CN107428837A - 循环trop‑2阳性癌细胞的分离、检测、诊断和/或鉴定 - Google Patents
循环trop‑2阳性癌细胞的分离、检测、诊断和/或鉴定 Download PDFInfo
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Abstract
本文描述了使用抗Trop‑2抗体或其抗原结合片段来分离、富集、检测、诊断和/或鉴定患有Trop‑2阳性癌症的患者的循环肿瘤细胞(CTC)的组合物和方法。优选地,所述抗体是RS7、162‑46.2或MAB650抗体。所述组合物和方法用于检测、诊断和/或治疗转移性Trop‑2+癌症,诸如乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、肺癌、前列腺癌、结肠癌、直肠癌、胃癌、食道癌、膀胱癌、肾癌、胰腺癌、甲状腺癌、上皮癌或头颈癌。
Description
相关申请
本专利要求根据35U.S.C.119(e)要求提交于2015年4月22日的美国临时专利申请62/151,169的权益,该专利申请的全文以引用的方式并入本文。
序列表
本申请含有序列表,所述序列表以ASCII格式通过EFS-Web提交并且由此以引用的方式整体并入。所述ASCII副本创建于2016年4月21日,命名为IMM359WO1_SL.txt,大小为44,906字节。
背景技术
技术领域
本发明涉及用于分离、检测、诊断和/或鉴定Trop-2+癌细胞,优选地来自循环的Trop-2+癌细胞的方法和组合物。该方法和组合物利用抗Trop-2抗体,该抗Trop-2抗体可以是单价的、二价的或多价的。在一个优选的实施方案中,抗Trop-2抗体是用于分析的单独抗TAA(肿瘤相关抗原)捕集抗体,该分析不包括使用抗除Trop-2之外的TAA的抗体混合物。在替代实施方案中,捕集抗体可以是包含抗Trop-2抗体或片段和抗不同的TAA的第二抗体或片段的双特异性抗体。更优选地,该抗体是啮齿动物、嵌合、人源化或人抗体或其抗原结合片段。Trop-2在癌细胞中的表达可使用已知的技术评估,包括但不限于通过流式细胞术或免疫组织化学和定量RT-PCR检测抗Trop-2抗体的结合。在受权利要求书保护的方法的实践中可利用已开发的分离和/或检测循环肿瘤细胞(CTC)的自动化系统和装置,包括但不限于MagSweeper装置(Illumina,Inc.,San Diego,CA)、系统(CynvenioBiosystems,Inc.,Westlake Village,CA)、系统(Veridex LLC,Raritan,NJ)、GILUPI CELLCOLLECTORTM(GILUPI GmbH,Potsdam,Germany)、系统(Apocell,Houston,TX)、ONCOCEETM微流体平台(BioCeptLaboratories,San Diego,CA)、VerIFAST系统(Casavant等人,2013,Lab Chip 13:391-6;2014,Lab Chip 14:99-105)或ISOFLUXTM系统(Fluxion,South San Francisco,CA)。最优选地,抗Trop-2抗体是鼠、嵌合或人源化RS7(hRS7)抗体,其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SASYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQ IDNO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,,SEQ ID NO:6)。然而,如下文所讨论,在替代实施方案中,可利用其他已知的抗Trop-2抗体。该方法和组合物适用于富集、分离、检测、诊断和/或鉴定各种表达Trop-2的转移性癌症,诸如乳腺癌(如,三阴性乳腺癌)、卵巢癌、宫颈癌、子宫内膜癌、肺癌、前列腺癌、结肠癌、直肠癌、胃癌、食道癌、膀胱癌、肾癌、胰腺癌、甲状腺癌、上皮癌和头颈癌。抗Trop-2抗体可与一个或多个标记检测抗体组合使用,或可通过与至少一种诊断剂缀合来直接标记。或者,双特异性抗体可包括一个Trop-2的结合位点和可靶向构建体上的另一个半抗原结合位点,该可靶向构建体通常是通过至少一种诊断剂标记的小肽。在某些替代实施方案中,Trop-2+CTC的检测可在使用抗Trop-2抗体或其片段进行Trop-2+癌症的治疗处理之后进行。优选地,抗体或片段缀合至至少一种治疗剂,诸如抗体、抗体片段、药物、毒素、核酸酶、激素、免疫调节剂、促凋亡剂、抗血管生成剂、硼化合物、光活性剂或染料或放射性同位素。更优选地,治疗剂是SN-38或P2PDOX。
相关技术
Trop-2(人滋养层细胞表面标记物)是最初在正常和恶性滋养层细胞中鉴定的细胞表面糖蛋白(Lipinski等人,1981,Proc Natl.Acad Sci USA 78:5147-50)。Trop-2在大多数人类恶性肿瘤,特别是上皮癌和腺癌中高度表达,并且据报道在正常组织中低至限制表达(参见例如,Cubas等人,2010,Molec Cancer 9:253;Stepan等人,2011,J HistochemCytochem 59:701-10;Varughese等人,2011,Am J Obst Gyn 205:567e-e7)。Trop-2的表达与癌症转移、肿瘤侵袭性增加和患者存活率下降相关(Cubas等人,2010;Varughese等人,2011)。据报道,Trop-2的致病作用至少部分通过ERK 1/2MAPK途径介导(Cubas等人,2010)。
已提出,在肿瘤进展早期,癌细胞可以低浓度存在于循环中(参见例如,Krishnamurthy等人,2013,Cancer Medicine 2:226-33;Alix-Panabieres & Pantel,2013,Clin Chem 50:110-18;Wang等人,2015年2月24日,Int J Clin Oncol,提前在线发表)。由于血样采集的相对非侵入性质,分离和检测CTC,以促进在疾病的早期进展癌症诊断并作为肿瘤进展的预测因子、疾病预后和/或对药物治疗的响应,引起了极大的关注(参见例如,Alix-Panabieres & Pantel,2013,Clin Chem 50:110-18;Winer-Jones等人,2014,PLoS One 9:e86717;美国专利申请公开No.2014/0357659)。
已开发分离和/或检测循环肿瘤细胞的各种技术和设备。该领域最近发表了很多综述(参见例如,Alix-Panabieres & Pantel,2013,Clin Chem 50:110-18;Joosse等人,2014,EMBO Mol Med 7:1-11;Truini等人,2014,Fron Oncol 4:242)。该技术涉及通常使用抗肿瘤细胞上表达的抗原的捕集抗体富集和/或分离CTC,以及使用磁性纳米颗粒、微流体装置、过滤、磁力分离、离心、流式细胞术和/或细胞分选装置分离(例如,Krishnamurthy等人,2013,Cancer Medicine 2:226-33;Alix-Panabieres & Pantel,2013,Clin Chem 50:110-18;Joosse等人,2014,EMBO Mol Med 7:1-11;Truini等人,2014,Fron Oncol 4:242;Powell等人,2012,PLoS ONE 7:e33788;Winer-Jones等人,2014,PLoS One 9:e86717;Gupta等人,2012,Biomicrofluidics 6:24133;Saucedo-Zeni等人,2012,Int J Oncol 41:1241-50;Harb等人,2013,Transl Oncol 6:528-38)。然后可使用多种已知方法分析富集或分离的CTC,如下文进一步讨论。用于CTC分离和检测的系统或设备包括系统(例如,Truini等人,2014,Front Oncol 4:242)、MagSweeper装置(例如,Powell等人,2012,PLoS ONE 7:e33788)、系统(Winer-Jones等人,2014,PLoS One9:e86717)、系统(例如,Gupta等人,2012,Biomicrofluidics 6:24133)、GILUPI CELLCOLLECTORTM(例如,Saucedo-Zeni等人,2012,Int J Oncol 41:1241-50)和ISOFLUXTM系统(Harb等人,2013,Transl Oncol 6:528-38)。
迄今为止,唯一的FDA批准的CTC检测技术涉及平台(VeridexLLC,Raritan,NJ),其利用附连到磁性纳米颗粒的抗EpCAM抗体来捕集CTC。结合细胞的检测使用抗细胞角蛋白(CK)和CD45的荧光标记抗体进行。使用强磁场分离出结合到磁性颗粒的荧光标记细胞,并通过数字荧光显微术法计数。系统已获得FDA批准用于检测转移性乳腺癌、前列腺癌和结直肠癌。
大多数CTC检测系统集中在抗EpCAM捕集抗体的使用(参见例如,Truini等人,2014,Front Oncol 4:242;Powell等人,2012,PLoS ONE 7:e33788;Alix-Panabieres &Pantel,2013,Clin Chem 50:110-18;Lin等人,2013,Biosens Bioelectron 40:63-67;Wang等人,2015年2月24日,Int J Clin Oncol,提前在线发表;Magbanua等人,2015,ClinCancer Res 21:1098-105;Harb等人,2013,Transl Oncol 6:528-38)。然而,并非所有转移性肿瘤都表达EpCAM(参见例如,Mikolajcyzyk等人,2011,J Oncol 2011:252361;Pecot等人,2011,Cancer Discovery 1:580-86;Gupta等人,2012,Biomicrofluidics 6:24133)。已尝试利用可选的方案来分离和检测EpCAM阴性CTC,诸如使用抗TAA的抗体组合。已利用抗多达10种不同的TAA的抗体以试图提高转移性循环肿瘤细胞的回收率(例如,Mikolajcyzyk等人,2011,J Oncol 2011:252361;Pecot等人,2011,Cancer Discovery 1:580-86;Krishnamurthy等人,2013,Cancer Medicine 2:226-33;Winer-Jones等人,2014,PLoS One9:e86717)。
此类方法是存在缺点的,包括制备和使用许多不同的抗体及其与磁性纳米颗粒的附连、微流体装置或其他分离技术的复杂性,以及使用广谱抗肿瘤抗体时针对正常细胞群的潜在交叉反应性。本领域存在使用抗单个TAA的抗体分离、检测、诊断和/或鉴定CTC的改善方法的需要,所述TAA在一系列广泛的肿瘤中表达。
发明内容
在各种实施方案中,本发明涉及使用抗Trop-2抗体和/或其抗原结合片段富集、分离、检测、诊断和/或鉴定Trop-2阳性循环肿瘤细胞(CTC)。抗Trop-2抗体可用于从循环富集和/或分离肿瘤细胞。结合CTC可通过许多已知的技术和/或设备检测,如下文详细讨论。可利用任何已知的检测分离CTC的生物标记物的方法,诸如FISH、FACS、荧光显微术、荧光检测、流式细胞术、免疫组织化学、基于微芯片的系统、RT-PCR、ELISA或本领域已知的用于检测癌细胞存在的任何其他技术。
在具体实施方案中,抗Trop-2抗体可以是鼠、嵌合或人源化RS7抗体(参见例如,美国专利No.7,238,785,其附图和实施例部分以引用的方式并入本文),其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SASYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQID NO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ IDNO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。然而,如下文所讨论,其他抗Trop-2抗体是已知的并且可以使用。
抗Trop-2抗体部分可以是单克隆抗体、抗原结合抗体片段、双特异性或多价抗体或其他基于抗体的分子。该抗体可以具有各种同种型,优选地人IgG1、IgG2、IgG3或IgG4,更优选地包含人IgG1铰链和恒定区序列。抗体或其片段可以是啮齿动物、嵌合、人源化或人抗体,以及其变型,诸如半IgG4抗体(称为“单一抗体”),如van der Neut Kolfschoten等人(Science 2007;317:1554-1557)所述。更优选地,抗体或其片段可设计或选为包含属于特定同种异型,诸如G1m3、G1m3,1、G1m3,2或G1m3,1,2的人恒定区序列。更优选地,该同种异型选自nG1m1、G1m3、nG1m1,2和Km3同种异型。
当双特异性抗体用于捕集CTC时,抗体可包含至少一种抗Trop-2抗体或其片段,以及至少一种抗不同的TAA的抗体或其片段。示例性TAA可包括碳酸酐酶IX、CCL19、CCL21、CSAp、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、IGF-1R、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD66a-e、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CXCR4、CXCR7、CXCL12、HIF-1-α、AFP、PSMA、CEACAM5、CEACAM-6、c-met、B7、纤连蛋白的ED-B、因子H、FHL-1、Flt-3、叶酸受体、GROB、HMGB-1、缺氧诱导因子(HIF)、胰岛素样生长因子-1(ILGF-1)、IFN-γ、IFN-α、IFN-β、IL-2、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、MIF、MUC1、MUC2、MUC3、MUC4、MUC5ac、NCA-95、NCA-90、Ia、EGP-1、EGP-2、HLA-DR、腱生蛋白、Le(y)、RANTES、T101、TAC、Tn抗原、Thomson-Friedenreich抗原、肿瘤坏死抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、EGFR、P1GF、补体因子C3、C3a、C3b、C5a或C5。优选地,TAA选自CEACAM5、MUC5ac、CD74、HLA-DR、CSAp、AFP(α-胎蛋白)、HER2、波形蛋白、EGFR、IGF-1R、PD-L1和PD-L2。
因为所检测的肿瘤将是Trop-2阳性的,所以它们可用抗Trop-2抗体,诸如抗Trop-2抗体-药物缀合物(ADC)处理。抗Trop-2抗体最初可用于检测和/或定量CTC中Trop-2的表达或基因拷贝数。此类分析可用于预测对治疗性抗Trop-2抗体的响应,以及监控肿瘤对治疗的响应。如下文所讨论,抗Trop-2抗体的免疫缀合物可包括任何已知的治疗剂,诸如化疗剂。许多用于癌症治疗的细胞毒性药物是本领域熟知的,并且任何此类已知的药物均可缀合至所关注的抗体。在一个优选的实施方案中,缀合至抗体的药物是喜树碱(camptothecin)或蒽环类药物,最优选地是SN-38或2-吡咯啉多柔比星(2-PDox)的前药形式(参见例如,美国专利No.8,877,202和8,750,496,每个专利的附图和实施例部分以引用的方式并入本文)。缀合至抗Trop-2抗体或抗体片段的药物可选自蒽环类药物、喜树碱、微管蛋白抑制剂、美登木素生物碱(maytansinoid)、刺孢霉素、奥里斯他汀、氮芥、乙烯亚胺衍生物、烷基磺酸盐、亚硝基脲、三氮烯、叶酸类似物、紫杉烷、COX-2抑制剂、嘧啶类似物、嘌呤类似物、抗生素、酶抑制剂、表鬼臼毒素、铂配位络合物、长春花生物碱、取代脲、甲基肼衍生物、肾上腺皮质抑制剂、激素拮抗剂、抗代谢物、烷基化剂、抗有丝分裂剂、抗血管生成剂、酪氨酸激酶抑制剂、mTOR抑制剂、热激蛋白(HSP90)抑制剂、蛋白酶体抑制剂、HDAC抑制剂、促凋亡剂及其组合。
抗Trop-2抗体用于检测、诊断、鉴定和/或治疗表达Trop-2的癌症,诸如乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、肺癌、前列腺癌、结肠癌、直肠癌、胃癌、食道癌、膀胱癌、肾癌、胰腺癌、甲状腺癌、上皮癌或头颈癌。该方法和组合物可特别用于检测和/或治疗转移性结直肠癌、三阴性乳腺癌、HER+、ER+、黄体酮+乳腺癌、转移性非小细胞肺癌(NSCLC)、转移性小细胞肺癌(SCLC)、转移性胰腺癌、转移性肾细胞癌、转移性胃癌、转移性食道癌、转移性尿道上皮癌或转移性前列腺癌。
具体实施方式
定义
除非另外指明,“一个”或“一种”意指一个(种)或多个(种)。
如本文所用,“约”意指加上或减去10%。例如,“约100”将包括在90和110之间的任何数字。
如本文所描述,抗体是指全长(即,天然存在的或通过正常免疫球蛋白基因片段重组方法形成的)免疫球蛋白分子(如,IgG抗体)或免疫球蛋白分子的免疫活性(即,特异性结合)部分,如抗体片段。
抗体片段是抗体的一部分,诸如F(ab’)2、Fab’、Fab、Fv、sFv等等。抗体片段也可包括单结构域抗体和IgG4半分子,如下文所讨论。无论结构如何,抗体片段与全长抗体识别的相同抗原结合。术语“抗体片段”也包括分离片段,该分离片段由抗体的可变区组成,诸如“Fv”片段由重链和轻链的可变区和重组单链多肽分子组成,其中轻链和重链可变区通过肽接头(“scFv蛋白”)连接。
嵌合抗体是一种重组蛋白,其所包含的可变区包括来源于一个物种的抗体优选地啮齿动物抗体的互补决定区(CDR),而抗体分子的恒定区来源于人抗体的那些恒定区。对于兽医应用,嵌合抗体的恒定区可来源于其他物种诸如猫或狗。
人源化抗体是一种重组蛋白,其中来源于一个物种的抗体(如啮齿动物抗体)的CDR从啮齿动物抗体的重链和轻链可变链转移到人重链和轻链可变区(如,框架区序列)。抗体分子的恒定区来源于人抗体的那些恒定区。在某些实施方案中,来自亲本(啮齿动物)抗体的有限数量框架区氨基酸残基可被取代到人抗体框架区序列中。
人抗体是例如从转基因小鼠获得的抗体,已将该转基因小鼠“工程化”以产生响应于抗原激发而生成特异性人抗体。在该技术中,将人重链和轻链基因座的元件引入来源于胚胎干细胞系的小鼠品系,该胚胎干细胞系包含内源性鼠重链和轻链基因座的靶向破坏。转基因小鼠可合成对特定抗原有特异性的人抗体,并且小鼠可用于生成分泌人抗体的杂交瘤。用于从转基因小鼠获得人抗体的方法如Green等人,Nature Genet.7:13(1994),Lonberg等人,Nature 368:856(1994)和Taylor等人,Int.Immun.6:579(1994)所述。完全人抗体也可通过基因或染色体转染方法,以及噬菌体展示技术构建,所有技术都是本领域已知的。参见例如,McCafferty等人,Nature 348:552-553(1990)从未免疫供体的免疫球蛋白可变区基因谱体外生成人抗体及其片段。在该技术中,将抗体可变区基因同框克隆至丝状噬菌体的主要或次要外壳蛋白基因,并且在噬菌体颗粒的表面上展示为功能抗体片段。因为丝状颗粒包含噬菌体基因组的单链DNA拷贝,所以根据抗体的功能性质的选择也导致选择编码表现出这些性质的抗体的基因。以此方式,噬菌体模拟B细胞的一些性质。噬菌体展示可以多种形式进行,综述可参见例如Johnson和Chiswell,Current Opinion inStructural Biology 3:5564-571(1993)。人抗体也可通过体外活化B细胞来生成。参见美国专利No.5,567,610和5,229,275,其实施例部分以引用的方式并入本文。
“诊断剂”是用于诊断疾病的原子、分子或化合物。可用的诊断剂包括但不限于放射性同位素、染料、造影剂、发光剂、化学发光剂、荧光化合物或分子和增强剂(如,顺磁离子)。优选地,诊断剂选自放射性同位素、增强剂和荧光化合物。
治疗剂是单独、与抗体部分同时或按顺序施用,或缀合至抗体部分即抗体或抗体片段或亚片段的化合物、分子或原子,并且用于治疗疾病。治疗剂的例子包括抗体、抗体片段、药物、毒素、核酸酶、激素、免疫调节剂、促凋亡剂、抗血管生成剂、硼化合物、光活性剂或染料和放射性同位素。治疗剂的使用如下文更详细地描述。
免疫缀合物是缀合至至少一种治疗和/或诊断剂的抗体、抗体片段或融合蛋白。
多特异性抗体是可同时结合至至少两个具有不同结构的靶标的抗体,所述靶标如两个不同的抗原、相同抗原上的两个不同表位或半抗原和/或抗原或表位。多特异性、多价抗体是具有超过一个结合位点的构建体,并且该结合位点具有不同的特异性。
双特异性抗体是可同时结合两个不同靶标的抗体。双特异性抗体(bsAb)和双特异性抗体片段(bsFab)可具有至少一个特异性结合于例如肿瘤相关抗原的臂和至少一个特异性结合于具有治疗剂或诊断剂的可靶向缀合物的另外的臂。许多双特异性融合蛋白可使用分子工程生成。
图例
图1.通过FISH分析Trop-2拷贝数。通过FISH分析MCF-7(Trop-2阳性)细胞。Trop-2拷贝数使用抗Trop-2和抗染色体-1特异性探针(Empire Genomics,Buffalo,NY)测定。
图2.通过FISH分析Trop-2拷贝数。通过FISH分析A549(Trop-2阴性)细胞。Trop-2拷贝数使用抗Trop-2和抗染色体-1特异性探针(Empire Genomics,Buffalo,NY)测定。
图3.通过FISH分析拓扑异构酶-I拷贝数。通过FISH分析MCF-7细胞。拓扑异构酶I(TOP1)拷贝数使用抗TOP1和抗染色体-20特异性探针(台湾台北)测定。
图4.通过FISH分析拓扑异构酶-I拷贝数。通过FISH分析A549细胞。拓扑异构酶I(TOP1)拷贝数使用抗TOP1和抗染色体-20特异性探针(台湾台北)测定。
抗Trop-2抗体
用于CTC分离和/或检测的主题方法和组合物利用至少一种结合至Trop-2的抗体或其片段,包括啮齿动物、嵌合、人或人源化抗体。在具体的优选实施方案中,抗Trop-2抗体可以是人源化RS7抗体(参见例如,美国专利No.7,238,785,该专利全文以引用的方式并入本文),其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SASYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQ ID NO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。
RS7抗体是针对人原发性鳞状细胞肺癌的粗膜制备而产生的鼠IgG1(Stein等人,Cancer Res.50:1330,1990)RS7抗体识别以簇13鉴定的46-48kDa糖蛋白。(Stein等人,Int.J.Cancer Supp.8:98-102,1994)该抗原被命名为EGP-1(上皮糖蛋白-1),但也称为Trop-2。
Trop-2是I-型跨膜蛋白,从人(Fornaro等人,Int J Cancer 1995;62:610-8)和小鼠细胞(Sewedy等人,Int J Cancer 1998;75:324-30)二者克隆。除了作为肿瘤相关钙信号转导蛋白(Ripani等人,Int J Cancer 1998;76:671-6)的作用之外,人Trop-2的表达还显示出对于肿瘤发生和结肠癌细胞的侵袭性是必要的,这可有效地减少抗Trop-2的细胞外结构域的多克隆抗体(Wang等人,Mol Cancer Ther 2008;7:280-5)。Trop-2在大部分人肿瘤和癌症的动物模型中高度表达(McDougall等人,2015,Dev Dyn 244:99-109)。
Trop-2作为实体瘤的标记物的应用(Cubas等人,Biochim Biophys Acta 2009;1796:309-14)由另外的报道证明,这些报道记录了Trop-2在乳腺癌(Huang等人,ClinCancer Res 2005;11:4357-64)、结直肠癌(Ohmachi等人,Clin Cancer Res 2006;12:3057-63;Fang等人,Int J Colorectal Dis 2009;24:875-84)和口腔鳞状细胞癌(Fong等人,Modern Pathol 2008;21:186-91)中过表达的临床意义。最新证据是特别值得注意的:表达高水平Trop-2的前列腺基底细胞的富集有助于体外和体内干细胞样活性(Goldstein等人,Proc Natl Acad Sci USA 2008;105:20882-7)。
流式细胞术和免疫组织化学染色研究显示,RS7MAb检测许多肿瘤类型上的抗原,并且与正常人组织的结合有限(Stein等人,1990)。Trop-2主要通过恶性肿瘤,诸如肺癌、胃癌、泌尿膀胱癌、乳腺癌、卵巢癌、子宫癌和前列腺癌表达。使用放射性标记鼠RS7MAb在动物模型中进行的定位和治疗研究显示出肿瘤靶向和治疗功效(Stein等人,1990;Stein等人,1991)。在动物模型中,药物缀合的RS7MAb也显示出人癌症异种移植物的靶向和治疗功效(Cardillo等人,Clinical Cancer Res.,17:3157-69,2011)。
在肺、乳腺、膀胱、卵巢、子宫、胃和前列腺肿瘤中显示出强RS7染色。(Stein等人,Int.J.Cancer 55:938,1993)肺癌病例包括鳞状细胞癌和腺癌二者。(Stein等人,Int.J.Cancer 55:938,1993)两种细胞类型均被强染色,表明RS7抗体不能鉴别非小细胞肺癌的组织类别。
虽然hRS7抗体是优选的,但其他抗Trop-2抗体也是已知的和/或可公开获取的,并且在替代实施方案中可用于主题方法和组合物。虽然人源化或人抗体对于减小的免疫原性是优选的,但在替代实施方案中可使用嵌合抗体,而啮齿动物MAb可用于体外和离体研究。如下文所讨论,抗体人源化的方法是本领域熟知的,并且可用于将可用的鼠或嵌合抗体转化为人源化形式。
抗Trop-2抗体可从许多来源商购获得,包括LS-C126418、LS-C178765、LS-C126416、LS-C126417(LifeSpan BioSciences,Inc.,Seattle,WA);10428-MM01、10428-MM02、10428-R001、10428-R030(Sino Biological Inc.,Beijing,China);MR54(eBioscience,San Diego,CA);sc-376181、sc-376746,Santa Cruz Biotechnology(SantaCruz,CA);MM0588-49D6(Novus Biologicals,Littleton,CO);ab79976和ab89928(Cambridge,MA)。
其他抗Trop-2抗体公开于专利文献中。例如,美国公开No.2013/0089872公开了保藏在International Patent Organism Depositary,Tsukuba,Japan的抗Trop-2抗体K5-70(登录号FERM BP-11251)、K5-107(登录号FERM BP-11252)、K5-116-2-1(登录号FERM BP-11253)、T6-16(登录号FERM BP-11346)和T5-86(登录号FERM BP-11254)。美国专利No.5,840,854公开了抗Trop-2单克隆抗体BR110(ATCC No.HB11698)。美国专利No.7,420,040公开了以登录号141205-05保藏在IDAC(International Depository Authority of Canada,Winnipeg,Canada)的杂交瘤细胞系AR47A6.4.2生成的抗Trop-2抗体。美国专利No.7,420,041公开了以登录号141205-03保藏在IDAC的杂交瘤细胞系AR52A301.5生成的抗Trop-2抗体。美国公开No.2013/0122020公开了抗Trop-2抗体3E9、6G11、7E6、15E2、18B1。编码代表性抗体的杂交瘤以登录号PTA-12871和PTA-12872保藏在美国典型培养物保藏中心(ATCC)。美国专利No.8,715,662公开了以保藏号PD 08019、PD 08020和PD 08021保藏在AID-ICLC(Genoa,Italy)的杂交瘤生成的抗Trop-2抗体。美国专利申请公开No.20120237518公开了抗Trop-2抗体77220、KM4097和KM4590。美国专利No.8,309,094(Wyeth)公开了通过序列表鉴定的抗体A1和A3。本段落上述引用的每个专利或专利申请的实施例部分以引用的方式并入本文。对于非专利公开,Lipinski等人(1981,Proc Natl.Acad Sci USA,78:5147-50)公开了抗Trop-2抗体162-25.3和162-46.2。最近,据报道,Pr1E11抗Trop-2抗体识别Trop-2上的独特表位(Ikeda等人,Biochem Biophys Res Comm 458:877-82)。
许多抗Trop-2抗体是本领域已知的和/或可公开获取的。如下文所讨论,用于制备抗已知抗原的抗体的方法是本领域常见的。人Trop-2蛋白的序列也是本领域已知的(参见例如,GenBank登录号CAA54801.1)。用于制备人源化、人或嵌合抗体的方法也是已知的。普通技术人员,在根据本领域的一般知识阅读本公开时,能够制造和使用抗Trop-2抗体的种属。
上文讨论的先前研究不包括使用用于分离或检测Trop-2阳性CTC的抗Trop-2抗体的任何公开。存在用于富集、分离、检测、诊断和/或鉴定Trop-2阳性CTC的组合物和方法的需要。
循环肿瘤细胞的分离和检测
抗Trop-2抗体可用于使用任何已知的CTC分离和检测技术富集、分离、检测和/或诊断Trop-2阳性CTC。已经开发出许多CTC检测系统,并且它们是可商购获得的。虽然大部分是使用特定的抗EpCAM抗体开发的,但可修饰组合物和方法以利用抗Trop-2抗体代替。因此,Trop-2阳性CTC的分离和检测可使用任何此类已知系统,或更多传统的细胞分离和检测方法进行。此类已知技术的非限制性例子在下文有所讨论。
本发明可使用基于亲和力的富集步骤,以及不包括富集步骤的方法,诸如(Pachmann等人,2005,Breast Cancer Res,7:R975)。使用磁装置进行基于亲和力的富集的方法包括系统(Veridex)、平台(Cynvenio Biosystems)和MagSweeper装置(Talasaz等人,PNAS,2009,106:3970)。不使用磁装置进行基于亲和力的富集的方法包括许多制造的微流体装置,诸如CTC-芯片(Stott等人,2010,Sci Transl Med,2:25ra23)、HB-芯片(Stott等人,2010,PNAS,107:18392)、NanoVelcro芯片(Lu等人,2013,Methods,64:144)、GEDI微装置(Kirby等人,2012,PLoSONE,7:e35976)和Biocept的ONCOCEETM技术(Pecot等人,2011,Cancer Discov,1:580)。
使用FDA批准的系统在非小细胞和小细胞肺癌患者中进行CTC检测如Truini等人(2014,Front Oncol 4:242)所讨论。将7.5ml外周血样品与涂覆有抗EpCAM抗体的磁性铁纳米颗粒混合。强磁场用于从EpCAM阴性细胞分离EpCAM阳性细胞。结合CTC的检测使用荧光标记抗CK和抗CD45抗体,以及细胞核的DAPI(4’,6’-二脒基-2-苯基吲哚)荧光标记进行。CTC通过荧光检测鉴定为CK阳性、CD45阴性和DAPI阳性。
VerIFAST系统用于在非小细胞肺癌(NSCLC)中进行循环肿瘤细胞(CTC)的诊断和药效动力学分析(Casavant等人,2013,Lab Chip 13:391-6;2014,Lab Chip 14:99-105)。VerIFAST平台利用表面张力对重力的微观尺度相对优势并排加载不混溶相。这拴住了邻近槽中的水性和油性场,以在两个水性孔之间形成虚拟过滤器(Casavant等人,2013,LabChip 13:391-6)。使用顺磁性颗粒(PMP)和附连的抗体或其他靶向部分,可通过油栅的简单往复移动从复合物背景靶向和分离特定的细胞群。在NSCLC例子中,链霉亲和素缀合至FLOWCOMPTM PMP(Life Technologies,USA),并且使用生物素化抗EpCAM抗体捕集细胞。手持磁体用于在水性槽之间转移结合到PMP的CTC。使用PMP释放缓冲液释放所收集的CTC,并且对EpCAM、EGFR或转录终止因子(TTF-1)染色。
VerIFAST平台将微孔膜整合到水性槽,以在不需要细胞转移或离心的情况下允许多流体转移。由于物理特征标度赋予相对于宏观尺度技术的高精度,此类微流体技术非常适于在样品损失最小的情况下捕集和评估CTC。VerIFAST平台从NSCLC患者的血液有效捕集CTC。
GILUPI CELLCOLLECTORTM(Saucedo-Zeni等人,2012,Int J Oncol 41:1241-50)基于涂覆有嵌合抗EpCAM抗体的功能化医疗Seldinger导线(FSMW)。该导线使用聚羧酸酯水凝胶层功能化,该聚羧酸酯水凝胶层使用EDC和NHS活化,以使抗体的共价结合。通过标准静脉套管将抗体涂覆的FSMW插入乳腺癌或NSCLC肺癌患者的肘静脉30分钟。在细胞结合到导线之后,通过EpCAM和/或细胞角蛋白的免疫细胞化学染色和细胞核染色鉴定CTC。使用配备有AxioCam数码相机系统和AxioVision 4.6软件的Axio Imager.Alm显微镜(Zeiss,Jena,Germany)分析荧光标记。FSMW系统能够从24名测试患者中的22名富集EpCAM阳性CTC,包括其中未诊断到癌细胞远端转移的早期癌症的那些患者。健康志愿者中未检测到CTC。FSMW系统的优点在于,不受离体血样体积的限制,该离体血样可使用可选的方法,诸如系统处理。预计在30分钟暴露期间接触FSMW的血液体积为1.5至3升。
MagSweeper装置(例如,Powell等人,2012,PLoS ONE 7:e33788)是利用抗体涂覆的磁性颗粒进行CTC检测的另一个系统。将九毫升全血在离体、室温下与4.5μM涂覆有BerEP4抗EpCAM抗体的(Invitrogen,Life Technologies,GrandIsland,NY)混合1小时。在用PBS稀释之后,通过扫磁装置(MagSweeper,参见Powel等人,2012的图1)捕集结合到的细胞。使用控制剪切力进行捕集-洗涤-释放两个循环,该控制剪切力释放非特异性结合的白细胞和RBC。将捕集的细胞释放到新鲜缓冲液,并且使用Axio Observer A1倒置显微镜(Zeiss)检查。手动吸出单个CTC并冷冻保存,然后通过基于芯片的高通量qRT-PCR分析87个基因的表达。
Gupta等人(2012,Biomicrofluidics 6:24133)讨论了APOSTREAMTM介电泳装置用于CTC收集和分析的用途。微流体流槽与介电泳(DEP)技术一起用于捕集CTC(参见图1,Gupta等人,2012)。该系统可以连续模式操作,用于从外周血流经分离和富集CTC。DEP通过采用不同细胞类型的频率相关介电性质分选具有独特生物物理性质的细胞,所述频率相关介电性质由形态性质和电导率的差异产生。这些差异引起CTC和正常细胞在微流体槽中发生差异化频率相关迁移。在45-85kHz的范围内的AC频率下,癌细胞受到正向(吸引)DEP力,这使它们向电极平面迁移,远离流过槽的水流。在相同的频率下,正常细胞受到负向(排斥)DEP力,这使它们向水流速度廓线移动,并移出槽。收集口用于移出分离的CTC,以便进一步分析。对于初始优化研究,将培养的癌细胞加标至正常血单核细胞,并以超过70%的效率回收。虽然Gupta公开的APOSTREAMTM系统不使用捕集抗体,但主题抗Trop-2抗体可潜在地用于提高CTC分离的效率和/或所分离的CTC的分离后鉴定。
Winer-Jones等人(2014,PLoS One 9:e86717)讨论了系统用于CTC的分离和鉴定的用途。系统使用流过流动池的高通量鞘流微流体,与抗EpCAM抗体捕集剂组合。生物素化抗EpCAM附连到链霉亲和素涂覆的IMAGTM微珠(BD,Franklin Lakes,NJ),并且与血样混合,该血样包含CFSE或FITC标记的加标肿瘤细胞。正常的有核细胞用DAPI标记。在抗体结合之后,在CTC流动池上处理血样,该流动池附连到载玻片。外部磁场用于捕集玻璃表面上的磁珠结合CTC,使其与包含正常细胞的层流分离。使用Eclipse E80i荧光显微镜(Nikon Instruments,Melville,NY)对捕集的细胞计数。
普通技术人员将认识到,任何这些系统,或用于CTC富集和/或分离的任何其他已知系统,可与用于富集、分离、检测和/或鉴定CTC的主题抗Trop-2抗体一起使用。当利用抗Trop-2捕集抗体时,结合的CTC可使用抗不同Trop-2表位,或抗其他已知肿瘤相关抗原的标记抗体检测和/或鉴定,所述肿瘤相关抗原包括但不限于碳酸酐酶IX、CCL19、CCL21、CSAp、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、IGF-1R、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD66a-e、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CXCR4、CXCR7、CXCL12、HIF-1-α、AFP、PSMA、CEACAM5、CEACAM-6、c-met、B7、纤连蛋白的ED-B、因子H、FHL-1、Flt-3、叶酸受体、GROB、HMGB-1、缺氧诱导因子(HIF)、胰岛素样生长因子-1(ILGF-1)、IFN-γ、IFN-α、IFN-β、IL-2、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、MIF、MUC1、MUC2、MUC3、MUC4、MUC5ac、NCA-95、NCA-90、Ia、EGP-1、EGP-2、HLA-DR、腱生蛋白、Le(y)、RANTES、T101、TAC、Tn抗原、Thomson-Friedenreich抗原、肿瘤坏死抗原、TNF-α、TRAIL受体(R1和R2)、VEGFR、EGFR、P1GF、补体因子C3、C3a、C3b、C5a和C5。
抗体制备
用于制备实际上抗任何靶标抗原诸如Trop-2的单克隆抗体的技术是本领域熟知的。参见例如,和Milstein,Nature 256:495(1975)和Coligan等人(编),CURRENTPROTOCOLS IN IMMUNOLOGY,第1卷,第2.5.1-2.6.7页(John Wiley & Sons 1991)。简而言之,单克隆抗体可通过以下步骤获得:用包含抗原的组合物注射小鼠,移除脾脏以获得B淋巴细胞,使B淋巴细胞与骨髓瘤细胞融合生成杂交瘤,克隆杂交瘤,选择生成抗原的抗体的阳性克隆,培养生成抗原的抗体的克隆,以及从杂交瘤培养物分离抗体。
MAb可通过许多广泛接受的技术从杂交瘤培养物分离和纯化。此类分离技术包括使用蛋白-A或蛋白-G Sepharose的亲和色谱法、尺寸排阻色谱法和离子交换色谱法。参见例如,Coligan第2.7.1-2.7.12页和第2.9.1-2.9.3页。另外参见Baines等人,“Purification of Immunoglobulin G(IgG)”,载于METHODS IN MOLECULAR BIOLOGY,第10卷,第79-104页(The Humana Press,Inc.1992)。
在免疫原的抗体初始产生之后,可对抗体测序,随后通过重组技术制备。鼠抗体和抗体片段的人源化和嵌合是本领域的技术人员已知的,如下文所讨论。
嵌合抗体
嵌合抗体是其中人抗体的可变区被例如小鼠抗体的可变区,包括小鼠抗体的互补决定区(CDR)代替的重组蛋白。当嵌合抗体施用给受试者时,表现出免疫原性减少和稳定性增加。用于克隆鼠免疫球蛋白可变区的一般技术已公开于例如Orlandi等人,Proc.Nat’lAcad.Sci.USA 6:3833(1989)。用于构建嵌合抗体的技术是本领域的技术人员熟知的。例如,Leung等人,Hybridoma 13:469(1994),通过将编码鼠LL2(抗CD22单克隆抗体)的Vκ和VH结构域的DNA序列与相应的人κ和IgG1恒定区组合生成LL2嵌合体。
人源化抗体
用于生成人源化MAb的技术是本领域熟知的(参见例如,Jones等人,Nature 321:522(1986),Riechmann等人,Nature 332:323(1988),Verhoeyen等人,Science 239:1534(1988),Carter等人,Proc.Nat’l Acad.Sci.USA89:4285(1992),Sandhu,Crit.Rev.Biotech.12:437(1992)和Singer等人,J.Immun.150:2844(1993))。嵌合或鼠单克隆抗体可通过将小鼠CDR从小鼠免疫球蛋白的重链和轻链可变链转移到对应的人抗体的可变区来人源化。嵌合单克隆抗体中的小鼠框架区(FR)也被人FR序列代替。由于简单地将小鼠CDR转移到人FR通常会导致抗体亲和力的减少或甚至丧失,另外的修饰对于恢复鼠抗体的初始亲和力可为必须的。这可通过将FR区中的一个或多个人残基取代为其鼠对应部分,以获得对其表位具有良好的结合亲和力的抗体来实现。参见例如Tempest等人,Biotechnology 9:266(1991)和Verhoeyen等人,Science 239:1534(1988)。用于取代的优选残基包括位于CDR残基侧链的1、2或3埃内,位于CDR序列附近,或预期与CDR残基相互作用的FR残基。
人抗体
使用组合方法或人免疫球蛋白基因座转化的转基因动物来制备完全人抗体的方法是本领域已知的(例如,Mancini等人,2004,New Microbiol.27:315-28;Conrad和Scheller,2005,Comb.Chem.High Throughput Screen.8:117-26;Brekke和Loset,2003,Curr.Opin.Pharmacol.3:544-50)。完全人抗体也可通过基因或染色体转染方法,以及噬菌体展示技术构建,所有技术都是本领域已知的。参见例如,McCafferty等人,Nature 348:552-553(1990)。在体内使用抗体的情况下,例如在Trop-2阳性癌症的检测之后的肿瘤治疗中,预期此类完全人抗体表现出甚至比嵌合或人源化抗体更小的副作用,并且作为基本上内源性人抗体在体内发挥作用。
在一个取代形式中,噬菌体展示技术可用于生成人抗体(例如,Dantas-Barbosa等人,2005,Genet.Mol.Res.4:126-40)。人抗体可从正常人或从表现出具体疾病状态诸如癌症的人生成(Dantas-Barbosa等人,2005)。从疾病个体构建人抗体的优点在于循环抗体谱可倾向于抗疾病相关抗原的抗体。
在该方法的一个非限制性例子中,Dantas-Barbosa等人(2005)构建了骨肉瘤患者的人Fab抗体片段的噬菌体展示库。一般来讲,总RNA从循环血淋巴细胞获得(出处同上)。重组Fab从μ、γ和κ链抗体谱克隆,并插入噬菌体展示库(出处同上)。将RNA转换为cDNA,并用于使用针对重链和轻链免疫球蛋白序列的特异性引物制备Fab cDNA文库(Marks等人,1991,J. Mol.Biol.222:581-97)。文库构建根据Andris-Widhopf等人(2000,载于:PhageDisplay Laboratory Manual,Barbas等人(编),第1版,Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,NY,第9.1至9.22页)进行。最终Fab片段用限制性核酸内切酶消化,并插入噬菌体基因组,以制备噬菌体展示库。此类文库可使用本领域已知的标准噬菌体展示方法筛选。噬菌体展示可以多种形式进行,其综述参见例如Johnson和Chiswell,Current Opinionin Structural Biology 3:5564-571(1993)。
人抗体也可通过体外活化B细胞来生成。参见美国专利No.5,567,610和5,229,275,这两个专利全文以引用的方式并入本文。熟练技术人员将认识到,这些技术是示例性的,并且可使用用于制备和筛选人抗体或抗体片段的任何已知方法。
在另一个取代形式中,经基因工程改造为生成人抗体的转基因动物可用于使用标准免疫方案制备抗基本上任何免疫原性靶标的抗体。用于从转基因小鼠获得人抗体的方法如Green等人,Nature Genet.7:13(1994),Lonberg等人,Nature 368:856(1994)和Taylor等人,Int.Immun.6:579(1994)所公开。此类系统的非限制性例子是来自Abgenix(Fremont,CA)的(例如,Green等人,1999,J.Immunol.Methods 231:11-23,该文献以引用的方式并入本文)。在和类似的动物中,小鼠抗体基因是失活的并且被功能性人抗体基因代替,而小鼠免疫系统的其余部分仍然是完整的。
用种系构建的YAC(酵母人工染色体)转化,该YAC包含人IgH和Igκ基因座的一部分,包括大部分可变区序列,以及附属基因和调控序列。人可变区谱可用于制备产生抗体的B-细胞,该B-细胞可通过已知技术处理为杂交瘤。使用靶标抗原免疫的将通过正常免疫应答生成人抗体,该人抗体可使用上文讨论的标准技术收集和/或制备。许多品系是可用的,每种品系能够生成不同类型的抗体。转基因制备的人抗体显示出具有治疗潜力,同时保持正常人抗体的药代动力学性质(Green等人,1999)。熟练技术人员将认识到,受权利要求书保护的组合物和方法不限于系统的使用,但可利用经基因工程改造为生成人抗体的任何转基因动物。
已知抗体和靶标抗原
如上文所讨论,在某些替代实施方案中,在检测循环Trop-2阳性肿瘤细胞之后,将抗Trop-2抗体用于治疗表达Trop-2的癌症。在一些实施方案中,目标癌症可表达一个或多个另外的肿瘤相关抗原(TAA),肿瘤治疗可靶向该肿瘤相关抗原。可用于治疗癌症的具体抗体包括但不限于LL1(抗CD74)、LL2或RFB4(抗CD22)、维妥珠单抗(hA20,抗CD20)、利妥昔单抗(抗CD20)、奥比妥珠单抗(GA101,抗CD20)、lambrolizumab(抗PD-1受体)、纳武单抗(nivolumab)(抗PD-1受体)、伊匹单抗(抗CTLA-4)、RS7(抗上皮糖蛋白-1(EGP-1,也称为Trop-2))、PAM4或KC4(均抗粘蛋白)、MN-14(抗癌胚抗原(CEA,也称为CD66e或CEACAM5)、MN-15或MN-3(抗CEACAM6)、Mu-9(抗结肠特异性抗原-p)、Immu 31(抗α-胎蛋白)、R1(抗IGF-1R)、A19(抗CD19)、TAG-72(如,CC49)、Tn、J591或HuJ591(抗PSMA(前列腺特异性膜抗原))、AB-PG1-XG1-026(抗PSMA二聚体)、D2/B(抗PSMA)、G250(抗碳酸酐酶IX MAb)、L243(抗HLA-DR)、阿仑单抗(抗CD52)、贝伐单抗(抗VEGF)、西妥昔单抗(抗EGFR)、吉妥珠单抗(抗CD33)、替伊莫单抗(抗CD20)、帕尼单抗(抗EGFR)、托西莫单抗(抗CD20)、PAM4(即克伐珠单抗,抗粘蛋白)和曲妥珠单抗(抗ErbB2)。此类抗体是本领域已知的(例如,美国专利No.5,686,072、5,874,540、6,107,090、6,183,744、6,306,393、6,653,104、6,730.300、6,899,864、6,926,893、6,962,702、7,074,403、7,230,084、7,238,785、7,238,786、7,256,004、7,282,567、7,300,655、7,312,318、7,585,491、7,612,180、7,642,239和美国专利申请公开No.20050271671、20060193865、20060210475、20070087001;每个专利的实施例部分以引用的方式并入本文)。所用的具体已知抗体包括hPAM4(美国专利No.7,282,567)、hA20(美国专利No.7,251,164)、hA19(美国专利No.7,109,304)、hIMMU-31(美国专利No.7,300,655)、hLL1(美国专利No.7,312,318)、hLL2(美国专利No.7,074,403)、hMu-9(美国专利No.7,387,773)、hL243(美国专利No.7,612,180)、hMN-14(美国专利No.6,676,924)、hMN-15(美国专利No.7,541,440)、hR1(美国专利申请12/772,645)、hRS7(美国专利No.7,238,785)、hMN-3(美国专利No.7,541,440)、AB-PG1-XG1-026(美国专利申请11/983,372,作为ATCC PTA-4405和PTA-4406保藏)和D2/B(WO 2009/130575),每个所引用的专利或专利申请的附图和实施例部分文本以引用的方式并入本文。
所用的另外抗体包括但不限于阿昔单抗(抗糖蛋白IIb/IIIa)、阿仑单抗(抗CD52)、贝伐单抗(抗VEGF)、西妥昔单抗(抗EGFR)、吉妥珠单抗(抗CD33)、替伊莫单抗(抗CD20)、帕尼单抗(抗EGFR)、利妥昔单抗(抗CD20)、托西莫单抗(抗CD20)、曲妥珠单抗(抗ErbB2)、lambrolizumab(抗PD-1受体)、纳武单抗(抗PD-1受体)、伊匹单抗(抗CTLA-4)、阿巴伏单抗(抗CA-125)、阿德木单抗(抗EpCAM)、阿特利珠单抗(抗IL-6受体)、贝那利珠单抗(抗CD125)、奥比妥珠单抗(GA101,抗CD20)、CC49(抗TAG-72)、AB-PG1-XG1-026(抗PSMA,美国专利申请11/983,372,以ATCC PTA-4405和PTA-4406保藏)、D2/B(抗PSMA,WO 2009/130575)、托珠单抗(抗IL-6受体)、巴利昔单抗(抗CD25)、达利珠单抗(抗CD25)、依法利珠单抗(抗CD11a)、GA101(抗CD20;Glycart Roche)、莫罗单抗-CD3(抗CD3受体)、那他珠单抗(抗α4整联蛋白)、奥马珠单抗(抗IgE);抗TNF-α抗体诸如CDP571(Ofei等人,2011,Diabetes 45:881-85)、MTNFAI、M2TNFAI、M3TNFAI、M3TNFABI、M302B、M303(Thermo Scientific,Rockford,IL)、英利昔单抗(Centocor,Malvern,PA)、赛妥珠单抗(UCB,Brussels,Belgium)、抗CD40L(UCB,Brussels,Belgium)、阿达木单抗(Abbott,Abbott Park,IL)和Benlysta(Human Genome Sciences)。
可被靶向的其他可用肿瘤相关抗原包括碳酸酐酶IX、B7、CCL19、CCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20(如,C2B8、hA20、1F5MAb)、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD47、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM6、CTLA-4、α-胎蛋白(AFP)、VEGF(如,纤连蛋白剪接变体)、ED-B纤连蛋白(如,L19)、EGP-1(Trop-2)、EGP-2(如,17-1A)、EGF受体(ErbB 1)(如,)、ErbB2、ErbB3、因子H、FHL-1、Flt-3、叶酸受体、Ga 733、GRO-β、HMGB-1、缺氧诱导因子(HIF)、HM1.24、HER-2/neu、组蛋白H2B、组蛋白H3、组蛋白H4、胰岛素样生长因子(ILGF)、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-1/R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节苷脂、HCG、L243结合的HLA-DR抗原、CD66抗原即CD66a-d或它们的组合、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞迁移抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5ac、胎盘生长因子(PlGF)、PSA(前列腺特异性抗原)、PSMA、PAM4抗原、PD-1受体、PD-L1、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体(R1和R2)、Trop-2、VEGFR、RANTES、T101以及癌症干细胞抗原、补体因子C3、C3a、C3b、C5a、C5和癌基因产物。
癌症干细胞起因于更具治疗耐受性前体恶性细胞群(Hill和Perris,J.Natl.CancerInst.2007;99:1435-40)具有可在某些癌症类型中靶向的抗原,诸如前列腺癌(Maitland等人,Ernst Schering Found.Sympos.Proc.2006;5:155-79)、非小细胞肺癌(Donnenberg等人,J. ControlRelease 2007;122(3):385-91)和胶质母细胞瘤(Beier等人,Cancer Res.2007;67(9):4010-5)中的CD133,以及结直肠癌(Dalerba等人,Proc.Natl.Acad.Sci.USA 2007;104(24)10158-63)、胰腺癌(Li等人,Cancer Res.2007;67(3):1030-7)以及头颈鳞状细胞癌(Prince等人,Proc.Natl.Acad.Sci.USA 2007;104(3)973-8)中的CD44。乳腺癌治疗的另一个可用靶标是Taylor等人(Biochem.J.2003;375:51-9)描述的LIV-1抗原。
检查点抑制剂抗体已用于癌症治疗。免疫检查点是指免疫系统中负责保持自身耐受性和调节免疫系统应答程度,以使外周组织损伤减至最小的抑制途径。然而,肿瘤细胞也可活化免疫系统检查点,以减少对肿瘤组织的免疫应答的有效性。抗细胞毒性T-淋巴细胞抗原4(CTLA4,也称为CD152)、程序性细胞死亡蛋白1(PD1,也称为CD279)、程序性细胞死亡1配体1(PD-L1,也称为CD274)和程序性细胞死亡1配体2(PD-L2)(Latchman等人,2001,NatImmunol 2:261-8)的示例性检查点抑制剂抗体可与一种或多种其他试剂组合使用,以增加对疾病细胞、组织或病原体的免疫应答的有效性。示例性抗PD1抗体包括lambrolizumab(MK-3475,MERCK)、纳武单抗(BMS-936558,BRISTOL-MYERS SQUIBB)、AMP-224(MERCK)和皮地珠单抗(CT-011,CURETECH LTD.)。抗PD1抗体可以例如从(AB137132)、(EH12.2H7,RMP1-14)和AFFYMETRIX EBIOSCIENCE(J105,J116,MIH4)商购获得。示例性抗PD-L1抗体包括MDX-1105(MEDAREX)、MEDI4736(MEDIMMUNE)、MPDL3280A(GENENTECH)和BMS-936559(BRISTOL-MYERS SQUIBB)。抗PD-L1抗体也可例如从AFFYMETRIXEBIOSCIENCE(MIH1)商购获得。示例性抗CTLA4抗体包括伊匹单抗(Bristol-Myers Squibb)和曲美木单抗(PFIZER)。抗PD1抗体可例如从(AB134090),SINO BIOLOGICALINC.(11159-H03H,11159-H08H)和THERMO SCIENTIFIC PIERCE(PA5-29572,PA5-23967,PA5-26465,MA1-12205,MA1-35914)商购获得。伊匹单抗最近被FDA批准用于转移性黑素瘤的治疗(Wada等人,2013,J Transl Med 11:89)。
巨噬细胞迁移抑制因子(MIF)是先天性和适应性免疫和细胞凋亡的重要调节因子。据报道,CD74是MIF的内源性受体(Leng等人,2003,J Exp Med 197:1467-76)。拮抗性抗CD74抗体对MIF介导的细胞内途径的治疗效果可用于治疗一系列广泛的疾病状态,诸如膀胱癌、前列腺癌、乳腺癌、肺癌和结肠癌(例如,Meyer-Siegler等人,2004,BMC Cancer 12:34;Shachar&Haran,2011,Leuk Lymphoma 52:1446-54)。米拉珠单抗(hLL1)是具有用于治疗MIF介导的疾病的治疗用途的示例性抗CD74抗体。
所用的各种其他抗体是本领域已知的(例如,美国专利No.5,686,072、5,874,540、6,107,090、6,183,744、6,306,393、6,653,104、6,730.300、6,899,864、6,926,893、6,962,702、7,074,403、7,230,084、7,238,785、7,238,786、7,256,004、7,282,567、7,300,655、7,312,318、7,585,491、7,612,180、7,642,239和美国专利申请公开No.20060193865;每个专利以引用的方式并入本文)。
所用的抗体可从广泛的已知来源商购获得。例如,许多分泌抗体的杂交瘤系可得自美国典型培养物保藏中心(American Type Culture Collection(ATCC,Manassas,VA))。许多抗各种疾病靶标,包括肿瘤相关抗原的抗体,保藏在ATCC和/或已公开可变区序列,并且可用于受权利要求书保护的方法和组合物。参见例如,美国专利No.7,312,318、7,282,567、7,151,164、7,074,403、7,060,802、7,056,509、7,049,060、7,045,132、7,041,803、7,041,802、7,041,293、7,038,018、7,037,498、7,012,133、7,001,598、6,998,468、6,994,976、6,994,852、6,989,241、6,974,863、6,965,018、6,964,854、6,962,981、6,962,813、6,956,107、6,951,924、6,949,244、6,946,129、6,943,020、6,939,547、6,921,645、6,921,645、6,921,533、6,919,433、6,919,078、6,916,475、6,905,681、6,899,879、6,893,625、6,887,468、6,887,466、6,884,594、6,881,405、6,878,812、6,875,580、6,872,568、6,867,006、6,864,062、6,861,511、6,861,227、6,861,226、6,838,282、6,835,549、6,835,370、6,824,780、6,824,778、6,812,206、6,793,924、6,783,758、6,770,450、6,767,711、6,764,688、6,764,681、6,764,679、6,743,898、6,733,981、6,730,307、6,720,155、6,716,966、6,709,653、6,693,176、6,692,908、6,689,607、6,689,362、6,689,355、6,682,737、6,682,736、6,682,734、6,673,344、6,653,104、6,652,852、6,635,482、6,630,144、6,610,833、6,610,294、6,605,441、6,605,279、6,596,852、6,592,868、6,576,745、6,572;856、6,566,076、6,562,618、6,545,130、6,544,749、6,534,058、6,528,625、6,528,269、6,521,227、6,518,404、6,511,665、6,491,915、6,488,930、6,482,598、6,482,408、6,479,247、6,468,531、6,468,529、6,465,173、6,461,823、6,458,356、6,455,044、6,455,040、6,451,310、6,444,206、6,441,143、6,432,404、6,432,402、6,419,928、6,413,726、6,406,694、6,403,770、6,403,091、6,395,276、6,395,274、6,387,350、6,383,759、6,383,484、6,376,654、6,372,215、6,359,126、6,355,481、6,355,444、6,355,245、6,355,244、6,346,246、6,344,198、6,340,571、6,340,459、6,331,175、6,306,393、6,254,868、6,187,287、6,183,744、6,129,914、6,120,767、6,096,289、6,077,499、5,922,302、5,874,540、5,814,440、5,798,229、5,789,554、5,776,456、5,736,119、5,716,595、5,677,136、5,587,459、5,443,953、5,525,338。这些抗体仅仅是示例性的,并且许多其他抗体及其杂交瘤是本领域已知的。熟练技术人员将认识到,抗几乎任何疾病相关抗原的抗体序列或分泌抗体的杂交瘤可通过在ATCC,NCBI和/或USPTO数据库中简单搜索抗所关注的选择疾病相关靶标的抗体来获得。可使用本领域熟知的标准技术扩增、切下克隆抗体的抗原结合结构域,并连接到表达载体,转染到改造的宿主细胞并用于蛋白质制备。
抗体同种异型
治疗抗体的免疫原性与输注反应的风险增加和治疗响应的持续时间减少相关(Baert等人,2003,N Engl J Med 348:602-08)。治疗抗体诱导宿主中免疫应答的程度可以部分由抗体的同种异型决定(Stickler等人,2011,Genes and Immunity 12:213-21)。抗体同种异型涉及抗体恒定区序列中特定位置的氨基酸序列变型。包含重链γ型恒定区的IgG抗体的同种异型被命名为Gm同种异型(1976,J Immunol 117:1056-59)。
对于常见的IgG1人抗体,最普遍的同种异型是G1m1(Stickler等人,2011,Genesand Immunity 12:213-21)。然而,G1m3同种异型在白种人(Caucasians)中也是常见的(Stickler等人,2011)。据报道,G1m1抗体包含当施用给非G1m1(nG1m1)接受者诸如G1m3患者时,往往会诱导免疫应答的同种异型序列(Stickler等人,2011)。当施用给G1ml患者时,非G1m1同种异型抗体不具有免疫原性(Stickler等人,2011)。
人G1ml同种异型包含重链IgG1的CH3序列中Kabat位置356处的氨基酸天冬氨酸和Kabat位置358处的氨基酸亮氨酸。nG1m1同种异型包含Kabat位置356处的氨基酸谷氨酸和Kabat位置358处的氨基酸甲硫氨酸。G1ml和nG1ml同种异型二者包含Kabat位置357处的谷氨酸残基,并且该同种异型有时称为DEL和EEM同种异型。对于示例性抗体利妥昔单抗(SEQID NO:7)和维妥珠单抗(SEQ ID NO:8),G1m1和nG1ml同种异型抗体的重链恒定区序列的非限制性例子如下所示。
利妥昔单抗重链可变区序列(SEQ ID NO:7)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKYTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
维妥珠单抗重链可变区(SEQ ID NO:8)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Jefferis和LefraNc(2009,MAb 1:1-7)综述了IgG同种异型的序列变型特征及其对免疫原性的作用。据他们报道,G1m3同种异型通过G1m17同种异型中Kabat位置214处的精氨酸残基,而非Kabat 214处的赖氨酸残基来鉴定。nGlm1,2同种异型通过Kabat位置356处的谷氨酸、Kabat位置358处的甲硫氨酸和Kabat位置431处的丙氨酸来鉴定。Glm1,2同种异型通过Kabat位置356处的天冬氨酸、Kabat位置358处的亮氨酸和Kabat位置431处的甘氨酸来鉴定。除重链恒定区序列变体之外,Jefferis和Lefranc(2009)还报道了κ轻链恒定区中的同种异型变体,其中Km1同种异型通过Kabat位置153处的缬氨酸和Kabat位置191处的亮氨酸来鉴定,Km1,2同种异型通过Kabat位置153处的丙氨酸和Kabat位置191处的亮氨酸来鉴定,并且Km3同种异型通过Kabat位置153处的丙氨酸和Kabat位置191处的缬氨酸来鉴定。
就治疗抗体而言,维妥珠单抗和利妥昔单抗分别为抗CD20的人源化和嵌合IgG1抗体,用于治疗一系列广泛的血液恶性肿瘤和/或自身免疫疾病。表1比较了利妥昔单抗与维妥珠单抗的同种异型序列。如表1所示,利妥昔单抗(G1m17,1)是DEL同种异型IgG1,在利妥昔单抗中Kabat位置214(重链CH1)处的赖氨酸以及维妥珠单抗中该处的精氨酸具有另外的序列变异。据报道,在受试者中维妥珠单抗的免疫原性小于利妥昔单抗(参见例如,Morchhauser等人,2009,J Clin Oncol 27:3346-53;Goldenberg等人,2009,Blood 113:1062-70;Robak & Robak,2011,BioDrugs 25:13-25),该效应归因于人源化和嵌合抗体之间的差异。然而,EEM和DEL同种异型之间的同种异型差异可能也解释了维妥珠单抗的低免疫原性。
表1.利要昔单抗与维妥珠单抗的同种异型
为了减小nG1m1基因型个体中治疗抗体的免疫原性,希望选择通过Kabat 214处的精氨酸鉴定的G1m3同种异型对应的抗体同种异型,以及通过Kabat位置356处的谷氨酸、Kabat位置358处的甲硫氨酸和Kabat位置431处的丙氨酸鉴定的nG1m1,2非同种异型。意外的是,据发现,G1m3抗体的长时间重复皮下注射施用不会导致显著免疫应答。在替代实施方案中,与G1m3同种异型有共同之处的人IgG4重链具有Kabat 214处的精氨酸、Kabat 356处的谷氨酸、Kabat359处的甲硫氨酸和Kabat 431处的丙氨酸。由于免疫原性似乎至少部分与这些位置处的残基相关,人IgG4重链恒定区序列用于治疗抗体也是优选的实施方案。G1m3IgG1抗体与IgG4抗体的组合也可用于治疗剂施用。
纳米抗体
纳米抗体是大小为约12-15kDa(长度为约110个氨基酸)的单结构域抗体。纳米抗体可选择性地结合至靶标抗原,如完整大小的抗体,并且具有类似的抗原亲和力。然而,由于其大小较小,因此能够更好地穿透实体肿瘤。较小的大小也有助于稳定纳米抗体,它比完整大小的抗体更耐pH和极端温度(Van Der Linden等人,1999,Biochim Biophys Act1431:37-46)。单结构域抗体最初根据如下发现开发:骆驼科(骆驼、羊驼、美洲驼)具有无轻链的完全功能抗体(例如,Hamsen等人,2007,Appl Microbiol Biotechnol77:13-22)。重链抗体由单个可变区(VHH)和两个恒定区(CH2和CH3)构成。像抗体那样,纳米抗体可开发和用作多价和/或双特异性构建体。纳米抗体的人源化形式正在商业开发中,其靶向许多靶标抗原,诸如IL-6R、vWF、TNF、RSV、RANKL、IL-17A&F和IgE(如,Ghent、Belgium),在癌症和其他疾病中具有潜在临床用途(例如,Saerens等人,2008,Curr Opin Pharmacol 8:600-8;Muyldermans,2013,Ann Rev Biochem 82:775-97;Ibanez等人,2011,J Infect Dis203:1063-72)。
纳米抗体的血浆半衰期小于完全大小的抗体,主要通过肾脏途径消除。因为它们缺乏Fc区,所以不表现出补体依赖性细胞毒性。
纳米抗体可通过以下步骤制备:用靶标抗原免疫骆驼、美洲驼、羊驼或鲨鱼,然后分离mRNA,克隆至文库并筛选抗原结合。纳米抗体序列可通过标准技术人源化(例如,Jones等人,1986,Nature 321:522;Riechmann等人,1988,Nature 332:323;Verhoeyen等人,1988,Science 239:1534;Carter等人,1992,Proc.Nat’l Acad.Sci.USA 89:4285;Sandhu,1992,Crit.Rev.Biotech.12:437;Singer等人,1993,J.Immun.150:2844)。由于骆驼科和人FR序列之间的高同源性,人源化相对直接。
在各种实施方案中,主题抗体可包括用于将缀合诊断剂靶向递送至靶标癌细胞的纳米抗体。所用的纳米抗体公开于例如美国专利No.7,807,162、7,939,277、8,188,223、8,217,140、8,372,398、8,557,965、8,623,361和8,629,244,每个专利的实施例部分以引用的方式并入本文。
抗体片段
抗体片段是抗体的抗原结合部分,诸如F(ab’)2、Fab’、F(ab)2、Fab、Fv、sFv、scFv等等。识别特定表位的抗体片段可通过已知技术制备。F(ab’)2片段,例如可通过胃蛋白酶消化抗体分子来制备。这些和其他方法例如在Goldenberg,美国专利No.4,036,945和4,331,647以及其中包含的参考文献有所描述。还可参见Nisonoff等人,ArchBiochem.Biophys.89:230(1960);Porter,Biochem.J.73:119(1959);Edelman等人,载于METHODS IN ENZYMOLOGY,第1卷,第422页(Academic Press 1967)和Coligan,第2.8.1-2.8.10和2.10.-2.10.4页。或者,可构建Fab’表达文库(Huse等人,1989,Science,246:1274-1281),以使快速和简易鉴定具有所需特异性的单克隆Fab’片段。
单链Fv分子(scFv)包括VL结构域和VH结构域。VL和VH结构域缔合形成靶标结合位点。这两个结构域还通过肽接头(L)共价连接。如果VL结构域是scFv分子的N-末端部分,则scFv分子表示为VL-L-VH,或如果VH结构域是scFv分子的N-末端部分,则表示为VH-L-VL。用于制备scFv分子和设计合适的肽接头的方法描述于美国专利No.4,704,692、美国专利No.4,946,778、R.Raag和M.Whitlow,“Single Chain Fvs.”FASEB,第9卷,73-80(1995)以及R.E.Bird和B.W.Walker,Single Chain Antibody Variable Regions,TIBTECH,第9卷:132-137(1991)。
其他抗体片段,例如单结构域抗体片段,是本领域已知的并且可用于受权利要求书保护的构建体。单结构域抗体(VHH)可以例如通过标准免疫技术从骆驼、羊驼或美洲驼获得。(参见例如,Muyldermans等人,TIBS 26:230-235,2001;Yau等人,J Immunol Methods281:161-75,2003;Maass等人,J Immunol Methods 324:13-25,2007)。VHH可具有强大的抗原结合能力,并且可与传统VH-VL对无法触及的新表位相互作用(Muyldermans等人,2001)。羊驼血清IgG包含约50%的骆驼科仅重链IgG抗体(HCAb)(Maass等人,2007)。可使用已知的抗原诸如TNF-α免疫羊驼,并且可分离结合至以及中和靶标抗原的VHH(Maass等人,2007)。已鉴定扩增几乎所有编码羊驼VHH的序列的PCR引物,并且可用于构建羊驼VHH噬菌体展示文库,该文库可用于通过本领域熟知的标准生物淘选技术进行抗体片段分离(Maass等人,2007)。
抗体片段也可通过全长抗体的蛋白水解或通过在大肠杆菌(E.coli)或另一种宿主中表达编码该片段的DNA来制备。抗体片段可通过常规方法使用胃蛋白酶或木瓜蛋白酶消化全长抗体来获得。例如,抗体片段可通过使用胃蛋白酶来酶切抗体来制备,从而得到大约100kD以F(ab’)2表示的片段。该片段还可使用硫醇还原剂,以及任选地巯基基团的封端基团切割,以生成大约50Kd Fab’单价片段,该巯基基团由二硫键的切割产生。或者,使用木瓜蛋白酶酶切直接生成两个单价Fab片段和Fc片段。
也可使用切割抗体的其他方法,诸如分离重链形成单价轻链-重链片段,另外切割片段或其他酶学、化学或基因技术,只要该片段结合完整的抗体识别的抗原即可。
抗体克隆和制备的一般技术
各种技术,诸如制备嵌合或人源化抗体,可涉及抗体克隆和构建的工序。所关注的抗体的抗原结合Vκ(可变轻链)和VH(可变重链)序列可通过许多分子克隆工序,诸如RT-PCR、5’-RACE和cDNA文库筛选获得。可通过PCR扩增克隆表达鼠MAb的细胞的MAb的V基因并测序。为确认其保真性,可在细胞培养中以嵌合Ab表达克隆的VL和VH基因,如Orlandi等人所述(Proc.Natl.Acad.Sci.,USA,86:3833(1989))。然后可根据V基因序列设计和构建人源化MAb,如Leung等人所述(Mol.Immunol.,32:1413(1995))。
cDNA可从任何已知的杂交瘤系或产生鼠MAb的转染细胞系通过一般分子克隆技术制备(Sambrook等人,Molecular Cloning,A laboratory manual,第2版(1989))。MAb的Vκ序列可使用引物VK1BACK和VK1FOR(Orlandi等人,1989)或延伸引物组扩增,如Leung等人(BioTechniques,15:286(1993))所述。VH序列可使用引物对VH1BACK/VH1FOR(Orlandi等人,1989)或退火至鼠IgG的恒定区的引物扩增,如Leung等人(Hybridoma,13:469(1994))所述。人源化V基因可通过长寡核苷酸模板合成和PCR扩增的组合构建,如Leung等人(Mol.Immunol.,32:1413(1995))所述。
Vκ的PCR产物可亚克隆至分期载体,诸如基于pBR327的包含Ig启动子、信号肽序列和简便限制性位点的分期载体VKpBR。VH的PCR产物可亚克隆至类似的分期载体,诸如基于pBluescript的VHpBS。可分别从VKpBR和VHpBS切下包含Vκ和VH序列以及启动子和信号肽序列的表达盒,并连接至适当的表达载体,诸如pKh和pG1g(Leung等人,Hybridoma,13:469(1994))。表达载体可共转染至适当的细胞,并监测上清液流体中嵌合人源化或人MAb的生成。或者,可切下Vκ和VH表达盒并亚克隆至单个表达载体,诸如pdHL2,如Gillies等人(J.Immunol.Methods 125:191(1989),还在Losman等人,Cancer,80:2660(1997)中示出)所述。
在替代实施方案中,表达载体可转染至宿主细胞,该宿主细胞预先改造为在无血清培养基中进行转染、生长和表达。可使用的示例性细胞系包括Sp/EEE、Sp/ESF和Sp/ESF-X细胞系(参见例如,美国专利No.7,531,327;7,537,930和7,608,425,每个专利的实施例部分以引用的方式并入本文)。这些示例性细胞系基于Sp2/0骨髓瘤细胞系,转染有突变的Bcl-EEE基因,暴露至甲氨蝶呤以扩增转染基因序列,并且预先改造为用于蛋白质表达的无血清细胞系。
双特异性和多特异性抗体
在某些替代实施方案中,抗Trop-2抗体或其片段可与例如半抗原结合抗体或其片段,诸如抗HSG或抗In-DTPA抗体共施用。此类双特异性抗体可用于预靶向技术,以便在体内施用Trop-2阳性肿瘤的诊断和/或治疗剂。在其他实施方案中,双特异性或多特异性抗体可直接用于抗癌症治疗。
许多制备双特异性或多特异性抗体的方法是已知的,如例如美国专利No.7,405,320所公开,该专利的实施例部分以引用的方式并入本文。双特异性抗体可通过四源杂交瘤方法制备,该方法涉及两种不同杂交瘤的融合,每种杂交瘤生成识别不同抗原位点的单克隆抗体(Milstein和Cuello,Nature,1983;305:537-540)。
用于制备双特异性抗体的另一种方法使用异双官能交联剂,该异双官能交联剂化学固定两种不同单克隆抗体(Staerz等人,Nature.1985;314:628-631;Perez等人,Nature.1985;316:354-356)。双特异性抗体也可通过以下步骤制备:将两种亲本单克隆抗体中的每种简化为各自的半分子,然后混合并使再氧化以获得杂交体结构(Staerz和Bevan.Proc Natl Acad Sci U S A.1986;83:1453-1457)。其他方法包括通过基因转移独特的选择性标记,该基因转移通过逆转录病毒来源的穿梭载体转移至各自的亲本杂交瘤,随后进行融合(DeMonte等人,Proc Natl Acad Sci U S A.1990,87:2941-2945);或使用包含不同抗体的重链和轻链基因的表达质粒转染杂交瘤细胞系来提高杂交体杂交瘤的生成效率。
同源的VH和VL结构域可与适当组合和长度(通常由超过12个氨基酸残基组成)的肽接头连接,以形成单链Fv(scFv),如上文所讨论。肽接头长度减小至小于12个氨基酸残基防止了相同链上VH和VL结构域的配对,并且迫使VH和VL结构域与其他链上的互补结构域的配对,从而形成功能多聚体。VH和VL结构域的多肽链,与3个和12个氨基酸残基之间的接头连接,主要形成二聚体(称为双体)。通过0个和2个氨基酸残基之间的接头,有助于形成三聚体(称为三体)和四聚体(称为四体),但除接头长度之外,寡聚化的准确模式似乎取决于V结构域(VH-接头-VL或VL-接头-VH)的组合以及方向。
这些制备多特异性或双特异性抗体的技术就低收率、纯化的必要性、低稳定性或技术的劳动密集性而言,具有许多困难。最近,利用通常称为的技术生成了实际上任何所需抗体、抗体片段和其他效应分子的组合,该技术在下文更详细地讨论。本领域已知的任何制备双特异性或多特异性抗体的技术可用于实施受本发明权利要求书保护的方法。
可使用技术制备双特异性或多特异性抗体或其他构建体(参见例如,美国专利No.7,550,143、7,521,056、7,534,866、7,527,787和7,666,400,每个专利的实施例部分以引用的方式并入本文)。一般来讲,该技术利用了cAMP依赖性蛋白激酶(PKA)的调节(R)亚基的二聚化和停靠结构域(DDD)序列和来源于许多AKAP蛋白中的任一者的锚定结构域(AD)序列之间发生的特异性和高亲和力结合相互作用(Baillie等人,FEBSLetters.2005;579:3264。Wong和Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。DDD和AD肽可附连到任何蛋白质、肽或其他分子,优选地作为包含AD或DDD序列的融合蛋白。因为DDD序列自发二聚化和结合至AD序列,所以该技术使在可附连到DDD或AD序列的任何选择分子之间形成复合物。
虽然标准复合物包括两个DDD连接的分子附连到一个AD连接的分子的三聚体,但复合物结构的变化使得形成二聚体、三聚体、四聚体、五聚体、六聚体和其他多聚体。在一些实施方案中,复合物可包括两种或更多种抗体、抗体片段或融合蛋白,所述抗体、抗体片段或融合蛋白结合至相同的抗原决定子或结合至两种或更多种不同的抗原。复合物也可包括一种或多种其他效应子,诸如蛋白质、肽、免疫调节剂、细胞因子、白介素、干扰素、结合蛋白、肽配体、载体蛋白、毒素、核糖核酸酶诸如豹蛙抗瘤酶(onconase)、抑制性寡核苷酸诸如siRNA、抗原或异种抗原、聚合物诸如PEG、酶、治疗剂、激素、细胞毒性剂、抗血管生成剂、促凋亡剂或任何其他分子或聚集体。
1968年首先从兔骨骼肌分离出PKA,其在研究得最深入的第二信使cAMP结合到R亚基触发的信号转导途径之一中起关键作用(Walsh等人,J.Biol.Chem.1968;243:3763)。全酶的结构由通过R亚基保持失活形式的两个催化亚基组成(Taylor,J.Biol.Chem.1989;264:8443)。据发现PKA的同工酶具有两种类型的R亚基(RI和RII),并且每种类型具有α和β同种型(Scott,Pharmacol.Ther.1991;50:123)。因此,PKA调节亚基的四种同种型为RIα、RIβ、RIIα和RIIβ。R亚基仅作为稳定的二聚体分离,并且二聚化结构域显示出由RIIα的前44个氨基末端残基组成(Newlon等人,Nat.Struct.Biol.1999;6:222)。如下文所讨论,其他调节亚基的氨基酸序列的类似部分涉及二聚化和停靠,每个调节亚基位于调节亚基的N-末端附近。cAMP与R亚基的结合引起一系列丝氨酸/苏氨酸激酶活性的活性催化亚基的释放,该活性催化亚基通过PKA的区室化适应选择的底物,所述PKA的区室化通过AKAP停靠来进行(Scott等人,J.Biol.Chem.1990;265;21561)。
自从1984年鉴定出第一个AKAP微管相关蛋白2以来(Lohmann等人,Proc.Natl.Acad.Sci USA.1984;81:6723),已在从酵母至人类的物种中鉴定出超过50个具有各种结构、定位于各个亚细胞位点,包括质膜、肌动蛋白细胞骨架、细胞核、线粒体和内质网的AKAP(Wong和Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。PKA的AKAP的AD是14-18位残基的两亲螺旋(Carr等人,J.Biol.Chem.1991;266:14188)。AD的氨基酸序列在每个AKAP中是完全不同的,所报告的对RII二聚体的结合亲和力在2至90nM的范围内(Alto等人,Proc.Natl.Acad.Sci.USA.2003;100:4445)。AKAP将仅结合至二聚体R亚基。对于人RIIα,AD结合至23个氨基末端残基形成的疏水表面(Colledge和Scott,Trends Cell Biol.1999;6:216)。因此,人RIIα的二聚化结构域和AKAP结合结构域均位于相同的N-末端44个氨基酸序列内(Newlon等人,Nat.Struct.Biol.1999;6:222;Newlon等人,EMBO J.2001;20:1651),它在本文中称为DDD。
我们开发了利用人PKA调节亚基的DDD和AKAP的AD作为良好的接头模组对的平台技术,该接头模组用于使任何两个实体(在下文中称为A和B)停靠为非共价复合物,该平台技术还可通过将半胱氨酸残基引入DDD和AD二者的战略位置锁定到复合物,以促进二硫键的形成。该方法的一般操作如下。实体A通过将DDD序列与A的前体连接以得到第一组分来构建,在下文中称为a。因为DDD序列将影响二聚体的自发形成,所以A将由a2构成。实体B通过将AD序列与B的前体连接以得到第二组分来构建,在下文中称为b。a2中包含的DDD的二聚体基序将形成用于结合至b中包含的AD序列的停靠位点,从而促进a2和b的迅速缔合,以形成由a2b构成的二元三聚体复合物。结合事件不可逆转地通过后续反应完成,以通过二硫桥共价固定两个实体,根据有效局部浓度原理,所述反应的进行非常有效,因为初始结合相互作用应将DDD和AD二者上的反应性硫醇基接近放置(Chmura等人,Proc.Natl.Acad.Sci.USA.2001;98:8480),以便进行位点特异性连接。使用接头、衔接子模组和前体的各种组合,可制备和使用许多不同化学计量的构建体(参见例如,美国No.7,550,143、7,521,056、7,534,866、7,527,787和7,666,400)。
通过使DDD和AD远离两个前体的官能团附连,预期此类位点特异性连接也保持了两个前体的初始活性。该方法实际上是模块化的,并且可能用于位点特异性和共价连接一系列广泛的物质,包括肽、蛋白质、抗体、抗体片段和具有一系列广泛的活性的其他效应子部分。利用下文所述的构建AD和DDD缀合的效应子的融合蛋白方法,可将实际上任何蛋白质或肽掺入到构建体。然而,该技术是非限制性的,并且可利用其他缀合方法。
许多制备融合蛋白的方法是已知的,包括核酸合成、杂交和/或扩增,以生成编码所关注的融合蛋白的合成双链核酸。此类双链核酸可插入表达载体,以便通过标准分子生物学技术生成融合蛋白(参见例如Sambrook等人,Molecular Cloning,A laboratorymanual,第2版,1989)。在此类优选的实施方案中,AD和/或DDD部分可附连到效应子蛋白或肽的N-末端或C-末端。然而,熟练技术人员将认识到,AD或DDD部分附连到效应子部分的位点可根据效应子部分和涉及效应子部分的生理活性的部分的化学性质而变化。许多效应子部分的位点特异性附连可使用本领域已知的技术进行,诸如使用二价交联试剂和/或其他化学缀合技术。
AD和DDD部分的结构-功能关系
对于不同类型的构建体,可利用不同的AD或DDD序列。示例性DDD和AD序列在下文提供。
DDD1
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:9)
DDD2
CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:10)
AD1
QIEYLAKQIVDNAIQQA(SEQ IDNO:11)
AD2
CGQIEYLAKQIVDNAIQQAGC(SEQ ID NO:12)
熟练技术人员将认识到,DDD1和DDD2基于蛋白激酶A的人RIIα同种型的DDD序列。然而,在替代实施方案中,DDD和AD部分可基于蛋白激酶A的人RIα形式的DDD序列和对应的AKAP序列,如下文的DDD3、DDD3C和AD3所示。
DDD3
SLRECELYVQKHNIQALLKDSIVQLCTARPERPMAFLREYFERLEKEEAK(SEQ ID NO:13)
DDD3C
MSCGGSLRECELYVQKHNIQALLKDSIVQLCTARPERPMAFLREYFERLEKEEAK(SEQ ID NO:14)
AD3
CGFEELAWKIAKMIWSDVFQQGC(SEQ IDNO:15)
在其他替代实施方案中,AD和/或DDD部的其他序列变体分可用于构建复合物。例如,人PKA DDD序列只有四种变体,对应于PKA RIα、RIIα、RIβ和RIIβ的DDD部分。RIIαDDD序列是上文公开的DDD1和DDD2的基础。四个人PKA DDD序列如下文所示。DDD序列表示RIIα的残基1-44、RIIβ的残基1-44、RIα的残基12-61和RIβ的残基13-66。(应注意,DDD1的序列由人PKA RIIα DDD部分稍微修饰而成。)
PKA RIα
SLRECELYVQKHNIQALLKDVSIVQLCTARPERPMAFLREYFEKLEKEEAK(SEQ ID NO:16)
PKA RIβ
SLKGCELYVQLHGIQQVLKDCIVHLCISKPERPMKFLREHFEKLEKEENRQILA(SEQ ID NO:17)
PKA RIIα
SHIQIPPGLTELLQGYTVEVGQQPPDLVDFAVEYFTRLREARRQ(SEQ ID NO:18)
PKA RIIβ
SIEIPAGLTELLQGFTVEVLRHQPADLLEFALQHFTRLQQENER(SEQ ID NO:19)
AD和DDD结构域的结构-功能关系是本研究的主题。(参见例如,Burns-Hamuro等人,2005,Protein Sci 14:2982-92;Carr等人,2001,J Biol Chem 276:17332-38;Alto等人,2003,Proc Natl Acad Sci USA 100:4445-50;Hundsrucker等人,2006,Biochem J396:297-306;Stokka等人,2006,Biochem J 400:493-99;Gold等人,2006,Mol Cell24:383-95;Kinderman等人,2006,Mol Cell 24:397-408,所述参考文献各自的完整文本以引用的方式并入本文。)
例如,Kinderman等人(2006,Mol Cell 24:397-408)研究了AD-DDD结合相互作用的晶体结构,并得出结论:人DDD序列包含许多对于二聚体形成或AKAP结合重要的保守氨基酸残基,在下文的SEQ ID NO:9加下划线。(参见Kinderman等人,2006的图1,该文献以引用的方式并入本文。)熟练技术人员将认识到,在设计DDD序列的序列变体时,希望避免改变任何加下划线的残基,而对于二聚化和AKAP结合不太重要的残基,可进行保守氨基酸取代。
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:9)
如下文更详细地讨论,已鉴定出二十个常见L-氨基酸中的每个的保守氨基酸取代。因此,根据Kinderman(2006)和保守氨基酸取代的数据,根据SEQ ID NO:9的可能的可选DDD序列如表2所示。在设计表2时,仅考虑高度保守的氨基酸取代。例如,带电残基仅取代相同电荷的残基,具有小侧链的残基被类似大小的残基取代,羟基侧链仅被其他羟基取代等。由于脯氨酸对氨基酸二级结构的独特作用,其他残基不能取代脯氨酸。有限数量的此类可能的可选DDD部分序列如下文SEQ ID NO:20至SEQ ID NO:39所示。熟练技术人员将认识到,在DDD部分的种属中,可通过标准技术例如使用商业化肽合成仪或熟知的定点诱变技术构建几乎无限数量的可选物类。氨基酸取代对AD部分结合的作用也可易于通过标准结合分析确定,例如如Alto等人(2003,Proc Natl Acad Sci USA 100:4445-50)所公开。
表2.DDD1(SEQ ID NO:9)中的保守氨基酸取代。共有序列如SEQ ID NO:94所公开。
THIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:20)
SKIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:21)
SRIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:22)
SHINIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:23)
SHIQIPPALTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:24)
SHIQIPPGLSELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:25)
SHIQIPPGLTDLLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:26)
SHIQIPPGLTELLNGYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:27)
SHIQTPPGLTELLQAYTVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:28)
SHIQIPPGLTELLQGYSVEVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:29)
SHIQIPPGLTELLQGYTVDVLRQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:30)
SHIQIPPGLTELLQGYTVEVLKQQPPDLVEFAVEYFTRLREARA(SEQ ID NO:31)
SHIQIPPGLTELLQGYTVEVLRNQPPDLVEFAVEYFTRLREARA(SEQ ID NO:32)
SHIQIPPGLTELLQGYTVEVLRQNPPDLVEFAVEYFTRLREARA(SEQ ID NO:33)
SHIQIPPGLTELLQGYTVEVLRQQPPELVEFAVEYFTRLREARA(SEQ ID NO:34)
SHIQIPPGLTELLQGYTVEVLRQQPPDLVDFAVEYFTRLREARA(SEQ ID NO:35)
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFLVEYFTRLREARA(SEQ ID NO:36)
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFIVEYFTRLREARA(SEQ ID NO:37)
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFVVEYFTRLREARA(SEQ ID NO:38)
SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVDYFTRLREARA(SEQ ID NO:39)
Alto等人(2003,Proc Natl Acad Sci USA 100:4445-50)进行了各种AKAP蛋白的AD序列的生物信息学分析,以设计RII选择性AD序列,该序列称为AKAP-IS(SEQ ID NO:11),DDD的结合常数为0.4nM。AKAP-IS序列设计为AKAP结合PKA的肽拮抗剂。其中取代往往会减少与DDD的结合的AKAP-IS序列中的残基在下文SEQ ID NO:11中加下划线。熟练技术人员将认识到,在设计AD序列的序列变体时,希望避免改变任何加下划线的残基,而对于DDD结合不太重要的残基,可进行保守氨基酸取代。表3示出了AKAP-IS(AD1,SEQ ID NO:19)的序列中可能的保守氨基酸取代,类似于上表2中的DDD1(SEQ ID NO:16)所示。
有限数量的此类可能的可选AD部分序列如下文SEQ ID NO:40至SEQ ID NO:57所示。另外,在可能的AD部分序列的种属中,熟练技术人员可根据Alto等人(2003)的数据制备、测试和使用许多物类。应当注意,Alto(2003)的图2示出了更多可根据实际结合实验制备,同时保持DDD部分的结合活性的可能的氨基酸取代。
AKAP-IS
QIEYLAKQIVDNAIQQA(SEQ ID NO:11)
表3.AD1(SEQ ID NO:11)中的保守氨基酸取代。如SEQ ID NO:95所公开的共有序列。
NIEYLAKQIVDNAIQQA(SEQ ID NO:40)
QLEYLAKQIVDNAIQQA(SEQ ID NO:41)
QVEYLAKQIVDNAIQQA(SEQ ID NO:42)
QIDYLAKQIVDNAIQQA(SEQ ID NO:43)
QIEFLAKQIVDNAIQQA(SEQ ID NO:44)
QIETLAKQIVDNAIQQA(SEQ ID NO:45)
QIESLAKQIVDNAIQQA(SEQ ID NO:46)
QIEYIAKQIVDNAIQQA(SEQ ID NO:47)
QIEYVAKQIVDNAIQQA(SEQ ID NO:48)
QIEYLARQIVDNAIQQA(SEQ ID NO:49)
QIEYLAKNIVDNAIQQA(SEQ ID NO:50)
QIEYLAKQIVENAIQQA(SEQ ID NO:51)
QIEYLAKQIVDQAIQQA(SEQ ID NO:52)
QIEYLAKQIVDNAINQA(SEQ ID NO:53)
QIEYLAKQIVDNAIQNA(SEQ ID NO:54)
QIEYLAKQIVDNAIQQL(SEQ ID NO:55)
QIEYLAKQIVDNAIQQI(SEQ ID NO:56)
QIEYLAKQIVDNAIQQV(SEQ ID NO:57)
Gold等人(2006,Mol Cell 24:383-95)利用结晶和肽筛选来开发SuperAKAP-IS序列(SEQ ID NO:58),表现出对PKA的RII同种型的选择性比RI同种型大五个数量级。加下划线的残基表示相对于AKAP-IS序列的氨基酸取代的位置,其增加了与RIIα的DDD部分的结合。在该序列中,N-末端Q残基编号为第4位残基,C-末端A残基为第20位残基。其中可进行取代以影响RIIα的亲和力的残基为残基8、11、15、16、18、19和20(Gold等人,2006)。预期在某些替代实施方案中,SuperAKAP-IS序列可取代AKAP-IS AD部分序列,以制备构建体。可取代AKAP-IS AD序列的其他可选的序列如SEQ ID NO:59-61所示。相对于AKAP-IS序列的取代加下划线。预期,正如SEQ ID NO:12所示的AD2序列,AD部分也可包括另外的N-末端残基半胱氨酸和甘氨酸以及C-末端残基甘氨酸和半胱氨酸。
Super AKAP-IS
QIEYVAKQIVDYAIHQA(SEQ ID NO:58)
可选的AKAP序列
QIEYKAKQIVDHAIHQA(SEQ ID NO:59)
QIEYHAKQIVDHAIHQA(SEQ ID NO:60)
QIEYVAKQIVDHAIHQA(SEQ ID NO:61)
Gold等人的图2公开了来自许多AKAP蛋白的另外的DDD结合序列,如下文所示。
RII特异性AKAP
AKAP-KL
PLEYQAGLLVQNAIQQAI(SEQ ID NO:62)
AKAP79
LLIETASSLVKNAIQLSI(SEQ ID NO:63)
AKAP-Lbc
LIEEAASRIVDAVIEQVK(SEQ ID NO:64)
RI特异性AKAP
AKAPce
ALYQFADRFSELVISEAL(SEQ ID NO:65)
RIAD
LEQVANQLADQIIKEAT(SEQ ID NO:66)
PV38
FEELAWKIAKMIWSDVF(SEQ ID NO:67)
双特异性AKAP
AKAP7
ELVRLSKRLVENAVLKAV(SEQ ID NO:68)
MAP2D
TAEEVSARIVQVVTAEAV(SEQ ID NO:69)
DAKAPI
QIKQAAFQLISQVILEAT(SEQ ID NO:70)
DAKAP2
LAWKIAKMIVSDVMQQ(SEQ ID NO:71)
Stokka等人(2006,Biochem J 400:493-99)也开发了结合PKA的AKAP的肽竞争剂,如SEQ ID NO:72-74所示。肽拮抗剂被命名为Ht31(SEQ ID NO:72)、RIAD(SEQ ID NO:73)和PV-38(SEQ ID NO:74)。Ht-31肽对于PKA的RII同种型表现出更大的亲和力,而RIAD和PV-38对于RI显示出更大的亲和力。
Ht31
DLIEEAASRIVDAVIEQVKAAGAY(SEQ ID NO:72)
RIAD
LEQYANQLADQIIKEATE(SEQ ID NO:73)
PV-38
FEELAWKIAKMIWSDVFQQC(SEQ ID NO:74)
Hundsrucker等人(2006,Biochem J 396:297-306)也开发了结合PKA的AKAP的其他肽竞争剂,其与PKA的RII形式的DDD的结合常数低至0.4nM。各种AKAP拮抗肽的序列在Hundsrucker等人的表1中提供,转载于下表4中。AKAPIS代表合成RII亚基结合肽。所有其他肽均来源于指定的AKAP的RII结合结构域。
表4.AKAP肽序列
肽序列
AKAPIS QIEYLAKQIVDNAIQQA(SEQ ID NO:11)
AKAPIS-P QIEYLAKQIPDN AIQQA(SEQ ID NO:75)
Ht31 KGADLIEEAASRIVDAVIEQVKAAG(SEQ ID NO:76)
Ht31-P KGADLIEEAASRIPDAPIEQVKAAG(SEQ ID NO:77)
AKAP7δ-wt-pep PEDAELVRLSKRLVENAVLKAVQQY(SEQ ID NO:78)
AKAP7δ-L304T-pep PEDAELVRTSKRLVENAVLKAVQQY(SEQ ID NO:79)
AKAP7δ-L308D-pep PEDAELVRLSKRDVENAVLKAVQQY(SEQ ID NO:80)
AKAP7δ-P-pep PEDAELVRLSKRLPENAVLKAVQQY(SEQ ID NO:81)
AKAP7δ-PP-pep PEDAELVRLSKRLPENAPLKAVQQY(SEQ ID NO:82)
AKAP7δ-L314E-pep PEDAELVRLSKRLVENAVEKAVQQY(SEQ ID NO:83)
AKAP1-pep EEGLDRNEEIKRAAFQIISQVISEA(SEQ ID NO:84)
AKAP2-pep LVDDPLEYQAGLLVQNAIQQAIAEQ(SfQ ID NO:85)
AKAP5-pep QYETLLIETASSLVKNAIQLSIEQL(SEQ ID NO:86)
AKAP9-pep LEKQYQEQLEEEVAKVIVSMSIAFA(SEQ ID NO:87)
AKAP10-pep NTDEAQEELAWKIAKMIVSDIMQQA(SEQ ID NO:88)
AKAP11-pep VNLDKKAVLAEKIVAEAIEKAEREL(SEQ ID NO:89)
AKAP12-pep NGILELETKSSKLVQNIIQTAVDQF(SEQ ID NO:90)
AKAP14-pep TQDKNYEDELTQVALALVEDVINYA(SEQ ID NO:91)
Rab32-pep ETSAKDNINIEEAARFLVEKILVNH(SEQ ID NO:92)
在不同AKAP蛋白的AD结构域中高度保守的残基在下文参考AKAP IS序列(SEQ IDNO:11)加下划线。残基与Alto等人(2003)的观察相同,但添加了C-末端丙氨酸残基。(参见Hundsrucker等人(2006)的图4,该文献以引用的方式并入本文。)具有特别高的RII DDD序列的亲和力的肽拮抗剂的序列为AKAP-IS、AKAP7δ-wt-pep、AKAP7δ-L304T-pep和AKAP7δ-L308D-pep。
AKAP-IS
QIEYLAKQIVDNAIQQA(SEQ ID NO:11)
Carr等人(2001,J Biol Chem 276:17332-38)检测了来自人和非人蛋白的不同AKAP-结合DDD序列之间的序列同源性程度并且鉴定在不同DDD部分中看起来似乎为最高度保守的DDD序列中的残基。其在以下通过参考SEQ ID NO:9的人PKARIIo DDD序列加下划线指示。特别保守的残基进一步以斜体指示。残基与Kinderman等人(2006)所表明的对结合AKAP蛋白重要的那些残基重叠,但不与其相同。熟练技术人员将认识到,在设计DDD的序列变体时,最优选的是避免改变最保守的残基(斜体),并且优选还避免改变保守残基(加下划线),而既未加下划线也不是斜体的残基可考虑进行保守氨基酸取代。
SHIQIPPGLTELLQGYTVEVLRQOPPDLVEFAVEYFTRLREARA(SEQ ID NO:9)
基于Carr等人(2001)的数据,针对DDD1(SEQ ID NO:9)序列的一组修饰的保守氨基酸取代在表5中示出。甚至对于这个缩减组的取代序列,存在超过65,000个可通过熟练技术人员在无需过多实验的情况下产生、测试和使用的可能替代DDD部分序列。熟练技术人员可容易地得到此类可选的DDD氨基酸序列,如上表2和表3所公开。
表5.DDD1(SEQ ID NO:9)中的保守氨基酸取代。共有序列如SEQ ID NO:96所公开。
熟练技术人员将认识到,DDD或AD氨基酸序列中的这些和其它氨基酸取代可用来使用本领域中标准的技术和仅通过常规实验来产生AD或DDD部分的属种内的替代种类。
可选的
结构
在某些替代实施方案中,可使用另外构建的抗体或抗体片段形成构建体,其中AD部分可附连到κ轻链的C-末端(Ck),而不是重链上Fc的C-末端。另外形成的构建体可以如2012年6月1日提交的临时美国专利申请序列号61/654,310、2012年6月20日提交的临时美国专利申请序列号61/662,086、2012年7月19日提交的临时美国专利申请序列号61/673,553和2012年8月13日提交的临时美国专利申请序列号61/682,531所公开制备,每个专利申请的完整文本以引用的方式并入本文。轻链缀合的构建体表现出增强的离体Fc效应子功能活性和改善的体内药代动力学、稳定性和抗淋巴瘤活性(Rossi等人,2013,Bioconjug Chem 24:63-71)。
Ck缀合的构建体可以如临时美国专利申请序列号61/654,310、61/662,086、61/673,553和61/682,531所公开制备。简而言之,Ck-AD2-IgG通过重组工程生成,由此AD2肽融合至κ轻链的C-末端。因为CK的天然C末端是半胱氨酸残基,其与CH1形成二硫桥,所以使用16个氨基酸残基的“铰链”接头将AD2与CK-VH1二硫桥间隔开。使用pdHL2载体构建Ck-AD2-IgG-维妥珠单抗和Ck-AD2-IgG-依帕珠单抗的哺乳动物表达载体,所述pdHL2载体此前用于表达同源CH3-AD2-IgG模组。合成包含pdHL2载体序列的2208-bp核苷酸序列,该载体序列的范围包括VK/CKBam HI限制性位点和Ck内含子的XhoI限制性位点3’,并且在CK的编码序列的3’末端插入铰链接头(EFPKPSTPPGSSGGAP,SEQ ID NO:93)和AD2的编码序列框内。通过Bam HI和XhoI限制性位点将该合成序列插入维妥珠单抗和依帕珠单抗的IgG-pdHL2表达载体。如CH3-AD2-IgG模组所述实施使用SpESFX-10的生产克隆生成。在分批旋转瓶培养中通过稳定转染的生产克隆生成Ck-AD2-IgG-维妥珠单抗和Ck-AD2-IgG-依帕珠单抗,并使用MabSelect(GE Healthcare)蛋白A亲和色谱以单个步骤从上清液流体纯化。
在前述用于22-(20)-(20)的相同方法(Rossi等人,2009,Blood 113:6161-71)之后,使Ck-AD2-IgG--依帕珠单抗与CH1-DDD2-Fab-维妥珠单抗(来源于维妥珠单抗的基于Fab的模组)缀合,生成bsHexAb 22*-(20)-(20),其中22*表示依帕珠单抗的Ck-AD2模组,并且每个(20)表示维妥珠单抗Fab的稳定二聚体。将22*-(20)-(20)的性质与22-(20)-(20)的性质比较,所述22-(20)-(20)是包含CH3-AD2-IgG-依帕珠单抗的同源Fc-bsHexAb,具有类似的组合和分子大小,但具有不同的构建。
在前述用于20-2b的相同方法(Rossi等人,2009,Blood 114:3864-71)之后,将Ck-AD2-IgG-维妥珠单抗与IFNα2b-DDD2(IFNα2b与DDD2肽在其C-末端融合的模组)缀合,生成20*-2b,其包括二聚体IFNα2b融合至每个轻链的维妥珠单抗。将20*-2b的性质与20-2b比较,所述20-2b是同源Fc-IgG-IFNα。
通过MabSelect亲和色谱从反应混合物分离bsHexAb和IgG-IFNα中的每个。两种Ck来源的原型,即包含依帕珠单抗(抗CD22)和维妥珠单抗(抗CD20)的四个Fab的抗CD22/CD20双特异性六价抗体,以及包含维妥珠单抗和四分子干扰素-α2b的靶向CD20的免疫细胞因子与其Fc来源的对应部分相比,显示出增强的离体Fc效应子功能,以及改善的体内药代动力学、稳定性和抗淋巴瘤活性。
氨基酸取代
在替代实施方案中,所公开的方法和组合物可涉及具有一个或多个取代氨基酸残基的蛋白质或肽的产生和使用。例如,用于制备构建体的DDD和/或AD序列可以如上文所讨论进行修饰。
熟练技术人员将认识到,一般来讲,氨基酸取代通常涉及一个氨基酸被具有相对类似性质的另一个氨基酸取代(即,保守氨基酸取代)。各种氨基酸的性质和氨基酸取代对蛋白质结构和功能的影响是本领域的广泛研究和知识的主题。
例如,可考虑氨基酸的亲水指数(Kyte&Doolittle,1982,J.Mol.Biol.,157:105-132)。氨基酸的相对亲水特征有助于所得的蛋白质的二级结构,继而限定蛋白质与其他分子的相互作用。每个氨基酸根据其疏水性和电荷特性分配亲水指数(Kyte & Doolittle,1982),这些指数为:异亮氨酸(+4.5)、缬氨酸(+4.2)、亮氨酸(+3.8)、苯丙氨酸(+2.8)、半胱氨酸/胱氨酸(+2.5)、甲硫氨酸(+1.9)、丙氨酸(+1.8)、甘氨酸(-0.4)、苏氨酸(-0.7)、丝氨酸(-0.8)、色氨酸(-0.9)、酪氨酸(-1.3)、脯氨酸(-1.6)、组氨酸(-3.2)、谷氨酸(-3.5)、谷氨酰胺(-3.5)、天冬氨酸(-3.5)、天冬酰胺(-3.5)、赖氨酸(-3.9)和精氨酸(-4.5)。在进行保守取代时,使用亲水指数在±2之内的氨基酸是优选的,在±1之内是更优选的,并且在±0.5之内是甚至更优选的。
氨基酸取代也可考虑氨基酸残基的亲水性(例如,美国专利No.4,554,101)。分配给氨基酸残基的亲水性值为:精氨酸(+3.0)、赖氨酸(+3.0)、天冬氨酸(+3.0)、谷氨酸(+3.0)、丝氨酸(+0.3)、天冬酰胺(+0.2)、谷氨酰胺(+0.2)、甘氨酸(0)、苏氨酸(-0.4)、脯氨酸(-0.5.+-.1)、丙氨酸(-0.5)、组氨酸(-0.5)、半胱氨酸(-1.0)、甲硫氨酸(-1.3)、缬氨酸(-1.5)、亮氨酸(-1.8)、异亮氨酸(-1.8)、酪氨酸(-2.3)、苯丙氨酸(-2.5)、色氨酸(-3.4)。氨基酸被具有相似亲水性的其他氨基酸取代是优选的。
其他考虑包括氨基酸侧链的大小。例如,通常不优选使用具有大体积侧链的氨基酸如色氨酸或酪氨酸取代具有紧凑侧链的氨基酸如甘氨酸或丝氨酸。各种氨基酸残基对蛋白质二级结构的影响也是考虑因素。通过实证研究,确定了不同氨基酸残基对蛋白质结构域采取α-螺旋、β-折叠或回折二级结构的趋势的作用,并且是本领域已知的(参见例如,Chou&Fasman,1974,Biochemistry,13:222-245;1978,Ann.Rev.Biochem.,47:251-276;1979,Biophys.J.,26:367-384)。
根据此类考虑因素和广泛经验研究,构建了保守氨基酸取代表并且是本领域已知的。例如:精氨酸和赖氨酸;谷氨酸和天冬氨酸;丝氨酸和苏氨酸;谷氨酰胺和天冬酰胺;以及缬氨酸、亮氨酸和异亮氨酸。或者:Ala(A)leu、ile、val;Arg(R)gln、asn、lys;Asn(N)his、asp、lys、arg、gln;Asp(D)asn、glu;Cys(C)ala、ser;Gln(Q)glu、asn;Glu(E)gln、asp;Gly(G)ala;His(H)asn、gln、lys、arg;Ile(I)val、met、ala、phe、leu;Leu(L)val、met、ala、phe、ile;Lys(K)gln、asn、arg;Met(M)phe、ile、leu;Phe(F)leu、val、ile、ala、tyr;Pro(P)ala;Ser(S)、thr;Thr(T)ser;Trp(W)phe、tyr;Tyr(Y)trp、phe、thr、ser;Val(V)ile、leu、met、phe、ala。
氨基酸取代的其他考虑因素包括残基是否位于蛋白质内部还是暴露于溶剂中。对于内部残基,保守取代将包括:Asp和Asn;Ser和Thr;Ser和Ala;Thr和Ala;Ala和Gly;Ile和Val;Val和Leu;Leu和Ile;Leu和Met;Phe和Tyr;Tyr和Trp。(参见例如,PROWL网站:rockefeller.edu)对于暴露于溶剂的残基,保守取代将包括:Asp和Asn;Asp和Glu;Glu和Gln;Glu和Ala;Gly和Asn;Ala和Pro;Ala和Gly;Ala和Ser;Ala和Lys;Ser和Thr;Lys和Arg;Val和Leu;Leu和Ile;Ile和Val;Phe和Tyr。(出处同上)已构建有助于氨基酸取代选择的各种矩阵,诸如PAM250计分矩阵、Dayhoff矩阵、Grantham矩阵、McLachlan矩阵、Doolittle矩阵、Henikoff矩阵、Miyata矩阵、Fitch矩阵、Jones矩阵、Rao矩阵、Levin矩阵和Risler矩阵(出处同上)。
在确定氨基酸取代时,也可考虑分子间或分子内键的存在,诸如在带正电的残基(如,His、Arg、Lys)和带负电的残基(如,Asp、Glu)之间形成离子键(盐桥)或在附近的半胱氨酸残基之间形成二硫键。
用任何氨基酸取代编码蛋白质序列中的任何其他氨基酸的方法是熟知的,并且是熟练技术人员进行的常规实验,例如通过定点诱变技术或通过合成,以及编码氨基酸取代的寡核苷酸的组合和剪接成表达载体构建体。
预靶向
可将双特异性或多特异性抗体用于预靶向技术。在这种情况下,一种或多种诊断和/或治疗剂可缀合至包含一种或多种半抗原的可靶向构建体。半抗原被还结合至肿瘤相关抗原或其他疾病相关抗原的双特异性或多特异性抗体的至少一个臂识别。在这种情况下,治疗剂通过结合可靶向构建体,间接结合至抗体。该方法称为预靶向。
预靶向是多步骤方法,最初开发用于解决直接靶向抗体的缓慢血液清除,这种缓慢血液清除促成对正常组织诸如骨髓不期望的毒性。通过预靶向,治疗剂附连到在几分钟内从血液清除的小递送分子(可靶向构建体)。首先施用预靶向双特异性或多特异性抗体,其具有可靶向构建体以及靶标抗原的结合位点,使游离的抗体从循环清除,然后施用可靶向构建体。
预靶向方法公开于例如Goodwin等人,美国专利No.4,863,713;Goodwin等人,J.Nucl.Med.29:226,1988;Hnatowich等人,J.Nucl.Med.28:1294,1987;Oehr等人,J.Nucl.Med.29:728,1988;Hnatowich等人,J.Nucl.Med.29:1951,1988;Sinitsyn等人,J.Nucl.Med.30:66,1989;Kalofonos等人,J.Nucl.Med.31:1791,1990;Schechter等人,Int.J.Cancer 48:167,1991;Paganelli等人,Cancer Res.51:5960,1991;Paganelli等人,Nucl.Med.Commun.12:211,1991;美国专利No.5,256,395;Stickney等人,Cancer Res.51:6650,1991;Yuan等人,Cancer Res.51:3119,1991;美国专利No.6,077,499、7,011,812、7,300,644、7,074,405、6,962,702、7,387,772、7,052,872、7,138,103、6,090,381、6,472,511、6,962,702和6,962,702中,每个文献均以引用的方式并入本文。
诊断或治疗受试者中的疾病或病症的预靶向方法可通过以下步骤提供:(1)将双特异性抗体或抗体片段施用于受试者;(2)任选地将清除组合物施用于受试者,并且使组合物从循环清除抗体;以及(3)将可靶向构建体施用于受试者,该可靶向构建体包含一种或多种螯合的或化学结合的治疗或诊断剂。
可靶向构建体
在某些实施方案中,可选择使用一种或多种用于预靶向的治疗或诊断剂标记的可靶向构建体肽,结合到具有一个或多个可靶向构建体肽的结合位点和一个或多个疾病或病症相关的靶标抗原的结合位点的双特异性抗体。双特异性抗体可用于预靶向技术,其中该抗体首先施用于受试者。可使双特异性抗体结合至靶标抗原,并且未结合抗体从循环清除足够长的时间。然后,可将靶向构建体诸如标记肽施用于受试者,并使其结合至双特异性抗体并且定位在疾病细胞或组织。
此类可靶向构建体可具有不同的结构,并且不仅被选择用于获取以高亲和力结合至可靶向构建体的抗体或片段,而且当在预靶向方法和双特异性抗体(bsAb)或多特异性抗体中使用时还被选择用于快速体内清除。疏水剂对于引起强免疫应答是最佳的,而亲水剂对于快速体内清除是优选的。因此,建立疏水和亲水特征之间的平衡。这可以部分通过使用亲水螯合剂偏移多个有机部分的固有疏水性来实现。另外,可选择具有相对溶液性质的可靶向构建体的亚组,例如包含氨基酸的肽,一些氨基酸是疏水的,一些氨基酸是亲水的。
可使用具有仅两个氨基酸残基,优选地两个至十个残基的肽,并且也可连接到其他部分,诸如螯合剂。接头应为低分子量缀合物,优选地具有小于50,000道尔顿,有利地小于约20,000道尔顿、10,000道尔顿或5,000道尔顿的分子量。更通常地,可靶向构建体肽将具有四个或更多个残基,以及用于结合至例如双特异性抗体的一个或多个半抗原。示例性半抗原可包括In-DTPA(铟-二亚乙基三胺五乙酸)或HSG(组胺琥珀酰基甘氨酸)。可靶向构建体也可包括一个或多个螯合部分,诸如DOTA(1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸)、NOTA(1,4,7-三氮杂-环壬烷-1,4,7-三乙酸)、TETA(对溴乙酰胺基-苄基-四乙胺四乙酸)、NETA([2-(4,7-双羧甲基[1,4,7]三氮杂环壬-1-基-乙基]-2-羰基甲基-氨基]乙酸)或其他已知螯合部分。螯合部分可用于例如结合至治疗和/或诊断放射性核素、顺磁离子或造影剂。
可靶向构建体的主链结构也可包含非天然氨基酸,如D-氨基酸,以提高肽的体内稳定性。在替代实施方案中,可使用其他主链结构,诸如从非天然氨基酸或肽构建的那些。
用作可靶向构建体的肽可使用固相载体和重复正交脱保护和偶联的标准技术,在自动化肽合成仪上便利地合成。随后用于缀合螯合部分或其他试剂的肽中的游离氨基基团有利地使用标准保护基团诸如Boc基封端,而N-末端残基可被乙酰化以提高血清稳定性。此类保护基团是熟练技术人员熟知的。参见Greene和Wuts Protective Groups in OrganicSynthesis,1999(John Wiley and Sons,N.Y.)。当制备随后在双特异性抗体系统中使用的肽时,有利地从树脂切下肽,以生成对应的C-末端酰胺,从而抑制体内羧肽酶活性。
在使用通过双特异性抗体预靶向的情况下,抗体将包含靶组织产生的或相关的抗原的第一结合位点和可靶向构建体上的半抗原的第二结合位点。示例性半抗原包括但不限于HSG和In-DTPA。产生HSG半抗原的抗体是已知的(如679抗体),并且可易于掺入到适当的双特异性抗体(参见例如,美国专利No.6,962,702、7,138,103和7,300,644,这些专利的实施例部分以引用的方式并入本文)。然而,其他半抗原以及与其结合的抗体是本领域已知的,并且是可使用的,诸如In-DTPA和734抗体(例如,美国专利No.7,534,431,该专利的实施例部分以引用的方式并入本文)。
免疫缀合物
各种实施方案可涉及使用免疫缀合物,包括附连到一种或多种诊断或治疗剂的抗Trop-2抗体或其抗原结合片段。在一些实施方案中,药物或其他试剂可通过载体部分附连到抗体或其片段。载体部分可以例如附连到还原的SH基团和/或碳水化合物侧链。载体部分可通过形成二硫键附连到还原抗体组分的铰链区。或者,此类试剂可使用异双官能交联剂,诸如N-琥珀酰基3-(2-吡啶二硫代)丙酸酯(SPDP)附连。Yu等人,Int.J.Cancer56:244(1994)。此类缀合的一般技术是本领域熟知的。参见例如,Wong,CHEMISTRY OF PROTEINCONJUGATION AND CROSS-LINKING(CRC Press 1991);Upeslacis等人,“Modification ofAntibodies by Chemical Methods”,载于MONOCLONAL ANTIBODIES:PRINCIPLES ANDAPPLICATIONS,Birch等人(编),第187-230页(Wiley-Liss,Inc.1995);Price,“Productionand Characterization of Synthetic Peptide-Derived Antibodies”,载于MONOCLONALANTIBODIES:PRODUCTION,ENGINEERING AND CLINICAL APPLICATION,Ritter等人(编),第60-84页(Cambridge University Press 1995)。或者,载体部分可通过抗体的Fc区中的碳水化合物部分缀合。
用于通过抗体碳水化合物部分将官能团缀合至抗体的方法是本领域的技术人员熟知的。参见例如,Shih等人,Int.J.Cancer41:832(1988);Shih等人,Int.J.Cancer46:1101(1990);以及Shih等人,美国专利No.5,057,313,该专利的实施例部分以引用的方式并入本文。一般方法涉及使具有氧化的碳水化合物部分的抗体与具有至少一个游离的胺官能团的载体聚合物反应。该反应形成初始席夫碱(亚胺)键,该键可通过还原成仲胺来稳定,以形成最终缀合物。
如果抗体组分是抗体片段,则Fc区可不存在。然而,可以将碳水化合物部分引入全长抗体或抗体片段的轻链可变区。参见例如,Leung等人,J.Immunol.154:5919(1995);美国专利No.5,443,953和6,254,868,这些专利的实施例部分以引用的方式并入本文。使用工程化的碳水化合物部分来附连治疗或诊断剂。
用于将载体部分附连到靶向分子的可选的方法涉及使用点击化学反应。点击化学方法最初构想为通过将小亚基以模组方式连接在一起来快速生成复合物的方法。(参见例如,Kolb等人,2004,Angew Chem Int Ed 40:3004-31;Evans,2007,Aust J Chem 60:384-95)各种形式的点击化学反应是本领域已知的,诸如Huisgen 1,3-偶极环加成铜催化反应(Tornoe等人,2002,J Organic Chem 67:3057-64),其通常称为“点击反应”。其他取代形式包括环加成反应,诸如Diels-Alder、亲核取代反应(特别是小张力环如环氧基和氮丙啶化合物)、脲化合物的羰基化学形成以及涉及碳-碳双键的反应,诸如硫醇-炔反应中的炔烃。
叠氮化物炔烃Huisgen环加成反应使用铜催化剂在存在还原剂的情况下催化末端炔烃基附连到第一分子的反应。在存在包含叠氮化物部分的第二分子的情况下,叠氮化物与活化的炔烃反应,形成1,4-二取代1,2,3-三唑。铜催化反应在室温下进行,并且具有足够的特异性,使得反应产物的纯化通常不是必须的。(Rostovstev等人,2002,Angew Chem IntEd 41:2596;Tornoe等人,2002,J Org Chem 67:3057。)叠氮化物和炔烃官能团对水介质中的生物分子为基本上惰性的,使反应在复合物溶液中进行。所形成的三唑在化学上是稳定的,未经受酶切,使得点击化学产物在生物系统中是高度稳定的。虽然铜催化剂对活细胞是有毒的,但基于铜的点击化学反应可在体外用于免疫缀合物形成。
已提出用于生物分子的共价修饰的无铜点击反应。(参见例如,Agard等人,2004,JAm Chem Soc 126:15046-47。)无铜反应使用环张力代替铜催化剂来促进[3+2]叠氮化物-炔烃环加成反应(出处同上)。例如,环辛炔是包含内部炔烃键的8碳环结构。闭环结构诱导了乙炔的显著键角变形,乙炔与叠氮化物基团反应形成三唑具有高度反应性。因此,环辛炔衍生物可用于无铜点击反应(出处同上)。
Ning等人(2010,Angew Chem Int Ed 49:3065-68)报道了另一种类型的无铜点击反应,涉及张力促进的炔烃-硝酮环加成反应。为解决初始环辛炔反应的缓慢速率,将吸电子基团邻近连接至三键(出处同上)。此类取代环辛炔的例子包括二氟化环辛炔、4-二苯并环辛炔醇和氮杂环辛炔(出处同上)。可选的无铜反应涉及张力促进的炔烃-硝酮环加成反应,得到N-烷基化异噁唑啉(出处同上)。据报道,该反应具有特别快的反应动力学,并且用于肽和蛋白质的位点特异性修饰的一锅三步骤方案(出处同上)。硝酮通过适当的醛与N-甲基羟胺的缩合反应制备,并且环加成反应在乙腈和水的混合物中进行(出处同上)。这些和其他已知的点击化学反应可用于在体外将载体部分附连到抗体。
Agard等人(2004,J Am Chem Soc 126:15046-47)显示,在存在全乙酰化N-叠氮基乙酰基甘露糖胺的情况下在CHO细胞中表达重组糖蛋白的结果是将N-叠氮基乙酰基唾液酸生物掺入糖蛋白的碳水化合物。叠氮基衍生化的糖蛋白与生物素化环辛炔特异性反应,形成生物素化糖蛋白,而无叠氮基部分的对照糖蛋白仍然未标记(出处同上)。Laughlin等人(2008,Science 320:664-667)使用类似的技术通过全乙酰化N-叠氮基乙酰基半乳糖胺温育来代谢标记斑马鱼胚胎中的细胞表面聚糖。叠氮基衍生化的聚糖与二氟化环辛炔(DIFO)试剂反应,使聚糖在体内可视化。
Diels-Alder反应也用于分子的体内标记。Rossin等人(2010,Angew Chem Int Ed49:3375-78)报道了携带反式环辛烯(TCO)反应性部分和111In标记的四嗪DOTA衍生物的肿瘤定位的抗TAG72(CC49)抗体之间的体内收率为52%。将TCO标记的CC49抗体施用给具有结肠癌异种移植物的小鼠,在1天后注射111In标记的四嗪探针(出处同上)。放射性标记探针与肿瘤定位的抗体的反应的结果是在肿瘤中产生显著的放射性定位,如在注射放射性标记探针三小时后活小鼠的SPECT成像所示,肿瘤与肌肉的比率为13∶1(出处同上)。结果确认了TCO和四嗪标记分子的体内化学反应。
使用标记部分的生物掺入进行的抗体标记技术在美国专利No.6,953,675中进一步公开(该专利的实施例部分以引用的方式并入本文)。此类“改造的”抗体制备为在糖基化位点上具有反应性酮基。该方法涉及在培养基中表达转染有表达载体的细胞,该表达载体编码CH1或Vκ结构域中具有一个或多个N-糖基化位点的抗体,该培养基包含糖类或糖类前体的酮衍生物。酮衍生化的糖类或前体包括N-乙酰丙酰基甘露糖胺和N-乙酰丙酰基岩藻糖。随后使改造的抗体与包含酮反应性部分的试剂,诸如酰肼、肼、羟氨基或硫代氨基脲基反应,形成标记靶向分子。附连到改造的抗体的示例性试剂包括螯合剂如DTPA、大药物分子诸如多柔比星-葡聚糖以及含酰基-酰肼的肽。改造技术不限于制备包含酮部分的抗体,而且还可用于将点击化学反应性基团,诸如硝酮、叠氮化物或环辛炔引入抗体或其他生物分子。
点击化学反应的修饰适用于体外或体内。反应性靶向分子可通过化学缀合或通过生物掺入形成。靶向分子,诸如抗体或抗体片段,可使用叠氮基部分、取代环辛炔或炔烃基或硝酮部分活化。在靶向分子包含叠氮基或硝酮基的情况下,对应的可靶向构建体将包含取代环辛炔或炔烃基,反之亦然。此类活化分子可通过活细胞中的代谢掺入制备,如上文所讨论。
或者,此类部分化学缀合至生物分子的方法是本领域熟知的,并且可利用任何此类已知的方法。免疫缀合物形成的一般方法公开于例如美国专利No.4,699,784、4,824,659、5,525,338、5,677,427、5,697,902、5,716,595、6,071,490、6,187,284、6,306,393、6,548,275、6,653,104、6,962,702、7,033,572、7,147,856和7,259,240,每个专利的实施例部分以引用的方式并入本文。
诊断剂
诊断剂可包括可用于标记检测抗体或直接标记CTC的任何可检测试剂,并且优选地选自放射性核素、放射性造影剂、顺磁离子、金属、荧光标记、化学发光标记、超声造影剂和光活性剂。此类诊断剂是熟知的,并且可使用任何此类已知的诊断剂。诊断剂的非限制性例子可包括放射性核素,诸如110In、111In、177Lu、18F、52Fe、62Cu、64Cu、67Cu、67Ga、68Ga、86Y、90Y、89Zr、94mTc、94Tc、99mTc、120I、123I、124I、125I、131I、154-158Gd、32P、11C、13N、15O、186Re、188Re、51Mn、52mMn、55Co、72As、75Br、76Br、82mRb、83Sr或其他γ-、β-或正电子发射体。所用的顺磁离子可包括铬(III)、锰(II)、铁(III)、铁(II)、钴(II)、镍(II)、铜(II)、钕(III)、钐(III)、镱(III)、钆(III)、钒(II)、铽(III)、镝(III)、钬(III)或铒(III)。金属造影剂可包括镧(III)、金(III)、铅(II)或铋(III)。超声造影剂可包括脂质体,诸如气体填充脂质体。射线不可透诊断剂可从化合物、钡化合物、镓化合物和铊化合物选择。
在某些实施方案中,荧光探针可以是染料(Thermo FisherScientific,Rockford,IL)。染料系列是高度极性的(亲水的)、与水性缓冲液相容的、不感光的,并且表现出高荧光强度。它们在宽泛的pH范围内仍然具有高荧光,并且是各种应用优选的。然而,熟练技术人员将认识到,许多荧光染料是已知的和/或可商购获得的,并且是可使用的。其他荧光剂包括但不限于丹磺酰氯、罗丹明异硫氰酸酯、Alexa350、Alexa 430、AMCA、氨基吖啶、BODIPY 630/650、BODIPY 650/665、BODIPY-FL、BODIPY-R6G、BODIPY-TMR、BODIPY-TRX、5-羧基-4’,5’-二氯-2’,7’-二甲氧基荧光素、5-羧基-2’,4’,5’,7’-四氯荧光素、5-羧基荧光素、5-羧基罗丹明、6-羧基罗丹明、6-羧基四甲基氨基、级联蓝、Cy2、Cy3、Cy5,6-FAM、丹磺酰氯、荧光素、HEX、6-JOE、NBD(7-硝基苯-2-噁-1,3-二唑)、俄勒冈绿(Oregon Green)488、俄勒冈绿500、俄勒冈绿514、太平洋蓝(Pacific Blue)、邻苯二甲酸、对苯二甲酸、间苯二甲酸、甲酚紫、甲酚蓝紫、亮甲酚蓝、对氨基苯甲酸、赤藓红、酞菁、偶氮甲碱、花菁、黄嘌呤、琥珀酰荧光素、稀土金属穴状化合物、铕三双吡啶二胺、铕穴状化合物或螯合物、二胺、双花菁、拉霍亚蓝(La Jolla blue)染料、异藻蓝蛋白、allococyanin B、藻蓝蛋白C、藻蓝蛋白R、硫胺素、藻红蓝蛋白、藻红蛋白R、REG、罗丹明绿、罗丹明异硫氰酸酯、罗丹明红、ROX、TAMRA、TET、TRIT(四甲基罗丹明异硫醇)、四甲基罗丹明和德克萨斯红(Texas Red)。(参见例如,美国专利No.5,800,992、6,319,668。)这些和其他发光标记可从商业来源获得,诸如Molecular Probes(Eugene,Oreg.)和EMD Biosciences(San Diego,Calif.)。
所用的化学发光标记可包括鲁米诺、异鲁米诺、芳族吖啶酯、咪唑、吖啶盐或草酸酯。
治疗剂
许多广泛的治疗剂可与抗Trop-2或其他抗TAA抗体同时或按顺序施用。或者,此类试剂可缀合至抗体,例如药物、毒素、寡核苷酸、免疫调节剂、激素、激素拮抗剂、酶、酶抑制剂、放射性核素、血管生成抑制剂等。治疗剂包括例如细胞毒性药物诸如长春花生物碱、蒽环类药物诸如多柔比星、2-PDox或pro-2-PDox、吉西他滨、表鬼臼毒素、紫杉烷、抗代谢物、烷基化剂、抗生素、SN-38、COX-2抑制剂、抗有丝分裂剂、抗血管生成和促凋亡剂,特别是多柔比星、甲氨蝶呤、紫杉醇、CPT-11、喜树碱衍生物(camptothecans)、蛋白酶体抑制剂、mTOR抑制剂、HDAC抑制剂、酪氨酸激酶抑制剂等等。其他可用的抗癌症细胞毒性药物包括氮芥、烷基磺酸盐、亚硝基脲、三氮烯、叶酸类似物、COX-2抑制剂、抗代谢物、嘧啶类似物、嘌呤类似物、铂配位络合物、mTOR抑制剂、酪氨酸激酶抑制剂、蛋白酶体抑制剂、HDAC抑制剂、喜树碱、激素等等。合适的细胞毒性剂如REMINGTON’S PHARMACEUTICAL SCIENCES,第19版(MackPublishing Co.1995)和GOODMAN AND GILMAN’S THE PHARMACOLOGICAL BASIS OFTHERAPEUTICS,第7版(MacMillan Publishing Co.1985)以及这些出版物的修订版所述。其他合适的细胞毒性剂诸如实验药物是本领域的技术人员已知的。在一个优选的实施方案中,喜树碱和相关化合物的缀合物诸如SN-38可缀合至抗Trop-2或其他抗TAA抗体。在另一个优选的实施方案中,将吉西他滨与SN-38-hRS7和/或90Y-hPAM4一起施用给受试者。
毒素可以是动物、植物或微生物来源的。所用的毒素包括蓖麻毒素、相思子毒素、核糖核酸酶(RNA酶)、DNA酶I、葡萄球菌肠毒素A、美洲商陆抗病毒蛋白、豹蛙抗瘤酶(onconase)、白树毒素(gelonin)、白喉毒素、假单胞菌外毒素和假单胞菌内毒素。参见例如,Pastan等人,Cell 47:641(1986),Goldenberg,CA--A Cancer Journal forClinicians 44:43(1994),Sharkey和Goldenberg,CA--A Cancer Journal forClinicians 56:226(2006)。合适的另外毒素是本领域的技术人员已知的,并且如美国专利No.6,077,499所公开,该专利的实施例部分以引用的方式并入本文。
如本文所用,术语“免疫调节剂”包括细胞因子、淋巴因子、单核因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素(IFN)、甲状旁腺激素、甲状腺素、胰岛素、胰岛素原、松弛素、松弛素原、促卵泡激素(FSH)、促甲状腺激素(TSH)、促黄体激素(LH)、肝生长因子、前列腺素、成纤维细胞生长因子、促乳素、胎盘催乳素、OB蛋白、转化生长因子(TGF)、TGF-α、TGF-β、胰岛素样生长因子(ILGF)、促红细胞生成素、促血小板生成素、肿瘤坏死因子(TNF)、TNF-α、TNF-β、苗勒管抑制物质、小鼠促性腺激素相关肽、抑制素、活化素、血管内皮生长因子、整联蛋白、白介素(IL)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、干扰素-α、干扰素-β、干扰素-γ、干扰素-λ、S1因子、IL-1、IL-1cc、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21和IL-25、LIF、kit配体、FLT-3、血管抑素、血小板反应蛋白、内皮他丁、淋巴毒素等等。
特别有用的治疗性放射性核素包括但不限于111In、177Lu、212Bi、213Bi、211At、62Cu、64Cu、67Cu、90Y、125I、131I、32P、33P、47Sc、111Ag、67Ga、142Pr、153Sm、161Tb、166Dy、166Ho、186Re、188Re、189Re、212Pb、223Ra、225Ac、59Fe、75Se、77As、89Sr、99Mo、105Rh、109Pd、143Pr、149Pm、169Er、194Ir、198Au、199Au、227Th和211Pb。治疗性放射性核素优选地具有在20至6,000keV的范围内、优选地在60至200keV的范围内(对于俄歇发射体)、在100-2,500keV的范围内(对于β发射体)和在4,000-6,000keV的范围内(对于α发射体)的衰变能。可用的β粒子发射核素的最大衰变能为优选地20-5,000keV、更优选地100-4,000keV以及最优选地500-2,500keV。另外优选的是基本上随俄歇发射粒子而衰变的放射性核素。例如,Co-58、Ga-67、Br-80m、Tc-99m、Rh-103m、Pt-109、In-111、Sb-119、I-125、Ho-161、Os-189m和Ir-192。可用的β粒子发射核素的衰变能为优选地<1,000keV、更优选地<100keV以及最优选地<70keV。另外优选的是基本上随α粒子的产生而衰变的放射性核素。此类放射性核素包括但不限于:Dy-152、At-211、Bi-212、Ra-223、Rn-219、Po-215、Bi-211、Ac-225、Fr-221、At-217、Bi-213、Fm-255和Th-227。可用的α粒子发射放射性核素的衰变能为优选地2,000-10,000keV、更优选地3,000-8,000keV以及最优选地4,000-7,000keV。
例如,可使用二亚乙基三胺五乙酸(DTPA)或更优选地使用DOTA将发射高能β粒子的90Y连接到抗体、抗体片段或融合蛋白。将90Y缀合至抗体或可靶向构建体的方法是本领域已知的,并且可使用任何此类已知的方法。(参见例如,美国专利No.7,259,249,该专利的实施例部分以引用的方式并入本文。还可参见等人,Clin Cancer Res.11:5215-22,2005;Sharkey等人,J Nucl Med.46:620-33,2005;Sharkey等人,J Nucl Med.44:2000-18,2003)
另外可能的治疗性放射性同位素包括11C、13N、15O、75Br、198Au、224Ac、126I、133I、77Br、113mIn、95Ru、97Ru、103Ru、105Ru、107Hg、203Hg、121mTe、122mTe、125mTe、165Tm、167Tm、168Tm、197Pt、109Pd、105Rh、142Pr、143Pr、161Tb、166Ho、199Au、57Co、58Co、51Cr、59Fe、75Se、201Tl、225Ac、76Br、169Yb等等。
在另一个实施方案中,放射致敏剂可与裸的或缀合抗体或抗体片段组合使用。例如,放射致敏剂可与放射性标记的抗体或抗体片段组合使用。与单独使用放射性标记的抗体或抗体片段治疗相比,加入放射致敏剂可产生增强功效。放射致敏剂如D.M.Goldenberg(编),CANCER THERAPY WITH RADIOLABELED ANTIBODIES,CRC Press(1995)所述。与该技术一起使用的所关注的其他典型放射致敏剂包括吉西他滨、5-氟尿苷和顺铂,并且与各种癌症治疗中的外部照射组合使用。
装载有硼附加物的载体、用于热中子活化治疗的抗体或其片段通常以类似的方式发挥作用。然而,在非靶向免疫缀合物清除之后,再进行中子照射将是有利的。可使用结合至抗癌症抗体的抗个体基因型抗体加速清除。一般原理的描述参见美国专利No.4,624,846。例如,硼附加物诸如碳硼烷可附连到抗体。碳硼烷可使用侧链上的羧基官能团制备,如本领域所熟知。碳硼烷附连到载体,诸如氨基葡聚糖可通过活化碳硼烷的羧基基团以及与载体上的胺缩合来实现。然后使中间体缀合物缀合至抗体。在施用抗体缀合物之后,通过热中子照射活化硼附加物,并且转化为放射性原子,该放射性原子通过α-放射衰变,产生高毒性短距离效应。
制剂和给药
在体内施用治疗抗体的情况下,合适的施用途径可包括但不限于口服、肠胃外给药、直肠给药、经粘膜给药、肠道施用、髓内注射、鞘内注射、直接心室内注射、静脉内注射、玻璃体内注射、腔内注射、腹膜内注射或肿瘤内注射。优选的施用途径是肠胃外给药,更优选地是静脉内注射。或者,可以局部而非全身方式施用化合物,例如通过将化合物直接注射到实体或血液肿瘤。
抗体可根据已知的方法配制,以制备药学上有用的组合物,据此在混合物中使抗体与药学上合适的赋形剂组合。无菌磷酸盐缓冲盐水是药学上合适的赋形剂的一个例子。其他合适的赋形剂是本领域熟知的。参见例如,Ansel等人,PHARMACEUTICAL DOSAGE FORMSAND DRUG DELIVERY SYSTEMS,第5版(Lea & Febiger 1990),和Gennaro(编),REMINGTON’SPHARMACEUTICAL SCIENCES,第18版(Mack Publishing Company 1990)以及它们的修订版。
在一个优选的实施方案中,在Good氏生物缓冲液(pH 6-7)中,使用选自N-(2-乙酰胺基)-2-氨基乙磺酸(ACES)、N-(2-乙酰胺基)亚氨基二乙酸(ADA)、N,N-双(2-羟乙基)-2-氨基乙磺酸(BES)、4-(2-羟乙基)哌嗪-1-乙磺酸(HEPES)、2-(N-吗啉代)乙磺酸(MES)、3-(N-吗啉代)丙磺酸(MOPS)、3-(N-吗啉代)-2-羟基丙磺酸(MOPSO)和哌嗪-N,N’-双(2-乙磺酸)[Pipes]的缓冲液配制抗体。更优选的缓冲液是MES或MOPS,优选地浓度在20至100mM的范围内,更优选地约25mM。最优选的是25mM MES,pH6.5。制剂还可包含25mM海藻糖和0.01%v/v聚山梨醇酯80作为赋形剂,由于加入赋形剂而使最终缓冲液浓度变为22.25mM。优选的保存方法是以缀合物的冻干制剂,保存在-20℃至2℃的温度范围下,最优选地保存在2℃至8℃的温度范围下。
抗体可配制为通过例如弹丸式注射、缓慢输注或连续输注静脉内给药。优选地,本发明的抗体在小于约4小时的时间内,更优选地在小于约3小时的时间内输注。例如,前25-50mg可在30分钟,优选地甚至15分钟内输注,其余的部分在接下来的2-3小时内输注。用于注射的制剂可以单位剂型提供,如在安瓿瓶或多剂容器中,并加入防腐剂。组合物可采取例如悬浮液、溶液或溶于油性或水性媒介物的乳液的形式,并且可包含配制剂诸如悬浮剂、稳定剂和/或分散剂。或者,活性成分可以是在使用前与合适的媒介物如不含热原的无菌水一起复原的粉末形式。
另外的制药方法可用于控制治疗缀合物的作用持续时间。控释制剂可通过使用聚合物结合或吸附抗体来制备。例如,生物相容性聚合物包括乙烯-乙酸乙烯酯共聚物基体和硬脂酸二聚体和癸二酸的聚酸酐共聚物基体。Sherwood等人,Bio/Technology 10:1446(1992)。抗体从此类基体释放的速率取决于抗体的分子量、基体内抗体的量以及分散颗粒的大小。Saltzman等人,Biophys.J.55:163(1989);Sherwood等人,出处同上。其他固体剂型如Ansel等人,PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS,第5版(Lea &Febiger 1990),和Gennaro(编),REMINGTON’S PHARMACEUTICAL SCIENCES,第18版(MackPublishing Company 1990)以及它们的修订版。
一般来讲,对于人类,所施用的抗体的剂量将根据诸如以下因素而变化:患者的年龄、体重、身高、性别、一般病情和既往病史。可能有利的是提供单次静脉内输注的抗体剂量在约0.3mg/kg至5mg/kg的范围内的处方但根据情况决定也可施用更低或更高的剂量。例如对于70kg患者,0.3-5mg/kg的剂量为21-350mg,或对于1.7-m患者,12-206mg/m2。剂量可根据需要重复,例如每周一次、2-10周,每周一次、8周或每周一次、4周。还可根据维持治疗的需要以更低的频率给予,诸如每隔一周一次、几个月,或每月一次或每季一次,几个月。优选的剂量可包括但不限于0.3mg/kg、0.5mg/kg、0.7mg/kg、1.0mg/kg、1.2mg/kg、1.5mg/kg、2.0mg/kg、2.5mg/kg、3.0mg/kg、3.5mg/kg、4.0mg/kg、4.5mg/kg和5.0mg/kg。更优选的剂量是每周给药0.6mg/kg和以更小频率的给药1.2mg/kg。可使用在0.3至5mg/kg范围内的任何剂量。该剂量优选地施用多次,每周一次。可使用4周、更优选地8周、更优选地16周或更长的最小剂量计划,其中剂量频率取决于大部分与血液毒性有关的毒性副作用以及由此的恢复。给药计划可包括在一个周期中每周给药一次或两次,该周期选自:(i)每周;(ii)每隔一周;(iii)一周治疗,然后两周、三周或四周停止治疗;(iv)两周治疗,然后一周、两周、三周或四周停止治疗;(v)三周治疗,然后一周、两周、三周、四周或五周停止治疗;(vi)四周治疗,然后一周、两周、三周、四周或五周停止治疗;(vii)五周治疗,然后一周、两周、三周、四周或五周停止治疗;以及(viii)每月。该周期可重复2、4、6、8、10或12次或更多次。
或者,抗体可以每2周或每3周一剂施用,重复总共至少3剂。或者,每周两次,持续4-6周。剂量可以每隔一周一次或甚至更低的频率施用,使患者可从任何药物相关毒性恢复。或者,可减少剂量计划,即每2周或每3周、2-3个月。给药计划可任选地以其他间隔重复,剂量可通过各种肠胃外路线给予,并且适当调整剂量和计划。
本文所述和要求保护的方法和组合物可用于治疗恶性或癌变前病症,并且用于防止进展为赘生性或恶性状态,包括但不限于上述那些疾病。此类用途表明了已知或怀疑之前进展为瘤变或癌症的病症,特别是出现包括增生、化生的非赘生性细胞生长,或最特别地发育异常的情况(此类异常生长病症的综述,参见Robbins和Angell,Basic Pathology,第2版,W.B.Saunders Co.,Philadelphia,第68-79页(1976))。
发育异常通常是癌症的预兆,并且主要可见于上皮中。这是最混乱的非赘生性细胞生长形式,涉及单个细胞均匀度和细胞构建取向的丧失。发育异常典型地在存在慢性过敏或炎症的情况下发生。在优选的实施方案中,本发明的方法用于抑制癌症,特别是上文列出的那些癌症的生长、进展和/或癌细胞转移。
试剂盒
各种实施方案可涉及包含适用于检测患者中的Trop-2阳性CTC的部件的试剂盒。示例性试剂盒可包含如本文所描述的至少一个抗Trop-2抗体。在某些实施方案中,该抗体可缀合至至少一种诊断剂。在替代实施方案中,可包括抑制Trop-2阳性CTC的第二抗体。第二抗体可结合至Trop-2的不同表位或结合至不同的TAA,并且可使用至少一种诊断剂标记。在某些实施方案中,抗Trop-2抗体或其抗原结合片段可以包含抗体的无菌液体制剂或冻干制剂的预填充注射器或小瓶的形式提供(例如,Kivitz等人,Clin.Ther.2006,28:1619-29)。
试剂盒部件可包装在一起或分成两个或更多个容器。在一些实施方案中,该容器可以是包含适用于复原的组合物的无菌冻干制剂的小瓶。试剂盒也可包含一种或多种适用于其他试剂的复原和/或稀释的缓冲液。可使用的其他容器包括但不限于小袋、托盘、盒、管等等。试剂盒部件可包装并且无菌保持在容器内。可包括的另一个部件是试剂盒的使用说明。
实施例
以下实施例是本发明的实施方案的展示,并且不限制权利要求的范围。
实施例1.抗Trop-2抗体的细胞结合分析
获得两种不同的抗人Trop-2的鼠单克隆抗体。从旋转瓶中生长的杂交瘤(ATCC,HB-187)纯化第一抗体162-46.2。第二抗体MAB650购自R&D Systems(Minneapolis,MN)。对于结合的比较,TROP-2阳性人胃癌,使用NCI-N87作为靶标。在结合分析前一天,将细胞(1.5×105/孔)接种至96孔板。第二天早上,使用162-46.2、MAB650和鼠RS7(0.03至66nM)(未示出)生成剂量/响应曲线。将这些一抗在4℃下与细胞一起温育1.5h。冲洗孔,并且在4℃下将抗小鼠HRP二抗加入所有孔1h。再次冲洗孔,然后加入发光底物。使用Envision读板机读取板,值以相对发光单位报道。
全部三个抗体具有类似的KD值,RS7为0.57nM、162-46.2为0.52nM并且MAB650为0.49nM(未示出)。然而,当比较162-46.2和MAB650与RS7的最大结合(Bmx)时,它们分别减少25%和50%(RS7的BMax为11,250、162-46.2为8,471并且MAB650为6,018),表明与RS7(未示出)相比具有不同的结合性质。
实施例2.血样的采集和保存。
从10名健康供体和20名转移性乳腺癌患者中的每名采集10mL血样,分配至CELLSAVETM保存管(Jassen Diagnostics LLC,Raritan,NJ)。将样品保存在室温下,在72h内处理血液采集(Allard等人,2004,Clin Cancer Res,10:6897)。或者,将10mL血样采集至采血管(Streck,Omaha,NE),保持在室温下,并且在7天内处理(Ng等人,2012J Immunol Methods,385:79)。血液也可采集至10mL K2EDTA(BD,Waltham,MA),在采集的4h内使用固定剂(Cynvenio Biosystems,Westlake Village,CA)固定,保存在室温下,并且在固定的96h内处理。
实施例3.健康供体血样的癌细胞加标。
SK-BR-3和BxPC-3细胞均表达高水平的Trop-2,将它们培养在指定培养基中,并使用胰蛋白酶收集。使用Guava EASYCYTETM流式细胞仪评估所得的细胞悬浮液的活力和细胞数。仅使用活力超过90%的细胞悬浮液。加标至正常血清的细胞数量为1至100个/mL。表达中等水平Trop-2的癌细胞,例如MCF-7、LoVo和LS 174T,表达低水平Trop-2的癌细胞,例如HT-29,或Trop-2阴性的癌细胞,例如A549和H460,也可用于加标血样。
实施例4.使用磁装置从加标的血样分离上皮癌细胞。
将上皮癌细胞加标的血样与生物素化tri-Fab hRS7(通过上述技术制备的生物素-E1/3),以及涂覆有链霉亲和素的铁磁流体(FF-SV)一起温育,从而以免疫磁性方法富集上皮细胞。简而言之,将7.5mL包含已知数量加标BxPC-3或SK-BR-3的血样与6mL缓冲液混合,以800×g离心10min。在移除血浆和缓冲液层后,加入生物素-E1/3和FF-SV并温育1h。随后,在磁力分离之后从标记的细胞移除未标记的细胞。然后通过进一步洗涤和离心从FF-SV分离生物素-E1/3标记的细胞,在使用DAPI、PE-抗CK18和APC-抗CD45标记后通过流式细胞术分析。缺乏CD45和表达细胞角蛋白(CK8、CK18、CK19)的有核细胞通常定义为CTC(Swaby&Cristofanilli,2011,BMC Medicine,9:43)。
实施例5.不使用磁装置从加标的血样分离上皮癌细胞。
将上皮癌细胞加标的血样与微涡产生的人字形芯片(HP-芯片)中的生物素-E1/3一起温育,该芯片使用亲和素化学改性,如Stott等人(2010,PNAS,107:18392)所述,或更优选地与生物素-E1/3一起温育1h,然后加入使用链霉亲和素官能化的NanoVelcro芯片,如Lu等人(2013,Methods,64:144)所述。在冲洗掉未结合的细胞后,分析结合的细胞的CTC,如实施例3所述。
实施例6.检测之前未富集的加标血样的上皮癌细胞。
使用氯化铵裂解BxPC-3加标的血样中的红细胞并离心。收集细胞沉淀物,并使用FITC-标记的E1/3温育。然后将悬浮液中的活细胞施加到聚赖氨酸处理的玻片,并使用激光扫描血细胞计数器分析(Pachmann等人,2005,Breast Cancer Res,7:R975)。或者,在红细胞裂解后,在存在FITC标记的亲和素的情况下,将所收集的细胞沉淀物与包含生物素化E1/3和一种或多种其他生物素化缀合物的混合物一起温育。然后通过激光扫描血细胞计数器分析悬浮液中的活细胞。
实施例7.使用靶向Trop-2和EGFR二者的双特异性构建体检测加标血样的上皮癌细胞
BxPC-3细胞加标的血样表达高水平的Trop-2和EGFR,将该血样与生物素化双特异性Tri-Fab(称为(E1)-225),以及涂覆有链霉亲和素(FF-SV)的铁磁流体一起温育,如实施例4所述。(E1)-225通过将CH1-DDD2-Fab-hRS7缀合至CHl-AD2-Fab-c225产生,从而提供分别与Trop-2和EGFR的二价和单价结合。与仅使用单特异性hRS7或c225(西妥昔单抗)的富集相比,双特异性(E1)-225能够捕集更多加标至血样的BxPC-3,并且CD45-阳性白细胞污染较少。
实施例8.使用系统检测Trop-2+CTC
仪器(目录No.A28188)、采血试剂盒(目录No.A28171)和试剂和耗材试剂盒(目录No.A28186、A28187)得自Life Technologies,ThemoFisher(Grand Island,NY)。试剂盒包括全血样的稳定化方案,以使样品的非冷冻运输(96小时窗口),以及缓冲液、试剂、小瓶、洗脱管和处理血样的流动池。
人源化RS7(hRS7)单克隆抗体(sacimzumab)使用试剂和耗材试剂盒提供的方案和试剂生物素化。生物素化hRS7(sacituzumab)用于代替试剂和耗材试剂盒提供的抗EpCAM生物素化抗体。或者,抗TROP-2生物素化抗体(目录No.BAF650,R&D Systems,Minneapolis,MN)用于代替抗EpCAM。
使用抗TROP-2生物素化抗体和上文讨论的仪器和试剂,根据制造商的说明分离来自实体肿瘤患者血液的循环肿瘤细胞。分离的肿瘤细胞从玻片释放,在使用DAPI、PE-抗CK18和APC-抗CD45标记后,通过流式细胞术确认,如实施例3所述。培养从第二血液标本释放的细胞,获得活细胞的集落,分离该集落并使用得自Empire Genomics(Buffalo,NY)的特异性探针通过FISH分析Trop-2和染色体-1的拷贝数。图1和图2是得自MCF-7(Trop-2阳性)和A549(Trop-2阴性)细胞的代表性结果,其分别示出了Trop-2基因的3个和2个拷贝。此外,拓扑异构酶-I(TOP1)和染色体-20的拷贝数也使用Abnova(台湾台北)提供的特异性探针确定和记录。图3和图4是在MCF-7和A549细胞中获得的代表性结果,其分别示出了TOP1基因的7个和3个拷贝。Trop-2和TOP1拷贝数的同时检测和定量使确定也表达TOP1的癌细胞,这可指示哪些患者肿瘤可对TOP1-抑制剂治疗(诸如使用伊立替康)产生特别响应或耐受性。当使用sacituzumab govitecan(IMMU-132)时,这是特别有用的,其靶向表达Trop-2的癌细胞并且将SN-38选择性递送至此类细胞。使用抗Trop-2hRS7抗体与试剂盒提供的抗EpCAM抗体比较从血样回收的肿瘤细胞。意外的是,使用抗Trop-2抗体回收的CTC大于使用抗EpCAM抗体回收。
实施例9.使用IMAGTM磁性颗粒分离Trop-2+CTC
从购自BD Pharmingen(San Jose,CA)的克隆162-46制备纯化的小鼠抗人Trop-2抗体。抗Trop-2抗体如实施例7所述生物素化。IMAGTM磁性颗粒(链霉亲和素颗粒Plus-DM)和BD IMAGTM细胞分离磁体购自BD Biosciences(San Jose,CA)。K2EDTA喷涂的10ml塑料全血管(目录No.366643)也购自BD。
为进行CTC的分离和分析,从肺癌患者采集10mL血样并保存在K2EDTA管中。使用Ficoll-Hypaque溶液通过密度梯度离心获得单核细胞。从Ficoll-Hypaque选择阳性CTC的方案如BD Technical Data Sheet Streptavidin Particles Plus-DM Material Number:557812所公开。在BD IMAGTM磁体上进行最终洗涤步骤后,将释放的细胞重悬于缓冲液中。
使用荧光标记的抗细胞角蛋白、荧光标记的亲和力纯化的山羊抗TROP-2、DAPI和/或抗CD45对细胞染色。采集捕集细胞的后续免疫荧光图像,然后根据荧光强度和细胞形态进行全面计算机辅助分析。
实施例10.Trop-2+CTC的检测和转移性表达Trop-2癌症的治疗
系统和循环肿瘤细胞试剂盒获自Veridex LLC(Raritan,NJ)。从怀疑患有NSCLC的65岁男性采集7.5ml血样并保存在CellSave管(Veridex LLC)中。抗Trop-2hRS7抗体代替试剂盒提供的抗EpCAM抗体。将血样与缀合至抗Trop-2抗体的磁性纳米颗粒混合。细胞用荧光标记的抗CD45和抗CK抗体染色,细胞核用DAPI细胞核染料荧光标记。在系统中产生强磁场,并用于分离结合到磁性纳米颗粒的细胞,然后通过FISH分析该细胞以确定Trop-2拷贝数,如上文实施例7所述。结果显示存在循环Trop-2+肿瘤细胞,每个细胞具有4个拷贝的Trop-2。CTC中存在高拷贝数的Trop-2表明,患者是使用抗Trop-2抗体进行治疗的良好候选者。
另外的临床检查显示存在IIIB期NSCLC(鳞状细胞癌)。碳铂/依托泊苷(3mo)以及7000cGy XRT的初始治疗使得响应持续10mo。然后除经历腰椎板切除术之外,患者从Tarceva维持治疗开始,继续直到他被考虑进入IMMU-132(hRS7-CL2A-SN-38)试验。他在5个月的Tarceva之后接受第一剂量的IMMU-132,此时右肺出现5.6-cm病灶以及大量胸膜腔积液。他在两个月后完成第6剂,此时首次CT显示主要目标病灶减小至3.2cm。Trop-2+CTC的周期分析显示IMMU-132治疗之后CTC数量显著减少。
该实施例示出了通过分析单个患者血液中的Trop-2+CTC和/或确定CTC中的Trop-2拷贝数,选择对IMMU-132或另一种治疗性抗Trop-2抗体治疗产生响应的患者的可行性。该实施例还示出了监测Trop-2+CTC的相对水平的可行性,它作为基于抗Trop-2的疗法的功效的指示。优选地,显示出阳性响应,包括但不限于完全响应(CR)、部分响应(PR)和/或稳定的疾病(SD)的患者将显示出Trop-2+CTC的水平减少至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或至少99%。在治疗是高度有效并且产生完全响应的情况下,可观察到Trop-2+CTC减少100%。
实施例11.使用VerIFAST系统分离和检测Trop-2+CTC
Casavant等人(2013,Lab Chip 13:391-6;2014,Lab Chip 14:99-105)公开的VerIFAST系统用于检测TNBC中的Trop-2+CTC。从一系列怀疑患有TNBC的患者或对照正常个体采集7.5ml血样,保存在CellSave管(Veridex LLC)中。如Casavant等人(2013,Lab Chip13:391-6)所公开制备生物素化抗Trop-2hRS7抗体。将血样与生物素化抗Trop-2抗体和链霉亲和素缀合的PMP(Casavant等人,2013,Lab Chip 13:391-6)混合,并且使用VerIFAST平台和手持磁体分离CTC。对细胞的肿瘤标记物染色,并且使用DAPI细胞核染料荧光标记细胞核。结果显示TNBC个体的血样中存在循环Trop-2+肿瘤细胞,但对照正常个体中则不存在。
实施例12.使用包含缀合至SN-38的hRS7抗体的IMMU-132抗Trop-2ADC进行临床试验
概述
本实施例报道了I期临床试验和正在进行的IMMU-1 32(sacituzumab govitecan)的II期扩展的结果,IMMU-132是通过pH敏感接头缀合至SN-38的人源化hRS7抗Trop-2抗体内在化的抗体-药物缀合物(ADC)(平均药物-抗体比率=7.6)。Trop-2是很多人恶性肿瘤以高密度(~1×105)、频率和特异性表达的I型跨膜钙转导蛋白,而正常组织表达有限。具有Capan-1人胰腺肿瘤异种移植物的裸小鼠的临床前研究揭示,IMMU-132能够将SN-38递送至肿瘤,比来源于最大耐受伊立替康治疗(未示出)的递送多136倍。
本实施例报道了多次既往治疗失败的25名患者(pt)的初始I期试验(一些包括拓扑异构酶-I/II抑制性药物),现在正在进行的II期扩展报道了69名患者,包括结直肠癌(CRC)、小细胞和非小细胞肺癌(分别为SCLC、NSCLC)、三阴性乳腺癌(TNBC)、胰腺癌(PDC)、食道癌和其他癌症。
如下文所详细讨论,血清中未检测到Trop-2,但在大部分存档的肿瘤中强烈表达(≥2+)。在3+3试验设计中,在第1天和第8天给予IMMU-132,重复21天循环,从8mg/kg/剂开始,然后12和18mg/kg,直到剂量限制性中性粒细胞减少。为优化最小延迟的累积处理,II期集中于8和10mg/kg(n分别=30和14)。此时在49名报道相关AE的患者中,28%出现中性粒细胞减少≥G3(4%G4)。最初这些患者中的最常见非血液毒性是疲劳(55%;≥G3=9%)、恶心(53%;≥G3=0%)、痢疾(47%;≥G3=9%)、脱发(40%)和呕吐(32%;≥G3=2%)。在6名患者中发现纯合UGT1A1*28/*28,其中2名患有较严重的血液和GI毒性。在I期和扩展期中,目前有48名患者(不包括PDC)可被RECIST/CT评估为最佳响应。七名(15%)患者具有部分响应(PR),包括CRC患者(N=1)、TNBC患者(N=2)、SCLC患者(N=2)、NSCLC患者(N=1)和食道癌患者(N=1),并且另外27名患者(56%)患有稳定的疾病(SD),总共38名患者(79%)具有疾病响应;13名CT可评估的PDC患者中的8名(62%)患有SD,在上次既往治疗中,与8.0周相比,中值进展时间(TTP)为12.7周。其余48名患者的TTP为12.6+周(从6.0至51.4周)。血浆CEA和CA19-9与响应相关。尽管给药达数月,但未检测到抗hRS7或抗SN-38抗体。在3天内从血清清除缀合物,符合其中每天释放50%的SN-38的体内动物研究,血清中>95%的SN-38结合到非葡萄糖醛酸形式的IgG,浓度比给予伊立替康的患者中报道的SN-38高100倍。这些结果显示,包含hRS7-SN-38的ADC在转移性实体瘤中具有治疗活性,具有可控制的痢疾和中性粒细胞减少。
药代动力学
将两种ELISA方法用于测定IgG(使用抗hRS7个体基因型抗体捕集)和完整的缀合物(使用抗SN-38IgG/具有抗hRS7个体基因型抗体的探针捕集)的清除。SN-38通过HPLC测定。总IMMU-132级分(完整的缀合物)的清除比IgG(未示出)更快,反映了SN-38从缀合物的已知逐渐释放。SN-38(未结合和总体)的HPLC测定显示出血清中>95%的SN-38结合到IgG。低浓度的SN-38G暗示,结合到IgG的SN-38受到保护,免于葡萄糖醛酸化。缀合物的ELISA和SN-38HPLC的比较显示二者重叠,暗示ELISA是监测SN-38清除的取代。
给药方案和患者调查的汇总提供于表6中。
表6.临床试验参数
临床试验状态
报道了总共69名不同的转移性癌症患者(包括25名I期患者),它们经受的既往治疗中值为3次。八名患者在CT评估之前具有临床进展和撤除。十三名CT可评估的胰腺癌患者单独报道。PDC患者中的中值TTP(进展时间)为11.9周(从2至21.4周),相比之下之前最后治疗的中值TTP为8周。
总共48名具有不同癌症的患者具有至少1次CT评估,由此确定最佳响应(未示出)和进展时间(TTP,未示出)。最佳响应数据汇总如下,在8名可评估TNBC(三阴性乳腺癌)患者中,有2名PR(部分响应)、4名SD(稳定的疾病)和2名PD(进行性疾病),总共响应[PR+SD]为6/8(75%)。对于SCLC(小细胞肺癌),在4名可评估患者中,有2名PR、0名SD和2名PD,总共响应为2/4(50%)。对于CRC(结直肠癌),在18名可评估患者中,有1名PR、11名SD和6名PD,总共响应为12/18(67%)。对于食道癌,在4名可评估患者中,有1名PR、2名SD和1名PD,总共响应为3/4(75%)。对于NSCLC(非小细胞肺癌),在5名可评估患者中,有1名PR、3名SD和1名PD,总共响应为4/5(80%)。全部治疗患者,在48名可评估患者中,有7名PR、27名SD和14名PD,总共响应为34/48(71%)。这些结果显示,抗TROP-2ADC(hRS7-SN-38)显示出对一系列广泛的人类患者实体肿瘤具有显著临床功效。
所报道的治疗副作用(不良事件)汇总于表7中。hRS7-SN-38的治疗功效以ADC的剂量实现,显示出不利副作用为可接受的低水平。相比之下,接受伊立替康剂量(每周125mg/m2×4,Q6W)的患者显示出不利影响的发生率更高,3/4级痢疾发生率为38%,中性粒细胞减少为31%并且中性粒细胞减少发热/感染为8%。
表7.IMMU-132的相关不良事件列表,起始剂量为8或10mg/kg
标准:3-4级不良事件>5%或任何3或4级不良事件(N=123名患者)
还汇总了剂量减少的数据。在76名起始剂量为8mg/kg的患者中,12名(16%)具有剂量减少。在33名起始剂量为10mg/kg的患者中,5名(15%)具有剂量减少。在9名起始剂量为12mg/kg的患者中,6名(67%)具有剂量减少。在3名起始剂量为18mg/kg的患者中,3名(100%)具有剂量减少。我们推断,在8和10mg/kg,很少出现剂量减少,这反映了在治疗水平的ADC具有温和、可预测和可控制的毒性特征。目前,分析了来自148名患者的425份血清样品,未检测到抗体响应于IMMU-132的证据,即使在重复给药之后,一些患者接受超过20剂ADC。
在迄今为止治疗的46名TNBC可评估患者中(I和II期),12名患者(26%)观察到客观响应,34名患者(74%)疾病得到控制,临床受益率(CR+PR+(SD≥6mo)]为46%,临床受益率(CR+PR+(SD≥4mo)]为63%。
在迄今为止治疗的19名NSCLC可评估患者中,6名患者(32%)观察到客观响应,14名患者(74%)疾病得到控制,临床受益率(CR+PR+(SD≥4mo)]为59%。
在迄今为止治疗的20名SCLC可评估患者中,6名患者(30%)观察到客观响应,11名患者(55%)疾病得到控制,临床受益率(CR+PR+(SD≥6mo)]为37%,临床受益率(CR+PR+(SD≥4mo)]为55%。
在迄今为止治疗的16名EAC可评估患者中,2名患者(13%)观察到客观响应,9名患者(56%)疾病得到控制,临床受益率(CR+PR+(SD≥4mo)]为44%。
抗Trop-2ADC的示例性部分响应通过CT数据(未示出)确认。作为CRC的示例性PR,初诊为CRC的62岁妇女经历初次半结肠切除。四个月后,由于肝脏转移她经历了肝脏切除,并接受7mo FOLFOX和1mo 5FU治疗。她出现多个病灶,主要位于肝脏中(3+Trop-2通过免疫组织分析)在初始诊断后,以8mg/kg的起始剂量进入hRS7-SN-38试验约1年。在她首次CT评估时,实现PR,目标病灶减少37%(未示出)。患者继续治疗,在10个月治疗后实现最大减少65%(未示出),CEA从781ng/mL减少至26.5ng/mL,然后进行3个月。
作为NSCLC的示例性PR,65岁男性被诊断为IIIB级NSCLC(鳞状细胞癌)。碳铂/依托泊苷(3mo)以及7000cGy XRT的初始治疗使得响应持续10mo。然后除经历腰椎板切除术之外,他从Tarceva维持治疗开始,继续直到他被考虑进入IMMU-132试验。他在5个月的Tarceva之后接受第一剂量的IMMU-132,此时右肺出现5.6cm病灶以及大量胸膜腔积液。他在两个月后完成第6剂,此时首次CT显示主要目标病灶减小至3.2cm(未示出)。
作为SCLC的示例性PR,65岁妇女被诊断为低分化SCLC。在接受卡铂/依托泊苷(Topo-II抑制剂)2个月之后终止,无响应,然后是托泊替康(Topo-I抑制剂)2个月之后终止,也无响应,她接受局部XRT(3000cGy)1个月之后终止。然而,在接下来一个月内进展继续。患者下个月从IMMU-132开始(12mg/kg;减少至6.8mg/kg;Trop-2表达3+),在两个月的IMMU-132之后,目标病灶减少38%,包括主要肺病灶中出现大量减少(未示出)。在接受12剂之后,患者进展3个月。
这些结果的意义在于,它们显示抗Trop-2ADC是有效的,即使在多次既往治疗之后失效或进展的患者中也是如此。
总之,在所用的剂量下,主要毒性是可控制的中性粒细胞减少,3级毒性很少。IMMU-132示出了三阴性乳腺癌、小细胞肺癌、非小细胞肺癌、结直肠癌和食道癌的复发/顽固患者中活性(PR和持久性SD)的证据,包括具有拓扑异构酶-I抑制剂治疗的复发既往史的患者。这些结果示出了抗Trop-2ADC对一系列广泛的耐受现有治疗的癌症的功效。
***
本领域的技术人员将显而易见的是,可对本发明的产物、组合物、方法和工序进行各种修改和变型。因此,本发明旨在涵盖此类修改和变型,前提条件是它们在所附权利要求书的范围及其等同形式内。
序列表
<110> IMMUNOMEDICS, INC.
<120> 循环TROP-2阳性癌细胞的
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多肽
<400> 7
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Ala Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 8
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 8
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 9
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 9
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 10
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 10
Cys Gly His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly
1 5 10 15
Tyr Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe
20 25 30
Ala Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40 45
<210> 11
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 11
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 12
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 12
Cys Gly Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile
1 5 10 15
Gln Gln Ala Gly Cys
20
<210> 13
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 13
Ser Leu Arg Glu Cys Glu Leu Tyr Val Gln Lys His Asn Ile Gln Ala
1 5 10 15
Leu Leu Lys Asp Ser Ile Val Gln Leu Cys Thr Ala Arg Pro Glu Arg
20 25 30
Pro Met Ala Phe Leu Arg Glu Tyr Phe Glu Arg Leu Glu Lys Glu Glu
35 40 45
Ala Lys
50
<210> 14
<211> 55
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 14
Met Ser Cys Gly Gly Ser Leu Arg Glu Cys Glu Leu Tyr Val Gln Lys
1 5 10 15
His Asn Ile Gln Ala Leu Leu Lys Asp Ser Ile Val Gln Leu Cys Thr
20 25 30
Ala Arg Pro Glu Arg Pro Met Ala Phe Leu Arg Glu Tyr Phe Glu Arg
35 40 45
Leu Glu Lys Glu Glu Ala Lys
50 55
<210> 15
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 15
Cys Gly Phe Glu Glu Leu Ala Trp Lys Ile Ala Lys Met Ile Trp Ser
1 5 10 15
Asp Val Phe Gln Gln Gly Cys
20
<210> 16
<211> 51
<212> PRT
<213> 智人
<400> 16
Ser Leu Arg Glu Cys Glu Leu Tyr Val Gln Lys His Asn Ile Gln Ala
1 5 10 15
Leu Leu Lys Asp Val Ser Ile Val Gln Leu Cys Thr Ala Arg Pro Glu
20 25 30
Arg Pro Met Ala Phe Leu Arg Glu Tyr Phe Glu Lys Leu Glu Lys Glu
35 40 45
Glu Ala Lys
50
<210> 17
<211> 54
<212> PRT
<213> 智人
<400> 17
Ser Leu Lys Gly Cys Glu Leu Tyr Val Gln Leu His Gly Ile Gln Gln
1 5 10 15
Val Leu Lys Asp Cys Ile Val His Leu Cys Ile Ser Lys Pro Glu Arg
20 25 30
Pro Met Lys Phe Leu Arg Glu His Phe Glu Lys Leu Glu Lys Glu Glu
35 40 45
Asn Arg Gln Ile Leu Ala
50
<210> 18
<211> 44
<212> PRT
<213> 智人
<400> 18
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Gly Gln Gln Pro Pro Asp Leu Val Asp Phe Ala Val
20 25 30
Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Arg Gln
35 40
<210> 19
<211> 44
<212> PRT
<213> 智人
<400> 19
Ser Ile Glu Ile Pro Ala Gly Leu Thr Glu Leu Leu Gln Gly Phe Thr
1 5 10 15
Val Glu Val Leu Arg His Gln Pro Ala Asp Leu Leu Glu Phe Ala Leu
20 25 30
Gln His Phe Thr Arg Leu Gln Gln Glu Asn Glu Arg
35 40
<210> 20
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 20
Thr His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 21
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 21
Ser Lys Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 22
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 22
Ser Arg Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 23
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 23
Ser His Ile Asn Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 24
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 24
Ser His Ile Gln Ile Pro Pro Ala Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 25
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 25
Ser His Ile Gln Ile Pro Pro Gly Leu Ser Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 26
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 26
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Asp Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 27
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 27
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Asn Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 28
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 28
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Ala Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 29
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 29
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Ser Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 30
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 30
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Asp Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 31
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 31
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Lys Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 32
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 32
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Asn Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 33
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 33
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Asn Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 34
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 34
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Glu Leu Val Glu Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 35
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 35
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Asp Phe Ala
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 36
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 36
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Leu
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 37
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 37
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ile
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 38
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 38
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Val
20 25 30
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 39
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 39
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Val Asp Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
35 40
<210> 40
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 40
Asn Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 41
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 41
Gln Leu Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 42
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 42
Gln Val Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 43
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 43
Gln Ile Asp Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 44
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 44
Gln Ile Glu Phe Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 45
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 45
Gln Ile Glu Thr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 46
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 46
Gln Ile Glu Ser Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 47
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 47
Gln Ile Glu Tyr Ile Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 48
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 48
Gln Ile Glu Tyr Val Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 49
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 49
Gln Ile Glu Tyr Leu Ala Arg Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 50
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 50
Gln Ile Glu Tyr Leu Ala Lys Asn Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 51
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 51
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Glu Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 52
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 52
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Gln Ala Ile Gln Gln
1 5 10 15
Ala
<210> 53
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 53
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Asn Gln
1 5 10 15
Ala
<210> 54
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 54
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Asn
1 5 10 15
Ala
<210> 55
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 55
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Leu
<210> 56
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 56
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Ile
<210> 57
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 57
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
1 5 10 15
Val
<210> 58
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 58
Gln Ile Glu Tyr Val Ala Lys Gln Ile Val Asp Tyr Ala Ile His Gln
1 5 10 15
Ala
<210> 59
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 59
Gln Ile Glu Tyr Lys Ala Lys Gln Ile Val Asp His Ala Ile His Gln
1 5 10 15
Ala
<210> 60
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 60
Gln Ile Glu Tyr His Ala Lys Gln Ile Val Asp His Ala Ile His Gln
1 5 10 15
Ala
<210> 61
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 61
Gln Ile Glu Tyr Val Ala Lys Gln Ile Val Asp His Ala Ile His Gln
1 5 10 15
Ala
<210> 62
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 62
Pro Leu Glu Tyr Gln Ala Gly Leu Leu Val Gln Asn Ala Ile Gln Gln
1 5 10 15
Ala Ile
<210> 63
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 63
Leu Leu Ile Glu Thr Ala Ser Ser Leu Val Lys Asn Ala Ile Gln Leu
1 5 10 15
Ser Ile
<210> 64
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 64
Leu Ile Glu Glu Ala Ala Ser Arg Ile Val Asp Ala Val Ile Glu Gln
1 5 10 15
Val Lys
<210> 65
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 65
Ala Leu Tyr Gln Phe Ala Asp Arg Phe Ser Glu Leu Val Ile Ser Glu
1 5 10 15
Ala Leu
<210> 66
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 66
Leu Glu Gln Val Ala Asn Gln Leu Ala Asp Gln Ile Ile Lys Glu Ala
1 5 10 15
Thr
<210> 67
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 67
Phe Glu Glu Leu Ala Trp Lys Ile Ala Lys Met Ile Trp Ser Asp Val
1 5 10 15
Phe
<210> 68
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 68
Glu Leu Val Arg Leu Ser Lys Arg Leu Val Glu Asn Ala Val Leu Lys
1 5 10 15
Ala Val
<210> 69
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 69
Thr Ala Glu Glu Val Ser Ala Arg Ile Val Gln Val Val Thr Ala Glu
1 5 10 15
Ala Val
<210> 70
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 70
Gln Ile Lys Gln Ala Ala Phe Gln Leu Ile Ser Gln Val Ile Leu Glu
1 5 10 15
Ala Thr
<210> 71
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 71
Leu Ala Trp Lys Ile Ala Lys Met Ile Val Ser Asp Val Met Gln Gln
1 5 10 15
<210> 72
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 72
Asp Leu Ile Glu Glu Ala Ala Ser Arg Ile Val Asp Ala Val Ile Glu
1 5 10 15
Gln Val Lys Ala Ala Gly Ala Tyr
20
<210> 73
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 73
Leu Glu Gln Tyr Ala Asn Gln Leu Ala Asp Gln Ile Ile Lys Glu Ala
1 5 10 15
Thr Glu
<210> 74
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 74
Phe Glu Glu Leu Ala Trp Lys Ile Ala Lys Met Ile Trp Ser Asp Val
1 5 10 15
Phe Gln Gln Cys
20
<210> 75
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 75
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Pro Asp Asn Ala Ile Gln Gln
1 5 10 15
Ala
<210> 76
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 76
Lys Gly Ala Asp Leu Ile Glu Glu Ala Ala Ser Arg Ile Val Asp Ala
1 5 10 15
Val Ile Glu Gln Val Lys Ala Ala Gly
20 25
<210> 77
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 77
Lys Gly Ala Asp Leu Ile Glu Glu Ala Ala Ser Arg Ile Pro Asp Ala
1 5 10 15
Pro Ile Glu Gln Val Lys Ala Ala Gly
20 25
<210> 78
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 78
Pro Glu Asp Ala Glu Leu Val Arg Leu Ser Lys Arg Leu Val Glu Asn
1 5 10 15
Ala Val Leu Lys Ala Val Gln Gln Tyr
20 25
<210> 79
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 79
Pro Glu Asp Ala Glu Leu Val Arg Thr Ser Lys Arg Leu Val Glu Asn
1 5 10 15
Ala Val Leu Lys Ala Val Gln Gln Tyr
20 25
<210> 80
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 80
Pro Glu Asp Ala Glu Leu Val Arg Leu Ser Lys Arg Asp Val Glu Asn
1 5 10 15
Ala Val Leu Lys Ala Val Gln Gln Tyr
20 25
<210> 81
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 81
Pro Glu Asp Ala Glu Leu Val Arg Leu Ser Lys Arg Leu Pro Glu Asn
1 5 10 15
Ala Val Leu Lys Ala Val Gln Gln Tyr
20 25
<210> 82
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 82
Pro Glu Asp Ala Glu Leu Val Arg Leu Ser Lys Arg Leu Pro Glu Asn
1 5 10 15
Ala Pro Leu Lys Ala Val Gln Gln Tyr
20 25
<210> 83
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 83
Pro Glu Asp Ala Glu Leu Val Arg Leu Ser Lys Arg Leu Val Glu Asn
1 5 10 15
Ala Val Glu Lys Ala Val Gln Gln Tyr
20 25
<210> 84
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 84
Glu Glu Gly Leu Asp Arg Asn Glu Glu Ile Lys Arg Ala Ala Phe Gln
1 5 10 15
Ile Ile Ser Gln Val Ile Ser Glu Ala
20 25
<210> 85
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 85
Leu Val Asp Asp Pro Leu Glu Tyr Gln Ala Gly Leu Leu Val Gln Asn
1 5 10 15
Ala Ile Gln Gln Ala Ile Ala Glu Gln
20 25
<210> 86
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 86
Gln Tyr Glu Thr Leu Leu Ile Glu Thr Ala Ser Ser Leu Val Lys Asn
1 5 10 15
Ala Ile Gln Leu Ser Ile Glu Gln Leu
20 25
<210> 87
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 87
Leu Glu Lys Gln Tyr Gln Glu Gln Leu Glu Glu Glu Val Ala Lys Val
1 5 10 15
Ile Val Ser Met Ser Ile Ala Phe Ala
20 25
<210> 88
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 88
Asn Thr Asp Glu Ala Gln Glu Glu Leu Ala Trp Lys Ile Ala Lys Met
1 5 10 15
Ile Val Ser Asp Ile Met Gln Gln Ala
20 25
<210> 89
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 89
Val Asn Leu Asp Lys Lys Ala Val Leu Ala Glu Lys Ile Val Ala Glu
1 5 10 15
Ala Ile Glu Lys Ala Glu Arg Glu Leu
20 25
<210> 90
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 90
Asn Gly Ile Leu Glu Leu Glu Thr Lys Ser Ser Lys Leu Val Gln Asn
1 5 10 15
Ile Ile Gln Thr Ala Val Asp Gln Phe
20 25
<210> 91
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 91
Thr Gln Asp Lys Asn Tyr Glu Asp Glu Leu Thr Gln Val Ala Leu Ala
1 5 10 15
Leu Val Glu Asp Val Ile Asn Tyr Ala
20 25
<210> 92
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 92
Glu Thr Ser Ala Lys Asp Asn Ile Asn Ile Glu Glu Ala Ala Arg Phe
1 5 10 15
Leu Val Glu Lys Ile Leu Val Asn His
20 25
<210> 93
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 93
Glu Phe Pro Lys Pro Ser Thr Pro Pro Gly Ser Ser Gly Gly Ala Pro
1 5 10 15
<210> 94
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
共有多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ser或Thr
<220>
<221> MOD_RES
<222> (2)..(2)
<223> His、Lys或Arg
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (8)..(8)
<223> Gly或Ala
<220>
<221> MOD_RES
<222> (10)..(10)
<223> Thr或Ser
<220>
<221> MOD_RES
<222> (11)..(11)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (14)..(14)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (15)..(15)
<223> Gly或Ala
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Thr或Ser
<220>
<221> MOD_RES
<222> (19)..(19)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (22)..(22)
<223> Arg或Lys
<220>
<221> MOD_RES
<222> (23)..(24)
<223> Asn或Gln
<220>
<221> MOD_RES
<222> (27)..(27)
<223> Asp或Glu
<220>
<221> MOD_RES
<222> (30)..(30)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (32)..(32)
<223> Ala、Leu、Ile或Val
<220>
<221> MOD_RES
<222> (34)..(34)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (37)..(37)
<223> Thr或Ser
<220>
<221> MOD_RES
<222> (38)..(38)
<223> Arg或Lys
<220>
<221> MOD_RES
<222> (40)..(40)
<223> Arg或Lys
<220>
<221> MOD_RES
<222> (41)..(41)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (42)..(42)
<223> Ala、Leu、Ile或Val
<220>
<221> MOD_RES
<222> (43)..(43)
<223> Arg或Lys
<220>
<221> MOD_RES
<222> (44)..(44)
<223> Ala、Leu、Ile或Val
<400> 94
Xaa Xaa Ile Xaa Ile Pro Pro Xaa Leu Xaa Xaa Leu Leu Xaa Xaa Tyr
1 5 10 15
Xaa Val Xaa Val Leu Xaa Xaa Xaa Pro Pro Xaa Leu Val Xaa Phe Xaa
20 25 30
Val Xaa Tyr Phe Xaa Xaa Leu Xaa Xaa Xaa Xaa Xaa
35 40
<210> 95
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
共有肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (2)..(2)
<223> Ile、Leu或Val
<220>
<221> MOD_RES
<222> (3)..(3)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Tyr、Phe、Thr或Ser
<220>
<221> MOD_RES
<222> (5)..(5)
<223> Leu、Ile或Val
<220>
<221> MOD_RES
<222> (7)..(7)
<223> Lys或Arg
<220>
<221> MOD_RES
<222> (8)..(8)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (11)..(11)
<223> Asp或Glu
<220>
<221> MOD_RES
<222> (12)..(12)
<223> Asn或Gln
<220>
<221> MOD_RES
<222> (15)..(16)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (17)..(17)
<223> Ala、Leu、Ile或Val
<400> 95
Xaa Xaa Xaa Xaa Xaa Ala Xaa Xaa Ile Val Xaa Xaa Ala Ile Xaa Xaa
1 5 10 15
Xaa
<210> 96
<211> 44
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
共有多肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> Ser或Thr
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (10)..(10)
<223> Thr或Ser
<220>
<221> MOD_RES
<222> (18)..(18)
<223> Val、Ile、Leu或Ala
<220>
<221> MOD_RES
<222> (23)..(23)
<223> Gln或Asn
<220>
<221> MOD_RES
<222> (33)..(33)
<223> Val、Ile、Leu或Ala
<220>
<221> MOD_RES
<222> (34)..(34)
<223> Glu或Asp
<220>
<221> MOD_RES
<222> (37)..(37)
<223> Thr或Ser
<220>
<221> MOD_RES
<222> (38)..(38)
<223> Arg或Lys
<220>
<221> MOD_RES
<222> (40)..(40)
<223> Arg或Lys
<220>
<221> MOD_RES
<222> (42)..(42)
<223> Ala、Leu、Ile或Val
<220>
<221> MOD_RES
<222> (44)..(44)
<223> Ala、Leu、Ile或Val
<400> 96
Xaa His Ile Xaa Ile Pro Pro Gly Leu Xaa Glu Leu Leu Gln Gly Tyr
1 5 10 15
Thr Xaa Glu Val Leu Arg Xaa Gln Pro Pro Asp Leu Val Glu Phe Ala
20 25 30
Xaa Xaa Tyr Phe Xaa Xaa Leu Xaa Glu Xaa Arg Xaa
35 40
Claims (52)
1.一种分离、检测或鉴定循环Trop-2+肿瘤细胞的方法,其包括:
a)将抗Trop-2抗体或其抗原结合片段暴露至怀疑患有Trop-2+癌症的受试者的血液;
b)使所述抗Trop-2抗体或其片段结合至Trop-2+循环肿瘤细胞(CTC);以及
c)检测结合到所述抗Trop-2抗体或其片段的CTC。
2.根据权利要求1所述的方法,还包括富集或分离所述CTC。
3.根据权利要求1所述的方法,其中所述抗Trop-2抗体或其片段附连到磁性纳米颗粒。
4.根据权利要求3所述的方法,其还包括使用磁场从正常细胞分离结合到所述磁性纳米颗粒的CTC。
5.根据权利要求1所述的方法,其中所述抗Trop-2抗体或其片段是RS7抗体,其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SASYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQ ID NO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。
6.根据权利要求1所述的方法,其中所述抗Trop-2抗体选自鼠RS7、hRS7、MAB650、K5-70、K5-107、K5-116-2-1、T6-16、T5-86、BR110、AR47A6.4.2、3E9、6G11、7E6、15E2、18B1、PD08019、PD 08020、PD 08021、77220、KM4097、KM4590、A1、A4、162-25.3、162-46.2和Pr1E11。
7.根据权利要求1所述的方法,其中所述抗Trop-2抗体是鼠、嵌合、人源化或人抗体。
8.根据权利要求1所述的方法,其中所述抗Trop-2抗体附连到至少一种选自放射性同位素、染料、造影剂、发光剂、化学发光剂、荧光剂和增强剂的诊断剂。
9.根据权利要求1所述的方法,还包括将所述CTC暴露至结合至肿瘤相关抗原的第二抗体或其抗原结合片段,其中所述第二抗体或其片段附连到至少一种选自放射性同位素、染料、造影剂、发光剂、化学发光剂、荧光剂和增强剂的诊断剂。
10.根据权利要求9所述的方法,其中所述TAA选自碳酸酐酶IX、B7、CCL19、CCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD47、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM6、CTLA-4、α-胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1(Trop-2)、EGP-2、EGF受体、ErbB2、ErbB3、因子H、Flt-1、Flt-3、叶酸受体、Ga 733、GRO-β、HMGB-1、缺氧诱导因子、HM1.24、HER-2/neu、组蛋白H2B、组蛋白H3、组蛋白H4、胰岛素样生长因子、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节苷脂、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞迁移抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5ac、胎盘生长因子、PSA(前列腺特异性抗原)、PSMA、PD-1受体、PD-L1、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体R1、TRAIL受体R2、VEGFR、RANTES、T101、补体因子C3、C3a、C3b、C5a、C5和癌基因产物。
11.根据权利要求9所述的方法,其中所述第二抗体或其片段结合至选自Trop-2、EpCAM、细胞角蛋白(CK)和CD45的TAA。
12.根据权利要求1所述的方法,其中所述CTC通过选自荧光显微术、FISH(荧光原位杂交)、免疫组织化学、FACS(荧光活化细胞分选)、流式细胞术、微流体分析和RT-PCR的方法检测。
13.根据权利要求1所述的方法,其还包括通过荧光标记的抗体分析所述CTC的上皮癌标记物。
14.根据权利要求13所述的方法,其中通过FISH(荧光原位杂交)分析所述CTC的上皮癌标记物。
15.根据权利要求1所述的方法,其还包括通过RT-PCR分析所述CTC的上皮癌标记物。
16.根据权利要求9所述的方法,其中所述抗Trop-2抗体是所述RS7抗体,并且所述第二抗体是结合至不同于RS7的表位的抗Trop-2抗体。
17.根据权利要求1所述的方法,其中所述Trop-2+癌症选自转移性TROP-2阳性癌症,包括胰腺癌、三阴性乳腺癌、转移性结直肠癌、HER+、ER+、黄体酮+乳腺癌、转移性非小细胞肺癌(NSCLC)、转移性胰腺癌、转移性食道癌、转移性尿道上皮癌、转移性肾细胞癌、转移性胃癌、转移性前列腺癌和转移性小细胞肺癌。
18.根据权利要求1所述的方法,其中所述抗Trop-2抗体或其片段离体暴露至血样。
19.根据权利要求1所述的方法,其中所述抗Trop-2抗体或其片段在体内暴露至血液。
20.根据权利要求1所述的方法,其中Trop-2+CTC的存在用于诊断转移性癌症。
21.根据权利要求1所述的方法,其中所述受试者是人受试者。
22.一种分离、检测或鉴定循环肿瘤细胞的方法,其包括:
a)将双特异性抗体暴露至怀疑患有Trop-2+癌症的受试者的血液,所述双特异性抗体包括(i)抗Trop-2抗体或其抗原结合片段;和(ii)抗TAA抗体或其抗原结合片段;
b)使所述双特异性抗体结合至循环肿瘤细胞(CTC);以及
c)检测结合到所述双特异性抗体的CTC。
23.根据权利要求22所述的方法,其中所述TAA选自碳酸酐酶IX、B7、CCL19、CCL21、CSAp、HER-2/neu、BrE3、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD47、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CEACAM5、CEACAM6、CTLA-4、α-胎蛋白(AFP)、VEGF、ED-B纤连蛋白、EGP-1(Trop-2)、EGP-2、EGF受体、ErbB2、ErbB3、因子H、Flt-1、Flt-3、叶酸受体、Ga 733、GRO-β、HMGB-1、缺氧诱导因子、HM1.24、HER-2/neu、组蛋白H2B、组蛋白H3、组蛋白H4、胰岛素样生长因子、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-2R、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-25、IP-10、IGF-1R、Ia、HM1.24、神经节苷脂、HCG、HLA-DR、CD66a-d、MAGE、mCRP、MCP-1、MIP-1A、MIP-1B、巨噬细胞迁移抑制因子(MIF)、MUC1、MUC2、MUC3、MUC4、MUC5ac、胎盘生长因子、PSA(前列腺特异性抗原)、PSMA、PD-1受体、PD-L1、NCA-95、NCA-90、A3、A33、Ep-CAM、KS-1、Le(y)、间皮素、S100、腱生蛋白、TAC、Tn抗原、Thomas-Friedenreich抗原、肿瘤坏死抗原、肿瘤血管生成抗原、TNF-α、TRAIL受体R1、TRAIL受体R2、VEGFR、RANTES、T101、补体因子C3、C3a、C3b、C5a、C5和癌基因产物。
24.根据权利要求22所述的方法,其中所述TAA选自CEACAM5、MUC5ac、CD74、HLA-DR、CSAp、AFP(α-胎蛋白)、HER2、波形蛋白、EGFR、IGF-1R、PD-L1和PD-L2。
25.根据权利要求22所述的方法,其中所述抗TAA抗体选自MN-14(抗CEACAM5)、PAM4(抗MUC5ac)、LL1(抗CD74)、L243(抗HLA-DR)、Mu-9(抗CSAp)、IMMU31(抗AFP)、曲妥珠单抗(抗HER2)、西妥昔单抗(抗EGFR)、帕尼单抗(抗EGFR)、R1(抗IGF-1R)。
26.根据权利要求1所述的方法,其还包括富集或分离所述CTC。
27.根据权利要求22所述的方法,其中所述双特异性抗体附连到磁性纳米颗粒。
28.根据权利要求27所述的方法,其还包括使用磁场从正常细胞分离结合到所述磁性纳米颗粒的CTC。
29.根据权利要求22所述的方法,其中所述抗Trop-2抗体或其片段是RS7抗体,其包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SASYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQ ID NO:3)以及重链CDR序列CDR1(NYGMN,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。
30.根据权利要求22所述的方法,其中所述抗Trop-2抗体选自鼠RS7、hRS7、MAB650、K5-70、K5-107、K5-116-2-1、T6-16、T5-86、BR110、AR47A6.4.2、3E9、6G11、7E6、15E2、18B1、PD08019、PD 08020、PD 08021、77220、KM4097、KM4590、A1、A4、162-25.3、162-46.2和Pr1E11。
31.根据权利要求22所述的方法,其中所述双特异性抗体附连到至少一种选自放射性同位素、染料、造影剂、发光剂、化学发光剂、荧光剂和增强剂的诊断剂。
32.根据权利要求22所述的方法,其中所述CTC通过选自荧光显微术、FISH(荧光原位杂交)、免疫组织化学、FACS(荧光活化细胞分选)、流式细胞术、微流体分析和RT-PCR的方法检测。
33.根据权利要求22所述的方法,其中所述Trop-2+癌症选自转移性Trop-2阳性癌症,包括胰腺癌、三阴性乳腺癌、转移性结直肠癌、HER+、ER+、黄体酮+乳腺癌、转移性非小细胞肺癌(NSCLC)、转移性胰腺癌、转移性食道癌、转移性尿道上皮癌、转移性肾细胞癌、转移性胃癌、转移性前列腺癌和转移性小细胞肺癌。
34.根据权利要求22所述的方法,其中所述双特异性抗体离体暴露至血样。
35.根据权利要求22所述的方法,其中所述双特异性抗体在体内暴露至血液。
36.根据权利要求1所述的方法,其中存在用于诊断转移性癌症。
37.根据权利要求22所述的方法,其中所述受试者是人受试者。
38.一种治疗Trop-2+肿瘤的方法,其包括:
a)将抗Trop-2抗体或其抗原结合片段暴露至怀疑患有Trop-2+癌症的受试者的血液;
b)使所述抗Trop-2抗体或其片段结合至Trop-2+循环肿瘤细胞(CTC);以及
c)检测结合到所述抗Trop-2抗体或其片段的CTC;以及
d)使用缀合至至少一种治疗剂的抗Trop-2抗体治疗所述受试者。
39.根据权利要求38所述的方法,其还包括分析所述CTC中Trop-2的拷贝数。
40.根据权利要求39所述的方法,其中具有高拷贝数Trop-2的Trop-2+CTC的存在是对治疗性抗Trop-2抗体产生响应的指示,其中高拷贝数是每个细胞3个或更多个拷贝。
41.根据权利要求38所述的方法,其还包括监测循环中Trop-2+CTC的存在,以确定所述肿瘤对治疗性抗Trop-2抗体的响应。
42.根据权利要求38所述的方法,其中所述治疗剂选自抗体、抗体片段、药物、毒素、激素、免疫调节剂、促凋亡剂、抗血管生成剂、硼化合物、光活性剂和放射性核素。
43.根据权利要求42所述的方法,其中所述药物选自蒽环类药物、喜树碱、微管蛋白抑制剂、美登木素生物碱、刺孢霉素、奥里斯他汀、氮芥、乙烯亚胺衍生物、烷基磺酸盐、亚硝基脲、三氮烯、叶酸类似物、紫杉烷、COX-2抑制剂、嘧啶类似物、嘌呤类似物、抗生素、酶抑制剂、表鬼臼毒素、铂配位络合物、长春花生物碱、取代脲、甲基肼衍生物、肾上腺皮质抑制剂、激素拮抗剂、抗代谢物、烷基化剂、抗有丝分裂剂、抗血管生成剂、酪氨酸激酶抑制剂、mTOR抑制剂、热激蛋白(HSP90)抑制剂、蛋白酶体抑制剂、HDAC抑制剂和促凋亡剂。
44.根据权利要求42所述的方法,其中所述药物选自5-氟尿苷、阿法替尼、阿普利啶、阿扎立平、阿那曲唑、蒽环类药物、阿西替尼、AVL-101、AVL-291、苯达莫司汀、博来霉素、硼替佐米、博舒替尼、苔藓虫素-1、白消安、刺孢霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、塞来考昔、苯丁酸氮芥、顺铂、COX-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、喜树碱衍生物、克唑替尼、环磷酰胺、阿糖胞苷、达卡巴嗪、达沙替尼、dinaciclib、多西他赛、更生霉素、柔红霉素、DM1、DM3、DM4、多柔比星、2-吡咯啉多柔比星(2-PDox)、2-PDox的前药形式(pro-2-PDox)、氰基-吗啉代多柔比星、多柔比星葡糖苷酸、内皮他丁、表柔比星葡糖苷酸、厄洛替尼、雌莫司汀、表鬼臼毒素、厄洛替尼、恩替诺特、雌激素受体结合剂、依托泊苷(VP16)、依托泊苷葡糖苷酸、依托泊苷磷酸盐、依西美坦、芬戈莫德、氟尿苷(FUdR)、3’,5’-O-二油酰基-FudR(FUdR-dO)、氟达拉滨、氟他胺、法尼基-蛋白质转移酶抑制剂、夫拉平度、福他替尼、ganetespib、GDC-0834、GS-1101、吉非替尼、吉西他滨、羟基脲、依鲁替尼、伊达比星、艾代拉里斯、异环磷酰胺、伊马替尼、拉帕替尼、来那度胺、亚叶酸、LFM-A13、洛莫司汀、氮芥、美法仑、巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、光辉霉素、丝裂霉素、米托坦、单甲基奥里斯他汀F(MMAF)、单甲基奥里斯他汀D(MMAD)、单甲基奥里斯他汀E(MMAE)、诺维本、来那替尼、尼洛替尼、亚硝基脲、奥拉帕尼、普卡霉素、丙卡巴肼、紫杉醇、PCI-32765、喷司他丁、PSI-341、雷洛昔芬、司莫司汀、SN-38、索拉非尼、链佐星、SU11248、舒尼替尼、他莫昔芬、替莫唑胺、反铂、沙利度胺、硫鸟嘌呤、塞替哌、替尼泊苷、托泊替康、尿嘧啶氮芥、伐他拉尼、长春瑞滨、长春碱、长春新碱、长春花生物碱和ZD1839。
45.根据权利要求42所述的方法,其中所述药物选自SN-38、前-2-吡咯啉多柔比星(pro-2-PDox)、紫杉醇、刺孢霉素、DM1、DM3、DM4、MMAE、MMAD和MMAF。
46.根据权利要求38所述的方法,其中所述癌症对至少一种抗癌症疗法的治疗具有耐受性。
47.根据权利要求38所述的方法,其中所述癌症是胰腺癌。
48.根据权利要求42所述的方法,其中所述放射性核素选自11C、13N、15O、32P、33P、47Sc、51Cr、57Co、58Co、59Fe、62Cu、67Cu、67Ga、67Ga、75Br、75Se、75Se、76Br、77As、77Br、80mBr、89Sr、90Y、95Ru、97Ru、99Mo、99mTc、103mRh、103Ru、105Rh、105Ru、107Hg、109Pd、109Pt、111Ag、111In、113mIn、119Sb、121mTe、122mTe、125I、125mTe、126I、131I、133I、142Pr、143Pr、149Pm、152Dy、153Sm、161Ho、161Tb、165Tm、166Dy、166Ho、167Tm、168Tm、169Er、169Yb、177Lu、186Re、188Re、189mOs、189Re、192Ir、194Ir、197Pt、198Au、199Au、199Au、201Tl、203Hg、211At、211Bi、211Pb、212Bi、212pb、213Bi、215po、217At、219Rn、221Fr、223Ra、224Ac、225Ac、255Fm和227Th。
49.根据权利要求42所述的方法,其中所述毒素选自蓖麻毒素、相思子毒素、α毒素、皂草素、核糖核酸酶(RNA酶)、DNA酶I、葡萄球菌肠毒素-A、美洲商陆抗病毒蛋白、白树毒素、白喉毒素、假单胞菌外毒素和假单胞菌内毒素。
50.根据权利要求42所述的方法,其中所述免疫调节剂选自细胞因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素(IFN)、白介素、促红细胞生成素和促血小板生成素。
51.根据权利要求50所述的方法,其中所述细胞因子选自人生长激素、N-甲硫氨酰基人生长激素、牛生长激素、甲状旁腺激素、甲状腺素、胰岛素、胰岛素原、松弛素、松弛素原、促卵泡激素(FSH)、促甲状腺激素(TSH)、促黄体激素(LH)、肝生长因子、前列腺素、成纤维细胞生长因子、促乳素、胎盘催乳素、OB蛋白、肿瘤坏死因子-α、肿瘤坏死因子-β、苗勒管抑制物质、小鼠促性腺激素相关肽、抑制素、活化素、血管内皮生长因子、整联蛋白、促血小板生成素(TPO)、NGF-β、血小板生长因子、TGF-α、TGF-β、胰岛素样生长因子-I、胰岛素样生长因子-II、促红细胞生成素(EPO)、骨生成诱导因子、干扰素-α、干扰素-β、干扰素-γ、巨噬细胞-CSF(M-CSF)、IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21、IL-25、LIF、FLT-3、血管抑素、血小板反应蛋白、内皮他丁、肿瘤坏死因子和淋巴毒素。
52.根据权利要求1所述的方法,其中所述抗Trop-2抗体或其片段结合至与抗Trop-2抗体相同的表位,所述抗Trop-2抗体包含轻链CDR序列CDR1(KASQDVSIAVA,SEQ ID NO:1)、CDR2(SASYRYT,SEQ ID NO:2)和CDR3(QQHYITPLT,SEQ ID NO:3)以及重链CDR序列CDR1(NYGM[N,SEQ ID NO:4)、CDR2(WINTYTGEPTYTDDFKG,SEQ ID NO:5)和CDR3(GGFGSSYWYFDV,SEQ ID NO:6)。
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CN107406508A (zh) * | 2014-12-04 | 2017-11-28 | 阿布鲁佐治疗诊断有限公司 | 人源化的抗trop‑2单克隆抗体及其应用 |
CN107406508B (zh) * | 2014-12-04 | 2022-04-05 | 地中海治疗诊断有限公司 | 人源化的抗trop-2单克隆抗体及其应用 |
CN109187710A (zh) * | 2017-12-28 | 2019-01-11 | 兰州大学 | 一种cd133质谱流式抗体、制备方法及应用 |
CN114585643A (zh) * | 2019-04-15 | 2022-06-03 | 塔尔金塔股份公司 | 整合素α10和侵袭性癌症形式 |
CN114127119A (zh) * | 2019-07-17 | 2022-03-01 | 生物发明国际公司 | 用于治疗特定患者的癌症的抗体组合 |
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CN111141906A (zh) * | 2020-01-06 | 2020-05-12 | 中南大学湘雅医院 | 一种小细胞肺癌患者外周血循环肿瘤细胞及pd-l1的检测试剂盒 |
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CN111647561B (zh) * | 2020-05-28 | 2022-12-20 | 大连理工大学 | 纳米抗体在细胞特异性捕获和细胞释放中的应用 |
WO2021259162A1 (zh) * | 2020-06-22 | 2021-12-30 | 四川百利药业有限责任公司 | 一种抗trop2抗体 |
CN117607441A (zh) * | 2024-01-23 | 2024-02-27 | 杭州华得森生物技术有限公司 | 一种循环肿瘤细胞trop-2免疫显色检测试剂 |
CN117607441B (zh) * | 2024-01-23 | 2024-04-12 | 杭州华得森生物技术有限公司 | 一种循环肿瘤细胞trop-2免疫显色检测试剂 |
Also Published As
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JP6746845B2 (ja) | 2020-08-26 |
EP3286224A4 (en) | 2018-11-14 |
AU2016252771B2 (en) | 2021-12-16 |
CA2981543A1 (en) | 2016-10-27 |
US20180149657A1 (en) | 2018-05-31 |
EP3286224A1 (en) | 2018-02-28 |
US20160313339A1 (en) | 2016-10-27 |
US9797907B2 (en) | 2017-10-24 |
US10436788B2 (en) | 2019-10-08 |
WO2016172427A1 (en) | 2016-10-27 |
US20190369103A1 (en) | 2019-12-05 |
AU2016252771A1 (en) | 2017-08-10 |
JP2018517888A (ja) | 2018-07-05 |
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