施方案中,抗体药物缀合物与一种或多种另外的治疗剂例如化学治疗剂联合给予。
抗体
本发明涉及抗-TF抗体药物缀合物,因此包含抗体和药物两者,其可尤其经由接头与彼此缀合。
使用公知的表达载体系统和宿主细胞,抗体可通过公知的重组技术制备。在一个实施方案中,使用De la Cruz Edmunds 等, 2006, Molecular Biotechnology 34: 179-190、EP216846、US5981216、WO 87/04462、EP323997、US5591639、US5658759、EP338841、US5879936和US5891693中公开的GS表达载体系统,在CHO细胞中制备抗体。
使用公知的技术从细胞介质分离和纯化抗体后,将它们经由如下文另外公开的接头与auristatin缀合。
本发明的单克隆抗体可例如由Kohler 等, Nature 256, 495 (1975)首次所述的杂交瘤方法产生,或者可由重组DNA方法产生。使用描述于例如Clackson 等, Nature 352,624-628 (1991)和Marks 等, J. Mol. Biol. 222, 581-597 (1991)的技术,亦可从噬菌体抗体文库中分离单克隆抗体。单克隆抗体可从任何合适的来源获得。因此,例如单克隆抗体可获自从鼠脾B细胞制备的杂交瘤,鼠脾B细胞获自用目标抗原免疫的小鼠,目标抗原例如呈在表面上表达抗原的细胞或编码目标抗原的核酸的形式。单克隆抗体亦可获自来源于免疫的人或非人哺乳动物(例如大鼠、狗、灵长类等)的表达抗体的细胞的杂交瘤。
在一个实施方案中,本发明的抗体是人抗体。使用携带人免疫系统而不是小鼠系统的部分的转基因或转染色体小鼠,可产生针对组织因子的人单克隆抗体。这样的转基因和转染色体小鼠包括本文分别称为HuMAb小鼠和KM小鼠的小鼠,且本文共同称为“转基因小鼠”。
HuMAb小鼠包含编码未重排的人重(μ和γ)和κ轻链免疫球蛋白序列连同灭活内源性µ和κ链基因座的靶向突变的人免疫球蛋白基因小基因座(minilocus) (Lonberg, N.等, Nature 368, 856-859 (1994))。因此,小鼠显示小鼠IgM或κ的降低表达,并且响应于免疫,所导入的人重链和轻链转基因经受类别转换和体细胞突变以产生高亲和力人IgG,κ单克隆抗体(Lonberg, N. 等 (1994), 同上; 综述于Lonberg, N. Handbook ofExperimental Pharmacology 113, 49-101 (1994) , Lonberg, N. 和Huszar, D.,Intern. Rev. Immunol. 第13卷 65-93 (1995) 和 Harding, F. 和 Lonberg, N. Ann.N.Y. Acad. Sci 764 536-546 (1995))。HuMAb小鼠的制备详细描述于Taylor, L. 等,Nucleic Acids Research 20, 6287-6295 (1992), Chen, J. 等, InternationalImmunology 5, 647-656 (1993), Tuaillon 等, J. Immunol. 152, 2912-2920 (1994),Taylor, L. 等, International Immunology 6, 579-591 (1994), Fishwild, D. 等,Nature Biotechnology 14, 845-851 (1996)。亦参见US 5,545,806、US 5,569,825、US 5,625,126、US 5,633,425、US 5,789,650、US 5,877,397、US 5,661,016、US 5,814,318、US5,874,299、US 5,770,429、US 5,545,807、WO 98/24884、WO 94/25585、WO 93/1227、WO 92/22645、WO 92/03918和WO 01/09187。
HCo7小鼠在其内源性轻链(κ)基因中具有JKD破坏(如描述于Chen 等, EMBO J.12, 821-830 (1993)),在其内源性重链基因中具有CMD破坏 (如描述于WO 01/14424的实施例1),具有KCo5人κ轻链转基因(如描述于Fishwild 等, Nature Biotechnology 14,845-851 (1996))和HCo7人重链转基因(如描述于US 5,770,429)。
HCo12小鼠在其内源性轻链(κ)基因中具有JKD破坏(如描述于Chen 等, EMBO J.12, 821-830 (1993)),在其内源性重链基因中具有CMD破坏 (如描述于WO 01/14424的实施例1),具有KCo5人κ轻链转基因(如描述于Fishwild 等, Nature Biotechnology 14,845-851 (1996))和HCo12人重链转基因(如描述于WO 01/14424的实施例2)。
通过共注射pHC2的80 kb插入物(Taylor 等 (1994) Int. Immunol., 6: 579-591)、pVX6的25 Kb插入物和yIgH24染色体的-460 kb酵母人工染色体片段,产生HCo17转基因小鼠系(亦参见US 2010/0077497)。该系被指定为(HCo17) 25950。然后将(HCo17) 25950系与包含CMD突变(描述于PCT公布WO 01109187的实施例1)、JKD突变(Chen 等 (1993)EMBO J 12: 811-820)和(KC05) 9272转基因(Fishwild 等 (1996) NatureBiotechnology 14: 845-851)的小鼠繁殖。所产生的小鼠在破坏内源性小鼠重链和κ轻链基因座的背景纯合子中表达人免疫球蛋白重链和κ轻链转基因。
HCo20转基因小鼠系是共注射小基因座 30重链转基因pHC2、包含种系可变区(Vh)的YAC yIgH10和小基因座构建体pVx6 (描述于 WO09097006)的结果。然后将(HCo20)系与包含CMD突变(描述于PCT公布WO 01/09187的实施例1)、JKD突变(Chen 等 (1993) EMBO J12: 811-820)和(KC05) 9272转基因(Fishwild 等 (1996) Nature Biotechnology 14:845-851)的小鼠繁殖。所产生的小鼠在破坏内源性小鼠重链和κ轻链基因座的背景纯合子中表达人10免疫球蛋白重链和κ轻链转基因。
为了产生具有Balb/c系有益作用的HuMab小鼠,将HuMab小鼠与KC05 [MlK](Balb)小鼠杂交以产生如WO09097006中所述的小鼠,KC05 [MlK] (Balb)小鼠是通过将KC05系(如描述于Fishwild 等 (1996) Nature Biotechnology 14:845-851)与野生型Balb/c小鼠回交产生的。使用该杂交,产生了HCo12、HCo17和 HCo20系的Balb/c杂合体。
在KM小鼠系中,如Chen 等, EMBO J. 12, 811-820 (1993)所述,内源性小鼠κ轻链基因已被纯合破坏,并如WO 01/09187的实施例1所述,内源性小鼠重链基因已被纯合破坏。如Fishwild 等, Nature Biotechnology 14, 845-851 (1996)所述,该小鼠系携带人κ轻链转基因(KCo5)。如WO 02/43478所述,该小鼠系亦携带由染色体14片段hCF (SC20)组成的人重链转染色体。
根据公知的技术,来自这些转基因小鼠的脾细胞可用于产生分泌人单克隆抗体的杂交瘤。通过产生目标免疫球蛋白重链和轻链序列为转基因的另一非人哺乳动物或植物并由此生产可回收形式的抗体,亦可转基因地产生本发明的人单克隆或多克隆抗体或者来源于其他物种的本发明的抗体。关于哺乳动物中的转基因生产,抗体可在山羊、牛或其他哺乳动物的奶中生产和回收。参见例如US 5,827,690、US 5,756,687、US 5,750,172和US 5,741,957。
另外,使用本领域公知的技术,通过展示-类型技术(包括但不限于噬菌体展示、逆转录病毒展示、核糖体展示和其他技术),可产生本发明的人抗体或者来源于其他物种的本发明的抗体,并可使所产生的分子经受另外的成熟例如亲和力成熟,因为这样的技术是本领域公知的(参见例如Hoogenboom 等, J. Mol. Biol. 227, 381 (1991) (噬菌体展示),Vaughan 等, Nature Biotech 14, 309 (1996) (噬菌体展示), Hanes 和 Plucthau,PNAS USA 94, 4937-4942 (1997) (核糖体展示), Parmley 和 Smith, Gene 73, 305-318 (1988) (噬菌体展示), Scott TIBS 17, 241-245 (1992), Cwirla 等, PNAS USA87, 6378-6382 (1990), Russel 等, Nucl. Acids Research 21, 1081-1085 (1993),Hogenboom 等, Immunol. Reviews 130, 43-68 (1992), Chiswell 和 McCaffertyTIBTECH 10, 80-84 (1992), 和 US 5,733,743)。如果展示技术被用于产生非人抗体,那么这样的抗体可被人源化。
本发明的抗体可为任何同种型。同种型的选择通常将受所需的效应子功能例如(ADCC诱导)指导。例示性的同种型是IgG1、IgG2、IgG3和IgG4。可使用人轻链恒定区κ或λ。若需要,可通过已知的方法转换本发明的抗-TF抗体的种类。例如,最初为IgM的本发明的抗体可类别转换为本发明的IgG抗体。另外,类别转换技术可用于将一种IgG亚类转换为另一种,例如从IgG1至IgG2。因此,通过同种型转换为例如IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM抗体,可改变本发明抗体的效应子功能以用于多种治疗用途。在一个实施方案中,本发明的抗体是IgG1抗体,例如IgG1,κ。
在一个实施方案中,本发明的抗体为全长抗体,优选IgG1抗体,尤其IgG1,κ抗体。术语全长抗体旨在理解为,指通常已知为天然、完整的抗体,即不是其中抗体的不同链已被人重排以产生新类型的抗体的抗体的片段或其他类型(参见例如Sidhu SS, NatureBiotechnology, 25, 5, 537-538, (2007),公开了展示的全长抗体)。在另一实施方案中,本发明的抗体是抗体片段或单链抗体。
使用常规技术,例如通过断裂可获得抗体片段,并以与本文关于完整抗体所述的相同方法筛查该片段的效用。例如,通过用胃蛋白酶处理抗体可产生F(ab')2片段。可处理所产生的F(ab')2片段以还原二硫键来产生Fab'片段。通过用木瓜蛋白酶处理IgG抗体可获得Fab片段;Fab'片段可用胃蛋白酶消化IgG抗体获得。F(ab')片段亦可经由硫醚键或二硫键通过结合下文所述的Fab'产生。Fab'片段是通过切割F(ab')2的铰链区的二硫键所获得的抗体片段。Fab'片段可通过用还原剂例如二硫苏糖醇处理F(ab')2片段获得。抗体片段亦可通过在重组细胞中表达编码这样的片段的核酸产生(参见例如 Evans 等, J. Immunol.Meth. 184, 123-38 (1995))。例如,编码F(ab')2片段部分的嵌合基因可包括编码H链CH1结构域和铰链区的DNA序列,之后是翻译终止密码子以产生这样的截短抗体片段分子。
本发明的抗体在WO 2010/066803 (Genmab A/S)中进一步公开和表征。
在一个实施方案中,抗-TF抗体是稳定化IgG4抗体。合适的稳定化IgG4抗体的实例是以下的抗体:其中如Kabat 等的EU索引中所示的人IgG4的重链恒定区的位置409上的精氨酸用赖氨酸、苏氨酸、甲硫氨酸或亮氨酸(优选赖氨酸)取代(描述于WO2006033386(Kirin)),和/或其中铰链区包含Cys-Pro-Pro-Cys序列。
在另外的实施方案中,稳定化IgG4抗-TF抗体是包含重链和轻链的IgG4抗体,其中所述重链包含具有在对应于409的位置上选自Lys、Ala、Thr、Met和Leu的残基和/或在对应于405的位置上选自Ala、Val、Gly、Ile和Leu的残基的人IgG4恒定区,和其中所述抗体任选包含一个或多个另外的取代、缺失和/或插入,但在铰链区不包含Cys-Pro-Pro-Cys序列。优选地,所述抗体包含对应于409的位置上的Lys或Ala残基或者抗体的CH3区已被人IgG1、人IgG2或人IgG3的CH3区替换。
在更另外的实施方案中,稳定化IgG4抗-TF抗体是包含重链和轻链的IgG4抗体,其中所述重链包含具有在对应于409的位置上选自Lys、Ala、Thr、Met和Leu的残基和/或在对应于405的位置上选自Ala、Val、Gly、Ile和Leu的残基的人IgG4恒定区,和其中所述抗体任选包含一个或多个另外的取代、缺失和/或插入,且其中所述抗体在铰链区包含Cys-Pro-Pro-Cys序列。优选地,所述抗体包含对应于409的位置上的Lys或Ala残基或者抗体的CH3区已被人IgG1、人IgG2或人IgG3的CH3区替换。
在另外的实施方案中,抗-TF抗体是非IgG4类型的抗体,例如IgG1、IgG2或IgG3,其已被突变使得介导效应子功能例如ADCC的能力已被降低或甚至消除。这样的突变例如已描述于Dall'Acqua WF 等, J Immunol. 177(2):1129-1138 (2006)和Hezareh M, J Virol.;75(24):12161-12168 (2001)。
缀合物
本发明提供抗-TF抗体药物缀合物。
在一个方面,本发明的抗-TF抗体药物缀合物包含与auristatin或auristatin肽类似物和衍生物(US5635483; US5780588)缀合的如本文公开的抗-TF抗体。Auristatin已显示干扰微管动力学、GTP水解以及核和细胞分裂(Woyke 等 (2001) Antimicrob. Agentsand Chemother. 45(12): 3580-3584)并具有抗癌(US5663149)和抗真菌活性(Pettit 等,(1998) Antimicrob. Agents and Chemother. 42:2961-2965。Auristatin药物部分可通过肽药物部分的N(氨基)端或C(端)经由接头与抗体连接。
例示性的auristatin实施方案包括N端连接的单甲基auristatin药物部分DE和DF,其公开于Senter 等, Proceedings of the American Association for CancerResearch. 第45卷, 摘要号623, 2004年3月28日提供,并描述于US 2005/0238649)。
一种例示性的auristatin实施方案是MMAE (单甲基auristatin E),其中波浪线表示与抗体药物缀合物的接头(L)共价连接:
另一种例示性的auristatin实施方案是MMAF (单甲基auristatin F),其中波浪线表示与抗体药物缀合物的接头(L)共价连接(US2005/0238649):
本发明的抗-TF抗体药物缀合物包含抑制细胞或细胞毒性的药物单元与抗体单元之间的接头单元。在一些实施方案中,接头在细胞内条件下是可切割的,使得接头的切割在细胞内环境中从抗体上释放药物单元。在又一实施方案中,接头单元是不可切割的,药物例如通过抗体降解而释放。在一些实施方案中,接头是可被存在于细胞内环境(例如溶酶体或内体或胞膜窖内)中的切割物质所切割的。接头可为,例如被细胞内肽酶或蛋白酶所切割的肽基接头,酶包括但不限于溶酶体或内体蛋白酶。在一些实施方案中,肽基接头为至少2个氨基酸长或者至少3个氨基酸长。切割物质可包括组织蛋白酶B和D以及纤溶酶,已知它们全部都水解二肽药物衍生物,引起靶细胞内部活性药物的释放(参见例如Dubowchik 和Walker, 1999, Pharm. Therapeutics 83:67-123)。在具体实施方案中,可被细胞内蛋白酶切割的肽基接头是Val-Cit (缬氨酸-瓜氨酸)接头或Phe-Lys (苯丙氨酸-赖氨酸)接头(参见例如 US6214345, 其描述具有Val-Cit接头和不同实例的Phe-Lys接头的多柔比星的合成)。Val-Cit和Phe-Lys接头的结构的实例包括但不限于下文所述的MC-vc-PAB、MC-vc-GABA、MC-Phe-Lys-PAB或MC-Phe-Lys-GABA,其中MC是马来酰亚胺基己酰基的缩写,vc是Val-Cit的缩写,PAB是对氨基苄基氨基甲酸酯的缩写和GABA是γ-氨基丁酸的缩写。使用治疗物质的细胞内蛋白水解释放的优势在于,当缀合时物质通常是减毒的,和缀合物的血清稳定性通常是高的。
在又一实施方案中,接头单元不是可切割的且药物是通过抗体降解所释放的(参见US 2005/0238649)。通常,这样的接头对细胞外环境不实质上敏感。在接头的上下文中本文使用的“对细胞外环境不实质上敏感”意指,当抗体药物缀合物化合物存在于细胞外环境(例如血浆)中时,抗体药物缀合物化合物的样品中的不超过20%、通常不超过约15%、更通常不超过约10%、和甚至更通常不超过约5%、不超过约3%或不超过约1%的接头被切割。是否接头对细胞外环境不实质上敏感可例如通过以下方法测定:将抗体药物缀合物化合物与血浆孵育预定的时间段(例如2、4、8、16或24小时),然后定量血浆中存在的游离药物的量。
包含MMAE或MMAF以及多种接头组分的另外的例示性实施方案具有下述结构(其中Ab意指抗体,代表药物-负载(或者抑制细胞或细胞毒性的药物/抗体分子的平均数量)的p是1-约8,例如p可为4-6,例如3-5或者p可为1、2、3、4、5、6、7或8)。
其中可切割的接头与auristatin结合的实例包括MC-vc-PAB-MMAF (亦指定为vcMMAF)和MC-vc-PAB-MMAF (亦指定为vcMMAE),其中MC是马来酰亚胺基己酰基的缩写,vc是基于Val-Cit (缬氨酸-瓜氨酸)的接头的缩写和PAB是对氨基苄基氨基甲酸酯的缩写:
Ab-MC-vc-PAB-MMAF (vcMMAF)
Ab-MC-vc-PAB-MMAE (vcMMAE)
其他实例包括与不可切割的接头结合的auristatin,例如mcMMAF (mc (MC在本上下文中与mc相同)是马来酰亚胺基己酰基的缩写):
Ab-MC-MMAF (mcMMAF)
抑制细胞或细胞毒性的药物负载由p代表,并为分子中的抑制细胞的药物部分/抗体的平均数量(亦指定为药物/抗体比,DAR)。抑制细胞或细胞毒性的药物负载可为1-20个药物部分/抗体,并可存在于具有有用官能团的氨基酸上,官能团例如但不限于赖氨酸或半胱氨酸中的氨基或巯基。
取决于缀合的方式,p可被抗体上的连接位点的数量所限制,例如当连接是本发明中的巯基时。通常,抗体不包含可与药物部分连接的许多巯基(游离和反应性半胱氨酸硫醇基),因为抗体中的多数半胱氨酸硫醇残基以二硫桥存在。因此,在特定实施方案中,在部分或完全还原条件下,可用还原剂例如二硫苏糖醇(DTT)或三羰基乙基膦(TCEP)还原抗体以产生反应性巯基残基。在特定实施方案中,本发明的ADC的药物负载为1-约8,例如p可为4-6,例如3-5,或者p可为1、2、3、4、5、6、7或8,因为在(部分)还原抗体后,最多8个巯基残基变得可得(有8个半胱氨酸参与链间二硫键)。
在一个实施方案中,药物接头部分是vcMMAE。vcMMAE药物接头部分和缀合方法公开于WO2004010957、US7659241、US7829531、US7851437和US 11/833,028 (SeattleGenetics, Inc.), (其通过引用结合到本文中),使用与上述文献中所公开的方法类似的方法,vcMMAE药物接头部分在半胱氨酸上与抗-TF抗体结合。
在一个实施方案中,药物接头部分是mcMMAF。mcMMAF药物接头部分和缀合方法公开于US7498298、US 11/833,954和WO2005081711 (Seattle Genetics, Inc.), (其通过引用结合到本文中),使用与上述文献中所公开的方法类似的方法,mcMMAF药物接头部分在半胱氨酸上与抗-TF抗体结合。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-011-vcMMAE。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-098-vcMMAE。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-111-vcMMAE。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-114-vcMMAE。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-011-mcMMAF。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-098-mcMMAF。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-111-mcMMAF。
在一个实施方案中,抗-TF抗体药物缀合物是HuMab-TF-114-mcMMAF。
在备选的实施方案中,抗-TF抗体与治疗部分(例如细胞毒素、化学治疗药物、细胞因子、免疫抑制剂或放射性同位素)缀合。这样的缀合物本文称为“免疫缀合物”。包括一个或多个细胞毒素的免疫缀合物称为“免疫毒素”。
细胞毒素或细胞毒性物质包括对细胞有害(例如杀死细胞)的任何物质。用于形成本发明的免疫缀合物的合适治疗物质包括:紫杉醇,细胞松弛素B,短杆菌肽D,溴化乙锭,依米丁,丝裂霉素,依托泊苷,替尼泊苷,长春新碱,长春碱,秋水仙碱,多柔比星,柔红霉素,二羟基炭疽菌素二酮,美坦辛或者其类似物或衍生物,米托蒽醌,光神霉素,放线菌素D,1-去氢睾酮,糖皮质激素,普鲁卡因,丁卡因,利多卡因,普萘洛尔,和嘌呤霉素,加利车霉素或者其类似物或衍生物;抗代谢物(例如氨甲喋呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、氟达拉滨、5-氟尿嘧啶、氨烯咪胺、羟基脲、门冬酰胺酶、吉西他滨或克拉屈滨),烷化剂(例如氮芥、塞替派、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU) 、环磷酰胺、白消安、二溴甘露醇、链脲霉素、达卡巴嗪(DTIC)、丙卡巴肼、丝裂霉素C、顺铂和其他铂衍生物(例如卡铂);以及多卡米星A,多卡米星SA,CC-1065 (亦称雷查霉素),或者CC-1065的类似物或衍生物,多拉司他汀,吡咯并[2,1-c][1,4]苯二氮䓬类(PDB)或其类似物,抗生素(例如更生霉素(以前放线菌素)、博来霉素、柔红霉素(以前道诺霉素)、多柔比星、伊达比星、光神霉素、丝裂霉素、米托蒽醌、普卡霉素、安曲霉素(AMC)),抗有丝分裂剂(例如微管蛋白抑制剂),例如白喉毒素和相关的分子(例如白喉A链及其活性片段和杂合分子);蓖麻毒蛋白毒素(例如蓖麻毒蛋白A或去糖基化蓖麻毒蛋白A链毒素),霍乱毒素,志贺样毒素(SLT-I、SLT-II、SLT-IIV),LT毒素,C3毒素,志贺毒素,百日咳毒素,破伤风毒素,大豆Bowman-Birk蛋白酶抑制剂,假单胞菌外毒素,alorin,皂草素,塑莲根毒素,gelanin,相思豆毒蛋白A链,塑莲根毒素A链,α-sarcin,油桐蛋白、石竹素蛋白、美洲商陆蛋白(PAPI、PAPII和PAP-S),苦瓜抑制剂、麻疯树毒蛋白,巴豆毒蛋白,肥皂草抑制剂,白树毒素,mitogellin,局限曲菌素,酚霉素和依诺霉素毒素。其他合适的缀合分子包括抗微生物/溶菌肽,例如CLIP、爪蟾抗菌肽2、二甲双胍、杀菌肽和P18;核糖核酸酶(RNase),DNase I,葡萄球菌肠毒素A,美洲商陆抗病毒蛋白,白喉毒素和假单胞杆菌内毒素。参见例如Pastan 等, Cell 47, 641 (1986) 和Goldenberg, Calif. A Cancer Journal for Clinicians 44, 43 (1994)。可与本文别处所述的本发明的抗-TF抗体药物缀合物联合给予的治疗物质例如抗癌细胞因子或趋化因子,亦是用于与本发明公开的抗体缀合的治疗部分的候选物。
在另一备选实施方案中,本发明公开的抗-TF抗体药物缀合物包含缀合的核酸或核酸相关的分子。在一个这样的实施方案中,缀合的核酸是细胞毒性的核糖核酸酶、反义核酸、抑制性RNA分子(例如siRNA分子)或免疫刺激性核酸(例如包含免疫刺激性CpG基序的DNA分子)。在另一备选实施方案中,本发明的抗-TF抗体与适配体或核酶而不是auristatin或者其功能肽类似物或衍生物缀合。
在另一备选实施方案中,提供包含一个或多个放射性标记的氨基酸的抗-TF抗体药物缀合物。放射性标记的抗-TF抗体可用于诊断和治疗目的(与放射性标记的分子缀合是另一可能的特征)。用于多肽的标记的非限制性实例包括3H、14C、15N、35S、90Y、99Tc、125I、131I和 186Re。用于制备放射性标记的氨基酸和相关的肽衍生物的方法是本领域已知的(参见例如Junghans 等, 载于Cancer Chemotherapy and Biotherapy 655-686 (第2版,Chafner 和 Longo, 主编, Lippincott Raven (1996)) 以及 US 4,681,581、US 4,735,210、US 5,101,827、US 5,102,990 (US RE35,500)、US 5,648,471和US 5,697,902。例如可通过氯胺T法缀合放射性同位素。
在一个实施方案中,抗体与放射性同位素或者包含放射性同位素的螯合物缀合。例如,抗体可与螯合剂接头例如DOTA、DTPA或tiuxetan缀合,该接头使得抗体能够与放射性同位素复合。抗体亦可或备选包含一种或多种放射性标记的氨基酸或其他放射性标记的分子或与之缀合。放射性标记的抗-TF抗体可用于诊断和治疗目的。放射性同位素的非限制性实例包括3H、14C、15N、35S、90Y、99Tc、125I、111In、131I、186Re、213Bs、225Ac和227Th。
抗-TF抗体亦可通过与聚合物共价缀合来化学修饰以例如增加其循环半寿期。例示性的聚合物以及将它们与肽连接的方法,阐明于例如US 4,766,106、US 4,179,337、US4,495,285和US 4,609,546。另外的聚合物包括聚氧乙基化多元醇和聚乙二醇(PEG) (例如具有约1,000-约40,000 (例如约2,000-约2,0000)分子量的PEG)。如果抗-TF抗体是片段,那么可例如使用该聚合物。
可使用用于将本发明公开的抗-TF抗体与缀合分子(例如上文所述的那些)进行缀合的本领域已知的任何方法,包括以下所述的方法:Hunter 等, Nature 144, 945(1962), David 等, Biochemistry 13, 1014 (1974), Pain 等, J. Immunol. Meth.40, 219 (1981) 和 Nygren, J. Histochem. 和 Cytochem. 30, 407 (1982)。这样的抗体可通过将其他部分与抗-TF抗体或其片段(例如抗-TF抗体H或L链)的N端侧或C端侧进行化学缀合来产生(参见例如 Antibody Engineering Handbook, Osamu Kanemitsu主编,Chijin Shokan (1994)出版)。当合适时,这样的缀合抗体衍生物亦可通过在内部残基或糖上进行缀合产生。
物质可与本发明公开的抗-TF抗体直接或间接偶联。第二物质的间接偶联的一个实例是经由间隔物部分与抗体中的半胱氨酸或赖氨酸残基偶联。在一个实施方案中,抗-TF抗体经由间隔物或接头与体内可活化为治疗药物的前药分子缀合。给药后,间隔物或接头被肿瘤细胞相关的酶或其他肿瘤特异性条件所切割,藉此形成活性药物。这样的前药技术和接头的实例描述于Syntarga BV, 等的WO02083180、WO2004043493、WO2007018431、WO2007089149、WO2009017394和WO201062171 (所有都通过引用结合到本文中)。合适的抗体前药技术和多卡米星类似物亦可发现于美国专利第6,989,452号(Medarex) (通过引用结合到本文中)。
在一个实施方案中,本发明的抗-TF抗体与螯合剂接头例如tiuxetan缀合,该接头使得抗体能够与放射性同位素缀合。
在另外的方面,本发明涉及编码本发明抗体的表达载体。例如若本发明的抗-TF抗体与不同于auristatin或者其功能肽类似物或衍生物的治疗部分缀合。在一个实施方案中,这样的表达载体可用于表达本发明的抗-TF抗体,其可然后与本文所述的部分缀合。
在一个实施方案中,本发明的表达载体包含编码一个或多个选自以下的氨基酸序列的核苷酸序列:SEQ ID NO: 1-4、5-8、33-36、37-40、41-44、45-48、73-76和77-80。
在另一特定实施方案中,本发明的表达载体包含编码一个或多个选自以下的VH氨基酸序列的核苷酸序列:SEQ ID NO: 1、5、37和33。
在一个特定实施方案中,本发明的表达载体包含编码一个或多个选自以下的VHCDR3氨基酸序列的核苷酸序列:SEQ ID NO: 4、8、40和36。
在另一特定实施方案中,本发明的表达载体包含编码一个或多个选自以下的VL氨基酸序列的核苷酸序列:SEQ ID NO: 41、45、77和73。
在另一实施方案中,本发明的表达载体包含编码一个或多个选自以下的VL CDR3氨基酸序列的核苷酸序列:SEQ ID NO: 44、48、80和76。
在一个特定实施方案中,本发明的表达载体包含编码一个或多个上文氨基酸序列的变体的核苷酸序列,所述变体具有至多25个氨基酸修饰,例如20,例如至多15、14、13、12或11个氨基酸修饰,例如10、9、8、7、6、5、4、3、2或1个氨基酸修饰,例如缺失或插入,优选取代,例如保守取代,或者与所述序列中任一个有至少80%同一性,例如与上述氨基酸序列中任一个有至少85%同一性或90%同一性或95%同一性,例如96%同一性或97%同一性或98%同一性或99%同一性。
在另外的实施方案中,表达载体另外包含编码抗体(例如人抗体)的轻链、重链或者轻链和重链两者的恒定区的核苷酸序列。
这样的表达载体可用于重组产生本发明的抗体。
本发明上下文中的表达载体可为任何合适的载体,包括染色体、非染色体和合成核酸载体(包含一组合适的表达控制元件的核酸序列)。这样的载体的实例包括SV40的衍生物、细菌质粒、噬菌体DNA、杆状病毒、酵母质粒、来源于质粒和噬菌体DNA的组合的载体和病毒核酸(RNA或DNA)载体。在一个实施方案中,编码抗-TF抗体的核酸包含于裸DNA或RNA载体中,该载体包括例如,线性表达元件(如描述于例如Sykes 和 Johnston, Nat Biotech 17,355-59 (1997))、紧凑的核酸载体(如描述于例如US 6,077, 835和/或WO 00/70087)、质粒载体例如pBR322、pUC 19/18或pUC 118/119、“midge”最小尺寸的核酸载体(如描述于例如Schakowski 等, Mol Ther 3, 793-800 (2001))或作为沉淀的核酸载体构建体,例如CaP04沉淀的构建体(如描述于例如WO 00/46147, Benvenisty 和 Reshef, PNAS USA 83,9551-55 (1986), Wigler 等, Cell 14, 725 (1978), 以及 Coraro 和Pearson,Somatic Cell Genetics 7, 603 (1981))。这样的核酸载体及其用法在本领域是公知的(参见例如US 5,589,466 和US 5,973,972)。
在一个实施方案中, 载体适合在细菌细胞中表达抗-TF抗体。这样的载体的实例包括表达载体例如BlueScript (Stratagene)、pIN载体 (Van Heeke 和 Schuster, JBiol Chem 264, 5503-5509 (1989)、pET载体 (Novagen, Madison WI) 等)。
表达载体亦可或备选为适合在酵母系统中表达的载体。可使用适合在酵母系统中表达的任何载体。合适的载体包括例如,包含组成型或诱导型启动子例如α因子、醇氧化酶和PGH的载体(综述于:F. Ausubel 等, 主编 Current Protocols in MolecularBiology, Greene Publishing and Wiley InterScience New York (1987), 和 Grant等, Methods in Enzymol 153, 516-544 (1987))。
核酸和/或载体亦可包含编码分泌/定位序列的核酸序列,其可靶向多肽例如初生多肽链至周质间隙或细胞培养基中。这样的序列是本领域已知的,并包括分泌前导肽或信号肽、细胞器靶向序列(例如核定位序列、ER滞留信号、线粒体运输序列、叶绿体运输序列)、膜定位/锚序列(例如终止转移序列、GPI锚序列)等。
在本发明的表达载体中,编码抗-TF抗体的核酸可包含任何合适的启动子、增强子和其他表达促进元件或者与之相关。这样的元件的实例包括强表达启动子(例如, 人CMVIE启动子/增强子以及RSV、SV40、SL3-3、MMTV和HIV LTR启动子)、有效的多聚腺苷酸(poly(A))终止序列、大肠杆菌(E. coli)中质粒产物的复制起点、作为选择性标志物的抗生素抗性基因和/或合宜的克隆位点(例如聚合接头)。核酸亦可包含与组成型启动子例如CMV IE相对的诱导型启动子(技术人员将认识到,这样的术语实际上是在特定条件下基因表达的程度描述)。
在一个实施方案中,编码抗-TF抗体的表达载体可位于宿主细胞或宿主动物中和/或经由病毒载体递送至宿主细胞或宿主动物中。
在更另外的方面,本发明涉及重组真核或原核宿主细胞,例如转染瘤,其产生本文所定义的本发明的抗-TF抗体或者本文所定义的本发明的双特异性分子。宿主细胞的实例包括酵母、细菌和哺乳动物细胞,例如CHO或HEK细胞。例如,在一个实施方案中,本发明提供包含稳定整合到细胞基因组中的核酸的细胞,该核酸包含编码表达本发明的抗-TF抗体的序列。在另一实施方案中,本发明提供包含非整合的核酸(例如质粒、粘粒、噬菌粒或线性表达元件)的细胞,非整合的核酸包含编码表达本发明的抗-TF抗体的序列。
在另外的方面,本发明涉及产生本文所定义的本发明抗体的杂交瘤。在更另外的方面,本发明涉及包含编码人重链和人轻链的核酸的转基因非人动物,其中动物或植物产生本发明的抗体。上文已描述这样的杂交瘤和转基因动物的产生。
在另外的方面,本发明涉及一种用于产生本发明的抗-TF抗体的方法,所述方法包括以下步骤:
a) 培养如本文上文所述的本发明的杂交瘤或宿主细胞,和
b) 从培养基中纯化本发明的抗体,并任选
c) 将抗-TF抗体转变为ADC。
药物组合物
在纯化抗-TF抗体药物缀合物时,使用公知的药物载体或赋形剂,它们可被配制成药物组合物。
根据常规技术,可用药学上可接受的载体或稀释剂以及任何其他已知的佐剂和赋形剂配制药物组合物,常规技术例如公开于Remington: The Science and Practice ofPharmacy, 第19版, Gennaro, 主编, Mack Publishing Co., Easton, PA, 1995中的那些。
药学上可接受的载体或稀释剂以及任何其他已知的佐剂和赋形剂应该适合本发明的抗体药物缀合物以及所选择的给药方式。药物组合物的载体和其他组分的适用性是基于抗原结合时对本发明所选择的化合物或药物组合物的所需生物学性质的显著负面影响的缺失所确定的(例如,少于实质的影响(10%以下相对抑制、5%以下相对抑制等))。
本发明的药物组合物亦可包含稀释剂、填充剂、盐、缓冲剂、洗涤剂(例如非离子洗涤剂,例如Tween-20或Tween-80)、稳定剂(例如糖或无蛋白的氨基酸)、防腐剂、组织固定剂、增溶剂和/或适合包含于药物组合物中的其他物质。
过表达TF的癌细胞可为本发明的抗-TF抗体药物缀合物的尤其好的靶标。因为每个细胞可结合更多的抗体。因此,在一个实施方案中,待用本发明的抗-TF抗体药物缀合物治疗的癌症患者是,例如在其肿瘤细胞的K-ras和/或p53中已诊断具有一个或多个突变的胰腺癌、肺癌或结直肠癌患者。TF表达是以依赖于MEK/促分裂原活化蛋白激酶(MAPK)和磷脂酰肌醇3'-激酶(PI3K)的方式,受驱使疾病进展的两个主要转化事件(K-ras致癌基因的激活和p53肿瘤抑制基因的灭活)的控制(Yu 等 (2005) Blood 105:1734)。
可变化本发明药物组合物中的抗体药物缀合物的实际剂量水平以便获得有效的抗体药物缀合物的量以对特定患者、组合物和给药方式实现所需的治疗反应,而对患者无毒性。所选择的剂量水平将取决于多种药代动力学因素,包括所使用的本发明特定组合物或其酰胺的活性、给药途径、给药时间、所使用的特定化合物的排出速率、治疗的持续时间、与所使用的特定组合物联合使用的其他药物、化合物和/或物质、治疗的患者的年龄、性别、体重、病况、一般健康和之前药物史等医药领域公知的因素。
可通过任何合适的途径和方式给予药物组合物。给予本发明抗体药物缀合物的合适途径是本领域公知的并可由本领域普通技术人员选择。
在一个实施方案中,本发明的药物组合物是胃肠外给予的。
本文使用的措辞“胃肠外给药”和“胃肠外给予”意指除肠内和局部给药外的给药方式,通常通过注射,并包括表皮、静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、腱内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、颅内、胸内、硬膜外和胸骨内注射和输注。
在一个实施方案中,药物组合物是通过静脉内或皮下注射或输注给予的。
药学上可接受的载体包括与本发明的抗体药物缀合物生理上相容的任何和所有合适的溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等张剂、抗氧化剂和吸收延迟剂等。
可在本发明的药物组合物中使用的合适水性和非水性载体的实例包括水、盐水、磷酸盐缓冲盐水、乙醇、葡萄糖、多元醇(例如甘油、丙二醇、聚乙二醇等)以及合适的混合物,植物油例如橄榄油、玉米油、花生油、棉籽油和芝麻油,羧甲基纤维素胶体溶液、黄蓍胶和可注射有机酯例如油酸乙酯,和/或多种缓冲剂。其他载体是药学领域公知的。
药学上可接受的载体包括无菌水性溶液或分散体以及用于临时制备无菌注射溶液或分散体的无菌粉末。用于药学上活性物质的这种介质和物质的使用是本领域已知的。除非任何常规介质或物质与本发明的抗-TF抗体药物缀合物不相容,否则预期其在本发明药物组合物中的使用。
可维持合适的流动性,例如通过使用包衣材料例如卵磷脂,在分散体的情况下通过维持所需的粒径,和通过使用表面活性剂。
本发明的药物组合物亦可包含药学上可接受的抗氧化剂,例如(1) 水溶性抗氧化剂,例如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等;(2) 油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-维生素E等;和(3) 金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的药物组合物亦可在组合物中包含等张剂,例如糖、多元醇例如甘露醇、山梨醇、甘油或氯化钠。
本发明的药物组合物亦可包含一种或多种适合所选择的给药途径的佐剂,例如防腐剂、润湿剂、乳化剂、分散剂、防腐剂或缓冲剂,其可增强药物组合物的储存期或有效性。本发明的抗-TF抗体药物缀合物可用可保护化合物免受快速释放的载体制备,例如控释制剂,包括植入物、透皮贴剂和微囊递送系统。这样的载体可包括明胶,单硬脂酸甘油酯,二硬脂酸甘油酯,生物可降解、生物相容的聚合物例如乙烯醋酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸单独或者其与蜡,或本领域公知的其他物质。用于制备这样的制剂的方法通常是本领域技术人员已知的。参见例如,Sustained and Controlled Release DrugDelivery Systems, J.R. Robinson, 主编., Marcel Dekker, Inc., New York, 1978。
在一个实施方案中,可配制本发明的抗-TF抗体药物缀合物以保证合适的体内分布。用于胃肠外给药的药学上可接受的载体包括无菌水性溶液或分散体以及用于临时制备无菌注射溶液或分散体的无菌粉末。用于药学上活性物质的这种介质和物质的使用是本领域已知的。除非任何常规介质或物质与活性化合物不相容,否则预期其在本发明药物组合物中的使用。亦可将互补性活性化合物掺入到组合物中。
用于注射的药物组合物通常必须是无菌的并在制造和储存的条件下是稳定的。可将组合物配制为适合高药物浓度的溶液剂、微乳剂、脂质体或其他有序结构。载体可为水性或非水性溶剂或者分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)及其合适的混合物、植物油例如橄榄油和可注射有机酯例如油酸乙酯。可维持合适的流动性,例如通过使用包衣例如卵磷脂,在分散剂的情况下通过维持所需的粒径,和通过使用表面活性剂。在许多情况下,可优选地在组合物中包括等张剂,例如糖、多元醇例如甘油、甘露醇、山梨醇或氯化钠。通过在组合物中包括延迟吸收的物质例如单硬脂酸酯盐和明胶,可引起注射组合物的延长吸收。通过在合适溶剂中以所需量掺入抗-TF抗体药物缀合物与一种成分(例如如上文列举的)或多种成分的组合,根据需要,之后微孔过滤灭菌,可制备无菌注射溶液。通常,通过将抗-TF抗体药物缀合物掺入到包含基本分散介质和所需其他成分(例如来自上文举例的那些)的无菌溶媒中,制备分散体。在用于制备无菌注射溶液的无菌粉末的情况下,制剂方法的实例是,从其之前无菌过滤的溶液得到活性成分与任何另外所需成分的粉末的真空干燥和冷冻干燥(冻干法)。
通过在合适溶剂中以所需量掺入抗-TF抗体药物缀合物与一种上文列举的成分或多种成分的组合,根据需要,之后微孔过滤灭菌,可制备无菌注射溶液。通常,通过将抗-TF抗体药物缀合物掺入到包含基本分散介质和来自上文举例的所需其他成分的无菌溶媒中,制备分散体。在用于制备无菌注射溶液的无菌粉末的情况下,制剂方法的实例是,从其之前无菌过滤的溶液得到抗-TF抗体药物缀合物与任何另外所需成分的粉末的真空干燥和冷冻干燥(冻干法)。
本发明的药物组合物可包含一种本发明的抗-TF抗体药物缀合物,或者多种本发明的抗-TF抗体药物缀合物的组合。
如上文所述,在另一方面,本发明涉及本文所定义的本发明的抗-TF抗体药物缀合物,其用作药物。
本发明的抗-TF抗体药物缀合物可用于多种目的。尤其,本发明的抗-TF抗体药物缀合物可用于治疗多种形式的癌症。在一个方面,本发明的抗-TF抗体药物缀合物用于治疗多种实体瘤类型例如:中枢神经系统的肿瘤、头颈癌、肺癌(例如非小细胞肺癌)、乳腺癌(例如三阴乳腺癌)、食道癌、胃癌、肝胆癌、胰腺癌、结直肠癌、膀胱癌、肾癌、前列腺癌、子宫内膜癌、卵巢癌、恶性黑色素瘤、肉瘤(软组织例如骨和肌肉)、未知原发来源(即未知原发)的肿瘤、白血病、骨髓癌(例如多发性骨髓瘤)、急性成淋巴细胞白血病、慢性成淋巴细胞白血病和非霍奇金淋巴瘤、急性髓性白血病(AML)、皮肤癌、神经胶质瘤、脑癌、子宫癌和直肠癌。
另外,可用本发明的抗-TF抗体药物缀合物靶向自身免疫炎症(例如肌病或多发性硬化)。
亦可用本发明靶向癌症相关的止血病症。
可用本发明的抗-TF抗体靶向另外的炎症疾病,例如肌病、类风湿性关节炎、骨关节炎、强直性脊柱炎、痛风、脊柱关节病(spondylarthropathris)、强直性脊柱炎、莱特尔氏综合征、牛皮癣性关节病、enterapathric脊柱炎、青少年关节病、反应性关节病、感染性或感染后关节炎(post-infectious arthritis)、结核性关节炎、病毒关节炎、真菌关节炎、梅毒关节炎、肾小球肾炎、末期肾病、系统性红斑狼疮、mb.克罗恩病、溃疡性结肠炎、炎性肠病、囊性纤维化、慢性阻塞性肺疾病(COPD)、哮喘、过敏性哮喘、支气管炎、急性支气管炎、慢性支气管炎、特发性肺纤维化或多发性硬化。
亦可用抗-TF抗体药物缀合物治疗血管疾病例如血管再狭窄、心肌血管疾病、大脑血管疾病、视网膜病和包括但不限于湿性AMD的黄斑变性。
本发明的抗-TF抗体药物缀合物亦可用于治疗具有心血管风险的患者,心血管风险例如动脉粥样硬化、高血压、糖尿病、血脂障碍和急性冠状动脉综合征,包括但不限于急性心肌梗死、中风。
本发明的抗-TF抗体药物缀合物亦可用于抑制血栓形成例如DVT、肾栓塞、肺栓塞、动脉血栓形成,或用于治疗发生于以下之后的血栓形成:动脉外科手术、外周血管旁路移植术或冠状动脉旁路移植术、动静脉分流、器具例如支架或导管的移除。
本发明的抗-TF抗体药物缀合物亦可用于抑制肾缺血再灌注损伤。
本发明的抗-TF抗体药物缀合物亦可用于治疗高脂蛋白血症或甲状旁腺功能亢进症。
本发明的抗-TF抗体药物缀合物亦可用于治疗血管炎、ANCA阳性血管炎或贝切特氏病。
本发明的抗-TF抗体药物缀合物亦可用于阻断创伤诱导的呼吸衰竭,例如急性呼吸窘迫综合征或急性肺损伤。
本发明的抗-TF抗体药物缀合物亦可用于阻断感染诱导的器官功能障碍,例如肾衰竭、急性呼吸窘迫综合征或急性肺损伤。
本发明的抗-TF抗体药物缀合物亦可用于治疗多种血栓栓塞性病症,例如由血管成形术、心肌梗死、不稳定心绞痛和冠状动脉狭窄引起的那些。
本发明的抗-TF抗体药物缀合物亦可用于预防性环境以治疗TF介导的系统性感染的并发症,例如脓毒症或肺炎。
本发明的抗-TF抗体药物缀合物亦可用作有血栓形成风险的动脉粥样硬化血管的患者的预防性治疗。
本发明的抗-TF抗体药物缀合物亦可用于治疗移植物抗宿主病。
本发明的抗-TF抗体药物缀合物亦可用于在胰岛移植中增加β细胞植入以预防心脏移植物血管病变(CAV)和急性移植排斥。
类似地,本发明涉及一种用于抑制表达TF的肿瘤细胞的生长和/或增殖的方法,其包括向有需要的个体给予本发明的抗-TF抗体药物缀合物。在一个实施方案中,所述肿瘤细胞涉及癌症,例如前列腺癌、肺癌(例如非小细胞肺癌)、乳腺癌(例如三阴乳腺癌)、结直肠癌(例如转移性结直肠癌)、胰腺癌、子宫内膜癌、卵巢癌、皮肤黑色素瘤、白血病骨髓癌(例如多发性骨髓瘤)、急性成淋巴细胞白血病、慢性成淋巴细胞白血病和非霍奇金淋巴瘤、皮肤癌、前列腺癌、神经胶质瘤、脑癌、肾癌、子宫癌、膀胱癌、急性髓细胞样白血病(AML)和直肠癌。
本发明亦涉及与人TF结合的抗-TF抗体药物缀合物用于制备用于治疗癌症(例如上文提及的具体癌症适应症之一)的药物的用途。
在一个实施方案中,待用抗-TF抗体药物缀合物治疗的患者的选择是基于其尿液和/或血液的TF水平。在一个特定实施方案中,待治疗的患者具有相对高水平的尿液和/或血液TF。例如,待治疗的患者可具有超过20 ng/mL (例如超过40 ng/mL,例如超过100 mg/mL,例如超过200 ng/mL)的尿液TF水平。备选地或此外,患者的血清TF水平可超过100 pg/mL,例如超过200 pg/mL。这可例如使用ELISA测定。用于进行测定的方法包括但不限于下文与诊断用途相关所述的那些方法。
然后,亦在本发明的范围内的是,用本发明的抗-TF抗体药物缀合物治疗具有较低水平的尿液和/或血液TF的患者。
在一个实施方案中,待用本发明的抗-TF抗体药物缀合物治疗的患者的选择可基于TF表达的水平。通过将患者暴露于放射性标记的抗-TF抗体,然后测量患者的放射性水平,可评价TF表达的水平。放射性标记的抗-TF抗体可为本发明所述的抗-TF抗体,即本文所述的抗-TF抗体药物缀合物的抗体,或者它可为另一抗-TF抗体。放射性标记的实例可为上文与放射性标记抗体相关所述的任何放射性标记。用于进行评价的方法包括但不限于下文与诊断用途相关所述的那些方法。
在本发明治疗方法的另一实施方案中,在治疗期间例如在预先确定的时间点上监测治疗的功效。在一个实施方案中,通过测量尿液或血液的TF水平(例如通过ELISA),可监测功效。用于进行监测的方法包括但不限于下文与诊断用途相关所述的那些方法。在另一实施方案中,通过可视化疾病区,例如通过进行一次或多次PET-CT扫描(例如使用标记的抗-TF抗体,例如本发明所述的标记的抗-TF抗体),可测定功效。此外,标记的抗-TF抗体(例如本文公开的标记的抗-TF抗体011、098、114和111)可用于检测产生TF的肿瘤,例如使用PET-CT扫描。
调整上文治疗和使用方法的剂量方案以提供最优的所需治疗反应。例如,可给予单剂量,可随时间推移给予多个分次剂量,或者根据治疗情况的紧急性所示,可成比例减少或增加剂量。可以剂量单位形式配制胃肠外组合物以便于剂量的给药和均一性。本文使用的剂量单位形式指,适合作为待治疗受试者的单位剂量的物理离散单位,各单位包含预定量的活性化合物,其经计算与所需的药物载体联合产生所需的治疗效果。本发明剂量单位形式的规格由以下决定并直接依赖于:(a) 活性化合物的独特特性和待实现的特定治疗效果,和(b) 配制例如用于治疗个体敏感性的活性化合物领域的内在限制。
抗-TF抗体药物缀合物的有效剂量和剂量方案取决于待治疗的疾病或病况,并可由本领域的技术人员确定。本发明化合物的治疗有效量的例示性、非限制性范围是约0.1-100 mg/kg,例如约0.1-50 mg/kg,例如约0.1-20 mg/kg,例如约0.1-10 mg/kg,例如约0.5-5 mg/kg,例如约5 mg/kg,例如约4 mg/kg,或约3 mg/kg,或约2 mg/kg,或约1 mg/kg,或约0.5 mg/kg,或约0.3 mg/kg。本发明抗-TF抗体药物缀合物的治疗有效量的例示性、非限制性范围是约0.02-30 mg/kg,例如约0.1-20 mg/kg,或约0.5-10 mg/kg,或约0.5-5 mg/kg,例如约1-2 mg/kg,尤其是本文公开的抗体011、098、114或111。
具有本领域普通技术的医师可容易确定和开予所需药物组合物的有效量。例如,医师可以低于实现所需的治疗效果所需的水平开始药物组合物中所使用的抗-TF抗体药物缀合物的剂量,并逐渐增加剂量直至实现所需的效果。通常,本发明组合物的适合每日剂量可为,作为有效产生治疗效果的最低剂量的化合物量。这样的有效剂量可通常取决于上文所述的因素。可例如静脉内、肌内、腹膜内或皮下给药,例如邻近靶位点给予。若需要,药物组合物的有效每日剂量可以以贯穿整天的合适间隔单独给予的2、3、4、5、6或更多个亚剂量给予,亚剂量任选呈单位剂量形式。虽然可单独给予本发明的抗-TF抗体药物缀合物,但是优选以上文所述的药物组合物形式给予抗-TF抗体药物缀合物。
在一个实施方案中,可以10-1500 mg/m2 (例如30-1500 mg/m2,或例如50-1000mg/m2,或例如10-500 mg/m2,或例如100-300 mg/m2)的周剂量通过输注给予抗-TF抗体药物缀合物。可重复这样的给药,例如1-8次,例如3-5次。可通过在2-24小时(例如2-12小时)的期间内连续输注,进行给药。
在一个实施方案中,可以30-1500 mg/m2 (例如50-1000 mg/m2,或100-300 mg/m2)的剂量每3周通过输注给予抗-TF抗体药物缀合物。可重复这样的给药,例如1-8次,例如3-5次。可通过在2-24小时(例如2-12小时)的期间内连续输注,进行给药
在一个实施方案中,可通过在长期间内例如超过24小时缓慢连续输注,给予抗-TF抗体药物缀合物,以便降低毒副作用。
在一个实施方案中,可以50 mg-2000 mg (例如50 mg、100 mg、200 mg、300 mg、500 mg、700 mg、1000 mg、1500 mg或2000 mg)的周剂量给予抗-TF抗体药物缀合物多达16次,例如4-10次,例如4-6次。可通过在2-24小时(例如2-12小时)的期间内连续输注,进行给药。必要时,例如6个月或12个月后可重复这样的方案1次或多次。通过测量给药时血液中本发明抗-TF抗体药物缀合物的量,例如通过取出生物学样品并使用靶向本发明抗-TF抗体药物缀合物的抗原结合区的抗-独特型抗体,可确定或调整剂量。
在一个实施方案中,可通过维持治疗(例如每周一次进行6个月或更长的期间)给予抗-TF抗体药物缀合物。
在一个实施方案中,可通过包括以下的方案给予抗-TF抗体药物缀合物:一次输注本发明的抗-TF抗体药物缀合物,之后输注本发明的抗-TF抗体,例如包含放射性同位素的本文所公开的抗体011、098、114或111。例如7-9天后可重复该方案。
作为非限制性实例,可以约0.1-100 mg/kg的量的本发明抗-TF抗体药物缀合物的周、双周、三周或月剂量提供本发明的治疗,量例如在开始治疗后的第1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40天中的至少1天或者备选地第1、2、3、4、5、6、7、8、9、10周或在一些情况下第11、12、13、14、15、16、17、18、19或20周中的至少1周,每天0.3-3 mg/kg,例如0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、45、50、60、70、80、90或100 mg/kg,或其任何组合,使用每24、12、8、6、4或2小时的单剂量或分次剂量或其任何组合。
肿瘤治疗的“有效量”亦可通过其稳定疾病进展的能力来测量。化合物抑制癌症的能力可在预测人肿瘤中的功效的动物模型系统中评价。备选地,可通过在技术人员已知的体外测定中检查化合物抑制细胞生长或诱导凋亡的能力,评价组合物的该特性。治疗化合物的治疗有效量可减少肿瘤大小,或另外减轻受试者的症状。本领域普通技术人员基于例如受试者的大小、受试者症状的严重性和特定的组合物或所选择的给药途径等因素能够确定这样的量。
亦可预防性给予抗-TF抗体药物缀合物以便降低发生癌症的风险、延缓癌症进展中事件发生的开始,和/或当癌症在消退期时降低复发的风险。这可尤其用于其中由于其他生物因素难以定位已知存在的肿瘤的患者。
抗-TF抗体药物缀合物亦可以联合治疗给予,即与待治疗的疾病或病况相关的其他治疗剂联合。因此,在一个实施方案中,抗-TF抗体药物缀合物药物是用于与一种或多种另外的治疗剂(例如细胞毒剂、化学治疗剂或抗血管生成剂)联合。
这种组合的给药可为同时的、单独的或序贯的。对于同时给药,视情况而定,药物可作为一个组合物或作为单独的组合物给予。本发明因此亦提供用于治疗如上文所述的涉及表达TF的细胞的病症的方法,该方法包括将本发明的抗-TF抗体药物缀合物与如下文所述的一种或多种另外的治疗剂联合给予。
在一个实施方案中,本发明提供一种用于治疗受试者中的涉及表达TF的细胞的病症的方法,该方法包括将治疗有效量的本发明的抗-TF抗体药物缀合物与至少一种化学治疗剂给予有需要的受试者。
在一个实施方案中,本发明提供一种用于治疗或预防癌症的方法,该方法包括将治疗有效量的本发明的抗-TF抗体药物缀合物与至少一种化学治疗剂给予有需要的受试者。
在一个实施方案中,本发明提供本发明的抗-TF抗体药物缀合物用于制备待与至少一种用于治疗癌症的化学治疗剂给予的药物组合物的用途。
在一个实施方案中,这样的化学治疗剂可选自抗代谢物,例如氨甲喋呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、氟达拉滨、5-氟尿嘧啶、氨烯咪胺、羟基脲、门冬酰胺酶、吉西他滨、克拉屈滨和类似的药物。
在一个实施方案中,这样的化学治疗剂可选自烷化剂,例如氮芥、塞替派、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲霉素、达卡巴嗪(DTIC)、丙卡巴肼、丝裂霉素C、顺铂和其他铂衍生物例如卡铂,和类似的药物。
在一个实施方案中,这样的化学治疗剂可选自抗有丝分裂剂,例如紫杉烷类(例如多西他赛和紫杉醇)和长春花生物碱类(例如长春地辛、长春新碱、长春碱和长春瑞滨)。
在一个实施方案中,这样的化学治疗剂可选自拓扑异构酶抑制剂,例如托泊替康或伊立替康。
在一个实施方案中,这样的化学治疗剂可选自抑制细胞药,例如依托泊苷和替尼泊苷。
在一个实施方案中,这样的化学治疗剂可选自生长因子抑制剂,例如ErbB1(EGFR)抑制剂(例如易瑞沙、爱比妥(西妥昔单抗)、特罗凯(tarceva)和类似的药物)、ErbB2(Her2/neu)抑制剂(例如赫赛汀和类似的药物)和类似的药物。
在一个实施方案中,这样的化学治疗剂可选自酪氨酸激酶抑制剂,例如伊马替尼(格列卫, Gleevec STI571)、拉帕替尼、PTK787/ZK222584和类似的药物。
在一个实施方案中,本发明提供一种用于治疗受试者中的涉及表达TF的细胞的病症的方法,该方法包括将治疗有效量的本发明的抗-TF抗体药物缀合物与至少一种血管生成、新血管形成和/或其他血管化的抑制剂给予有需要的受试者。
这样的血管生成抑制剂的实例是尿激酶抑制剂,基质金属蛋白酶抑制剂(例如马立马司他、新伐司他、BAY 12-9566、AG 3340、BMS-275291和类似的药物),内皮细胞迁移和增殖抑制剂(例如TNP-470、角鲨胺、2-甲氧雌二醇、考布他汀、内皮他丁、血管他丁、青霉胺、SCH66336 (Schering-Plough Corp, Madison, NJ)、R115777 (Janssen Pharmaceutica,Inc, Titusville, NJ)和类似的药物),血管生成生长因子拮抗剂(例如ZD6474、SU6668、针对血管生成物质和/或其受体(例如VEGF、bFGF和血管生成素-1)的抗体、沙利度胺、沙利度胺类似物(例如CC-5013)、Sugen 5416、SU5402、抗血管生成核酶(例如angiozyme)、干扰素α(例如干扰素α2a)、苏拉明和类似的药物),VEGF-R激酶抑制剂和其他抗血管生成酪氨酸激酶抑制剂(例如SU011248),内皮特异性整联蛋白/生存信号转导抑制剂(例如vitaxin和类似的药物)、铜拮抗剂/螯合剂(例如四硫钼酸盐、卡托普利和类似的药物),羧胺基三唑(CAI),ABT-627,CM101,白介素12 (IL-12),IM862,PNU145156E以及抑制血管生成的核苷酸分子(例如反义-VEGF-cDNA、编码血管他丁的cDNA、编码p53的cDNA和编码缺陷型VEGF受体-2的cDNA)和类似的药物。
这样的血管生成、新血管形成和/或其他血管化的抑制剂的其他实例是抗血管生成肝素衍生物和相关的分子(例如肝素酶III),替莫唑胺,NK4,巨噬细胞迁移抑制因子(MIF),环氧化酶-2抑制剂,缺氧诱导型因子1抑制剂,抗血管生成大豆异黄酮,奥替普拉,烟曲霉素及其类似物,生长抑素类似物,戊聚糖多聚硫酸酯,替可加兰钠,达肝素钠,肿瘤抑素,血小板反应蛋白,NM-3,康普瑞汀,血管能抑素(canstatin),阿瓦斯丁,针对其他相关靶标的抗体(例如抗-α-v/β-3整联蛋白和抗-kininostatin mAb)和类似的药物。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为抗肿瘤免疫原,例如癌抗原/肿瘤相关抗原(例如上皮细胞黏附分子(EpCAM/TACSTD1)、粘蛋白1 (MUC1)、癌胚抗原(CEA)、肿瘤相关糖蛋白72 (TAG-72)、gp100、Melan-A、MART-1、KDR、RCAS1、MDA7、癌相关病毒疫苗(例如人乳头瘤病毒疫苗)、肿瘤来源的热休克蛋白和类似的药物。亦可或备选地在这样的实施方案中使用本文别处所述的多种其他合适的癌抗原/肿瘤相关抗原和本领域已知的类似分子。抗癌免疫原性肽亦包括抗-独特型“疫苗”,例如BEC2抗-独特型抗体、米妥昔单抗、CeaVac和相关的抗-独特型抗体、抗MG7抗体的抗-独特型抗体和其他抗癌抗-独特型抗体(参见例如Birebent 等, Vaccine.21(15), 1601-12 (2003), Li 等, Chin Med J (Engl). 114(9), 962-6 (2001),Schmitt 等, Hybridoma. 13(5), 389-96 (1994), Maloney 等, Hybridoma. 4(3),191-209 (1985), Raychardhuri 等, J Immunol. 137(5), 1743-9 (1986), Pohl 等,Int J Cancer. 50(6), 958-67 (1992), Bohlen 等, Cytokines Mol Ther. 2(4), 231-8 (1996)和Maruyama, J Immunol Methods. 264(1-2), 121-33 (2002))。这样的抗-独特型Ab可任选与载体缀合,载体可为合成的(通常惰性)分子载体、蛋白(例如匙孔䗩血蓝蛋白(KLH) (参见例如Ochi 等, Eur J Immunol. 17(11), 1645-8 (1987))或细胞(例如红血球–参见例如Wi 等, J Immunol Methods. 122(2), 227-34 (1989))。
在本发明的一个实施方案中,抗-TF抗体药物缀合物与免疫-肿瘤药物联合,例如Yervoy (伊匹木单抗),其通过诱导针对癌症的T细胞免疫来潜在起作用。用抗-TF抗体药物缀合物联合免疫刺激性药物来进行细胞减少可为患者提供显著的临床益处。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为抗癌细胞因子、趋化因子或其组合。合适的细胞因子和生长因子的实例包括IFNγ、IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNα (例如INFα2b)、IFNβ、GM-CSF、CD40L、Flt3配体、干细胞因子、安西司亭和TNFα。合适的趋化因子可包括来自人CXC和C-C趋化因子家族的Glu-Leu-Arg (ELR)-阴性趋化因子,例如IP-10、MCP-3、MIG和SDF-1α。合适的细胞因子包括细胞因子衍生物、细胞因子变体、细胞因子片段和细胞因子融合蛋白。通过例如描述于US5,968,502、US 6,063,630、US 6,187,305和EP 0505500的“基因激活”和同源重组基因上调技术,可备选或另外进行本文涉及编码天然存在肽的核酸的这些和其他方法或应用。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为细胞周期控制/凋亡调节物(或“调节剂”)。细胞周期控制/凋亡调节物可包括靶向和调节细胞周期控制/凋亡调节物的分子,例如(i) cdc-25 (例如NSC663284),(ii) 过度刺激细胞周期的细胞周期蛋白依赖性激酶(例如黄酮吡多(L868275,HMR1275)、7-羟基十字孢碱(UCN-01, KW-2401)和roscovitine (R-roscovitine,CYC202))和(iii) 端粒酶调节剂(例如BIBR1532、SOT-095、GRN163和描述于例如US 6,440,735和US 6,713,055中的组合物)。干扰凋亡途径的分子的非限制性实例包括TNF相关的诱导凋亡的配体(TRAIL)/凋亡-2配体(Apo-2L)、激活TRAIL受体的抗体、IFN和抗反义Bcl-2。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为激素调节剂,例如用于抗-雄激素和抗-雌激素治疗的药物。这样的激素调节剂的实例是他莫西芬、艾多昔芬、氟维司群、屈洛昔芬、托瑞米芬、雷洛昔芬、己烯雌酚、乙炔雌二醇/炔雌醇、抗雄激素物质(例如氟他胺/eulexin)、黄体酮(例如己酸羟孕酮、甲羟孕酮/普维拉、甲地孕酮/梅格施)、肾上腺皮质类固醇(例如氢化可的松、泼尼松)、黄体生成素释放激素(及其类似物和其他LHRH激动剂例如布舍瑞林和戈舍瑞林)、芳香酶抑制剂(例如阿那曲唑/瑞宁得、氨鲁米特/cytraden、依西美坦)、激素抑制剂(例如奥曲肽/善得定)和类似的药物。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为抗无变应性剂(例如破坏肿瘤和癌抗原耐受性的小分子化合物、蛋白、糖蛋白或抗体)。这样的化合物的实例是阻断CTLA-4活性的分子,例如MDX-010/Yervoy(伊匹木单抗) (Phan 等, PNAS USA 100, 8372 (2003)),其通过诱导针对癌症的T细胞免疫来潜在起作用。用抗-TF抗体药物缀合物联合免疫刺激性药物来进行细胞减少可为患者提供显著的临床益处。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为包含肿瘤抑制基因的核酸或载体,例如编码人重组野生型p53/SCH58500的复制缺陷型腺病毒等;靶向致癌基因、突变或失调基因的反义核酸;或靶向突变或失调基因的siRNA。肿瘤抑制剂靶标的实例包括,例如BRCA1、RB1、BRCA2、DPC4 (Smad4)、MSH2、MLH1和DCC。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为抗癌核酸,例如genasense (奥利美生/G3139)、LY900003 (ISIS3521)、ISIS 2503、OGX-011 (ISIS 112989)、LE-AON/LEraf-AON (脂质体包封的c-raf 反义寡核苷酸/ISIS-5132)、MG98和靶向PKCα、簇蛋白、IGFBP、蛋白激酶A、细胞周期蛋白D1或Bcl-2h的其他反义核酸。
在一个实施方案中,用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可为抗癌抑制性RNA分子(参见例如Lin 等, Curr Cancer DrugTargets. 1(3), 241-7 (2001), Erratum in: Curr Cancer Drug Targets. 3(3), 237(2003), Lima 等, Cancer Gene Ther. 11(5), 309-16 (2004), Grzmil 等, Int JOncol. 4(1), 97-105 (2004), Collis 等, Int J Radiat Oncol Biol Phys. 57(第2增刊), S144 (2003), Yang 等, Oncogene. 22(36), 5694-701 (2003) 和 Zhang 等,Biochem Biophys Res Commun. 303(4), 1169-78 (2003))。
本发明的组合物和联合给药方法亦包括给予核酸疫苗,例如编码这样的癌抗原/肿瘤相关抗原的裸DNA疫苗(参见例如US 5,589,466, US 5,593,972, US 5,703,057, US5,879,687, US 6,235,523, 和 US 6,387,888)。在一个实施方案中,联合给药方法和/或联合组合物包含自体疫苗组合物。在一个实施方案中,联合组合物和/或联合给药方法包括全细胞疫苗或表达细胞因子的细胞(例如表达重组IL-2的成纤维细胞、表达重组细胞因子的树突细胞等) (参见例如Kowalczyk 等, Acta Biochim Pol. 50(3), 613-24 (2003),Reilly 等, Methods Mol Med. 69, 233-57 (2002) 和 Tirapu 等, Curr Gene Ther. 2(1), 79-89 (2002)。可用于本发明联合方法的这样的自体细胞方法的另一实例是MyVax®个性化免疫治疗法(之前称为GTOP-99) (Genitope Corporation – Redwood City, CA,USA)。
在一个实施方案中,本发明提供其中本发明的抗-TF抗体药物缀合物与病毒、病毒蛋白等联合或共给予的联合组合物和联合给药方法。通常能够在体内进行一轮或仅几轮复制并靶向肿瘤细胞的复制缺陷型病毒,可例如为这样的组合物和方法的有用组分。这样的病毒剂可包含编码免疫刺激剂例如GM-CSF和/或IL-2的核酸,或与之相关。天然的溶瘤病毒和这样的重组溶瘤病毒(例如HSV-1病毒、呼肠孤病毒、复制缺陷型和复制敏感型腺病毒等)可为这样的组合物和方法的有用组分。因此,在一个实施方案中,本发明提供其中抗-TF抗体药物缀合物与溶瘤病毒联合或共给予的联合组合物和联合给药方法。这样的病毒的实例包括溶瘤腺病毒和疱疹病毒,其可或可不为改良病毒(参见例如Shah 等, J Neurooncol.65(3), 203-26 (2003), Stiles 等, Surgery. 134(2), 357-64 (2003), Sunarmura等, Pancreas. 28(3), 326-9 (2004), Teshigahara 等, J Surg Oncol. 85(1), 42-7(2004), Varghese 等, Cancer Gene Ther. 9(12), 967-78 (2002), Wildner 等,Cancer Res. 59(2), 410-3 (1999), Yamanaka, Int J Oncol. 24(4), 919-23 (2004)和 Zwiebel 等, Semin Oncol. 28(4), 336-43 (2001)。
本发明的联合组合物和联合给药方法亦可涉及“全细胞”和“过继性”免疫治疗法。例如,这样的方法可包括免疫系统细胞(例如肿瘤浸润淋巴细胞(TIL)、例如CD4+和/或 CD8+T细胞(例如用肿瘤特异性抗原和/或遗传增强扩繁的T细胞)、表达抗体的B细胞或产生/递呈其他抗体的细胞、树突细胞(DC) (例如表达抗细胞因子的重组树突细胞、用DC扩繁剂例如GM-CSF和/或Flt3-L培养的树突细胞和/或肿瘤相关的负载抗原的树突细胞)、抗肿瘤NK细胞、所谓的杂合细胞或者它们的组合)的输注或再输注。细胞裂解物亦可用于这样的方法和组合物。可用于这种方面的临床试验中的细胞“疫苗”包括Canvaxin™、APC-8015(Dendreon)、HSPPC-96 (Antigenics)和Melacine®细胞裂解物。从癌细胞脱落的抗原及其混合物(参见例如Bystryn 等, Clinical Cancer Research 第7卷, 1882-1887, 2001年7月),任选与佐剂例如明矾混合,亦可为这样的方法和联合组合物中的组分。
在一个实施方案中,可联合施用内部接种疫苗法将本发明的抗-TF抗体药物缀合物递送至患者。内部接种疫苗指,诱导的肿瘤或癌细胞死亡,例如药物诱导的或辐射诱导的患者的肿瘤细胞的细胞死亡,其通常导致引起针对以下的免疫反应:(i) 作为整体的肿瘤细胞或(ii) 包括以下的肿瘤细胞的部分,(a) 分泌的蛋白、糖蛋白或其他产物,(b) 膜相关的蛋白或糖蛋白或者与膜相关或插入膜中的其他组分,和/或(c) 细胞内蛋白或其他细胞内成分。内部接种疫苗诱导的免疫反应可为体液介导的(即抗体-补体介导的)或细胞介导的(例如识别内部杀死的肿瘤细胞或其部分的内源性细胞毒性T淋巴细胞的发育和/或增加)。除了放射治疗外,可用于诱导所述肿瘤细胞死亡和内部接种疫苗的药物和物质的非限制性实例是,常规的化学治疗剂、细胞周期抑制剂、抗血管生成剂、单克隆抗体、凋亡诱导剂和信号转导抑制剂。
可与用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂相关的其他抗癌剂的实例是,分化诱导剂,视黄酸类似物(例如全反式视黄酸、13-顺式视黄酸和类似的药物),维生素D类似物(例如西奥骨化醇和类似的药物),ErbB3、ErbB4、IGF-IR、胰岛素受体、PDGFRa、PDGFRβ、Flk2、Flt4、FGFR1、FGFR2、FGFR3、FGFR4、TRKA、TRKC、c-met、Ron、Sea、Tie、Tie2、Eph、Ret、Ros、Alk、LTK、PTK7的抑制剂和类似的药物。
可与用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂相关的其他抗癌剂的实例是,组织蛋白酶B,组织蛋白酶D脱氢酶活性的调节剂,谷胱甘肽-S-转移酶(例如谷氨酰半胱氨酸合成酶和乳酸脱氢酶)和类似的药物。
可与用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂相关的其他抗癌剂的实例是雌莫司汀和表柔比星。
可与用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂相关的其他抗癌剂的实例是,HSP90抑制剂像17-烯丙基氨基格尔德霉素,针对肿瘤抗原例如PSA、CA125、KSA等的抗体,整联蛋白像整联蛋白β1,VCAM抑制剂和类似的药物。
可与用于与本发明的抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂相关的其他抗癌剂的实例是,钙神经素抑制剂(例如伐司朴达、PSC 833以及其他MDR-1或p糖蛋白抑制剂),TOR抑制剂(例如西罗莫司、依维莫司和雷帕霉素),“淋巴细胞归巢”机制抑制剂(例如FTY720)以及对细胞信号转导具有影响的药物例如黏附分子抑制剂(例如抗-LFA等)。
在一个实施方案中,本发明的抗-TF抗体药物缀合物用于与以下的一种或多种其他治疗抗体联合使用,例如贝伐单抗(Avastin®)、扎芦木单抗、西妥昔单抗(Erbitux®)、帕尼单抗(Vectibix™)、奥法木单抗(Arzerra®)、扎木单抗、daratumumab (HuMax-CD38)、雷珠单抗(Lucentis®)、达克珠单抗(Zenapax®)、巴利昔单抗(Simulect®)、英夫利昔单抗(Remicade®)、阿达木单抗(Humira®)、那他珠单抗(Tysabri®)、奥马珠单抗(Xolair®)、依法珠单抗(Raptiva®)、尼妥珠单抗、利妥昔单抗(Rituxan®/MabThera®)和/或曲妥珠单抗(Herceptin®)。可与本发明的抗-TF抗体药物缀合物联合使用的其他治疗抗体是公开于WO98/40408 (可结合天然人TF的抗体)、WO04/094475 (能够与人组织因子结合的抗体,与正常血浆对照相比,其不抑制因子介导的血液凝固)、WO03/093422 (与TF:VIIa复合物结合的亲和力大于与TF单独结合的亲和力的抗体)、WO03/037361 (用于治疗涉及凋亡的TF激动剂或拮抗剂)或WO 2010/066803 (针对组织因子的人单克隆抗体)中的那些抗体。
在一个实施方案中,可与递送一种或多种促进抗-TF抗体药物缀合物或联合组合物到肿瘤内部的物质一起给予抗-TF抗体缀合物。这样的方法可例如与递送能够松弛肿瘤的松弛素联合进行(参见例如US 6,719,977)。在一个实施方案中,本发明的抗-TF抗体药物缀合物可与细胞穿透肽(CPP)键合。细胞穿透肽和相关的肽(例如工程细胞穿透抗体)公开于例如Zhao 等, J Immunol Methods. 254(1-2), 137-45 (2001), Hong 等, CancerRes. 60(23), 6551-6 (2000). Lindgren 等, Biochem J. 377(Pt 1), 69-76 (2004),Buerger 等, J Cancer Res Clin Oncol. 129(12), 669-75 (2003), Pooga 等, FASEBJ. 12(1), 67-77 (1998) and Tseng 等, Mol Pharmacol. 62(4), 864-72 (2002)。
在一个实施方案中,本发明提供一种用于治疗受试者中的涉及表达TF的细胞的病症的方法,该方法包括向有需要的受试者给予治疗有效量的本发明的抗-TF抗体药物缀合物和至少一种抗炎剂。
在一个实施方案中,这样的抗炎剂可选自:阿司匹林和其他水杨酸盐、Cox-2抑制剂(例如罗非昔布和塞来昔布)、NSAID (例如布洛芬、非诺洛芬、萘普生、舒林酸、双氯芬酸、吡罗昔康、酮洛芬、二氟尼柳、萘丁美酮、依托度酸、奥沙普秦和吲哚美辛)、抗-IL6R抗体、抗-IL8抗体(例如描述于WO2004058797中的抗体,例如10F8)、抗-IL15抗体(例如描述于WO03017935和WO2004076620中的抗体)、抗-IL15R抗体、抗-CD4抗体(例如扎木单抗)、抗-CD11a抗体(例如依法珠单抗)、抗-α-4/β-1整联蛋白(VLA4)抗体(例如那他珠单抗)、用于治疗炎性疾病的CTLA4-Ig、泼尼松龙、泼尼松、改变病情抗风湿药(DMARD)例如氨甲蝶呤、羟氯喹、柳氮磺吡啶、嘧啶合成抑制剂(例如来氟米特)、IL-1受体阻断剂(例如阿那白滞素)、TNF-α阻断剂(例如依那西普、英夫利昔单抗和阿达木单抗)和类似的药物。
在一个实施方案中,本发明提供一种用于治疗受试者中的涉及表达TF的细胞的病症的方法,该方法包括向有需要的受试者给予治疗有效量的本发明的抗-TF抗体药物缀合物和至少一种免疫抑制剂和/或免疫调节剂。
在一个实施方案中,这样的免疫抑制剂和/或免疫调节剂可选自:环孢菌素A、硫唑嘌呤、霉酚酸、霉酚酸吗乙酯、皮质类固醇例如泼尼松、氨甲蝶呤、金盐、柳氮磺吡啶、抗疟药、布喹那、来氟米特、咪唑立宾、15-脱氧精弧菌素、6-巯基嘌呤、环磷酰胺、雷帕霉素、他克莫司(FK-506)、OKT3、抗-胸腺细胞球蛋白、胸腺喷丁、胸腺素-α和类似的药物。
在一个实施方案中,这样的免疫抑制剂和/或免疫调节剂可选自免疫抑制性抗体,例如与IL-2受体的p75结合的抗体,针对CD25的抗体(例如描述于WO2004045512中的那些抗体,例如AB1、AB7、AB11和AB12),或者与例如MHC、CD2、CD3、CD4、CD7、CD28、B7、CD40、CD45、IFNγR、TNFαR 或TNFR (由两个亚基CD120a和CD120b组成)、IL-4R、IL-5R, IL-6R、IL-7R、IL-8R、IL-10R、CD11a或CD58结合的抗体,或者与它们的配体结合的抗体。
在一个实施方案中,这样的免疫抑制剂和/或免疫调节剂可选自:可溶性IL-15R、IL-10R、B7分子(B7-1、B7-2、其变体及其片段)、ICOS和OX40,以及阴性T细胞调节物抑制剂(例如针对CTLA4的抗体)和类似的药物。
在一个实施方案中,本发明提供一种用于治疗受试者中的涉及表达TF的细胞的病症的方法,该方法包括向有需要的受试者给予治疗有效量的本发明的抗-TF抗体药物缀合物和抗-C3b(i)抗体。
在一个实施方案中,用于与抗-TF抗体药物缀合物联合使用治疗如上文所述的病症的治疗剂可选自:组蛋白去乙酰化酶抑制剂(例如丁酸苯酯)和/或DNA修复剂(例如DNA修复酶和相关的组合物例如dimericine)。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-011-vcMMAE。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-098-vcMMAE。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-111-vcMMAE。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-114-vcMMAE。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-011-mcMMAF。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-098-mcMMAF。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-111-mcMMAF。
在一个实施方案中,用于与任一个上文提及药物联合治疗的抗-TF抗体药物缀合物是HuMab-TF-114-mcMMAF。
包括给予治疗有效量的本发明抗-TF抗体药物缀合物的用于治疗如上文所述的病症的本发明方法亦可包括,抗癌定向光动力治疗(例如抗癌激光治疗–其任选可借助于光增敏剂实施,参见例如Zhang 等, J Control Release. 93(2), 141-50 (2003))、抗癌声波和冲击波治疗(参见例如Kambe 等, Hum Cell. 10(1), 87-94 (1997))和/或抗癌营养食品治疗(参见例如Roudebush 等, Vet Clin North Am Small Anim Pract. 34(1), 249-69, viii (2004) 和 Rafi, Nutrition. 20(1), 78-82 (2004)。同样地,抗-TF抗体药物缀合物可用于制备用于治疗如上文所述的病症的药物组合物,其与抗癌定向光动力治疗(例如抗癌激光治疗–其任选可借助于光增敏剂实施)、抗癌声波和冲击波治疗和/或抗癌营养食品治疗一起给予。
在一个实施方案中,本发明提供一种用于治疗受试者的涉及表达TF的细胞的病症的方法,该方法包括向有需要的受试者给予治疗有效量的抗-TF抗体药物缀合物(例如本发明的抗-TF抗体药物缀合物)和放射性治疗。
在一个实施方案中,本发明提供一种用于治疗或预防癌症的方法,该方法包括向有需要的受试者给予治疗有效量的本发明的抗-TF抗体药物缀合物和放射性治疗。
在一个实施方案中,本发明提供本发明的抗-TF抗体药物缀合物用于制备用于待与放射性治疗联合给予的治疗癌症的药物组合物的用途。
放射性治疗可包括放射患者或向其给予放射性药物。放射源可在所治疗患者的外部或内部(放射治疗可例如以外部光束放射治疗(EBRT)或近距离放射治疗(BT)的形式)。可用于实施这样的方法的放射性元素包括,例如镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘-123、碘-131和铟-111。
在另外的实施方案中,本发明提供一种用于治疗或预防癌症的方法,该方法包括联合外科手术向有需要的受试者给予治疗有效量的本发明的抗-TF抗体药物缀合物。
如上文所述,本发明的药物组合物可以联合治疗给予,即联合一种或多种与待治疗的疾病或病况相关的药物,其作为单独药物组合物或一种或多种如上文所述的另外的治疗剂与本发明的化合物共配制。这样的联合治疗可需要较低剂量的本发明化合物和/或共给予的药物,从而避免与各种单药治疗相关的可能毒性或并发症。
除了上文的联合治疗外,其他相关的联合治疗包括下述:
•用于治疗胰腺癌,本发明的抗-TF抗体药物缀合物联合抗代谢物例如5-氟尿嘧啶和/或吉西他滨,可联合一种或多种选自以下的化合物:90Y-hPAM4、ARC-100、ARQ-197、AZD-6244、bardoxolone methyl、西妥木单抗、(IMC-A12)、folitixorin calcium、GVAX、伊匹木单抗、KRX-0601、merbarone、MGCD-0103、MORAb-009、PX-12、Rh-Apo2L、TLN-4601、trabedersen、伏洛昔单抗 (M200)、WX-671、培美曲塞、卢比替康、伊沙匹隆、OCX-0191Vion、216586-46-8、拉帕替尼、马妥珠单抗、伊马替尼、索拉非尼、曲妥珠单抗、exabepilone、厄洛替尼、阿瓦斯丁和西妥昔单抗
•用于治疗结直肠癌,本发明的抗-TF抗体药物缀合物联合一种或多种选自以下的化合物:吉西他滨、贝伐单抗、FOLFOX、FOLFIRI、XELOX、IFL、奥沙利铂、伊立替康、5-FU/LV、卡培他滨、UFT、EGFR靶向剂(例如西妥昔单抗、帕尼单抗、尼妥珠单抗、扎芦木单抗)、VEGF抑制剂或酪氨酸激酶抑制剂例如舒尼替尼。
•用于治疗乳腺癌,本发明的抗-TF抗体药物缀合物联合一种或多种选自以下的化合物:抗代谢物、蒽环类、紫杉烷类、烷化剂、埃坡霉素、抗激素药物(弗隆(femar)、它莫西芬等)、ErbB2 (Her2/neu)抑制剂(例如赫赛汀和类似的药物)、CAF/FAC (cyclofosfamide、多柔比星、5FU) AC (cyclo, doxo)、CMF (cyclo、氨甲喋呤、5FU)、多西他赛+卡培他滨、GT(紫杉醇,、吉西他滨) FEC (cyclo、epi、5FU)联合赫赛汀、紫杉醇+/-卡铂、长春瑞滨、多西他赛、CT联合拉帕替尼、卡培他滨。
•用于治疗膀胱,本发明的抗-TF抗体药物缀合物联合一种或多种选自以下的化合物:抗代谢物(吉西他滨、力比泰、氨甲喋呤)、铂类似物(顺铂、卡铂)、EGFr抑制剂(例如西妥昔单抗或扎芦木单抗)、VEGF抑制剂(例如阿瓦斯丁)、多柔比星、酪氨酸激酶抑制剂(例如吉非替尼、曲妥珠单抗)、抗有丝分裂剂(例如紫杉烷类(例如紫杉醇)和长春花生物碱类(例如长春碱))。
•用于治疗前列腺癌,本发明的抗-TF抗体药物缀合物联合一种或多种选自以下的化合物:激素/抗激素治疗(例如抗雄激素物质、黄体生成素释放激素(LHRH)激动剂)和化疗药物(例如紫杉烷类、米托蒽醌、雌莫司汀、5FU、长春碱、伊沙匹隆)。
•用于治疗卵巢癌,本发明的抗-TF抗体药物缀合物联合一种或多种选自以下的化合物:抗有丝分裂剂,例如紫杉烷类、长春花生物碱类、楷莱、托泊替康。
诊断用途
本发明的抗-TF抗体亦可用于诊断目的。本文所述的抗-TF抗体可在一个实施方案中与检测剂或标签而不是药物缀合,藉此使其适用于诊断目的。在一个实施方案中,抗-TF抗体或与检测剂缀合的抗-TF抗体的诊断用途可与本发明的其他方法之一(尤其是本发明抗-TF抗体药物缀合物的药物用途)联合使用。与检测剂缀合的抗-TF抗体可在一些情况下允许直接检测抗-TF抗体与TF的结合,下文给出“检测剂”或“标签”的实例,下文中提及“抗-TF抗体”亦可在相关情况下包括提及“与检测剂或标签缀合的抗-TF抗体”。术语“诊断用途”亦包括测量例如血浆、尿液中的TF水平,或与选择用于治疗的患者相关的活组织检查中的TF表达水平,或测量如上文所述的治疗的功效,和例如放射性标记的抗-TF抗体用于例如选择用于如上文所述的治疗的患者的用途。因此,在另一方面,本发明涉及包含本文所定义的抗-TF抗体的诊断组合物,其中诊断组合物可在一个特定实施方案中与本发明的抗-TF抗体药物缀合物联合使用。
在一个实施方案中,通过检测TF水平或者在其膜表面上包含TF的细胞水平,本发明的抗-TF抗体可用于体内或体外诊断其中表达TF的细胞在致病中起积极作用的疾病。这可例如通过以下实现:在允许抗-TF抗体与TF之间的复合物形成的条件下将待测试的样品(任选与对照样品一起)与抗-TF抗体接触。然后检测复合物形成(例如,使用ELISA)。当连同测试样品一起使用对照样品时,在两个样品中检测复合物,且样品之间的复合物形成中的任何统计上显著差异是测试样品中存在TF的指示。
因此,在另一方面,本发明的抗-TF抗体亦可在用于检测样品中TF抗原或者表达TF的细胞的存在的方法中使用,该方法包括:
- 在允许抗体与TF之间的复合物形成的条件下,将样品与本发明的抗-TF抗体或本发明的双特异性分子接触;和
- 分析是否已形成复合物。
在一个实施方案中,体外进行该方法。
更具体地,本发明的抗-TF抗体亦可在以下方法中使用:用于鉴定和诊断侵袭性细胞和组织以及本发明的抗-TF抗体所靶向的其他细胞的方法,和用于监测治疗性处理的进展、治疗后状况、发生癌症的风险、癌症进展等的方法。
在这样的诊断测定的一个实例中,本发明的抗-TF抗体可在诊断组织的侵袭性细胞的水平的方法中使用。这样的方法包括,形成抗-TF抗体与潜在包含TF的组织之间的免疫复合物,并检测免疫复合物的形成,其中免疫复合物的形成与组织中的侵袭性细胞的存在相关。使用标记的分离抗体和标准成像技术,可体内进行接触,或者可在组织样品上体外进行接触。
通过任何合适的技术,本发明的抗-TF抗体亦可用于检测任何合适生物样品中的包含TF的肽和肽片段。由本发明提供的常规免疫测定的实例包括但不限于,使用抗-TF抗体的ELISA、RIA、FACS测定、等离振子共振测定、层析测定、组织免疫组织化学、蛋白质印记和/或免疫沉淀。本发明的抗-TF抗体可用于检测来自人的TF和TF片段。在这样的技术中使用的抗-TF抗体和/或第二抗体的合适标签包括但不限于,多种酶、辅基、荧光物质、化学发光物质和放射性物质。合适酶的实例包括辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶或乙酰胆碱酯酶;合适辅基复合物的实例包括链霉亲和素/生物素和抗生物素蛋白/生物素;合适荧光物质的实例包括,伞形酮、荧光素、异硫氰酸荧光素、罗丹明、二氯三嗪基胺荧光素、丹磺酰氯或藻红蛋白;化学发光物质的实例包括鲁米诺;和合适放射性物质的实例包括125I、131I、35S和3H。
通过使用可检测物质标记的TF肽标准品和未标记的抗-TF抗体的竞争性免疫测定,抗-TF抗体亦可用于生物样品中的测定。在这样的测定中,使生物样品、标记的TF肽标准品和抗-TF抗体混合,并测定与未标记的抗-TF抗体结合的标记的TF标准品的量。生物样品中的TF肽的量反比于与抗-TF抗体结合的标记的TF标准品的量。
抗-TF抗体在肿瘤的体内成像中特别有用。与TF相关的肿瘤的体内成像可通过任何合适的技术进行。例如,99Tc-标记或者用另一发射γ射线的同位素标记可用于标记肿瘤的抗-TF抗体或者来自肿瘤的第二标记的(例如FITC标记的)抗-TF抗体:TF复合物,并用通常使用低能高分辨准直器或者低能通用准直器的γ闪烁照相机(例如Elscint Apex409ECT设备)成像。然后可评估染色组织的作为肿瘤中TF相关肽的量的指示物的放射性计数。凭借这样的技术获得的图像可用于评估患者、哺乳动物或组织中的TF的生物分布,例如在使用TF或TF片段的情况下作为侵袭性癌细胞存在的生物标志物。这种技术的变化可包括在γ照相技术上使用核磁共振成像(MRI)以改善成像。类似的免疫闪烁成像方法和原理描述于,例如Srivastava (主编), Radiolabeled Monoclonal Antibodies For ImagingAnd Therapy (Plenum Press 1988), Chase, "Medical Applications ofRadioisotopes," 载于Remington's Pharmaceutical Sciences, 第18版, Gennaro 等,(主编), 第624-652页 (Mack Publishing Co., 1990), 和Brown, "Clinical Use ofMonoclonal Antibodies," 载于Biotechnology And Pharmacy 227-49, Pezzuto 等,(主编) (Chapman & Hall 1993)。这样的图像亦可用于其它抗癌剂的靶向递送,本文描述了其它抗癌剂的实例(例如凋亡剂、毒素或CHOP化学治疗组合物)。此外,这样的图像亦可或备选充当移除肿瘤的外科技术的基础。另外,这样的体内成像技术可允许以下情形中的肿瘤的鉴定和定位,其中患者被鉴定为患肿瘤(由于存在其它生物标志物、转移等)但该肿瘤不能为传统分析技术所鉴定。所有这些方法是本发明的特征,这样的方法可尤其与本发明抗-TF抗体药物缀合物联合使用治疗患者。
本发明所提供的体内成像和其他诊断方法在人患者(例如,之前未诊断为癌症的患者或者在癌症的恢复/消退期的患者)的微转移的检测中是特别有用的。可接近90%的所有癌细胞的恶性癌细胞,例如已被证明用抗-TF抗体组合物很好染色。用本文所述的单克隆抗-TF抗体检测可指示侵略性/侵袭性癌的存在,并亦或备选提供针对这样的微转移使用相关的单克隆抗-TF抗体的可行性的指示。
在一个实施方案中,本发明的抗-TF抗体可用于体内成像方法,其中本发明的抗-TF抗体与促进检测的放射不透明物质缀合,例如通过注射到血流中将缀合的抗体给予宿主,并测定宿主中标记的抗体的存在和位置。通过该技术和本文提供的任何其他诊断方法,本发明的抗-TF抗体可在用于筛查人患者或取自人患者的生物样品中的疾病相关的细胞的存在的方法中使用。
为了诊断成像,可将放射性同位素与抗-TF抗体直接或通过使用中间官能团间接地结合。有用的中间官能团包括螯合剂,例如乙二胺四乙酸和二乙烯三胺五乙酸(参见例如US 5,057,313)。
除了放射性同位素和放射性不透明物质外,可使用与以下缀合的抗-TF抗体进行诊断方法:染料(例如生物素-链霉亲和素复合物)、造影剂、荧光化合物或分子以及用于核磁共振成像(MRI)的增强剂(例如顺磁离子) (参见例如美国专利第6,331,175号,其描述MRI技术以及与MRI增强剂缀合的抗体的制备)。这样的诊断/检测剂可选自核磁共振成像中使用的物质和荧光化合物。为了用放射性金属或顺磁离子装载抗-TF抗体,可必要的将抗体与具有长尾的试剂反应,该长尾与用于结合离子的多种螯合基团连接。这样的尾可为聚合物,例如多聚赖氨酸、多糖或者具有可与螯合基团结合的侧基的其他衍生化或可衍生链,螯合基团例如卟啉、聚胺、冠醚、双硫代缩氨基脲(bisthiosemicarbazone)、聚肟等用于该目的的已知基团。可使用标准化学将螯合物与抗-TF抗体偶联。
因此,本发明提供诊断的抗-TF抗体缀合物,其中抗-TF抗体与造影剂(例如用于增强核磁共振成像、计算机断层扫描或超声造影的物质)或放射性核素缀合,放射性核素可为,例如发射γ、β、α、俄歇电子或正电子的同位素。
在另一方面,本发明涉及一种用于检测样品中TF抗原或者表达TF的细胞的存在的试剂盒,其包含:
- 本发明的抗-TF抗体或本发明的双特异性分子;和
- 试剂盒的使用说明书,其中该试剂盒尤其亦包含本发明的与检测剂或造影剂缀合的抗-TF抗体。
在一个实施方案中,本发明的抗-TF抗体亦可在用于诊断癌症的试剂盒中使用,该试剂盒包含含有抗-TF抗体的容器以及一种或多种用于检测抗-TF抗体与TF肽结合的试剂。这样的试剂盒可尤其另外包含本发明的抗-TF抗体药物缀合物。试剂可包括,例如荧光标签、酶标签或其他可检测标签。试剂亦可包括第二或第三抗体或者用于酶反应的试剂,其中酶反应产生可被可视化的产物。在一个实施方案中,本发明提供一种诊断试剂盒,其包含:合适容器中的呈标记或未标记形式的一种或多种本发明的抗-TF抗体、间接测定的孵育试剂以及在这样的测定中取决于标签的性质用于检测的底物或衍生剂。亦可包含对照试剂和使用说明书。
亦可供应与抗-TF抗体(例如缀合/标记的抗-TF抗体)一起使用的诊断试剂盒用于检测细胞活性或者用于检测组织样品或宿主中的TF肽的存在。在这样的诊断试剂盒以及本文他处所述的用于治疗用途的试剂盒中,抗-TF抗体通常可单独或联合对靶细胞或肽特异的另外抗体以冻干形式在容器中提供。通常,亦可包含药学上可接受的载体(例如惰性稀释剂)和/或其组分,例如Tris、磷酸盐或碳酸盐缓冲液,稳定剂,防腐剂,杀生物剂,杀生物剂,惰性蛋白(例如血清白蛋白)等(通常在用于混合的单独容器中)以及另外的试剂(亦通常在单独的容器中)。在特定的试剂盒中,亦包含能够与抗-TF抗体结合的第二抗体,其通常在单独的容器中存在。第二抗体通常与标签缀合并以类似于本发明的抗-TF抗体的方式配制。使用上文和本文其他地方所述的方法,抗-TF抗体可用于定义癌/肿瘤细胞的亚类以及表征这样的细胞和相关的组织/生长。
通过从患者移除组织标本并向这样的标本提供本发明的标记的抗-TF抗体(与检测剂缀合的抗-TF抗体)的组合,可实现原位检测。可通过向生物样品施用或涂上本发明的标记的抗-TF抗体,提供本发明的抗-TF抗体。通过使用这样的程序,可测定不仅TF或TF片段的存在而且这样的肽在检测组织中的分布(例如在评估癌细胞扩散的情况下)。使用本发明,普通技术人员将容易理解,可修改任何多种组织学方法(例如染色程序)以便实现原位检测。
本发明通过下述实施例进一步说明,其不应该解释为进一步限制。
实施例
实施例1
组织因子(TF)的表达构建体
产生了用于在HEK、NS0或CHO细胞中表达TF或其细胞外结构域的全密码子优化的构建体。由这些构建体编码的蛋白与TF的Genbank登录号NP_001984相同。构建体包含用于克隆的合适限制性位点和最优Kozak序列(Kozak, 1987)。将构建体在哺乳动物表达载体pEE13.4 (Lonza Biologics) (Bebbington, Renner 等 1992)中克隆,获得pEE13.4TF。将PCR用于从合成构建体扩增编码TF细胞外结构域(ECD) (氨基酸1-251)的部分,加有包含6个His残基的C端His标签(TFECDHis)。将构建体在pEE13.4中克隆,并进行完全测序以证实构建体的正确性。
实施例2
HEK-293F细胞中的瞬时表达
FreestyleTM 293-F (适应于悬浮生长和化学成分确定的Freestyle培养基的HEK-293亚克隆,(HEK-293F))细胞从Invitrogen获得,并根据制造商的说明书,使用293fectin(Invitrogen),用合适的质粒DNA转染。在抗体表达的情况下,如实施例10所述,共表达合适的重链和轻链载体。
实施例3
NS0细胞中的半稳定表达
将pEE13.4TF在NS0细胞中稳定转染,并在谷氨酰胺不存在而7.5 µM的甲基氨基亚砜(methylsulphoximine, MSX)存在时,基于生长选择稳定的克隆。维持选择压力的同时将克隆合并物在悬浮培养中培养。通过FACS分析测试合并物的TF表达,并获得合并用于另外的用途。
实施例4
CHO细胞中的稳定表达
将pEE13.4TF在CHO-K1SV (Lonza Biologics)细胞中稳定转染,并在谷氨酰胺不存在而50 µM MSX存在下基于生长选择稳定的克隆。挑选和扩繁单克隆,并如下文所述,通过FACS分析测试单克隆的TF表达。选择和获得高表达的克隆用于另外的用途。
实施例5
加His标签的TF的纯化
将TFECDhis在HEK-293F细胞中表达。TFECDHis中的his-标签能够使得用固定化金属亲和层析纯化。在该方法中,固定到层析树脂上的螯合剂带有Co2+阳离子。将包含TFECDHis的上清液以分批方式(即溶液)与树脂孵育。加His标签的蛋白与树脂珠强力结合,而存在于培养上清液中的其他蛋白不强力结合。孵育后,从上清液中重新得到珠,并装填到柱内。将柱洗涤以便移除弱结合蛋白。然后用包含咪唑的缓冲液洗脱强力结合的TFECDHis蛋白,咪唑竞争His与Co2+的结合。在脱盐柱上通过缓冲液交换从蛋白中移除洗脱液。
实施例6
转基因小鼠的免疫程序
抗体042、092-A09、098和101来源于下述免疫:将3只HCo20小鼠(2只雄性和1只雌性,品系GG2713)、3只HCo17小鼠(2只雄性和1只雌性,品系GG2714)、3只HCo12-BALB/c小鼠(3只雄性,品系GG2811)、3只HCo7 (3只雄性,品系GG2201)和3只HCo12小鼠(3只雄性,品系GG2198) (Medarex, San José, CA, USA; 关于参考文献参见上文HuMab小鼠段落)每两星期交替的用5x106半稳定转染的NS0-TF细胞或者用20 µg的TFECDHis蛋白免疫。共计进行8次免疫,4次腹膜内(IP)免疫,4次尾底部的皮下(SC)免疫。用细胞的第一次免疫在弗氏完全佐剂(CFA; Difco Laboratories, Detroit, MI, USA)中进行。对于所有其他免疫,IP注射PBS中的细胞,并使用弗氏不完全佐剂(IFA; Difco Laboratories, Detroit, MI, USA),SC注射TFECDHis。当发现血清效价足够时(在如实施例7所述的抗原特异性筛查测定中对至少2次序贯、双周筛查事件发现1/50或更低的血清稀释液为阳性),融合之前4和3天,将小鼠用100 μL PBS中的10 μg TFECDHis蛋白静脉内(IV)另外加强免疫2次。
抗体109、111和114来源于下述免疫:将3只HCo20小鼠(3只雌性)、3只HCo17小鼠(3只雌性)、3只HCo12-BALB/c小鼠(3只雌性)、3只HCo7 (3只雄性)和3只HCo12小鼠(3只雌性)每两星期用5x106半稳定转染的NS0-TF细胞免疫。用细胞的第一次免疫在CFA中进行,对于所有其他(7)次免疫,IP注射PBS中的细胞。当发现血清效价足够时(如上文所定义),融合之前4和3天,将小鼠用100 μL PBS中的1x106瞬时半稳定转染的NS0-TF细胞IV另外加强免疫2次。
抗体011、017-D12和025来源于下述免疫:将3只HCo20小鼠(3只雄性)、3只HCo17小鼠(2只雄性和1只雌性)、3只HCo12-BALB/c小鼠(3只雌性)、3只HCo7 (3只雄性)和3只HCo12小鼠(2只雄性和1只雌性)每两星期用20 µg的TFECDHis蛋白免疫。用蛋白的第一次(腹膜内)免疫在CFA中进行,对于所有其他(7)次免疫,交替的皮下和腹膜内注射IFA中的蛋白。当发现血清效价足够时(如上文所定义),融合之前4和3天,将小鼠用100 μL PBS中的10 μgTFECDHis蛋白静脉内(IV)另外加强免疫2次。
实施例7
均相抗原特异性筛查测定
免疫的小鼠的血清或者HuMab(人单克隆抗体)杂交瘤或转染瘤培养上清液中抗-TF抗体的存在是通过使用荧光微体积测定技术(FMAT; Applied Biosystems, FosterCity, CA, USA)的均相抗原特异性筛查测定(四象限)所测定的。
对于此,使用3个基于细胞的测定和1个基于珠的测定的组合。在基于细胞的测定中,测定与TH1015-TF (瞬时表达TF的HEK-293F细胞,如上文所述产生)和A431 (其在细胞表面上表达TF)以及HEK293野生型细胞(不表达TF,阴性对照)的结合。在基于珠的测定中,测定与偶联于链霉亲和素珠上的生物素化TF (SB1015-TF)的结合。
将样品加入细胞/珠中以允许与TF结合。随后,使用荧光缀合物(山羊抗-人IgG-Cy5; Jackson ImmunoResearch)检测HuMab的结合。将小鼠抗-人TF抗体(ERL; 与Genmab的Alexa-647偶联)用作阳性对照,将HuMAb-小鼠合并的血清和小鼠-chrompure-Alexa647抗体用作阴性对照。将样品使用Applied Biosystems 8200 Cellular Detection System(8200 CDS)扫描并将“计数 x 荧光”用作读出值。
实施例8
HuMab杂交瘤产生
使具有足够抗原特异性效价形成(如上文所定义)的HuMab小鼠安乐死并收集腹主动脉和腔静脉侧翼的脾和淋巴结。基本上根据制造商的说明书,通过使用CEEF 50Electrofusion System (Cyto Pulse Sciences, Glen Burnie, MD, USA)的电融合,进行脾细胞和淋巴结细胞与小鼠骨髓瘤细胞系的融合。基于标准方案(例如,如描述于ColiganJ.E., Bierer, B.E., Margulies, D.H., Shevach, E.M. 和 Strober, W., 主编Current Protocols in Immunology, John Wiley & Sons, Inc., 2006),进行所产生的HuMab杂交瘤的选择和培养。
实施例9
纯化的抗体的质谱法
在Sciclone ALH 3000工作站(Caliper Lifesciences, Hopkinton, USA)上使用包含蛋白G树脂的PhyTip柱(PhyNexus Inc., San Jose, USA),纯化来自6-孔或Hyperflask台的0.8 ml包含抗体的上清液的小量等分试样。根据制造商的说明书使用PhyTtip柱,但用以下缓冲液替换缓冲液:结合缓冲液PBS (B.Braun, Medical B.V., Oss,Netherlands)和洗脱缓冲液0.1M 甘氨酸-HCl pH 2.7 (Fluka Riedel-de Haën, Buchs,Germany)。纯化后,将样品用2M Tris-HCl pH 9.0 (Sigma-Aldrich, Zwijndrecht,Netherlands)中和。备选地,在一些情况下,使用蛋白A亲和柱层析纯化较大体积的培养上清液。
纯化后,将样品放置在384孔板(Waters, 100 ul 平方孔板, 批# 186002631)中。将样品在37℃用N-糖苷酶F (Roche 产品号 11365177001)去糖基化过夜。加入(1 µl/孔)DTT (15 mg/ml)并在37℃孵育1小时。将样品(5或6 ul)在60℃在具有BEH300 C18, 1.7µm,2.1x 50 mm柱的Acquity UPLC™ (Waters, Milford, USA)上去盐。将具有0.1%甲酸(Fluka, 产品号 56302, Buchs, Germany)的MQ水和LC-MS级乙腈(Biosolve, 产品号01204101,Valkenswaard, The Netherlands)分别用作洗脱剂A和B。在以正离子模式操作的micrOTOF™质谱仪(Bruker, Bremen, Germany)上在线记录飞行时间电喷雾电离质谱。分析之前,将900-3000 m/z刻度用ES调谐混合物(Agilent Technologies, Santa Clara,USA)校准。使用查找5-80 kDa分子量的最大熵算法,用DataAnalysis™软件版本3.4(Bruker)去卷积质谱。
去卷积后,将所有样品所得到的重链和轻链质量进行比较以便找到重复抗体。在重链的比较中,考虑可能存在的C端赖氨酸变体。这得到一列独特的抗体,其中独特定义为重链和轻链的独特组合。假如发现重复抗体,那么来自其他测试的结果用于决定哪个是继续实验最好的材料。
118 TF特异性杂交瘤的重链和轻链分子量的MS分析产生70种独特抗体(独特的重链/轻链组合)。这些抗体在鉴定我们的先导候选物(TF特异性抗体)的多种功能性测定中被表征。
实施例10
抗-TF HuMab可变结构域的序列分析以及在表达载体中的克隆
从5x106杂交瘤细胞中制备抗-TF HuMab的总RNA,并根据制造商的说明书,使用SMART RACE cDNA扩增试剂盒(Clontech),从100 ng总RNA制备5’-RACE-互补DNA (cDNA)。VH (重链可变区)和VL (轻链可变区)编码区由PCR扩增,并使用Zero Blunt PCR克隆试剂盒(Invitrogen)将其克隆到pCR-Blunt II-TOPO载体(Invitrogen)中。对于各HuMab,测序16种VL克隆和8种VH克隆。序列在本文序列表和图1中给出。
表1A和表1B (下文)给出抗体序列信息和大多数同源种系序列的概述。
表1A 重链同源性
表1B 轻链同源性
对序列表的引用:(图1中的序列)
在图1中,017-D12克隆被称为“017”,和类似地092-A09克隆被称为“092”。
抗-TF HuMab 092-A09是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 17的VH序列和SEQ ID No: 57的VL序列。
抗-TF HuMab 101是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 21的VH序列和SEQ ID No: 61的VL序列。
抗-TF HuMab 025是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 25的VH序列和SEQ ID No: 65的VL序列。
抗-TF HuMab 109是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 29的VH序列和SEQ ID No: 69的VL序列。
抗-TF HuMab 017-D12是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 9的VH序列和SEQ ID No: 49的VL序列。
抗-TF HuMab 114是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 1的VH序列和SEQ ID No: 41的VL序列。
抗-TF HuMab 042是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 13的VH序列和SEQ ID No: 53的VL序列。
抗-TF HuMab 011是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 5的VH序列和SEQ ID No: 45的VL序列。
抗-TF HuMab 098是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 33的VH序列和SEQ ID No: 73的VL序列。
抗-TF HuMab 111是全长、全人单克隆IgG1,κ抗体,其包含SEQ ID No: 37的VH序列和SEQ ID No: 77的VL序列。
实施例11
抗体的纯化
将培养上清液在0.2 µm终端过滤器上过滤,并装载于5 ml蛋白A柱(rProtein AFF, Amersham Bioscience)上,用0.1 M 柠檬酸-NaOH, pH 3洗脱。将洗脱物用2M Tris-HCl, pH 9立即中和,并对12.6 mM NaH2PO4, 140 mM NaCl, pH 7.4 (B.Braun)透析过夜。透析后,将样品在0.2 µm终端过滤器上无菌过滤。纯度由SDS-PAGE测定,浓度由浊度法和280nm的吸光度测量。将纯化的抗体等分成小份并在-80℃保存。一旦解冻,将纯化的抗体等分试样在4℃保存。如实施例9中所述,进行质谱以鉴定由杂交瘤表达的抗体重链和轻链的分子量。
实施例12
抗-TF HuMab与TF的细胞外结构域在ELISA中的结合
所获得的抗-TF HuMab的特异性由ELISA评价。将ELISA板(Microlon; GreinerBio-One)用PBS, pH 7.4中的0.5 μg/mL的TFECDHis在+4℃包被过夜。将包被的ELISA板清空,将其用PBS中的2% (v/v)鸡血清(Gibco, Paisley, Scotland)室温封闭1小时,将其用包含0.05% Tween 20的PBS (PBST)洗涤。随后,将在PBSTC (补充2% (v/v)鸡血清和0.05%(v/v) Tween-20的PBS)中系列稀释的HuMab在振荡条件(300 rpm)下室温孵育1小时。使用在PBSTC中1:5,000稀释的HRP-缀合的山羊-抗-人IgG抗体(Jackson ImmunoResearch)检测结合的HuMab,将其在振荡条件(300 rpm)下室温孵育1小时。将反应在暗处在室温用ABTS(Roche Diagnostics)进一步显色,15-30分钟后通过加入2% (w/v)草酸终止反应,然后测量405 nm的吸光度。将HuMab-KLH (针对KLH(匙孔䗩血蓝蛋白)的人单克隆抗体)用作阴性对照。将小鼠抗-人TF (ERL)用作阳性对照(HRP标记的抗-小鼠IgG作为缀合物)。使用GraphPad Prism V4.03软件,使用非线性回归(具有可变斜率的S型剂量-反应)来分析结合曲线。
从图3中可以看出,所有的抗-TF抗体结合TFECDHis。HuMab的EC50值是3组实验的平均值,并变化于0.13-0.17 nM (下文表2)
表2:
实施例13
抗-TF HuMab与膜结合的TF的结合
使用TF转染的CHO细胞,或表达TF的肿瘤细胞系MDA-MB-231,(萤光素酶转染的)A431和Bx-PC3,通过FACS分析测定抗-TF HuMab与膜结合的TF的结合。
将细胞在PBS中重悬(2 x 106细胞/mL),放在96孔V底板中(50 µL/孔)。将50 µL的FACS缓冲液(补充0.1% BSA和0.02%叠氮化钠的PBS)中系列稀释的HuMab加入细胞中并在冰上孵育30分钟。用FACS缓冲液洗涤3次后,加入50 µL的FACS缓冲液中1:100稀释的藻红蛋白(PE)-缀合的山羊抗-人IgGFc (Jackson ImmunoResearch)。冰上30分钟(在暗处)后,将细胞洗涤3次,并在FACSCalibur (BD Biosciences)上通过流式细胞术检测HuMab的特异性结合。将HuMab-KLH用作阴性对照。将小鼠抗-人TF 之后的PE-缀合的抗-小鼠IgGFc用作阳性对照。使用GraphPad Prism V4.03软件(GraphPad Software, San Diego, CA, USA),使用非线性回归(具有可变斜率的S型剂量-反应)来分析结合曲线。
图4显示TF特异性HuMab与MDA-MB-231细胞的结合曲线的一个实例。
表3给出TF特异性HuMab与TF转染的CHO细胞(S1015-TF)、MDA-MB-231、A431和Bx-PC3细胞的结合的EC50值概述。
表3 –通过FACS分析TF-特异性HuMab与不同细胞类型的结合所确定的EC50和最大平均荧光强度(max MFI)值的概述
EC50值以nM计。MDA-MB-231、BxPC3和A431细胞的Max MFI在30 μg/mL抗体,S1015-TF的Max MFI在7.5 μg/mL抗体。
实施例14
对FVIIa与TF结合的抑制
通过抗-TF HuMab抑制FVIIa与MDA-MB-231细胞上的TF的结合是由FACS分析所测量的。将MDA-MB-231细胞在PBS中洗涤以移除血清,并放置在96孔板中(100,000细胞/孔)。将细胞用DMEM/0.1% BSA中的抗-TF HuMab孵育15分钟,之后用DMEM/0.1% BSA中的100 nMFVIIa在4℃孵育30分钟。将细胞用PBS/0.1% BSA/0.02%叠氮化钠(FACS缓冲液)洗涤,并用10 μg/mL兔抗-FVIIa (Abcam [ab7053])孵育。将细胞用FACS缓冲液洗涤,并用1:50稀释的PE标记的山羊抗-兔IgG (Jackson [111-116-144])孵育。将细胞用FACS缓冲液洗涤,并在FACSCanto II (Becton Dickinson)上测量平均荧光强度(MFI)。
使用GraphPad Prism (非线性回归分析),计算需要获得50%抑制(IC50)的抗体浓度。
图5和表4显示,HuMab-TF-098 (IC50: 1.2 µg/mL)、-114 (IC50不能被测定)和-011 (IC50: 0.6 μg/mL)有效抑制FVIIa与MDA-MB-231细胞结合,而HuMab-TF-013、-044和-111不(或至低得多的程度)抑制FVIIa结合
a) 不能被计算
表4 –抗-TF-HuMab抑制FVIIa结合的IC50值的概况。
显示的数据是在一个代表性实验中测量的抗-TF HuMab抑制100 nM FVIIa与MDA-MB-231细胞上的TF结合的IC50值(μg/mL)。
实施例15
抗-κ-ETA’测定中的抗体介导的内化和通过抗-TF HuMab的细胞杀死
为了测定是否抗-TF HuMab适合抗体-药物缀合物方法,使用利用κ定向的假单胞菌-外毒素A的通用体外基于细胞的杀死测定(抗-κ-ETA’)。在该测定中,使用与截短形式的假单胞菌-外毒素A缀合的高亲和力抗-人κ轻链结构域。在内化时,抗-κ-ETA’结构域-抗体缀合物经受蛋白水解和二硫键还原,将催化结构域与结合结构域分开。催化结构域经由KDEL滞留基序从高尔基体系统运送至内质网,并随后移位至细胞溶胶,在那它抑制蛋白合成并诱导凋亡(Kreitman RJ. BioDrugs. 2009; 23(1): 1-13. RecombinantImmunotoxins Containing Truncated Bacterial Toxins for the Treatment ofHematologic Malignancies(用于治疗恶性血液病的包含截短细菌毒素的重组免疫毒素))。
对不同的抗-TF HuMab测试抗体介导的内化和通过毒素的细胞杀死。测试具有可比较的TF表达水平的3种不同的细胞系。这些细胞亦表达EGFR (以不同的水平),允许使用结合EGFR并据知诱导EGFR内化的阳性对照抗体(2F8)。细胞系上表达的TF和EGFR分子的数量由Qifi试剂盒(Dako, Glostrup, Denmark)测定;A431细胞:平均TF分子/细胞大约500,000,平均EGFR分子/细胞大约500,000;BxPC3:平均TF分子/细胞大约500,000,平均EGFR分子/细胞大约200,000;MDA-MB-231:平均TF分子/细胞大约500,000,平均EGFR分子/细胞大约100,000。将细胞以最优浓度(A431: 2,500细胞/孔; BxPC3: 3,000细胞/孔; MDA-MB-231: 5,000细胞/孔)在96孔组织培养板(Greiner Bio-one)的细胞培养基中接种并允许粘附。为了鉴定使得毒素能够内化和进行杀死的抗-TF HuMab,在加入细胞之前,将不存在抗体时不诱导非特异性细胞死亡的固定浓度(0.5 μg/mL [A431和BxPC3]; 0.25 μg/mL[MDA-MB-231])的抗-κ-ETA’与滴定量的抗-TF HuMab孵育30分钟。3天后,根据制造商的说明书,用AlamarBlue (BioSource International, San Francisco, US)定量活细胞的量。使用具有标准AlamarBlue设置的EnVision 2101 Multilabel读数仪(PerkinElmer,Turku, Finland)监测荧光。包括作为阳性对照的具有抗-κ-ETA’的2F8。将同种型对照抗体(IgG1-b12)用作阴性对照。
图6和表5显示,除了一个(HuMab-TF-087)抗-κ-ETA’-预孵育的抗-TF HuMab外,所有的抗-κ-ETA’-预孵育的抗-TF HuMab都能够以剂量依赖的方式杀死A431、BxPC3和MDA-MB-231细胞。抗-κ-ETA’-预孵育的HuMab-TF-98、-114和-011 (对A431细胞的EC50为9 x 10-5-4 x 10-4 μg/mL)比抗-κ-ETA’-预孵育的HuMab-TF-013、-111和-044 (对A431细胞的EC50为2.0 x 10-2-9.8 x 10-2 μg/mL)诱导更有效的杀死。抗-κ-ETA’-预孵育的HuMab-TF-087不诱导细胞杀死。
对于各细胞系:A431 (a)、BxPC3 (b)和MDA-MB-231 (c),显示一个代表性的实验。显示的数据是用抗-κ-ETA’-预孵育的抗-TF HuMab处理的细胞的一式三份孔的平均荧光强度(MFI) ± S.E.M.。较高的虚线表示在不存在抗-κ-ETA’-预孵育的抗-TF HuMab下获得的最大信号;较低的虚线表示用十字孢碱获得的最大杀死。
表5 –由抗-κ-ETA’-预孵育的抗-TF HuMab诱导的EC50值和细胞杀死的百分比概况
a) 不能被计算。
显示的数据是在一个代表性实验中测量的用抗-κ-ETA’-预孵育的抗-TF HuMab处理的所示细胞系的EC50值(以μg/mL)和最大百分比杀死。细胞杀死的百分比(%杀死)计算如下:
(MFI未处理的 – MFI缀合的HuMab处理的) / (MFI未处理的 – MFI十字孢碱处理的)。
实施例16
抗-TF ADC的制备
在HEK-293F细胞(HuMab-011、HuMab-111和IgG1-b12)中或者使用稳定的CHO细胞系(HuMab-098)瞬时产生HuMab-011、HuMab-098、HuMab-111和阴性对照IgG1-b12。根据标准程序,通过蛋白A层析纯化抗体,最终得到大约400 mg的纯化抗体。接着,将抗体与vcMMAE和mcMMAF分别缀合。将大约200 mg的HuMab-011、HuMab-098或HuMab-111与vcMMAE或mcMMAF缀合。根据文献(Sun 等 (2005) Bioconjugate Chem. 16: 1282-1290; McDonagh 等,(2006) Protein Eng. Design Sel. 19: 299-307; Alley 等, (2008) BioconjugateChem. 19: 759-765)中描述的步骤,使药物接头vcMMAE或mcMMAF与还原的抗体的半胱氨酸烷基化。通过加入过量的N-乙酰半胱氨酸来猝灭反应。通过纯化移除任何残留的未缀合药物,并将最终的抗-TF抗体药物缀合物在PBS中配制。随后分析抗-TF抗体药物缀合物的浓度(通过280 nm的吸光度)、药物/抗体比(‘DAR’) (通过反相层析(RP-HPLC)和疏水作用层析(HIC))、未缀合的药物量(通过反相层析)、百分比聚集(通过尺寸排阻层析,SEC-HPLC)和内毒素水平(通过LAL)。结果在下文表6中示出。
表6 –抗体药物缀合物的不同特性的概述
实施例17
抗-TF ADC与TF的重组细胞外结构域的结合,由ELISA测定
抗-TF ADC与TF的结合由ELISA测量(包被TF的重组细胞外结构域),并与未缀合的抗-TF HuMab的结合比较。将ELISA板(Greiner BioOne)用1.25 μg/mL PBS中的重组TFECDHis (B. Braun Melsungen AG) (100 μL/孔)在4℃包被O/N。将ELISA板用包含0.05%Tween-20的PBS (PBST)洗涤3次,振荡(300 rpm)的同时用200 μL/孔 PBST室温封闭1小时,用PBST洗涤3次并清空。随后,以PBST中的系列稀释加入100 μL 抗-TF ADC或未缀合的抗-TF HuMab,并在振荡的同时室温孵育90分钟。将ELISA板用PBST洗涤3次并清空。通过在测定缓冲液中加入HRP缀合的小鼠-抗人IgG1 (100 μL; 0.015 μg/mL; Sanquin; # M1328)并在振荡的同时室温孵育1小时,检测结合的抗-TF ADC和未缀合的HuMab。将板用PBST洗涤3次,清空,用100 μL ABTS溶液(50 ml ABTS缓冲液[Roche] 和一片ABTS 片[50 mg;Roche])孵育。在暗处室温孵育30分钟后,通过用100μL/孔草酸(2% [w/v]; Riedel deHaen)在暗处孵育10分钟来终止反应。将板在ELISA读数仪(Biotek Instruments, EL808Absorbance Microplate Reader)上测量OD 405 nm。
将IgG1-b12 (与非相关抗原结合的抗体)用作阴性对照(未缀合的以及ADC形式)。
通过使用GraphPad Prism 5软件(GraphPad Software, San Diego, CA, USA)的非线性回归(具有可变斜率的S型剂量-反应)来分析结合曲线。
图7显示结合曲线,表明所有的抗-TF HuMab和ADC在ELSIA中在类似的范围内与TF细胞外结构域结合(EC50值为370-470 ng/mL)。
表7显示与TF的细胞外结构域结合的抗-TF HuMab和ADC的EC50值。EC50值以ng/mL计。
表 7 –由ELISA测定的TF特异性HuMab和ADC与TF的细胞外结构域的结合的EC50值概况。
实施例18
在体外杀死测定中的抗体介导的内化和通过抗-TF ADC的细胞杀死
为了测定抗-TF ADC诱导细胞毒性的能力,进行体外基于细胞的杀死测定。
对于不同的抗-TF ADC,测试3种细胞系的细胞杀死。A431细胞获自DeutscheSammlung von Mikroorganimsmen und Zellkulturen GmbH (DSMZ: ACC 91),HPAF-II和NCI-H441细胞获自美国典型培养物保藏中心(ATCC: CRL-1997和HTB-174)。将细胞以最优浓度(A431: 2.5 x 103细胞/孔; HPAF-II和NCI-H441: 5 x 103细胞/孔)在96孔组织培养板(Greiner Bio-one)的细胞培养基中接种并允许粘附。加入系列稀释的抗-TF ADC,并在37℃孵育72小时(A431和HPAF-II)或96小时(NCI-H441)。根据制造商的说明书,用AlamarBlue (BioSource International, San Francisco, US)定量活细胞的量。使用具有标准AlamarBlue设置的EnVision 2101 Multilabel读数仪(PerkinElmer, Turku,Finland)监测荧光。将IgG1-b12 (与非相关抗原结合的抗体) ADC用作阴性对照。将十字孢碱(Sigma, # S6942)用于诱导最大细胞杀死。
A431和HPAF-II细胞系两者都表达超过200,000个组织因子分子/细胞,并可因此被认为表达高水平的组织因子。
NCI-H441细胞表达大约80,000个组织因子分子/细胞,并因此被认为表达中等水平的组织因子。
图8和表8显示,所有的抗-TF ADC能够以剂量依赖的方式杀死A431、HPAF-II和NCI-H441细胞。HuMab-TF-098和-011 (对A431细胞的IC50为9-22 ng/mL,对HPAF-II细胞为1-5 ng/mL和对NCI-H441细胞为1-10 ng/mL)比HuMab-TF-111 (对A431细胞的IC50为46-83ng/mL,对HPAF-II细胞为4-15 ng/mL和对NCI-H441细胞为416 ng/mL)诱导稍更有效的杀死。对于各细胞系:A431 (a) 和HPAF-II (b),显示一个代表性的实验。显示的数据是用抗-TF ADC处理的细胞的一式两份孔的百分比存活 ± S.E.M.。
表8 –由抗-TF ADC诱导的IC50值和细胞杀死的百分比概况
a) 不能被计算。
显示的数据是在一个代表性实验中测量的用抗-TF ADC处理的所示细胞系的IC50值(以ng/mL)和最大百分比杀死(以10 μg/mL的浓度)。细胞杀死的百分比(%杀死)计算如下:
(MFI未处理的 – MFI抗-TF ADC处理的) / (MFI未处理的 – MFI十字孢碱处理的) x 100%。
实施例19
用抗-TF ADC治疗性处理SCID小鼠中的A431和HPAF-II肿瘤异种移植物
在SCID小鼠的建立皮下(SC) A431和HPAF-II异种移植物肿瘤中测定抗-TF ADC的体内功效。在雌性SCID小鼠的右翼SC注射200 μL PBS中的5 x 106 A431 (获自DSMZ)或2 x106 HPAF-II (获自ATCC)肿瘤细胞,之后是抗-TF ADC或对照(IgG1-b12; ADC和未缀合的形式)的4次注射,当A431异种移植物的肿瘤大小为大约200-250 mm3 (第11、14、18和21天)或者HPAF-II异种移植物的肿瘤大小为大约100-150 mm3 (第13、16、20和23天(100 μL中的60 μg/小鼠,腹膜内(IP)))时开始。至少每周两次测定肿瘤体积。肿瘤体积(mm3)是通过卡尺(PLEXX)测量为:0.52 x (长度) x (宽度)2。
图9显示,所有的抗-TF ADC有效抑制建立的皮下A431 (a)和HPAF-II (b)肿瘤的肿瘤生长。显示的数据是平均肿瘤体积± S.E.M./组(n = 7只小鼠/组)。在HPAF-II模型中,vcMMAE缀合物比mcMMAF缀合物显著更加有效抑制肿瘤生长。
实施例20
抗-TF先导克隆(lead clone) ADC和IgG1-b12 ADC的稳定性
在< -65℃和5℃储存10天、1、2和3个月时,测试MMAE-和MMAF-缀合的材料的稳定性。在本实施例中,仅显示3个月数据,因为对于所有中间时间点获得了类似的结果。此外,在重复冷冻-解冻循环时,测试材料的稳定性。
将制备的ADC批次(各与两种不同接头缀合的四种IgG批次,表6)低温冷冻。对于稳定性测试,将批次解冻并在PBS中稀释至1 mg/mL。将稀释的材料在冷冻管中等分为300 μL部分并将管放置在< -65℃或5℃的温度下储存。对于冷冻-解冻,将每批的3管在< -65℃O/N冷冻,然后在室温自助解冻。将冷冻-解冻循环重复另外两次(样品共计冷冻-解冻3次)。在研究开始时(t=0),通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)、高效尺寸排阻层析(HP-SEC)以及在结合ELISA中与组织因子(TFECDHis)结合来分析所有材料。对在< -65℃和5℃储存3个月(t=3个月)的样品以及冷冻-解冻样品进行相同的分析。
使用其中样品在中性pH运行的改良Laemli法(Laemli 1970 Nature 227(5259):680-5),在还原和非还原条件下,在4-12% NuPAGE Bis-Tris凝胶(Invitrogen, Breda,The Netherlands)上进行SDS-PAGE。将SDS-PAGE凝胶用考马斯染色以及使用OptigoImaging System (Isogen Life Science)数字成像。
使用与TSK HP-SEC柱(G3000SWxl; Tosoh Bioscience, 经由Omnilabo, Breda,The Netherlands)和Waters 2487双重λ吸光度检测器(Waters)相连接的Waters Alliance2695或2795分离装置(Waters, Etten-Leur, The Netherlands),进行HP-SEC。以1 mL/min运行样品。使用Empower软件版本2处理结果,并以总峰高的百分比表示每个峰的结果。
如上文实施例17中所述,通过ELISA分析与TF细胞外结构域的重组蛋白的结合。
图10 a-d显示,未缀合的和缀合的抗-TF先导克隆以及IgG1-b12在稳定性研究开始时(t=0)的SDS-PAGE分析。在非还原的SDS-PAGE (a,b)上,未缀合的IgG1作为约150 kDa的完整IgG条带迁移。正如预期的,ADC大部分解离为较小尺寸的IgG片段(125 kDa=HHL, 99kDa=HH, 67 kDa=HL, 51 kDa=H和25 kDa=L),归因于变性的SDS-PAGE条件和ADC分子的非共价性质(破坏的二硫键) (图10 a,b)。还原的SDS-PAGE分析(图10 c,d)显示未缀合的轻链(L0)和具有一个药物(MMAE或MMAF)连接的轻链(L1)的条带。对于未缀合的重链(H0)和MMAE缀合的形式(H1、H2和H3),观察到部分解析。MMAF缀合的和未缀合的重链形式不能很好的解析但作为50 kDa的扩散带呈现。
在两种温度(< -65℃和5℃)储存3个月后的样品的SDS-PAGE结果与t=0数据是可比较的,如图10 e-f所示。同样对于冷冻-解冻样品,与起始材料相比,通过SDS-PAGE分析未观察到差异(数据未显示)。
图11显示在t=0和t=3月,在两种温度下,ADC批次的HP-SEC图叠加。在天然HP-SEC条件下,ADC材料(t=0)作为具有少量二聚IgG分子的单体IgG分子的一个峰洗脱。对于3个月储存时的MMAE和MMAF缀合的HuMab-TF-098 (a, b)和HuMab-TF-011 (c, d),未观察到变化。然而,HuMab-TF-111 (e, f)和IgG1-b12 (g, h)的ADC材料在t=3月时显示回收(峰高)的减少。该较低的回收已在t=10天的样品中观察到,并在延长储存多达3个月后保持不变。
从HP-SEC峰图计算单体IgG分子的百分比(%单体),数据在表9中总结。为了比较,显示未缀合材料的%单体。数据显示,> 95%的ADC材料由完整单体IgG分子组成。%单体在< -65℃和5℃储存3个月后保持不变化,表明那时未形成聚集体。
冷冻/解冻样品的HP-SEC分析显示,所有样品的IgG峰回收与t=0的回收类似(数据未显示)。然而,冷冻-解冻HuMab TF-ADC材料得到稍低的%单体(1.5-3.6%),如表9所示。这归因于少量的聚集体的形成(如由HP-SEC鉴定的二聚体IgG分子,数据未显示)。
通过ELISA测试未缀合的以及缀合的HuMab-TF-098、-011和-111与TF细胞外结构域的重组蛋白(TFECDHis)的结合。在< -65℃和5℃储存3个月后,与t=0的结合能力相比,结合能力未变化,如图12所示。对于冷冻-解冻样品获得类似的结果(数据未显示)。
稳定性实验显示,1 mg/mL的ADC材料在< -65℃和5℃至少3个月是稳定的,如由SDS-PAGE、HP-SEC和与TFECDHis的结合所测定。少量的聚集体形成由重复的冷冻解冻材料所诱导。
表9:ADC样品的HP-SEC分析。
显示的数据是百分比单体分子。
实施例21
抗-TF ADC在治疗性处理SCID小鼠中的HPAF-II肿瘤异种移植物的剂量反应
通过用不同剂量的抗-TF ADC处理SCID小鼠中的建立的SC HPAF-II异种移植物肿瘤,进一步分析抗-TF ADC的体内功效。如上文所述建立HPAF-II肿瘤异种移植物,之后是两种不同剂量的抗-TF vcMMAE ADC (100 μL中的6和20 μg/小鼠[加入IgG1-b12至终剂量为60 μg IgG1/小鼠], IP)或者对照未缀合的mAb (IgG1-b12; 100 μL中的60 μg/小鼠, IP)的4次注射;当肿瘤大小为大约100-150 mm3 (第10、13、17和21天)时开始。至少每周两次测定肿瘤体积。肿瘤体积(mm3)是通过卡尺(PLEXX)测量为:0.52 x (长度) x (宽度)2。
图13显示,20 μg剂量的所有3种vcMMAE缀合物都有效抑制建立的皮下HPAF-II肿瘤的肿瘤生长。6 μg剂量的所有3种vcMMAE缀合物能够稍延缓但不能抑制肿瘤生长。
等同物
本领域技术人员将认识到,或者使用不超过常规实验能够确定,本文所述发明的具体实施方案的许多等同物。这样的等同物旨在由下述权利要求所涵盖。亦预期从属权利要求中所公开的实施方案的任何组合在本发明的范围内。
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Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Gly Tyr Phe Leu Leu Trp Tyr Phe Asp Leu Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 10
<211> 8
<212> PRT
<213> 人
<400> 10
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 11
<211> 8
<212> PRT
<213> 人
<400> 11
Ile Ser Gly Ser Gly Asp Ser Thr
1 5
<210> 12
<211> 13
<212> PRT
<213> 人
<400> 12
Ala Lys Asp Gly Tyr Phe Leu Leu Trp Tyr Phe Asp Leu
1 5 10
<210> 13
<211> 118
<212> PRT
<213> 人
<400> 13
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser Gly Ser Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ala Pro Trp Thr Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 14
<211> 8
<212> PRT
<213> 人
<400> 14
Gly Phe Thr Phe Ser Ser Tyr Gly
1 5
<210> 15
<211> 8
<212> PRT
<213> 人
<400> 15
Ile Ser Gly Ser Gly Gly Thr Thr
1 5
<210> 16
<211> 11
<212> PRT
<213> 人
<400> 16
Ala Lys Ala Pro Trp Thr Tyr Tyr Phe Asp Tyr
1 5 10
<210> 17
<211> 118
<212> PRT
<213> 人
<400> 17
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Thr Pro Trp Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 18
<211> 8
<212> PRT
<213> 人
<400> 18
Gly Phe Thr Phe Asn Asn Tyr Ala
1 5
<210> 19
<211> 8
<212> PRT
<213> 人
<400> 19
Ile Ser Gly Ser Gly Gly Arg Thr
1 5
<210> 20
<211> 11
<212> PRT
<213> 人
<400> 20
Ala Lys Thr Pro Trp Gly Tyr Tyr Phe Asp Tyr
1 5 10
<210> 21
<211> 118
<212> PRT
<213> 人
<400> 21
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Ala Lys Gly Leu Asp Trp Val
35 40 45
Ser Gly Ile Ser Gly Ser Gly Val Thr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Thr Pro Trp Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Ile
100 105 110
Leu Val Ala Val Ser Ser
115
<210> 22
<211> 8
<212> PRT
<213> 人
<400> 22
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 23
<211> 8
<212> PRT
<213> 人
<400> 23
Ile Ser Gly Ser Gly Val Thr Thr
1 5
<210> 24
<211> 11
<212> PRT
<213> 人
<400> 24
Ala Lys Thr Pro Trp Gly Tyr Tyr Phe Asp Tyr
1 5 10
<210> 25
<211> 120
<212> PRT
<213> 人
<400> 25
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Asn Asp Gly Tyr Asn Asp Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Gln Leu Gly Arg Gly Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 26
<211> 8
<212> PRT
<213> 人
<400> 26
Gly Phe Thr Phe Ser Arg Tyr Ala
1 5
<210> 27
<211> 8
<212> PRT
<213> 人
<400> 27
Ile Ser Asn Asp Gly Tyr Asn Asp
1 5
<210> 28
<211> 13
<212> PRT
<213> 人
<400> 28
Ala Arg Asp Gly Gln Leu Gly Arg Gly Tyr Phe Asp Tyr
1 5 10
<210> 29
<211> 120
<212> PRT
<213> 人
<400> 29
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Pro Ala Ser Gly Phe Thr Phe Ser Ile Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Val Ser Asn Asp Gly Tyr Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asp Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Gln Leu Gly Arg Gly Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 30
<211> 8
<212> PRT
<213> 人
<400> 30
Gly Phe Thr Phe Ser Ile Tyr Ala
1 5
<210> 31
<211> 8
<212> PRT
<213> 人
<400> 31
Val Ser Asn Asp Gly Tyr Asn Lys
1 5
<210> 32
<211> 13
<212> PRT
<213> 人
<400> 32
Ala Arg Asp Gly Gln Leu Gly Arg Gly Tyr Phe Asp Tyr
1 5 10
<210> 33
<211> 118
<212> PRT
<213> 人
<400> 33
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ser Phe Asn Asn Tyr
20 25 30
Pro Ile Phe Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Ala Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Gly Asp Asp Leu Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Ser Val Ser Ser
115
<210> 34
<211> 8
<212> PRT
<213> 人
<400> 34
Gly Gly Ser Phe Asn Asn Tyr Pro
1 5
<210> 35
<211> 8
<212> PRT
<213> 人
<400> 35
Ile Ile Pro Ile Leu Gly Ile Thr
1 5
<210> 36
<211> 11
<212> PRT
<213> 人
<400> 36
Ala Gly Gly Asp Asp Leu Asp Ala Phe Asp Ile
1 5 10
<210> 37
<211> 120
<212> PRT
<213> 人
<400> 37
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Asn Arg Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val
35 40 45
Ala Val Ile Ser Asn Asp Gly Ile Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp His Thr Met Val Arg Gly Ala Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 38
<211> 8
<212> PRT
<213> 人
<400> 38
Gly Phe Thr Phe Asn Arg Tyr Ala
1 5
<210> 39
<211> 8
<212> PRT
<213> 人
<400> 39
Ile Ser Asn Asp Gly Ile Asn Lys
1 5
<210> 40
<211> 13
<212> PRT
<213> 人
<400> 40
Ala Arg Asp His Thr Met Val Arg Gly Ala Phe Asp Tyr
1 5 10
<210> 41
<211> 107
<212> PRT
<213> 人
<400> 41
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 7
<212> PRT
<213> 人
<400> 42
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 43
<211> 3
<212> PRT
<213> 人
<400> 43
Gly Ala Ser
1
<210> 44
<211> 8
<212> PRT
<213> 人
<400> 44
Gln Gln Tyr Gly Ser Ser Leu Thr
1 5
<210> 45
<211> 107
<212> PRT
<213> 人
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Arg
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 46
<211> 6
<212> PRT
<213> 人
<400> 46
Gln Gly Ile Ser Ser Arg
1 5
<210> 47
<211> 3
<212> PRT
<213> 人
<400> 47
Ala Ala Ser
1
<210> 48
<211> 9
<212> PRT
<213> 人
<400> 48
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 49
<211> 108
<212> PRT
<213> 人
<400> 49
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 50
<211> 7
<212> PRT
<213> 人
<400> 50
Gln Ser Val Arg Ser Ser Tyr
1 5
<210> 51
<211> 3
<212> PRT
<213> 人
<400> 51
Gly Ala Ser
1
<210> 52
<211> 9
<212> PRT
<213> 人
<400> 52
Gln Gln Tyr Gly Ser Ser Pro Arg Thr
1 5
<210> 53
<211> 108
<212> PRT
<213> 人
<400> 53
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 54
<211> 7
<212> PRT
<213> 人
<400> 54
Gln Ser Val Gly Ser Ser Ser
1 5
<210> 55
<211> 3
<212> PRT
<213> 人
<400> 55
Gly Ala Ser
1
<210> 56
<211> 9
<212> PRT
<213> 人
<400> 56
Gln Gln Tyr Gly Ser Ser Pro Arg Thr
1 5
<210> 57
<211> 107
<212> PRT
<213> 人
<400> 57
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Arg
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 58
<211> 6
<212> PRT
<213> 人
<400> 58
Gln Gly Ile Ser Ser Arg
1 5
<210> 59
<211> 3
<212> PRT
<213> 人
<400> 59
Ala Ala Ser
1
<210> 60
<211> 9
<212> PRT
<213> 人
<400> 60
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 61
<211> 108
<212> PRT
<213> 人
<400> 61
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 62
<211> 6
<212> PRT
<213> 人
<400> 62
Gln Gly Ile Ser Ser Trp
1 5
<210> 63
<211> 3
<212> PRT
<213> 人
<400> 63
Ala Ala Ser
1
<210> 64
<211> 10
<212> PRT
<213> 人
<400> 64
Gln Gln Tyr Asn Ser Tyr Pro Leu Tyr Thr
1 5 10
<210> 65
<211> 107
<212> PRT
<213> 人
<400> 65
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 66
<211> 6
<212> PRT
<213> 人
<400> 66
Gln Ser Val Ser Ser Tyr
1 5
<210> 67
<211> 3
<212> PRT
<213> 人
<400> 67
Asp Ala Ser
1
<210> 68
<211> 9
<212> PRT
<213> 人
<400> 68
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 69
<211> 107
<212> PRT
<213> 人
<400> 69
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Ile Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 70
<211> 6
<212> PRT
<213> 人
<400> 70
Gln Ser Val Ser Ser Tyr
1 5
<210> 71
<211> 3
<212> PRT
<213> 人
<400> 71
Asp Ala Ser
1
<210> 72
<211> 9
<212> PRT
<213> 人
<400> 72
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 73
<211> 107
<212> PRT
<213> 人
<400> 73
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 74
<211> 6
<212> PRT
<213> 人
<400> 74
Gln Gly Ile Ser Ser Trp
1 5
<210> 75
<211> 3
<212> PRT
<213> 人
<400> 75
Ala Ala Ser
1
<210> 76
<211> 9
<212> PRT
<213> 人
<400> 76
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 77
<211> 107
<212> PRT
<213> 人
<400> 77
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 78
<211> 6
<212> PRT
<213> 人
<400> 78
Gln Ser Val Ser Ser Tyr
1 5
<210> 79
<211> 3
<212> PRT
<213> 人
<400> 79
Asp Ala Ser
1
<210> 80
<211> 9
<212> PRT
<213> 人
<400> 80
Gln Gln Arg Ser Asn Trp Pro Leu Thr
1 5
<210> 81
<211> 327
<212> PRT
<213> 人
<400> 81
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 82
<211> 315
<212> PRT
<213> 人
<400> 82
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
100 105 110
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
115 120 125
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
130 135 140
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
145 150 155 160
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
165 170 175
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
180 185 190
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
195 200 205
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
210 215 220
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
225 230 235 240
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
245 250 255
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
260 265 270
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
275 280 285
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
290 295 300
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
305 310 315
Claims (28)
1.一种包含抗体的抗体药物缀合物,所述抗体与组织因子结合并包含:
(i) SEQ ID NO: 34所示的氨基酸序列的CDR1区、SEQ ID NO: 35所示的氨基酸序列的CDR2区和SEQ ID NO: 36所示的氨基酸序列的CDR3区的VH区,和SEQ ID NO: 74所示的氨基酸序列的CDR1区、SEQ ID NO: 75所示的氨基酸序列的CDR2区和SEQ ID NO: 76所示的氨基酸序列的CDR3区的VL区,
其中所述抗体经由接头与auristatin缀合。
2.权利要求1的抗体药物缀合物,其中所述抗体包含:
VH区,其氨基酸序列如SEQ ID NO: 33所示和VL区,其氨基酸序列如SEQ ID NO: 73所示。
3.权利要求1或2的抗体药物缀合物,其中所述抗体是全长抗体。
4.权利要求1或2的抗体药物缀合物,其中所述抗体是全人单克隆IgG1抗体。
5.权利要求4的抗体药物缀合物,其中IgG1抗体是IgG1,κ。
8.权利要求1或2的抗体药物缀合物,其中接头与通过部分还原抗-TF抗体所获得的抗-TF抗体的巯基残基连接。
10.权利要求9的抗体药物缀合物,其中接头- auristatin是权利要求9中所定义的vcMMAE。
12.一种药物组合物,其包含权利要求1-11中任一项所定义的抗体药物缀合物和药学上可接受的载体。
13.权利要求1-11中任一项所定义的抗体药物缀合物在制备用于治疗癌症的药物中的用途。
14.权利要求13的用途,其中所述癌症选自:中枢神经系统的肿瘤、头颈癌、肺癌、乳腺癌、食道癌、胃癌、肝胆癌、胰腺癌、膀胱癌、肾癌、前列腺癌、卵巢癌、恶性黑色素瘤、肉瘤、未知原发来源的肿瘤、骨髓癌、急性成淋巴细胞白血病、急性髓性白血病、慢性成淋巴细胞白血病和非霍奇金淋巴瘤、皮肤癌、子宫癌和直肠癌。
15.权利要求14的用途,中枢神经系统的肿瘤是脑癌;肺癌是非小细胞肺癌;乳腺癌是三阴乳腺癌。
16.权利要求13的用途,其中所述癌症是胰腺癌。
17.权利要求13的用途,其中所述癌症是结直肠癌。
18.权利要求13的用途,其中所述癌症是卵巢癌。
19.权利要求13的用途,其中所述癌症是乳腺癌。
20.权利要求13的用途,其中所述癌症是前列腺癌。
21.权利要求13的用途,其中所述癌症是膀胱癌。
22.权利要求13的用途,其中所述癌症是结直肠癌或子宫内膜癌。
23.权利要求13的用途,其中所述癌症是神经胶质瘤。
24.权利要求13的用途,其中所述药物是用于与一种或多种另外的治疗剂联合治疗癌症。
25.有效量的权利要求1-11中任一项的抗体药物缀合物在制备用于诱导表达组织因子的肿瘤细胞的细胞死亡或者抑制其生长和/或增殖的药物中的用途。
26.有效量的权利要求1-11中任一项的抗体药物缀合物在制备治疗权利要求14-23中任何疾病的药物中的用途。
27.权利要求26的用途,其中所述抗体药物缀合物与一种或多种另外的治疗剂联合给予。
28.权利要求24或27的用途,其中另外的治疗剂是化学治疗剂。
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