CN101528921B - 人非小细胞肺癌中的易位和突变的ros激酶 - Google Patents
人非小细胞肺癌中的易位和突变的ros激酶 Download PDFInfo
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Abstract
根据本发明,在人非小细胞肺癌(NSCLC)中已经鉴定出新基因易位(4p15,6q22),这种基因易位导致了结合钠依赖的磷酸盐转运蛋白同工型NaPi-3b蛋白(SLC34A2)的部分和原癌基因酪氨酸蛋白激酶ROS前体(ROS)激酶的融合蛋白。预期SLC34A2-ROS融合蛋白驱动NSCLC肿瘤亚型的增殖和存活。因此,本发明部分提供了分离的多核苷酸和编码公开的突变ROS激酶多肽的载体、检测它的探针、分离的突变多肽、重组的多肽、和检测融合和截短多肽的试剂。公开的鉴定新的融合蛋白使检测在生物样品中存在这些突变的ROS激酶多肽成为新的方法,使筛选能抑制蛋白质的化合物的方法成为新的方法,以及使抑制以突变的多核苷酸或者多肽为特征的癌症发展的方法成为新的方法,这些也由本发明提供。
Description
相关申请
本申请要求2006年1月20号提交的USSN60/760,634(目前未决定)的优选权及其益处,USSN60/760,634的公开引入本文作为参考。
发明领域
本申请基本上涉及癌症中涉及的蛋白质和基因,本申请还涉及癌症的检测、诊断和治疗。
发明背景
许多癌症的特征在于导致细胞过程控制异常或者导致细胞生长和增殖失控的细胞信号途径的破坏。这些破坏经常是由于特定的信号蛋白如激酶的活性改变引起的。这些癌症中之一是非小细胞肺癌(NSCLC)。NSCLC是美国癌症患者死亡的首要原因,并且约占所有肺癌的大约87%。在美国每年新增加约151,000名NSCLC患者,据估计仅美国每年因该病死亡的患者超过120,000人。见"Cancer Facts and Figures2005,"American CancerSociety。NSCLC包括三种不同的亚型,通常在转移后才能被检测到,因此诊断后的两年内的死亡率为75%。
已知导致激酶融合蛋白异常信号活性的基因易位可以直接导致某些癌症。例如,已直接证实BCR-ABL癌蛋白,一种酪氨酸激酶融合蛋白,是人慢性髓性白血病(CML)的致病因子。据发现在至少90-95%的CM病例中LBCR-ABL癌蛋白是通过9号染色体上的c-ABL蛋白酪氨酸激酶的基因序列易位到22号染色体的BCR序列上产生的,产生所谓的Philadelphia染色体。参见如Kurzock等N.Engl.J.Med.319:990-998(1988)。在急性淋巴性白血病和AML病例中都能发现易位。
已经描述了导致突变或融合蛋白的基因易位也出现在许多其它的癌症中。例如,Falini等,Blood99(2):409-426(2002),概括了已知出现在血癌中的易位。到目前为止,仅描述了小量的存在于肺癌中的基因易位和突变的蛋白,包括涉及Notch3的t(15;19)的易位。参考Dang等,J.Natl.Can.Instit.92(16):1355-1357(2000)。在小细胞肺癌和非小细胞肺癌中都发现RNA结合蛋白-6(RBM-6)表达和/或活性缺陷。参考Drabkin等,Oncogene8(16):2589-97(1999)。然而,到目前为止,还没有描述在人NSCLC癌症中涉及蛋白激酶的易位。
在人的卵巢癌中已经发现SLC34A2表达和/或活性缺陷。参见Rangel等,Oncogene22(46):7225-7232(2003)。同样地,已描述了在成胶质细胞瘤中由于FIG-ROS del(6)(q21,q21)易位导致的ROS激酶表达缺陷。参见Charest等,Genes Chromos.Canc.37(1):58-71(2003)。还描述了能够在小鼠中驱动肿瘤生长的ROS激酶的截短形式。参见Birchmeier等,Mol.Cell.Bio.6(9):3109-3115(1986)。到目前为止,在ROS激酶中还没有已知的激活点突变。
鉴定人癌症中的易位和突变是非常需要的,因为这可以开发靶向所述融合或突变蛋白的新的治疗剂和鉴定具有所述基因易位的患者的新的诊断剂。例如,BCR-ABL已经成为用于开发治疗白血病的治疗剂的靶。最近,(Imatinib mesylate,STI-571),一种ABL激酶的小分子抑制剂,已经被批准用于治疗CML。这种药是最先设计干扰促进癌细胞生长的信号途径的新的抗增殖药。这种药物的发展表现出比传统用于CML和ALL的治疗方法、化疗和放疗显著的进步,传统用于CML和ALL的治疗方法、化疗和放疗由于熟知的副作用令人苦恼,并由于它们不能特异性靶向导致恶性肿瘤的根本原因从而经常导致有限的效果。同样地,为了鉴定患者最可能应答的靶向抑制剂如已经描述了特异性检测患者中BCR-ABL融合蛋白的试剂和方法。
因此,还需要鉴定在人癌症包括肺癌如NSCLC发展中导致融合或突变蛋白的新的基因易位,和需要发展用于研究和检测所述融合蛋白的新的试剂和方法。鉴定所述融合蛋白能够使选择用于靶向治疗的患者以及筛选抑制所述突变/融合蛋白的新药的新方法成为可能。
发明简述
根据本发明,在人非小细胞肺癌(NSCLC)中已经鉴定出新基因易位(4p15,6q22),该易位导致了组合了钠依赖性磷酸盐转运蛋白同工型NaPi-3b蛋白(SLC34A2)的部分和原癌基因酪氨酸蛋白激酶ROS前体(ROS)激酶的融合蛋白。估计这两种SLC34A2-ROS融合蛋白保留了ROS酪氨酸激酶活性并驱动表达所述融合蛋白的癌症亚型中NSCLC的增殖和存活。
因此,本发明部分提供了分离的多核苷酸和编码公开的突变ROS多肽的载体、检测它们的探针和方法、分离的突变ROS多肽、重组突变多肽、和检测突变ROS多核苷酸和多肽的试剂。公开的鉴定新的突变ROS激酶蛋白和SLC34A2易位使检测在生物样品中存在突变ROS多核苷酸或者多肽的新方法成为可能,使筛选抑制突变激酶蛋白的方法成为可能,以及使抑制以表达突变ROS多核苷酸或者多肽为特征的癌症的发展的方法成为可能,所述突变ROS多核苷酸或者多肽也由本发明提供。本发明的各个方面和实施方案将在下文更详细地描述。
附图说明
图1分别表示SLC34A2基因和ROS基因在染色体4p和6q的位置(A组),全长SLC34A2和ROS蛋白的结构域位置以及两个SLC34A2-ROS融合蛋白变体的结构域位置(组B和组C)。在第一个变体(长的)中,融合接头(fusion junction)位于ROS的跨膜结构域上游的第1750个残基处,而在第二个变体(短的)中,接头位于第1853个残基处。
图2A是人SLC34A2-ROS融合蛋白第一个变体(长的)的氨基酸序列(一个字母编码)(SEQ ID NO:1)(上组),并指出了编码DNA序列(SEQID NO:2)(下组);SLC34A2部分的残基为斜体,而ROS的激酶结构域的残基为粗体。
图2B是人SLC34A2-ROS融合蛋白第二个变体(短的)的氨基酸序列(一个字母编码)(SEQ ID NO:3)(上组),并指出了编码DNA序列(SEQID NO:4)(下组);SLC34A2部分的残基为斜体,而ROS的激酶结构域的残基为粗体。
图3是人SLC34A2蛋白的氨基酸序列(一个字母编码)(SEQ ID NO:5)(SwissProt登录号为095436)(上组),并指出了编码DNA序列(SEQ ID NO:6)(GeneBank登录号NM_006424)(下组);下划线部分是易位的残基。
图4A是人ROS激酶的氨基酸序列(一个字母编码)(SEQ ID NO:7)(SwissProt登录号P08922);下划线的是第一个变体(长的)易位涉及的残基,而下划线粗体的为第二个变体(短的)易位涉及的残基。
图4B是人ROS激酶的编码DNA序列(SEQ ID NO:8)(GeneBank登录号NM_002944);下划线的是第一个变体(长的)易位涉及的残基,而下划线粗体的残基为第二个变体(短的)易位涉及的残基。
图5是人NSCLC细胞系(HCC78)提取物的蛋白质印迹分析,该图表示了具有比全长/野生型ROS低很多的分子量的ROS型的表达。
图6是通过5′RACE产物用ROS引物经历2轮PCR后检测ROS的凝胶图;给出了所使用的引物(SEQ ID NO:13-15)。
图7是通过RT-PCR检测由SLC34A2和ROS易位形成的融合基因的凝胶图;给出了两种变体(长的和短的)各自的外显子4/外显子32融合接头的蛋白(和DNA)序列(SEQ ID NO:9和SEQ ID NO:10)和外显子4/外显子34融合接头的蛋白(和DNA)序列(SEQ ID NO:11和SEQ ID NO:12)。
图8是表示SLC34A2基因中外显子1-4和ROS基因中的外显子32-34的位置,这些外显子参与了形成融合蛋白的易位;箭头指出了用于PCR扩增所述融合蛋白变体的引物位置,并且给出了引物序列(SEQ ID NO:17-20)。
图9是表示SLC34A2-ROS融合蛋白(长(短)变体)在转染的293细胞(人胚胎肾细胞)中表达的凝胶图,并与对照作比较(泳道1和2)。
图10表示在人NSCLC细胞系中siRNA对突变ROS激酶的抑制作用:A组表示在转染siRNA后细胞抑制图,B组表示ROS的特异性敲低(knock-down)和增加凋亡(在突变ROS驱动的细胞系中)的免疫印迹,C组是表示ROS下游的信号分子活性降低的免疫印迹。
图11是使用双色断裂-分离探针(2-color break-a-part probe)通过FISH特异性检测SLC34A2-ROS融合/易位(在人NSCLC细胞系中)的图像。
发明详述
根据本发明,以前已知的能导致突变激酶融合蛋白SLC34A2-ROS的基因易位已在人非小细胞肺癌(NSCLC)中被鉴定,非小细胞肺癌是肺癌的亚型。发生在染色体(4p15)和染色体(6q22)之间的易位产生了两个融合蛋白变体,该融合蛋白变体组合了钠依赖性磷酸盐转运蛋白同工型NaPi-3b蛋白(SLC34A2)的N端和原癌基因酪氨酸蛋白激酶ROS前体(ROS)激酶的跨膜和激酶结构域,其中所述钠依赖性磷酸盐转运蛋白同工型NaPi-3b蛋白是具有690个氨基酸的磷酸盐转运蛋白,所述原癌基因酪氨酸蛋白激酶ROS前体激酶是具有2347个氨基酸的受体酪氨酸激酶。得到的SLC34A2-ROS融合蛋白分别具有724个氨基酸(长的变体)和621个氨基酸(短的变体),估计这两种SLC34A2-ROS融合蛋白保留了激酶活性并驱动表达所述融合蛋白的人NSCLC肿瘤亚型的增殖和存活。
尽管一些导致涉及ROS激酶的异常融合蛋白的基因易位已被描述,包括在成胶质细胞瘤中FIG-ROS del(6)(q21,q21)的易位(参见Charestetal.,(2003),同上.)和ROS的截短的活性型式(参见Birchmeier et al.,同上.),最近公开的SLC34A2-ROS易位和融合蛋白是新的,该融合激酶是第一次被报道存在人NSCLC。SLC34A2是磷酸盐转运蛋白,在人肺和小肠中表达,其具有钠依赖活性。在卵巢癌中已发现SLC34A2表达和/或活性缺陷。参见Rangel等,同上。ROS是跨膜受体酪氨酸激酶,属于胰岛素受体亚家族(subfamily),参与了细胞增殖和分化过程。ROS在人、各种不同组织的上皮细胞中表达。在成胶质细胞瘤和中枢神经系统的肿瘤中已发现ROS表达和/或活性缺陷。参见如Charest等(2003),同上。
如下文进一步的描述,目前已分离和测序了SLC34A2-ROS易位基因和融合蛋白,并已经制备了表达突变激酶蛋白的cDNA。因此,本发明一部分提供了编码SLC34A2-ROS融合多肽的分离多核苷酸,能与所述多核苷酸杂交的核酸探针,以及使用所述多核苷酸制备重组突变ROS多肽的方法、载体和宿主细胞。本发明另一部分还提供了包括编码SLC34A2-ROS融合多肽的氨基酸序列的分离的多肽、重组突变多肽和能特异结合和/或检测SLC34A2-ROS融合多肽但不结合或者检测野生型SLC34A2或野生型ROS的分离的试剂。本发明的这些方面将在下文进一步详细地描述,这些方面对于进一步研究由突变ROS激酶表达/或活性所驱动的癌症机制以鉴定肺癌和以SLC34A2-ROS易位和/或融合蛋白为特征的其它癌症特别有用,在下文中还将进一步描述本发明的实施方法。
鉴定新的ROS激酶突变体和易位对于有效地诊断和治疗以易位和/或融合蛋白为特征的疾病如NSCLC具有非常重要的意义。NSCLC是美国癌症患者死亡的主要原因,NSCLC难以诊断,经常在转移后才能被诊断,从而增加了有效治疗和治愈该疾病的难度。因此,NSCLC在诊断后两年内的死亡率为75%。参见American Cancer Society,同上。尽管目前靶向EGFR-抑制剂已被批准用于治疗NSCLC,但是据估计这种治疗对于患有表达突变ROS激酶(不是或者除EGFR外)并受该激酶部分或全部驱动的肿瘤的患者可能部分或完全无效。
因此,在NSCLC中由于基因易位导致形成、预期能驱动NSCLC肿瘤亚型的增殖和存活的SLC34A2-ROS融合蛋白的发现使准确鉴定哺乳动物肺癌(如NSCLC)以及表达SLC34A2-ROS融合蛋白或截短的ROS激酶的其它癌症的重要新方法成为可能。这些肿瘤很可能对突变ROS激酶的激酶活性的抑制剂起反应。尽可能早地鉴定受突变ROS激酶驱动的癌症的能力将有力地支持在临床上确定哪种治疗剂或者组合哪些治疗剂对于特定患者是最合适的,从而有助于避免开出靶向其他激酶的抑制剂的处方,而所述其他激酶事实上不是驱动该癌症的主要信号分子。
因此,本发明部分地提供了采用本发明的融合特异性和突变特异性试剂检测癌症中存在的SLC34A2-ROS易位(t(4,6)(p15,q22))和/或融合多肽的方法。这种方法可以被用于例如鉴定癌症如NSCLC肿瘤,这种肿瘤可能对突变蛋白的ROS激酶活性的抑制剂起反应。本发明还部分地提供了确定一种化合物是否能抑制以SLC34A2-ROS融合多肽为特征的癌症的发展的方法。本发明还提供了通过抑制突变多肽的表达和/或活性抑制表达SLC34A2-ROS融合多肽的癌症的发展的方法。这些方法详细描述如下。
在下文中将更详细地描述本发明的其它方面、优点和实施方案。所有引用的参考文献以全文并入本文参考。
定义
“抗体”是指所有类型的免疫球蛋白,包括IgG、IgM、IgA、IgD和IgE,包括其Fab或抗原识别片段,包括嵌合、多克隆和单克隆抗体。本文所使用的术语“人源化抗体”是指为了与人抗体更相似在非抗原结合区的氨基酸被取代但保留了原有结合能力的抗体分子。
术语“生物活性”是指具有天然存在分子的结构、调节或者生物化学功能的蛋白质。同样,“免疫学活性”是指天然、重组或合成的SLC34A2-ROS融合多肽或截短的ROS多肽、或者其任何寡肽能够在适当的动物或细胞中诱导特异性免疫反应并结合特异抗体的能力。
术语“生物样品”采用其最广泛的意义,意指被怀疑含有SLC34A2-ROS融合体或截短的ROS多核苷酸或多肽或其片段的生物样品,可以包括细胞、从细胞中分离的染色体(例如,伸展的中期染色体)、基因组DNA(在溶液中或结合到固体支持物上如用于Southern分析)、RNA(在溶液中或结合到固体支持物上如用于northern分析)、cDNA(在溶液中或结合到固体支持物上)、细胞提取物、血液、尿、骨髓或组织等。
涉及癌症和突变ROS多核苷酸或者多肽使用的“以、、、为特征”是指存在SLC34A2-ROS基因易位和/或表达的融合多肽的癌症,与之相对的是不存在所述基因易位和/或融合多肽的癌症。所述融合多肽的存在可以全部或者部分地驱动所述癌症的生长和存活。
“共有”是指一种核酸序列,其被重新排序以分辨不需要的碱基,或者是使用XL-PCRTM(Perkin Elmer,Norwalk,Conn.)在5′和/或3′方向进行延伸并重新排序,或者是用GELVIEWTM Fragment Assembly系统(GCG,Madison,Wis.)从多于一个Incyte克隆的重叠序列组装,或者被延长并进行了组装。
“ROS激酶抑制治疗剂”是指任何包含一或多种化学或生物化合物的组合物,所述化合物直接或间接抑制单独存在和/或作为SLC34A2-ROS融合蛋白的一部分的野生型或截短的ROS的表达和/或活性。
“衍生物”是指编码SLC34A2-ROS融合多肽的核酸序列或编码多肽本身的化学修饰。这种修饰的实例可以是用烷基、酰基或氨基对氢进行取代。核酸衍生物编码的多肽保留了天然分子的必要生物特性。
本文公开的多肽、多核苷酸或试剂中涉及的“可检测标记”意指化学、生物或其它修饰,包括但不限于荧光、质量、残基、染料、放射同位素、标记或标签修饰等,通过这些可检测感兴趣分子的存在。
SLC34A2-ROS融合多肽在生物样品中的“表达”意指与融合多肽不显著表达的对照样品相比所述融合多肽显著表达。
“重同位素标记的肽”(与AQUA肽可交换使用)意指包含至少一种重同位素标记的肽,该重同位素标记适合绝对量化或检测蛋白质,如WO/03016861、"Absolute Quantification of Proteins and Modified FormsThereofby Multistage Mass Spectrometry"(Gygi et al.)所述,在下文还将进一步讨论。关于所述AQUA肽涉及的术语“特异性检测”意指所述肽只检测和量化含有AQUA肽序列的多肽和蛋白质,且基本上不检测不含有AQUA肽序列的多肽和蛋白质。
“分离的”(或“基本上纯化的”)是指离开天然环境的、被分离的或分开的核酸或氨基酸序列。其优选至少60%、更优选75%、最优选90%或更高地不含有与它们天然结合的其它成分。
“模拟物”是指结构源自SLC34A2-ROS融合多肽或其部分的结构的分子,由此该分子能发挥与易位相关蛋白质样分子的一些或所有作用。
“突变ROS”多核苷酸或者多肽意指本文所述的SLC34A2-ROS融合多核苷酸或者多肽。
“多核苷酸”(或“核苷酸序列”)是指寡聚核苷酸、核苷酸、或者多核苷酸、和其片段或部分;和指基因组或者合成的DNA或RNA,其可以是单链或双链,可以代表有义链或反义链。
“多肽”(或“氨基酸序列”)是指寡肽、肽、多肽、或蛋白质序列、和其片段或部分;和天然存在的或合成的分子。本文中“氨基酸序列”是指天然存在的蛋白质分子的氨基酸序列,“氨基酸序列”和类似术语如“多肽”或“蛋白质”并不将氨基酸序列限制为与所述蛋白质分子相关的完整天然氨基酸序列。
“SLC34A2-ROS融合多核苷酸”是指本文所述的基本上纯化的SLC34A2-ROS易位基因产物或融合多核苷酸的核酸序列,所述易位基因产物或融合多核苷酸从任何物种中获得,尤其是哺乳动物,包括牛、绵羊、猪、鼠、马,并优选人;并可以从任何来源获得如天然、合成、半合成或重组来源。
“SLC34A2-ROS融合多肽”是指本文所述的基本上纯化的SLC34A2-ROS融合多肽的氨基酸序列,所述融合多肽从任何物种中获得,尤其是哺乳动物,包括牛、绵羊、猪、鼠、马,并优选人;并可以从任何来源获得如天然、合成、半合成或重组来源。
在提到抗体和蛋白或肽相互作用时的术语“特异性结合”(或者“特异性结合”或“特异结合”)意指所述相互作用依赖于蛋白质上特定结构(即抗原决定簇或表位)的存在,也就是抗体识别并结合特异蛋白结构而不是一般蛋白质。对于与不是特异性的序列或抗原决定簇的抗体结合的术语“不结合”意指与抗体与抗体特异性的抗原决定簇或序列的结合相比基本上不反应。
关于序列或探针杂交条件的术语“严格条件”是指在大约Tm减去5℃(低于探针或者序列的溶解温度的(Tm)5℃)到约低于Tm的20℃-25℃的范围的“严格性”。典型的严格条件为:在42℃在含有:50%甲酰胺、5X.SSC(750mM NaCl,75mM柠檬酸三钠)、50mM磷酸钠(pH7.6)、5X Denhardt′s溶液、10%硫酸葡聚糖和20微克/毫升变性剪切鲑精DNA的溶液中保温过夜,然后在约65℃用0.1X SSC的洗涤滤膜。本领域技术人员可以理解的是:为了鉴别或者检测相同或相关多核苷酸序列,可改变杂交的严格性。
SLC34A2-ROS融合多肽的“变体”是指一或多个氨基酸改变的氨基酸序列。变体可以具有“保守”改变,其中取代的氨基酸具有相似的结构或化学性质,例如用异亮氨酸置换亮氨酸。在少数情况下,变体可以具有“非保守”改变,例如用色氨酸置换甘氨酸。类似少量的改变还可以包括氨基酸缺失或插入,或者二者。可以使用本领域已知的计算机程序例如DNASTAR软件找到确定哪些氨基酸残基可以被取代、插入或缺失而不丧失生物活性或者免疫活性的教导。
A、人NSCLC中的突变ROS激酶的鉴定。
本文公开的新的人基因易位发生在人NSCLC的染色体(4p15)和染色体(6q22)之间,并导致了组合了SLC34A2的N端(外显子1-4)和ROS的跨膜结构域和激酶结构域(分别为外显子32-43或者外显子34-43)的两种变体融合蛋白的表达,所述易位是在检测人一种肺癌亚型非小细胞肺癌(NSCLC)的细胞系(HCC78)提取物中的总的磷酸化肽谱(profile)时被意外地发现的。在图1中给出了涉及这种易位的染色体、基因和选择性剪接产物(长的和短的)。
使用最近描述的从复杂混合物中分离和质谱表征修饰的肽的技术阐述了这种细胞系的磷酸化谱。(参见美国专利公开号20030044848,Rush et al.,"Immunoaffinity Isolation of Modified Peptides from Complex Mixtures"(the"IAP"technique),在本文实施例1中进一步进行描述。应用使用磷酸酪氨酸特异性抗体(CELL SIGNALING TECHNOLOGY,INC.,Beverly,MA,2003/04Cat.#9411)的IAP技术鉴定了HCC78细胞系表达ROS激酶(与大多数不表达ROS激酶的其它细胞系相反),但是该激酶明显是截短的(参见图5)。这种筛选在所述细胞系中鉴定了许多其它被激活的激酶,包括ROS。通过5′RACE分析ROS的5′序列,然后鉴定了所述激酶融合到SLC34A2的N端(参见图6)。
然后通过Western印迹分析证实了SLC34A2-ROS融合多肽在HCC78细胞系中表达以检测两种ROS激酶的表达(HCC78细胞中的融合蛋白),并使用p-酪氨酸特异性抗体通过免疫沉淀证实其磷酸化(参见实施例2;图5)。通过PCR扩增、分离并测序SLC34A2-ROS融合基因(参见实施例4,图7(上组))。如图1的B组所示,SLC34A2-ROS易位组合了SLC34A2的N端(氨基酸1-126)与ROS的跨膜结构域和激酶结构域(分别为氨基酸1750-2347或氨基酸1853-2347)(参见SEQ ID NO:3和5),产生两个融合变体(长的和短的)(见图1的C组)。易位保留了SLC34A2的5′端大多数跨膜结构域。得到的SLC34A2-ROS融合蛋白分别含有724个氨基酸和621个氨基酸(见图1的C组和图2A-B(SEQ ID NO:1和3)),预期这些融合蛋白保留了ROS的激酶活性。图8给出了涉及的外显子和融合接头。
将编码SLC34A2-ROS融合蛋白的长变体的cDNA转染到293细胞中(人胚胎肾细胞)以建立表达具有预期分子量的SLC34A2-ROS融合蛋白,该蛋白存在于HCC78细胞中,见图9。
SLC34A2-ROS融合蛋白的ROS激酶活性的抑制可以通过根据已知技术采用siRNA沉默方法或者采用具有针对ROS的活性的靶向激酶抑制剂在HCC78细胞系中证实。这些测试结果(见实施例3)证实了融合蛋白事实上驱动了这种NSCLC细胞系的增殖和存活。人NSCLC肿瘤的总的磷酸肽谱和FISH分析表明少部分的患者事实上的确存在这种突变(见实施例7和9),因此ROS抑制剂治疗对这些患者有益。
B、分离的多核苷酸。
本发明部分提供了编码SLC34A2-ROS融合多肽的分离的多核苷酸,能与所述多核苷酸杂交的核苷酸探针,和使用所述多核苷酸产生重组融合多肽的方法、载体和宿主细胞。
除非另有说明,本文中通过测序DNA分子确定的所有核苷酸序列是使用自动DNA测序仪(如Applied Biosystems,Inc.的Model373)确定的;本文中确定的所有DNA分子编码的多肽的氨基酸序列是使用自动肽测序仪确定的。对于由自动分析方法确定任何DNA序列,正如本领域所知,本文所确定的任意核苷酸序列可能有一些错误。用自动分析方法确定的核苷酸序列典型地与测序DNA分子的真正核苷酸序列至少大约90%相同,更典型地至少大约95%至至少大约99.9%相同。所述真正序列可以通过其它方法包括本领域熟知的手动DNA测序方法更精确地测定。还如本领域所熟知,与真正序列相比,在确定的核苷酸序列中单碱基插入或缺失将导致在该核苷酸序列翻译过程中移码,从而导致由确定的核苷酸序列编码的预测氨基酸序列与由测序DNA分子编码的真正氨基酸序列从所述插入或缺失位点开始完全不同。
除非另有说明,本文所述的每一个核苷酸序列都是脱氧核糖核苷酸序列(简写为A、G、C和T)。然而,核酸分子或多核苷酸的“核苷酸序列”意指DNA分子或多核苷酸、脱氧核糖核苷酸的序列;和RNA分子或多核苷酸、核糖核苷酸的相应序列(A、G、C和U),其中在特定的脱氧核糖核苷酸序列中每一个胸腺嘧啶脱氧核糖核苷酸(T)被核糖核苷酸尿嘧啶(U)置换。例如,当提及具有序列SEQ ID NO:2或4或者用脱氧核糖核苷酸简写表示的RNA分子是指具有其中SEQ ID NO:2或4的每一个脱氧核糖核苷酸A、G或C被相应的核糖核苷酸A、G或C置换及每一个脱氧核糖核苷酸T被核糖核苷酸U置换的序列的RNA分子。
在一个实施方案中,本发明提供了一种分离的多核苷酸,其包括与选自以下一组的序列至少为95%相同的核苷酸序列:
(a)编码SLC34A2-ROS融合多肽的核苷酸序列,所述融合多肽包括SEQ ID NO:1或者SEQ ID NO:3的氨基酸序列;
(b)编码SLC34A2-ROS融合多肽的核苷酸序列,该核苷酸序列包括SEQ ID NO:2或者SEQ ID NO:4的核苷酸序列;
(c)编码SLC34A2-ROS融合多肽的核苷酸序列,所述融合多肽包括SLC34A2的N端氨基酸序列(SEQ ID NO:5的第1-126残基)和ROS的激酶结构域(SEQ ID NO:7的第1945-2222残基);
(d)包括SLC34A2的N端核苷酸序列(SEQ ID NO:6的第1-378残基)和ROS的激酶结构域核苷酸序列(SEQ ID NO:8的第6032-6865残基)的核苷酸序列;
(e)包括含有SLC34A2-ROS融合多核苷酸的融合接头(SEQ ID NO:2的第376-381残基或者SEQ ID NO:4的第376-381残基)的至少六个连续核苷酸的核苷酸序列;
(f)编码多肽的核苷酸序列,所述多肽包含含有SLC34A2-ROS融合多肽的融合接头(SEQ ID NO:1的第126-127残基或者SEQ ID NO:3的第126-127残基)的至少六个连续氨基酸;
(g)与上述核苷酸序列(a)-(f)中任一序列互补的核苷酸序列。
使用本文提供的信息,如图2A-B中的核苷酸序列(SEQ ID NO:2和4)、本发明的编码本发明突变ROS多肽的核酸分子可以使用标准克隆和筛选方法获得,如用于用mRNA作为起始物质克隆cDNA的方法。作为本发明的示例说明,在图2A-2B中描述的多核苷酸(SEQ ID NO:2和4)从人NSCLC细胞系(在下文的实施例4中进一步描述)的基因组DNA中分离。融合基因也可以在其它肺癌或其它癌症的基因组DNA或cDNA文库中被鉴定,所述其它癌症是存在SLC34A2-ROS易位(4p15,6q22)或者缺失或选择性易位导致了缺少野生型激酶的细胞外结构域的截短的ROS激酶的表达的癌症。
确定的SLC34A2-ROS易位基因产物的核苷酸序列(SEQ ID NO:2和SEQ ID NO:4)分别编码具有724个氨基酸(见图2A(SEQ ID NO:1)和图1)和621个氨基酸(见图2B(SEQ ID NO:3)和图1)的两种激酶融合蛋白变体(长的和短的)。SLC34A2-ROS融合多核苷酸包括编码野生型SLC34A2蛋白质的N端(外显子1-4)的核苷酸序列的部分(见图3(SEQ ID NO:6))和编码野生型ROS蛋白质的跨膜结构域和激酶结构域(分别为外显子32-43或外显子34-43)的核苷酸序列的部分(见图4(SEQ ID NO:8)。见图1。激酶结构域包括在第一个(长的)变体融合蛋白(由第一个变体融合多核苷酸的第964-1797核苷酸编码)的第322-599残基和在第二个(短的)变体融合蛋白(由第二个变体融合多核苷酸的第655-1488核苷酸编码)的第219-496残基。
如本文所述,本发明部分地提供了SLC34A2-ROS融合蛋白的成熟形式。根据信号假想,哺乳动物细胞分泌的蛋白质具有信号前导序列或者分泌前导序列,当生长的蛋白质链一旦开始被运出粗糙内质网,该前导序列就从成熟蛋白质上切除。大多数的哺乳动物细胞甚至昆虫细胞以相同的特异性切割分泌的蛋白质。然而,在某些情况下,分泌蛋白质的切割不是完全一致的,从而导致两或多种成熟蛋白质。此外,很早就知道分泌蛋白质的切割特异性最终由完整蛋白质的一级结构决定,也就是它是该多肽氨基酸序列所固有的。因此,本发明部分地提供了编码成熟SLC34A2-ROS融合多肽的核苷酸序列,所述融合多肽具有ATCC保藏号为PTA-7877的cDNA克隆编码的氨基酸序列,该cDNA克隆在2006年9月20根据布达佩斯条约保藏在美国典型培养物保藏中心(Manassas,Virginia,U.S.A.)。
具有保藏的cDNA克隆编码的氨基酸序列的成熟SLC34A2-ROS多肽意指由哺乳动物细胞(如下文所述的COS细胞)表达由保藏的宿主细胞的载体中含有的所述克隆的人DNA序列所编码的完全开放读框而产生的所述融合蛋白的成熟形式。
如本文所述,本发明的多核苷酸可以是RNA形式如mRNA或DNA形式包括例如通过克隆或合成产生的cDNA和基因组DNA。DNA可以为双链或单链。单链DNA或者RNA可以为编码链,也称为有义链,或者非编码链,也称为反义链。
本发明的分离的多核苷酸为核酸分子、DNA或RNA,其已从其天然环境中移出。例如,载体中含有的重组DNA分子被认为是符合本发明目的的分离的。分离的DNA分子的其他实例包括保持在异源宿主细胞中的重组DNA分子或者溶液中的纯化的(部分纯化的或者基本上纯化的)DNA分子。分离的RNA分子包括本发明的DNA分子的体内或体外RNA转录物。本发明的分离的核酸分子还包括那些合成的分子。
本发明的分离的多核苷酸包括如图2A-B所示的DNA分子(SEQ ID NO:2和4)、包括图1所示成熟SLC34A2-ROS融合蛋白(SEQ ID NO:1和3)的编码序列的DNA分子和包括基本上与上述序列不同但由于遗传密码的简并性而仍属于本发明的突变ROS多肽的序列的DNA分子。在本领域中遗传密码是众所周知的,因此对于本领域的技术人员来说产生所述简并变体是常规的。
在另一个实施方案中,本发明提供一种编码SLC34A2-ROS融合多肽的分离的多核苷酸,其包括在上述保藏的cDNA克隆中含有的SLC34A2-ROS易位核苷酸序列。优选地,所述核酸分子编码由保藏的cDNA克隆编码的成熟融合多肽。在另一种实施方案中,本发明提供编码SLC34A2-ROS融合多肽的分离的多核苷酸,所述融合多肽包括SLC34A2的N端氨基酸序列(SEQ ID NO:5的第1-126残基)和ROS激酶结构域(SEQ ID NO:7的第1945-2222残基)。在一个实施方案中,所述包括ROS激酶结构域的多肽包括SEQ ID NO:7的1750-2347或1853-2347残基(见图1,B组)。在另一个实施方案中,上述SLC34A2的N端氨基酸序列和ROS的激酶结构域分别由包含SEQ ID NO:6的第1-378核苷酸的核苷酸序列和包含SEQ ID NO:8的第6032-6865核苷酸的核苷酸序列编码。
本发明还提供分离的多核苷酸,其包括具有与本发明的突变ROS融合多肽互补的序列的核苷酸序列。这种分离的分子,尤其是DNA分子通过与染色体原位杂交用作基因作图的探针,通过例如Northern印迹分析检测人组织中的SLC34A2-ROS融合蛋白或截短的ROS激酶多肽的表达。
本发明还涉及本文所述分离的核酸分子的片段。本发明的分离的SLC34A2-ROS多核苷酸或截短的ROS多核苷酸的片段是长度至少为约15个核苷酸、更优选为至少约20个核苷酸、更优选为至少约30核苷酸,更优选为至少约40个核苷酸的片段,该片段用于上述的诊断探针和引物。当然。根据本发明,长度为约50-1500个核苷酸的更长的片段也是有用的,它们为对应于保藏的cDNA的SLC34A2-ROS核苷酸序列的大部分(如果不是全部的话)的片段或者如图2A-B所示(SEQ ID NO:2和4)。例如,长度为至少20个核苷酸的片段是包括至少20个或更多个连续的产生所述片段的核苷酸序列中的碱基。
对于本领域的技术人员来说,产生这种DNA片段是常规的程序,可以通过例如限制性核酸内切酶切割或通过超声剪切从保藏的cDNA克隆或者根据本文公开序列合成获得的DNA而实现。或者,通过合成直接产生这种片段。
本发明优选的核酸片段或者探针包括编码SLC34A2-ROS易位产物的融合接头的核酸分子(见图1,B组和C组,和图7,下组)。例如,在某些优选的实施方案中,本发明的分离的多核苷酸包括包含至少六个连续核苷酸的核苷酸序列/片段,所述连续核苷酸包括SLC34A2-ROS融合多核苷酸(见图7,下组)的融合接头(SEQ ID NO:2的376-381残基或者SEQ ID NO:4的376-381残基)。在另一个优选的实施方案中,本发明的分离的多核苷酸包括编码包含至少六个连续氨基酸的多肽的核苷酸序列/片段,所述连续氨基酸包括SLC34A2-ROS融合多肽(见图7,下组(SEQ ID NO:9和11))的融合接头(SEQ ID NO:1的第126-127残基或者SEQ ID NO:3的第126-127残基)。
在另一方面,本发明提供了在严格杂交条件下与本文所述的本发明的突变ROS激酶多核苷酸的一部分杂交的分离的多核苷酸。“严格杂交条件”是指在42℃在含有50%甲酰胺、5X.SSC(750mM NaCl,75mM柠檬酸三钠)、50mM磷酸钠(pH7.6)、5X Denhardt′s溶液、10%硫酸葡聚糖和20微克/毫升变性剪切鲑精DNA的溶液中保温过夜,然后在约65℃用0.1X SSC的洗涤滤膜。
与多核苷酸的“一部分”杂交的多核苷酸是指与参考多核苷酸的至少约15个核苷酸(nt)、优选至少约20nt、更优选至少约30nt、更优选约30-70nt杂交的多核苷酸(DNA或RNA)。这些用作上述的诊断探针和引物(例如用于PCR)并将在下文中更详细地讨论。
当然,与参考多核苷酸(例如图2A-B所述的成熟SLC34A2-ROS融合多核苷酸(SEQ ID NO:2和4))的大部分例如长度为50-750nt的部分或者与全长参考多核苷酸杂交的多核苷酸也可以用作本发明的探针,它们为对应于保藏的cDNA的核苷酸序列的大部分(如果不是全部的话)或者为图2A-2B(SEQ ID NO:2和4)或图7(下组)(SEQ ID NO:10和12)所示的核苷酸序列的多核苷酸。
例如,所谓“长度为至少20个核苷酸”的多核苷酸的部分是指参考多核苷酸的核苷酸序列的20个或更多个连续核苷酸。如本文所示,这种部分可按照常规DNA杂交技术用作诊断的探针或者根据例如在全文并入本文参考的MOLECULAR CLONING,A LABORATORY MANUAL,2nd.edition,Sambrook,J.,Fritsch,E.F.and Maniatis,T.,eds.,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.(1989)中所述用于通过聚合酶链反应(PCR)扩增靶序列的诊断引物。当然,仅与聚A序列(如在图2所示的SLC34A2-ROS序列(SEQ ID NO:2或4)的3′末端聚(A)片段)或者T(或U)残基的互补部分杂交的多核苷酸不包含在用于杂交本发明的核酸一部分的多核苷酸中,因为这种多核苷酸与任何含有聚(A)片段的核酸分子或其互补片段(例如,尤其是任何双链cDNA克隆)杂交。
如本文所示,本发明的编码本发明的突变ROS激酶多肽的核酸分子可以包括但不限于那些本身编码成熟多肽的氨基酸序列的分子;成熟多肽和额外序列的编码序列如编码前导序列或者分泌序列的那些,如前-、或者原-、或者前-原-蛋白质序列;成熟多肽的编码序列,具有或不具有上述的额外编码序列,具有额外的非编码序列,包括但不限于例如内含子和非编码5′和3′序列,例如转录的、非翻译序列,其在转录、mRNA加工包括剪接和聚腺苷酸化信号例如核糖体结合和mRNA的稳定性中起作用;编码例如提供额外功能性的额外氨基酸的额外编码序列。
因此,编码所述多肽的序列可以融合到标记序列上,如编码有助于所述融合多肽纯化的肽的序列。在本发明这方面的某些优选的实施方案中,所述标记氨基酸序列为六组氨酸肽,例如在pQE载体(Qiagen,Inc.)中提供的标签(tag),其它标记序列许多都可以通过商购获得。例如,如Gentz等,Proc.Natl.Acad.Sci.USA86:821-824(1989)中所述,六组氨酸有助于便捷地纯化融合蛋白。“HA”标签是另一种对纯化有用的肽,该肽对应于流感血凝素蛋白的表位,Wilson等在Cell37:767(1984)中描述。如在下文所讨论,其它的这种融合蛋白包括融合到Fc的N端或者C端的SLC34A2-ROS融合多肽本身。
本发明还涉及本发明核酸分子的变体,其编码本文公开的SLC34A2-ROS融合多肽或者截短的ROS激酶多肽的部分、类似物或衍生物。变体可以是天然存在的,例如天然等位基因变体。所谓“等位基因变体”是指生物染色体上占据给定基因座上的一个基因的几种可选择形式之一。见例如GENES II,Lewin,B.,ed.,John Wiley&Sons,New York(1985)。非天然存在的变体可以使用本领域已知的基因诱变技术制备。
所述变体包括那些通过核苷酸取代、缺失或添加产生的变体。所述取代、缺失或添加可能涉及一或多个核苷酸。所述变体可以在编码区、非编码区或者二者中发生改变。在编码区的改变可以产生保守的或者非保守的氨基酸取代、缺失或者添加。尤其优选那些沉默取代、添加或者缺失,这种改变不会改变本文公开的突变ROS激酶多肽的性质和活性(例如激酶活性)。在这一方面还尤其优选保守取代。
本发明的其他实施方案包括分离的多核苷酸,其包括与本发明的突变ROS多核苷酸(例如编码具有如图2A-B所示完整氨基酸序列(SEQ ID NO:1或3)的RB-ROS融合多肽的核苷酸序列;或者编码SLC34A2的N端和ROS的激酶结构域的核苷酸序列(见图1,B组;和图3和4)或者与示例性序列互补的核苷酸)的核苷酸序列)至少90%相同、更优选至少95%、96%、97%、98%或99%相同的核苷酸序列。
具有与编码突变ROS激酶多肽的参考核苷酸序列至少例如95%相同的核苷酸序列的多核苷酸是指多核苷酸的核苷酸序列与参考序列相同,除了所述多核苷酸序列可以包括在编码突变ROS多肽的参考核苷酸序列的每100个核苷酸中至多5个点突变。也就是说,为了获得具有与参考核苷酸序列至少95%相同的核苷酸序列的多核苷酸,参考序列中至多5%的核苷酸可以被缺失或用另一种核苷酸取代,或者参考序列总核苷酸的至多5%的核苷酸可以插入到参考序列中。参考序列的这些突变可以在参考核苷酸序列的5′或3′末端位置,或者那些末端位置之间的任何位置,单个散布在参考序列的核苷酸中或者散布在参考序列的一或多个连续基团中。
在实践中,任何特定核酸分子是否与例如图2A-B所示的核苷酸序列(SEQ ID NO:2或4)或者与上述的保藏的cDNA克隆的核苷酸序列至少90%、95%、96%、97%、98%或99%相同都可以使用已知的计算机程序如Bestfit程序(Wisconsin Sequence Analysis Package,Version 8 for Unix,Genetics Computer Group,University Research Park,575Science Drive,Madison,Wis.53711)常规确定。Bestfit使用Smith and Waterman,AdvancesinApplied Mathematics2:482-489(1981)的局部同源性算法以发现两个序列之间的同源性最好的片段。当使用Bestfit或者任何其它序列比对程序确定特定序列是否例如与本发明的参考SLC34A2-ROS融合多核苷酸序列是否是95%相同,当然允许设置参数以便相同性百分比通过全长参考核苷酸序列以及允许高达参考序列中总核苷酸数的5%的同源性缺口(gap)进行计算。
在本发明的范围内,本发明包括与以下序列至少90%、95%、96%、97%、98%或99%相同的核酸分子,而不论这些序列是否编码具有ROS激酶活性的多肽,所述序列为图2A-2B所示的核酸序列(SEQ ID NO:2或4),或者SEQ ID NO:2的379-2172核苷酸或者SEQ ID NO:4的第379-1863核苷酸,或者保藏的cDNA的核酸序列。这是因为即使一种特定的核酸分子不编码具有ROS激酶活性的融合多肽,本领域技术人员仍然知道如何使用该核酸分子例如作为杂交探针或聚合酶链反应(PCR)引物。本发明的不编码具有激酶活性的多肽的核酸分子的用途包括(1)在cDNA文库中分离SLC34A2-ROS易位基因或其等位基因变体;(2)原位杂交(例如"FISH")伸展的中期染色体以提供SLC34A2-ROS易位基因的精确染色体定位,如Verma等,HUMAN CHROMOSOMES:A MANUAL OF BASIC TECHNIQUES,Pergamon Press,New York(1988)所述;和Northern印迹分析以检测SLC34A2-ROS融合蛋白的mRNA在特定组织中的表达。
然而,优选的核酸分子具有与本发明的突变ROS激酶多肽或者保藏的cDNA的核酸序列至少95%相同的序列,事实上所述优选的核酸分子编码具有ROS激酶活性的融合多肽。如在某些生物分析中检测的那样,这些活性可以与本文所公开的SLC34A2-ROS融合蛋白(全长蛋白、成熟蛋白,或者保留了激酶活性的蛋白片段)的活性相似但不必需相同。例如,ROS的激酶活性可以通过确定它磷酸化一或多种含有酪氨酸的肽底物如“Src-相关肽”(RRLIEDAEYAARG)的能力检测,含有酪氨酸的肽底物是许多受体和非受体酪氨酸激酶的底物。
由于遗传密码简并性,本领域技术人员将很快认识到大量的具有与保藏的cDNA的核酸序列或者图2A-B所示核酸序列(SEQ ID NO:2和4)至少90%、95%、96%、97%、98%或99%相同的序列的核酸分子编码具有ROS激酶活性的融合多肽。事实上,由于这些核苷酸序列的简并变体都编码相同的多肽,即使不进行上述的比较分析这对于本领域的技术人员而言也是清楚的。本领域技术人员还将认识到对于那些不是简并变体的核酸分子,也有合理数量的将编码保留ROS激酶活性的多肽。这是因为本领域技术人员完全能意识到氨基酸取代可能性很小或者不可能显著影响蛋白质的功能(例如一个脂肪族氨基酸用另一个脂肪族氨基酸置换)。
例如,关于如何产生表型上的沉默氨基酸取代的指南描述在Bowie等,"Deciphering the Message in Protein Sequences:Tolerance to Amino AcidSubstitutions,"Science247:1306-1310(1990)中,该文献描述了两种主要的用于研究氨基酸序列对于改变的耐受能力的方法。第一种方法依赖于进化过程,其中通过自然选择接受或拒绝突变。第二种方法使用基因工程技术在克隆的基因的特定位点导入氨基酸变化,选择或筛选以鉴定保留了功能性的序列。这些研究已揭示了蛋白质对于氨基酸取代具有令人意想不到的耐受力。熟悉这些技术的技术人员也将理解在蛋白质的某些位点可能允许哪些氨基酸变化。例如,大多数的隐藏氨基酸残基需要非极性侧链,而表面侧链的特征通常很少是保守的。其它的这种表型沉默取代描述在Bowie等,同上并且在其中引用的参考文献中。
本领域熟知的并通常能获得的DNA测序方法可以用于实施本发明的任何多核苷酸的实施方案。所述方法可以使用酶例如DNA聚合酶I的Klenow片段、SEQUENASE(US Biochemical Corp,Cleveland,Ohio)、Taq聚合酶(Perkin Elmer)、耐热T7聚合酶(Amersham,Chicago,III.)或者重组聚合酶和校正外切核酸酶的组合如Gibco BRL(Gaithersburg,Md.)销售的ELONGASE Amplification System。优选地,所述方法采用设备如HamiltonMicro Lab2200(Hamilton,Reno,Nev.)、Peltier Thermal Cycler(PTC200;MJResearch,Watertown,Mass.)和ABI377DNA测序仪(Perkin Elmer)自动进行。编码本发明的突变ROS多肽的多核苷酸序列可以使用部分核苷酸序列延长并使用本领域熟知的各种方法检测上游序列如启动子和调节元件。例如,可以使用的一种方法“限制位点”PCR,采用通用引物以识别与已知基因座邻近的未知序列(Sarkar,G.,PCR Methods Applic.2:318-322(1993))。尤其是在接头序列引物和对已知区域特异的引物存在下首先扩增基因组DNA。示例性的引物为本文实施例4所描述的那些。然后,用相同的接头引物和位于第一种引物内的另一种特异引物对扩增的序列进行第二轮PCR。用适当的RNA聚合酶对每一轮PCR的产物进行转录,并用逆转录酶测序。
还可以使用基于已知区域的不同引物(divergent primers)用反向PCR扩增或延伸序列(Trigliaetal.,Nucleic Acids Res.16:8186(1988))。可以使用OLIGO4.06引物分析软件(National Biosciences Inc.,Plymouth,Minn.)或者另外的适当程序将引物设计成长度为22-30个核苷酸,GC含量为50%或更高,在约68-72℃对靶序列退火。所述方法使用几种限制性酶以在基因的已知区域产生适当的片段。然后通过分子内连接将片段环化并用作PCR模板。
另一种可以使用的方法是捕获PCR,其涉及扩增与人和酵母人工染色体DNA中已知序列邻近的DNA片段(Lagerstrom et al.,PCR Methods Applic.9:111-119(1991))。在这种方法中,在进行PCR之前,可以使用多重限制酶消化和连接将工程化的双链序列置于DNA分子中的未知部分。另一种可以用于识别未知序列的方法在Parker等Nucleic Acids Res19:3055-3060(1991))中描述。此外,可以使用PCR、嵌套引物和PROMOTERFINDER文库在基因组DNA中步行(Clontech,Palo Alto,Calif.)。这种方法避免了需要筛选文库并能用于找到内含子/外显子连接点。
当筛选全长cDNA时,优选使用已被选择大小以包括更大的cDNA的文库。此外,优选随机引物文库(random-primed library),因为其含有更多的含有基因5′区的序列。在oligod(T)文库不能产生全长cDNA的情况下尤其优选使用随机引物文库。基因组文库可能对于延伸序列至5′和3′非转录调节区域有用。
可以使用可商购的毛细电泳系统分析大小或证实测序或PCR产物的核苷酸序列。尤其是毛细测序可以使用可流动聚合物进行电泳分离,四种由激光激活的不同的荧光染料(一种染料对应于一种核苷酸)和通过电荷耦合器件相机检测发射波长。使用适当软件(例如GENOTYPERTM andSEQUENCE NAVIGATORTM,Perkin Elmer)可以将输出/光强转化为电子信号,并且从负载样品到计算机分析和电子数据显示的整个过程都可以通过计算机控制。毛细电泳尤其优选用于测序在特定样品中以有限量存在的少量DNA。
C、载体和宿主细胞
本发明还提供了包含本发明分离的多核苷酸的重组载体、用重组载体遗传工程化的宿主细胞和通过重组技术生产重组SLC34A2-ROS多肽或其片段。
可以使用熟知的技术如感染、转导、转染、移位、电穿孔和转化将重组构建体导入宿主细胞。载体可以是例如噬菌体、质粒、病毒或逆转录病毒载体。逆转录病毒载体可以具有复制能力或者复制缺陷的。对于后者,病毒增殖通常只有在互补宿主细胞中才发生。
所述多核苷酸可以被连接到含有可选择标记的载体中以在宿主中增殖。通常以沉淀如磷酸钙沉淀或者以与带电脂质的复合物导入质粒载体。如果载体是病毒,则其可以用适当的包装细胞系在体外包装然后再转导入宿主细胞中。
优选的载体包含对感兴趣的多核苷酸是顺式作用的控制区域。适当的反式作用因子可以由宿主提供、由互补载体提供或者在载体导入到宿主中时由载体本身提供。关于这方面的某些优选的实施方案中,载体提供特异表达,这种特异表达可以是可诱导的和/或细胞类型特异的。在这些载体中尤其优选那些被易于操纵的环境因子如温度和营养添加物诱导的载体。
可用于本发明的表达载体包括染色体型载体、附加型载体和病毒衍生的载体,如衍生自细菌质粒的载体、噬菌体、酵母附加体、酵母染色体元件、病毒如杆状病毒、乳多空病毒、疫苗病毒、腺病毒、禽痘病毒、假狂犬病病毒和逆转录病毒以及衍生自其组合的载体如粘粒和噬菌粒。
包括本发明的SLC34A2-ROS多核苷酸或截短的ROS多核苷酸的DNA插入体应当被可操纵地连接到适当的启动子上,如噬菌体λPL启动子、大肠杆菌(E.coli)lac、trp和tac启动子、SV40早期和晚期启动子、逆转录病毒LTR启动子等。其它适当的启动子为本领域技术人员所知。所述表达构建体还包括用于转录起始和终止的位点以及在转录区用于翻译的核糖体结合位点。由构建体表达的成熟转录物的编码部分优选包括在开始的翻译起始和在待翻译多肽末端的适当位置的终止密码子(UAA,UGA或UAG)。
如本文所述,所述表达载体优选包括至少一种可选择标记。这些标记包括二氢叶酸还原酶或者用于真核细胞培养的新霉素抗性基因和用于大肠杆菌和其它细菌培养的四环素或氨苄青霉素抗性基因。适当宿主的代表实例包括但不限于细菌细胞如大肠杆菌、链霉菌和鼠伤寒沙门氏菌(Salmonella typhimurium)细胞;真菌细胞,如酵母细胞;昆虫细胞如果蝇S2细胞和秋粘虫(Spodoptera)Sf9细胞;动物细胞如CHO、COS和Bowes黑素瘤细胞;和植物细胞。用于上述宿主细胞的适当培养基和培养条件为本领域所知。
优选用于细菌的载体包括由Qiagen提供的pQE70、pQE60和pQE-9;由Stratagene提供的pBS载体、Phagescript载体、Bluescript载体、pNH8A、pNH16a、pNH18A和pNH46A;和Pharmacia提供的ptrc99a、pKK223-3、pKK233-3、pDR540和pRIT5。优选的真核载体为由Stratagene提供的pWLNEO、pSV2CAT、pOG44、pXT1和pSG;和由Pharmacia提供的pSVK3、pBPV、pMSG和pSVL。其它合适的载体对于本领域技术人员来说是明显的。
适合用于本发明的已知细菌启动子包括大肠杆菌lac1和lacZ启动子、T3和T7启动子、gpt启动子、λPR和PL启动子和trp启动子。适当的真核启动子包括CMV立即早期启动子、HSV胸苷激酶启动子、早期和晚期SV40启动子、逆转录病毒LTR启动子如Rous肉瘤病毒(RSV)的启动子和金属硫蛋白启动子如小鼠金属硫蛋白-I启动子。
在酵母酿酒酵母(Saccharomyces cerevisiae)中,可以使用大量含有组成型和诱导型启动子如α因子、醇氧化酶和PGH的载体。综述可以参考Ausubel等(1989)CURRENT PROTOCOLS IN MOLECULAR BIOLOGY,John Wiley&Sons,New York,N.Y,and Grantet al.,Methods Enzymol.153:516-544(1997)。
可以通过磷酸钙转染、DEAE-葡聚糖介导的转染、阳离子脂质介导的转染、电穿孔、转导、感染和其它方法将构建体导入到宿主细胞中。所述方法描述在许多标准的实验室手册中,如Davis等,BASIC METHODS INMOLECULAR BIOLOGY(1986)。
可以通过将增强子序列插入所述载体中以增强由高等真核细胞对编码本发明的SLC34A2-ROS融合多肽的DNA的转录。增强子为DNA顺式作用元件,通常为约10-300bp,增加给定宿主细胞类型的启动子的转录活性。增强子的实例包括定位在复制起点后侧第100-270碱基对的SV40增强子、巨细胞病毒早期启动子增强子、在复制起点后侧的多瘤增强子和腺病毒增强子。
为了将翻译的蛋白质分泌导内质网的内腔、周质间隙或者细胞外环境中,可以在表达多肽中掺入适当的分泌信号。所述信号对所述多肽可以是内源性的或者是异源信号。
所述多肽可以修饰的形式表达,如融合蛋白(例如GST-融合体),并且可以不但包括分泌信号也可以包括额外的异源功能区域。例如,可以在所述多肽的N末端加入额外的氨基酸尤其是带电氨基酸的区域以改善在宿主细胞中、在纯化或后续处理和保存过程中的稳定性和持久性。此外可以在所述多肽上添加肽部分以助于纯化。这些区域可以在所述多肽的最后制备前被除去。为了分泌或排泄、改善稳定性并促进纯化,将肽部分添加到多肽上的方法等是本领域技术人员所熟知的常规技术。一种优选的融合蛋白包括用于稳定蛋白的免疫球蛋白的异源区域。
例如EP-A-O 464 533(加拿大同族专利2045869)公开了包含免疫球蛋白分子的恒定区的几个部分和另一种人蛋白或其部分的融合蛋白。在许多情况下,融合蛋白的Fc部分对于用于治疗和诊断非常有益,并因此产生了例如改进的药代动力学特性(EP-A 0232 262)。另一方面,对于一些用途,需要能够在融合蛋白以所述有益方式表达、检测和纯化后删除Fc部分。当Fc部分被证实有碍于治疗和诊断例如当融合蛋白被用作免疫抗原时就是这种情况。例如在药物发现中,人蛋白如hIL5-与Fc部分融合以通过高通量筛选分析方法鉴定hIL-5的拮抗剂。参见Bennett et al.,Journal of MolecularRecognition8:52-58(1995)和Johanson et al.,The Journal of BiologicalChemistry270(16):9459-9471(1995)。
可以通过包括硫酸铵或乙醇沉淀、酸提取、阴离子或阳离子交换层析、磷酸纤维素层析、疏水相互作用层析、亲合层析、羟磷灰石层析和凝集素层析等的熟知方法将SLC34A2-ROS多肽从重组细胞培养物中回收和纯化。最优选使用高效液相色谱("HPLC")进行纯化。本发明的多肽包括天然纯化的产物、化学合成过程的产物和通过重组技术从原核宿主或真核宿主制备的产物,所述宿主包括例如细菌、酵母、高等植物、昆虫和哺乳细胞。根据在重组生产过程中所使用的宿主,本发明的多肽可以是糖基化的或非糖基化的。此外,本发明的多肽还可以包括初始修饰的甲硫氨酸残基,在某些情况下,这是宿主介导过程的结果。
因此,在一个实施方案中,本发明提供了一种在适合SLC34A2-ROS融合多肽表达和回收所述多肽的条件下培养重组宿主细胞(如下所述)制备重组SLC34A2-ROS融合多肽的方法。适于所述宿主细胞生长和重组多肽在这些细胞中表达的培养条件是本领域技术人员所熟知的。参见例如CURRENT PROTOCOLS IN MOLECULAR BIOLOGY,Ausubel FM et al.,eds.,Volume2,Chapter16,Wiley Interscience.
D、分离的多肽
本发明还部分提供分离的SLC34A2-ROS融合多肽及其片段。在一个实施方案中,本发明提供分离的多肽,其包括与选自以下一组的序列至少为95%相同的氨基酸序列:
(a)编码SLC34A2-ROS融合多肽的氨基酸序列,所述融合多肽包括SEQ ID NO:1或者SEQ ID NO:3的氨基酸序列;
(b)编码SLC34A2-ROS融合多肽的氨基酸序列,所述融合多肽包括SLC34A2的N端氨基酸序列(SEQ ID NO:5的1-126残基)和ROS的激酶结构域(SEQ ID NO:7的1945-2222残基);和
(c)编码包含SLC34A2-ROS融合多肽的融合接头(SEQ ID NO:1的126-127残基或者SEQ ID NO:3的126-127残基)的至少六个连续氨基酸的多肽的氨基酸序列;
在一个优选的实施方案中,本发明提供了一种分离的SLC34A2-ROS融合多肽,该融合多肽具有有上述保藏的cDNA(ATCC保藏号PTA-7877)编码的氨基酸序列。在另一个优选的实施方案中,提供了本发明的重组突变多肽,该多肽可以使用上述重组载体或重组宿主细胞制备。
本领域技术人员将会认识到SLC34A2-ROS融合多肽的一些氨基酸序列可以变化而不明显影响所述突变蛋白的结构或功能。如果考虑序列中的这些变化,应当注意的是存在一些决定蛋白活性的关键区域(例如ROS的激酶结构域)。通常可以置换形成三级结构的残基,只要所使用的残基表现相似功能。在另一些情况下,如果所述变化位于所述蛋白的非关键区域,所述残基的类型可以完全不重要。
因此,本发明还包括SLC34A2-ROS融合多肽的变体,这些变体基本表现出ROS激酶活性或者包括SLC34A2和ROS蛋白的区域,如下文所述的蛋白质部分。这种突变包括缺失、插入、颠倒、重复和类型取代(例如一种亲水残基取代为另一种,但是作为规则,不能把强的亲水性残基取代为强的疏水性残基)。少量改变或这种“中性”氨基酸取代通常对活性影响很小。
典型地,以下置换通常是被看作保守取代,如脂肪族氨基酸Ala、Val、Leu和Ile中的一种取代另一种;羟基残基Ser和Thr的相互取代、酸性残基Asp和Glu的相互取代、酰胺残基Asn和Gin之间的取代、碱性残基Lys和Arg的相互取代以及芳香残基Phe和Tyr之间的置换。本领域技术人员熟知保守氨基酸取代的实例为:芳香氨基酸:苯丙氨基酸、色氨酸、酪氨酸;疏水氨基酸:亮氨酸、异亮氨酸、缬氨酸;极性氨基酸:谷氨酰胺、天冬酰胺;碱性氨基酸:精氨酸、赖氨酸、组氨酸;酸性氨基酸:天冬氨酸、谷氨酸;小氨基酸:丙氨酸、丝氨酸、苏氨酸、甲硫氨酸和甘氨酸。如上文详细描述的那样,关于氨基酸改变为可能是表型沉默(即不可能对功能产生明显的恶化作用)其它的指导可见于Bowie等,Science247,同上。
本发明的多肽优选以分离的形式提供,并优选为基本上纯化的。本发明的重组产生的SLC34A2-ROS融合多肽可以通过Smith和Johnson在Gene67:31-40(1988)中所述的一步法基本上纯化。
本发明的多肽包括图2A-B(可包括或不包括前导序列)的SLC34A2-ROS融合多肽(SEQ ID NO:1和3)、由保藏的cDNA克隆(ATCCNo.PTA-7877)编码的融合多肽、编码包含SLC34A2的N末端氨基酸序列(SEQ ID NO:5的1-126残基)和ROS的激酶结构域(SEQ ID NO:7的1945-2222残基)的SLC34A2-ROS融合多肽的氨基酸序列、和编码包括至少六个连续氨基酸的多肽的氨基酸序列,所述至少六个连续氨基酸包含SLC34A2-ROS融合多肽(参见图7,下组)的融合接头(SEQ ID NO:1的126-127残基或者SEQ ID NO:3的126-127残基),以及具有与上述序列至少90%相似性、更优选至少95%相似性、更优选至少96%、97%、98%或99%相似性的多肽。
两种多肽的“%相似性”意指使用Bestfit程序(Wisconsin SequenceAnalysis Package,Version8for Unix,Genetics Computer Group,UniversityResearch Park,575Science Drive,Madison,Wis.53711)和为确定相似性设置的默认值比较两种多肽的氨基酸序列所产生的相似性分数。Bestfit使用Smith和Waterman(Advances in Applied Mathematics2:482-489(1981))的局部同源性算法以找到两个序列之间最佳相似性片段。
具有与本发明突变ROS多肽的参考氨基酸序列至少例如95%“相同”的氨基酸序列的多肽意指所述多肽的氨基酸序列与参考序列相同,除了所述多肽序列可以包括在SLC34A2-ROS融合多肽的参考氨基酸序列的每100个氨基酸中至多5个氨基酸变化。也就是说,为了获得具有与参考氨基酸序列至少95%相同的氨基酸序列的多肽,在参考序列中至多5%的氨基酸残基可以被缺失或用另一种氨基酸取代,或者至多5%的参考序列总氨基酸残基数的氨基酸可以插入到参考序列中。参考序列的这些变化可以在参考氨基酸序列的氨基或羧基末端位置,或者单个散布在参考序列的残基中或者散布在参考序列的一或多个连续基团中。
当使用Bestfit或者任何其它序列比对程序确定特定序列是否与本发明的参考序列是例如95%相同时,当然允许将参数设置为相同性百分比通过全长参考氨基酸序列和高达参考序列中氨基酸残基总数的5%的同源性缺口进行计算。
本发明的SLC34A2-ROS融合多肽可以用作在SDS-PAGE凝胶或者在分子筛凝胶过滤柱中的分子量标记,例如使用本领域技术人员熟知的方法。
如下文将详细描述的那样,本发明的多肽还可以用作产生融合多肽特异性试剂,例如多克隆抗体和单克隆抗体,这种试剂可用于如下文所述的检测突变ROS多肽表达的分析或者作为能够增强或抑制突变ROS蛋白功能/活性的激动剂和拮抗剂。而且,所述的多肽可以用于酵母双杂交系统以“捕获”SLC34A2-ROS融合多肽结合蛋白,该蛋白也是本发明的候选激动剂和拮抗剂。酵母双杂交系统由Fields和Song在Nature340:245-246(1989)中描述。
在另一方面,本发明提供了一种肽或者多肽,其包括本发明多肽的含有表位的部分,即包括SLC34A2-ROS融合多肽变体的融合接头的表位(见图7,下组)。多肽部分的表位是本发明多肽的免疫原性或抗原性表位。“免疫原性表位”定义为蛋白质的一部分,当所述整个蛋白质是免疫原时该部分能引起抗体反应。据认为这些免疫原性表位局限于分子中的几个位点。在另一方面,蛋白质分子中能结合抗体的区域被定义为“抗原性表位”。通常蛋白质中的免疫原性表位数少于抗原性表位数。见例如Geysen等,Proc.Natl.Acad.Sci.USA81:3998-4002(1983)。本发明融合多肽特异性抗体的制备详细描述在下文中。
由含有抗原性表位的肽或者多肽产生的抗体可用于检测模逆蛋白,针对不同肽的抗体可用于跟踪经历翻译后加工的蛋白前体的不同区域的命运。肽和抗肽抗体可以用于模拟蛋白的多种定性或定量分析中,例如竞争性分析,由于在免疫沉淀分析中甚至短肽(例如约9个氨基酸)可以结合并代替更长的肽。参见例如Wilson等,Cell37.767-778(1984),777页。本发明的抗肽抗体还可用于纯化模拟蛋白,例如使用本领域熟知的方法通过吸附层析进行。免疫分析的模式将在下文中进一步详细地描述。
重组突变ROS激酶多肽也属于本发明的范围,可以使用本发明的融合多核苷酸按照上述B部分所述制备。例如,本发明提供了一种通过在适合融合多肽表达和回收所述多肽的条件下培养重组宿主细胞(如上所述)制备重组SLC34A2-ROS融合多肽的方法。适合宿主细胞生长和重组多肽从所述细胞表达的培养条件是本领域技术人员熟知的。
E、突变-特异性试剂
用于所公开方法中的突变ROS多肽-特异性试剂包括融合多肽特异性抗体和对应于或适于在生物样品中检测和定量SLC34A2-ROS融合多肽表达的AQUA肽(重同位素标记的肽)等。融合多肽特异性试剂可以是能特异性结合、检测和/或定量生物样品中表达的SLC34A2-ROS融合多肽的存在/水平的任何生物学或化学试剂。所述术语包括但不限于下文所述的优选抗体和AQUA肽试剂,等价试剂也属于本发明的范围。
抗体
适用于本发明方法的试剂包括SLC34A2-ROS融合多肽特异性抗体。本发明的融合-特异性抗体是特异性结合本发明的SLC34A2-ROS融合多肽(例如SEQ ID NO:1或3)但基本上不结合野生型SLC34A2或野生型ROS的分离的抗体。其它合适的试剂包括表位-特异性抗体,其特异性结合野生型ROS蛋白序列的细胞外结构域(该结构域不存在于本文公开的截短的ROS激酶中)的表位,因此能够检测在样品中野生型ROS的存在(或不存在)。
人SLC34A2-ROS融合多肽-特异性抗体还可以结合其它哺乳动物例如鼠或兔的高度同源和等价的表位肽序列,反之亦然。可用于本发明方法的抗体包括(a)单克隆抗体;(b)特异性结合靶多肽(例如SLC34A2-ROS融合多肽的融合接头(见图7,下组)的纯化的多克隆抗体;(c)如上述(a)-(b)中的能结合其它非人类动物(如小鼠和大鼠)的等价和高度同源的表位或者磷酸化位点的抗体;和(d)上述(a)-(c)的能结合被本文公开的示例性抗体结合的抗原(或者更优选保温)的片段。
本文所使用的术语“抗体”是指免疫球蛋白的所有类型,包括IgG、IgM、IgA、IgD和IgE。所述抗体可以是单克隆抗体或者多克隆抗体,并且可以是任何来源的,包括(例如)小鼠、大鼠、兔、马或人,或者可以是嵌合抗体。参见例如M.Walker et al.,Molec.ImmunoL26:403-11(1989);Morrision etal.,Proc.Nat′l.Acad.Sci.81:6851(1984);Neuberger etal.,Nature312:604(1984))。所述抗体可以是按照美国专利号4,474,893(Reading)或4,816,567(Cabilly等)所公开的方法制备的重组单克隆抗体。所述抗体还可以是按照美国专利号4,676,980(Segel等)公开的方法化学构建的特异性抗体。
本发明的SLC34A2-ROS融合多肽特异性抗体的优选表位位点为基本上由人SLC34A2-ROS融合多肽序列(SEQ ID NO:1或3)的约11-17个氨基酸组成的肽片段,该片段包括所述融合接头(位于第一和第二融合蛋白变体的第126个残基(参见图1(C组)和图7(下组))。应当理解的是能特异性结合含有SLC34A2-ROS融合多肽的融合接头的更短或更长的肽/表位的抗体属于本发明的范围。
本发明不限于抗体的使用,还包括等价分子,如蛋白结合结构域或核酸适体,其以融合蛋白或者截短的蛋白特异性方式结合与用于本发明结合方法的SLC34A2-ROS融合多肽特异性抗体或者ROS截短点表位特异性抗体结合的表位本质上相同的表位。参见如Neuberger等,Nature312:604(1984)。这种等价非抗体试剂可以适合用于本发明下述的方法中。
用于本发明方法中的多克隆抗体可以按照标准技术制备,通过用含有所需融合蛋白特异性表位(例如融合接头(见图7,下组)的抗原免疫适当的动物(例如兔、山羊等),从该动物收集免疫血清,及从该免疫血清中分离多克隆抗体并纯化具有所需要特异性的多克隆抗体进行。所述抗原可以是按照熟知技术选择和构建的包括所需表位序列的合成肽抗原。参见例如ANTIBODIES:A LABORATORY MANUAL,Chapter5,p.75-76,Harlow&Lane Eds.,Cold Spring Harbor Laboratory(1988);Czernik,MethodsInEnzymology,201:264-283(1991);Merrifield,J.Am.Chem.Soc.85:21-49(1962))。如本文所述制备的多克隆抗体可以按照下文所述进行筛选和分离。
单克隆抗体还可以有利地用于本发明的方法中,并且可以按照熟知的Kohler和Milstein的方法在杂交瘤细胞系中制备。Nature265:495-97(1975);Kohler and Milstein,Eur.J.Immunol.6:511(1976);还可以参考CURRENTPROTOCOLS IN MOLECULAR BIOLOGY,Ausubel et al.Eds.(1989)。这样制备的单克隆抗体是高度特异性的,能提高本发明提供的分析方法的选择性和特异性。例如,将含有适当抗原(例如含有SLC34A2-ROS融合多肽的融合接头的合成肽)的溶液注射小鼠,在足够的时间(按照常规的方法保持)后处死小鼠并获取脾细胞。通常在聚乙二醇存在下,脾细胞通过与骨髓瘤细胞融合而永生以产生杂交瘤细胞。兔的融合杂交瘤可以如C.Knight的1997年10月7日授权的美国专利号5,675,063所述制备。然后使杂交瘤生长在适当的选择培养基中,如次黄嘌呤-氨基蝶呤-胸苷(HAT),按照下文所述上清筛选具有所需特异性的单克隆抗体。可以按照常规方法如沉淀、离子交换或亲合层析等将分泌的抗体从组织培养上清中回收。
还可以采用本领域熟知的重组技术在大肠杆菌中制备单克隆Fab片段。参见例如W.Huse,Science246:1275-81(1989);Mullinax et al.,Proc.Nat′lAcad.Sci.87:8095(1990)。如果优选一种同种型的单克隆抗体用于特定应用,可以通过从最初的融合中选择而直接制备特定的同种型,或者从分泌不同同种型的单克隆抗体的亲代杂交瘤中通过使用同胞选择技术分离类别-转换变体间接制备特定的同种型(Steplewski,etal.,Proc.Nat′l.Acad.Sci.,82:8653(1985);Spiraetal.,J.Immunol.Methods,74:307(1984))。单克隆抗体的抗原结合位点可以通过PCR克隆,单链抗体可以制备为噬菌体展示重组抗体或者大肠杆菌中的可溶抗体(参见例如ANTIBODY ENGINEERINGPROTOCOLS,1995,Humana Press,Sudhir Paul editor.)。
而且美国专利No.5,194,392,Geysen(1990)还描述了检测或确定单体(氨基酸或其它化合物)序列的通用方法,所述单体是互补于感兴趣抗体的特定互补位(抗原结合位点)的表位的拓扑学等价物(即“模拟表位”)。更通常地,所述方法涉及检测或确定单体的序列,其是互补于感兴趣特定受体的配体结合位点的拓扑等价物。类似地,美国专利No.5,480,971,Houghten等(1996)公开了线性C1-C-烷基过度烷基化(peralkylated)寡肽以及这种肽的组和文库,以及使用这种寡肽组和文库检测优先结合感兴趣受体分子的过度烷基化的寡肽的序列。因此,本发明含有表位的肽的非肽类似物可以按照这些方法常规制备。
用于本发明方法的抗体,无论是多克隆抗体还是单克隆抗体都可以按照标准技术用于筛选表位和融合蛋白特异性。参见例如Czemik et al.,Methods in Enzymology,201:264-283(1991)。例如,可以通过ELISA针对肽文库筛选所述抗体以确保对于两种所需抗原的特异性,如果需要,可以筛选只与本发明SLC34A2-ROS融合多肽反应而不与野生型SLC34A2或者野生型ROS反应的反应性。还可使用Western印迹针对含有靶蛋白的细胞制品测试所述抗体以确定只与所需靶具有反应性并确保与其它涉及ROS的融合蛋白没有明显结合。融合蛋白特异性抗体的制备、筛选和使用是本领域技术人员所熟知的,并已被描述。参见例如美国专利公开号20050214301,Wetzel等,2005年9月29日。
用于本发明方法的融合多肽特异性抗体表现出与其它融合蛋白中的类似融合表位或者与形成所述融合接头的野生型SLC34A2和野生型ROS中的表位有限的交叉反应性。这是意料之中的,因为大多数抗体都表现出一定程度的交叉反应性,因此抗肽抗体经常与免疫肽具有高同源性或相同性的表位交叉反应。参见例如Czemik,同上。与其它融合蛋白的交叉反应性易于用采用已知分子量标记的Western印迹表征。可以检测交叉反应蛋白的氨基酸顺序以确定与抗体结合的SLC34A2-ROS融合多肽序列高度同源或者相同的位点。可以在肽柱上通过使用抗体纯化的阴性选择除去非所需的交叉反应性(例如选择能结合野生型SLC34A2和/或野生型ROS的抗体)。
用于本文公开方法中的本发明的SLC34A2-ROS融合多肽-特异性抗体理想状态下对人融合多肽具有特异性,但不限于仅仅与人融合多肽本身结合。本发明包括也能与在其它哺乳动物(例如小鼠、大鼠和猴)中保守的和高度同源或相同的表位结合的抗体的制备和使用。在其它种属与本文公开的人SLC34A2-ROS融合多肽序列(SEQ ID NO:1和3)高度同源或相同的序列可以通过标准序列比对方法如使用BLAST容易地鉴定。
用在本发明方法中的抗体可以进一步通过并验证用于特定的分析形式中,例如FC、IHC和/或ICC。SLC34A2-ROS融合多肽-特异性抗体在这种方法中的应用进一步描述在下文的F部分。抗体还可以有利地缀合荧光染料(如Alexa488、PE)或标记如量子点(quantum dots)与其它信号传递物质(磷酸-AKT、磷酸-Erk1/2)和/或细胞标记(细胞角蛋白)抗体用于多参数分析,这些将进一步描述在下文的F部分。
在实施本发明的方法时,野生型SLC34A2和/或野生型ROS在给定生物样品中的表达和/或活性还可以使用针对于这些野生型蛋白的抗体(磷酸特异性或者全部)有利地检测。例如,CSF受体磷酸化位点特异性抗体是可以商购的(参见CELL SIGNALING TECHNOLOGY,INC.,Beverly MA,2005/06Catalogue,#′s3151、3155和3154;和Upstate Biotechnology,2006Catalogue,#06-457)。这些抗体还可以按照上文所述的标准方法制备。人SLC34A2和ROS的氨基酸序列被公开(参见图3和4,并参见SwissProt登录号),以及其它种属这些蛋白质的序列。
在生物样品(例如肿瘤样品)中野生型SLC34A2和野生型ROS表达和/或激活以及SLC34A2-ROS融合多肽表达的检测可以提供关于是否是融合蛋白单独驱动肿瘤或者野生型ROS也被激活并驱动肿瘤的信息。这些信息在临床上可用于评价是靶向融合蛋白或者靶向野生型蛋白,或者靶向二者是最可能有益于抑制肿瘤的发展并可选择适当的治疗方法及其组合。特异于不存在于本发明公开的截短ROS激酶中的野生型ROS激酶细胞外结构域的抗体尤其可用于确定突变ROS激酶的存在/不存在。
应当理解的是可以使用多于一种的抗体实施上述方法。例如,可以同时使用一或多种SLC34A2-ROS融合多肽特异性抗体与一或多种特异于另一种激酶、受体或激酶底物的抗体检测在生物样品包括来自癌症的细胞中这种其它信号分子的活性,所述另一种激酶、受体或激酶底物被怀疑或潜在在SLC34A2-ROS融合多肽表达的癌症中被激活。
本领域技术人员将能理解的是上述本发明的SLC34A2-ROS融合多肽及其含有表位的融合接头的片段可以与免疫球胆白(IgG)的恒定结构域的部分组合形成嵌合多肽。这些融合蛋白有助于纯化并显示增加的体内半衰期。这里显示了例如由人CD4-多肽的头两个结构域和哺乳动物免疫球胆白的重链或轻链的恒定区域的多个结构域组成的嵌合蛋白(EPA394,827;Traunecker et al.,Nature331:84-86(1988))。由于IgG部分而具有由二硫键连接的二聚体结构的融合蛋白比单独的单体SLC34A2-ROS融合多肽更有效地结合并中和其它分子(Fountoulakis et al.,J Biochem270:3958-3964(1995))。
重同位素标记的肽(AQUA肽)。
用于实施公开的方法中的SLC34A2-ROS融合动态特异性试剂还可以包括适合绝对定量在生物样品中表达的SLC34A2-ROS融合多肽的重同位素标记的肽。适于绝对定量复杂混合物中的蛋白质(AQUA)的AQUA肽的制备和使用已被描述。参见,WO/03016861,"Absolute Quantification ofProteins and Modified Forms Thereof by Multistage Mass Spectrometry,"Gygi等,还描述在Gerber等Proc.Natl.Acad.Sci.U.S.A.100:6940-5(2003)(它们的教导以其全文引入本文作为参考)中。
AQUA方法使用将已知量的至少一种重同位素标记的肽链(其具有可由LC-SRM层析检测的独特特征(signature))导入到消化的生物样品中以通过与肽标准物比较确定生物样品中的具有相同序列和蛋白质修饰的肽的绝对量。简单地说,AQUA方法包括两步:肽内标准选择和验证和方法开发;和使用肽内标准检测并定量样品中的靶蛋白。这种方法是非常有效的检测和定量复杂生物混合物如细胞裂解物中的给定肽/蛋白的方法,并且可用于例如定量在用药物处理后导致的蛋白质磷酸化的变化,或者用于定量在不同生物状态中蛋白质水平的不同。
通常,为了开发出适当内标,根据氨基酸序列和消化将用的特定蛋白酶选择靶蛋白序列中特定的肽(或修饰肽)。然后通过固相肽合成方法产生一个残基被含有稳定同位素(13C、15N)的相同残基置换的肽。结果是这种肽在化学上与通过蛋白质水解形成的天然对应物相似,但容易通过7-Da质量漂移经MS区别。然后用LC-MS/MS评价新合成的AQUA内标肽。该方法通过反向色谱、离子化效应和碰撞诱导解离的片段化提供肽保留的定性信息。选择天然和内标肽组的信息量多、丰富的片段离子,然后作为层析保留函数快速连续特异性监测以形成基于肽标准物的独特谱的选择反应监测(LC-SRM)方法。
AQUA策略的第二步是应用该方法测量复杂混合物中蛋白质或修饰蛋白质的量。通常使用SDS-PAGE凝胶电泳分级分离全细胞裂解物,并切除与蛋白质迁移一致的凝胶区域。之后是在AQUA肽存在下凝胶内蛋白水解和LC-SRM分析(参见Gerber等,同上)。将AQUA肽加入到通过蛋白水解酶消化全细胞裂解物获得的复杂肽混合物并进行上述的免疫亲和纯化。通过消化(例如胰蛋白酶消化)形成的天然肽的保留时间和片段化模式与先前测定的AQUA内标肽的相同;因此,采用SRM试验进行LC-MS/MS分析能高度特异性地和灵敏地测量内标和直接来自非常复杂的肽混合物的分析物。
由于加入了绝对量的AQUA肽(例如250fmol),曲线下的面积比可用于确定原始细胞裂解物中蛋白质或者磷酸化形式的蛋白质的精确表达水平。此外,凝胶内消化形成天然肽时存在内标,凝胶片断肽提取效率、处理样品过程中的绝对损失(包括真空离心)和在导入LC-MS系统过程中的变化对天然和AQUA肽丰度的确定比率没有影响。
AQUA肽标准是为了通过IAP-LC-MS/MS方法在靶肽中先前已确定的已知序列而开发的。如果该位点被修饰,将会形成一个在该位点内掺入修饰形式的特定残基的AQUA肽,并形成第二个掺入未修饰形式残基的AQUA肽。以这种方式,使用两种标准检测并定量生物样品中位点修饰和未修饰的形式。
肽内标还可以通过检测蛋白质的一级氨基酸序列并确定由蛋白酶水解产生的肽边界而形成。或者,用蛋白酶真正消化蛋白质,然后可以测序所产生的特定肽片段。合适的蛋白酶包括但不限于丝氨酸蛋白酶(例如胰蛋白酶、hepsin)、金属蛋白酶(例如PUMP1)、胰凝乳蛋白酶、组织蛋白酶、胃蛋白酶、嗜热菌蛋白酶和羧肽酶等。
按照一或多种标准选择靶蛋白中的肽序列以优化肽作为内标的用途。优选地,选择肽的大小以最小化所述肽序列在其它非靶肽中重复的机会。因此,肽优选为至少约6个氨基酸。还可以最优化所述肽的大小以最大化离子化频率。因此,肽大于约20个氨基酸不是优选的。优选范围为约7-15个氨基酸。所选择的肽序列在质谱分析中不可能是化学反应性的,因此避免使用含有半胱氨酸、色氨酸或甲硫氨酸的序列。
可以选择不包括靶区域的修饰区域的肽序列以便可以使用所述肽内标确定所有形式蛋白质的量。或者,含有修饰氨基酸的肽内标可以只检测和定量靶蛋白的修饰形式。可以一起使用修饰和未修饰区域的肽标准物确定特定样品中修饰的程度(即确定蛋白质总量中有多少被修饰形式表示)。例如,可以使用已知在特定位点磷酸化的蛋白的磷酸化和非磷酸化形式的肽标准物定量样品中磷酸化形式的量。
使用一或多种标记的氨基酸(即标记是肽的实际部分)标记肽,或者不太优选在根据标准方法合成后附上标记。优选地,标记为根据以下考虑选择的改变质量的标记:所述重量对于将通过MS分析产生的片段迁移到低背景光谱区是独特的;离子质量信号成分是优选在MS分析中表现出独特离子质量特征的标记部分的部分;标记的组成原子的质量总和优选与所有可能的氨基酸的片段具有唯一的区别。结果,标记的氨基酸和肽通过离子/质谱方式在获得的质谱中易于与未标记的区分。优选地,离子质谱特征成分赋予蛋白质片段的质量与20种天然氨基酸的任一种的残基质量不匹配。
所述标记在MS的片段化条件下是稳定的,不会产生不利的片段化。标记化学应当在一系列条件下尤其是变性条件下是有效的,被标记的标签优选在所选择的MS缓冲体系保持可溶。标记优选不抑制蛋白质中的离子化效应并且不是发生化学反应性的。标记可以含有两种或多种不同同位素物质的混合物以在每一个标记的片段位置产生独特的质谱模式。稳定的同位素如2H、13C、15N、17O、18O或34S是优选的标记。还可以制备掺入不同同位素标记的肽内标对。重同位素标记可以掺入的优选氨基酸残基包括亮氨酸、脯氨酸、缬氨酸和苯丙胺酸。
肽内标用它们的质荷比(m/z)表征,还优选用它们在色谱柱(例如HPLC柱)中的保留时间表征。与相同序列的未标记肽共洗脱的内标被选为最佳内标。然后通过适当的方法如使用例如氩气或氦气作为碰撞气体的碰撞诱导解离(CID)片段化所述肽而分析内标。然后采用例如多步质谱法(MSn)分析片段以获得片段离子谱以得到肽片段化特征。优选地,肽片段在m/z比上具有明显不同以使得对用于每一片段的峰很好地分离,并获得对靶肽独特的特征。如果在第一步没有获得适当的片段特征,则进行额外的MS步骤直到获得独特的特征。
在MS/MS和MS3谱中的片段离子典型地对于感兴趣肽是高度特异的,并且结合LC方法使得检测和定量复杂蛋白质混合物如含有成千上万种蛋白质的细胞裂解物中的靶肽/蛋白质是高度选择性的。可以分析任何潜在含有感兴趣靶蛋白质/肽的生物样品。优选使用粗的或者部分纯化的细胞提取物。通常,样品含有至少0.01mg的蛋白质,典型地浓度为0.1-10mg/mL,并且可调节为所需的缓冲液浓度和pH。
然后将已知量的相应于待检测/定量的靶蛋白的标记的肽内标优选为约10飞摩加入到生物样品如细胞裂解物中。然后用一或多种蛋白酶消化掺入样品适当的时间以进行消化。然后进行分离(例如通过HPLC、反相HPLC、毛细管电泳、离子交换层析等)以将标记的内标和它相应的靶肽从样品中与其它肽分离。微毛细管LC是优选方法。
然后通过监测MS中选择的反应检测每一个分离的肽。这包括使用通过肽内标定性获得的现有知识并随后使用MS继续在感兴趣的肽和内标的MS/MS或MSn谱中监控特定离子。在洗脱后,计算肽标准和靶肽峰值曲线下面积(AUG)。两个面积的比值提供了可以对于分析中采用的细胞数和蛋白质分子量标准化的绝对量,以提供准确的蛋白质拷贝数/细胞。AQUA方法更详细地描述在Gygi等,和Gerber等同上。
可以如上述所需制备AQUA内肽标准(重同位素标记肽)以检测本发明突变ROS多肽内的任何量任何独特位点(例如SLC34A2-ROS融合多肽中的融合接头)。例如,可以制备相应于SLC34A2-ROS融合多肽的融合接头序列(见图7(下组))的AQUA磷酸肽。可以针对SLC34A2-ROS融合接头制成肽标准,在AQUA方法中使用这种标准检测并定量生物样品中的融合接头(即SLC34A2-ROS融合多肽的存在)。
例如,本发明的示例性AQUA肽包括氨基酸序列LVGDDF(见图7,下组),其相应于直接在SLC34A2-ROS(见SEQ ID NO:11)第二个(短的)变体中融合接头每一侧侧翼的三个氨基酸。应当理解的是还可以构建含有融合接头序列(和其下游或上游的额外残基)的较长的AQUA肽。类似地,或者可以构建含有小于该序列的所有残基(但仍然含有融合接头点本身)的较小的AQUA肽。这种较长的或者较小的AQUA肽属于本发明的范围,并且优选的AQUA肽的选择和制备可以如上述进行(见Gygi等,Gerber等,同上.).
核酸探针。
本发明提供的融合特异性试剂还包括适合检测在上文B部分详细描述的SLC34A2-ROS多核苷酸的核酸探针和引物。在下文F部分描述了这些探针在分析如荧光原位杂交(FISH)或PCR扩增中的特异用途。
本发明还提供一种用于检测生物样品中SLC34A2-ROS融合多核苷酸和/或多肽的试剂盒,该试剂盒包括至少一种本发明的融合多核苷酸特异性试剂或者多肽特异性试剂,和一或多种第二种试剂。用于试剂盒中的适当的第二种试剂是本领域技术人员熟知的,包括例如缓冲液、可检测的第二抗体或探针、激酶、激活剂和激酶底物等。
F、诊断应用和分析模式。
本发明的方法可以用本领域技术人员熟知的各种不同分析形式进行。
免疫测定
用于本发明方法的免疫测定可以是均质免疫测定(homogenousimmunoaasay)或者异质免疫测定(heterogeneous immonuassay)。在均质免疫测定中,免疫反应通常涉及突变ROS多肽特异试剂(例如SLC34A2-ROS融合多肽特异抗体)、标记的分析物和感兴趣的生物样品。来自标计的信号根据抗体与标记的分析物之间的结合直接或间接地被修饰。免疫反应及其程度的检测都在均质溶液中进行。可以使用的免疫化学标记包括自由基、放射同位素、荧光染料、酶、噬菌体和辅酶等。还可以有利地使用半导体纳米晶体标记或者“量子点”,其制备和使用已被详细描述。一般见K.Barovsky,Nanotech.Law&Bus.1(2):Article14(2004)和本文引述的专利。
在异质分析方法中,所述试剂通常是生物样品、突变ROS激酶多肽特异性试剂(例如抗体)和适于制备可检测信号的手段。在下文进一步描述可以使用的生物样品。抗体通常固定到支持物上,如珠、平板和载玻片,并在液相中与怀疑含有抗原的样品接触。然后将支持物从液相中分离,检测支持相或液相使用产生可检测信号的手段产生的可检测信号。信号与生物样品中分析物的存在相关。产生可检测信号的手段包括使用放射性标记、荧光标记、酶标记、量子点等。例如,如果被检测的抗原含有第二个结合位点,那么结合该位点的抗体可以缀合可检测基团,并在分离步骤前将所述抗体加入到液相反应溶液中。在固相支持物上可检测基团的存在表示在检测的样品中存在抗原。适当的免疫测定的实例为放射免疫测定、免疫荧光方法、酶联免疫测定等。
可用于进行本文公开的方法的免疫测定形式及其变体为本领域熟知。通常参见E.Maggio,Enzyme-Immunoassay,(1980)(CRC Press,Inc.,BocaRaton,Fla.);还可以参见例如美国专利No.4,727,022(Skold等,"Methods forModulating Ligand-Receptor Interactions and their Application");美国专利No.4,659,678(Forrest et al.,"Immunoassay ofAntigens");美国专利No.4,376,110(Davidetal.,"Immunometric Assays Using Monoclonal Antibodies")。适合形成试剂-抗体复合物的条件为本领域技术人员熟知。参见id。SLC34A2-ROS融合多肽特异性单克隆抗体可用于“双位点(two-sites)”或“三明治”分析方法中,单一的杂交瘤细胞系作为标记的单克隆抗体和结合的单克隆抗体来源。这些分析方法描述在美国专利No.4,376,110中。可检测试剂的浓度应当足够,以便SLC34A2-ROS融合多肽的结合相对于背景可以被检测到。
用于本文公开的方法中的抗体可以是按照已知的技术如沉淀缀合到适合诊断分析的固体支持物上(例如珠、平板、载玻片或由材料如胶乳或聚苯乙烯形成的孔)。同样,抗体或者其它SLC34A2-ROS融合多肽结合试剂也可以按照已知技术缀合到可以检测基团如放射性标记(如35S、125I、131I)、酶标记(如辣根过氧化物酶、碱性磷酸酶)和荧光标记(例如荧光素)。
基于细胞的分析,如流式细胞术(FC)、免疫组织化学(INC)或者免疫荧光(IF)尤其适合实施本发明方法,因为这些测定形式适合临床,能在体内检测突变ROS多肽的表达,并能避免由于操纵从例如肿瘤样品获得的细胞获得提取物时导致人为的活性变化的风险。因此,在一些优选的实施方案中,本发明的方法通过用流式细胞术(FC)、免疫组织化学(IHC)或者免疫荧光(IF)测定形式进行。
可以在用靶向抑制ROS激酶活性的药物处理前、处理中和处理后用流式细胞术(FC)检测哺乳肿瘤中突变ROS多肽的表达。例如,可以通过流式细胞术分析来源于细针头抽吸的肿瘤细胞的SLC34A2-ROS融合多肽的表达和/或激活,以及如果需要检测鉴定癌细胞类型的标记等。可以按照标准方法进行流式细胞术。参见例如Chow等,Cytometry(Communications inClinical Cytometry)46:72-78(2001)。简单地说,例如可采用以下方案进行细胞计数分析:用2%多聚甲醛在37℃固定细胞10分钟,然后在90%甲醇在冰上透化30分钟。然后用SLC34A2-ROS融合多肽特异性第一抗体染色细胞,洗涤并用荧光标记的第二抗体标记。然后按照所使用仪器的特定方法用流式细胞仪(例如Beckman Coulter FC500)分析细胞。这种分析将鉴定肿瘤中表达的SLC34A2-ROS融合多肽的水平。在用ROS抑制治疗剂处理肿瘤后,类似的分析将揭示表达SLC34A2-ROS融合多肽的肿瘤对靶向ROS激酶抑制剂的反应。
在用靶向抑制ROS激酶活性的药物处理前、处理中和处理后可以使用免疫组织化学(IHC)染色检测哺乳动物癌症(例如NSCLC)中突变ROS激酶多肽的表达和/或激活状态。可以按照熟知技术进行IHC。参见例如ANTIBODIES:A LABORATORY MANUAL,Chapter10,Harlow&Lane Eds.,Cold Spring Harbor Laboratory(1988)。简单地说,例如石蜡包埋的组织(例如来自活组织检查的肿瘤组织)通过对组织切片用二甲苯然后用乙醇脱蜡用于免疫组织化学染色;先用水然后用PBS水化;通过在柠檬酸钠缓冲液中加热载玻片暴露抗原;在过氧化氢中保温切片;在封闭溶液中封闭;将载玻片在抗SLC34A2-ROS融合多肽的第一抗体和第二抗体中保温;最后按照生产商的使用说明书使用ABC抗生物素蛋白/生物素方法检测。
在用靶向抑制ROS激酶活性的药物处理前、处理中和处理后,还可以使用免疫荧光(IF)测定方法确定哺乳动物癌症中SLC34A2-ROS融合多肽的表达和/或激活状态。可以按照熟知技术进行IF。参见例如J.M.polka and S.Van Noorden(1997)INTRODUCTION TO IMMUNOCYTOCHEMISTRY,2nd10Ed.;ROYAL MICROSCOPY SOCIETY MICROSCOPY HANDBOOK37,BioScientific/Springer-Verlag。简单地说,例如患者样品可以先用多聚甲醛然后用甲醇固定后,在封闭溶液例如马血清中封闭,与抗SLC34A2-ROS融合多肽的第一抗体保温后用荧光素染料例如Alexa488标记的第二抗体保温,然后用落射荧光显微镜分析。
用于上述分析方法中的抗体可以有利地缀合到荧光染料(例如Alexa488、PE)或者其它标记如量子点以与其它信号传导(EGFR、磷酸-AKT、磷酸-Erk1/2)和/或细胞标记(细胞角蛋白)抗体用于多参数分析中。
用于测量突变ROS激酶多肽的各种其它方法包括酶联免疫测定(ELISA)、放射免疫测定(RIA)和荧光激活细胞分选术(FAGS)是本领域熟知的,并提供了用于诊断SLC34A2-ROS融合多肽表达的改变或异常水平的基础。SLC34A2-ROS融合多肽表达的正常或标准值通过在适合复合物形成的条件下组合来自正常哺乳动物对象优选人的体液或者细胞提取物与针对SLC34A2-ROS融合多肽的抗体确定。标准复合物形成的量可以通过各种方法定量,但优选使用光量法。将在来自活组织检查的对象、对照和疾病样品中表达的SLC34A2-ROS融合多肽的量与标准值比较。标准值与对象值的偏差建立了用于诊断疾病的参数。
肽和核苷酸分析
类似地,用于检测/定量生物样品包括来自肿瘤的细胞中表达的突变ROS多肽的AQUA肽可以按照上文中E部分详细描述的方法制备和用于标准AQUA分析方法中。因此,在本发明方法的一些优选的实施方案中,SLC34A2-ROS融合多肽特异性试剂包括重同位素标记的磷酸肽(AQUA肽),其相应于包含上文E部分描述的SLC34A2-ROS融合多肽的融合接头的肽序列。
用于本发明方法的突变ROS激酶多肽特异性试剂还可以是能直接杂交并检测生物样品中的融合或截短多肽表达转录物的mRNA、寡核苷酸或DNA探针。所述探针在上文B部分详细讨论。简单地说,例如福尔马林固定的、石蜡包埋的患者样品可以用荧光素标记的RNA探针探查,用甲酰胺、SSC和PBS洗涤后用荧光显微镜分析。
编码突变ROS激酶多肽的多核苷酸可以用于诊断的目的。可以使用的多核苷酸包括寡核苷酸序列、反义RNA和DNA分子和PNA。所述多核苷酸可以用于检测和定量其中SLC34A2-ROS融合多肽或者截短的ROS多肽的表达可能与疾病相关的活组织检查的组织中的基因表达。所述诊断分析方法可以用于区分SLC34A2-ROS融合多肽的存在、不存在和过表达,并检测在治疗干涉中对SLC34A2-ROS融合多肽水平的调节。
在一个优选的实施方案中,可以使用能够检测多核苷酸序列包括编码SLC34A2-ROS融合多肽或截短的ROS激酶多肽或者密切相关分子的基因组序列的PCR探针杂交以鉴定编码突变ROS多肽的核酸序列。所述探针的构建与使用描述在上述B部分。无论探针是来源于高度特异的区域,例如融合接头的10个独特核苷酸,还是来源于特异性较低的区域,例如3′编码区,探针的特异性以及杂交或扩增(最强、高、中等或低)严格性将决定探针是否仅鉴定编码突变ROS激酶多肽的天然序列、等位基因或相关序列。
探针还可以用于检测相关序列,并优选含有至少50%的任一个突变ROS多肽编码序列的核苷酸。本发明的杂交探针可以是DNA或RNA和来自SEQ ID NO:2或4的核苷酸序列,最优选包括融合接头(见图7,下组),或来自包括在上文B部分描述的启动子、增强子元件和天然SLC34A2和ROS多肽的内含子的基因组序列。
本发明的SLC34A2-ROS融合多核苷酸或者截短的ROS多核苷酸可以用于以下方法中以检测改变的突变ROS激酶多肽表达,所述方法包括Southern或者Northern分析、斑点印迹或者其它基于膜的技术;PCR技术;或者dip stick、针、ELISA或者使用来自患者活组织检查的体液或者组织的芯片分析。这些定性或者定量方法是本领域所熟知的。在特定方面,编码突变ROS多肽的核苷酸序列可以用于检测各种癌症包括肺癌包括NSCLC的激活或者诱导的方法。突变ROS多核苷酸可以通过标准方法标记,并在适合形成杂交复合物的条件下加入到来自患者的体液或组织样品中。在保温适当时间后,洗涤样品并定量信号,与标准值比较。如果活组织检查的样品或者提取的样品中信号量与可比较的对照样品相比明显改变,核苷酸序列与样品中的核苷酸序列杂交,并且样品中编码SLC34A2-ROS融合多肽或者截短的ROS激酶多肽的核苷酸序列水平发生改变表示存在相关疾病。这些分析方法还可用于评价在动物研究、临床试验或者单个患者的监测治疗中特定治疗方案的效力。
为了提供用于诊断以表达突变ROS多肽为特征的疾病的基础,建立了正常或者标准表达谱。这可以通过在适合杂交或扩增的条件下组合来自正常对象动物或人的体液或者细胞提取物与编码SLC34A2-ROS融合多肽或者截短的ROS激酶多肽的序列或其片段实现。可以通过比较来自正常对象的值与来自使用已知量的基本上纯化多核苷酸的试验中的值而定量标准杂交。从正常样品获得的标准值可以与来自有患有疾病症状的患者的样品获得的值比较。标准值和对象的值之间的偏差用于确定存在疾病。
一旦疾病被证实,则启动治疗方案,定期重复杂交分析以评价患者表达水平是否开始接近在正常患者中观察的水平。来自连续分析的结果可以用于表示经历几天到几个月的一段时间内的治疗效果。
本发明突变ROS多核苷酸的额外诊断用途可以包括使用聚合酶链反应(PCR),这对于本领域技术人员是另一种优选的标准分析形式。参见例如MOLECULAR CLONING,A LABORATORY MANUAL,2nd.edition,Sambrook,J.,Fritsch,E.F.and Maniatis,T.,eds.,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.(1989)。PCR寡聚物可以是化学合成的、酶产生的或者通过重组产生的。寡聚物优选由两种核苷酸序列组成,一种具有有义方向(5′到3′)而另一种具有反义方向(3′到5′),在最佳条件下使用以鉴定特定基因或条件。在严格程度较低的条件下可以使用相同的两种寡聚物、嵌套寡聚物组或寡聚物的简并库检测和/或定量密切相关的DNA或RNA序列。
可以使用定量SLC34A2-ROS融合多肽或者截短的ROS激酶多肽表达的方法包括放射性标记或者生物素标记核苷酸、共扩增对照核酸和外推试验结果的标准曲线(Melby etal.,J.lmmunol.Methods,159:235-244(1993);Duplaaetal.Anal.Biochem.229-236(1993))。多个样品的定量速度可以通过采用ELISA形式分析加速,在ELISA分析中感兴趣的寡聚物存在于不同稀释物中,分光光度分析和比色反应给出快速定量。
在本发明的另一个实施方案中,可以使用本发明突变ROS多核苷酸产生杂交探针,用于对天然基因组序列作图。可以使用已知技术将所述序列作图至特定染色体或者染色体的特异区域。所述技术包括荧光原位杂交(FISH)、FACS或者人工染色体构建如酵母人工染色体、细菌人工染色体、细菌P1构建或者单染色体cDNA文库,这些被综合概括在Price,C.M.,Blood Rev.7:127-134(1993)和Trask,B.J.,Trends Genet.7:149-154(1991)中。
在一个优选的实施方案中,使用FISH(如在Verma etal.HUMANCHROMOSOMES:A MANUAL OF BASIC TECHNIQUES,Pergamon Press,New York,N.Y.(1988)中所述)并且可以与其它物理染色体作图技术和基因图数据关联。基因图数据的例子可见于1994Genome Issue of Science(265:1981f)。编码SLC34A2-ROS融合多肽或者截短的ROS多肽的基因在物理染色体图上的位置与特定疾病、或者对特定疾病的易患性的关联有助于划定与遗传病相关的DNA区域。可以使用本发明的核苷酸序列检测正常、携带者、或者感染个体的基因序列间的不同。
染色体制备物的原位杂交和物理作图技术如使用建立的染色体标记的连锁分析可用于延伸基因图。通常,即使人特定染色体的数量和臂并不了解,另一种哺乳动物如小鼠的染色体上的一个基因的取代可以揭示相关标记。可以通过物理作图将新序列分配到染色体臂或者其部分中。这给通过位置克隆或者其它基因发现技术寻找疾病基因的研究者提供了有价值的信息。一旦通过遗传连锁初步将疾病和综合症定位到特定基因组区域例如AT到11q22-23(Gatti等,Nature336:577-580(1988)),任何作图到该区域的序列可能代表可进行进一步研究的相关或者调节基因。还可以使用本发明的核苷酸序列检测在正常、携带者或感染个体中由于易位、颠倒等导致的染色体位置中的差异。
生物样品
用于本发明方法中的生物样品可以从任何其中癌症以存在或可能存在或正在产生SLC34A2-ROS融合蛋白为特征的哺乳动物中获得。在一个实施方案中,所述哺乳动物是人,人可以是为治疗肺癌如NSCLC采用ROS抑制治疗剂的候选者。所述人候选者可以是目前用ROS激酶抑制剂治疗或者考虑用ROS激酶抑制剂治疗的患者。在另一个实施方案中,所述哺乳动物是大型动物,如马或牛,而在其它实施方案中,所述哺乳动物是小型动物,如狗或者猫,所有这些动物都是已知能发展癌症包括肺癌的。
任何包含来自哺乳动物癌症的细胞(或细胞提取物)的生物样品都适合用于本发明的方法中。在一个实施方案中,生物样品包括来自肿瘤活组织检查的细胞。活组织检查物可以按照标准临床技术从哺乳乳动物器官的原发性肿瘤或者从以转移到其它组织的继发性肿瘤获得。在另一个实施方案中,生物样品包括从来源于肿瘤细针头吸取物获得的细胞,获得这些吸取物的技术是本领域熟知的(参见Cristallini等,Acta Cytol.36(3):416-22(1992))。
生物样品还可以包括从渗出液如胸膜渗出液获得的细胞。胸膜渗出液(胸腔中肺外形成的液体,其含有肿瘤细胞)已知在许多晚期肺癌(包括NSCLC)患者中形成,并且存在这种渗出液预示结果不良结果并且存活时间短。获取胸膜渗出液样品的标准技术已经被描述并且是本领域熟知的(参见Sahn,Clin Chest Med.3(2):443-52(1982))。还可以使用所述肿瘤标记、细胞角蛋白标记或者其它负选择方法(参见Ma等,Anticancer Res.23(1A):49-62(2003))从血清获得循环肿瘤细胞。对于白血病患者来说尤其优选血清和骨髓样品。在成胶质细胞瘤中发现ROS的异常表达。参见Charest等,同上。
生物样品可以包括来自其中SLC34A2-ROS融合多肽或者截短的ROS激酶多肽表达和/或激活但野生型ROS激酶不表达和/或激活的癌症的细胞(或细胞提取物)。或者,样品可以包括来自突变ROS多肽和野生型ROS激酶都表达和/或激活、或者野生型ROS激酶和/或SLC34A2表达和/或激活但突变ROS多肽不表达和/或激活的癌症的细胞。
上述生物样品的细胞提取物可以按照标准技术制成粗制品或者部分(或者完全)纯化的制品,并用于本发明方法中。或者,包括整个细胞的生物样品可用于优选的分析形式如上述免疫组织化学(IHC)、流式细胞技术(FC)和免疫荧光(IF)。这些全细胞分析方法是有利的,因为这些方法使对肿瘤细胞的操作最少化因此减少了改变细胞体内信号传递/激活状态和/或导入人为信号的风险。全细胞分析方法是有利的,还因为这些方法只表征肿瘤细胞而不表征肿瘤细胞和正常细胞的混合物中的表达和信号传递。
在实施所公开的方法确定一种化合物是否抑制以SLC34A2-ROS易位和/或融合多肽为特征的肿瘤的进展中,还可以有利地使用含有来自哺乳动物异种移植物(或者骨髓移植物)的细胞的生物样品。优选的异种移植物(或移植受体)是携带表达突变ROS激酶多肽的人肿瘤(或白血病)小型动物如小鼠。携带人肿瘤的异种移植物是本领域熟知的(参见Kai,CancerTreat Res.72:155-69(1995)),并且携带人肿瘤的哺乳动物异种移植物的制备被很好地描述(参见Winograd等,In Vivo.1(1):1-13(1987))。类似地,骨髓移植模型的产生和使用被很好地描述(参见例如Schwaller等,EMBO J.17:5321-333(1998);Kelly等,Blood99:310-318(2002))。以SLC34A2-ROS易位和/或融合多肽“为特征的癌症”意指与不存在易位和/或融合多肽的癌症相比,存在这种突变ROS基因和/或表达的多肽的癌症。
在含有来自哺乳癌症肿瘤的细胞的生物样品中评价突变ROS多核苷酸存在或多肽表达时,为对比目的而需要使用代表不存在这种易位和/或融合蛋白的细胞的对照样品。理想地,对照样品包含来自特定癌症的亚型(例如NSCLC)的细胞,该亚型表示所述变异(例如SLC34A2-ROS易位)不存在和/或所述融合多肽不表达的亚型。比较对照样品和测试生物样品中的水平,从而鉴定所述突变多核苷酸和/或多肽是否存在。或者,由于SLC34A2-ROS融合多核苷酸和/或多肽不可能存在大多数的癌症中,类似不表达突变ROS多肽(或携带突变多核苷酸)的任何组织都可以用作对照。
下文所述的方法对于以突变ROS多核苷酸和/或多肽为特征的癌症具有有价值的诊断用途,并且对于治疗决定也是有价值的。例如,生物样品可以从以前没有被诊断为患有以SLC34A2-ROS易位和/或融合多肽为特征的癌症、也没有接受对这种癌症的治疗的对象中获得,因此所述方法用于诊断地确定这种对象的肿瘤属于突变ROS多核苷酸和/或多肽存在/表达的肿瘤亚型(例如NSCLC肿瘤)。
或者,生物样品可以从被诊断为患有受一种类型激酶如EFGR驱动的癌症并且接受了治疗如EGFR抑制剂治疗(例如TarcevaTM、IressaTM)以治疗所述癌症的对象中获得,因此本发明的方法用于鉴定对象的肿瘤是否也以SLC34A2-ROS易位和/或融合多肽为特征,因此可能对现有的治疗完全反应和/或是否其他或额外的ROS激酶抑制治疗是需要的或者可批准的。本发明的方法还可以用于监测在用包含ROS激酶抑制治疗剂或治疗机组合的组合物治疗对象后表达突变ROS多肽的癌症的发展或抑制。
这种诊断分析方法可以在初步评价或外科检视程序之前或之后进行。本发明的鉴定方法可以有利地用作诊断方法以鉴定患有受SLC34A2-ROS融合蛋白驱动的癌症如NSCLC的患者,该患者很可能对靶向与抑制ROS激酶活性的治疗剂起反应。选择所述患者的能力对未来靶向ROS的治疗剂的效力的临床评价以及在未来对患者开出这种药物的处方也是有用的。
诊断剂
选择性鉴定存在SLC34A2-ROS易位和/或融合多肽的癌症的能力使得为诊断目的准确鉴定这种肿瘤的新方法成为可能,并且获得用于确定这种肿瘤是否可能对于ROS抑制治疗剂组合物起反应的信息,或者在给予单独药物治疗癌症时可能对靶向不同激酶的抑制剂部分地或者完全不起反应。
因此在一个实施方案中,本发明提供了一种检测在癌症中存在突变ROS多核苷酸和/或多肽的方法,该方法包括如下步骤:
(a)从患有癌症的患者中获得生物样品,并
(b)利用至少一种检测本发明突变ROS多核苷酸或者多肽的试剂确定SLC34A2-ROS融合多核苷酸和/或多肽是否存在生物样品中。
在一些优选的实施方案中,所述癌症是肺癌,如非小细胞肺癌(NSCLC)。在其它优选的实施方案中,突变ROS激酶多肽的存在确定了癌症可能对含有至少一种ROS激酶抑制治疗剂的组合物起反应。
在一些优选的实施方案中,本发明的诊断方法在流式细胞术(FC)、免疫组织化学(INC)或免疫荧光(IF)分析中实施。在另一个优选的实施方案中,检测SLC34A2-ROS融合多肽的活性。在其它优选的实施方案中,本发明的诊断方法在荧光原位杂交(FISH)或聚合酶链反应(PCR)分析中实施。
本发明进一步提供了一种确定一种化合物是否能抑制以SLC34A2-ROS融合多核苷酸或多肽为特征的癌症的进展的方法,该方法包括确定所述化合物在所述癌症中是否能抑制所述SLC34A2-ROS融合体的表达和/或活性的步骤。在一个优选的实施方案中,使用至少一种能检测本发明SLC34A2-ROS融合多核苷酸或多肽的试剂确定对SLC34A2-ROS融合多肽的表达和/或活性的抑制。适合抑制ROS激酶活性的化合物将在下文G部分详细讨论。
用于本发明方法中的突变ROS多核苷酸探针和多肽特异性试剂在上述B和D部分详细地讨论。在一个优选的实施方案中,SLC34A2-ROS融合多肽特异性试剂包括融合多肽特异性抗体。在另一个优选的实施方案中,所述融合多肽特异性试剂包括相应于SLC34A2-ROS融合多肽的融合接头(见图7(下组))的重同位素标记的磷酸肽(AQUA肽)。
上文描述的本发明方法还可以任选地包括测定所述生物样品中其它激酶如野生型ROS和EGFR或者其它下游信号分子的表达或激活水平的步骤。给定生物样品中SLC34A2-ROS融合多肽表达/激活和其它激酶和途径的表达/激活的谱可以提供哪些激酶和途径驱动疾病从而哪些治疗方案可能是最有益的有价值信息。
化合物筛选
发现本文所述的新的SLC34A2-ROS融合多肽还使得开发抑制这些突变ROS蛋白活性尤其是ROS激酶活性的新化合物成为可能。因此,本发明还部分地提供了确定一种化合物是否抑制以SLC34A2-ROS融合多核苷酸和/或多肽为特征的癌症的进展的方法,该方法包括确定所述化合物是否抑制所述SLC34A2-ROS融合蛋白在所述癌症中的表达和/或活性的步骤。在一个优选的实施方案中,使用至少一种能检测本发明突变ROS多核苷酸和/或突变ROS多肽的试剂确定SLC34A2-ROS融合多肽的表达和/或活性的抑制。在上文已描述本发明优选的试剂。适合用于抑制ROS激酶活性的化合物在下文G部分详细描述。
化合物可以例如是激酶抑制剂如小分子或抗体抑制剂。可以是对多种不同激酶具有活性的泛激酶(pan-kinase)抑制剂,或者是激酶特异性抑制剂。ROS激酶抑制剂化合物在下文G部分详细讨论。可以在用抑制剂治疗前或后获取患者生物样品,然后用上述方法分析抑制剂对ROS激酶活性的生物作用,包括下游底物蛋白的磷酸化。这种药物动力学分析可以用于确定药物的生物活性剂量,其优选是最大耐受剂量。这些信息对于通过阐述药物作用机制请求获得药物批准有用。鉴定具有所需抑制特性的化合物进一步描述在下文G部分。
G、癌症的治疗抑制
根据本发明,现已表明SLC34A2-ROS融合多肽至少存在人NSCLC的一种亚型中。因此,可以通过抑制在癌症中ROS激酶的活性体内抑制表达SLC34A2-ROS融合蛋白的哺乳动物癌症(例如NSCLC)的发展。以表达突变ROS激酶为特征的癌症中ROS活性可以通过将癌症(如肿瘤)与ROS激酶抑制治疗剂相接触而抑制。因此,本发明部分地提供了一种通过抑制癌症中ROS激酶的表达和/或活性而抑制表达SLC34A2-ROS融合多肽的癌症的发展的方法。
ROS激酶抑制治疗剂可以是含有至少一种能在体内直接或间接抑制ROS激酶的表达和/或活性的生物或化学化合物的任何组合物,所述化合物的示例性种类将在下文描述。这种化合物包括治疗剂,其直接作用于ROS激酶本身,或者作用于改变ROS活性的蛋白或分子,或者通过抑制ROS的表达间接地作用。这种组合物还包括只含有单一ROS激酶抑制化合物的组合物,以及含有多种治疗剂(包括针对其它RTK的那些)的组合物,其还可以包括非特异性治疗剂如化疗剂或普通所转录抑制剂。
小分子抑制剂
在一些优选的实施方案中,用于本发明方法中的ROS抑制治疗剂是靶向小分子抑制剂。小分子靶向抑制剂是一类典型抑制靶酶活性的小分子,其通过特异性并经常是可逆地结合酶的催化位点和/或结合ATP结合裂缝或者能阻止该酶形成对于发挥活性必需的构型的酶内部的其它结合位点抑制靶酶活性。示例性小分子靶向激酶抑制剂是Gleevec(Imatinib,STI-571),其抑制CSF1R和BCR-ABL,其特性已详细描述。参见Dewar等,Blood105(8):3127-32(2005)。
小分子抑制剂可以通过X射线晶体学或者计算机建模ROS激酶三维结构合理设计,或者可以通过高通量筛选抑制ROS的化合物文库发现。这些方法是本领域熟知的并已被描述。ROS抑制的特异性可以通过例如检测该化合物在一组激酶中抑制ROS活性而不抑制其它激酶活性的能力和/或通过检测包括NSCLC肿瘤细胞的生物样品中ROS活性的抑制而确定,如上所述。所述筛选的方法在下文进一步描述。
抗体抑制剂
用于本发明方法中的ROS激酶抑制治疗剂还可以是靶向抗体,其特异性结合ROS活性所需的重要催化位点或者结合位点或结构域,并且通过阻止配体、底物或者第二种分子接近α和/或阻止酶形成其活性必需的构型而抑制激酶。人源化靶特异性抗体的制备、筛选和治疗用途已被详细描述。参见Merluzzi等,Adv Clin Path.4(2):77-85(2000)。用于人源化靶特异性抑制抗体的高通量制备和筛选的技术和系统可以商购获得,例如Morphosys,Inc的Human Combinatorial Antibody Library()。
各种抗受体激酶的靶向抗体的制备和它们用于抑制靶向受体的活性已被描述。参见例如美国专列公开No.20040202655,“Antibodies to IGF-IReceptor for the Treatment ofCancers”,2004年10月14号,Morton等;美国专列公开No.20040086503,“Human anti-Epidermal Growth FactorReceptor Single-Chain Antibodies”,2004年4月15号,Raisch等,美国专列公开No.20040033543,“Treatment of Renal Carcinoma Using AntibodiesAgainst the EGFr”,2004年2月19号,Schwab等。制备和使用受体酪氨酸激酶活性抑制抗体的标准方法是本领域熟知的。参见例如欧洲专列No.EP1423428,“Antibodies that Block Receptor Tyrosine Kinase Activation,Methods of Screening for and Uses Thereof”2004年6月2号,Borges等。
还可以使用噬菌体展示方法制备ROS特异性抗体抑制剂,噬菌体文库构建和重组抗体选择的方案在熟知的参考文献CURRENT PROTOCOLS INIMMUNOLOGY,Colligan等(Eds.),John Wiley&Sons,Inc.(1992-2000)第17章第17.1部分中提供。还参见美国专列No.6,319,690,2001年11月20,Little等,美国专列No.6,300,064,2001年10月9,Knappik等;美国专列No.5,840,479,1998年11月24号,Little等;美国专列公开No.20030219839,2003年11月27,Bowdish等。
可以制备和筛选展示在噬菌体表面的抗体片段文库(参见例如美国专利6,300,064,2001年10月9号,Knappik等)结合受体蛋白酪氨酸激酶(例如ROS)的可溶二聚体形式。结合用于筛选的RTK的可溶二聚体形式的抗体片段鉴定为用于阻断细胞中的靶RTK组成型激活的候选分子。参见欧洲专列No.EP1423428,Borges等,同上。
然后可进一步筛选在上述抗体文库的筛选中鉴定的ROS结合靶向抗体在体外激酶分析和体内细胞系和/或肿瘤中阻断ROS活性的能力。ROS抑制可以通过例如检测所述抗体治疗剂在一组激酶中抑制ROS激酶活性而不抑制其它激酶的活性的能力和/或通过检测包含癌细胞的生物样品中ROS活性的抑制而确定,如上所述。筛选用于ROS激酶抑制的这种化合物的方法还描述在上文中。
间接抑制剂
用于公开的方法中的ROS抑制化合物还可以是通过抑制除ROS激酶本身以外的蛋白或分子的活性间接抑制ROS活性的化合物。这种抑制治疗剂可以是靶向抑制剂,其调节磷酸化或去磷酸化(从而激活或失活)ROS本身或者干扰与配体结合的关键调节激酶的活性。与其它受体酪氨酸激酶一样,ROS通过接头蛋白和下游激酶的网络调节下游信号。结果,可以通过靶向这些相互作用或下游蛋白抑制由于ROS活性诱导的细胞生长和存活。
还可以通过使用抑制对于ROS形成其活性构象所需的激活分子的结合的化合物间接地抑制ROS激酶活性。例如,已描述了制备和使用抗-PDGF抗体。参见美国专列公开No.20030219839,“Anti-PDGF Antibodies andMethods for Producing Engineered Antibodies”,Bowdish等。抑制配体(PDGF)与受体的结合直接下调受体活性。
ROS活性的间接抑制剂可以通过X射线晶体学或者计算机建模ROS三维结构合理设计,或者可以通过高通量筛选能抑制关键上游调节酶和/或必需结合分子从而抑制ROS激酶活性的化合物文库发现。这些方法是本领域熟知的并已被描述。这些治疗剂的ROS抑制作用可以通过例如检测该化合物在一组激酶中抑制ROS活性而不抑制其它激酶活性的能力和/或通过检测包含癌症细胞例如NSCLC细胞的生物样品中ROS活性的抑制而证实,如上所述。鉴定抑制以SLC34A2-ROS易位和/或融合多肽和/或截短的ROS多核苷酸和/或多肽为特征的癌症的化合物的方法在下文描述。
反义和/或转录抑制剂
ROS抑制治疗剂还可以包括反义和/或转录抑制化合物,其通过阻断编码ROS的基因和/或SLC34A2-ROS融合基因的转录抑制ROS激酶活性。各种受体激酶包括VEGFR、EGFR和IGFR和FGFR通过用于治疗癌症的反义治疗剂的抑制已被描述。参见例如美国专利No.6,734,017、6,710,174、6,617,162、6,340,67、5,783,683、5,610,288。
可以按照熟知技术设计、构建和使用反义寡核苷酸作为针对靶基因的治疗药物。参见例如Cohen,J.,Trends in Pharmacol.Sci.10(11):435-437(1989);Marcus-Sekura,Anal.Biochem.172:289-295(1988);Weintraub,H.,Sci.AM.pp.40-46(1990);Van Der Krol等,BioTechniques6(10):958-976(1988);Skorskietal.,Proc.Natl.Acad.Sci.USA(1994)91:4504-4508。最近描述了使用EGFR的反义RNA抑制剂在体内抑制人肿瘤生长。参见美国专列公开No.20040047847,“Inhibition of Human Squamous Cell Carcinoma Growth Invivo by Epidermal Growth Factor Receptor Antisense RNA Transcribed from aPol III Promoter”,2004年3月11日,He等。类似地可以根据上述方法制备针对哺乳动物ROS基因(参见图4(SEQ ID NO:8)或者SLC34A2-ROS融合多核苷酸或截短的ROS多核苷酸(参见图2(SEQ ID NO:2或4)或者截短的的包含至少一种反义寡核苷酸的ROS抑制治疗剂。包含ROS抑制反义化合物的药物组合物可以如下文进一步描述制备和给药。
小干扰RNA
小干扰RNA分子(siRNA)组合物通过RNA干扰过程抑制ROS的翻译并因而抑制其活性,其也可以用于本发明方法中。已经详细描述了RNA干扰和通过导入包含与编码靶蛋白的mRNA互补的序列的外源小双链RNA分子选择地沉默靶蛋白表达。参见例如美国专利公开No.20040038921,“Composition and Method for Inhibiting Expression of a Target Gene”,2004年2月26号,Kreutzer等,美国专利公开No.20020086356,“RNASequence-Specific Mediators of RNA Interference”,2003年6月12号,Tuschl等;美国专列公开20040229266,“RNA Interference Mediating Small RNAMolecules”,2004年11月18号,Tuschl等。
例如,如实施例3所述,siRNA介导的SLC34A2-ROS融合蛋白表达的沉默在表达该融合蛋白的人NSCLC细胞系中可能有效。
已表明双链RNA分子(dsRNA)以高度保守的调节机制即熟知的RNA干扰(RNAi)阻断基因表达。简单地说,RNAse III切酶(Dicer)将dsRNA加工成约22个核苷酸的小干扰RNA(siRNA),其作为引导序列通过RNA诱导性沉默复合物RISC诱导靶特异性mRNA切割(参见Hammond等,Nature(2000)404:293-296)。RNAi涉及催化型反应,从而通过连续地切割较长dsRNA产生新的siRNA。因此,与反义分子不同,RNAi以非化学剂量方式降解靶RNA。当给予细胞或生物体时,外源dsRNA通过RNAi指导内源性信使RNA(mRNA)的序列特异性降解。
目前已可以商购获得大量的靶特异性siRNA产品,包括用于在哺乳细胞中表达和使用的载体和系统。参见例如Promega,Inc.(www.promega.com);Dharmacon,Inc.(www.dharmacon.com)。用于RNAi的dsRNA的设计、构建和使用的详细技术指南可以得到。参见例如Dharmacon的“RNAi Technical Reference&Application Guide”;Promega的“RNAi:A Guide to Gene Silencing”。ROS抑制siRNA产品也可以商购获得,并可用于本发明方法中。参见例如Dharmacon,Inc.,Lafayette,CO(Cat Nos.M-003162-03,MU-003162-03,D-003162-07thru-10(siGENOMETMSMARTselection和SMARTpoolsiRNAs)。
最近已建立了长度小于49个核苷酸、优选为19-25核苷酸的小dsRNA,其包含至少一种基本上与靶mRNA序列的一部分相同的序列,并且该dsRNA最佳在末端具有至少一个1-4个核苷酸的突出,这种dsRNA在介导哺乳动物中RNAi时最有效。参见美国专利公开No.20040038921,Kreutzer等,同上;美国专利公开No.20040229266,Tuschl等,同上。这种dsRNA的构建及其在体内沉默靶蛋白表达的药物制剂中的应用详细描述在这些出版物中。
如果在哺乳动物中被靶向的基因的序列是已知的,例如可以制备21-23nt的RNA并测试其在哺乳细胞如人或其它灵长类细胞中介导RNAi的能力。如果需要,可以在适当动物模型中测试那些示出介导RNAi的21-23nt的RNA分子以进一步评价其体内效力。已知的靶位点可用于设计靶向这些位点的siRNA分子,所述已知的靶位点为例如根据对其它核酸分子如核酶或反义分子的研究被确定为有效靶位点的靶位点,或者那些已知与疾病或病症相关的靶位点如含有突变或缺失的那些位点。
或者,可以通过例如计算机折叠算法合理设计/预测对于筛选感兴趣靶mRNA的靶位点有效的dsRNA的序列。使用定制的Perl脚本或者可商购的序列分析程序如Oligo、MacVector或GCG Wisconsin Package,靶序列可以通过计算机(in silico)分列为所有特定长度片段或亚序列(subsequence)如23个核苷酸片段的列表。
可以用各种参数确定哪些位点是靶RNA序列中最合适的靶位点。这些参数包括但不限于二级或三级RNA结构、靶序列的核苷酸碱基组成、靶序列的不同区域之间的同源性程度、或者在RNA转录物中靶序列的相对位置。根据这些确定,可以通过使用例如体外RNA切割分析、细胞培养或动物模型选择RNA转录物中任何数量的靶位点以筛选siRNA分子的效力。参见例如美国专列公开No.20030170891,2003年9月11号,McSwiggen J。最近还描述了确定和筛选RNAi靶位点的算法。参见美国专列公开No.20040236517,“Selection of Target Sites for Antisense Attack of RNA”,2004年11月25号,Drlica等。
通常可用的基因转移技术包括磷酸钙、DEAE-葡聚糖、电穿孔、微注射和病毒方法(Graham等(1973)Virol.52:456;McCutchan等,(1968),J.Natl.Cancer Inst.41:351;Chu at al.(1987),Nucl.Acids Res.15:1311;Fraley等(1980),J.Biol.Chem.255:10431;Capecchi(1980),Cell22:479)。还可以使用阳离子脂质体将DNA导入细胞(Feigner等(1987),Proc.Natl.Acad.Sci USA84:7413)。商业上可用的阳离子脂质制剂包括Tfx50(Promega)或Lipofectamin200(Life Technologies)。或者,可以使用病毒载体将dsRNA运送到细胞并介导RNAi。参见美国专列公开No.20040023390,“siRNA-mediated Gene Silencing with Viral Vectors”,2004年2月4号,Davidson等。
用于哺乳动物细胞中RNAi的转染和载体/表达系统是可商购的并已经详细地描述。参见例如Dharmacon,Inc.,DharmaFECTTM system;Promega,Inc.,siSTRIKETM U6 Hairpin system;还可以参见Gou等(2003)10FEBS.548,113-118,Sui,G.等,A DNA vector-based RNAi technology to suppress geneexpression in mammalian cells(2002)Proc.Natl.Acad Sci.99,5515-5520;Yu等,(2002)Proc.Natl.Acad.Sci.99,6047-6052;Paul,C.等(2002)NatureBiotechnology19,505-508;McManus等(2002)RNA8,842-850。
使用制备的dsRNA分子在哺乳动物中进行siRNA干扰可以通过将含有dsRNA的药物制剂给予哺乳动物实现。药物组合物以足以抑制靶基因的表达的剂量给药。典型地,dsRNA以小于5mg dsRNA/每天每公斤体重的剂量给药,并且足以抑制或完全抑制靶基因的表达。通常,dsRNA合适的剂量为0.01-2.5毫克/每天每公斤受试者体重,优选为0.1-200微克/每天每公斤体重,更优选为0.1-100微克/每天每公斤体重,更优选为1.0-50微克/每天每公斤体重,和最优选为1.0-25微克/每天每公斤体重。含有dsRNA的药物组合物一天给药一次,或者以多种亚剂量给药,例如使用本领域熟知的缓释制剂。这些药物组合物的制备和给药可以按照如下进一步描述的标准技术进行。
这种dsRNA可以通过以下方式用于抑制癌症中的ROS表达和活性,所述方式为如上述制备包含治疗有效量的这种dsRNA的药物制品,并通过例如直接注射肿瘤将该制品给予患有表达SLC34A2-ROS融合蛋白或截短的ROS激酶多肽的癌症的人对象。最近描述了使用siRNA抑制剂类似地抑制其它受体酪氨酸激酶如VEGFR和EGFR。参见美国专列公开No.20040209832,2004年10月21号,McSwiggen等;美国专列公开No.20030170891,2003年9月11号,McSwiggen;美国专列公开No.20040175703,2004年9月9号,Kreutzer等。
治疗组合物,给药。
用于本发明方法中的ROS激酶抑制治疗组合物可以通过本领域已知的任何手段给予哺乳动物,所述手段包括但不限于口腔或腹膜途径,包括静脉内、肌内、腹膜内、皮下、经皮、气道(气雾剂)、直肠、阴道和局部(包括口腔和舌下)给药。
对于口服,ROS抑制治疗剂通常以片剂或胶囊的形式以粉状或颗粒、或以水溶液或悬液的形式提供。用于口服的片剂可以包括用药学上可接受的赋型剂如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、风味剂、着色剂和防腐剂混合的活性成分。适当的惰性稀释剂包括碳酸钠和碳酸钙,磷酸钠和磷酸钙,和乳糖;而玉米淀粉和褐藻酸是合适的崩解剂。粘合剂可以包括淀粉和明胶;而如果存在润滑剂,通常为硬脂酸镁、硬脂酸或滑石。如果需要,所述片剂可以用如甘油单硬脂酸酯和甘油二硬脂酸酯包被以延长胃肠道中的吸收。
用于口服的胶囊包括活性成分与固体稀释剂混合的硬明胶胶囊和活性成分与水或油如花生油、液体石蜡或橄榄油混合的软明胶胶囊。对于肌内、腹膜内、皮下和静脉内给药,本发明的药物组合物通常以缓冲到合适pH和等渗的无菌水溶液或悬浮液的形式提供。适当的水性载体包括Ringer′s溶液和等渗氯化钠。所述载体可以仅由水性缓冲液组成(“仅”意指不存在可能影响或介导ROS抑制治疗剂吸收的辅剂或包囊化物质)。这种物质包括例如下文描述的胶束(micellar)结构如脂质体或衣壳。含水悬浮液可以包括悬浮剂如纤维素衍生物、藻酸钠、聚乙烯吡咯烷酮和西黄芪胶树胶,和润湿剂如卵磷脂。用于含水悬浮剂的适当防腐剂包括乙基和正丙基对羟基苯甲酸酯。
ROS激酶抑制治疗剂组合物还可以包括包囊化制剂以保护治疗剂(例如dsRNA化合物)以防止该化合物被快速地从体内除去,所述包囊化制剂如控制释放制剂,包括埋植物和微囊化的输送系统。可以用可生物降解和生物相容的聚合物如乙烯醋酸乙烯酯、聚酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。制备这些制剂的方法对于本领域技术人员来说是明显的。这些材料还可以通过商购获得,如从Alza Corporation和Nova Pharmaceuticals,Inc获得。还可以使用脂质体悬浮液(包括用病毒抗原的单克隆抗体靶向感染细胞的脂质体)作为药学上可接受的载体。这可以按照本领域熟知的技术制备,例如美国专利No.4,522,811、PCT公开WO91/06309和欧洲专利公开EP-A-43075所述。包囊化的制剂可以包括病毒外壳蛋白。病毒外壳蛋白可以来自或与病毒有关,如多瘤病毒,或可以是部分或者完全人工的。例如,外壳蛋白可以是多瘤病毒的病毒蛋白1和/或病毒蛋白2或其衍生物。
ROS抑制组合物还可以包括用于给予对象的输送载体(包括脂质体)、载体和稀释剂及其盐和/或可以存在于药学上可接受的制剂中。例如,输送核酸分子的方法描述在Akhtar等1992,Trends Cell Bio.,2,139;DELIVERYSTRATEGIES FOR ANTISENSE OLIGONUCLEOTIDE THERAPEUTICS,ed.Akbtar,1995,Maurer et al.,1999,Mol.Membr.Biol.,16,129-140;Hoflandand Huang,1999,Handb.Exp.Pharmacol.,137,165-192;和Lee等,2000,ACS Symp.Ser.,752,184-192,Beigelman等。美国专利No.6,395,713和Sullivan等,PCT WO94/02595进一步描述了输送核酸分子的一般方法。这些方法事实上可以用于输送任何核酸分子。
ROS抑制治疗剂可以通过各种本领域技术人员已知的方法输送到哺乳动物肿瘤,所述方法包括但不限于在脂质体中包囊化,通过离子电渗或者通过掺入到其它载体如水凝胶、环化糊精、可生物降解的纳米胶囊和生物粘合微球体中、或者通过蛋白质载体(O′Hare和Normand,国际PCT公开No.WO00/53722)。或者,所述治疗/载体组合通过直接注射或通过使用灌输泵局部输送。不管是通过皮下、肌内或者皮内直接注射所述组合物都可以使用标准针头和注射器方法学,或者通过无针头技术如由Conry等,在1999,Clin.Cancer Res.,5,2330-2337和由Barry等在国际PCT公开No.WO99/31262中描述的那些技术进行。
ROS激酶抑制治疗剂的药学上可接受的制剂包括上述化合物的盐,例如酸加成盐,例如盐酸盐、氢溴酸盐、乙酸盐和苯磺酸盐。药物组合物或制剂是指以适合如系统给予的给予形式给予细胞或包括例如人的患者的组合物或制剂。合适的形式部分取决于使用或进入的途径,例如口服、经皮或通过注射。这种形式应当不会妨碍所述组合物或制剂到达靶细胞。例如,注射到血流中的药物组合物应当是可溶的。其它因素是本领域熟知的,并且包括一些考虑如毒性和抑制组合物或制剂发挥效应的形式。
导致系统吸收的给药途径(即药物在血流中的系统吸收或积聚后分布到整个机体中)是所需的,并且包括但不限于:经脉内、皮下、腹膜内、吸入、口腔、肺内和肌内。这些给药途径的每一种都将ROS抑制治疗剂暴露给能接近的疾病组织或肿瘤。已表明药物进入到循环系统中的速率是分子量和大小的函数。使用脂质体或者其它包括本发明化合物的药物载体可以潜在地将药物定位到例如某些组织类型,如网状内皮系统(RES)组织。能促进药物连接到细胞例如淋巴细胞和巨噬细胞的表面的脂质体制剂也是有用的。这种方法可以通过利用巨噬细胞和淋巴细胞特异性免疫识别不正常细胞如癌症细胞的优势将药物以增强的方式输送到靶细胞。
“药学上可接受的制剂”是指能将本发明的核酸分子有效地分布到最适合它们所需活性的物理位置的组合物或制剂。适合用于本发明核酸分子的制剂的物质的非限制性实例包括:P-糖蛋白抑制剂(例如Pluronic P85),其能促进药物进入NCS(Jolliet-Riant和Tillement,1999,Fundam.Clin.Pharmacol.,13,16-26);可生物降解的聚合物,例如适于在脑内埋植后持续释放的聚(DL-丙交酯-共乙交酯)微球体(Emerich等,1999,Cell Transplant,6,47-58)(Alkermes,Inc.Cambridge,Mass.);和负载纳米颗粒,如由聚丁基氰基丙烯酸酯形成的那些,其能将药物输送通过血脑屏障并且能改变神经元吸收机制(Prog Neuro-psychopharmacol Biol Psychiatry,23,941-949,1999)。用于输送用于本发明方法中的ROS抑制化合物的策略的其它非限制性实例包括由Boado等在1998,J.Pharm.Sci.,87,1308-1315;Tyleratal.,1999,FEBS Lett.,421,280-284,Pardridge等在1995,PNAS USA.,92,5592-5596;Boado,1995,Adv.DrugDelivery Rev.,15,73-107;Aldrian-Herrada等在1998,Nucleic Acids Res.,26,4910-4916和Tyler等,1999,PNAS USA,96,7053-7058中描述的材料。
包括表面修饰的含有聚(乙二醇)脂质(PEG-修饰的,或者长循环脂质体或者秘密脂质体(stealth liposomes))的脂质体的治疗组合物也适合用于本发明的方法中。这些制剂提供了一种增加药物在靶组织中循环的方法。这类药物载体抵抗单核吞噬细胞系统(MPS或RES)的调理作用和清除作用,从而延长包囊化药物的血液循环时间并增加组织暴露(Lasic等Chem.Rev.1995,95,2601-2627;Ishiwata等Chem.Pharm.Bull.1995,43,1005-1011)。已表明这些脂质体可能通过在新血管化靶组织中外渗和捕获而选择性在肿瘤中积累(Lasic等,Science1995,267,1275-1276;Oku等,1995,Biochim.Biophys.Acta,1238,86-90)。尤其与已知在MPS组织中积累的常规阳离子脂质体相比(Liu等,J.Biol.Chem.1995,42,24864-24870;Choi等,国际PCT公开No.WO96/10391;Ansell等,国际PCT公开No.WO96/10390;Holland等,国际PCT公开No.WO96/10392),长时间循环的脂质体促进DNA和RNA的药物动力学和药物代谢动力学。根据其在代谢迅速的MPS组织如肝和脾中避免积累的能力,长时间循环脂质体与阳离子脂质体相比还可能更大程度地保护药物防止被核酸酶降解。
治疗组合物可以包括在药学上可接受的载体或稀释剂中的药学有效量的所需化合物。用于治疗应用的可接受的载体或稀释剂是药学领域熟知的,并且描述在例如REMINGTON′S PHARMACEUTICAL SCIENCES,MackPublishing Co.(A.R.Gennaro edit.1985)。例如可以提供防腐剂、稳定剂、染料和风味剂。这些包括苯甲酸钠、山梨酸和对羟基苯甲酸酯。此外,可以使用抗氧化剂和悬浮剂。
药学有效量是指防止、抑制疾病发生或者治疗疾病(在一定程度上减轻症状,优选减轻所有症状)所需的剂量。药学有效量取决于疾病类型、所使用的组合物、给药途径、治疗的哺乳动物类型、在考虑情况下特异哺乳动物的物理特征、共同治疗药物和其它药物领域技术人员将意识到的因素。通常,取决于带负电荷聚合物的能力,给予活性成分的量为0.1-100mg/kg体重/天。
为约0.1-140mg/kg体重/天量级的剂量水平对于治疗上述病症有用(约0.5mg-7g/患者/天)。能组合载体材料以产生单剂量形式的活性成分的量根据治疗的宿主和给药的特定模式而变化。剂量单位形式通常含有约1-500mg的活性成分。应当理解的是对于任何特定患者的特定剂量水平取决于各种因素,包括所使用的特定化合物的活性、年龄、体重、综合健康状况、性别、饮食、给药时间、给药途径、排泄速度、药物组合和处于治疗中的特定疾病的严重程度。
对于给非人类动物的给药,组合物还可以添加到动物的饲料和饮水中。很便利地制成动物饲料和饮水组合物以使动物在饮食时摄取治疗合适量的组合物。还可以将所述组合物制成预混合物添加到饲料或饮水中。
用于本发明中的ROS抑制治疗剂可以包括上述单一化合物,或者多种化合物的组合,无论为同类抑制剂(即抗体抑制剂)还是不同类抑制剂(即抗体抑制剂和小分子抑制剂)。化合物的这种组合可以增加抑制表达融合蛋白癌症的进展的总体治疗效果。例如,治疗组合物可以为小分子抑制剂,如单独的STI-571()或者与其它靶向ROS活性的类似物和/或EGFR的小分子抑制剂如TarcevaTM或IressaTM的组合。治疗组合物除了一或多种靶向抑制剂外还可以包括一或多种非特异性化疗剂。最近表明这种组合在多种癌症中提供了协同肿瘤杀伤效果。这种组合在体内抑制ROS活性和肿瘤生长的效力可以按照下文所述评价。
突变ROS激酶抑制化合物的鉴定
本发明还部分地提供了一种确定化合物是否能抑制以SLC34A2-ROS易位和/或融合多肽为特征的癌症的进展的方法,该方法通过确定化合物是否能抑制癌症中SLC34A2-ROS融合多肽的活性实现。在一些优选的实施方案中,通过检测包括来自骨髓、血液或肿瘤的细胞的生物样品确定ROS的活性抑制。在另一个优选的实施方案中,使用至少一种本发明的突变ROS多核苷酸或者多肽特异性试剂确定ROS活性的抑制。
测试化合物可以是上述的任何类型的治疗剂或组合物。评价化合物在体外或体内效力的方法在本领域中已经建立并是熟知的。例如,可以使用ROS激酶被激活的细胞或细胞提取物检测一种组合物在体外抑制ROS的能力。可以使用一组化合物以检测这些化合物对ROS的特异性(与其它靶如EGFR或PDGFR相反)。
另一种可以使用的药物筛选技术提供了高通量筛选具有与感兴趣蛋白适当结合亲和力的化合物,如公开的PCT申请W084/03564所述。在这种方法中,用于突变的ROS多肽,大量的不同小分子测试化合物在固相基底如塑料针或一些其它表面上合成。测试化合物与突变ROS多肽或其片段反应,并洗涤。然后通过本领域已知方法检测结合的突变多肽(例如SLC34A2-ROS融合多肽)。纯化的突变ROS多肽还能直接包被到平板上以用于上述药物筛选技术。或者,可以使用非中和抗体以捕获肽并将它固定到固体支持物上。
然后检测被发现在体外是ROS活性的有效抑制剂的化合物在体内抑制表达SLC34A2-ROS融合多肽的癌症的进展的能力,这是通过使用例如携带由SLC34A2-ROS融合蛋白驱动的人类NSCLC肿瘤的哺乳动物异种移植物实现的。在该方法中,将已知受SLC34A2-ROS融合蛋白驱动的细胞系皮下置于小鼠中。然后这些细胞长成肿瘤块,可以通过肉眼监视。然后可以用药物处理小鼠。药物处理对肿瘤大小的效果可以从外部观察。处死小鼠并取出肿瘤通过IHC和Western印迹进行分析。类似地,可以通过标准方法制备哺乳动物骨髓移植物以检测药物在表达突变ROS激酶的血液肿瘤中的反应。通过这种方式,可以观察药物在最接近患者的生物环境中的效果。可以通过用磷酸化特异性抗体的分析确定药物改变肿瘤细胞中或周围基质细胞中信号传导的能力。还可以通过分析凋亡特异性标记如切割的caspase3和切割的PARP观测药物诱导细胞死亡或抑制细胞增殖的效力。
可以通过在细胞培养或者实验动物中的标准药学方法确定这些化合物的毒性和治疗效力,例如确定LD50(50%种群致死剂量)和ED50(50%种群治疗有效剂量)。毒性和治疗效果的剂量比是治疗指数,并且可以表示为LD50/ED50比率。表现出高治疗指数的化合物是优选的。
所有上文和下文引述的参考文献的教导并入本文作为参考。下述的实施例只是为了进一步说明本发明并不是为了限制本发明的范围,本发明的范围由所附的权利要求所限定。本发明包括本文所述方法的各种修饰和改变,这对于本领域普通的技术人员来说是显而易见的。
实施例1
通过总磷酸肽谱鉴定NSCLC细胞系中的ROS激酶活性
使用最近描述的并有效的从复杂混合物中进行分离和修饰肽的质谱特征技术检测包括HCC78的几种人NSCLC细胞系中激酶激活的总磷酸化谱("IAP"技术,参见Rush等,同上)。使用磷酸酪氨酸特异性抗体(CELLSIGNALING TECHNOLOGY,INC.,Beverly,MA,2003/04Cat.#9411)进行IAP技术以从NSCLC细胞系的提取物中分离并随后确定含有磷酸酪氨酸的肽。
特别地,使用IAP方法有利于鉴定NSCLC细胞系中激活的酪氨酸激酶以鉴定这种疾病中的新的驱动物。
细胞培养
将从DSMZ(German National Resource Centre for Biological Material)获得的HCC78细胞生长在有10%胎牛血清(FBS)(Sigma)的RPMI-1640培养基(invitrogen)中。
磷酸肽免疫沉淀
将总数为2×108个细胞用尿素裂解缓冲液(20mM HEPES pH8.0、9M尿素、1mM钒酸钠、2.5mM焦磷酸钠、1mMβ-甘油磷酸酯)中以1.25×108个细胞/ml裂解,并超声。以20,000xg离心澄清超声裂解物,并按前述还原并烷基化蛋白质(参见Rush等,Nat.Biotechnol.23(1):94-101(2005))。用20mM HEPES pH8.0将样品稀释到尿素终浓度为2M。以1:100v/v将胰蛋白酶(1mg/ml于0.001M HCI中)加入澄清的裂解物中。在室温下消化样品过夜。
消化后,将裂解物酸化到TFA的终浓度为1%。使用Sep-Pak C18柱按前述进行肽的纯化(参见Rush等,同上)。纯化后,将所有的洗脱液(8%、12%、15%、18%、22%、25%、30%、35%和40%的于0.1%TFA中的乙腈)合并并冻干。将干燥的肽重悬在1.4ml MOPS缓冲液(50mM MOPS/NaOH pH7.2,10mM Na2HPO4,50mM NaCl)中,并通过在12,000xg下离心10分钟除去不溶物质。
将来自腹水的磷酸酪氨酸单克隆抗体P-Tyr-100(Cell SignalingTechnology)在4℃过夜以非共价偶联到4mg/ml珠的蛋白G琼脂糖珠(Roche)上。偶联后,使用PBS洗涤抗体-树脂两次,用MOPS缓冲液洗涤三次。将于MOPS IP缓冲液中的1:1浆样的固定抗体(40μl,160μg)加入到溶解的肽级分中,并在4℃将混合物保温过夜。将固定的抗体珠用MOPS缓冲液洗涤三次,然后ddH2O洗涤两次。通过每次使用40μl的0.1%TFA保温20分钟从珠洗脱肽两次,合并级分。
LC-MS/MS质谱分析
于IP洗脱液(40μl)中的肽使用Stop and Go extraction tips(StageTips)从洗脱的抗体中浓缩和分离(see Rappsilber et al.,Anal.Chem.,75(3):663-70(2003))。用1μl的60%MeCN、0.1%TFA将肽从微柱洗脱于7.6μl的0.4%乙酸/0.005%七氟丁酸(HFBA)。使用具有惰性样品注射阀(Dionex)的Famos自动进样仪将样品加入具有Magic C18AQ反相树脂(Michrom Bioresources)的10cm×75μm的PicoFrit毛细柱中。用以280nl/min输送的于0.4%乙酸、0.005%HFBA(Ultimate,Dionex)中的45-min线性梯度乙腈展开柱子。
用LCQ Deca XP和离子捕获分光计(ThermoFinnigan)并采用top-four方法以数据依赖方式收集串联质谱,动态排除重复计数为1和0.5min的重复持续时间。
数据分析和分配
使用(以作为BioWorks3.0一部分提供的Sequest Browser package(v.27,rev.12))TurboSequest(ThermoFinnigan)评价MS/MS光谱。使用SequestBrowser program CreateDta以下述参数将单个的MS/MS光谱从原始数据文件夹中提取:底MW为700、顶MW为4,500、最少离子数为20;最小TIC为4×105和前体电荷状态unspecified。在将样品注射到最终的稀释梯度前从原始数据文件夹的开始部分提取光谱。不使用lonQuest和VuDta程序进一步选择MS/MS光谱进行Sequest分析。使用下述的TurboSequest参数评价MS/MS光谱:肽质量允差(mass tolerance),2.5;片段离子允差0.0;每修饰的差别氨基酸的最大数目,4;mass type parent,平均值;mass typefragment,平均值;内部裂解位点的最大数目,10;在相关分析中考虑来自b和y离子的水和氨中性丢失(neutral lost)。除了收集自弹性蛋白酶消化物的光谱之外,具体说明了蛋白水解酶。
针对2004年8月24日公布的NCBI人数据库进行了检索,该数据库包含27,175个允许氧化的甲硫氨酸(M+16)和磷酸化(Y+80)作为动态修饰的蛋白质。
在蛋白质组学研究中,期望仅仅基于观察在一个实验结果中的单个肽来验证蛋白质鉴定,以便指示蛋白质事实上存在于样品中。这已导致了仍未被普遍接受的验证肽分配的统计方法以及关于本发明实施例中所遵循的公开蛋白质和肽鉴定结果的指南的发展(见Carr et al.,Mol.Cell Proteomics3:531-533(2004))。然而,因为免疫亲和策略将磷酸化的肽与未磷酸化的肽分开,所以只观察来自蛋白质的一个磷酸肽是通常结果,这是由于许多磷酸化的肽只有一个酪氨酸-磷酸化位点。
由此,使用额外的标准来验证磷酸肽分配是适当的。如果以下这些额外标准中的任何可以满足,则分配可能是正确的:(i)相同序列分配给具有不同电荷状态的共洗脱离子,因为MS/MS光谱随电荷状态显著变化;(ii)由于来自不完全蛋白水解或使用除胰蛋白酶之外的蛋白酶的序列重叠,所述位点见于超过一个肽序列中;(iii)由于同源但非相同的蛋白质同工型,所述位点见于超过一个肽序列中;(iv)由于在物种中同源但非相同的蛋白质,所述位点见于超过一个肽序列中;和(v)由于离子阱质谱仪产生高度可重现的MS/MS谱,经合成的对应于分配序列的磷酸肽的MS/MS分析验证位点。最后的标准常规用来证实特别感兴趣的新的位点分配。
由Sequest做的所有光谱和所有序列分配被输入相关数据库。分配的序列在保守两步法之后被接受或拒绝。在第一步中,高分序列分配的子集通过过滤XCorr值进行选择,对于+1的电荷状态XCorr值最小为1.5,对于+2为2.2,对于+3为3.3,以使最大的RSp值为10。如果下述的标准中任何一个被满足,子集中的分配被拒绝,所述标准为:(i)光谱含有至少一个主峰(至少为光谱中最强的离子强度的10%),该主峰不能作为a、b或y离子、作为a、b或y离子的水或氨中性丢失的离子或者作为多质子化离子(multiply protonated ion)被作图到分配序列;(ii)光谱不含有一系列等价于至少六个不间断残基的b或y离子;或者(iii)在我们进行的所有研究中至少有五次没有观察到序列(除了由于不完全蛋白水解或者使用除胰蛋白酶外的蛋白酶导致的重叠序列)。第二步,如果低分光谱表现出与在其它研究中收集的高分光谱高度相似性,就接受具有低于阈值的分配,这模仿真实参考文库搜索战略(true reference library-searching strategy)。所有支持最终的分配序列表(此处未显示)的光谱将由至少三个科学家评价以建立其可信度。
上述的IAP分析从HCC78细胞(没有显示数据)中鉴定了454个非冗余含磷酸酪氨酸肽,395个磷酸酪氨酸位点和240个酪氨酸磷酸化蛋白,大多数都是新的。这些酪氨酸磷酸化激酶中,有几种包括ROS激酶是通常用MS分析其它NSCLC细胞系中检测不到的(数据未公开)。
实施例2
用Western印迹分析NSCLC细胞系中的ROS激酶表达
通过使用特异于ROS和其它受体酪氨酸激酶(RTK)以及下游激酶的抗体进行Western印迹分析细胞提取物证实HCC78NSCLC细胞系而不是其他NSCLC细胞系表达激活的ROS激酶的观察。
用添加Protease ArrestTM(G.Biosciences)的1X细胞裂解缓冲液(CellSignaling Technology)裂解HCC78细胞,并用电泳分离。所有用于免疫印迹的抗体和试剂都来自于Cell Signaling Technology,Inc.(Beverly,MA)。按照“Western Immunoblotting Protocol”(CellSignaling Technology,Inc.,2005-2006目录)所述进行Western印迹。抗ROS抗体得自Santa Cruz Biotechnology,Inc。
图5表明Western印迹结果。在多种不同的NSCLC细胞系中,只有HCC78表达ROS蛋白质。HCC78中的ROS蛋白比野生型ROS蛋白具有小得多的分子量,表示是融合蛋白。
Western印迹证实ROS融合蛋白是酪氨酸磷酸化的。通过磷酸酪氨酸抗体免疫沉淀HCC78细胞的蛋白裂解物,并用总ROS抗体进行免疫印迹。从pY-IP中如用ROS抗体从总裂解物中检测出相同条带,具有较小迁移的IPed条带也表明蛋白质的磷酸化。
实施例3
使用siRNA对表达异常ROS激酶的哺乳动物NSCLC细胞系的生长抑制
为了证实截短型的ROS驱动HCC78细胞系的细胞生长和存活,检测siRNA沉默抑制这些细胞生长的能力。RNA干扰下调ROS的表达。下述ROS siRNA购自Proligo,Inc.,其在括号中表示相应的ROS序列:5′AAGCCCGGAUGGCAACGUUTT3′(ROS1(6318-6340)(SEQ ID NO:23);5′AAGCCUGAAGGCCUGAACUTT3′(ROS1(7181-7203)(SEQ ID NO:24)。
在转染前一天将2×105个细胞接种到12孔平板中。使用MirusTransIT-TKO Transfection Reagent转染100nM ROS1siRNA。转染48小时后,将细胞转移到饥饿培养基中再24小时。通过胰蛋白酶消化收集细胞并计数,然后细胞裂解物用于WB以检测ROS蛋白质水平。
免疫印迹分析表明在将siRNA转染到HCC78细胞后72小时,ROS的表达特异并且显著地降低,而对照细胞系H2066不表达ROS蛋白(参见图10,B组)。如预期,这伴随下游物质如p-Erk1/2和p-Akt磷酸化的减少(参见图10,C组)。此外,如预期,用ROS siRNA处理导致HCC78细胞系凋亡增加(但在对照细胞系H2066中没有),通过检测切割的PARP确定(参见图10,B组)。用ROS siRNA转染后3天杀死80%细胞,如图10,A组所述。这些结果表明在HCC78细胞系中,突变/截短的ROS激酶驱动这些NSCLC细胞的增殖和生长,这种增殖和生长可以通过使用siRNA抑制ROS激酶表达而抑制。
实施例4
SLC34A2-ROS融合基因的分离和测序
鉴于在NSCLC细胞系(HCC78)中检测到存在截短形式的ROS激酶,在编码ROS的激酶结构域的序列上进行5′快速扩增cDNA末端以确定是否存在嵌合ROS转录物。
快速扩增互补DNA末端
使用RNeasy Mini Kit(Qiagen)从HCC78细胞系提取RNA。使用DNeasyTissue Kit(Qiagen)提取DNA。使用5′RACE系统(Invitrogen)快速扩增cDNA末端,对于cDNA合成的引物为ROS-GSP1,对于嵌套PCR反应的引物为ROS-GSP2和ROS-GSP3。
PCR分析
对于RT-PCR,使用2.5μg的总RNA并使用SuperScriptTM II第一链合成系统(Invitrogen)用oligo(dT)20合成第一链cDNA。然后,使用引物对SLCROS-F1和SLCROS-R1、SLCROS-F2和SLCROS-R2扩增SLC34A2-ROS融合基因。
构建体
使用Platinum Taq DNA高保真聚合酶(Invitrogen)和引物对SLC-Fb和ROS-Rb(具有Bg1II限制位点)从HCC78细胞的cDNA通过PCR扩增SLC34A2-ROS融合基因的可读框。这个PCR产物被克隆到逆转录病毒载体MSCV-Neo中。引物为:
ROS-GSP1:ACCCTTCTCGGTTCTTCGTTTCCA(SEQ ID NO:13)
ROS-GSP2:GCAGCTCAGCCAACTCTTTGTCTT(SEQ ID NO:14)
ROS-GSP3:TGCCAGACAAAGGTCAGTGGGATT(SEQ ID NO:15)
SLCROS-F1:TCCATCCCAGCACCTGCGGAG(SEQ ID NO:16)
SLCROS-R1:CTCAACTCTCTATTTCCCAAACAACGC(SEQ ID NO:17)
SLCROS-F2:CATGGCTCCCTGGCCTGAATTG(SEQ ID NO:18)
SLCROS-R2:CAACGCTATTAATCAGACCCATCTCC(SEQ ID NO:19)
SLC-Fb:GAAGATCTCTGACCATGGCTCCCTGGCCTGAA(SEQ ID NO:20)
ROS-Rb:GAAGATCTACGCTATTAATCAGACCCATCTCC(SEQ ID NO:21)
图7表示在扩增两轮后检测的PCR扩增产物。得到产物的序列分析表明ROS的c-末端融合到SLC34A2基因的N-末端(参见图1,B组和C组)。SLC34A2-ROS融合基因是符合读框的,并且将SLC34A2的前126个氨基酸融合到ROS的最后598和495个氨基酸(见图1,B组),分别产生了两种变体融合蛋白(长的,短的)。SLC34A2定位到染色体4p15,而ROS在染色体6q22。因此,通过t(4;6)(p15;q22)产生了融合基因。见图8,上组。
SLC34A2和ROS的融合体通过对RNA的逆转录酶PCR证实。
实施例5
SLC34A2-ROS融合蛋白驱动转染的293细胞生长和存活。
为了证实SLC34A2-ROS融合蛋白的表达能将正常细胞转化为癌表型,用上述编码SLC34A2-ROS融合蛋白的长变体的cDNA构建体转染人胚胎肾细胞(293细胞)。
将上述SLC34A2-ROS cDNA构建体(编码长变体融合蛋白)插入MSCV病毒载体,并使用SuperFect转染试剂(Qiaqen)将该构建体转染HEK293细胞。48小时后,收集转染的HEK293细胞,并通过Western印迹确定所期望分子量的重组SLC34A2-ROS融合蛋白(长变体)的表达(见图9)。
实施例6
SLC34A2-ROS融合蛋白驱动转化的哺乳动物细胞系的生长和存活。
为了证实SLC34A2-ROS融合蛋白的表达可以将正常细胞转化为癌表型,可以使用上述cDNA构建体转化3T3细胞。将细胞培养在添加10%的胎牛血清(FCS)(Invitrogen)的DMEM培养基(Invitrogen)中。
如前述制备逆转录病毒上清及转导。参见Schwaller等,Embo J.17(18):5321-33(1998)。分别使用逆转录病毒上清转化3T3细胞,所述逆转录病毒上清含有MSCV-Neo或MSCV-Neo/SLC34A2-ROS(长的)或者MSCV-Neo/ROS(短的)载体,然后筛选G418(500μg/ml)。稳定转化的细胞将用于软琼脂分析以确定SLC34A2-ROS将转化3T3细胞。
这种分析将确定SLC34A2-ROS融合蛋白的表达是否转化了3T3细胞,由此细胞生长将不依赖贴壁。然后进行Western印迹分析检测ROS、SLC34A2、SHP-1和其它可能的ROS下游靶的磷酸化状态。
实施例7
使用FISH分析检测SLC34A2-ROS融合蛋白在人癌样品中的表达。
使用前述荧光原位杂交(FISH)测定方法检测人NSCLC肿瘤样品中SLC34A2-ROS融合蛋白的存在。参见例如Verma等,HUMANCHROMOSOMES:A MANUAL OF BASIC TECHNIQUES,Pergamon Press,New York,N.Y.(1988)。检测了200多个石蜡包埋的人NSCLC肿瘤样品。
为了分析涉及ROS的重排,设计了双色断裂分离探针(break-apartprobe)。分别使用Spectrum Orange dUTP或Spectrum Green dUTP标记近端探针(proximal probe)(BAC克隆RP1-179P9)和两个远端探针(distal probe)(BAC克隆RP1l-323O17,RP1-94G16)。按照制造商用法说明(Vysis)并进行如下修饰使用FFPE切片通过切口翻译和分裂间期FISH标记探针。简单地说,将石蜡包埋的组织切片再水化,并在0.01M柠檬酸盐缓冲液(pH6.0)中微波抗原复性11分钟。在37℃用蛋白酶(4mg/ml胃蛋白酶,2000-3000U/mg)消化切片25分钟、脱水并用FISH探针在37℃杂交18小时。洗涤后,使用于Vectashield封固剂(Vector Laboratories,Burlingame,CA)中的4′,6-二脒基-2-苯基吲哚(DAPI;15mg/ml)对核复染。
ROS重排探针含有两种在野生型序列中ROS基因断裂点相反位点上的不同标记探针(参见图4B和图1)。当杂交时,天然ROS区域将出现橙色/绿色融合信号,而在这个基因座的重排(如在SLC34A2-ROS融合蛋白中)将出现单独的橙色和绿色信号。参见图11。
FISH分析揭示了在研究的样品群体中这种ROS突变发生率低。123例肿瘤中的两例或者1.6%的肿瘤含有融合突变。然而,已知在世界范围内NSCLC的发生率很高(仅在美国,每年超过151,00新病例),可以预期有大量的患者携带这种突变ROS,这些患者可能从ROS抑制治疗剂方案中获益。
实施例8
使用PCR分析检测突变ROS激酶在人癌症样品中的表达。
可以如前述使用基因组或逆转录酶(RT)聚合酶链反应(PCR)检测人癌症样品中截短的ROS激酶和/或SLC34A2-ROS融合蛋白的存在。参见例如Cools等,N.Engl.J.Med.348:1201-1214(2003)。
简单地说,例如可以使用标准技术从患有NSCLC的患者中获得肿瘤或胸膜渗出液样品。构建针对截短的ROS激酶或SLC34A2-ROS融合蛋白的PCR探针。可以使用RNeasy Mini Kit(Qiagen)从肿瘤或胸膜渗出液样品中提取RNA。可以使用DNeasy Tissue Kit(Qiagen)提取DNA。对于RT-PCR,可以使用例如2.5μg总RNA并使用例如SuperScriptTM III第一链合成系统(Invitrogen)用oligo(dT)20合成第一链cDNA。然后使用引物对例如SLC34A2-F1和ROS-P3(见上述实施例4)扩增SLC34A2-ROS融合基因。对于基因组PCR,可以使用Platinum Taq DNA高保真聚合酶(Invitrogen)并采用引物对例如gSLC34A2-F1和gROS-R1或者Gslc34A2-F1和gROS-R2(参见上述实施例4)扩增融合基因。
这种分析将鉴定患有以表达截短的ROS激酶(和/或SLC34A2-ROS融合蛋白为特征的癌症的患者,这种患者是使用ROS抑制治疗剂治疗的候选者。
实施例9
采用总磷酸肽谱检测突变ROS激酶在人癌症样品中的表达
为了进一步确定在人NSCLC中ROS融合突变的发生率,使用上述总磷酸肽谱的IAP技术检测一组34个人NSCLC肿瘤(参见实施例1)以鉴定在这些肿瘤中的ROS磷酸肽。肿瘤样品(速冻切割的肿瘤并保存在液氮中)从中国临床合作者(湖南长沙中南大学湘雅二医院)获得。
使用Polytron匀浆器在3ml尿素裂解缓冲液中匀浆约300毫克的冷冻组织。将细胞裂解物澄清、还原并烷基化,然后用胰蛋白酶在室温下消化过夜。通过免疫组织细胞化学使用标准方法对这34个肿瘤预筛选磷酸酪氨酸信号是阳性的。
这些样品的总磷酸酪氨酸作谱按照上述实施例1所述的方法进行。作谱结果表明34个样品中的一个样品具有ROS磷酸肽和SLC34A2磷酸肽(参见下表1(其它检测的磷酸肽未示出),并且示出下游分子如IRS-1和IRS-2磷酸肽。如期望,这种肿瘤的酪氨酸谱特征与NSCLC细胞系HCC78的非常相似(参见表1)。FISH分析也显示肿瘤具有ROS易位(参见实施例7)。可以使用RT-PCR、DNA测序分析进一步确定在患者中ROS激活(其它携带ROS易位的患者)是由于SLC34A2/ROS异常转录所致。
表1 人NSCLC肿瘤的磷酸肽谱
HCC78 CS042
名称 登录号 位置 肽 (细胞系) (肿瘤)
ROS PO8922 1923 GLAAGVGLANACyAIHTLPTQEEIENLPAFPR 1 1
DIyKNDYYR;DIyKNDYyR;DIyKNDyYR;
ROS PO8922 2110 DIyKNDyyRKRGEGLLPVR 12 4
ROS PO8922 2114 DIYKNDyYR;DIyKNDyYR;DIyKNDyyRKRGEGLLPVR 11 3
ROS PO8922 2115 DIyKNDYyR;DIyKNDyyRKRGEGLLPVR 1 1
EGLNyMVLATECGQGEEK;
NREGLNyMVLATECGQGEEK;
EGLNyMVLATECGQGEEKSEGPLGSQESESCGLR;
ROS PO8922 2274 NREGLNyMVLATECGQGEEKSEGPLGSQESESCGLR 20
QVAyCPSGKPEGLNYACLTHSGYGDGSD;
QVAyCPSGKPEGLNYACLTHSGyGDGSD;
ROS PO8922 2323 QVAyCPSGKPEGLNyACLTHSGYGDGSD 4 1
QVAYCPSGKPEGLNyACLTHSGYGDGSD;
QVAYCPSGKPEGLNyACLTHSGyGDGSD;
ROS PO8922 2334 QVAyCPSGKPEGLNyACLTHSGYGDGSD 7 2
QVAYCPSGKPEGLNyACLTHSGyGDGSD;
ROS PO8922 2342 QVAyCPSGKPEGLNYACLTHSGyGDGSD 3
IRS-1 P35568 612 GGHHRPDSSTLHTDDGyMPMSPGVAPVPSGR 1
IRS-1 P35568 632 KGSGDyMPMSPK 2 1
VDPNGyMMMSPSGGCSPDIGGGPSSSSSSSNAVPSGT
IRS-1 P35568 662 SYGK 3
IRS-2 Q9Y4H2 598 QRPVPQPSSASLDEyTLMR 1
IRS-2 Q9Y4H2 653 SSSSNLGADDGyMPMTPGAALAGSGSGSCR 4 5
IRS-2 Q9Y4H2 675 SDDyMPMSPASVSAPK 3 4
IRS-2 Q9Y4H2 742 ASSPAESSPEDSGyMR 3 3
APYTCGGDSDQyVLMSSPVGR;
IRS-2 Q9Y4H2 823 SYKAPYTCGGDSDQyVLMSSPVGR 2 5
SLC34A2 O95436 54 IELLPSySTATLIDEPTEVDDPWNLPTLQDSGIK 1 1
序列表
<110>细胞信号技术有限公司
<120>人非小细胞肺癌中的易位和突变的ROS激酶
<130>CST-232
<150>60/760,634
<151>2006-01-20
<160>21
<170>PatentIn version 3.3
<210>1
<211>724
<212>PRT
<213>Homo sapiens
<400>1
Met Ala Pro Trp Pro Glu Leu Gly Asp Ala Gln Pro Asn Pro Asp Lys
1 5 10 15
Tyr Leu Glu Gly Ala Ala Gly Gln Gln Pro Thr Ala Pro Asp Lys Ser
20 25 30
Lys Glu Thr Asn Lys Thr Asp Asn Thr Glu Ala Pro Val Thr Lys Ile
35 40 45
Glu Leu Leu Pro Ser Tyr Ser Thr Ala Thr Leu Ile Asp Glu Pro Thr
50 55 60
Glu Val Asp Asp Pro Trp Asn Leu Pro Thr Leu Gln Asp Ser Gly Ile
65 70 75 80
Lys Trp Ser Glu Arg Asp Thr Lys Gly Lys Ile Leu Cys Phe Phe Gln
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Gly Ile Gly Arg Leu Ile Leu Leu Leu Gly Phe Leu Tyr Phe Phe Val
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Cys Ser Leu Asp Ile Leu Ser Ser Ala Phe Gln Leu Val Gly Ala Gly
115 120 125
Val Pro Asn Lys Pro Gly Ile Pro Lys Leu Leu Glu Gly Ser Lys Asn
130 135 140
Ser Ile Gln Trp Glu Lys Ala Glu Asp Asn Gly Cys Arg Ile Thr Tyr
145 150 155 160
Tyr Ile Leu Glu Ile Arg Lys Ser Thr Ser Asn Asn Leu Gln Asn Gln
165 170 175
Asn Leu Arg Trp Lys Met Thr Phe Asn Gly Ser Cys Ser Ser Val Cys
180 185 190Thr Trp Lys Ser Lys Asn Leu Lys Gly Ile Phe Gln Phe Arg Val Val
195 200 205
Ala Ala Asn Asn Leu Gly Phe Gly Glu Tyr Ser Gly Ile Ser Glu Asn
210 215 220
Ile Ile Leu Val Gly Asp Asp Phe Trp Ile Pro Glu Thr Ser Phe Ile
225 230 235 240
Leu Thr Ile Ile Val Gly Ile Phe Leu Val Val Thr Ile Pro Leu Thr
245 250 255
Phe Val Trp His Arg Arg Leu Lys Asn Gln Lys Ser Ala Lys Glu Gly
260 265 270
Val Thr Val Leu Ile Asn Glu Asp Lys Glu Leu Ala Glu Leu Arg Gly
275 280 285
Leu Ala Ala Gly Val Gly Leu Ala Asn Ala Cys Tyr Ala Ile His Thr
290 295 300
Leu Pro Thr Gln Glu Glu Ile Glu Asn Leu Pro Ala Phe Pro Arg Glu
305 310 315 320
Lys Leu Thr Leu Arg Leu Leu Leu Gly Ser Gly Ala Phe Gly Glu Val
325 330 335
Tyr Glu Gly Thr Ala Val Asp Ile Leu Gly Val Gly Ser Gly Glu Ile
340 345 350
Lys Val Ala Val Lys Thr Leu Lys Lys Gly Ser Thr Asp Gln Glu Lys
355 360 365
Ile Glu Phe Leu Lys Glu Ala His Leu Met Ser Lys Phe Asn His Pro
370 375 380
Asn Ile Leu Lys Gln Leu Gly Val Cys Leu Leu Asn Glu Pro Gln Tyr
385 390 395 400
Ile Ile Leu Glu Leu Met Glu Gly Gly Asp Leu Leu Thr Tyr Leu Arg
405 410 415
Lys Ala Arg Met Ala Thr Phe Tyr Gly Pro Leu Leu Thr Leu Val Asp
420 425 430
Leu Val Asp Leu Cys Val Asp Ile Ser Lys Gly Cys Val Tyr Leu Glu
435 440 445
Arg Met His Phe Ile His Arg Asp Leu Ala Ala Arg Asn Cys Leu Val
450 455 460
Ser Val Lys Asp Tyr Thr Ser Pro Arg Ile Val Lys Ile Gly Asp Phe465 470 475 480
Gly Leu Ala Arg Asp Ile Tyr Lys Asn Asp Tyr Tyr Arg Lys Arg Gly
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Glu Gly Leu Leu Pro Val Arg Trp Met Ala Pro Glu Ser Leu Met Asp
500 505 510
Gly Ile Phe Thr Thr Gln Ser Asp Val Trp Ser Phe Gly Ile Leu Ile
515 520 525
Trp Glu Ile Leu Thr Leu Gly His Gln Pro Tyr Pro Ala His Ser Asn
530 535 540
Leu Asp Val Leu Asn Tyr Val Gln Thr Gly Gly Arg Leu Glu Pro Pro
545 550 555 560
Arg Asn Cys Pro Asp Asp Leu Trp Asn Leu Met Thr Gln Cys Trp Ala
565 570 575
Gln Glu Pro Asp Gln Arg Pro Thr Phe His Arg Ile Gln Asp Gln Leu
580 585 590
Gln Leu Phe Arg Asn Phe Phe Leu Asn Ser Ile Tyr Lys Ser Arg Asp
595 600 605Glu Ala Asn Asn Ser Gly Val Ile Asn Glu Ser Phe Glu Gly Glu Asp
610 615 620
Gly Asp Val Ile Cys Leu Asn Ser Asp Asp Ile Met Pro Val Ala Leu
625 630 635 640
Met Glu Thr Lys Asn Arg Glu Gly Leu Asn Tyr Met Val Leu Ala Thr
645 650 655
Glu Cys Gly Gln Gly Glu Glu Lys Ser Glu Gly Pro Leu Gly Ser Gln
660 665 670
Glu Ser Glu Ser Cys Gly Leu Arg Lys Glu Glu Lys Glu Pro His Ala
675 680 685
Asp Lys Asp Phe Cys Gln Glu Lys Gln Val Ala Tyr Cys Pro Ser Gly
690 695 700
Lys Pro Glu Gly Leu Asn Tyr Ala Cys Leu Thr His Ser Gly Tyr Gly
705 710 715 720
Asp Gly Ser Asp
<210>2
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<213>Homo sapiens
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atggctccct ggcctgaatt gggagatgcc cagcccaacc ccgataagta cctcgaaggg 60
gccgcaggtc agcagcccac tgcccctgat aaaagcaaag agaccaacaa aacagataac 120
actgaggcac ctgtaaccaa gattgaactt ctgccgtcct actccacggc tacactgata 180
gatgagccca ctgaggtgga tgacccctgg aacctaccca ctcttcagga ctcggggatc 240
aagtggtcag agagagacac caaagggaag attctctgtt tcttccaagg gattgggaga 300
ttgattttac ttctcggatt tctctacttt ttcgtgtgct ccctggatat tcttagtagc 360
gccttccagc tggttggagc tggagtccca aataaaccag gcattcccaa attactagaa 420
gggagtaaaa attcaataca gtgggagaaa gctgaagata atggatgtag aattacatac 480
tatatccttg agataagaaa gagcacttca aataatttac agaaccagaa tttaaggtgg 540
aagatgacat ttaatggatc ctgcagtagt gtttgcacat ggaagtccaa aaacctgaaa 600
ggaatatttc agttcagagt agtagctgca aataatctag ggtttggtga atatagtgga 660
atcagtgaga atattatatt agttggagat gatttttgga taccagaaac aagtttcata 720
cttactatta tagttggaat atttctggtt gttacaatcc cactgacctt tgtctggcat 780
agaagattaa agaatcaaaa aagtgccaag gaaggggtga cagtgcttat aaacgaagac 840
aaagagttgg ctgagctgcg aggtctggca gccggagtag gcctggctaa tgcctgctat 900
gcaatacata ctcttccaac ccaagaggag attgaaaatc ttcctgcctt ccctcgggaa 960
aaactgactc tgcgtctctt gctgggaagt ggagcctttg gagaagtgta tgaaggaaca 1020
gcagtggaca tcttaggagt tggaagtgga gaaatcaaag tagcagtgaa gactttgaag 1080
aagggttcca cagaccagga gaagattgaa ttcctgaagg aggcacatct gatgagcaaa 1140
tttaatcatc ccaacattct gaagcagctt ggagtttgtc tgctgaatga accccaatac 1200
attatcctgg aactgatgga gggaggagac cttcttactt atttgcgtaa agcccggatg 1260
gcaacgtttt atggtccttt actcaccttg gttgaccttg tagacctgtg tgtagatatt 1320
tcaaaaggct gtgtctactt ggaacggatg catttcattc acagggatct ggcagctaga 1380
aattgccttg tttccgtgaa agactatacc agtccacgga tagtgaagat tggagacttt 1440
ggactcgcca gagacatcta taaaaatgat tactatagaa agagagggga aggcctgctc 1500
ccagttcggt ggatggctcc agaaagtttg atggatggaa tcttcactac tcaatctgat 1560
gtatggtctt ttggaattct gatttgggag attttaactc ttggtcatca gccttatcca 1620
gctcattcca accttgatgt gttaaactat gtgcaaacag gagggagact ggagccacca 1680
agaaattgtc ctgatgatct gtggaattta atgacccagt gctgggctca agaacccgac 1740
caaagaccta cttttcatag aattcaggac caacttcagt tattcagaaa ttttttctta 1800
aatagcattt ataagtccag agatgaagca aacaacagtg gagtcataaa tgaaagcttt 1860
gaaggtgaag atggcgatgt gatttgtttg aattcagatg acattatgcc agttgcttta 1920
atggaaacga agaaccgaga agggttaaac tatatggtac ttgctacaga atgtggccaa 1980
ggtgaagaaa agtctgaggg tcctctaggc tcccaggaat ctgaatcttg tggtctgagg 2040
aaagaagaga aggaaccaca tgcagacaaa gatttctgcc aagaaaaaca agtggcttac 2100
tgcccttctg gcaagcctga aggcctgaac tatgcctgtc tcactcacag tggatatgga 2160
gatgggtctg attaa 2175
<210>3
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<213>Homo sapiens
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Met Ala Pro Trp Pro Glu Leu Gly Asp Ala Gln Pro Asn Pro Asp Lys
1 5 10 15
Tyr Leu Glu Gly Ala Ala Gly Gln Gln Pro Thr Ala Pro Asp Lys Ser
20 25 30
Lys Glu Thr Asn Lys Thr Asp Asn Thr Glu Ala Pro Val Thr Lys Ile
35 40 45
Glu Leu Leu Pro Ser Tyr Ser Thr Ala Thr Leu Ile Asp Glu Pro Thr
50 55 60
Glu Val Asp Asp Pro Trp Asn Leu Pro Thr Leu Gln Asp Ser Gly Ile
65 70 75 80
Lys Trp Ser Glu Arg Asp Thr Lys Gly Lys Ile Leu Cys Phe Phe Gln
85 90 95
Gly Ile Gly Arg Leu Ile Leu Leu Leu Gly Phe Leu Tyr Phe Phe Val
100 105 110
Cys Ser Leu Asp Ile Leu Ser Ser Ala Phe Gln Leu Val Gly Asp Asp
115 120 125
Phe Trp Ile Pro Glu Thr Ser Phe Ile Leu Thr Ile Ile Val Gly Ile
130 135 140
Phe Leu Val Val Thr Ile Pro Leu Thr Phe Val Trp His Arg Arg Leu
145 150 155 160
Lys Asn Gln Lys Ser Ala Lys Glu Gly Val Thr Val Leu Ile Asn Glu
165 170 175
Asp Lys Glu Leu Ala Glu Leu Arg Gly Leu Ala Ala Gly Val Gly Leu
180 185 190
Ala Asn Ala Cys Tyr Ala Ile His Thr Leu Pro Thr Gln Glu Glu Ile
195 200 205
Glu Asn Leu Pro Ala Phe Pro Arg Glu Lys Leu Thr Leu Arg Leu Leu
210 215 220
Leu Gly Ser Gly Ala Phe Gly Glu Val Tyr Glu Gly Thr Ala Val Asp
225 230 235 240
Ile Leu Gly Val Gly Ser Gly Glu Ile Lys Val Ala Val Lys Thr Leu
245 250 255
Lys Lys Gly Ser Thr Asp Gln Glu Lys Ile Glu Phe Leu Lys Glu Ala
260 265 270
His Leu Met Ser Lys Phe Asn His Pro Asn Ile Leu Lys Gln Leu Gly
275 280 285
Val Cys Leu Leu Asn Glu Pro Gln Tyr Ile Ile Leu Glu Leu Met Glu
290 295 300
Gly Gly Asp Leu Leu Thr Tyr Leu Arg Lys Ala Arg Met Ala Thr Phe
305 310 315 320
Tyr Gly Pro Leu Leu Thr Leu Val Asp Leu Val Asp Leu Cys Val Asp
325 330 335
Ile Ser Lys Gly Cys Val Tyr Leu Glu Arg Met His Phe Ile His Arg
340 345 350
Asp Leu Ala Ala Arg Asn Cys Leu Val Ser Val Lys Asp Tyr Thr Ser
355 360 365
Pro Arg Ile Val Lys Ile Gly Asp Phe Gly Leu Ala Arg Asp Ile Tyr
370 375 380
Lys Asn Asp Tyr Tyr Arg Lys Arg Gly Glu Gly Leu Leu Pro Val Arg
385 390 395 400
Trp Met Ala Pro Glu Ser Leu Met Asp Gly Ile Phe Thr Thr Gln Ser
405 410 415
Asp Val Trp Ser Phe Gly Ile Leu Ile Trp Glu Ile Leu Thr Leu Gly
420 425 430
His Gln Pro Tyr Pro Ala His Ser Asn Leu Asp Val Leu Asn Tyr Val
435 440 445
Gln Thr Gly Gly Arg Leu Glu Pro Pro Arg Asn Cys Pro Asp Asp Leu
450 455 460
Trp Asn Leu Met Thr Gln Cys Trp Ala Gln Glu Pro Asp Gln Arg Pro
465 470 475 480
Thr Phe His Arg Ile Gln Asp Gln Leu Gln Leu Phe Arg Asn Phe Phe
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Leu Asn Ser Ile Tyr Lys Ser Arg Asp Glu Ala Asn Asn Ser Gly Val
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Ile Asn Glu Ser Phe Glu Gly Glu Asp Gly Asp Val Ile Cys Leu Asn
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Ser Asp Asp Ile Met Pro Val Ala Leu Met Glu Thr Lys Asn Arg Glu
530 535 540
Gly Leu Asn Tyr Met Val Leu Ala Thr Glu Cys Gly Gln Gly Glu Glu
545 550 555 560
Lys Ser Glu Gly Pro Leu Gly Ser Gln Glu Ser Glu Ser Cys Gly Leu
565 570 575
Arg Lys Glu Glu Lys Glu Pro His Ala Asp Lys Asp Phe Cys Gln Glu
580 585 590
Lys Gln Val Ala Tyr Cys Pro Ser Gly Lys Pro Glu Gly Leu Asn Tyr
595 600 605
Ala Cys Leu Thr His Ser Gly Tyr Gly Asp Gly Ser Asp
610 615 620
<210>4
<211>1866
<212>DNA
<213>Homo sapiens
<400>4
atggctccct ggcctgaatt gggagatgcc cagcccaacc ccgataagta cctcgaaggg 60
gccgcaggtc agcagcccac tgcccctgat aaaagcaaag agaccaacaa aacagataac 120
actgaggcac ctgtaaccaa gattgaactt ctgccgtcct actccacggc tacactgata 180
gatgagccca ctgaggtgga tgacccctgg aacctaccca ctcttcagga ctcggggatc 240
aagtggtcag agagagacac caaagggaag attctctgtt tcttccaagg gattgggaga 300
ttgattttac ttctcggatt tctctacttt ttcgtgtgct ccctggatat tcttagtagc 360
gccttccagc tggttggaga tgatttttgg ataccagaaa caagtttcat acttactatt 420
atagttggaa tatttctggt tgttacaatc ccactgacct ttgtctggca tagaagatta 480
aagaatcaaa aaagtgccaa ggaaggggtg acagtgctta taaacgaaga caaagagttg 540
gctgagctgc gaggtctggc agccggagta ggcctggcta atgcctgcta tgcaatacat 600
actcttccaa cccaagagga gattgaaaat cttcctgcct tccctcggga aaaactgact 660
ctgcgtctct tgctgggaag tggagccttt ggagaagtgt atgaaggaac agcagtggac 720
atcttaggag ttggaagtgg agaaatcaaa gtagcagtga agactttgaa gaagggttcc 780
acagaccagg agaagattga attcctgaag gaggcacatc tgatgagcaa atttaatcat 840
cccaacattc tgaagcagct tggagtttgt ctgctgaatg aaccccaata cattatcctg 900
gaactgatgg agggaggaga ccttcttact tatttgcgta aagcccggat ggcaacgttt 960
tatggtcctt tactcacctt ggttgacctt gtagacctgt gtgtagatat ttcaaaaggc 1020
tgtgtctact tggaacggat gcatttcatt cacagggatc tggcagctag aaattgcctt 1080
gtttccgtga aagactatac cagtccacgg atagtgaaga ttggagactt tggactcgcc 1140
agagacatct ataaaaatga ttactataga aagagagggg aaggcctgct cccagttcgg 1200
tggatggctc cagaaagttt gatggatgga atcttcacta ctcaatctga tgtatggtct 1260
tttggaattc tgatttggga gattttaact cttggtcatc agccttatcc agctcattcc 1320
aaccttgatg tgttaaacta tgtgcaaaca ggagggagac tggagccacc aagaaattgt 1380
cctgatgatc tgtggaattt aatgacccag tgctgggctc aagaacccga ccaaagacct 1440
acttttcata gaattcagga ccaacttcag ttattcagaa attttttctt aaatagcatt 1500
tataagtcca gagatgaagc aaacaacagt ggagtcataa atgaaagctt tgaaggtgaa 1560
gatggcgatg tgatttgttt gaattcagat gacattatgc cagttgcttt aatggaaacg 1620
aagaaccgag aagggttaaa ctatatggta cttgctacag aatgtggcca aggtgaagaa 1680
aagtctgagg gtcctctagg ctcccaggaa tctgaatctt gtggtctgag gaaagaagag 1740
aaggaaccac atgcagacaa agatttctgc caagaaaaac aagtggctta ctgcccttct 1800
ggcaagcctg aaggcctgaa ctatgcctgt ctcactcaca gtggatatgg agatgggtct 1860
gattaa 1866
<210>5
<211>690
<212>PRT
<213>Homo sapiens
<400>5
Met Ala Pro Trp Pro Glu Leu Gly Asp Ala Gln Pro Asn Pro Asp Lys
1 5 10 15
Tyr Leu Glu Gly Ala Ala Gly Gln Gln Pro Thr Ala Pro Asp Lys Ser
20 25 30
Lys Glu Thr Asn Lys Thr Asp Asn Thr Glu Ala Pro Val Thr Lys Ile
35 40 45
Glu Leu Leu Pro Ser Tyr Ser Thr Ala Thr Leu Ile Asp Glu Pro Thr
50 55 60
Glu Val Asp Asp Pro Trp Asn Leu Pro Thr Leu Gln Asp Ser Gly Ile
65 70 75 80
Lys Trp Ser Glu Arg Asp Thr Lys Gly Lys Ile Leu Cys Phe Phe Gln
85 90 95
Gly Ile Gly Arg Leu Ile Leu Leu Leu Gly Phe Leu Tyr Phe Phe Val
100 105 110
Cys Ser Leu Asp Ile Leu Ser Ser Ala Phe Gln Leu Val Gly Gly Lys
115 120 125
Met Ala Gly Gln Phe Phe Ser Asn Ser Ser Ile Met Ser Asn Pro Leu
130 135 140
Leu Gly Leu Val Ile Gly Val Leu Val Thr Val Leu Val Gln Ser Ser
145 150 155 160
Ser Thr Ser Thr Ser Ile Val Val Ser Met Val Ser Ser Ser Leu Leu
165 170 175
Thr Val Arg Ala Ala Ile Pro Ile Ile Met Gly Ala Asn Ile Gly Thr
180 185 190
Ser Ile Thr Asn Thr Ile Val Ala Leu Met Gln Val Gly Asp Arg Ser
195 200 205
Glu Phe Arg Arg Ala Phe Ala Gly Ala Thr Val His Asp Phe Phe Asn
210 215 220
Trp Leu Ser Val Leu Val Leu Leu Pro Val Glu Val Ala Thr His Tyr
225 230 235 240
Leu Glu Ile Ile Thr Gln Leu Ile Val Glu Ser Phe His Phe Lys Asn
245 250 255
Gly Glu Asp Ala Pro Asp Leu Leu Lys Val Ile Thr Lys Pro Phe Thr
260 265 270
Lys Leu Ile Val Gln Leu Asp Lys Lys Val Ile Ser Gln Ile Ala Met
275 280 285
Asn Asp Glu Lys Ala Lys Asn Lys Ser Leu Val Lys Ile Trp Cys Lys
290 295 300
Thr Phe Thr Asn Lys Thr Gln Ile Asn Val Thr Val Pro Ser Thr Ala
305 310 315 320
Asn Cys Thr Ser Pro Ser Leu Cys Trp Thr Asp Gly Ile Gln Asn Trp
325 330 335
Thr Met Lys Asn Val Thr Tyr Lys Glu Asn Ile Ala Lys Cys Gln His
340 345 350
Ile Phe Val Asn Phe His Leu Pro Asp Leu Ala Val Gly Thr Ile Leu
355 360 365
Leu Ile Leu Ser Leu Leu Val Leu Cys Gly Cys Leu Ile Met Ile Val
370 375 380
Lys Ile Leu Gly Ser Val Leu Lys Gly Gln Val Ala Thr Val Ile Lys
385 390 395 400
Lys Thr Ile Asn Thr Asp Phe Pro Phe Pro Phe Ala Trp Leu Thr Gly
405 410 415
Tyr Leu Ala Ile Leu Val Gly Ala Gly Met Thr Phe Ile Val Gln Ser
420 425 430
Ser Ser Val Phe Thr Ser Ala Leu Thr Pro Leu Ile Gly Ile Gly Val
435 440 445
Ile Thr Ile Glu Arg Ala Tyr Pro Leu Thr Leu Gly Ser Asn Ile Gly
450 455 460
Thr Thr Thr Thr Ala Ile Leu Ala Ala Leu Ala Ser Pro Gly Asn Ala
465 470 475 480
Leu Arg Ser Ser Leu Gln Ile Ala Leu Cys His Phe Phe Phe Asn Ile
485 490 495
Ser Gly Ile Leu Leu Trp Tyr Pro Ile Pro Phe Thr Arg Leu Pro Ile
500 505 510
Arg Met Ala Lys Gly Leu Gly Asn Ile Ser Ala Lys Tyr Arg Trp Phe
515 520 525
Ala Val Phe Tyr Leu Ile Ile Phe Phe Phe Leu Ile Pro Leu Thr Val
530 535 540
Phe Gly Leu Ser Leu Ala Gly Trp Arg Val Leu Val Gly Val Gly Val
545 550 555 560
Pro Val Val Phe Ile Ile Ile Leu Val Leu Cys Leu Arg Leu Leu Gln
565 570 575
Ser Arg Cys Pro Arg Val Leu Pro Lys Lys Leu Gln Asn Trp Asn Phe
580 585 590
Leu Pro Leu Trp Met Arg Ser Leu Lys Pro Trp Asp Ala Val Val Ser
595 600 605
Lys Phe Thr Gly Cys Phe Gln Met Arg Cys Cys Tyr Cys Cys Arg Val
610 615 620
Cys Cys Arg Ala Cys Cys Leu Leu Cys Gly Cys Pro Lys Cys Cys Arg
625 630 635 640
Cys Ser Lys Cys Cys Glu Asp Leu Glu Glu Ala Gln Glu Gly Gln Asp
645 650 655
Val Pro Val Lys Ala Pro Glu Thr Phe Asp Asn Ile Thr Ile Ser Arg
660 665 670
Glu Ala Gln Gly Glu Val Pro Ala Ser Asp Ser Lys Thr Glu Cys Thr
675 680 685
Ala Leu
690
<210>6
<211>2280
<212>DNA
<213>Homo sapiens
<400>6
cgggccaggt ttccaggctc ggccgccgcc tccatcccag cacctgcgga gggagcgctg 60
accatggctc cctggcctga attgggagat gcccagccca accccgataa gtacctcgaa 120
ggggccgcag gtcagcagcc cactgcccct gataaaagca aagagaccaa caaaacagat 180
aacactgagg cacctgtaac caagattgaa cttctgccgt cctactccac ggctacactg 240
atagatgagc ccactgaggt ggatgacccc tggaacctac ccactcttca ggactcgggg 300
atcaagtggt cagagagaga caccaaaggg aagattctct gtttcttcca agggattggg 360
agattgattt tacttctcgg atttctctac tttttcgtgt gctccctgga tattcttagt 420
agcgccttcc agctggttgg aggaaaaatg gcaggacagt tcttcagcaa cagctctatt 480
atgtccaacc ctttgttggg gctggtgatc ggggtgctgg tgaccgtctt ggtgcagagc 540
tccagcacct caacgtccat cgttgtcagc atggtgtcct cttcattgct cactgttcgg 600
gctgccatcc ccattatcat gggggccaac attggaacgt caatcaccaa cactattgtt 660
gcgctcatgc aggtgggaga tcggagtgag ttcagaagag cttttgcagg agccactgtc 720
catgacttct tcaactggct gtccgtgttg gtgctcttgc ccgtggaggt ggccacccat 780
tacctcgaga tcataaccca gcttatagtg gagagcttcc acttcaagaa tggagaagat 840
gccccagatc ttctgaaagt catcactaag cccttcacaa agctcattgt ccagctggat 900
aaaaaagtta tcagccaaat tgcaatgaac gatgaaaaag cgaaaaacaa gagtcttgtc 960
aagatttggt gcaaaacttt taccaacaag acccagatta acgtcactgt tccctcgact 1020
gctaactgca cctccccttc cctctgttgg acggatggca tccaaaactg gaccatgaag 1080
aatgtgacct acaaggagaa catcgccaaa tgccagcata tctttgtgaa tttccacctc 1140
ccggatcttg ctgtgggcac catcttgctc atactctccc tgctggtcct ctgtggttgc 1200
ctgatcatga ttgtcaagat cctgggctct gtgctcaagg ggcaggtcgc cactgtcatc 1260
aagaagacca tcaacactga tttccccttt ccctttgcat ggttgactgg ctacctggcc 1320
atcctcgtcg gggcaggcat gaccttcatc gtacagagca gctctgtgtt cacgtcggcc 1380
ttgacccccc tgattggaat cggcgtgata accattgaga gggcttatcc actcacgctg 1440
ggctccaaca tcggcaccac caccaccgcc atcctggccg ccttagccag ccctggcaat 1500
gcattgagga gttcactcca gatcgccctg tgccactttt tcttcaacat ctccggcatc 1560
ttgctgtggt acccgatccc gttcactcgc ctgcccatcc gcatggccaa ggggctgggc 1620
aacatctctg ccaagtatcg ctggttcgcc gtcttctacc tgatcatctt cttcttcctg 1680
atcccgctga cggtgtttgg cctctcgctg gccggctggc gggtgctggt tggtgtcggg 1740
gttcccgtcg tcttcatcat catcctggta ctgtgcctcc gactcctgca gtctcgctgc 1800
ccacgcgtcc tgccgaagaa actccagaac tggaacttcc tgccgctgtg gatgcgctcg 1860
ctgaagccct gggatgccgt cgtctccaag ttcaccggct gcttccagat gcgctgctgc 1920
tactgctgcc gcgtgtgctg ccgcgcgtgc tgcttgctgt gtggctgccc caagtgctgc 1980
cgctgcagca agtgctgcga ggacttggag gaggcgcagg aggggcagga tgtccctgtc 2040
aaggctcctg agacctttga taacataacc attagcagag aggctcaggg tgaggtccct 2100
gcctcggact caaagaccga atgcacggcc ttgtagggga cgccccagat tgtcagggat 2160
ggggggatgg tccttgagtt ttgcatgctc tcctccctcc cacttctgca ccctttcacc 2220
acctcgagga gatttgctcc ccattagcga atgaaattga tgcagtccta aaaaaaaaaa 2280
<210>7
<211>2347
<212>PRT
<213>Homo sapiens
<400>7
Met Lys Asn Ile Tyr Cys Leu Ile Pro Lys Leu Val Asn Phe Ala Thr
1 5 10 15
Leu Gly Cys Leu Trp Ile Ser Val Val Gln Cys Thr Val Leu Asn Ser
20 25 30
Cys Leu Lys Ser Cys Val Thr Asn Leu Gly Gln Gln Leu Asp Leu Gly
35 40 45
Thr Pro His Asn Leu Ser Glu Pro Cys Ile Gln Gly Cys His Phe Trp
50 55 60
Asn Ser Val Asp Gln Lys Asn Cys Ala Leu Lys Cys Arg Glu Ser Cys
65 70 75 80
Glu Val Gly Cys Ser Ser Ala Glu Gly Ala Tyr Glu Glu Glu Val Leu
85 90 95
Glu Asn Ala Asp Leu Pro Thr Ala Pro Phe Ala Ser Ser Ile Gly Ser
100 105 110
His Asn Met Thr Leu Arg Trp Lys Ser Ala Asn Phe Ser Gly Val Lys
115 120 125
Tyr Ile Ile Gln Trp Lys Tyr Ala Gln Leu Leu Gly Ser Trp Thr Tyr
130 135 140
Thr Lys Thr Val Ser Arg Pro Ser Tyr Val Val Lys Pro Leu His Pro
145 150 155 160
Phe Thr Glu Tyr Ile Phe Arg Val Val Trp Ile Phe Thr Ala Gln Leu
165 170 175
Gln Leu Tyr Ser Pro Pro Ser Pro Ser Tyr Arg Thr His Pro His Gly
180 185 190
Val Pro Glu Thr Ala Pro Leu Ile Arg Asn Ile Glu Ser Ser Ser Pro
195 200 205
Asp Thr Val Glu Val Ser Trp Asp Pro Pro Gln Phe Pro Gly Gly Pro
210 215 220
Ile Leu Gly Tyr Asn Leu Arg Leu Ile Ser Lys Asn Gln Lys Leu Asp
225 230 235 240
Ala Gly Thr Gln Arg Thr Ser Phe Gln Phe Tyr Ser Thr Leu Pro Asn
245 250 255
Thr Ile Tyr Arg Phe Ser Ile Ala Ala Val Asn Glu Val Gly Glu Gly
260 265 270
Pro Glu Ala Glu Ser Ser Ile Thr Thr Ser Ser Ser Ala Val Gln Gln
275 280 285
Glu Glu Gln Trp Leu Phe Leu Ser Arg Lys Thr Ser Leu Arg Lys Arg
290 295 300
Ser Leu Lys His Leu Val Asp Glu Ala His Cys Leu Arg Leu Asp Ala
305 310 315 320
Ile Tyr His Asn Ile Thr Gly Ile Ser Val Asp Val His Gln Gln Ile
325 330 335
Val Tyr Phe Ser Glu Gly Thr Leu Ile Trp Ala Lys Lys Ala Ala Asn
340 345 350
Met Ser Asp Val Ser Asp Leu Arg Ile Phe Tyr Arg Gly Ser Gly Leu
355 360 365
Ile Ser Ser Ile Ser Ile Asp Trp Leu Tyr Gln Arg Met Tyr Phe Ile
370 375 380
Met Asp Glu Leu Val Cys Val Cys Asp Leu Glu Asn Cys Ser Asn Ile
385 390 395 400
Glu Glu Ile Thr Pro Pro Ser Ile Ser Ala Pro Gln Lys Ile Val Ala
405 410 415
Asp Ser Tyr Asn Gly Tyr Val Phe Tyr Leu Leu Arg Asp Gly Ile Tyr
420 425 430
Arg Ala Asp Leu Pro Val Pro Ser Gly Arg Cys Ala Glu Ala Val Arg
435 440 445
Ile Val Glu Ser Cys Thr Leu Lys Asp Phe Ala Ile Lys Pro Gln Ala
450 455 460
Lys Arg Ile Ile Tyr Phe Asn Asp Thr Ala Gln Val Phe Met Ser Thr
465 470 475 480
Phe Leu Asp Gly Ser Ala Ser His Leu Ile Leu Pro Arg Ile Pro Phe
485 490 495
Ala Asp Val Lys Ser Phe Ala Cys Glu Asn Asn Asp Phe Leu Val Thr
500 505 510
Asp Gly Lys Val Ile Phe Gln Gln Asp Ala Leu Ser Phe Asn Glu Phe
515 520 525
Ile Val Gly Cys Asp Leu Ser His Ile Glu Glu Phe Gly Phe Gly Asn
530 535 540
Leu Val Ile Phe Gly Ser Ser Ser Gln Leu His Pro Leu Pro Gly Arg
545 550 555 560
Pro Gln Glu Leu Ser Val Leu Phe Gly Ser His Gln Ala Leu Val Gln
565 570 575
Trp Lys Pro Pro Ala Leu Ala Ile Gly Ala Asn Val Ile Leu Ile Ser
580 585 590
Asp Ile Ile Glu Leu Phe Glu Leu Gly Pro Ser Ala Trp Gln Asn Trp
595 600 605
Thr Tyr Glu Val Lys Val Ser Thr Gln Asp Pro Pro Glu Val Thr His
610 615 620
Ile Phe Leu Asn Ile Ser Gly Thr Met Leu Asn Val Pro Glu Leu Gln
625 630 635 640
Ser Ala Met Lys Tyr Lys Val Ser Val Arg Ala Ser Ser Pro Lys Arg
645 650 655
Pro Gly Pro Trp Ser Glu Pro Ser Val Gly Thr Thr Leu Val Pro Ala
660 665 670
Ser Glu Pro Pro Phe Ile Met Ala Val Lys Glu Asp Gly Leu Trp Ser
675 680 685
Lys Pro Leu Asn Ser Phe Gly Pro Gly Glu Phe Leu Ser Ser Asp Ile
690 695 700
Gly Asn Val Ser Asp Met Asp Trp Tyr Asn Asn Ser Leu Tyr Tyr Ser
705 710 715 720
Asp Thr Lys Gly Asp Val Phe Val Trp Leu Leu Asn Gly Thr Asp Ile
725 730 735
Ser Glu Asn Tyr His Leu Pro Ser Ile Ala Gly Ala Gly Ala Leu Ala
740 745 750
Phe Glu Trp Leu Gly His Phe Leu Tyr Trp Ala Gly Lys Thr Tyr Val
755 760 765
Ile Gln Arg Gln Ser Val Leu Thr Gly His Thr Asp Ile Val Thr His
770 775 780
Val Lys Leu Leu Val Asn Asp Met Val Val Asp Ser Val Gly Gly Tyr
785 790 795 800
Leu Tyr Trp Thr Thr Leu Tyr Ser Val Glu Ser Thr Arg Leu Asn Gly
805 810 815
Glu Ser Ser Leu Val Leu Gln Thr Gln Pro Trp Phe Ser Gly Lys Lys
820 825 830
Val Ile Ala Leu Thr Leu Asp Leu Ser Asp Gly Leu Leu Tyr Trp Leu
835 840 845
Val Gln Asp Ser Gln Cys Ile His Leu Tyr Thr Ala Val Leu Arg Gly
850 855 860
Gln Ser Thr Gly Asp Thr Thr Ile Thr Glu Phe Ala Ala Trp Ser Thr
865 870 875 880
Ser Glu Ile Ser Gln Asn Ala Leu Met Tyr Tyr Ser Gly Arg Leu Phe
885 890 895
Trp Ile Asn Gly Phe Arg Ile Ile Thr Thr Gln Glu Ile Gly Gln Lys
900 905 910
Thr Ser Val Ser Val Leu Glu Pro Ala Arg Phe Asn Gln Phe Thr Ile
915 920 925
Ile Gln Thr Ser Leu Lys Pro Leu Pro Gly Asn Phe Ser Phe Thr Pro
930 935 940
Lys Val Ile Pro Asp Ser Val Gln Glu Ser Ser Phe Arg Ile Glu Gly
945 950 955 960
Asn Ala Ser Ser Phe Gln Ile Leu Trp Asn Gly Pro Pro Ala Val Asp
965 970 975
Trp Gly Val Val Phe Tyr Ser Val Glu Phe Ser Ala His Ser Lys Phe
980 985 990
Leu Ala Ser Glu Gln His Ser Leu Pro Val Phe Thr Val Glu Gly Leu
995 1000 1005
Glu Pro Tyr Ala Leu Phe Asn Leu Ser Val Thr Pro Tyr Thr Tyr
1010 1015 1020
Trp Gly Lys Gly Pro Lys Thr Ser Leu Ser Leu Arg Ala Pro Glu
1025 1030 1035
Thr Val Pro Ser Ala Pro Glu Asn Pro Arg Ile Phe Ile Leu Pro
1040 1045 1050
Ser Gly Lys Cys Cys Asn Lys Asn Glu Val Val Val Glu Phe Arg
1055 1060 1065
Trp Asn Lys Pro Lys His Glu Asn Gly Val Leu Thr Lys Phe Glu
1070 1075 1080
Ile Phe Tyr Asn Ile Ser Asn Gln Ser Ile Thr Asn Lys Thr Cys
1085 1090 1095
Glu Asp Trp Ile Ala Val Asn Val Thr Pro Ser Val Met Ser Phe
1100 1105 1110
Gln Leu Glu Gly Met Ser Pro Arg Cys Phe Ile Ala Phe Gln Val
1115 1120 1125
Arg Ala Phe Thr Ser Lys Gly Pro Gly Pro Tyr Ala Asp Val Val
1130 1135 1140
Lys Ser Thr Thr Ser Glu Ile Asn Pro Phe Pro His Leu Ile Thr
1145 1150 1155
Leu Leu Gly Asn Lys Ile Val Phe Leu Asp Met Asp Gln Asn Gln
1160 1165 1170
Val Val Trp Thr Phe Ser Ala Glu Arg Val Ile Ser Ala Val Cys
1175 1180 1185
Tyr Thr Ala Asp Asn Glu Met Gly Tyr Tyr Ala Glu Gly Asp Ser
1190 1195 1200
Leu Phe Leu Leu His Leu His Asn Arg Ser Ser Ser Glu Leu Phe
1205 1210 1215
Gln Asp Ser Leu Val Phe Asp Ile Thr Val Ile Thr Ile Asp Trp
1220 1225 1230
Ile Ser Arg His Leu Tyr Phe Ala Leu Lys Glu Ser Gln Asn Gly
1235 1240 1245
Met Gln Val Phe Asp Val Asp Leu Glu His Lys Val Lys Tyr Pro
1250 1255 1260
Arg Glu Val Lys Ile His Asn Arg Asn Ser Thr Ile Ile Ser Phe
1265 1270 1275
Ser Val Tyr Pro Leu Leu Ser Arg Leu Tyr Trp Thr Glu Val Ser
1280 1285 1290
Asn Phe Gly Tyr Gln Met Phe Tyr Tyr Ser Ile Ile Ser His Thr
1295 1300 1305
Leu His Arg Ile Leu Gln Pro Thr Ala Thr Asn Gln Gln Asn Lys
1310 1315 1320
Arg Asn Gln Cys Ser Cys Asn Val Thr Glu Phe Glu Leu Ser Gly
1325 1330 1335
Ala Met Ala Ile Asp Thr Ser Asn Leu Glu Lys Pro Leu Ile Tyr
1340 1345 1350
Phe Ala Lys Ala Gln Glu Ile Trp Ala Met Asp Leu Glu Gly Cys
1355 1360 1365
Gln Cys Trp Arg Val Ile Thr Val Pro Ala Met Leu Ala Gly Lys
1370 1375 1380
Thr Leu Val Ser Leu Thr Val Asp Gly Asp Leu Ile Tyr Trp Ile
1385 1390 1395
Ile Thr Ala Lys Asp Ser Thr Gln Ile Tyr Gln Ala Lys Lys Gly
1400 1405 1410
Asn Gly Ala Ile Val Ser Gln Val Lys Ala Leu Arg Ser Arg His
1415 1420 1425
Ile Leu Ala Tyr Ser Ser Val Met Gln Pro Phe Pro Asp Lys Ala
1430 1435 1440
Phe Leu Ser Leu Ala Ser Asp Thr Val Glu Pro Thr Ile Leu Asn
1445 1450 1455
Ala Thr Asn Thr Ser Leu Thr Ile Arg Leu Pro Leu Ala Lys Thr
1460 1465 1470
Asn Leu Thr Trp Tyr Gly Ile Thr Ser Pro Thr Pro Thr Tyr Leu
1475 1480 1485
Val Tyr Tyr Ala Glu Val Asn Asp Arg Lys Asn Ser Ser Asp Leu
1490 1495 1500
Lys Tyr Arg Ile Leu Glu Phe Gln Asp Ser Ile Ala Leu Ile Glu
1505 1510 1515
Asp Leu Gln Pro Phe Ser Thr Tyr Met Ile Gln Ile Ala Val Lys
1520 1525 1530
Asn Tyr Tyr Ser Asp Pro Leu Glu His Leu Pro Pro Gly Lys Glu
1535 1540 1545
Ile Trp Gly Lys Thr Lys Asn Gly Val Pro Glu Ala Val Gln Leu
1550 1555 1560
Ile Asn Thr Thr Val Arg Ser Asp Thr Ser Leu Ile Ile Ser Trp
1565 1570 1575
Arg Glu Ser His Lys Pro Asn Gly Pro Lys Glu Ser Val Arg Tyr
1580 1585 1590
Gln Leu Ala Ile Ser His Leu Ala Leu Ile Pro Glu Thr Pro Leu
1595 1600 1605
Arg Gln Ser Glu Phe Pro Asn Gly Arg Leu Thr Leu Leu Val Thr
1610 1615 1620
Arg Leu Ser Gly Gly Asn Ile Tyr Val Leu Lys Val Leu Ala Cys
1625 1630 1635
His Ser Glu Glu Met Trp Cys Thr Glu Ser His Pro Val Thr Val
1640 1645 1650
Glu Met Phe Asn Thr Pro Glu Lys Pro Tyr Ser Leu Val Pro Glu
1655 1660 1665
Asn Thr Ser Leu Gln Phe Asn Trp Lys Ala Pro Leu Asn Val Asn
1670 1675 1680
Leu Ile Arg Phe Trp Val Glu Leu Gln Lys Trp Lys Tyr Asn Glu
1685 1690 1695
Phe Tyr His Val Lys Thr Ser Cys Ser Gln Gly Pro Ala Tyr Val
1700 1705 1710
Cys Asn Ile Thr Asn Leu Gln Pro Tyr Thr Ser Tyr Asn Val Arg
1715 1720 1725
Val Val Val Val Tyr Lys Thr Gly Glu Asn Ser Thr Ser Leu Pro
1730 1735 1740
Glu Ser Phe Lys Thr Lys Ala Gly Val Pro Asn Lys Pro Gly Ile
1745 1750 1755
Pro Lys Leu Leu Glu Gly Ser Lys Asn Ser Ile Gln Trp Glu Lys
1760 1765 1770
Ala Glu Asp Asn Gly Cys Arg Ile Thr Tyr Tyr Ile Leu Glu Ile
1775 1780 1785
Arg Lys Ser Thr Ser Asn Asn Leu Gln Asn Gln Asn Leu Arg Trp
1790 1795 1800
Lys Met Thr Phe Asn Gly Ser Cys Ser Ser Val Cys Thr Trp Lys
1805 1810 1815
Ser Lys Asn Leu Lys Gly Ile Phe Gln Phe Arg Val Val Ala Ala
1820 1825 1830
Asn Asn Leu Gly Phe Gly Glu Tyr Ser Gly Ile Ser Glu Asn Ile
1835 1840 1845
Ile Leu Val Gly Asp Asp Phe Trp Ile Pro Glu Thr Ser Phe Ile
1850 1855 1860
Leu Thr Ile Ile Val Gly Ile Phe Leu Val Val Thr Ile Pro Leu
1865 1870 1875
Thr Phe Val Trp His Arg Arg Leu Lys Asn Gln Lys Ser Ala Lys
1880 1885 1890
Glu Gly Val Thr Val Leu Ile Asn Glu Asp Lys Glu Leu Ala Glu
1895 1900 1905
Leu Arg Gly Leu Ala Ala Gly Val Gly Leu Ala Asn Ala Cys Tyr
1910 1915 1920
Ala Ile His Thr Leu Pro Thr Gln Glu Glu Ile Glu Asn Leu Pro
1925 1930 1935
Ala Phe Pro Arg Glu Lys Leu Thr Leu Arg Leu Leu Leu Gly Ser
1940 1945 1950
Gly Ala Phe Gly Glu Val Tyr Glu Gly Thr Ala Val Asp Ile Leu
1955 1960 1965
Gly Val Gly Ser Gly Glu Ile Lys Val Ala Val Lys Thr Leu Lys
1970 1975 1980
Lys Gly Ser Thr Asp Gln Glu Lys Ile Glu Phe Leu Lys Glu Ala
1985 1990 1995
His Leu Met Ser Lys Phe Asn His Pro Asn Ile Leu Lys Gln Leu
2000 2005 2010
Gly Val Cys Leu Leu Asn Glu Pro Gln Tyr Ile Ile Leu Glu Leu
2015 2020 2025
Met Glu Gly Gly Asp Leu Leu Thr Tyr Leu Arg Lys Ala Arg Met
2030 2035 2040
Ala Thr Phe Tyr Gly Pro Leu Leu Thr Leu Val Asp Leu Val Asp
2045 2050 2055
Leu Cys Val Asp Ile Ser Lys Gly Cys Val Tyr Leu Glu Arg Met
2060 2065 2070
His Phe Ile His Arg Asp Leu Ala Ala Arg Asn Cys Leu Val Ser
2075 2080 2085
Val Lys Asp Tyr Thr Ser Pro Arg Ile Val Lys Ile Gly Asp Phe
2090 2095 2100
Gly Leu Ala Arg Asp Ile Tyr Lys Asn Asp Tyr Tyr Arg Lys Arg
2105 2110 2115
Gly Glu Gly Leu Leu Pro Val Arg Trp Met Ala Pro Glu Ser Leu
2120 2125 2130
Met Asp Gly Ile Phe Thr Thr Gln Ser Asp Val Trp Ser Phe Gly
2135 2140 2145
Ile Leu Ile Trp Glu Ile Leu Thr Leu Gly His Gln Pro Tyr Pro
2150 2155 2160
Ala His Ser Asn Leu Asp Val Leu Asn Tyr Val Gln Thr Gly Gly
2165 2170 2175
Arg Leu Glu Pro Pro Arg Asn Cys Pro Asp Asp Leu Trp Asn Leu
2180 2185 2190
Met Thr Gln Cys Trp Ala Gln Glu Pro Asp Gln Arg Pro Thr Phe
2195 2200 2205
His Arg Ile Gln Asn Gln Leu Gln Leu Phe Arg Asn Phe Phe Leu
2210 2215 2220
Asn Ser Ile Tyr Gln Cys Arg Asp Glu Ala Asn Asn Ser Gly Val
2225 2230 2235
Ile Asn Glu Ser Phe Glu Gly Glu Asp Gly Asp Val Ile Cys Leu
2240 2245 2250
Asn Ser Asp Asp Ile Met Pro Val Val Leu Met Glu Thr Lys Asn
2255 2260 2265
Arg Glu Gly Leu Asn Tyr Met Val Leu Ala Thr Glu Cys Gly Gln
2270 2275 2280
Gly Glu Glu Lys Ser Glu Gly Pro Leu Gly Ser Gln Glu Ser Glu
2285 2290 2295
Ser Cys Gly Leu Arg Lys Glu Glu Lys Glu Pro His Ala Asp Lys
2300 2305 2310
Asp Phe Cys Gln Glu Lys Gln Val Ala Tyr Cys Pro Ser Gly Lys
2315 2320 2325
Pro Glu Gly Leu Asn Tyr Ala Cys Leu Thr His Ser Gly Tyr Gly
2330 2335 2340
Asp Gly Ser Asp
2345
<210>8
<211>7368
<212>DNA
<213>Homo sapiens
<400>8
caagctttca agcattcaaa ggtctaaatg aaaaaggcta agtattattt caaaaggcaa 60
gtatatccta atatagcaaa acaaacaaag caaaatccat cagctactcc tccaattgaa 120
gtgatgaagc ccaaataatt catatagcaa aatggagaaa attagaccgg ccatctaaaa 180
atctgccatt ggtgaagtga tgaagaacat ttactgtctt attccgaagc ttgtcaattt 240
tgcaactctt ggctgcctat ggatttctgt ggtgcagtgt acagttttaa atagctgcct 300
aaagtcgtgt gtaactaatc tgggccagca gcttgacctt ggcacaccac ataatctgag 360
tgaaccgtgt atccaaggat gtcacttttg gaactctgta gatcagaaaa actgtgcttt 420
aaagtgtcgg gagtcgtgtg aggttggctg tagcagcgcg gaaggtgcat atgaagagga 480
agtactggaa aatgcagacc taccaactgc tccctttgct tcttccattg gaagccacaa 540
tatgacatta cgatggaaat ctgcaaactt ctctggagta aaatacatca ttcagtggaa 600
atatgcacaa cttctgggaa gctggactta tactaagact gtgtccagac cgtcctatgt 660
ggtcaagccc ctgcacccct tcactgagta cattttccga gtggtttgga tcttcacagc 720
gcagctgcag ctctactccc ctccaagtcc cagttacagg actcatcctc atggagttcc 780
tgaaactgca cctttgatta ggaatattga gagctcaagt cccgacactg tggaagtcag 840
ctgggatcca cctcaattcc caggtggacc tattttgggt tataacttaa ggctgatcag 900
caaaaatcaa aaattagatg cagggacaca gagaaccagt ttccagtttt actccacttt 960
accaaatact atctacaggt tttctattgc agcagtaaat gaagttggtg agggtccaga 1020
agcagaatct agtattacca cttcatcttc agcagttcaa caagaggaac agtggctctt 1080
tttatccaga aaaacttctc taagaaagag atctttaaaa catttagtag atgaagcaca 1140
ttgccttcgg ttggatgcta tataccataa tattacagga atatctgttg atgtccacca 1200
gcaaattgtt tatttctctg aaggaactct catatgggcg aagaaggctg ccaacatgtc 1260
tgatgtatct gacctgagaa ttttttacag aggttcagga ttaatttctt ctatctccat 1320
agattggctt tatcaaagaa tgtatttcat catggatgaa ctggtatgtg tctgtgattt 1380
agagaactgc tcaaacatcg aggaaattac tccaccctct attagtgcac ctcaaaaaat 1440
tgtggctgat tcatacaatg ggtatgtctt ttacctcctg agagatggca tttatagagc 1500
agaccttcct gtaccatctg gccggtgtgc agaagctgtg cgtattgtgg agagttgcac 1560
gttaaaggac tttgcaatca agccacaagc caagcgaatc atttacttca atgacactgc 1620
ccaagtcttc atgtcaacat ttctggatgg ctctgcttcc catctcatcc tacctcgcat 1680
cccctttgct gatgtgaaaa gttttgcttg tgaaaacaat gactttcttg tcacagatgg 1740
caaggtcatt ttccaacagg atgctttgtc ttttaatgaa ttcatcgtgg gatgtgacct 1800
gagtcacata gaagaatttg ggtttggtaa cttggtcatc tttggctcat cctcccagct 1860
gcaccctctg ccaggccgcc cgcaggagct ttcggtgctg tttggctctc accaggctct 1920
tgttcaatgg aagcctcctg cccttgccat aggagccaat gtcatcctga tcagtgatat 1980
tattgaactc tttgaattag gcccttctgc ctggcagaac tggacctatg aggtgaaagt 2040
atccacccaa gaccctcctg aagtcactca tattttcttg aacataagtg gaaccatgct 2100
gaatgtacct gagctgcaga gtgctatgaa atacaaggtt tctgtgagag caagttctcc 2160
aaagaggcca ggcccctggt cagagccctc agtgggtact accctggtgc cagctagtga 2220
accaccattt atcatggctg tgaaagaaga tgggctttgg agtaaaccat taaatagctt 2280
tggcccagga gagttcttat cctctgatat aggaaatgtg tcagacatgg attggtataa 2340
caacagcctc tactacagtg acacgaaagg cgacgttttt gtgtggctgc tgaatgggac 2400
ggatatctca gagaattatc acctacccag cattgcagga gcaggggctt tagcttttga 2460
gtggctgggt cactttctct actgggctgg aaagacatat gtgatacaaa ggcagtctgt 2520
gttgacggga cacacagaca ttgttaccca cgtgaagcta ttggtgaatg acatggtggt 2580
ggattcagtt ggtggatatc tctactggac cacactctat tcagtggaaa gcaccagact 2640
aaatggggaa agttcccttg tactacagac acagccttgg ttttctggga aaaaggtaat 2700
tgctctaact ttagacctca gtgatgggct cctgtattgg ttggttcaag acagtcaatg 2760
tattcacctg tacacagctg ttcttcgggg acagagcact ggggatacca ccatcacaga 2820
atttgcagcc tggagtactt ctgaaatttc ccagaatgca ctgatgtact atagtggtcg 2880
gctgttctgg atcaatggct ttaggattat cacaactcaa gaaataggtc agaaaaccag 2940
tgtctctgtt ttggaaccag ccagatttaa tcagttcaca attattcaga catcccttaa 3000
gcccctgcca gggaactttt cctttacccc taaggttatt ccagattctg ttcaagagtc 3060
ttcatttagg attgaaggaa atgcttcaag ttttcaaatc ctgtggaatg gtccccctgc 3120
ggtagactgg ggtgtagttt tctacagtgt agaatttagt gctcattcta agttcttggc 3180
tagtgaacaa cactctttac ctgtatttac tgtggaagga ctggaacctt atgccttatt 3240
taatctttct gtcactcctt atacctactg gggaaagggc cccaaaacat ctctgtcact 3300
tcgagcacct gaaacagttc catcagcacc agagaacccc agaatattta tattaccaag 3360
tggaaaatgc tgcaacaaga atgaagttgt ggtggaattt aggtggaaca aacctaagca 3420
tgaaaatggg gtgttaacaa aatttgaaat tttctacaat atatccaatc aaagtattac 3480
aaacaaaaca tgtgaagact ggattgctgt caatgtcact ccctcagtga tgtcttttca 3540
acttgaaggc atgagtccca gatgctttat tgccttccag gttagggcct ttacatctaa 3600
ggggccagga ccatatgctg acgttgtaaa gtctacaaca tcagaaatca acccatttcc 3660
tcacctcata actcttcttg gtaacaagat agttttttta gatatggatc aaaatcaagt 3720
tgtgtggacg ttttcagcag aaagagttat cagtgccgtt tgctacacag ctgataatga 3780
gatgggatat tatgctgaag gggactcact ctttcttctg cacttgcaca atcgctctag 3840
ctctgagctt ttccaagatt cactggtttt tgatatcaca gttattacaa ttgactggat 3900
ttcaaggcac ctctactttg cactgaaaga atcacaaaat ggaatgcaag tatttgatgt 3960
tgatcttgaa cacaaggtga aatatcccag agaggtgaag attcacaata ggaattcaac 4020
aataatttct ttttctgtat atcctctttt aagtcgcttg tattggacag aagtttccaa 4080
ttttggctac cagatgttct actacagtat tatcagtcac accttgcacc gaattctgca 4140
acccacagct acaaaccaac aaaacaaaag gaatcaatgt tcttgtaatg tgactgaatt 4200
tgagttaagt ggagcaatgg ctattgatac ctctaaccta gagaaaccat tgatatactt 4260
tgccaaagca caagagatct gggcaatgga tctggaaggc tgtcagtgtt ggagagttat 4320
cacagtacct gctatgctcg caggaaaaac ccttgttagc ttaactgtgg atggagatct 4380
tatatactgg atcatcacag caaaggacag cacacagatt tatcaggcaa agaaaggaaa 4440
tggggccatc gtttcccagg tgaaggccct aaggagtagg catatcttgg cttacagttc 4500
agttatgcag ccttttccag ataaagcgtt tctgtctcta gcttcagaca ctgtggaacc 4560
aactatactt aatgccacta acactagcct cacaatcaga ttacctctgg ccaagacaaa 4620
cctcacatgg tatggcatca ccagccctac tccaacatac ctggtttatt atgcagaagt 4680
taatgacagg aaaaacagct ctgacttgaa atatagaatt ctggaatttc aggacagtat 4740
agctcttatt gaagatttac aaccattttc aacatacatg atacagatag ctgtaaaaaa 4800
ttattattca gatcctttgg aacatttacc accaggaaaa gagatttggg gaaaaactaa 4860
aaatggagta ccagaggcag tgcagctcat taatacaact gtgcggtcag acaccagcct 4920
cattatatct tggagagaat ctcacaagcc aaatggacct aaagaatcag tccgttatca 4980
gttggcaatc tcacacctgg ccctaattcc tgaaactcct ctaagacaaa gtgaatttcc 5040
aaatggaagg ctcactctcc ttgttactag actgtctggt ggaaatattt atgtgttaaa 5100
ggttcttgcc tgccactctg aggaaatgtg gtgtacagag agtcatcctg tcactgtgga 5160
aatgtttaac acaccagaga aaccttattc cttggttcca gagaacacta gtttgcaatt 5220
taattggaag gctccattga atgttaacct catcagattt tgggttgagc tacagaagtg 5280
gaaatacaat gagttttacc atgttaaaac ttcatgcagc caaggtcctg cttatgtctg 5340
taatatcaca aatctacaac cttatacttc atataatgtc agagtagtgg tggtttataa 5400
gacgggagaa aatagcacct cacttccaga aagctttaag acaaaagctg gagtcccaaa 5460
taaaccaggc attcccaaat tactagaagg gagtaaaaat tcaatacagt gggagaaagc 5520
tgaagataat ggatgtagaa ttacatacta tatccttgag ataagaaaga gcacttcaaa 5580
taatttacag aaccagaatt taaggtggaa gatgacattt aatggatcct gcagtagtgt 5640
ttgcacatgg aagtccaaaa acctgaaagg aatatttcag ttcagagtag tagctgcaaa 5700
taatctaggg tttggtgaat atagtggaat cagtgagaat attatattag ttggagatga 5760
tttttggata ccagaaacaa gtttcatact tactattata gttggaatat ttctggttgt 5820
tacaatccca ctgacctttg tctggcatag aagattaaag aatcaaaaaa gtgccaagga 5880
aggggtgaca gtgcttataa acgaagacaa agagttggct gagctgcgag gtctggcagc 5940
cggagtaggc ctggctaatg cctgctatgc aatacatact cttccaaccc aagaggagat 6000
tgaaaatctt cctgccttcc ctcgggaaaa actgactctg cgtctcttgc tgggaagtgg 6060
agcctttgga gaagtgtatg aaggaacagc agtggacatc ttaggagttg gaagtggaga 6120
aatcaaagta gcagtgaaga ctttgaagaa gggttccaca gaccaggaga agattgaatt 6180
cctgaaggag gcacatctga tgagcaaatt taatcatccc aacattctga agcagcttgg 6240
agtttgtctg ctgaatgaac cccaatacat tatcctggaa ctgatggagg gaggagacct 6300
tcttacttat ttgcgtaaag cccggatggc aacgttttat ggtcctttac tcaccttggt 6360
tgaccttgta gacctgtgtg tagatatttc aaaaggctgt gtctacttgg aacggatgca 6420
tttcattcac agggatctgg cagctagaaa ttgccttgtt tccgtgaaag actataccag 6480
tccacggata gtgaagattg gagactttgg actcgccaga gacatctata aaaatgatta 6540
ctatagaaag agaggggaag gcctgctccc agttcggtgg atggctccag aaagtttgat 6600
ggatggaatc ttcactactc aatctgatgt atggtctttt ggaattctga tttgggagat 6660
tttaactctt ggtcatcagc cttatccagc tcattccaac cttgatgtgt taaactatgt 6720
gcaaacagga gggagactgg agccaccaag aaattgtcct gatgatctgt ggaatttaat 6780
gacccagtgc tgggctcaag aacccgacca aagacctact tttcatagaa ttcaggacca 6840
acttcagtta ttcagaaatt ttttcttaaa tagcatttat aagtccagag atgaagcaaa 6900
caacagtgga gtcataaatg aaagctttga aggtgaagat ggcgatgtga tttgtttgaa 6960
ttcagatgac attatgccag ttgctttaat ggaaacgaag aaccgagaag ggttaaacta 7020
tatggtactt gctacagaat gtggccaagg tgaagaaaag tctgagggtc ctctaggctc 7080
ccaggaatct gaatcttgtg gtctgaggaa agaagagaag gaaccacatg cagacaaaga 7140
tttctgccaa gaaaaacaag tggcttactg cccttctggc aagcctgaag gcctgaacta 7200
tgcctgtctc actcacagtg gatatggaga tgggtctgat taatagcgtt gtttgggaaa 7260
tagagagttg agataaacac tctcattcag tagttactga aagaaaactc tgctagaatg 7320
ataaatgtca tggtggtcta taactccaaa taaacaatgc aacgttcc 7368
<210>9
<211>20
<212>PRT
<213>Homo sapiens
<400>9
Ile Leu Ser Ser Ala Phe Gln Leu Val Gly Ala Gly Val Pro Asn Lys
1 5 10 15
Pro Gly Ile Pro
20
<210>10
<211>60
<212>DNA
<213>Homo sapiens
<400>10
attcttagta gcgccttcca gctggttgga gctggagtcc caaataaacc aggcattccc 60
<210>11
<211>20
<212>PRT
<213>Homo sapiens
<400>11
Ile Leu Ser Ser Ala Phe Gln Leu Val Gly Asp Asp Phe Trp Ile Pro
1 5 10 15
Glu Thr Ser Phe
20
<210>12
<211>60
<212>DNA
<213>Homo sapiens
<400>12
attcttagta gcgccttcca gctggttgga gatgattttt ggataccaga aacaagtttc 60
<210>13
<211>24
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>13
acccttctcg gttcttcgtt tcca 24
<210>14
<211>24
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>14
gcagctcagc caactctttg tctt 24
<210>15
<211>24
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>15
tgccagacaa aggtcagtgg gatt 24
<210>16
<211>21
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>16
tccatcccag cacctgcgga g 21
<210>17
<211>27
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>17
ctcaactctc tatttcccaa acaacgc 27
<210>18
<211>22
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>18
catggctccc tggcctgaat tg 22
<210>19
<211>26
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>19
caacgctatt aatcagaccc atctcc 26
<210>20
<211>32
<212>DNA
<213>Artificial
<220>
<223>Primer sequence
<400>20
gaagatctct gaccatggct ccctggcctg aa 32
<210>21
<211>32
<212>PRT
<213>Artificial
<220>
<223>Primer sequence
<400>21
Gly Ala Ala Gly Ala Thr Cys Thr Ala Cys Gly Cys Thr Ala Thr Thr
1 5 10 15
Ala Ala Thr Cys Ala Gly Ala Cys Cys Cys Ala Thr Cys Thr Cys Cys
20 25 30
Claims (19)
1.一种分离的多核苷酸,该多核苷酸由选自以下组的核苷酸序列组成:
(a)编码SLC34A2-ROS融合多肽的核苷酸序列,所述融合多肽由SEQID NO:1或者SEQ ID NO:3的氨基酸序列组成;
(b)编码SLC34A2-ROS融合多肽的核苷酸序列,所述核苷酸序列由SEQ ID NO:2或者SEQ ID NO:4的核苷酸序列组成;和
(c)与上述核苷酸序列(a)或(b)互补的核苷酸序列。
2.分离的多核苷酸,其由美国典型培养物保藏中心保藏号PTA-7877所含有的cDNA克隆的编码核苷酸序列组成。
3.一种包含权利要求1的多核苷酸的重组载体。
4.包含权利要求3的载体的重组宿主细胞。
5.一种分离的多肽,该多肽由选自以下组的氨基酸序列组成:
SEQ ID NO:1和SEQ ID NO:3。
6.分离的多肽,其由美国典型培养物保藏中心保藏号为PTA-7877所含有的cDNA编码的SLC34A2-ROS融合多肽序列组成。
7.寡核苷酸对,其中第一寡核苷酸是有义方向并且第二寡核苷酸是反义方向,其中所述寡核苷酸对将在聚合酶链反应(PCR)中扩增权利要求1的SLC34A2-ROS融合多核苷酸或者至少其含有所述融合接头的部分。
8.检测权利要求1的多核苷酸的试剂在制备用于如下方法中的物质中的用途,所述方法是检测在患有或被怀疑患有癌症的患者中存在突变的ROS多核苷酸的方法,该方法包括确定在所述患者的生物样品中是否存在SLC34A2-ROS融合多核苷酸。
9.根据权利要求8所述的用途,其中所述癌症为肺癌。
10.根据权利要求9所述的用途,其中所述肺癌是非小细胞肺癌(NSCLC)。
11.根据权利要求8所述的用途,其中所述方法通过原位杂交荧光(FISH)或者聚合酶链反应(PCR)检测方法实施的。
12.检测权利要求5的多肽的试剂在制备用于如下方法中的物质中的用途,所述方法是检测在患有或被怀疑患有癌症的患者中存在突变的ROS多肽的方法,该方法包括确定在所述患者的生物样品中是否存在SLC34A2-ROS融合多肽。
13.权利要求12的用途,其中所述癌症为肺癌。
14.根据权利要求13所述的用途,其中所述肺癌是非小细胞肺癌(NSCLC)。
15.根据权利要求12所述的用途,其中所述方法通过流式细胞术(FC)、免疫组织化学(IHC)或者免疫荧光(IF)检测方法实施。
16.根据权利要求12所述的用途,其中所述SLC34A2-ROS融合多肽的活性被检测。
17.ROS抑制治疗剂在制备用于检测化合物是否抑制以权利要求1的SLC34A2-ROS融合多核苷酸和/或权利要求5的SLC34A2-ROS融合多肽为特征的癌症的发展的方法中使用的药物中的用途,该方法包括鉴定所述化合物是否抑制所述癌症中的所述SLC34A2-ROS融合多肽的表达和/或活性的步骤。
18.根据权利要求17所述的用途,其中对所述SLC34A2-ROS融合多肽的表达和/或活性的抑制作用是通过使用至少一种检测权利要求1所述的多核苷酸和/或权利要求5所述的多肽的试剂进行鉴定的。
19.抑制权利要求5的SLC34A2-ROS融合多肽在非小细胞肺癌中表达和/或活性的物质在制备用于抑制表达所述SLC34A2-ROS融合多肽的癌症的发展的组合物中的用途。
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