CN101305020B - 用于诊断和治疗的肿瘤相关抗原的鉴定 - Google Patents
用于诊断和治疗的肿瘤相关抗原的鉴定 Download PDFInfo
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Abstract
本发明涉及其表达与癌症疾病相关的基因产物。本发明还涉及其中基因产物被表达或异常表达的疾病特别是癌症疾病的治疗和诊断。
Description
尽管存在常规治疗操作程序的跨学科方法和穷尽使用,但是癌症仍在死亡的主要原因中。更近来的治疗概念旨在通过使用重组肿瘤疫苗和其他特异性措施例如抗体疗法将患者的免疫系统整合入总体治疗概念内。此类策略成功的先决条件是由患者的免疫系统识别肿瘤特异性或肿瘤相关抗原或表位,所述患者免疫系统的效应子功能有待通过干预而增强的。肿瘤细胞在生物学上基本上不同于它们所来源的非恶性细胞。这些差异是由于在肿瘤发展期间获得的遗传改变,并且还尤其导致癌细胞中定性或定量改变的分子结构的形成。由具有肿瘤的宿主的特异性免疫系统识别的这类肿瘤相关结构被称为肿瘤相关抗原。肿瘤相关抗原的特异性识别涉及细胞和体液机制,其是2种在功能上相互连接的单元:CD4+和CD8+T淋巴细胞分别识别在II和I类MHC(主要组织相容性复合物)分子上呈递的加工过的抗原,而B淋巴细胞产生与未加工的抗原直接结合的循环抗体分子。肿瘤相关抗原的潜在临床治疗重要性起因于下述事实:通过免疫系统识别赘生性细胞上的抗原导致细胞毒性效应子机制的起始,并且在T辅助细胞的存在下,可以引起癌细胞的清除(Pardoll,Nat.Med.4:525-31,1998)。因此,肿瘤免疫学的中心目标是在分子上限定这些结构。这些抗原的分子性质很长时间以来都是高深莫测的。只有在开发了合适的克隆技术后才可能通过分析细胞毒性T淋巴细胞(CTL)的靶结构(van derBruggen等人,Science 254:1643-7,1991)或通过使用循环自身抗体(Sahin等人,Curr.Opin.Immunol.9:709-16,1997)作为探针,来就肿瘤相关抗原系统地筛选肿瘤的cDNA表达文库。为此,从新鲜肿瘤组织制备cDNA表达文库并且在合适的系统中作为蛋白质重组地表达。从患者中分离的免疫效应子,即具有肿瘤特异性裂解模式的CTL克隆或循环自身抗体,用于克隆各自的抗原。
近年来通过这些方法在各种瘤形成中限定了多种抗原。
然而,在常规方法中用于抗原鉴定的探针是来自通常具有晚期癌症的患者的免疫效应子(循环自身抗体或CTL克隆)。许多数据指出,肿瘤可以例如导致T细胞的耐受和无反应性,并且在疾病进展过程中,特别是可以引起有效的免疫识别的那些特异性从免疫效应子储库(repertoire)中丧失。目前的患者研究仍未产生先前发现并使用的肿瘤相关抗原的真实作用的任何可靠证据。因此,不能排除引起自发性免疫应答的蛋白质是错误的靶结构。
本发明的目的是提供用于癌症诊断和治疗的靶结构。
这个目的通过权利要求的主题来达到。
根据本发明鉴定了在肿瘤细胞中选择性地或异常地表达的基因,并因此提供了肿瘤相关抗原。这些基因和/或它们的基因产物和/或其衍生物和/或片段可用作用于治疗和诊断方法的靶结构。
根据本发明鉴定的肿瘤相关抗原具有由核酸编码的氨基酸序列,所述核酸选自:(a)包含选自序列表的SEQ ID NO:1、5、9、13、17、21、25、28、30、35、39、41、45、49、61、62和64-67的核酸序列、其部分或衍生物的核酸,(b)在严紧条件下与(a)的核酸杂交的核酸,(c)相关于(a)或(b)的核酸来说为简并的核酸,和(d)与(a)、(b)或(c)的核酸互补的核酸。在一个优选实施方案中,根据本发明鉴定的肿瘤相关抗原具有由核酸编码的氨基酸序列,所述核酸选自序列表的SEQ ID NO:1、5、9、13、17、21、25、28、30、35、39、41、45、49、61、62和64-67。在一个进一步的优选实施方案中,根据本发明鉴定的肿瘤相关抗原包含选自序列表的SEQ IDNO:2、6、10、14、18、22、26、29、31、36、40、42、46、50-60、63、68和69的氨基酸序列、其部分或衍生物。
本发明总的来说涉及根据本发明鉴定的肿瘤相关抗原或其部分或衍生物,编码根据本发明鉴定的肿瘤相关抗原或其部分或衍生物的核酸或针对所述编码核酸的核酸,针对根据本发明鉴定的肿瘤相关抗原或其部分或衍生物的抗体或T细胞,和/或表达根据本发明鉴定的肿瘤相关抗原或其部分或衍生物的宿主细胞,用于治疗、预防、诊断和/或监控瘤形成疾病的用途。这还可以涉及这些抗原、核酸、抗体、T细胞和/或宿主细胞中的2种或更多种的组合的用途,在一个实施方案中,还与下述相组合:除根据本发明鉴定的那些之外的肿瘤相关抗原,编码其的核酸或针对所述编码核酸的核酸,针对所述肿瘤相关抗原的抗体或T细胞,和/或表达所述肿瘤相关抗原的宿主细胞。
在涉及针对根据本发明鉴定的肿瘤相关抗原或其部分或衍生物的抗体的用途的那些本发明实施方案中,还可以使用针对根据本发明鉴定的肿瘤相关抗原或其部分或衍生物的T细胞受体,任选地与MHC分子复合。
特别适合于治疗、预防、诊断和/或监控的是根据本发明鉴定的肿瘤相关抗原的部分,其相应于肿瘤相关抗原的非跨膜部分特别是细胞外部分或者由所述部分组成。因此,根据本发明,根据本发明鉴定的肿瘤相关抗原的部分(其相应于肿瘤相关抗原的非跨膜部分特别是细胞外部分或者由所述部分组成),或编码根据本发明鉴定的肿瘤相关抗原的核酸的相应部分对于治疗、预防、诊断和/或监控是优选的。类似地,使用针对根据本发明鉴定的肿瘤相关抗原的部分的抗体是优选的,所述肿瘤相关抗原的部分相应于肿瘤相关抗原的非跨膜部分特别是细胞外部分或者由所述部分组成。
关于治疗、预防和/或诊断的优选疾病是其中根据本发明鉴定的一种或多种肿瘤相关抗原选择性地表达或异常表达的那些疾病。
此外,本发明涉及这样的核酸和蛋白质或肽,其由于已知基因的改变的剪接(剪接变体)或使用备选开放读码框的改变的翻译而产生。在这个方面,本发明涉及这样的核酸,其包含选自序列表的SEQ ID NO:28和49的核酸序列。此外,在这个方面,本发明涉及这样的蛋白质或肽,其包含选自序列表的SEQ ID NO:29和50的氨基酸序列。
基因的改变的剪接导致改变的转录物序列(剪接变体)。在其改变的序列区域中剪接变体的翻译导致改变的蛋白质,所述改变的蛋白质可能在结构和功能方面明显不同于原始蛋白质。肿瘤相关剪接变体可以产生肿瘤相关转录物和肿瘤相关蛋白质/抗原。这些可以用作分子标记用于检测肿瘤细胞和用于肿瘤的治疗靶向作用。来自患者的样品中的肿瘤细胞的检测可以根据本发明来进行,例如在使用剪接变体特异性寡核苷酸通过PCR扩增来提取核酸后。
根据本发明,所有序列依赖性检测系统适合于检测。除PCR外,这些为例如基因芯片/微阵列系统、Northern印迹、RNA酶保护测定法(RDA)及其他。所有检测系统具有下述共同点:检测基于与至少一种剪接变体特异性核酸序列的特异性杂交。然而,肿瘤细胞还可以根据本发明通过识别由剪接变体编码的特异性表位的抗体来进行检测。所述抗体可以通过使用对于所述剪接变体来说特异性的肽进行免疫接种来制备。这样的氨基酸序列特别适合于免疫接种,所述氨基酸序列明显不同于基因产物的一种或多种变体,所述变体优选在健康细胞中产生。在此处,用抗体检测肿瘤细胞可以对从患者中分离的样品来进行或用静脉内施用的抗体成像。
除了诊断可用性外,具有新的或改变的表位的剪接变体是用于免疫疗法的吸引人的靶,因为这些表位可以用于对如本文所述的抗体或T淋巴细胞进行靶向。在被动免疫疗法中,识别剪接变体特异性表位的抗体或T淋巴细胞在此处是过继性地转移的。如在其他抗原的情况下,还可以利用包括这些表位的多肽通过使用标准技术来产生抗体。备选地,可以利用编码包含所述表位的肽的核酸用于免疫接种。用于体外或体内产生表位特异性T淋巴细胞的各种技术是已知的并且得到详细描述(例如Kessler JH等人,2001,Sahin等人,1997),并且同样地基于利用包含剪接变体特异性表位的肽或编码所述肽的核酸。包含剪接变体特异性表位的肽或编码所述肽的核酸还可以在主动免疫疗法(例如,疫苗接种,疫苗疗法)中用作药学上活性的物质。
在一个方面,本发明涉及包含试剂的药物组合物,所述试剂识别根据本发明鉴定的肿瘤相关抗原或编码所述肿瘤相关抗原的核酸,并且对于表达或异常表达根据本发明鉴定的肿瘤相关抗原的细胞优选地是选择性的。在一个进一步的方面,本发明涉及包含试剂的药物组合物,所述试剂(I)抑制根据本发明鉴定的肿瘤相关抗原的表达或活性,和/或(II)具有肿瘤抑制或肿瘤破坏活性,并且对于表达或异常表达根据本发明鉴定的肿瘤相关抗原的细胞是选择性的,和/或(III)当施用时,选择性地增加MHC分子与根据本发明鉴定的肿瘤相关抗原或其部分例如肽表位之间的复合物的量。在具体实施方案中,所述试剂可以引起细胞死亡的诱导、细胞生长的减少、对细胞膜的损害或细胞因子的分泌,并且优选具有肿瘤抑制性活性。在一个实施方案中,所述试剂是与编码所述肿瘤相关抗原的核酸选择性地杂交的反义核酸。在一个进一步的实施方案中,所述试剂是优选包含有义RNA链和反义RNA链的siRNA,其中有义和反义RNA链形成RNA双链体,并且其中有义RNA链包含基本上等同于在编码所述肿瘤相关抗原的核酸中约29-约25个邻接核苷酸的靶序列的核苷酸序列,优选为编码所述肿瘤相关抗原的mRNA。在一个进一步的实施方案中,所述试剂是与所述肿瘤相关抗原选择性地结合的抗体,特别是补体激活的或缀合有毒素的抗体,其与所述肿瘤相关抗原选择性地结合。在一个优选实施方案中,与所述肿瘤相关抗原选择性地结合的抗体与在治疗上有用的物质偶联,和/或募集针对表达或异常表达所述肿瘤相关抗原的所述细胞的天然或人工效应子机制。在一个进一步的实施方案中,所述试剂是细胞毒性T淋巴细胞,其识别被细胞上的MHC分子所结合的肿瘤相关抗原或其部分,并且裂解以这种方式标记的细胞。在一个进一步的实施方案中,所述试剂是T辅助淋巴细胞,其增强特异性地识别所述肿瘤相关抗原或其部分的其他细胞的效应子功能。
在一个进一步的实施方案中,所述试剂包括2种或更多种试剂,所述2种或更多种试剂各自识别不同的肿瘤相关抗原和/或抑制不同的肿瘤相关抗原的表达或活性,和/或具有肿瘤抑制或肿瘤破坏活性,并且对于表达或异常表达不同的肿瘤相关抗原的细胞是选择性的,和/或当施用时,选择性地增加MHC分子与不同的肿瘤相关抗原或其部分之间的复合物的量,其中至少一种所述不同的肿瘤相关抗原是根据本发明鉴定的肿瘤相关抗原。优选地,选择性地局限于肿瘤的肿瘤相关抗原充当标记以用于募集针对该特定位置的效应子机制。本发明包括其中所述试剂自身不具有抑制肿瘤相关抗原的活性或者肿瘤抑制或肿瘤破坏活性的能力但介导此类效应,特别是通过将效应子机制(特别是具有细胞损伤潜能的那些)募集至特定位置(特别是肿瘤或肿瘤细胞)。
根据本发明鉴定的肿瘤相关抗原的活性可以是蛋白质或肽的活性。在一个实施方案中,这种活性是酶促活性。
根据本发明,短语“抑制表达或活性”包括完全或基本上完全抑制表达或活性和表达或活性的减少。
当施用时选择性地增加MHC分子与根据本发明鉴定的肿瘤相关抗原或其部分之间的复合物的量的试剂,包含选自下述的一种或多种组分:(i)肿瘤相关抗原或其部分,(ii)编码所述肿瘤相关抗原或其部分的核酸,(iii)表达所述肿瘤相关抗原或其部分的宿主细胞,和(iv)分离的在来自所述肿瘤相关抗原的肽表位与MHC分子之间形成的复合物。
本发明进一步涉及药物组合物,其包含选自下述的一种或多种组分:(i)根据本发明鉴定的肿瘤相关抗原或其部分,(ii)编码根据本发明鉴定的肿瘤相关抗原或其部分的核酸,(iii)与根据本发明鉴定的肿瘤相关抗原或其部分结合的抗体,(iv)与编码根据本发明鉴定的肿瘤相关抗原的核酸选择性地杂交的反义核酸,(v)针对编码根据本发明鉴定的肿瘤相关抗原的核酸的siRNA,(vi)表达根据本发明鉴定的肿瘤相关抗原或其部分的宿主细胞,和(vii)分离的在根据本发明鉴定的肿瘤相关抗原或其部分与MHC分子之间形成的复合物。
在一个实施方案中,编码根据本发明鉴定的肿瘤相关抗原或其部分的核酸存在于药物组合物中,所述核酸在表达载体中并且与启动子功能性地连接。在一个进一步的实施方案中,编码根据本发明鉴定的肿瘤相关抗原或其部分的核酸以在病毒中的形式存在于药物组合物中,如下文进一步描述的。
在一个进一步的实施方案中,存在于本发明的药物组合物中的宿主细胞分泌肿瘤相关抗原或其部分,在表面上表达肿瘤相关抗原或其部分,并且优选地另外表达与所述肿瘤相关抗原或其所述部分结合的MHC分子。在一个实施方案中,宿主细胞内源性地表达MHC分子。在一个进一步的实施方案中,宿主细胞以重组方式表达MHC分子和/或肿瘤相关抗原或其部分。宿主细胞优选是非增殖性的。在一个优选实施方案中,宿主细胞是抗原呈递细胞,特别是树突状细胞、单核细胞或巨噬细胞。
在一个进一步的实施方案中,存在于本发明的药物组合物中的抗体是单克隆抗体。在进一步的实施方案中,抗体是嵌合或人源化抗体,天然抗体或合成抗体的片段。抗体可以与治疗上或诊断上有用的试剂(在本文中也称为治疗或诊断剂)相偶联。
存在于本发明的药物组合物中的反义核酸可以包含编码根据本发明鉴定的肿瘤相关抗原的核酸的6-50个,特别是10-30个,15-30个和20-30个邻接核苷酸的序列。
在进一步的实施方案中,直接或经由核酸的表达而由本发明的药物组合物提供的肿瘤相关抗原或其部分与细胞表面上的MHC分子结合,所述结合优选引起溶细胞性应答和/或诱导细胞因子释放。
在靶向根据SEQ ID NO:1的核酸的siRNA的具体实施方案中,有义RNA链具有SEQ ID NO:70的序列,和反义RNA链具有SEQ ID NO:71的序列,或者有义RNA链具有SEQ ID NO:72的序列,和反义RNA链具有SEQ ID NO:73的序列。
本发明的药物组合物可以包含药学上相容的承载体(carrier)和/或佐剂。
本发明的药物组合物优选用于治疗或预防特征在于选择性表达或异常表达肿瘤相关抗原的疾病。在一个优选实施方案中,所述疾病是瘤形成疾病,优选癌症。
在一个优选实施方案中,本发明的药物组合物是可以在治疗上或预防上使用的疫苗的形式。此类疫苗优选地包含根据本发明鉴定的肿瘤相关抗原或其部分,和/或编码根据本发明鉴定的肿瘤相关抗原或其部分的核酸。在具体实施方案中,核酸存在于病毒或宿主细胞中。
本发明进一步涉及治疗、预防、诊断或监控即测定疾病的消退、进展、进程和/或发作的方法,所述疾病的特征在于根据本发明鉴定的一种或多种肿瘤相关抗原的表达或异常表达,优选瘤形成疾病,特别是癌症。在一个实施方案中,治疗或预防包括施用本发明的药物组合物。
根据本发明的所述诊断方法和/或监控方法一般涉及检测和/或测定一种或多种参数的量,所述参数选自(i)核酸,其编码根据本发明鉴定的肿瘤相关抗原或其部分,(ii)根据本发明鉴定的肿瘤相关抗原或其部分,(iii)针对根据本发明鉴定的肿瘤相关抗原或其部分的抗体,和(iv)T淋巴细胞,优选地细胞毒性或T辅助淋巴细胞,其对于在从患者中分离的生物样品中根据本发明鉴定的肿瘤相关抗原或其部分和/或肿瘤相关抗原或其部分与MHC分子之间的复合物是特异的,所述生物样品优选地来自具有所述疾病、怀疑具有所述疾病或因所述疾病而生病或者具有关于所述疾病的潜在性的患者。用于完成量的所述检测或测定的手段在本文中得到描述并且对于技术人员来说是显而易见的。
优选地,所述核酸、所述肿瘤相关抗原或其所述部分、所述抗体和/或所述T淋巴细胞的存在,和/或与没有所述疾病的患者相比较,所述核酸、所述肿瘤相关抗原或其所述部分、所述抗体和/或所述T淋巴细胞的量增加是关于存在所述疾病或所述疾病的发展潜在性的指示。
本发明的诊断和/或监控方法还包括这样的实施方案,其中通过检测或测定所述核酸、所述肿瘤相关抗原或其所述部分、所述抗体和/或所述T淋巴细胞的量,可以评估和/或预测所述疾病的转移行为,其中优选地,所述核酸、所述肿瘤相关抗原或其所述部分、所述抗体和/或所述T淋巴细胞的存在,和/或与没有所述疾病或没有所述疾病的转移的患者相比较,所述核酸、所述肿瘤相关抗原或其所述部分、所述抗体和/或所述T淋巴细胞的量增加是关于所述疾病的转移行为或所述疾病的转移行为的潜在性的指示。
在具体实施方案中,量的所述检测或测定包括(i)使生物样品与试剂接触,所述试剂与编码所述肿瘤相关抗原或其所述部分的所述核酸、所述肿瘤相关抗原或其所述部分、所述抗体或其所述部分或所述T淋巴细胞特异性地结合,和(ii)检测所述试剂与所述核酸或其部分、所述肿瘤相关抗原或其部分、所述抗体或其部分或所述T淋巴细胞之间的复合物的形成,或测定所述复合物的量。在一个实施方案中,所述疾病的特征在于表达或异常表达2种或更多种不同的肿瘤相关抗原,并且量的检测或测定包括检测或测定下述物质的量:编码所述2种或更多种不同的肿瘤相关抗原或其部分的2种或更多种核酸,2种或更多种不同的肿瘤相关抗原或其部分,与所述2种或更多种不同的肿瘤相关抗原或其部分结合的2种或更多种抗体,和/或对于所述2种或更多种不同的肿瘤相关抗原或其部分特异的2种或更多种T淋巴细胞,或其与MHC分子的复合物。在一个进一步的实施方案中,将从患者中分离的生物样品与相当的正常生物样品相比较。
根据本发明的监控方法优选地包括在第一个时间点上检测和/或测定第一个样品中一种或多种上文提及的参数的量和在第二个时间点上检测和/或测定另一样品中一种或多种上文提及的参数的量,其中疾病的进程通过比较这2个样品来确定。
根据本发明,核酸或其部分的检测或者核酸或其部分的量的测定可以使用与所述核酸或其所述部分特异性杂交的寡或多核苷酸探针来进行,或者可以通过所述核酸或其所述部分的选择性扩增,例如通过PCR扩增来进行。在一个实施方案中,寡或多核苷酸探针包含所述核酸的6-50个,特别是10-30个,15-30个和20-30个邻接核苷酸的序列。
在具体实施方案中,待在本发明的方法中检测的肿瘤相关抗原或其部分或者其量待在本发明的方法中测定的肿瘤相关抗原或其部分细胞内地存在于细胞表面上或者以与MHC分子的复合物存在。根据本发明,肿瘤相关抗原或其部分的检测或者肿瘤相关抗原或其部分的量的测定可以使用与所述肿瘤相关抗原或其所述部分特异性地结合的抗体来进行。
根据本发明,抗体的检测或者抗体的量的测定可以使用与所述抗体特异性地结合的蛋白质或肽来进行。
根据本发明,对于肿瘤相关抗原或其部分和/或其与MHC分子的复合物来说特异的T淋巴细胞的检测或者所述T淋巴细胞的量的测定可以使用呈递所述肿瘤相关抗原或其所述部分与MHC分子之间的复合物的细胞来进行。T淋巴细胞可以另外地通过下述方法来检测:检测其增殖、其细胞因子产生、和其由使用MHC分子与肿瘤相关抗原或其部分的复合物的特异性刺激而引发的细胞毒性活性。T淋巴细胞还可以借助于重组MHC分子或装载有一种或多种肿瘤相关抗原的免疫原性片段的2种或更多种MHC分子的复合物来检测。
在本发明的方法中用于检测或测定所述量的试剂,例如寡或多核苷酸探针、抗体、蛋白质或肽或者细胞优选以可检测的方式进行标记,特别是通过可检测标记例如放射性标记或酶促标记来进行标记。
在一个具体方面,本发明涉及治疗、预防、诊断或监控特征在于根据本发明鉴定的肿瘤相关抗原的表达或异常表达的疾病的方法,所述方法包括施用与所述肿瘤相关抗原或其部分结合并且与治疗或诊断剂偶联的抗体。所述抗体可以是单克隆抗体。在进一步的实施方案中,所述抗体是嵌合或人源化抗体或者天然抗体的片段。
在某些实施方案中,本发明的诊断或监控疾病的方法用包含或怀疑包含播散性肿瘤细胞或转移性肿瘤细胞的生物样品来进行,所述疾病的特征在于根据本发明鉴定的肿瘤相关抗原的表达或异常表达。此类生物样品包括例如,血液、血清、骨髓、痰、支气管抽吸物和/或支气管灌洗液。
在一个具体方面,本发明涉及治疗具有特征在于根据本发明鉴定的肿瘤相关抗原的表达或异常表达的疾病的患者的方法,所述方法包括(i)提供包含免疫反应性细胞的样品,所述样品得自所述患者或得自相同物种的另一个个体,特别是健康个体,或不同物种的个体,(ii)在有利于产生针对所述肿瘤相关抗原或其部分的溶细胞性T细胞的条件下,使所述样品与表达所述肿瘤相关抗原或其部分的宿主细胞接触,和(iii)以适合于使表达所述肿瘤相关抗原或其部分的细胞裂解的量将所述溶细胞性T细胞引入所述患者内。在一个实施方案中,所述方法包括克隆获得的溶细胞性T细胞的T细胞受体并且将编码所述T细胞受体的核酸转移给T细胞(其得自所述患者或得自相同物种的另一个个体,特别是健康个体,或不同物种的个体),所述T细胞因此接受了所希望的特异性,并且当在(iii)下时可以被引入患者内。
在一个实施方案中,宿主细胞内源性地表达MHC分子。在一个进一步的实施方案中,宿主细胞重组地表达MHC分子和/或肿瘤相关抗原或其部分。优选地,宿主细胞通过MHC分子在其表面上呈递肿瘤相关抗原或其部分。宿主细胞优选地是非增殖性的。在一个优选实施方案中,宿主细胞是抗原呈递细胞,特别是树突状细胞、单核细胞或巨噬细胞。
本发明还涉及治疗特征在于根据本发明鉴定的肿瘤相关抗原的表达或异常表达的疾病的方法,所述方法包括(i)鉴定来自患者的表达异常量的肿瘤相关抗原的细胞,(ii)分离所述细胞的样品,(iii)培养所述细胞,和(iv)以适合于引发针对所述细胞的免疫应答的量将所述细胞引入患者内。
本发明进一步涉及选自下述的核酸:(a)包含选自SEQ ID NO:1、5、9、13、17、21、25、28、30、35、39、41、45、49、61、62和64-67的核酸序列、其部分或衍生物的核酸,(b)在严紧条件下与(a)的核酸杂交的核酸,(c)相关于(a)或(b)的核酸来说为简并的核酸,和(d)与(a)、(b)或(c)的核酸互补的核酸。此外,本发明涉及编码蛋白质或多肽的核酸,所述蛋白质或多肽包含选自SEQ ID NO:2、6、10、14、18、22、26、29、31、36、40、42、46、50-60、63、68和69的氨基酸序列,其部分或衍生物。
在一个进一步的方面,本发明涉及包含本发明的核酸的重组核酸分子,特别是DNA或RNA分子。
本发明还涉及包含本发明的核酸或重组核酸分子的宿主细胞。
宿主细胞还可以包含编码MHC分子的核酸。在一个实施方案中,宿主细胞内源性地表达MHC分子。在一个进一步的实施方案中,宿主细胞重组地表达本发明的MHC分子和/或核酸或重组核酸分子或其部分。优选地,宿主细胞是非增殖性的。在一个优选实施方案中,宿主细胞是抗原呈递细胞,特别是树突状细胞、单核细胞或巨噬细胞。
在一个进一步的实施方案中,本发明涉及这样的寡核苷酸,其与根据本发明鉴定的核酸杂交并且可以用作基因探针或用作“反义”分子。以与根据本发明鉴定的核酸或其部分杂交的寡核苷酸引物或能胜任的探针形式存在的核酸分子可以用于找到与根据本发明鉴定的所述核酸同源的核酸,例如通过PCR扩增、Southern和Northern杂交。杂交可以在低严紧性条件下,更优选地在中等严紧性条件下,和最优选地在高严紧性条件下进行。
在一个进一步的方面,本发明涉及由选自下述的核酸编码的蛋白质或肽:(a)包含选自SEQ ID NO:1、5、9、13、17、21、25、28、30、35、39、41、45、49、61、62和64-67的核酸序列、其部分或衍生物的核酸,(b)在严紧条件下与(a)的核酸杂交的核酸,(c)相关于(a)或(b)的核酸来说为简并的核酸,和(d)与(a)、(b)或(c)的核酸互补的核酸。在一个优选实施方案中,本发明涉及蛋白质或肽,其包含选自SEQ ID NO:2、6、10、14、18、22、26、29、31、36、40、42、46、50-60、63、68和69的氨基酸序列,其部分或衍生物。
在一个进一步的方面,本发明涉及根据本发明鉴定的肿瘤相关抗原的免疫原性片段。所述片段优选地与MHC分子或抗体结合,优选地与人HLA受体或人抗体结合。根据本发明,片段优选地包含至少6个,特别是至少8个,至少10个,至少12个,至少15个,至少20个,至少30个或至少50个氨基酸的序列。
在这个方面,本发明特别地涉及肽,其具有或包含选自序列表的SEQ ID NO:51-60、68和69的序列,其部分或衍生物。
在一个进一步的方面,本发明涉及与根据本发明鉴定的肿瘤相关抗原或其部分结合的试剂。在一个优选实施方案中,所述试剂是蛋白质或肽,特别是抗体、T细胞受体或MHC分子。在进一步的实施方案中,所述抗体是单克隆、嵌合或人源化抗体,由组合技术生产的抗体,或抗体片段。在一个优选实施方案中,本发明涉及与下述成分的复合物选择性地结合的抗体:(i)根据本发明鉴定的肿瘤相关抗原或其部分和(ii)根据本发明鉴定的所述肿瘤相关抗原或其所述部分所与之结合的MHC分子,其中所述抗体不单独与(i)或(ii)结合。
特别地,本发明涉及这样的试剂,特别是抗体,其与具有或包含选自序列表的SEQ ID NO:51-60、68和69的序列、其部分或衍生物的肽结合。
根据本发明,术语“结合”优选地涉及特异性结合。“特异性结合”意指,和与另一种靶的结合相比较,试剂例如抗体与其所特异于的靶例如表位更强烈地结合。如果试剂与第一种靶结合的解离常数(KD)低于关于第二种靶的解离常数,那么与第二种靶相比较,所述试剂与第一种靶更强烈地结合。优选地,所述试剂与之特异性结合的靶的解离常数(KD)以超过10倍,优选超过20倍,更优选超过50倍,更加优选超过100倍、200倍、500倍或1000倍地低于所述试剂不与之特异性结合的靶的解离常数(KD)。
此类特异性抗体可以例如通过使用前述肽进行免疫接种来获得。
本发明进一步涉及与根据本发明鉴定的肿瘤相关抗原或其部分结合的本发明试剂或本发明抗体与治疗或诊断剂之间的缀合物。在一个实施方案中,治疗或诊断剂是毒素。
在一个进一步的方面,本发明涉及用于检测根据本发明鉴定的肿瘤相关抗原的表达或异常表达的试剂盒,所述试剂盒包含用于检测或测定下述物质的量的试剂:(i)编码所述肿瘤相关抗原或其部分的核酸,(ii)所述肿瘤相关抗原或其部分,(iii)与所述肿瘤相关抗原或其部分结合的抗体,和/或(iv)对于所述肿瘤相关抗原或其部分或其与MHC分子的复合物特异的T细胞。在一个实施方案中,用于检测核酸或其部分的试剂是用于选择性地扩增所述核酸的核酸分子,其特别是包含所述核酸的6-50个,特别是10-30,15-30个和20-30个邻接核苷酸的序列。
发明详述
根据本发明,“参考”例如参考样品或参考生物体可以用于与来自测试样品或测试生物体即患者的在本发明方法中获得的结果相关联和比较。通常,参考生物体是健康生物体,特别是未患有癌症的生物体。
“参考值”可以通过测量足够大量的参考根据经验从参考测定。优选地,参考值通过测量至少2个、优选至少3个、优选至少5个、优选至少8个、优选至少12个、优选至少20个、优选至少30个、优选至少50个、或优选至少100个参考来测定。
根据本发明,核酸的“衍生物”意指,在所述核酸中存在单个或多个例如至少2个、至少4个、或至少6个,并且优选高达3个、高达4个、高达5个、高达6个、高达10个、高达15个、或高达20个核苷酸置换、删除和/或添加。此外,术语“衍生物”还包括在核苷酸碱基、糖或磷酸上的核酸的化学衍生。术语“衍生物”还包括包含非天然存在的核苷酸和核苷酸类似物的核酸。
根据本发明,核酸优选是脱氧核糖核酸(DNA)或核糖核酸(RNA)。根据本发明,核酸包括基因组DNA、cDNA、mRNA、重组生产和化学合成的分子。根据本发明,核酸可以呈现为单链或双链以及线性或共价环状闭合分子。
如本文所使用的,术语“RNA”意指包含至少一个核糖核苷酸残基的分子。“核糖核苷酸”意指在β-D-呋喃核糖部分的2′-位置上具有羟基的核苷酸。该术语包括双链RNA,单链RNA,分离的RNA例如部分纯化的RNA,基本上纯的RNA,合成的RNA,重组产生的RNA,以及经由一个或多个核苷酸的添加、删除、置换和/或改变而不同于天然存在的RNA的改变的RNA。此类改变可以包括例如给RNA的一个或多个末端,或者内部地例如在RNA的一个或多个核苷酸上添加非核苷酸材料。RNA分子中的核苷酸还可以包含非标准的核苷酸,例如非天然存在的核苷酸或化学合成的核苷酸或脱氧核糖核苷酸。这些改变的RNA可以被称为类似物或天然存在的RNA的类似物。
根据本发明描述的核酸优选是分离的。根据本发明,术语“分离的核酸”意指,所述核酸是(i)例如通过聚合酶链式反应(PCR)体外扩增的,(ii)通过克隆重组产生的,(iii)例如通过切割和凝胶电泳分级而纯化的,或(iv)例如通过化学合成而合成的。分离的核酸是可用于通过重组DNA技术进行操作的核酸。
如果2个序列能够彼此杂交并形成稳定的双链体,那么该核酸与另一种核酸是“互补的”,其中杂交优选在允许多核苷酸之间的特异性杂交的条件(严紧条件)下进行。严紧条件例如在MolecularCloning:A Laboratory Manual,J.Sambrook等人,编辑,第2版,Cold Spring Harbor Laboratory press,Cold Spring Harbor,NewYork,1989;或Current Protocols in Molecular Biology,F.M.Ausubel等人,编辑,John Wiley和Sons,Inc.,New York中描述,并且例如指于65℃在杂交缓冲液(3.5x SSC,0.02%Ficoll,0.02%聚乙烯吡咯烷酮,0.02%牛血清白蛋白,2.5mM NaH2PO4(pH 7),0.5%SDS,2mM EDTA)中杂交。SSC是0.15M氯化钠/0.15M柠檬酸钠,pH 7。杂交后,DNA已被转移至其上的膜例如在2×SSC中于室温洗涤,并且随后在0.1-0.5×SSC/0.1×SDS中于直到68℃的温度下洗涤。
根据本发明,互补的核酸具有至少40%,特别是至少50%,至少60%,至少70%,至少80%,至少90%,和优选至少95%,至少98%或至少99%的相同核苷酸。
术语“同一性百分比”意指在最佳比对后获得的在所比较的2个序列之间相同的核苷酸或氨基酸残基的百分比,这个百分比完全是统计学上的,并且2个序列之间的差异是随机分布的并在其整个长度上。2个核苷酸或氨基酸序列之间的序列比较通过在使它们最佳比对后比较这些序列来常规地进行,所述比较通过区段或通过“比较窗”来进行以便鉴定并比较序列相似性的局部区域。除了人工外,用于比较的序列的最佳比对可以通过下述方法来进行:Smith和Waterman,1981,Ads App.Math.2,482的局部同源性算法,Neddleman和Wunsch,1970,J.Mol.Biol.48,443的局部同源性算法,Pearson和Lipman,1988,Proc.Natl Acad.Sci.USA 85,2444的相似性搜索方法,或使用这些算法的计算机程序(GAP、BESTFIT、FASTA、BLAST P、BLASTN和TFASTA,在Wisconsin Genetics Software Package中,GeneticsComputer Group,575 Science Drive,Ma dison,Wis.)。
同一性百分比通过下述方法计算:测定所比较的2个序列之间相同位置的数目,将这个数目除以被比较的位置的数目,并将获得的结果乘以100,以便获得这2个序列之间的同一性百分比。
根据本发明,编码肿瘤相关抗原的核酸可以单独存在或与其他核酸特别是异源核酸相组合地存在。在优选实施方案中,核酸与表达控制序列或调节序列功能性地连接,所述表达控制序列或调节序列相对于所述核酸是同源或异源的。如果编码序列和调节序列以使得所述编码序列的表达或转录在所述调节序列的控制或影响下这样的方式互相共价连接,那么它们“功能性地”互相连接。如果编码序列将被翻译成功能蛋白质,那么在具有与所述编码序列功能性地连接的调节序列的情况下,所述调节序列的诱导导致所述调节序列的转录,而不引起所述编码序列中的移码或所述编码序列不能被翻译成所需蛋白质或肽。
根据本发明,术语“表达控制序列”或“调节序列”包括启动子、增强子以及调节基因表达的其他控制元件。在本发明的具体实施方案中,表达控制序列可以被调节。调节序列的确切结构可以依物种或细胞类型而变,但一般包含分别参与转录和翻译起始的5’非转录和5’非翻译序列,例如TATA盒、加帽序列、CAAT序列等。更具体而言,5’非转录调节序列包含启动子区域,其包括用于功能性地连接的基因的转录控制的启动子序列。调节序列还可以包含增强子序列或上游激活子序列。
根据本发明,核酸可以进一步与另一种核酸相组合地存在,所述另一种核酸编码控制由所述核酸编码的蛋白质或肽从宿主细胞中分泌的肽。根据本发明,核酸还可以与另一种核酸相组合地存在,所述另一种核酸编码引起所编码的蛋白质或肽锚定在宿主细胞的细胞膜上或区室化到所述细胞的特定细胞器内的肽。类似地,与表示报道基因或任何“标签”的核酸的组合是可能的。
在一个优选实施方案中,根据本发明,重组核酸分子是载体,适当时具有启动子,所述载体控制核酸例如编码根据本发明鉴定的肿瘤相关抗原的核酸的表达。术语“载体”在此处以其最一般的含义使用并且包括用于核酸的任何中间媒介物,其使得所述核酸能够例如被引入原核和/或真核细胞内,并且适当时被整合到基因组内。这类载体优选在细胞中进行复制和/或表达。中间媒介物可以进行调整以例如用于电穿孔,用微粒轰击,脂质体施用,借助于农杆菌的转移或经由DNA或RNA病毒的插入。载体包括质粒、噬菌粒、噬菌体或病毒基因组。
编码根据本发明鉴定的肿瘤相关抗原的核酸可以用于转染宿主细胞。核酸在此处意指重组DNA和RNA。重组RNA可以通过DNA模板的体外转录来制备。此外,在应用前它可以通过使序列稳定、加帽和多腺苷酸化来进行修饰。
根据本发明,术语“宿主细胞”涉及可以用内源核酸转化或转染的任何细胞。根据本发明,术语“宿主细胞”包括原核细胞(例如大肠杆菌)或真核细胞(例如树突状细胞、B细胞、CHO细胞、COS细胞、K562细胞、酵母细胞和昆虫细胞)。特别优选的是哺乳动物细胞例如来自人、小鼠、仓鼠、猪、山羊、灵长类的细胞。细胞可以来源于多种组织类型并且包括灵长类细胞和细胞系。具体例子包括角质形成细胞、外周血白细胞、骨髓干细胞和胚胎干细胞。在进一步的实施方案中,宿主细胞是抗原呈递细胞,特别是树突状细胞、单核细胞或巨噬细胞。核酸可以以单个拷贝或2个或更多个拷贝的形式存在于宿主细胞中,并且在一个实施方案中,在宿主细胞中进行表达。
根据本发明,术语“表达”以其最一般的含义使用并且包括RNA或RNA和蛋白质的产生。它还包括核酸的部分表达。此外,表达可以瞬时或稳定地进行。在哺乳动物细胞中优选的表达系统包括pcDNA 3.1和pRc/CMV(Invitrogen,Carlsbad,CA),其包含选择标记例如赋予针对G418的抗性(并因此使得能够选择出稳定转染的细胞系)的基因和巨细胞病毒(CMV)的增强子-启动子序列。
在其中MHC分子呈递肿瘤相关抗原或其部分的本发明的那些情况下,表达载体还可以包含编码所述MHC分子的核酸序列。编码MHC分子的核酸序列可以存在于与编码肿瘤相关抗原或其部分的核酸相同的表达载体上,或者这2种核酸可以存在于不同的表达载体上。在后面一种情况下,可以将2种表达载体共转染到细胞内。如果宿主细胞既不表达肿瘤相关抗原或其部分也不表达MHC分子,那么编码其的2种核酸可以在相同的表达载体上或在不同的表达载体上被转染到细胞内。如果细胞已表达MHC分子,那么只有编码肿瘤相关抗原或其部分的核酸序列可以被转染到细胞内。
本发明还包括用于扩增编码肿瘤相关抗原的核酸的试剂盒。此类试剂盒包含例如一对扩增引物,其与编码肿瘤相关抗原的核酸杂交。所述引物优选包含所述核酸的6-50个,特别是10-30个,15-30个和20-30个邻接核苷酸的序列,并且是非重叠的,以便避免引物二聚体的形成。引物之一将与编码肿瘤相关抗原的核酸的一条链杂交,和另一个引物将与互补链杂交,它们的排列允许扩增编码肿瘤相关抗原的核酸。
“反义分子”或“反义核酸”可以用于调节,特别是减少核酸的表达。根据本发明,术语“反义分子”或“反义核酸”指寡核苷酸,其是寡核糖核苷酸、寡脱氧核糖核苷酸、经修饰的寡核糖核苷酸或经修饰的寡脱氧核糖核苷酸,并且在生理条件下与包含特定基因的DNA或所述基因的mRNA杂交,从而抑制所述基因的转录和/或所述mRNA的翻译。根据本发明,“反义分子”还包括构建体,其包含相对于其天然启动子为反向的核酸或其部分。核酸或其部分的反义转录物可以与指定该酶的天然存在的mRNA形成双链体,从而防止mRNA积聚或翻译成活性酶。另一种可能性是使用核酶以用于使核酸失活。根据本发明优选的反义寡核苷酸具有靶核酸的6-50个,特别是10-30个,15-30个和20-30个邻接核苷酸的序列,并且优选与靶核酸或其部分完全互补。
在优选实施方案中,反义寡核苷酸与N-末端或5’上游位点例如翻译起始位点、转录起始位点或启动子位点杂交。在进一步的实施方案中,反义寡核苷酸与3’非翻译区或mRNA剪接位点杂交。
在一个实施方案中,本发明的寡核苷酸由核糖核苷酸、脱氧核糖核苷酸或其组合组成,其中1个核苷酸的5’末端和另一个核苷酸的3’末端通过磷酸二酯键互相连接。这些寡核苷酸可以以常规方式合成或重组产生。
在优选实施方案中,本发明的寡核苷酸是“经修饰的”寡核苷酸。此处,寡核苷酸可以以非常不同的方式进行修饰,而不损害其与其靶结合的能力,以便增加例如其稳定性或治疗效能。根据本发明,术语“经修饰的寡核苷酸”意指这样的寡核苷酸,其中(i)至少2个其核苷酸通过合成的核苷间键(即不是磷酸二酯键的核苷间键)互相连接,和/或(ii)通常在核酸中未发现的化学基团与该寡核苷酸共价连接。优选的合成的核苷间键是硫代磷酸酯、烷基膦酸酯、二硫代磷酸酯、磷酸酯、烷基硫代膦酸酯、氨基磷酸酯、氨基甲酸酯、碳酸酯、磷酸三酯、乙酰胺化物(acetamidates)、羧甲基酯和肽。
术语“经修饰的寡核苷酸”还包括具有经共价修饰的碱基和/或糖的寡核苷酸。“经修饰的寡核苷酸”包括,例如,具有这样的糖残基的寡核苷酸,所述糖残基在3’位置上与除羟基外的低分子量有机基团和在5’位置上与磷酸基团共价结合。经修饰的寡核苷酸可以包含例如2’-0-烷基化的核糖残基或代替核糖的另一种糖例如阿拉伯糖。
应当理解,上文关于寡核苷酸而描述的所有实施方案也可以应用于多核苷酸。
如本文所使用的,“小干扰RNA”或“siRNA”意指分离的RNA分子,优选地长度大于10个核苷酸,更优选地长度大于15个核苷酸,和最优选地长度为18、19、20、21、22、23、24、25、26、27、28、29或30个核苷酸,其用于鉴定待降解的靶基因或mRNA。19-25个核苷酸对于siRNA是最优选的大小。
根据本发明,siRNA可以包含部分纯化的RNA,基本上纯的RNA,合成的RNA,或重组产生的RNA,以及经由一个或多个核苷酸的添加、删除、置换和/或改变而不同于天然存在的RNA的改变的RNA。此类改变可以包括例如给siRNA的一个或多个末端或者给siRNA的一个或多个内部核苷酸添加非核苷酸材料;使得siRNA对核酸酶消化具有抵抗力的修饰(例如,使用2’-取代的核糖核苷酸或针对糖-磷酸主链的修饰);或用脱氧核糖核苷酸置换siRNA中的一个或多个核苷酸。此外,如上文对于经修饰的寡核苷酸所描述的,siRNA还可以进行修饰以增加其稳定性,特别是通过引入一个或多个硫代磷酸酯键。
siRNA的1条或2条链还可以包含3’-突出端。如本文所使用的,“3’-突出端”指从RNA链的3’-末端延伸的至少一个未配对的核苷酸。因此,在一个实施方案中,siRNA包含至少一个3’-突出端,其长度为1-约6个核苷酸(其包括核糖核苷酸或脱氧核苷酸),优选地长度为1-约5个核苷酸,更优选地长度为1-约4个核苷酸,和特别优选地长度为约2-约4个核苷酸。在其中siRNA分子的2条链包含3’-突出端的实施方案中,突出端的长度对于每条链可以是相同的或不同的。在一个最优选的实施方案中,3’-突出端存在于siRNA的2条链上,并且长度为2个核苷酸。例如,本发明的siRNA的每条链可以包含二脱氧胸苷酸(“TT”)或二尿苷酸(“uu”)的3’-突出端。
为了增强siRNA的稳定性,3’-突出端还可以针对降解进行稳定化。在一个实施方案中,突出端通过包含嘌呤核苷酸,例如腺苷或鸟苷核苷酸进行稳定化。备选地,用经修饰的类似物置换嘧啶核苷酸,例如用2’-脱氧胸苷置换在3’-突出端中的尿苷核苷酸是被耐受的,并且不影响RNAi降解的效率。特别地,2’-脱氧胸苷中2’-羟基的不存在显著增强了3’-突出端在组织培养基中的核酸酶抵抗力。
siRNA的有义和反义链可以包含2个互补的单链RNA分子,或可以包含单个分子,其中2个互补部分是碱基配对的并通过单链“发夹”区域共价连接。也就是说,有义区和反义区可以经由连接体分子进行共价连接。连接体分子可以是多核苷酸或非核苷酸连接体。不希望被任何理论所束缚,认为后一种类型的siRNA分子的发夹区域通过“Dicer”蛋白质(或其等价物)在细胞内进行切割,以形成2个独个碱基配对的RNA分子的siRNA。
如本文所使用的,“靶mRNA”指这样的RNA分子,其为用于下调的靶。
siRNA还可以从pol III表达载体中进行表达而无靶向位点中的变化,因为从pol III启动子的RNA表达仅当第一个被转录的核苷酸是嘌呤时才被认为是有效的。
根据本发明,siRNA可以被靶向至任何靶mRNA序列(“靶序列”)中的约19-25个邻接核苷酸的任何链串。用于选择关于siRNA的靶序列的技术例如于在2002年10月11日修改的Tuschl T.等人,″ThesiRNA User Guide ″中给出,所述参考文献的完整公开内容引入本文作为参考。“The siRNA User Guide”在万维网上于由Dr.Thomas Tuschl,Laboratory of RNA Molecular Biology,Rockefeller University,New York,USA维持的网站处可获得,并且可以通过访问RockefellerUniversity的网站并使用关键词“siRNA”进行搜索而找到。因此,本发明的siRNA的有义链包含基本上等同于靶mRNA中的约19-约25个核苷酸的任何邻接链串的核苷酸序列。
一般地,在靶mRNA上的靶序列可以选自相应于靶mRNA的给定cDNA序列,优选从起始密码子下游(即,在3’-方向上)50-100nt开始。然而,靶序列可以位于5’-或3’-非翻译区,或在起始密码子附近的区域中。
siRNA可以使用本领域技术人员已知的许多技术来获得。例如,siRNA可以使用本领域已知的方法来化学合成或重组产生,例如在Tuschl等人的美国公开申请2002/0086356中描述的果蝇体外系统,所述专利的完整公开内容引入本文作为参考。
优选地,使用适当保护的核糖核苷亚磷酰胺和常规的DNA/RNA合成仪来化学合成siRNA。siRNA可以被合成为2个分开的、互补的RNA分子,或者具有2个互补区的单个RNA分子。
备选地,还可以使用任何合适的启动子从重组环状或线性DNA质粒表达siRNA。根据本发明,当本文提及施用siRNA或将siRNA掺入药物组合物中时,包括此类实施方案。用于从质粒表达本发明siRNA的合适启动子包括例如,U6或H1 RNA pol III启动子序列和巨细胞病毒启动子。
其他合适的启动子的选择在本领域的技能之内。本发明的重组质粒还可以包含可诱导或可调节的启动子,以用于在特定的组织或特定的细胞内环境中表达siRNA。
从重组质粒表达的siRNA可以通过标准技术从培养的细胞表达系统中进行分离,或者可以在细胞内表达。使用重组质粒将siRNA递送给体内细胞在下文更详细地讨论。siRNA可以从重组质粒表达为2个分开的、互补的RNA分子,或者具有2个互补区的单个RNA分子。
适合于表达siRNA的质粒的选择,将用于表达siRNA的核酸序列插入质粒内的方法,以及将重组质粒递送给目的细胞的方法在本领域的技能内。
siRNA还可以在体内在细胞内从重组病毒载体表达。重组病毒载体包含编码siRNA的序列和用于表达siRNA序列的任何合适的启动子。重组病毒载体还可以包含可诱导或可调节的启动子,以用于在特定的组织或特定的细胞内环境中表达siRNA。siRNA可以从重组病毒载体表达为2个分开的、互补的RNA分子,或者具有2个互补区的单个RNA分子。
术语“肽”包括寡肽和多肽,并且指包含通过肽键共价连接的2个或更多个,优选3个或更多个,优选4个或更多个,优选6个或更多个,优选8个或更多个,优选10个或更多个,优选13个或更多个,优选16个或更多个,优选21个或更多个,以及高达优选8、10、20、30、40或50个,特别是100个氨基酸的物质。术语“蛋白质”指大的肽,优选具有超过100个氨基酸残基的肽,但一般而言术语“肽”和“蛋白质”是同义词并且在本文中可互换使用。
优选地,根据本发明描述的蛋白质和肽是已经分离的。术语“分离的蛋白质”或“分离的肽”意指,蛋白质或肽已与其天然环境相分开。分离的蛋白质或肽可以处于基本上纯化的状态。术语“基本上纯化的”意指,蛋白质或肽基本上不含它在自然界中或在体内所与之结合的其他物质。
此类蛋白质或肽可以例如用于产生抗体以及用于免疫或诊断测定法或用作治疗剂。根据本发明描述的蛋白质和肽可以从生物样品例如组织或细胞匀浆中分离,并且还可以在多种原核或真核表达系统中重组地表达。
为了本发明的目的,蛋白质或肽或者氨基酸序列的“衍生物”包括氨基酸插入变体、氨基酸删除变体和/或氨基酸置换变体。
氨基酸插入变体包含氨基和/或羧基末端融合以及还包含在特定的氨基酸序列中单个或者2个或更多个氨基酸的插入。在氨基酸序列变体具有插入的情况下,一个或多个氨基酸残基被插入氨基酸序列中的特定位点中,尽管进行随机插入并合适地筛选所得产物也是可能的。氨基酸删除变体的特征在于从序列中去除一个或多个氨基酸。氨基酸置换变体的特征在于去除序列中的至少一个残基并且在其位置中插入另一个残基。优选考虑氨基酸序列中在同源蛋白质或肽之间并非保守的位置中处的修饰,和/或用具有相似性质例如疏水性、亲水性、电负性、侧链体积等的其他氨基酸替换氨基酸(保守置换)。保守置换例如涉及将一个氨基酸交换为下面在与待置换的氨基酸相同的组中列出的另一个氨基酸:
1.小的脂肪族、非极性或略微极性的残基:Ala,Ser,Thr(Pro,Gly)
2.带负电荷的残基及其酰胺:Asn,Asp,Glu,Gln
3.带正电荷的残基:His,Arg,Lys
4.大的脂肪族、非极性残基:Met,Leu,Ile,Val(Cys)
5.大的芳香族残基:Phe,Tyr,Trp。
由于它们在蛋白质结构中的特定角色,3个残基显示于括号中。Gly是唯一不含侧链的残基,并且因此给链赋予了弹性。Pro具有极大地限制链的不寻常的几何学。Cys可以形成二硫桥。
上述的氨基酸变体可以借助于已知的肽合成技术容易地制备,例如通过固相合成(Merrifield,1964)或相似方法或通过重组DNA操作。用于制备具有置换、插入或删除的蛋白质和肽的DNA序列的操作在例如Sambrook等人(1989)中详细描述。
根据本发明,蛋白质和肽的“衍生物”还包括与所述蛋白质或肽结合的任何分子(例如碳水化合物、脂质和/或蛋白质或肽)的单个或多个置换、删除和/或添加。术语“衍生物”还延伸至所述蛋白质和肽的所有功能性化学等价物。
根据本发明,肿瘤相关抗原的部分或片段优选具有它所由之衍生的蛋白质或肽的功能性质。此类功能性质包括与抗体的相互作用、与其他肽或蛋白质的相互作用、核酸的选择性结合和酶促活性。特定的性质是与MHC分子形成复合物的能力,并且适当时,优选地通过刺激细胞毒性或T辅助细胞来产生免疫应答。本发明的肿瘤相关抗原的部分或片段优选包含肿瘤相关抗原的至少6个,特别是至少8个,至少10个,至少12个,至少15个,至少20个,至少30个或至少50个连续氨基酸的序列。本发明的肿瘤相关抗原的部分或片段优选包含肿瘤相关抗原的高达8个,特别是高达10个,高达12个,高达15个,高达20个,高达30个或高达55个连续氨基酸的序列。肿瘤相关抗原的部分或片段优选地是相应于抗原的非跨膜部分特别是细胞外部分的肿瘤相关抗原的部分,或者由所述部分组成。
根据本发明的肿瘤相关抗原的优选部分或片段不仅特别适合于在体内刺激细胞毒性T-淋巴细胞,而且还适合于产生扩展的且刺激的T-淋巴细胞以用于治疗上采用的离体转移。
根据本发明,编码肿瘤相关抗原的核酸的部分或片段涉及这样的核酸部分,其至少编码肿瘤相关抗原和/或所述肿瘤相关抗原的部分或片段,如上定义的。编码肿瘤相关抗原的核酸的部分或片段优选是相应于开放读码框的核酸部分。
根据本发明,特定的实施方案应当涉及提供衍生自肿瘤相关抗原的“显性失活”蛋白质或肽。显性失活蛋白质或肽是失活的蛋白质或肽变体,它通过与细胞机制相互作用而将活性蛋白质或肽从其与细胞机制的相互作用中替代出来,或者它与活性蛋白质或肽竞争,从而减少所述活性蛋白质的效应。
包含与靶蛋白特异性地结合的特异性抗体的抗血清可以通过各种标准方法来制备;参见,例如,Philip Shepherd的“MonoclonalAntibodies:A Practical Approach”,Christopher Dean ISBN0-19-963722-9;Ed Harlow的“Antibodies:A Laboratory Manual”,David Lane,ISBN:0879693142;和Edward Harlow的“UsingAntibodies:A Laboratory Manual:Portable Protocol NO”,DavidLane,Ed Harlow ISBN 0879695447。由此可以产生亲合且特异性的抗体,其识别以其天然形式存在的复合膜蛋白质(Azorsa等人,J.Immunol.Methods 229:35-48,1999;Anderson等人,J.Immunol.143:1899-1904,1989;Gardsvoll,J.Immunol.Methods 234:107-116,2000)。这不仅与待在治疗上进行使用的抗体的制备特别相关,而且还与许多诊断应用相关。在这方面,可以用完整蛋白质,用细胞外的部分序列以及用表达生理学折叠形式的靶分子的细胞进行免疫。
单克隆抗体使用杂交瘤技术常规地进行制备。(关于技术细节参见:Philip Shepherd的“Monoclonal Antibodies:A PracticalApproach”,Christopher Dean ISBN 0-19-963722-9;Ed Harlow的“Antibodies:A Laboratory Manual”,David Lane ISBN:0879693142;Edward Harlow的“Using Antibodies:A Laboratory Manual:PortableProtocol NO”,David Lane,Ed Harlow ISBN:0879695447)。
已知只有抗体分子的一小部分(互补位)参与抗体与其表位的结合(参照Clark,W.R.(1986),The Experimental Foundations ofModern Immunology,Wiley&Sons,Inc.,New York;Roitt,I.(1991),Essential Immunology,第7版,Blackwell ScientificPublications,Oxford)。pFc′和Fc区是例如补体级联的效应子,但并不参与抗原结合。从中己酶促去除了pFc′区或以不含pFc′区的方式产生的抗体被称为F(ab′)2片段,携带完整抗体的2个抗原结合位点。类似地,从中己酶促去除了Fc区或以不含所述Fc区的方式产生的抗体被称为Fab片段,携带完整抗体分子的1个抗原结合位点。进一步地,Fab片段由抗体的共价结合的轻链和所述抗体的重链的一部分组成,被称为Fd。Fd片段是抗体特异性的主要决定子(单个Fd片段可以结合高达10个不同的轻链,而不改变抗体的特异性),并且当被分离出时Fd片段保留与表位结合的能力。
互补决定区(CDR)位于抗体的抗原结合部分内,其与抗原表位和构架区(FR)直接相互作用,所述FR维持互补位的三级结构。IgG免疫球蛋白的重链和轻链的Fd片段包含4个构架区(FR1-FR4),它们在每种情况下由3个互补决定区(CDR1-CDR3)分隔开。CDR,特别是CDR3区,更加特别是重链的CDR3区,在很大程度上负责抗体特异性。
哺乳动物抗体的非CDR区已知能够被具有相同或不同特异性的抗体的相似区域替换,其中原始抗体的表位特异性被保留。这使得能够开发“人源化”抗体,其中非人CDR与人FR和/或Fc/pFc′区共价连接以产生功能抗体。
作为另一个例子,WO 92/04381描述了人源化的鼠类RSV抗体的产生和用途,在所述人源化的鼠类RSV抗体中至少部分鼠类FR区被替换为人起源的FR区。这类抗体包括具有抗原结合能力的完整抗体的片段,通常被称为“嵌合”抗体。
根据本发明,术语“抗体”还包括抗体的F(ab′)2、Fab、Fv和Fd片段,嵌合抗体,其中Fc和/或FR和/或CDR1和/或CDR2和/或轻链-CDR3区被替换为同源的人或非人序列,嵌合F(ab′)2-片段抗体,其中FR和/或CDR1和/或CDR2和/或轻链-CDR3区被替换为同源的人或非人序列,嵌合Fab-片段抗体,其中FR和/或CDR1和/或CDR2和/或轻链-CDR3区被替换为同源的人或非人序列,以及嵌合Fd-片段抗体,其中FR和/或CDR1和/或CDR2区被替换为同源的人或非人序列。术语“抗体”还包括“单链”抗体。
本发明还包括与肿瘤相关抗原特异性地结合的蛋白质和肽。这类结合物质可以例如由简并的肽文库来提供,所述简并的肽文库可以在溶液中以固定形式或作为噬菌体展示文库简单地制备。同样地可以制备具有一个或多个氨基酸的肽的组合文库。还可以制备拟肽和非肽的合成残基的文库。
抗体也可以与特异性诊断物质相偶联,以用于展示出表达肿瘤相关抗原的细胞和组织。它们还可以与治疗上有用的物质相偶联。
诊断物质包括任何标记,其作用为:(i)提供可检测的信号;(ii)与第二种标记相互作用以修饰由第一种或第二种标记提供的可检测信号,例如FRET(荧光共振能量转移);(iii)通过电荷、疏水性、形状或其他物理参数来影响迁移率,例如电泳迁移率;或(iv)提供捕获部分,例如亲和力、抗体/抗原、或离子复合作用。适合作为标记的结构为,例如荧光标记,发光标记,生色团标记,放射性同位素标记,同位素标记,优选稳定的同位素标记,等压标记,酶标记,颗粒标记,特别是金属颗粒标记,磁性颗粒标记,聚合物颗粒标记,小有机分子例如生物素,受体的配体或结合分子例如细胞粘附蛋白质或凝集素,包含核酸和/或氨基酸残基的标记序列,其可以通过使用结合剂等进行检测。诊断物质包含但不限于,硫酸钡,碘西他酸,碘番酸,碘泊酸钙,泛影酸钠,泛影葡胺,甲泛葡胺,酪泮酸钠和放射性诊断剂,包括正电子发射体例如氟-18和碳-11,γ发射体例如碘-123,锝-99m,碘-131和铟-111,用于核磁共振的核素例如氟和钆。
根据本发明,术语“治疗上有用的物质”意指可以发挥治疗效果的任何分子。根据本发明,治疗上有用的物质优选地被选择性地导向表达一种或多种肿瘤相关抗原的细胞,并且包括抗癌剂、经放射性碘标记的化合物、毒素、细胞抑制性或溶细胞性药物等。抗癌剂包括例如,氨鲁米特、硫唑嘌呤、硫酸博来霉素、白消安、卡莫司汀、苯丁酸氮芥、顺铂、环磷酰胺、环孢霉素、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、多柔比星、紫杉醇、依托泊苷、氟尿嘧啶、干扰素-α、洛莫司汀、巯基嘌呤、氨甲蝶呤、米托坦、盐酸丙卡巴肼、硫鸟嘌呤、硫酸长春碱和硫酸长春新碱。其他抗癌剂例如在Goodman和Gilman,“The Pharmacological Basis of Therapeutics”,第8版,1990,McGraw-Hill,Inc.,特别是第52章(Antineoplastic Agents(Paul Calabresi和Bruce A.Chabner)中描述。毒素可以是蛋白质例如美洲商陆抗病毒蛋白、霍乱毒素、百日咳毒素、蓖麻毒蛋白、白树毒蛋白、相思豆毒蛋白、白喉外毒素或假单胞菌外毒素。毒素残基也可以是发射高能量的放射性核素例如钴-60。
术语“主要组织相容性复合物”或“MHC”涉及在所有脊椎动物中存在的基因复合物。通过结合肽并将它们呈递用于由T细胞受体(TCR)识别,MHC蛋白或分子参与在正常免疫反应中淋巴细胞和抗原呈递细胞之间的信号传导。MHC分子在细胞内的加工区室内结合肽,并将这些肽呈现在抗原呈递细胞的表面上以用于由T细胞识别。人MHC区域也称为HLA,位于第6染色体上并且包括I类和II类区域。在本发明的所有方面的一个优选实施方案中,MHC分子是HLA分子。
如本文所使用的,“减少”或“抑制”意指与参考样品(例如,未用siRNA处理的样品)相比较,在水平上例如在蛋白质或mRNA水平上引起优选20%或更多,更优选50%或更多,和最优选75%或更多的总体减少的能力。RNA或蛋白质表达的这种减少或抑制可以通过被靶向的mRNA切割或降解而发生。关于蛋白质表达或核酸表达的测定法是本领域已知的,并且包括例如ELISA,关于蛋白质表达的Western印迹分析,和关于RNA的Northern印迹或RNA酶保护测定法。
根据本发明,术语“患者”意指人类、非人灵长类或另一种动物,特别是哺乳动物例如牛、马、猪、绵羊、山羊、狗、猫或啮齿类动物如小鼠和大鼠。在一个特别优选的实施方案中,患者是人类。
根据本发明,“异常表达”意指与健康个体中的状态相比较,表达是改变的,优选增加的。
根据本发明,术语“增加的”或“增加的量”优选指增加至少10%,特别是至少20%、至少50%或至少100%。如果它在测试样品中是可检测的,而在参考样品中不存在或无法检测,那么与参考样品相比较,物质的量在测试样品例如生物样品中也是增加的。
根据本发明,术语“疾病”指其中肿瘤相关抗原被表达或异常表达的任何病理状态。根据本发明,“异常表达”意指与健康个体中的状态相比较,表达是改变的,优选增加的。表达的增加指增加至少10%,特别是至少20%、至少50%或至少100%。在一个实施方案中,肿瘤相关抗原仅在患病个体的组织中表达,而在健康个体中的表达被抑制。此类疾病的一个例子是癌症,其中根据本发明,术语“癌症”包括白血病,精原细胞瘤,黑素瘤,畸胎瘤,淋巴瘤,成神经细胞瘤,神经胶质瘤,直肠癌,子宫内膜癌,肾癌,肾上腺癌,甲状腺癌,血癌,皮肤癌,脑癌,子宫颈癌,肠癌,肝癌,结肠癌,胃癌,肠癌,头与颈癌,胃肠癌,淋巴结癌,食道癌,结肠直肠癌,胰腺癌,耳、鼻与喉(ENT)癌,乳腺癌,前列腺癌,子宫癌,卵巢癌和肺癌及其转移灶。其的例子是肺癌、乳房癌、前列腺癌、结肠癌、肾细胞癌、子宫颈癌,或上述癌症类型或肿瘤的转移灶。根据本发明,术语癌症还包括癌症转移灶。
“肿瘤”意指细胞或组织的异常群体,其通过快速的、不受控制的细胞增殖而生长并且在起始新生长的刺激停止后继续生长。肿瘤显示部分或完全缺乏结构组织和与正常组织的功能协调,并且通常形成不同的组织团块,其可以是良性的或恶性的。
“转移”意指癌细胞从其最初位点传播至身体的另一个部分。转移灶的形成是非常复杂的过程,并且取决于恶性细胞从原发性肿瘤上的脱离,细胞外基质的侵袭,内皮基底膜的渗透以进入体腔和脉管,以及随后在通过血液运输后靶器官的浸润。最后,新肿瘤在靶位点处的生长取决于血管发生。即使在摘除原发性肿瘤后,肿瘤转移也常常发生,因为肿瘤细胞或组分可以保持并发展转移潜能。在一个实施方案中,根据本发明,术语“转移”涉及“远端转移”,其涉及远离原发性肿瘤和局部淋巴结系统的转移。
根据本发明,生物样品可以是组织样品(包括体液)和/或细胞样品,并且可以以常规方式来获得,所述常规方式例如为通过组织活检,包括钻取活检,以及通过获取血液、支气管抽吸物、痰、尿、粪便或其他体液。根据本发明,术语“生物样品”还包括生物样品的级分。
根据本发明,术语“免疫反应性细胞”意指使用合适的刺激可以成熟为免疫细胞(例如B细胞、T辅助细胞或溶细胞性T细胞)的细胞。免疫反应性细胞包括CD34+造血干细胞、未成熟的和成熟的T细胞、以及未成熟的和成熟的B细胞。如果希望产生识别肿瘤相关抗原的溶细胞性或T辅助细胞,那么在有利于溶细胞性T细胞和T辅助细胞的产生、分化和/或选择的条件下,使免疫反应性细胞与表达肿瘤相关抗原的细胞接触。当暴露于抗原时,T细胞前体至溶细胞性T细胞的分化类似于免疫系统的克隆选择。
术语“T细胞”和“T淋巴细胞”在本文中可互换使用,并且包括T辅助细胞和细胞毒性T细胞,所述细胞毒性T细胞包括溶细胞性T细胞。
某些治疗方法基于患者的免疫系统的反应,这导致抗原呈递细胞例如呈递一种或多种肿瘤相关抗原的癌细胞的裂解。在这种背景中,例如给具有细胞异常的患者施用对肿瘤相关抗原和MHC分子的复合物特异的自体细胞毒性T淋巴细胞。此类细胞毒性T淋巴细胞在体外的产生是已知的。使T细胞分化的方法的例子可以在WO-A-9633265中找到。一般地,包含细胞例如血细胞的样品取自患者,并且使所述细胞与呈递复合物和可以引起细胞毒性T淋巴细胞(例如树突状细胞)繁殖的细胞接触。靶细胞可以是被转染的细胞例如COS细胞。这些被转染的细胞在其表面上呈递所需复合物,并且当与细胞毒性T淋巴细胞接触时,刺激后者的繁殖。随后给患者施用经克隆扩增的自体细胞毒性T淋巴细胞。
在选择抗原特异性的细胞毒性T淋巴细胞的另一种方法中,I类MHC分子/肽复合物的荧光四聚物用于获得细胞毒性T淋巴细胞的特异性克隆(Altman等人,Science 274:94-96,1996;Dunbar等人,Curr.Biol.8:413-416,1998)。
本发明还包括被称为过继性转移的治疗方法(Greenberg,J.Immunol.136(5):1917,1986;Riddel等人,Science257:238,1992;Lynch等人,Eur.J.Immunol.21:1403-1410,1991;Kast等人,Cell 59:603-614,1989),其中呈递所需复合物的细胞(例如树突状细胞)与待治疗的患者的细胞毒性T淋巴细胞相组合,导致特异性的细胞毒性T淋巴细胞的繁殖。随后将繁殖的细胞毒性T淋巴细胞施用于具有细胞异常的患者,所述细胞异常的特征在于呈递特异性复合物的特定异常细胞。细胞毒性T淋巴细胞随后使异常细胞裂解,从而达到所需治疗效果。
此外,呈递所需复合物的细胞(例如树突状细胞)可以与健康个体或另一个物种(例如小鼠)的细胞毒性T淋巴细胞相组合,这可以导致具有高亲和力的特异性的细胞毒性T淋巴细胞的繁殖。可以克隆这些繁殖的特异性T淋巴细胞的高亲和力T细胞受体并任选地人源化至不同程度,并且随后将如此获得的T细胞受体经由基因转移例如使用逆转录病毒载体转导到患者的T细胞内。过继性转移随后可以使用这些经遗传改变的T淋巴细胞来进行(Stanislawski等人,NatImmunol.2:962-70,2001;Kessels等人,Nat Immunol.2:957-61,2001)。
过继性转移并非是可以根据本发明进行应用的唯一疗法形式。细胞毒性T淋巴细胞还可以以本身已知的方式在体内产生。一种方法使用表达复合物的非增殖性细胞。此处使用的细胞将是通常表达复合物的那些,例如受辐射的肿瘤细胞或用对于呈递复合物所必需的1种或2种基因(即抗原性肽和呈递性MHC分子)转染的细胞。另一种优选形式是以重组RNA的形式导入肿瘤相关抗原,所述重组RNA可以例如通过脂质体转移或通过电穿孔引入细胞内。所得到的细胞呈递目的复合物并且被随后繁殖的自体细胞毒性T淋巴细胞所识别。
通过使肿瘤相关抗原或其片段与佐剂相组合以便使得能够掺入体内的抗原呈递细胞中,可以达到类似效应。肿瘤相关抗原或其片段可以表现为蛋白质、DNA(例如在载体内)或RNA。加工肿瘤相关抗原以产生关于MHC分子的肽配偶体,而其片段无需进一步加工即可被呈递。特别地,如果这些可以与MHC分子结合,那么是后面一种情况。优选考虑其中完整抗原被树突状细胞在体内进行加工的施用形式,因为这还可以产生T辅助细胞应答,其是有效的免疫应答所需的(Ossendorp等人,Immunol Lett.74:75-9,2000;Ossendorp等人,J.Exp.Med.187:693-702,1998)。一般而言,可以通过例如皮内注射来给患者施用有效量的肿瘤相关抗原。然而,还可以节内注射到淋巴结中(Maloy等人,Proc Natl Acad Sci USA 98:3299-303,2001)。
根据本发明描述的药物组合物和治疗方法还可以用于免疫接种或疫苗接种,以在治疗上处理或预防本文所述疾病。根据本发明,术语“免疫接种”或“疫苗接种”优选涉及针对抗原的免疫应答的增加或激活。可以使用动物模型用于通过用肿瘤相关抗原或编码其的核酸来测试对于癌症的免疫效应。例如,可以将人癌细胞引入小鼠中以产生肿瘤,并且可以施用编码肿瘤相关抗原的一种或多种核酸。对于癌细胞的效应(例如肿瘤大小的减少)可以作为通过核酸进行免疫接种的效能的量度来进行测量。
作为用于免疫接种或疫苗接种的组合物的一部分,优选地将一种或多种肿瘤相关抗原或其刺激性片段连同一种或多种佐剂一起施用,以诱导免疫应答或增加免疫应答。佐剂是掺入抗原内或连同后者一起施用并增强免疫应答的物质。佐剂可以通过提供抗原储库(细胞外或巨噬细胞中)、激活巨噬细胞和/或刺激特定的淋巴细胞来增强免疫应答。佐剂是已知的,并且包括但不限于,单磷酰脂质A(MPL,SmithKlineBeecham),皂苷类例如QS21(SmithKline Beecham)、DQS21(SmithKlineBeecham;WO 96/33739)、QS7、QS17、QS18和QS-L1(So等人,Mol.Cells 7:178-186,1997),不完全弗氏佐剂,完全弗氏佐剂,维生素E,montanide,明矾,CpG寡核苷酸(参照Kreig等人,Nature 374:546-9,1995)以及由生物可降解的油例如角鲨烯和/或生育酚制备的各种油包水乳状液。优选地,肽在与DQS 21/MPL的混合物中施用。DQS 21与MPL的比率通常为1∶10-10∶1,优选1∶5-5∶1,并且特别是约1∶1。对于给人的施用,疫苗制剂通常包含约1μg-约100μg的DQS 21和MPL。
还可以施用刺激患者的免疫应答的其他物质。例如由于它们对于淋巴细胞的调节性质,在疫苗接种中可以使用细胞因子。此类细胞因子包括例如,显示增加疫苗的保护作用的白介素-12(IL-12)(参照Science 268:1432-1434,1995)、GM-CSF和IL-18。
存在增强免疫应答并因此可以在疫苗接种中使用的许多化合物。所述化合物包括以蛋白质或核酸的形式提供的共刺激分子例如B7-1和B7-2(分别为CD80和CD86)。
本发明还提供了核酸、蛋白质或肽的施用。蛋白质和肽可以以本身已知的方式进行施用。在一个实施方案中,核酸通过离体方法来施用,即通过从患者中取出细胞,遗传修饰所述细胞以便掺入肿瘤相关抗原,并将经改变的细胞重新引入患者内。这一般包括将基因的功能拷贝在体外引入患者的细胞内,并且将经遗传改变的细胞重新引入患者内。基因的功能拷贝在调节元件的功能控制下,这允许基因在经遗传改变的细胞中表达。转染和转导方法是技术人员已知的。本发明还提供了通过使用载体例如病毒和靶控制的脂质体在体内施用核酸。根据本发明,如果提及核酸的施用或掺入药物组合物中,那么这包括其中核酸存在于此类载体中的实施方案。
在一个优选实施方案中,用于施用编码肿瘤相关抗原的核酸的病毒或病毒载体选自腺病毒,腺伴随病毒,痘病毒,包括痘苗病毒和减毒的痘病毒,塞姆利基森林病毒,逆转录病毒,辛德比斯病毒和Ty病毒样粒子。特别优选考虑腺病毒和逆转录病毒。逆转录病毒通常是复制缺陷的(即它们不能产生感染性颗粒)。
在体外或体内将核酸引入细胞内的方法包括核酸磷酸钙沉淀物的转染,与DEAE结合的核酸的转染,用携带目的核酸的上述病毒的转染或感染,脂质体介导的转染等。在具体实施方案中,优选考虑将核酸导向特定细胞。在此类实施方案中,用于将核酸施用给细胞的承载体(例如逆转录病毒或脂质体)可以具有结合的靶控制分子。例如,分子例如对靶细胞上的表面膜蛋白特异的抗体或针对在所述靶细胞上的受体的配体,可以被掺入核酸承载体内或与核酸承载体附着。优选的抗体包括选择性地结合肿瘤相关抗原的抗体。如果希望经由脂质体施用核酸,那么结合至与内吞作用相关的表面膜蛋白的蛋白质可以被掺入脂质体制剂中,以便使得能够实现靶控制和/或摄取。此类蛋白质包括对于特定的细胞类型特异的衣壳蛋白或其片段,针对内在化的蛋白质的抗体,引导至细胞内位点的蛋白质等。
本发明的治疗组合物可以以药学上相容的制剂进行施用。此类制剂通常可以包含药学上相容浓度的盐,缓冲物质,防腐剂,承载体,补充性免疫增强物质例如佐剂,例如CpG寡核苷酸、细胞因子、趋化因子、皂苷、GM-CSF和/或RNA,以及适当时其他治疗上活性的化合物。
本发明的治疗上活性的化合物可以经由任何常规途径进行施用,包括通过注射或输注。施用可以例如口服、静脉内、腹膜内、肌内、皮下或经皮来进行。优选地,抗体通过肺气雾剂进行治疗施用。反义核酸优选通过缓慢的静脉内施用来进行施用。
本发明的组合物以有效量进行施用。“有效量”指单独或连同进一步的剂量一起达到所需反应或所需效应的量。在治疗特征在于一种或多种肿瘤相关抗原的表达的特定疾病或特定病状的情况下,所需反应优选涉及疾病进程的抑制。这包含减缓疾病的进展,和特别是疾病进展的中断或逆转。疾病或病状治疗中的所需反应还可以是延迟所述疾病或所述病状的发作,或阻止所述疾病或所述病状的发作。根据本发明,癌症的诊断或治疗还可以包括已形成或将形成的癌症转移灶的诊断或治疗。根据本发明,术语“治疗”包括治疗性和预防性处理,即预防。
本发明的组合物的有效量取决于待治疗的病状、疾病的严重度、患者的个体参数(包括年龄、生理条件、大小和重量)、治疗的持续时间、伴随疗法(如果存在)的类型、施用的具体途径和类似因素。
本发明的药物组合物优选是无菌的并且包含有效量的治疗上活性的物质,以产生所需反应或所需效应。
本发明的组合物的施用剂量可以取决于各种参数例如施用类型、患者状态、所需施用时间段等。在使用起始剂量时患者中的反应不足的情况下,可以使用更高的剂量(或通过不同的、更局部化的施用途径达到的有效地更高的剂量)。
一般地,配制并施用1ng-1mg,优选10ng-100μg的肿瘤相关抗原的剂量,以用于治疗或用于产生或增加免疫应答。如果希望施用编码肿瘤相关抗原的核酸(DNA和RNA),那么配制并施用1ng-0.1mg的剂量。
本发明的药物组合物一般以药学上相容的量和药学上相容的组合物进行施用。术语“药学上相容的”指不对药物组合物的活性成分的作用具有影响的无毒材料。这类制剂通常可以包含盐、缓冲物质、防腐剂、承载体以及适当时其他治疗上活性的化合物。当在医学中使用时,盐应当是药学上相容的。然而,并非药学上相容的盐可以用于制备药学上相容的盐,并且包括在本发明中。这类药理学和药学上相容的盐包括但不限于由下述酸制备的那些:盐酸、氢溴酸、硫酸、硝酸、磷酸、马来酸、乙酸、水杨酸、柠檬酸、甲酸、丙二酸、琥珀酸等。药学上相容的盐也可以制备为碱金属盐或碱土金属盐,例如钠盐,钾盐或钙盐。
本发明的药物组合物可以包含药学上相容的承载体。根据本发明,术语“药学上相容的承载体”指适合于给人施用的一种或多种相容的固体或液体填充剂、稀释剂或成胶囊物质。术语“承载体”指具有天然或合成性质的有机或无机组分,其中合并有活性成分以促进应用。本发明的药物组合物的组分通常是这样的,即使得不发生实质上损害所需药物功效的相互作用。
本发明的药物组合物可以包含合适的缓冲物质,例如盐形式的乙酸、盐形式的柠檬酸、盐形式的硼酸和盐形式的磷酸。
适当时,药物组合物还可以包含合适的防腐剂,例如苯扎氯铵、三氯叔丁醇、对羟基苯甲酸酯和硫柳汞。
药物组合物通常以一致的剂型提供,并且可以以本身已知的方式进行制备。本发明的药物组合物例如可以为胶囊、片剂、锭剂、溶液、悬浮液、糖浆、酏剂的形式或乳状液的形式。
适合于肠胃外施用的组合物通常包含活性化合物的无菌的水或非水制剂,其优选与受者的血液等渗。相容的承载体和溶剂的例子是林格溶液和等渗的氯化钠溶液。此外,通常将无菌的不挥发性油用作溶液或悬浮液介质。
本发明通过下文的图和实施例详细描述,所述图和实施例仅用于举例说明目的并不意味着是限制性的。由于说明书和实施例,同样包括在本发明中的进一步的实施方案对于技术人员是容易获得的。
附图
图1.ISC-468mRNA表达
A.使用ISC-468特异性引物的RT-PCR研究显示出在除胎盘外所有受试正常组织内没有显著的表达。
B.在头与颈、肝、肾和结肠癌中的ISC-468mRNA表达。
C.在乳腺、卵巢和胃癌中的ISC-468mRNA表达。
图2.在正常对照组织和乳腺癌中的ISC-468mRNA表达的定量PCR分析
使用ISC-468特异性引物的实时PCR研究显示出在正常睾丸、胎盘、胃和PBMC中,以及在所有乳腺癌活检中的选择性mRNA表达。
图3.在正常睾丸和前列腺癌中的特异性ISC-507表达
使用基因特异性ISC-507引物的RT-PCR分析显示出专一地在正常睾丸(A)和前列腺癌(B)活检中的cDNA扩增。
图4.ISC-507的定量表达
使用ISC-507特异性引物的定量RT-PCR显示出在睾丸、淋巴结和前列腺样品以及前列腺癌样品中的选择性表达。
图5.在正常睾丸和各种肿瘤样品中的ISC-466表达
使用ISC-466特异性引物的RT-PCR分析显示出在除胎盘外的正常组织内没有表达(A),但在头与颈癌活检和肾癌活检中有表达(B)。不同的表达也在乳腺和肺癌细胞系中,以及在卵巢癌细胞系中检测到(C和D)。
图6.ISC-518mRNA表达
使用ISC-518特异性引物的RT-PCR分析显示出在除睾丸外的正常组织内没有表达。
图7.ISC-518的定量表达
定量RT-PCR显示出在正常睾丸和1个肝癌库中的高且选择性的表达。
图8.在正常和肿瘤组织中的ISC-477表达
使用ISC-477特异性引物的RT-PCR研究显示出在胎盘和卵巢正常组织(A)中的选择性表达,和在所研究的胃癌(B),乳腺、结肠和肺癌(C)中,以及在卵巢和胰腺癌样品(D)中的高表达。
图9.ISC-489mRNA表达
使用ISC-489特异性引物的RT-PCR研究显示出在胎盘对照组织中的选择性表达,以及另外地在肺癌样品(A,C),胃癌(B,C),头与颈肿瘤(C)和肝癌样品(C)中的各种表达水平。
图10.在正常睾丸和各种肿瘤样品中的ISC-461表达
使用ISC-461特异性引物的RT-PCR研究显示出在胎盘对照组织中的选择性表达,以及另外地在乳腺癌和黑素瘤(B)中,以及在乳腺癌、肺癌和黑素瘤细胞系(C)和卵巢癌细胞系(D)中的各种表达水平。
图11.在胎盘和癌衍生样品中的ISC-465mRNA表达
使用ISC-465特异性引物的RT-PCR研究显示出在胎盘(A)中以及在衍生自乳腺癌、黑素瘤、肺癌或胃癌的某些细胞系(B)中的选择性表达。
图12.Mem-030的定量表达
A.用Mem-030特异性引物的定量RT-PCR显示出在所有研究的头与颈癌样品中的显著过表达。分析下述正常组织:膀胱、脑、骨髓、子宫颈、结肠、十二指肠、心脏、肺、淋巴结、乳腺、肌肉、卵巢、PBMC、激活的PBMC、胎盘、前列腺、视网膜、脾、胃、睾丸、胸腺和扁桃体。
B.在食道、肝、子宫癌和黑素瘤衍生组织中的Mem-030盛行
图13.Mem-055的定量表达
用Mem-055特异性引物的定量RT-PCR显示出在正常对照组织中的高且选择性的表达,以及在胃和肺癌衍生组织中的显著过表达(A)。Mem-055还在肝癌、卵巢癌和乳腺癌样品中过表达(B)。
图14.Mem-062mRNA表达
使用Mem-062特异性引物的RT-PCR分析显示出在睾丸中的选择性表达和在肺癌衍生组织中的弱表达(A)。Mem-064转录物的强且显著的表达水平在各种卵巢肿瘤中是可检测的(B)。
图15.在正常睾丸和肾细胞癌中的特异性Mem-068表达
使用基因特异性Mem-068引物的RT-PCR分析显示出在正常睾丸中的cDNA扩增,在胎盘(A)、肾细胞癌和胃癌(B)中很弱。
图16.在正常睾丸和各种肿瘤样品中的Mem-071表达
使用Mem-071特异性引物的RT-PCR分析显示出在除睾丸外的正常组织内没有表达(A)。不同的表达也在肾细胞癌样品和胃癌中检测到(B)。
图17.Mem-072mRNA表达
使用Mem-072特异性引物的RT-PCR分析显示出在正常组织内没有表达(A)以及在各种肺癌样品中具有显著表达(A+B)。
图18.在正常和肿瘤组织中的Mem-106表达
使用Mem-106特异性引物的RT-PCR研究显示出在除睾丸外的正常组织内没有表达(A),并且在卵巢和前列腺癌中以及在黑素瘤和结肠癌细胞系中检查到高表达(B)。
图19.Mem-131mRNA表达
使用Mem-131特异性引物的RT-PCR研究显示出在除激活的PBMC外的所有受试正常组织内没有显著表达。在乳腺和肺癌中的Mem-131mRNA表达。在肺和卵巢癌中的Mem-131mRNA表达。
图20.ISC-468mRNA表达
使用ISC-468特异性引物的(A)RT-PCR和(B)实时PCR研究显示出在正常睾丸、胎盘中,和在80%的乳腺癌活检中的选择性mRNA表达。
图21.ISC-468表达的免疫荧光分析
(A)通过对经ISC-468-eGFP转染的细胞进行染色证实了抗ISC-468抗体的特异性。(B)用ISC-468特异性RNAi双链体或者非沉默性对照双链体转染的经MeOH固定的细胞的染色。(C)用ISC-468特异性RNAi双链体或者非沉默对照双链体转染的未固定的细胞的染色。
图22.ISC-468表达的免疫组织化学分析
在正常乳腺组织中于(A)100x、(B)200x下没有可检测的表达。相反地,在乳腺癌样本中于(C)100x、(D)200x下观察到强且均匀的膜染色。
图23.RNAi诱导的ISC-468mRNA表达的降低
与对照细胞相比较,用ISC-468特异性siRNA双链体转染细胞导致ISC-468mRNA表达的明显降低。
图24.细胞增殖分析
与对照细胞相比较,用ISC-468特异性siRNA双链体转染细胞导致细胞增殖的明显削弱。
图25.细胞周期分析
与对照细胞相比较,用ISC-468特异性siRNA双链体转染细胞在(A)MCF-7和(B)BT-549乳腺癌细胞中导致G1/S停滞。
图26.AKT磷酸化
与对照细胞相比较,用ISC-468特异性siRNA双链体转染细胞导致AKT磷酸化的明显削弱。
图27.抗体介导的增殖抑制
与用无关的对照抗体孵育的细胞相比较,用ISC-468特异性抗体来孵育MCF-7乳腺癌细胞导致增殖减少。
图28.细胞增殖分析
与对照细胞相比较,用ISC-468特异性siRNA双链体转染细胞导致(A)趋化性、(B)化动性和(C)侵袭的明显削弱。
图29.雌激素受体相关性
在乳腺癌样品中的ISC-468mRNA表达水平与雌激素受体状态相关。显示出了中值、10和90百分位数以及误差条。
图30.17β-雌二醇处理
通过用100nM 17β-雌二醇处理雌激素受体阳性的乳腺癌细胞系MCF-7诱导了ISC-468mRNA表达。在雌激素受体阴性的细胞系MDA-MB-231中没有看到诱导。
图31.序列
显示出了本文所参考的序列。
实施例
材料和方法
本文提及的技术和方法以本身已知的方式来进行,并且例如在Sambrook等人,Molecular Cloning:A Laboratory Manual,第2版(1989)Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y中描述。包括使用试剂盒和试剂的所有方法根据制造商的信息来进行。
RNA提取,poly-d(T)引发的cDNA的制备和常规RT-PCR分析
通过使用异硫氰酸胍作为离液剂从天然组织材料中提取总RNA(Chomczynski和Sacchi,Anal.Biochem.162:156-9,1987)。在用酸性苯酚提取和用异丙醇沉淀后,将所述RNA溶解于经DEPC处理的水中。
来自4μg总RNA的第一链cDNA合成在20μl反应混合物中根据制造商的信息通过Superscript II(Invitrogen)来进行。使用的引物是dT(18)寡核苷酸。cDNA的完整性和品质通过在30个PCR循环中扩增p53来检查((SEQ ID NO:33,34),杂交温度67℃)。
第一链cDNA的文档从许多正常组织和肿瘤实体中制备。对于表达研究,0.5μl的这些cDNA在30μl反应混合物中进行扩增,使用GOI特异性引物(参见下文)和1U HotStarTaq DNA聚合酶(Qiagen)。每种反应混合物包含150μM dNTPs,0.3μM每种引物和3μl 10x反应缓冲液。
选择引物以便位于2个不同的外显子中,并且作为假阳性结果的原因的污染性基因组DNA的干扰的消除通过作为模板对非逆转录的DNA进行测试来证实。于95℃15分钟以激活HotStarTaq DNA聚合酶后,进行35个PCR循环(于94℃0.5分钟,于特定的杂交温度0.5分钟,于72℃0.5分钟,和于72℃最后延伸6分钟)。
20μl的这种反应体系在经溴化乙锭染色的琼脂糖凝胶上进行分级和分析。
随机六聚物引发的cDNA的制备和定量实时PCR
几种基因的表达通过实时PCR来进行定量。PCR产物使用SYBRGreen作为嵌入性报道染料进行检测。SYBR Green的报道荧光在溶液中被抑制,并且染料只有在与双链DNA片段结合后才是有活性的。将在每个PCR循环后由于使用GOI特异性引物的特异性扩增而引起的SYBR Green荧光增加用于定量。靶基因的表达绝对地或相对于对照基因的表达进行定量,所述对照基因在待研究的组织中具有恒定的表达。在使用ΔΔ-Ct方法(PE Biosystems,USA)针对作为所谓的持家基因的18s RNA进行样品标准化后,测量表达。反应一式两份地进行并且一式三份地进行测定。QuantiTect SYBR Green PCR试剂盒(Qiagen,Hilden)依照制造商的说明书来使用。使用随机引物(Invitrogen)使用上述方案来合成cDNA。在30μl的总体积中使用稀释的cDNA的各5μl部分用于PCR:有义引物300nM,反义引物300nM;最初变性95℃15分钟;95℃30秒;退火30秒;72℃30秒;40个循环。所使用的引物的序列在分别的实施例中指出。
克隆和序列分析
通过常规方法进行全长和基因片段的克隆。为了确定序列,使用校正聚合酶pfu(Stratagene)扩增相应的反基因。PCR完成后,通过HotStarTaq DNA聚合酶使腺苷与扩增子的末端连接,以便依照制造商的说明书将片段克隆到TOPO-TA载体内。通过商业服务进行测序。使用常规的预测程序和算法来分析序列。
细胞增殖分析
用siRNA双链体转染后24小时,将1×104细胞在补充有各种浓度的FCS的培养基中培养48小时。在Wallac Victor2多标记计数器(Perkin Elmer)上根据制造商的说明书使用DELFIA细胞增殖试剂盒(Perkin Elmer),通过测量BrdU向新合成的DNA链中的掺入来分析增殖。
细胞周期分析和凋亡
在补充有各种浓度的FCS的培养基中培养细胞,48小时后收获,并在流式细胞术DNA含量分析前用碘化丙锭染色。使用CellQuest-Software(Becton Dickinson)定量凋亡细胞和处于细胞周期的S/G2/M期中的细胞。
细胞迁移
使用在实验前在无血清培养基中培养12小时的细胞,用8.0μm孔膜(BD Biosciences)在跨孔(transwell)小室中进行细胞迁移测定法。对于siRNA实验,在如上所述用siRNA双链体转染后24小时,将细胞转移至无血清条件。向上部小室中加入在400μl无血清培养基中的4×104细胞。底部小室包含补充有FCS,PDGF-BB(Sigma-Aldrich)或SDF-1α/CXCL12(R&D Systems)作为化学引诱物的800μl培养基。24小时后,在冰冷的甲醇中固定迁移至膜底侧的细胞;切割膜,置于显微镜载玻片上,并加上Hoechst(Dako)以用于荧光显微术。对于每张膜,计数在5个随机视野(100x放大率)中的细胞。所有实验一式三份地进行。使用相同的实验设定分析对细胞的化动性的影响,其中(i)不向上部和下部小室中添加化学引诱物,和(ii)向上部和下部小室中加入化学引诱物。
体外侵袭测定法
使用在实验前在无血清培养基中培养12小时的细胞,用8.0μm孔膜(BD Biosciences)在跨孔(transwell)小室中进行体内侵袭测定法。用100μl在无血清培养基中稀释至1mg/ml的Matrigel(BDBiosciences)制备上部小室。小室于37℃孵育5小时以进行胶凝。对于siRNA实验,在如上所述用siRNA双链体转染后24小时,将细胞转移至无血清条件。向上部小室中加入在400μl无血清培养基中的1×105细胞。底部小室包含补充有FCS作为化学引诱物的800μl培养基。24小时后,在冰冷的甲醇中固定在膜底侧的受侵袭的细胞;切割膜,置于显微镜载玻片上,并加上Hoechst(Dako)以用于荧光显微术。对于每张膜,计数在5个随机视野(100x放大率)中的细胞。所有实验一式三份地进行。
实施例1:将I SC-468鉴定为治疗和诊断的癌症靶
ISC-468(SEQ ID NO:1)编码212个氨基酸的蛋白质(SEQ ID NO:2),并且具有23.6kDa的分子量。
它先前被描述为在妊娠期间表达的胎盘特异性蛋白质(Fant等人,Mol Reprod Dev.63:430-6,2002)。
如通过生物信息学工具(TMpred,SOUSI)所分析的,该蛋白质被预测具有来自aa1-23的可切割信号肽,随后为短的推定的跨膜结构域(aa 25-47)。剩余的蛋白质被预测是细胞外的,并且因此可以根据本发明用作关于单克隆抗体的靶结构。
根据本发明,在RT-PCR分析中使用关于ISC-468的基因特异性引物对(SEQ ID NO:3,4),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。如所预期的,胎盘被证实为表达这种基因的唯一健康组织(图1)。无论什么,在任何其他正常器官组织中没有检测到显著表达。最令人惊讶的是,当研究癌症样本时,发现在许多不同的肿瘤类型中高且显著的表达水平,包括结肠、胰腺、食道、胃、肺、乳腺、卵巢、头与颈、肾、前列腺和肝癌(图1和2以及表1)。在60个乳腺癌样品中的ISC-468表达的定量实时RT-PCR分析揭示,所有样品中的80%表达显著水平的ISC-468(图20A,B)。
表1:在正常和肿瘤组织中的ISC-468表达
正常组织 | 表达 |
脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | - |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | - |
胸腺 | - |
乳腺 | - |
卵巢 | - |
子宫 | - |
肿瘤类型 | 表达 |
结肠癌 | + |
胰腺癌 | + |
食道癌 | + |
胃癌 | + |
肺癌 | + |
乳腺癌 | +++ |
卵巢癌 | + |
头与颈癌 | + |
肾癌 | + |
前列腺癌 | + |
肝癌 | ++ |
皮肤 | - |
肺 | - |
胎盘 | +++ |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
在肿瘤中ISC-468转录物的选择性且高的表达不是先前已知的,并且可以根据本发明用于分子诊断方法例如RT-PCR,以检测血清和骨髓中的播散性肿瘤细胞以及检测其他组织中的转移灶。这种分子可以进一步用作特异性靶以用于治疗方法。
选择尤其是下述肽用于产生根据本发明的ISC-468特异性抗体:SEQ ID NO:58、59、60、68、69、2。通过经ISC-468-eGFP转染的细胞的免疫荧光分析来证实抗体的特异性(图21A)。
在内源性表达性乳腺癌细胞系MCF-7和BT-549中ISC-468的亚细胞定位通过免疫荧光分析来分析。MeOH固定的(图21B)或非固定的(图21C)细胞的染色揭示出ISC-468位于所述表达性细胞的质膜上。染色的特异性通过RNAi诱导的ISC-468表达降低来证实,导致质膜染色的丧失。
此外,ISC-468特异性抗体用于在正常乳腺和乳腺癌的临床样品中ISC-468表达的免疫组织化学分析。ISC-468的表达在正常乳腺样本中是无法检测的(图22A,B)。相反地,乳腺癌样本显示出ISC-468的强且均匀的表达(图22C,D)。信号在表达性癌细胞的质膜上增强,证实ISC-468是在癌细胞中选择性地表达的膜蛋白。
ISC-468的细胞外结构域可以根据本发明用作靶结构,以用于通过单克隆抗体的免疫诊断和治疗。此外,ISC-468可以根据本发明用作疫苗(RNA,DNA,蛋白质,肽),以用于诱导肿瘤特异性的免疫应答(T和B细胞介导的免疫应答)。
通过用特异性地靶向ISC-468mRNA的siRNA双链体(SEQ ID NO:70-73)转染细胞来达到RNAi诱导的ISC-468表达降低。内源性表达性乳腺癌细胞系MCF-7和BT-549的转染导致ISC-468mRNA表达的稳定且特异性的减少(图23)。
为了了解ISC-468表达的生理学作用,执行几种基于RNAi的体外细胞测定法。如在基于BrdU的增殖测定法中所分析的,与各自的对照相比较,用siRNA双链体转染乳腺癌细胞系MCF-7和BT-549导致细胞增殖明显减少(图24)。基于FACS的细胞周期分析显示,细胞增殖的取消起因于G1/S停滞(图25A,B)。此外,可以显示,RNAi诱导的ISC-468降低在内源性表达性癌细胞中通过抑制AKT磷酸化而深深地影响AKT信号传导途径(图26)。此外,与无关的对照抗体相比较,当细胞与针对ISC-468特异性肽(SEQ ID NO:68,69)而产生的ISC-468特异性抗体一起孵育时,MCF-7细胞的增殖被减弱(图27)。这些结果指出,ISC-468可能通过介导AKT信号传导途径等的由生长因子诱导的激活而为关于癌细胞增殖的关键因素。ISC-468自身可能表示用于生长因子、趋化因子或其他物质的受体、共同受体或膜结合的分子伴侣。
此外,分析了ISC-468表达对于癌细胞的迁移能力的影响。如在跨孔迁移测定法中所评估的,在乳腺癌细胞系MCF-7和BT-549中由RNAi诱导的ISC-468表达降低导致细胞的趋化性、化动性和侵袭的明显削弱(图28A,B,C)。趋化性、化动性和侵袭是关于癌细胞转移至其他器官的关键因素。因此,在癌细胞中ISC-468的表达可能是关于癌细胞转移的阳性因素。
在乳腺癌中,可以显示,ISC-468的表达与肿瘤的雌激素受体状态相关。在60个乳腺癌样品中ISC-468表达的定量实时RT-PCR分析揭示,雌激素受体阳性的乳腺癌显示出比受体阴性肿瘤明显更高的ISC-468表达水平(图29)。因此,通过用17β-雌二醇处理可以在雌激素受体阳性的乳腺癌细胞系MCF-7中诱导ISC-468的表达(图30)。
实施例2:将ISC-507鉴定为治疗和诊断的癌症靶
ISC-507(SEQ ID NO:5)编码分子量为85.6kDa的754aa的蛋白质(SEQ ID NO:6)。
ISC-507是具有解联蛋白和金属蛋白酶活性的锌结合蛋白家族的成员,其可以充当粘附蛋白和/或肽链内切酶。这个家族的成员被描述为参与许多生物过程,包括受精、神经发生、肌肉发育和免疫应答(Seals等人,Genes Dev.17(1):7-30,2003)。
ISC-507具有1个跨膜结构域(aa 671-687)、大的N-末端细胞外区域和较短的C-末端胞质区域。
ISC-507表达被报道特异性地局限于哺乳动物附睾(邻近于睾丸的小腺体),它关键地参与精子的成熟。根据参考文献,ISC-507从附睾转移至精子表面并且在顶体反应期间在精子头部中重新分布(Adachi等人,Mol Reprod Dev.64:414-21,2003)。
使用ISC-507特异性引物(SEQ ID NO:7,8)的RT-PCR研究证实了在睾丸中的选择性表达,和在任何其他正常组织中不存在ISC-507(表2,图3),除了在前列腺和淋巴结衍生组织中的弱表达(表2,图4)外。
然而,最令人惊讶的是,我们在大量前列腺癌中观察到ISC-507的表达(图3,4)。这种蛋白质以前未被报道涉及癌症。
表2:在正常和肿瘤组织中的ISC-507表达
正常组织 | 表达 |
脑 | - |
小脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
肿瘤类型 | 表达 |
结肠癌 | - |
胰腺癌 | - |
食道癌 | - |
胃癌 | - |
肺癌 | - |
乳腺癌 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | +++ |
胸腺 | - |
乳腺 | - |
卵巢 | - |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | - |
淋巴结 | + |
脾 | - |
PBMC | - |
前列腺 | + |
卵巢癌 | - |
子宫癌 | - |
头与颈癌 | - |
肾癌 | - |
前列腺癌 | +++ |
肝癌 | - |
缺乏关于正常组织的毒性以及在前列腺癌中ISC-507的频繁且显著的表达使得这种蛋白质根据本发明成为有价值的诊断和治疗标记物。这根据本发明包括检测在血清、骨髓、尿液中的播散的肿瘤细胞,以及通过RT-PCR检测在其他器官中的转移。此外,ISC-507的细胞外结构域可以根据本发明用作靶结构,以用于通过单克隆抗体的免疫诊断和治疗。此外,ISC-507可以根据本发明用作疫苗(RNA,DNA,蛋白质,肽),以用于诱导肿瘤特异性的免疫应答(T和B细胞介导的免疫应答)
用于检测ISC-507的抗体可以用下述肽和蛋白质来产生:SEQ IDNO:51、52、53、54、55、6、56和57。
根据本发明,与ISC-507结合的抗体可以用于治疗或诊断目的。
实施例3:将ISC-466鉴定为治疗和诊断的癌症靶
ISC-466(SEQ ID NO:9)编码分子量为48.2kDa的426aa的蛋白质(SEQ ID NO:10)。
它属于妊娠特异性糖蛋白家族。人妊娠特异性糖蛋白(PSG)是主要在妊娠期间由胎盘合体细胞滋养层产生的分子群体,并且是免疫球蛋白超家族的部分(Beauchemin等人,Exp Cell Res.252(2):243-9,1999)。
与其他PSG一样,ISC-466也被报道局限于胎盘。
根据本发明,在RT-PCR分析中使用关于ISC-466的基因特异性引物对(SEQ ID NO:11,12),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。RT-PCR分析揭示出在正常胎盘中ISC-466转录物的表达,以及在胸腺和卵巢中的弱表达(表3,图5A)。在任何其他正常器官组织中没有检测到显著表达。最令人惊讶的是,当研究癌细胞系时,我们发现在许多肿瘤类型中高且显著的表达水平,包括乳腺癌(图5C)、肺癌(图5C)、卵巢癌(图5D)以及头与颈癌和肾癌(图5B)。
表3:在正常和肿瘤组织中的ISC-466表达
正常组织 | 表达 |
脑 | - |
胸腺 | + |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
肿瘤类型 | 表达 |
结肠癌 | + |
胰腺癌 | + |
食道癌 | + |
胃癌 | - |
肺癌 | ++ |
乳腺癌 | +++ |
卵巢癌 | ++ |
子宫颈癌 | - |
头与颈癌 | +++ |
肾癌 | ++ |
睾丸 | +++ |
胸腺 | - |
乳腺 | - |
卵巢 | + |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | - |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
前列腺癌 | + |
肝癌 | - |
黑素瘤 | + |
与ISC-466牵涉结肠直肠癌这一观察结果(Salahshor等人,BMCCancer.5:66,2005)相反,我们的研究揭示ISC-466根据本发明作为用于头与颈癌、乳腺癌、卵巢癌、前列腺癌和黑素瘤的诊断和治疗标记物。
实施例4:将ISC-518鉴定为治疗和诊断的癌症靶
ISC-518(SEQ ID NO:13)编码237aa的翻译产物(SEQ ID NO:14)。然而,迄今为止没有可用的关于组织分布的数据和与癌症的关联。
ISC-518是假定的、经生物信息学预测的基因/蛋白质。序列分析揭示出,该蛋白质具有跨膜结构域(aa 102-118)。细胞外C-末端的特征在于出现在细胞表面糖蛋白中的功能结构域。
根据本发明,在RT-PCR分析中使用关于ISC-518的基因特异性引物对(SEQ ID NO:15,16),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。我们发现表达这种基因的唯一正常组织是睾丸,而在任何其他正常器官中没有检测到ISC-518的显著表达(图6)。最令人惊讶的是,当研究癌症样本时,我们发现在肝癌中高且显著的表达水平(图7)。
表4:在正常和肿瘤组织中的ISC-518表达
正常组织 | 表达 |
脑 | - |
小脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | +++ |
胸腺 | - |
乳腺 | - |
卵巢 | - |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | - |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
肿瘤类型 | 表达 |
结肠癌 | - |
胰腺癌 | - |
食道癌 | - |
胃癌 | + |
肺癌 | + |
乳腺癌 | + |
卵巢癌 | + |
子宫癌 | - |
头与颈癌 | - |
肾癌 | - |
前列腺癌 | + |
肝癌 | ++ |
生物信息学研究显示,由ISC-518表达的蛋白质表示细胞表面分子。这种表面分子的先前未知的选择性表达使得它成为用于治疗目的以及用于开发检测肿瘤细胞的诊断方法和消除肿瘤细胞的治疗方法的靶。
实施例5:将ISC-477鉴定为治疗和诊断的癌症靶
ISC-477(SEQ ID NO:17)编码130aa的翻译产物(SEQ ID NO:18)。ISC-477是假定的蛋白质。没有公众可用的关于组织分布的数据和与癌症的关联。
结构分析揭示出可能是跨膜区或信号肽的疏水区域。
根据本发明,在RT-PCR分析中使用关于ISC-477的基因特异性引物对(SEQ ID NO:19,20),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。我们发现表达这种基因的唯一正常组织是胎盘和卵巢。相反地,在任何其他正常器官中没有检测到ISC-477的显著表达(图8A)。最令人惊讶的是,当研究癌症样本时,我们发现在肺、卵巢、结肠和胃癌中高且显著的表达水平(图8A-D)。表达水平明显高于在正常卵巢中的表达。
表5:在正常和肿瘤组织中的ISC-477表达
正常组织 | 表达 |
脑 | - |
小脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
肿瘤类型 | 表达 |
结肠癌 | ++ |
胰腺癌 | + |
食道癌 | - |
胃癌 | ++ |
肺癌 | +++ |
乳腺癌 | ++ |
卵巢癌 | ++ |
肾癌 | - |
前列腺癌 | - |
肝癌 | - |
睾丸 | - |
胸腺 | - |
乳腺 | - |
卵巢 | ++ |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | +++ |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
实施例6:将ISC-489鉴定为治疗和诊断的癌症靶
ISC-489(SEQ ID NO:21)编码363aa的翻译产物(SEQ ID NO:22)。该蛋白质是新近描述的G蛋白偶联受体家族的成员。然而,没有公众可用的关于组织分布的数据和与癌症的关联。
根据本发明,在RT-PCR分析中使用关于ISC-489的基因特异性引物对(SEQ ID NO:23,24),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。我们发现表达这种基因的唯一正常组织是胎盘和食道(弱表达)。相反地,在任何其他正常器官中没有检测到ISC-489的显著表达(图9A)。最令人惊讶的是,当研究癌症样本时,我们发现在头与颈癌和胃癌中高且显著的表达水平(图9B,9C)。
作为G蛋白偶联受体家族的成员,ISC-489是具有7个跨膜结构域和几个细胞外环的膜内在蛋白质,其可以在细胞表面上被靶向。
表6:在正常和肿瘤组织中的ISC-489表达
正常组织 | 表达 |
脑 | - |
肿瘤类型 | 表达 |
结肠癌 | + |
食道 | + |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | - |
胸腺 | - |
乳腺 | - |
卵巢 | - |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | +++ |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
胃癌 | ++ |
肺癌 | + |
乳腺癌 | - |
卵巢癌 | - |
头与颈癌 | +++ |
肾癌 | + |
前列腺癌 | - |
肝癌 | + |
在头与颈癌中ISC-489的明显表达和出人预料的高发生率使得这种蛋白质根据本发明成为高度感兴趣的诊断和治疗标记物。
实施例7:将ISC-461鉴定为治疗和诊断的癌症靶
ISC-461(SEQ ID NO:25)编码分子量为47.1kDA的419aa的蛋白质(SEQ ID NO:26)。
它属于妊娠特异性糖蛋白家族。人妊娠特异性糖蛋白(PSG)是主要在妊娠期间由胎盘合体细胞滋养层产生的分子群体,并且是免疫球蛋白超家族的部分(Beauchemin等人,Exp Cell Res.252(2):243-9,1999)。
与其他PSG一样,ISC-461也被报道局限于胎盘。
根据本发明,在RT-PCR分析中使用关于ISC-461的基因特异性引物对(SEQ ID NO:11,27),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。如所预期的,胎盘被证实为表达这种基因,除了在睾丸和卵巢中的弱表达外(图10A和10B)。无论什么,在任何其他正常器官组织中没有检测到显著表达。最令人惊讶的是,当研究癌症衍生组织和癌症细胞系时,我们发现在许多肿瘤类型中高且显著的表达水平,包括乳腺癌(图10C)、卵巢癌(图10D)和黑素瘤(图10B,10C)。
表7:在正常和肿瘤组织中的ISC-461表达
正常组织 | 表达 |
脑 | - |
小脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | + |
胸腺 | - |
乳腺 | - |
卵巢 | + |
肿瘤类型 | 表达 |
结肠癌 | - |
胰腺癌 | + |
食道癌 | + |
胃癌 | + |
肺癌 | + |
乳腺癌 | ++ |
卵巢癌 | ++ |
肾癌 | - |
前列腺癌 | - |
肝癌 | - |
黑素瘤 | ++ |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | +++ |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
根据本发明的进一步目的是鉴定ISC-461的剪接变体,其可以用于诊断和治疗。
基于剪接变体的研究,我们可以鉴定出剪接形式(SEQ ID NO:28)和由此编码的蛋白质(SEQ ID NO:29)。
实施例8:将ISC-465鉴定为治疗和诊断的癌症靶
ISC-465(SEQ ID NO:30)编码分子量为47.0kDA的419aa的蛋白质(SEQ ID NO:31)。
它属于妊娠特异性糖蛋白家族。人妊娠特异性糖蛋白(PSG)是主要在妊娠期间由胎盘合体细胞滋养层产生的分子群体,并且是免疫球蛋白超家族的部分(Beauchemin等人,Exp Cell Res.252(2):243-9,1999)。
与其他PSG一样,ISC-465也被报道局限于胎盘。
根据本发明,在RT-PCR分析中使用关于ISC-465的基因特异性引物对(SEQ ID NO:11,32),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。如所预期的,胎盘被证实为表达这种基因,除了在正常卵巢中的弱表达外(图11A)。无论什么,在任何其他正常器官组织中没有检测到显著表达。最令人惊讶的是,当研究癌症衍生组织和癌细胞系时,我们发现在许多肿瘤类型(图11A,11B),特别是乳腺癌(图11B)中高且显著的表达水平。
表8:在正常和肿瘤组织中的ISC-465表达
正常组织 | 表达 |
脑 | - |
小脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | |
胃 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | + |
胸腺 | - |
乳腺 | - |
卵巢 | + |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | +++ |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
肿瘤类型 | 表达 |
结肠癌 | - |
胰腺癌 | + |
食道癌 | + |
胃癌 | + |
肺癌 | + |
乳腺癌 | ++ |
卵巢癌 | ++ |
肾癌 | - |
前列腺癌 | - |
肝癌 | - |
黑素瘤 | + |
在肿瘤中ISC-465转录物的选择性且高的表达不是先前已知的,并且可以根据本发明用于分子诊断方法例如RT-PCR,以检测血清和骨髓中的播散性肿瘤细胞以及检测其他组织中的转移灶。这种分子可以进一步用作特异性靶以用于治疗方法。
实施例9:将Mem-030鉴定为治疗和诊断的癌症靶
Mem-030(SEQ ID NO:35)编码分子量为67.9kDA的592aa的蛋白质(SEQ ID NO:36)。
Mem-030属于GBP蛋白质,其是大的GTP酶,所述GTP酶能够结合GTP、GDP和GMP并且催化GTP水解成GDP以及GMP(Cheng等人,JBiol.Chem.260:15834-9,1985)。GTP酶在细胞增殖、分化、信号转导和细胞内的蛋白质转运中起重要作用,并且是干扰素可诱导的(Boehm等人,J Immunol.161(12):6715-23,1998)。
此外,Mem-030还抵抗炎性细胞因子如IFN-g、白介素1-b(IL-1b)和肿瘤坏死因子-a(TNF-a)1对于内皮细胞的增殖效应(Guenzi等人,EMBO J.20(20):5568-77,2001)。
根据本发明,在实时RT-PCR分析中使用关于Mem-030的基因特异性引物对(SEQ ID NO:37,38),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。Mem-030显示出普遍存在的表达模式(图12A,表9)。
最令人惊讶的是,当研究癌症衍生组织和癌细胞系时,我们发现在许多肿瘤类型(图12A,12B),特别是头与颈癌中高且显著的过表达水平。
表9:在正常和肿瘤组织中的Mem-030表达
正常组织 | 表达 |
脑 | + |
心肌 | + |
骨骼肌 | + |
心肌 | + |
胃 | + |
结肠 | + |
胰腺 | + |
肿瘤类型 | 表达 |
结肠癌 | + |
胰腺癌 | + |
食道癌 | ++ |
胃癌 | + |
肺癌 | + |
乳腺癌 | + |
卵巢癌 | + |
肾 | + |
肝 | + |
睾丸 | + |
胸腺 | + |
乳腺 | + |
卵巢 | + |
子宫 | + |
皮肤 | + |
肺 | + |
胎盘 | + |
淋巴结 | + |
脾 | + |
PBMC | + |
前列腺 | + |
子宫癌 | ++ |
头与颈癌 | +++ |
肾癌 | + |
前列腺癌 | + |
肝癌 | ++ |
黑素瘤 | ++ |
由于生物信息学和参考文献分析,Mem-030的同源基因也可能是吸引人的治疗靶(SEQ ID NO:39),并且编码分子量为66.6kDA的586aa的蛋白质(SEQ ID NO:40)。
生物信息学研究显示,这2种蛋白质均表示细胞表面分子。这种表面分子的先前未知的选择性过表达使得它成为用于治疗目的以及用于开发检测肿瘤细胞的诊断方法和消除肿瘤细胞的治疗方法的靶。
实施例10:将Mem-055鉴定为治疗和诊断的癌症靶
Mem-055(SEQ ID NO:41)编码分子量为27.9kDA的250aa的蛋白质(SEQ ID NO:42)。
由这种基因编码的蛋白质是溶酶体硫醇还原酶,其在低pH下可以还原蛋白质二硫键。该酶在抗原呈递细胞中组成性地表达,并且在其他细胞类型中由γ-干扰素诱导。这种酶在II类MHC限制的抗原加工中具有重要作用(Arunachalam等人,Proc Natl Acad Sci USA.97(2):745-50,2000)。
通过使用生物信息学工具(TMPRED,SOUSI)分析推定的信号序列和跨膜结构域,预测了Mem-055的定位和蛋白质拓扑学。Mem-055可能具有细胞外的C-末端。
根据本发明,在实时RT-PCR分析中使用关于Mem-055的基因特异性引物对(SEQ ID NO:43,44),以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。Mem-055显示出普遍存在的表达模式(图13A,表10)。
最令人惊讶的是,当研究癌症衍生组织内的Mem-055表达时,我们发现在许多肿瘤类型(图13A,13B),特别是胃癌中高且显著的过表达水平。
表10:在正常和肿瘤组织中的Mem-055表达
正常组织 | 表达 |
脑 | + |
心肌 | + |
骨骼肌 | + |
心肌 | + |
胃 | + |
结肠 | + |
胰腺 | + |
肾 | + |
肝 | + |
睾丸 | + |
胸腺 | + |
乳腺 | + |
卵巢 | + |
子宫 | + |
皮肤 | + |
肿瘤类型 | 表达 |
结肠癌 | + |
胰腺癌 | + |
食道癌 | + |
胃癌 | +++ |
肺癌 | ++ |
乳腺癌 | ++ |
卵巢癌 | ++ |
子宫癌 | + |
头与颈癌 | + |
肾癌 | + |
前列腺癌 | + |
肝癌 | ++ |
黑素瘤 | + |
肺 | + |
胎盘 | + |
淋巴结 | + |
脾 | + |
PBMC | + |
前列腺 | + |
由于推定的细胞外结构域和在不同癌症类型中出人预料的过表达,Mem-055是用于治疗和诊断目的的靶结构。
实施例11:将Mem-062鉴定为治疗和诊断的癌症靶
Mem-062(SEQ ID NO:45)编码分子量为30.7kDA的271aa的蛋白质(SEQ ID NO:46)。
通过基于计算机的筛选方法,Mem-062先前可以被鉴定并且描述为是睾丸、前列腺和胎盘特异性表达的(Bera等人,Biochem BiophysRes Commun.312(4):1209-15,2003)。
根据本发明,在RT-PCR分析中使用关于Mem-062的基因特异性引物对(SEQ ID NO:47,48)。令人惊讶的是,Mem-062显示出癌症-睾丸特异性的表达模式(图14A,表11)。在任何其他正常器官组织中没有检测到表达。最令人惊讶的是,当研究癌症衍生组织时,我们发现特别是在卵巢癌中显著的Mem-062表达水平(图14B)。
表11:在正常和肿瘤组织中的Mem-062表达
正常组织 | 表达 |
脑 | - |
心肌 | - |
骨骼肌 | - |
心肌 | - |
胃 | - |
肿瘤类型 | 表达 |
结肠癌 | + |
胰腺癌 | - |
食道癌 | - |
胃癌 | - |
肺癌 | - |
结肠 | - |
胰腺 | - |
肾 | - |
肝 | - |
睾丸 | - |
胸腺 | - |
乳腺 | - |
卵巢 | - |
子宫 | - |
皮肤 | - |
肺 | - |
胎盘 | - |
淋巴结 | - |
脾 | - |
PBMC | - |
前列腺 | - |
乳腺癌 | - |
卵巢癌 | ++ |
子宫癌 | - |
头与颈癌 | - |
肾癌 | - |
前列腺癌 | - |
肝癌 | - |
黑素瘤 | - |
备选的剪接导致备选的转录物(SEQ ID NO:49)及其相应的翻译产物(SEQ ID NO:50)。
实施例12:将Mem-068鉴定为治疗和诊断的癌症靶
Mem-068(SEQ ID NO:61)是新近鉴定的cDNA克隆。
通过生物信息学预测方法(Genscan),Mem-068可以被描述为在第9染色体上的多个外显子基因(SEQ ID NO:62)。推导的蛋白质序列(SEQ ID NO:63)具有751aa并且形成分子量为82.4kDA的蛋白质。
根据本发明,在RT-PCR分析中使用关于Mem-068的基因特异性引物对。令人惊讶的是,Mem-068显示出癌症-睾丸特异性的表达模式(图15A,表12)。在除胎盘(弱表达)外的任何其他正常器官组织中没有检测到表达。最令人惊讶的是,当研究癌症衍生组织时,我们发现特别是在肾细胞癌和胃癌中显著水平的所表达的Mem-068(图15B)。
表12:在正常和肿瘤组织中的Mem-068表达
正常组织 | 表达 |
脑 | - |
乳腺 | |
结肠 | - |
肾 | - |
肝 | - |
肺 | - |
淋巴结 | - |
卵巢 | - |
胰腺 | - |
胎盘 | + |
PBMC | - |
激活的PBMC | - |
前列腺 | - |
骨骼肌 | - |
皮肤 | - |
胃 | - |
脾 | - |
睾丸 | + |
子宫 | - |
肿瘤类型 | 表达 |
结肠癌 | + |
肾细胞癌 | ++ |
胃癌 | + |
肺癌 | + |
乳腺癌 | - |
卵巢癌 | - |
黑素瘤 | - |
前列腺癌 | - |
根据跨膜预测程序,TMpred Mem-068可能在细胞表面上表达,这使得它成为用于治疗或诊断目的的感兴趣的靶。
实施例13:将Mem-071鉴定为治疗和诊断的癌症靶
Mem-071(SEQ ID NO:64)是新的cDNA克隆,其在第1染色体上的2个外显子中编码。
根据本发明,在RT-PCR分析中使用关于Mem-071的基因特异性引物对,以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。我们发现表达这种基因的唯一正常组织是睾丸(图16A)。相反地,当研究癌症样本时,我们发现在肾细胞癌和胃癌中高且显著的表达水平(图16B)。
表13:在正常和肿瘤组织中的Mem-071表达
正常组织 | 表达 |
脑 | - |
乳腺 | - |
结肠 | - |
肾 | - |
肝 | - |
肺 | - |
淋巴结 | - |
卵巢 | - |
胰腺 | - |
胎盘 | - |
PBMC | - |
激活的PBMC | - |
前列腺 | - |
骨骼肌 | - |
皮肤 | - |
胃 | - |
脾 | - |
睾丸 | + |
子宫 | - |
肿瘤类型 | 表达 |
结肠癌 | - |
肾细胞癌 | ++ |
胃癌 | + |
肺癌 | - |
乳腺癌 | - |
卵巢癌 | - |
黑素瘤 | - |
前列腺癌 | - |
在肾细胞癌中Mem-071的出人预料的高发生率使得这种蛋白质根据本发明成为高度感兴趣的诊断和治疗标记物。
实施例14:将Mem-072鉴定为治疗和诊断的癌症靶
Mem-072(SEQ ID NO:65)是近鉴定的基因,其在第16染色体上的3个外显子中编码。
根据本发明,在RT-PCR分析中使用关于Mem-072的基因特异性引物对,以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。在所有受试正常组织中没有发现表达(图17A,表14)。当研究癌症衍生组织和癌细胞系时,我们发现在肺癌样品中高且显著的表达水平(图17B)。
表14:在正常和肿瘤组织中的Mem-072表达
正常组织 | 表达 |
脑 | - |
乳腺 | - |
结肠 | - |
肾 | - |
肝 | - |
肺 | - |
淋巴结 | - |
卵巢 | - |
胰腺 | - |
胎盘 | - |
PBMC | - |
激活的PBMC | - |
前列腺 | - |
骨骼肌 | - |
肿瘤类型 | 表达 |
结肠癌 | - |
肾细胞癌 | - |
胃癌 | - |
肺癌 | ++ |
乳腺癌 | - |
卵巢癌 | - |
黑素瘤 | - |
前列腺癌 | - |
皮肤 | - |
胃 | - |
脾 | - |
睾丸 | - |
子宫 | - |
在肺肿瘤中Mem-072的选择性且高的表达不是先前已知的,并且可以根据本发明用于分子诊断方法例如RT-PCR,以检测血清和骨髓中的播散性肿瘤细胞以及检测其他组织中的转移灶。这种分子可以进一步用作特异性靶以用于治疗方法。
实施例15:将Mem-106鉴定为治疗和诊断的癌症靶
Mem-106(SEQ ID NO:66)是新近鉴定的cDNA,其是在第2染色体上以无内含子方式编码的。
根据本发明,在RT-PCR分析中使用关于Mem-106的基因特异性引物对。令人惊讶的是,Mem-106显示出癌症-睾丸特异性的表达模式(图18A,表15)。在任何其他正常器官组织中没有检测到表达。最令人惊讶的是,当研究癌症衍生组织时,我们发现特别是在卵巢癌中显著的Mem-106表达水平(图18B)。
表15:在正常和肿瘤组织中的Mem-106表达
正常组织 | 表达 |
乳腺 | - |
结肠 | - |
肾 | - |
肝 | - |
肺 | - |
淋巴结 | - |
卵巢 | - |
肿瘤类型 | 表达 |
结肠癌 | + |
肾细胞癌 | - |
胃癌 | - |
肺癌 | - |
乳腺癌 | - |
卵巢癌 | ++ |
黑素瘤 | ++ |
胰腺 | - |
胎盘 | - |
PBMC | - |
激活的PBMC | - |
前列腺 | - |
骨骼肌 | - |
皮肤 | - |
胃 | - |
脾 | - |
睾丸 | ++ |
子宫 | - |
前列腺癌 | - |
因为在不同的癌症类型中出人预料的过表达,因而Mem-106是用于治疗和诊断目的的靶结构。
实施例16:将Mem-131鉴定作治疗和诊断的癌症靶
Mem-131(SEQ ID NO:67)是新近鉴定的cDNA克隆。Mem-131是在第15染色体上的2外显子基因。
根据本发明,在RT-PCR分析中使用关于Mem-131的基因特异性引物对,以扩增来源于广泛的正常和肿瘤组织实验对象组的cDNA。RT-PCR分析揭示出仅在正常的激活的PBMC中具有Mem-131转录物的表达(表16,图19A)。在任何其他正常器官组织中没有检测到显著表达。最令人惊讶的是,当研究癌症样品时,我们发现在许多肿瘤类型中高且显著的表达水平,包括乳腺癌(图19B)、肺癌(图19B+C)和卵巢癌(图19C)。
表16:在正常和肿瘤组织中的Mem-131表达
正常组织 | 表达 |
乳腺 | - |
肿瘤类型 | 表达 |
肺癌 | ++ |
十二指肠 | - |
膀胱 | - |
皮肤 | - |
脑 | - |
骨髓 | - |
结肠 | - |
肝 | - |
肺 | - |
淋巴结 | - |
胃 | - |
脾 | - |
心肌 | - |
肾 | - |
食道 | - |
卵巢 | - |
胰腺 | - |
PBMC | - |
激活的PBMC | ++ |
胎盘 | - |
肌肉 | - |
睾丸 | - |
胸腺 | - |
乳腺癌 | ++ |
卵巢癌 | ++ |
我们的研究揭示了Mem-131根据本发明作为关于肺、乳腺和卵巢癌的诊断和治疗标记物。
序列表
<110>Ganymed Pharmaceuticals AG et al.
<120>用于诊断和治疗的肿瘤相关抗原的鉴定
<130>342-28PCT
<140>
<141>2006-09-06
<150>EP05019786.2
<151>2005-09-12
<160>73
<170>PatentIn version 3.3
<210>1
<211>1126
<212>DNA
<213>智人
<400>1
atatatcaga ccatcagaag gatttgtata aagagtgact ctcctatgaa ggtaaaggcc 60
acccctcttc agttccagtg actgagatac atttttccaa tcctgggggc aaatacagac 120
acagcaagtt ccttcttccc tttggaaatt tggcagctgc cttcaccagt gagcacaaag 180
ccacatttca aaggaaactg acaaattatc cccagctgcc agaagaagaa atcctcactg 240
gacggcttcc tgtttcctgt ggttcattat ctgattggct gcagggatga aagtttttaa 300
gttcatagga ctgatgatcc tcctcacctc tgcgttttca gccggttcag gacaaagtcc 360
aatgactgtg ctgtgctcca tagactggtt catggtcaca gtgcacccct tcatgctaaa 420
caacgatgtg tgtgtacact ttcatgaact acacttgggc ctgggttgcc ccccaaacca 480
tgttcagcca cacgcctacc agttcaccta ccgtgttact gaatgtggca tcagggccaa 540
agctgtctct caggacatgg ttatctacag cactgagata cactactctt ctaagggcac 600
gccatctaag tttgtgatcc cagtgtcatg tgctgccccc caaaagtccc catggctcac 660
caagccctgc tccatgagag tagccagcaa gagcagggcc acagcccaga aggatgagaa 720
atgctacgag gtgttcagct tgtcacagtc cagtcaaagg cccaactgcg attgtccacc 780
ttgtgtcttc agtgaagaag agcataccca ggtcccttgt caccaagcag gggctcagga 840
ggctcaacct ctgcagccat ctcactttct tgatatttct gaggattggt ctcttcacac 900
agatgatatg attgggtcca tgtgatcctc aggtttgggg tctcctgaag atgctatttc 960
tagaattagt atatagtgta caaatgtctg acaaataagt gctcttgtga ccctcatgtg 1020
agcacttttg agaaagagaa acctatagca acttcatgaa ttaagccttt ttctatattt 1080
ttatattcat gtgtaaacaa aaaataaaat aaaattctga tcgcat 1126
<210>2
<211>212
<212>PRT
<213>智人
<400>2
Met Lys Val Phe Lys Phe Ile Gly Leu Met Ile Leu Leu Thr Ser Ala
1 5 10 15
Phe Ser Ala Gly Ser Gly Gln Ser Pro Met Thr Val Leu Cys Ser Ile
20 25 30
Asp Trp Phe Met Val Thr Val His Pro Phe Met Leu Asn Asn Asp Val
35 40 45
Cys Val His Phe His Glu Leu His Leu Gly Leu Gly Cys Pro Pro Asn
50 55 60
His Val Gln Pro His Ala Tyr Gln Phe Thr Tyr Arg Val Thr Glu Cys
65 70 75 80
Gly Ile Arg Ala Lys Ala Val Ser Gln Asp Met Val Ile Tyr Ser Thr
85 90 95
Glu Ile His Tyr Ser Ser Lys Gly Thr Pro Ser Lys Phe Val Ile Pro
100 105 110
Val Ser Cys Ala Ala Pro Gln Lys Ser Pro Trp Leu Thr Lys Pro Cys
115 120 125
Ser Met Arg Val Ala Ser Lys Ser Arg Ala Thr Ala Gln Lys Asp Glu
130 135 140
Lys Cys Tyr Glu Val Phe Ser Leu Ser Gln Ser Ser Gln Arg Pro Asn
145 150 155 160
Cys Asp Cys Pro Pro Cys Val Phe Ser Glu Glu Glu His Thr Gln Val
165 170 175
Pro Cys His Gln Ala Gly Ala Gln Glu Ala Gln Pro Leu Gln Pro Ser
180 185 190
His Phe Leu Asp Ile Ser Glu Asp Trp Ser Leu His Thr Asp Asp Met
195 200 205
Ile Gly Set Met
210
<210>3
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>3
aaatttggca gctgccttca c 21
<210>4
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>4
tgatgccaca ttcagtaaca c 21
<210>5
<211>2582
<212>DNA
<213>智人
<400>5
atccctgcag tggaagtgag gaggaagaaa ggtgaactcc ttttctcaag cacttctgct 60
ctcctctacc agaatcactc agaatgcttc ccgggtgtat attcttgatg attttactca 120
ttcctcaggt taaagaaaag ttcatccttg gagtagaggg tcaacaactg gttcgtccta 180
aaaagcttcc tctgatacag aagcgagata ctggacacac ccatgatgat gacatactga 240
aaacgtatga agaagaattg ttgtatgaaa taaaactaaa tagaaaaacc ttagtccttc 300
atcttctaag atccagggag ttcctaggct caaattacag tgaaacattc tactccatga 360
aaggagaagc gttcaccagg catcctcaga tcatggatca ttgtttttac caaggatcca 420
tagtacacga atatgattca gctgccagta tcagtacgtg taatggtcta aggggattct 480
tcagaataaa cgaccaaaga tacctcattg aaccagtgaa atactcagat gagggagaac 540
atttggtgtt caaatataac ctgagggtgc cgtatggtgc caattattcc tgtacagagc 600
ttaattttac cagaaaaact gttccagggg ataatgaatc tgaagaagac tccaaaataa 660
aaggcatcca tgatgaaaag tatgttgaat tgttcattgt tgctgatgat actgtgtatc 720
gcagaaatgg tcatcctcac aataaactaa ggaaccgaat ttggggaatg gtcaattttg 780
tcaacatgat ttataaaacc ttaaacatcc atgtgacgtt ggttggcatt gaaatatgga 840
cacatgaaga taaaatagaa ctatattcaa atatagaaac taccttattg cgtttttcat 900
tttggcaaga aaagatcctt aaaacacgga aggattttga tcatgttgta ttactcagtg 960
ggaagtggct ctactcacat gtgcaaggaa tttcttatcc agggggtatg tgcctgccct 1020
attattccac cagtatcatt aaggatcttt tacctgacac aaacataatt gcaaacagaa 1080
tggcacatca actggggcat aaccttggga tgcagcatga cgagttccca tgcacctgtc 1140
cttcaggaaa atgcgtgatg gacagtgatg gaagcattcc tgcactgaaa ttcagtaaat 1200
gcagccaaaa ccaataccac cagtacttga aggattataa gccaacatgc atgctcaaca 1260
ttccatttcc ttacaatttt catgatttcc aattttgtgg aaacaagaag ttggatgagg 1320
gtgaagagtg tgactgtggc cctgctcagg agtgtactaa tccttgctgt gatgcacaca 1380
catgtgtact gaagccagga tttacttgtg cagaaggaga atgctgtgaa tcttgtcaga 1440
taaaaaaagc agggtccata tgcagaccgg cgaaagatga atgtgatttt cctgagatgt 1500
gcactggcca ctcgcctgcc tgtcctaagg accagttcag ggtcaatgga tttccttgca 1560
agaactcaga aggctactgt ttcatgggga aatgtccaac tcgtgaggat cagtgctctg 1620
aactatttga tgatgatgca atagagagtc atgatatctg ctacaagatg aatacaaaag 1680
gaaataaatt tggatactgc aaaaacaagg aaaacagatt tcttccctgt gaggagaaag 1740
atgtcagatg tggaaagatc tactgcactg gaggggagct ttcctctctc cttggagaag 1800
acaagactta tcaccttaag gatccccaga agaatgctac tgtcaaatgc aaaactattt 1860
ttttatacca tgattctaca gacattggcc tggtggcgtc aggaacaaaa tgtggagagg 1920
gaatggtgtg caacaatggt gaatgtctaa acatggaaaa ggtctatatc tcaaccaatt 1980
gcccctctca gtgcaatgaa aatcctgtgg atggccacgg actccagtgc cactgtgagg 2040
aaggacaggc acctgtagcc tgtgaagaaa ccttacatgt taccaatatc accatcttgg 2100
ttgttgtgct tgtcctggtt attgtcggta tcggagttct tatactatta gttcgttacc 2160
gaaaatgtat caagttgaag caagttcaga gcccacctac agaaaccctg ggagtggaga 2220
acaaaggata ctttggtgat gagcagcaga taaggactga gccaatcctg ccagaaattc 2280
atttcctaaa taaacctgca agtaaagatt caagaggaat cgcagatccc aatcaaagtg 2340
ccaagtgagc ttgaagttgg atatccaaaa tggccgtgca agcttaggct ggggattctg 2400
gatgcaacgt ctttacaacc ttacctagat atctgctact cacatttttg gtagtgtttc 2460
aaacgttctt tatccagaca gacaatgttt aagagaaaca acttatttct gttaatattt 2520
accggtagaa ttcacaccct ctatcataaa catatgctgc agaaaaaaaa aaaaaaaaaa 2580
aa 2582
<210>6
<211>754
<212>PRT
<213>智人
<400>6
Met Leu Pro Gly Cys Ile Phe Leu Met Ile Leu Leu Ile Pro Gln Val
1 5 10 15
Lys Glu Lys Phe Ile Leu Gly Val Glu Gly Gln Gln Leu Val Arg Pro
20 25 30
Lys Lys Leu Pro Leu Ile Gln Lys Arg Asp Thr Gly His Thr His Asp
35 40 45
Asp Asp Ile Leu Lys Thr Tyr Glu Glu Glu Leu Leu Tyr Glu Ile Lys
50 55 60
Leu Asn Arg Lys Thr Leu Val Leu His Leu Leu Arg Ser Arg Glu Phe
65 70 75 80
Leu Gly Ser Asn Tyr Ser Glu Thr Phe Tyr Ser Met Lys Gly Glu Ala
85 90 95
Phe Thr Arg His Pro Gln Ile Met Asp His Cys Phe Tyr Gln Gly Ser
100 105 110
Ile Val His Glu Tyr Asp Ser Ala Ala Ser Ile Ser Thr Cys Asn Gly
115 120 125
Leu Arg Gly Phe Phe Arg Ile Asn Asp Gln Arg Tyr Leu Ile Glu Pro
130 135 140
Val Lys Tyr Ser Asp Glu Gly Glu His Leu Val Phe Lys Tyr Asn Leu
145 150 155 160
Arg Val Pro Tyr Gly Ala Asn Tyr Ser Cys Thr Glu Leu Asn Phe Thr
165 170 175
Arg Lys Thr Val Pro Gly Asp Asn Glu Ser Glu Glu Asp Ser Lys Ile
180 185 190
Lys Gly Ile His Asp Glu Lys Tyr Val Glu Leu Phe Ile Val Ala Asp
195 200 205
Asp Thr Val Tyr Arg Arg Asn Gly His Pro His Asn Lys Leu Arg Asn
210 215 220
Arg Ile Trp Gly Met Val Asn Phe Val Asn Met Ile Tyr Lys Thr Leu
225 230 235 240
Asn Ile His Val Thr Leu Val Gly Ile Glu Ile Trp Thr His Glu Asp
245 250 255
Lys Ile Glu Leu Tyr Ser Asn Ile Glu Thr Thr Leu Leu Arg Phe Ser
260 265 270
Phe Trp Gln Glu Lys Ile Leu Lys Thr Arg Lys Asp Phe Asp His Val
275 280 285
Val Leu Leu Ser Gly Lys Trp Leu Tyr Ser His Val Gln Gly Ile Ser
290 295 300
Tyr Pro Gly Gly Met Cys Leu Pro Tyr Tyr Ser Thr Ser Ile Ile Lys
305 310 315 320
Asp Leu Leu Pro Asp Thr Asn Ile Ile Ala Asn Arg Met Ala His Gln
325 330 335
Leu Gly His Asn Leu Gly Met Gln His Asp Glu Phe Pro Cys Thr Cys
340 345 350
Pro Ser Gly Lys Cys Val Met Asp Ser Asp Gly Ser Ile Pro Ala Leu
355 360 365
Lys Phe Ser Lys Cys Ser Gln Asn Gln Tyr His Gln Tyr Leu Lys Asp
370 375 380
Tyr Lys Pro Thr Cys Met Leu Asn Ile Pro Phe Pro Tyr Asn Phe His
385 390 395 400
Asp Phe Gln Phe Cys Gly Asn Lys Lys Leu Asp Glu Gly Glu Glu Cys
405 410 415
Asp Cys Gly Pro Ala Gln Glu Cys Thr Asn Pro Cys Cys Asp Ala His
420 425 430
Thr Cys Val Leu Lys Pro Gly Phe Thr Cys Ala Glu Gly Glu Cys Cys
435 440 445
Glu Ser Cys Gln Ile Lys Lys Ala Gly Ser Ile Cys Arg Pro Ala Lys
450 455 460
Asp Glu Cys Asp Phe Pro Glu Met Cys Thr Gly His Ser Pro Ala Cys
465 470 475 480
Pro Lys Asp Gln Phe Arg Val Asn Gly Phe Pro Cys Lys Asn Ser Glu
485 490 495
Gly Tyr Cys Phe Met Gly Lys Cys Pro Thr Arg Glu Asp Gln Cys Ser
500 505 510
Glu Leu Phe Asp Asp Asp Ala Ile Glu Ser His Asp Ile Cys Tyr Lys
515 520 525
Met Asn Thr Lys Gly Asn Lys Phe Gly Tyr Cys Lys Asn Lys Glu Asn
530 535 540
Arg Phe Leu Pro Cys Glu Glu Lys Asp Val Arg Cys Gly Lys Ile Tyr
545 550 555 560
Cys Thr Gly Gly Glu Leu Ser Ser Leu Leu Gly Glu Asp Lys Thr Tyr
565 570 575
His Leu Lys Asp Pro Gln Lys Asn Ala Thr Val Lys Cys Lys Thr Ile
580 585 590
Phe Leu Tyr His Asp Ser Thr Asp Ile Gly Leu Val Ala Ser Gly Thr
595 600 605
Lys Cys Gly Glu Gly Met Val Cys Asn Asn Gly Glu Cys Leu Asn Met
610 615 620
Glu Lys Val Tyr Ile Ser Thr Asn Cys Pro Ser Gln Cys Asn Glu Asn
625 630 635 640
Pro Val Asp Gly His Gly Leu Gln Cys His Cys Glu Glu Gly Gln Ala
645 650 655
Pro Val Ala Cys Glu Glu Thr Leu His Val Thr Asn Ile Thr Ile Leu
660 665 670
Val Val Val Leu Val Leu Val Ile Val Gly Ile Gly Val Leu Ile Leu
675 680 685
Leu Val Arg Tyr Arg Lys Cys Ile Lys Leu Lys Gln Val Gln Ser Pro
690 695 700
Pro Thr Glu Thr Leu Gly Val Glu Ash Lys Gly Tyr Phe Gly Asp Glu
705 710 715 720
Gln Gln Ile Arg Thr Glu Pro Ile Leu Pro Glu Ile His Phe Leu Asn
725 730 735
Lys Pro Ala Ser Lys Asp Ser Arg Gly Ile Ala Asp Pro Asn Gln Ser
740 745 750
Ala Lys
<210>7
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>7
gtgcagaagg agaatgctgt g 21
<210>8
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>8
tccacatctg acatctttct c 21
<210>9
<211>1731
<212>DNA
<213>智人
<400>9
agaaggagga aggacagcac agctgacagc cgtgctcaga cagcttctgg atcccaggct 60
catctccaca gaggagaaca cacaggcagc agagaccatg gggcccctcc cagccccttc 120
ctgcacacag cgcatcacct ggaaggggct cctgctcaca gcatcacttt taaacttctg 180
gaacccgccc accactgccg aagtcacgat tgaagcccag ccacccaaag tttctgaggg 240
gaaggatgtt cttctacttg tccacaattt gccccagaat cttcctggct acttctggta 300
caaaggggaa atgacggacc tctaccatta cattatatcg tatatagttg atggtaaaat 360
aattatatat gggcctgcat acagtggaag agaaacagta tattccaacg catccctgct 420
gatccagaat gtcacccgga aggatgcagg aacctacacc ttacacatca taaagcgagg 480
tgatgagact agagaagaaa ttcgacattt caccttcacc ttatacttgg agactcccaa 540
gccctacatc tccagcagca acttaaaccc cagggaggcc atggaggctg tgcgcttaat 600
ctgtgatcct gagactctgg acgcaagcta cctatggtgg atgaatggtc agagcctccc 660
tgtgactcac aggttgcagc tgtccaaaac caacaggacc ctctatctat ttggtgtcac 720
aaagtatatt gcaggaccct atgaatgtga aatacggaac ccagtgagtg ccagtcgcag 780
tgacccagtc accctgaatc tcctcccgaa gctgcccatc ccctacatca ccatcaacaa 840
cttaaacccc agggagaata aggatgtctt agccttcacc tgtgaaccta agagtgagaa 900
ctacacctac atttggtggc taaacggtca gagcetcccc gtcagtcccg gggtaaagcg 960
acccattgaa aacaggatac tcattctacc cagtgtcacg agaaatgaaa caggacccta 1020
tcaatgtgaa atacaggacc gatatggtgg cctccgcagt aacccagtca tcctaaatgt 1080
cctctatggt ccagacctcc ccagaattta cccttcattc acctattacc gttcaggaga 1140
aaacctcgac ttgtcctgct tcacggaate taacccaccg gcagagtatt tttggacaat 1200
taatgggaag tttcagcaat caggacaaaa gctctttatc ccccaaatta ctagaaatca 1260
tagcgggctc tatgcttgct ctgttcataa ctcagccact ggcaaggaaa tctccaaatc 1320
catgacagtc aaagtctctg gtccctgcca tggagacctg acagagtctc agtcatgact 1380
gcaacaactg agacactgag aaaaagaaca ggctgatacc ttcatgaaat tcaagacaaa 1440
gaagaaaaaa actcaatgtt attggactaa ataatcaaaa ggataatgtt ttcataattt 1500
tttattggaa aatgtgctga ttctttgaat gttttattct ccagatttat gaactttttt 1560
tcttcagcaa ttggtaaagt atacttttat aaacaaaaat tgaaatattt gcttttgctg 1620
tctatctgaa tgccccagaa ttgtgaaact attcatgagt attcataggt ttatggtaat 1680
aaagttattt gcacatgttc caaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 1731
<210>10
<211>426
<212>PRT
<213>智人
<400>10
Met Gly Pro Leu Pro Ala Pro Ser Cys Thr Gln Arg Ile Thr Trp Lys
1 5 10 15
Gly Leu Leu Leu Thr Ala Ser Leu Leu Asn Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Glu Val Thr Ile Glu Ala Gln Pro Pro Lys Val Ser Glu Gly
35 40 45
Lys Asp Val Leu Leu Leu Val His Asn Leu Pro Gln Asn Leu Pro Gly
50 55 60
Tyr Phe Trp Tyr Lys Gly Glu Met Thr Asp Leu Tyr His Tyr Ile Ile
65 70 75 80
Ser Tyr Ile Val Asp Gly Lys Ile Ile Ile Tyr Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Thr Val Tyr Ser Asn Ala Ser Leu Leu Ile Gln Asn Val
100 105 110
Thr Arg Lys Asp Ala Gly Thr Tyr Thr Leu His Ile Ile Lys Arg Gly
115 120 125
Asp Glu Thr Arg Glu Glu Ile Arg His Phe Thr Phe Thr Leu Tyr Leu
130 135 140
Glu Thr Pro Lys Pro Tyr Ile Ser Ser Ser Asn Leu Asn Pro Arg Glu
145 150 155 160
Ala Met Glu Ala Val Arg Leu Ile Cys Asp Pro Glu Thr Leu Asp Ala
165 170 175
Ser Tyr Leu Trp Trp Met Asn Gly Gln Ser Leu Pro Val Thr His Arg
180 185 190
Leu Gln Leu Ser Lys Thr Asn Arg Thr Leu Tyr Leu Phe Gly Val Thr
195 200 205
Lys Tyr Ile Ala Gly Pro Tyr Glu Cys Glu Ile Arg Asn Pro Val Ser
210 215 220
Ala Ser Arg Ser Asp Pro Val Thr Leu Asn Leu Leu Pro Lys Leu Pro
225 230 235 240
Ile Pro Tyr Ile Thr Ile Asn Asn Leu Asn Pro Arg Glu Asn Lys Asp
245 250 255
Val Leu Ala Phe Thr Cys Glu Pro Lys Ser Glu Asn Tyr Thr Tyr Ile
260 265 270
Trp Trp Leu Asn Gly Gln Ser Leu Pro Val Ser Pro Gly Val Lys Arg
275 280 285
Pro Ile Glu Asn Arg Ile Leu Ile Leu Pro Ser Val Thr Arg Asn Glu
290 295 300
Thr Gly Pro Tyr Gln Cys Glu Ile Gln Asp Arg Tyr Gly Gly Leu Arg
305 310 315 320
Ser Asn Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Leu Pro Arg
325 330 335
Ile Tyr Pro Ser Phe Thr Tyr Tyr Arg Ser Gly Glu Asn Leu Asp Leu
340 345 350
Ser Cys Phe Thr Glu Ser Asn Pro Pro Ala Glu Tyr Phe Trp Thr Ile
355 360 365
Asn Gly Lys Phe Gln Gln Ser Gly Gln Lys Leu Phe Ile Pro Gln Ile
370 375 380
Thr Arg Asn His Ser Gly Leu Tyr Ala Cys Ser Val His Asn Ser Ala
385 390 395 400
Thr Gly Lys Glu Ile Ser Lys Ser Met Thr Val Lys Val Ser Gly Pro
405 410 415
Cys His Gly Asp Leu Thr Glu Ser Gln Ser
420 425
<210>11
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>11
ctcctcyatg gtccagacct c 21
<210>12
<211>22
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>12
gttgcagtca tgactgagac tc 22
<210>13
<211>1634
<212>DNA
<213>智人
<400>13
atgacagtga ctccacagta tctaccagaa tacaagggca agcatccaaa atgtgactca 60
ctggtggtgt tccgcaatgt gtgcgtctgt gtgtccaccg cgacaggcat cagtacattg 120
gatcagagtg tcgctttcag ttgtaacgga cttcatcaca tcacaaattg tactcgttct 180
catcctttta agaaagttca gacccaggaa aatttccata gtaccttaat gaaaaagata 240
gaaatcagtg ggacgtgtct ttcctttcat ctccttttcg gcttggaaat cagaatgaga 300
aggattgttt ttgctggtgt tatcttattc cgcctcttag gtgttatctt attccgcctc 360
ttaggtgtta tcttattcgg ccgcttaggt gacctgggaa cctgccagac aaaacctggt 420
cagtactgga aagaagaggt ccacattcaa gatgttggag gtttgatttg cagagcatgc 480
aatctttcac tgcccttcca tggatgtcttttagacctgg gaacctgcca ggcagaacct 540
ggtcagtact gtaaagaaga ggtccacatt caaggtggca ttcaatggta ttcagtcaaa 600
ggctgcacaa agaacacatc agagtgcttc aagagtactc tcgtcaagag aattctgcaa 660
ctgcatgaac ttgtaactac tcactgctgc aatcattctt tgtgcaattt ctgagtcagt 720
ggcccatatc taaaatgctt ggcagatcaa tcagtctcga agcctgacct ggctatcaca 780
aaatgatggc tattgtcaat tagcccactt cagaaacctc agacccttgt aggtagaagg 840
aattttgatc tgaaattgac tttggttttc aatattccca atatctcccc caccacctcc 900
aactcatctg agaaatagcc ctttcaacac catttctctc ctctcctcct tctgcttaat 960
ttaccttcct accacaaggc tacaaagaag gaaaaatgtt agtgattctc caagtcaaac 1020
taggcatgtc acctctaact actttcattt ccctcaataa ttccatactc caaaatatgg 1080
ttacaaatgt ttcacaagac agcaagtgac ctgagaatat tcatttggtt tccaaagcaa 1140
actgccttgc tcctttgggg tgatttatgg tatagaagaa actgacttaa catatactat 1200
agggaaaaaa taagccatga atcagcaagc caggcctgcg ggaaaagtat gaacccaaac 1260
aggaaagggc tgaggcaggt ggtagggctg gcacttattt cttccatctg cctcagagtt 1320
tatccaaatt ttgaattttc cgtaccttaa ccatgcctaa atgctttggc ttgttcaatt 1380
ttggcagatt aagcagttca aggtaagcag agaagtaagt tcccaaccac aaggaattta 1440
aaaggagtag gaacgtactt tgaactacat ttcccatttt gcgatcatta cgtcttctat 1500
tacaatgccc tactttggca gcatgaagag tactgcatta atttaattta atttaaaatt 1560
taatttaaaa ctgtctttct ctgtattttc aggagtttga aaattcaaaa aataaataat 1620
aaatgtcaat aaaa 1634
<210>14
<211>237
<212>PRT
<213>智人
<400>14
Met Thr Val Thr Pro Gln Tyr Leu Pro Glu Tyr Lys Gly Lys His Pro
1 5 10 15
Lys Cys Asp Ser Leu Val Val Phe Arg Asn Val Cys Val Cys Val Ser
20 25 30
Thr Ala Thr Gly Ile Ser Thr Leu Asp Gln Ser Val Ala Phe Ser Cys
35 40 45
Asn Gly Leu His His Ile Thr Asn Cys Thr Arg Ser His Pro Phe Lys
50 55 60
Lys Val Gln Thr Gln Glu Asn Phe His Ser Thr Leu Met Lys Lys Ile
65 70 75 80
Glu Ile Ser Gly Thr Cys Leu Ser Phe His Leu Leu Phe Gly Leu Glu
85 90 95
Ile Arg Met Arg Arg Ile Val Phe Ala Gly Val Ile Leu Phe Arg Leu
100 105 110
Leu Gly Val Ile Leu Phe Arg Leu Leu Gly Val Ile Leu Phe Gly Arg
115 120 125
Leu Gly Asp Leu Gly Thr Cys Gln Thr Lys Pro Gly Gln Tyr Trp Lys
130 135 140
Glu Glu Val His Ile Gln Asp Val Gly Gly Leu Ile Cys Arg Ala Cys
145 150 155 160
Asn Leu Ser Leu Pro Phe His Gly Cys Leu Leu Asp Leu Gly Thr Cys
165 170 175
Gln Ala Glu Pro Gly Gln Tyr Cys Lys Glu Glu Val His Ile Gln Gly
180 185 190
Gly Ile Gln Trp Tyr Ser Val Lys Gly Cys Thr Lys Asn Thr Ser Glu
195 200 205
Cys Phe Lys Ser Thr Leu Val Lys Arg Ile Leu Gln Leu His Glu Leu
210 215 220
Val Thr Thr His Cys Cys Asn His Ser Leu Cys Asn Phe
225 230 235
<210>15
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>15
gacaaaacct ggtcagtact g 21
<210>16
<211>23
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>16
cccattgaat gccaccttga atg 23
<210>17
<211>744
<212>DNA
<213>智人
<400>17
atcaggttca acgcagtgac tgctcagtag aagccatggc tcgcagacac tgcttctcct 60
actggttact ggtatgctgg ttggtggtaa ctgtggcaga aggacaagaa gaggtattta 120
cgcttcctgg agattcacaa aataatgcgg acgctaccga ctgccagatc tttacactca 180
cccctccacc tgccccgagg agtccggtca caagggccca gcccatcaca aagacaccca 240
ggtgtccctt ccattttttt ccacgaaggc ccagaatcca ttttaggttt ccaaacagac 300
ctttcgtccc ttcaaggtgt aaccaccgtt ttccattcca gccattttat tggccacacc 360
gttaccttac ttataggtat ttccccagaa gaagactcca gagaggaagc tcatctgagg 420
aaagctgaga gggaagagaa acccaaacat actgaagcaa aaaaaagcct atccttcaga 480
aaaaagcaac aaaaagattt ctgttttatc tttcgaaact aaaactattg gatttgaaga 540
ttaagtatcc taaacatcac tgactagaaa ctgttctctt tgtcagcagt gaagatattg 600
gatcataggt tattgatggt tgcaaaattg gacaataacc acgttatttt tatcctcaac 660
ctcttatggt cacaggatat ttatgcaaat aaaatcttta aatgggaaaa aaaaaaaaaa 720
aaaaaaaaaa aaaaaaaaaa aaaa 744
<210>18
<211>130
<212>PRT
<213>智人
<400>18
Met Ala Arg Arg His Cys Phe Ser Tyr Trp Leu Leu Val Cys Trp Leu
1 5 10 15
Val Val Thr Val Ala Glu Gly Gln Glu Glu Val Phe Thr Leu Pro Gly
20 25 30
Asp Ser Gln Asn Asn Ala Asp Ala Thr Asp Cys Gln Ile Phe Thr Leu
35 40 45
Thr Pro Pro Pro Ala Pro Arg Ser Pro Val Thr Arg Ala Gln Pro Ile
50 55 60
Thr Lys Thr Pro Arg Cys Pro Phe His Phe Phe Pro Arg Arg Pro Arg
65 70 75 80
Ile His Phe Arg Phe Pro Asn Arg Pro Phe Val Pro Ser Arg Cys Asn
85 90 95
His Arg Phe Pro Phe Gln Pro Phe Tyr Trp Pro His Arg Tyr Leu Thr
100 105 110
Tyr Arg Tyr Phe Pro Arg Arg Arg Leu Gln Arg Gly Ser Ser Ser Glu
115 120 125
Glu Ser
130
<210>19
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>19
taactgtggc agaaggacaa g 21
<210>20
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>20
agatgagctt cctctctgga g 21
<210>21
<211>1955
<212>DNA
<213>智人
<400>21
acagaagcgc gcagagtccc atcctgccac gccacgagga gagaagaagg aaagatacag 60
tgttaggaaa gagacctccc tcgcccctac gccccgcgcc cctgcgcctc gcttcagcct 120
caggacagtc ctgccgggac ggtgagcgca ttcagcaccc tggacagcac cgcggttgcg 180
ctgcctccag ggcggccccg ggctgctcct gctccgcaga gctacgccct ccccccgggt 240
gccccggacc ctgcacttgc cgccgctttc ctcgcgctgc tctggacctt gctagccggc 300
tctgcacctc ccagaagccg tgggcgcgcc gctcagctgc tccatcgcct cactttccca 360
ggctcgcgcc cgaagcagag ccatgagaac cccagggtgc ctggcgagcc gctagcgcca 420
tgggccccgg cgaggcgctg ctggcgggtc tcctggtgat ggtactggcc gtggcgctgc 480
tatccaacgc actggtgctg ctttgttgcg cctacagcgc tgagctccgc actcgagcct 540
caggcgtcct cctggtgaat ctgtctctgg gccacctgct gctggcggcg ctggacatgc 600
ccttcacgct gctcggtgtg atgcgcgggc ggacaccgtc ggcgcccggc gcatgccaag 660
tcattggctt cctggacacc ttcctggcgt ccaacgcggc gctgagcgtg gcggcgctga 720
gcgcagacca gtggctggca gtgggcttcc cactgcgcta cgccggacgc ctgcgaccgc 780
gctatgccgg cctgctgctg ggctgtgcct ggggacagtc gctggccttc tcaggcgctg 840
cacttggctg ctcgtggctt ggctacagca gcgccttcgc gtcctgttcg ctgcgcctgc 900
cgcccgagcc tgagcgtccg cgcttcgcag ccttcaccgc cacgctccat gccgtgggct 960
tcgtgctgcc gctggcggtg ctctgcctca cctcgctcca ggtgcaccgg gtggcacgca 1020
gacactgcca gcgcatggac accgtcacca tgaaggcgct cgcgctgctc gccgacctgc 1080
accccagtgt gcggcagcgc tgcctcatcc agcagaagcg gcgccgccac cgcgccacca 1140
ggaagattgg cattgctatt gcgaccttcc tcatctgctt tgccccgtat gtcatgacca 1200
ggctggcgga gctcgtgccc ttcgtcaccg tgaacgccca gtggggcatc ctcagcaagt 1260
gcctgaccta cagcaaggcg gtggccgacc cgttcacgta ctctctgctc cgccggccgt 1320
tccgccaagt cctggccggc atggtgcacc ggctgctgaa gagaaccccg cgcccagcat 1380
ccacccatga cagctctctg gatgtggccg gcatggtgca ccagctgctg aagagaaccc 1440
cgcgcccagc gtccacccac aacggctctg tggacacaga gaatgattcc tgcctgcagc 1500
agacacactg agggcctggc agggctcatc gcccccacct tctaagaagc cctgtggaaa 1560
gggcactggc cctgccacag agatgccact ggggaccccc agacaccagt ggcttgactt 1620
tgagctaagg ctgaagtaca ggaggaggag gaggagaggg ccggatgtgg gtgtggacag 1680
cagtagtggc ggaggagagc tcggggctgg gctgcctggc tgctgggtgg ccccgggaca 1740
gtggcttttc ctctctgaac cttagcttcc tcacccttgt tctggggtca tggcgatgct 1800
tcgagacagt gggtagggaa gtgccctgtg tggcatatgg tactcgtggg cgtgctataa 1860
gtgactgctg ttcatgtggg tgaggtggtc actcttgctc agggtctgtt gtgcagccca 1920
gatggacacc tgtttctcca aaaaaaaaaa aaaaa 1955
<210>22
<211>363
<212>PRT
<213>智人
<400>22
Met Gly Pro Gly Glu Ala Leu Leu Ala Gly Leu Leu Val Met Val Leu
1 5 10 15
Ala Val Ala Leu Leu Ser Asn Ala Leu Val Leu Leu Cys Cys Ala Tyr
20 25 30
Ser Ala Glu Leu Arg Thr Arg Ala Ser Gly Val Leu Leu Val Asn Leu
35 40 45
Ser Leu Gly His Leu Leu Leu Ala Ala Leu Asp Met Pro Phe Thr Leu
50 55 60
Leu Gly Val Met Arg Gly Arg Thr Pro Ser Ala Pro Gly Ala Cys Gln
65 70 75 80
Val Ile Gly Phe Leu Asp Thr Phe Leu Ala Ser Asn Ala Ala Leu Ser
85 90 95
Val Ala Ala Leu Ser Ala Asp Gln Trp Leu Ala Val Gly Phe Pro Leu
100 105 110
Arg Tyr Ala Gly Arg Leu Arg Pro Arg Tyr Ala Gly Leu Leu Leu Gly
115 120 125
Cys Ala Trp Gly Gln Ser Leu Ala Phe Ser Gly Ala Ala Leu Gly Cys
130 135 140
Ser Trp Leu Gly Tyr Ser Ser Ala Phe Ala Ser Cys Ser Leu Arg Leu
145 150 155 160
Pro Pro Glu Pro Glu Arg Pro Arg Phe Ala Ala Phe Thr Ala Thr Leu
165 170 175
His Ala Val Gly Phe Val Leu Pro Leu Ala Val Leu Cys Leu Thr Ser
180 185 190
Leu Gln Val His Arg Val Ala Arg Arg His Cys Gln Arg Met Asp Thr
195 200 205
Val Thr Met Lys Ala Leu Ala Leu Leu Ala Asp Leu His Pro Ser Val
210 215 220
Arg Gln Arg Cys Leu Ile Gln Gln Lys Arg Arg Arg His Arg Ala Thr
225 230 235 240
Arg Lys Ile Gly Ile Ala Ile Ala Thr Phe Leu Ile Cys Phe Ala Pro
245 250 255
Tyr Val Met Thr Arg Leu Ala Glu Leu Val Pro Phe Val Thr Val Asn
260 265 270
Ala Gln Trp Gly Ile Leu Ser Lys Cys Leu Thr Tyr Ser Lys Ala Val
275 280 285
Ala Asp Pro Phe Thr Tyr Ser Leu Leu Arg Arg Pro Phe Arg Gln Val
290 295 300
Leu Ala Gly Met Val His Arg Leu Leu Lys Arg Thr Pro Arg Pro Ala
305 310 315 320
Ser Thr His Asp Ser Ser Leu Asp Val Ala Gly Met Val His Gln Leu
325 330 335
Leu Lys Arg Thr Pro Arg Pro Ala Ser Thr His Asn Gly Ser Val Asp
340 345 350
Thr Glu Asn Asp Ser Cys Leu Gln Gln Thr His
355 360
<210>23
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>23
ccgtatgtca tgaccaggct g 21
<210>24
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>24
aagtcaagcc actggtgtct g 21
<210>25
<211>2059
<212>DNA
<213>智人
<400>25
agcacagaag gaggaaggac agcacagctg acagccgtac tcaggaagct tctggatcct 60
aggcttatct ccacagagga gaacacacaa gcagcagaga ccatggggcc cctctcagcc 120
cctccctgca cacagcgcat cacctggaag ggggtcctgc tcacagcatc acttttaaac 180
ttctggaatc cgcccacaac tgcccaagtc acgattgaag cccagccacc caaagtttct 240
gaggggaagg atgttcttct acttgtccac aatttgcccc agaatcttgc tggctacatt 300
tggtacaaag ggcaaatgac atacctctac cattacatta catcatatgt agtagacggt 360
caaagaatta tatatgggcc tgcatacagt ggaagagaaa gagtatattc caatgcatcc 420
ctgctgatcc agaatgtcac gcaggaggat gcaggatcct acaccttaca catcataaag 480
cgacgcgatg ggactggagg agtaactgga catttcacct tcaccttaca cctggagact 540
cccaagccct ccatctccag cagcaactta aatcccaggg aggccatgga ggctgtgatc 600
ttaacctgtg atcctgcgac tccagccgca agctaccagt ggtggatgaa tggtcagagc 660
ctccctatga ctcacaggtt gcagctgtcc aaaaccaaca ggaccctctt tatatttggt 720
gtcacaaagt atattgcagg accctatgaa tgtgaaatac ggaacccagt gagtgccagc 780
cgcagtgacc cagtcaccct gaatctcctc ccaaagctgt ccaagcccta catcacaatc 840
aacaacttaa accccagaga gaataaggat gtcttaacct tcacctgtga acctaagagt 900
aagaactaca cctacatttg gtggctaaat ggtcagagcc tccctgtcag tcccagggta 960
aagcgaccca ttgaaaacag gatcctcatt ctacccaatg tcacgagaaa tgaaacagga 1020
ccttatcaat gtgaaatacg ggaccgatat ggtggcatcc gcagtgaccc agtcaccctg 1080
aatgtcctct atggtccaga cctccccagc atttaccctt cattcaccta ttaccgttca 1140
ggagaaaacc tctacttgtc ctgcttcgcc gagtctaacc cacgggcaca atattcttgg 1200
acaattaatg ggaagtttca gctatcagga caaaagctct ctatccccca aataactaca 1260
aagcatagtg ggctctatgc ttgctctgtt cgtaactcag ccactggcaa ggaaagctcc 1320
aaatccatca cagtcaaagt ctctgactgg atattaccct gaattctact agttcctcca 1380
attccatttt ctcccatgga atcacgaaga gcaagaccca ctctgttcca gaagccctat 1440
aagctggagg tggacaactc gatgtaaatt tcatgggaaa acccttgtac ctgacatgtg 1500
agccactcag aactcaccaa aatgttcgac accataacaa cagctactca aactgtaaac 1560
caggataaca agttgatgac ttcacactgt ggacagtttt tccaaagatg tcagaacaag 1620
actccccatc atgataaggc tcccacccct cttaaccgtc cttgctcatg cctgcctctt 1680
tcacttggca ggataatgca gtcattagaa tttcacatgt agtagcttct gagggtaaca 1740
acagagtgtc agatatgtca tctcaacctc aaacttttac gtaacatctc aggggaaatg 1800
tggctctctc catcttgcat acagggctcc caatagaaat gaacacagag atattgcctg 1860
tgtgtttgca gagaagatgg tttctataaa gagtaggaaa gctgaaatta tagtagagtc 1920
tcctttaaat gcacattgtg tggatggctc tcaccatttc ctaagagata cagtgtaaaa 1980
cgtgacagta atactgattc tagcagaata aaacatgtac cacatttgct aaaaaaaaaa 2040
aaaaaaaaaa aaaaaaaaa 2059
<210>26
<211>419
<212>PRT
<213>智人
<400>26
Met Gly Pro Leu Ser Ala Pro Pro Cys Thr Gln Arg Ile Thr Trp Lys
1 5 10 15
Gly Val Leu Leu Thr Ala Ser Leu Leu Asn Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Gln Val Thr Ile Glu Ala Gln Pro Pro Lys Val Ser Glu Gly
35 40 45
Lys Asp Val Leu Leu Leu Val His Asn Leu Pro Gln Asn Leu Ala Gly
50 55 60
Tyr Ile Trp Tyr Lys Gly Gln Met Thr Tyr Leu Tyr His Tyr Ile Thr
65 70 75 80
Ser Tyr Val Val Asp Gly Gln Arg Ile Ile Tyr Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Arg Val Tyr Ser Asn Ala Ser Leu Leu Ile Gln Asn Val
100 105 110
Thr Gln Glu Asp Ala Gly Ser Tyr Thr Leu His Ile Ile Lys Arg Arg
115 120 125
Asp Gly Thr Gly Gly Val Thr Gly His Phe Thr Phe Thr Leu His Leu
130 135 140
Glu Thr Pro Lys Pro Ser Ile Ser Ser Ser Asn Leu Asn Pro Arg Glu
145 150 155 160
Ala Met Glu Ala Val Ile Leu Thr Cys Asp Pro Ala Thr Pro Ala Ala
165 170 175
Ser Tyr Gln Trp Trp Met Asn Gly Gln Ser Leu Pro Met Thr His Arg
180 185 190
Leu Gln Leu Ser Lys Thr Asn Arg Thr Leu Phe Ile Phe Gly Val Thr
195 200 205
Lys Tyr Ile Ala Gly Pro Tyr Glu Cys Glu Ile Arg Asn Pro Val Ser
210 215 220
Ala Ser Arg Ser Asp Pro Val Thr Leu Asn Leu Leu Pro Lys Leu Ser
225 230 235 240
Lys Pro Tyr Ile Thr Ile Asn Asn Leu Asn Pro Arg Glu Asn Lys Asp
245 250 255
Val Leu Thr Phe Thr Cys Glu Pro Lys Ser Lys Asn Tyr Thr Tyr Ile
260 265 270
Trp Trp Leu Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Val Lys Arg
275 280 285
Pro Ile Glu Asn Arg Ile Leu Ile Leu Pro Asn Val Thr Arg Asn Glu
290 295 300
Thr Gly Pro Tyr Gln Cys Glu Ile Arg Asp Arg Tyr Gly Gly Ile Arg
305 310 315 320
Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Leu Pro Ser
325 330 335
Ile Tyr Pro Ser Phe Thr Tyr Tyr Arg Ser Gly Glu Asn Leu Tyr Leu
340 345 350
Ser Cys Phe Ala Glu Ser Asn Pro Arg Ala Gln Tyr Ser Trp Thr Ile
355 360 365
Asn Gly Lys Phe Gln Leu Ser Gly Gln Lys Leu Ser Ile Pro Gln Ile
370 375 380
Thr Thr Lys His Ser Gly Leu Tyr Ala Cys Ser Val Arg Asn Ser Ala
385 390 395 400
Thr Gly Lys Glu Ser Ser Lys Ser Ile Thr Val Lys Val Ser Asp Trp
405 410 415
Ile Leu Pro
<210>27
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>27
gttgttaccc tcagaagcta c 21
<210>28
<211>1780
<212>DNA
<213>智人
<400>28
agcacagaag gaggaaggac agcacagctg acagccgtac tcaggaagct tctggatcct 60
aggcttatct ccacagagga gaacacacaa gcagcagaga ccatggggcc cctctcagcc 120
cctccctgca cacagcgcat cacctggaag ggggtcctgc tcacagcatc acttttaaac 180
ttctggaatc cgcccacaac tgcccaagtc acgattgaag cccagccacc caaagtttct 240
gaggggaagg atgttcttct acttgtccac aatttgcccc agaatcttgc tggctacatt 300
tggtacaaag ggcaaatgac atacctctac cattacatta catcatatgt agtagacggt 360
caaagaatta tatatgggcc tgcatacagt ggaagagaaa gagtatattc caatgcatcc 420
ctgctgatcc agaatgtcac gcaggaggat gcaggatcct acaccttaca catcataaag 480
cgacgcgatg ggactggagg agtaactgga catttcacct tcaccttaca cctggagact 540
cccaagccct ccatctccag cagcaactta aatcccaggg aggccatgga ggctgtgatc 600
ttaacctgtg atcctgcgac tccagccgca agctaccagt ggtggatgaa tggtcagagc 660
ctccctatga ctcacaggtt gcagctgtcc aaaaccaaca ggaccctctt tatatttggt 720
gtcacaaagt atattgcagg accctatgaa tgtgaaatac ggaacccagt gagtgccagc 780
cgcagtgacc cagtcaccct gaatctcctc catggtccag acctccccag catttaccct 840
tcattcacct attaccgttc aggagaaaac ctctacttgt cctgcttcgc cgagtctaac 900
ccacgggcac aatattcttg gacaattaat gggaagtttc agctatcagg acaaaagctc 960
tctatccccc aaataactac aaagcatagt gggctctatg cttgctctgt tcgtaactca 1020
gccactggca aggaaagctc caaatccatc acagtcaaag tctctgactg gatattaccc 1080
tgaattctac tagttcctcc aattccattt tctcccatgg aatcacgaag agcaagaccc 1140
actctgttcc agaagcccta taagctggag gtggacaact cgatgtaaat ttcatgggaa 1200
aacccttgta cctgacatgt gagccactca gaactcacca aaatgttcga caccataaca 1260
acagctactc aaactgtaaa ccaggataac aagttgatga cttcacactg tggacagttt 1320
ttccaaagat gtcagaacaa gactccccat catgataagg ctcccacccc tcttaaccgt 1380
ccttgctcat gcctgcctct ttcacttggc aggataatgc agtcattaga atttcacatg 1440
tagtagcttc tgagggtaac aacagagtgt cagatatgtc atctcaacct caaactttta 1500
cgtaacatct caggggaaat gtggctctct ccatcttgca tacagggctc ccaatagaaa 1560
tgaacacaga gatattgcct gtgtgtttgc agagaagatg gtttctataa agagtaggaa 1620
agctgaaatt atagtagagt ctcctttaaa tgcacattgt gtggatggct ctcaccattt 1680
cctaagagat acagtgtaaa acgtgacagt aatactgatt ctagcagaat aaaacatgta 1740
ccacatttgc taaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1780
<210>29
<211>326
<212>PRT
<213>智人
<400>29
Met Gly Pro Leu Ser Ala Pro Pro Cys Thr Gln Arg Ile Thr Trp Lys
1 5 10 15
Gly Val Leu Leu Thr Ala Ser Leu Leu Asn Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Gln Val Thr Ile Glu Ala Gln Pro Pro Lys Val Ser Glu Gly
35 40 45
Lys Asp Val Leu Leu Leu Val His Asn Leu Pro Gln Asn Leu Ala Gly
50 55 60
Tyr Ile Trp Tyr Lys Gly Gln Met Thr Tyr Leu Tyr His Tyr Ile Thr
65 70 75 80
Ser Tyr Val Val Asp Gly Gln Arg Ile Ile Tyr Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Arg Val Tyr Ser Asn Ala Ser Leu Leu Ile Gln Asn Val
100 105 110
Thr Gln Glu Asp Ala Gly Ser Tyr Thr Leu His Ile Ile Lys Arg Arg
115 120 125
Asp Gly Thr Gly Gly Val Thr Gly His Phe Thr Phe Thr Leu His Leu
130 135 140
Glu Thr Pro Lys Pro Ser Ile Ser Ser Ser Asn Leu Asn Pro Arg Glu
145 150 155 160
Ala Met Glu Ala Val Ile Leu Thr Cys Asp Pro Ala Thr Pro Ala Ala
165 170 175
Ser Tyr Gln Trp Trp Met Asn Gly Gln Ser Leu Pro Met Thr His Arg
180 185 190
Leu Gln Leu Ser Lys Thr Asn Arg Thr Leu Phe Ile Phe Gly Val Thr
195 200 205
Lys Tyr Ile Ala Gly Pro Tyr Glu Cys Glu Ile Arg Asn Pro Val Ser
210 215 220
Ala Ser Arg Ser Asp Pro Val Thr Leu Asn Leu Leu His Gly Pro Asp
225 230 235 240
Leu Pro Ser Ile Tyr Pro Ser Phe Thr Tyr Tyr Arg Ser Gly Glu Asn
245 250 255
Leu Tyr Leu Ser Cys Phe Ala Glu Ser Asn Pro Arg Ala Gln Tyr Ser
260 265 270
Trp Thr Ile Asn Gly Lys Phe Gln Leu Ser Gly Gln Lys Leu Ser Ile
275 280 285
Pro Gln Ile Thr Thr Lys His Ser Gly Leu Tyr Ala Cys Ser Val Arg
290 295 300
Asn Ser Ala Thr Gly Lys Glu Ser Ser Lys Ser Ile Thr Val Lys Val
305 310 315 320
Ser Asp Trp Ile Leu Pro
325
<210>30
<211>1989
<212>DNA
<213>智人
<400>30
attcgggcct aggctcatct ccacagagga gaacacgcag ggagcagaga ccatggggcc 60
cctctcagcc cctccctgca cacagcatat aacctggaaa gggctcctgc tcacagcatc 120
acttttaaac ttctggaacc cgcccaccac agcccaagtc acgattgaag cccagccacc 180
aaaagtttct gaggggaagg atgttcttct acttgtccac aatttgcccc agaatcttac 240
tggctacatc tggtacaaag gacaaatcag ggacctctac cattatgtta catcatatgt 300
agtagacggt caaataatta aatatgggcc tgcatacagt ggacgagaaa cagtatattc 360
caatgcatcc ctgctgatcc agaatgtcac ccaggaagac acaggatcct acactttaca 420
catcataaag cgaggtgatg ggactggagg agtaactgga cgtttcacct tcaccttata 480
cctggagact cccaaaccct ccatctccag cagcaatttc aaccccaggg aggccacgga 540
ggctgtgatc ttaacctgtg atcctgagac tccagatgca agctacctgt ggtggatgaa 600
tggtcagagc ctccctatga ctcacagctt gcagctgtct gaaaccaaca ggaccctcta 660
cctatttggt gtcacaaact atactgcagg accctatgaa tgtgaaatac ggaacccagt 720
gagtgccagc cgcagtgacc cagtcaccct gaatctcctc ccgaagctgc ccaagcccta 780
catcaccatc aataacttaa accccaggga gaataaggat gtctcaacct tcacctgtga 840
acctaagagt gagaactaca cctacatttg gtggctaaat ggtcagagcc tcccggtcag 900
tcccagggta aagcgacgca ttgaaaacag gatcctcatt ctacccagtg tcacgagaaa 960
tgaaacagga ccctatcaat gtgaaatacg ggaccgatat ggtggcatcc gcagtgaccc 1020
agtcaccctg aatgtcctct atggtccaga cctccccaga atttaccctt cgttcaccta 1080
ttaccattca ggacaaaacc tctacttgtc ctgctttgcg gactctaacc caccggcaca 1140
gtattcttgg acaattaatg ggaagtttca gctatcagga caaaagcttt ctatccccca 1200
gattactaca aagcatagcg ggctctatgc ttgctctgtt cgtaactcag ccactggcaa 1260
ggaaagctcc aaatccgtga cagtcagagt ctctgactgg acattaccct gaattctact 1320
agttcctcca attccatctt ctcccatgga acctcaaaga gcaagaccca ctctgttcca 1380
gaagccctat aagtcagagt tggacaactc aatgtaaatt tcatgggaaa atccttgtac 1440
ctgatgtctg agccactcag aactcaccaa aatgttcaac accataacaa cagctgctca 1500
aactgtaaac aaggaaaaca agttgatgac ttcacactgt ggacagtttt tcccaagatg 1560
tcagaataag actccccatc atgatgaggc tctcacccct cttagctgtc cttgcttgtg 1620
cctgcctctt tcacttggca ggataatgca gtcattagaa tttcacatgt agtataggag 1680
cttctgaggg taacaacaga gtgtcagata tgtcatctca acctcaaact tttacataac 1740
atctcaggag gaaatgtggc tctctccatc ttgcatacag ggctcccaat agaaatgaac 1800
acagagatat tgcctgtgtg tttgcagaga agatggtttc tataaagagt aggaaagctg 1860
aaattatagt agagtcccct ttaaatgcac attgtgtgga tggctctcac catttcctaa 1920
gagatacatt gtaaaacgtg acagtaagac tgattctagc agaataaaac atgtactaca 1980
tttgctaaa 1989
<210>31
<211>419
<212>PRT
<213>智人
<400>31
Met Gly Pro Leu Ser Ala Pro Pro Cys Thr Gln His Ile Thr Trp Lys
1 5 10 15
Gly Leu Leu Leu Thr Ala Ser Leu Leu Asn Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Gln Val Thr Ile Glu Ala Gln Pro Pro Lys Val Ser Glu Gly
35 40 45
Lys Asp Val Leu Leu Leu Val His Asn Leu Pro Gln Asn Leu Thr Gly
50 55 60
Tyr Ile Trp Tyr Lys Gly Gln Ile Arg Asp Leu Tyr His Tyr Val Thr
65 70 75 80
Ser Tyr Val Val Asp Gly Gln Ile Ile Lys Tyr Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Thr Val Tyr Ser Asn Ala Ser Leu Leu Ile Gln Asn Val
100 105 110
Thr Gln Glu Asp Thr Gly Ser Tyr Thr Leu His Ile Ile Lys Arg Gly
115 120 125
Asp Gly Thr Gly Gly Val Thr Gly Arg Phe Thr Phe Thr Leu Tyr Leu
130 135 140
Glu Thr Pro Lys Pro Ser Ile Ser Ser Ser Asn Phe Asn Pro Arg Glu
145 150 155 160
Ala Thr Glu Ala Val Ile Leu Thr Cys Asp Pro Glu Thr Pro Asp Ala
165 170 175
Ser Tyr Leu Trp Trp Met Asn Gly Gln Ser Leu Pro Met Thr His Ser
180 185 190
Leu Gln Leu Ser Glu Thr Asn Arg Thr Leu Tyr Leu Phe Gly Val Thr
195 200 205
Asn Tyr Thr Ala Gly Pro Tyr Glu Cys Glu Ile Arg Asn Pro Val Ser
210 215 220
Ala Ser Arg Ser Asp Pro Val Thr Leu Asn Leu Leu Pro Lys Leu Pro
225 230 235 240
Lys Pro Tyr Ile Thr Ile Asn Asn Leu Asn Pro Arg Glu Asn Lys Asp
245 250 255
Val Ser Thr Phe Thr Cys Glu Pro Lys Ser Glu Asn Tyr Thr Tyr Ile
260 265 270
Trp Trp Leu Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Val Lys Arg
275 280 285
Arg Ile Glu Asn Arg Ile Leu Ile Leu Pro Ser Val Thr Arg Asn Glu
290 295 300
Thr Gly Pro Tyr Gln Cys Glu Ile Arg Asp Arg Tyr Gly Gly Ile Arg
305 310 315 320
Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Leu Pro Arg
325 330 335
Ile Tyr Pro Ser Phe Thr Tyr Tyr His Ser Gly Gln Asn Leu Tyr Leu
340 345 350
Ser Cys Phe Ala Asp Ser Asn Pro Pro Ala Gln Tyr Ser Trp Thr Ile
355 360 365
Asn Gly Lys Phe Gln Leu Ser Gly Gln Lys Leu Ser Ile Pro Gln Ile
370 375 380
Thr Thr Lys His Ser Gly Leu Tyr Ala Cys Ser Val Arg Asn Ser Ala
385 390 395 400
Thr Gly Lys Glu Ser Ser Lys Ser Val Thr Val Arg Val Ser Asp Trp
405 410 415
Thr Leu Pro
<210>32
<211>21
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>32
taccctcaga agctcctata c 21
<210>33
<211>20
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>33
cgtgagcgct tcgagatgttcc g 21
<210>34
<211>20
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>34
cctaaccagc tgcccaactg tag 23
<210>35
<211>2881
<212>DNA
<213>智人
<400>35
acagaagtgc tagaagccag tgctcgtgaa ctaaggagaa aaagaacaga caagggaaca 60
gcctggacat ggcatcagag atccacatga caggcccaat gtgcctcatt gagaacacta 120
atgggcgact gatggcgaat ccagaagctc tgaagatcct ttctgccatt acacagccta 180
tggtggtggt ggcaattgtg ggcctctacc gcacaggcaa atcctacctg atgaacaagc 240
tggctggaaa gaaaaagggc ttctctctgg gctccacggt gcagtctcac actaaaggaa 300
tctggatgtg gtgtgtgccc caccccaaga agccaggcca catcctagtt ctgctggaca 360
ccgagggtct gggagatgta gagaagggtg acaaccagaa tgactcctgg atcttcgccc 420
tggccgtcct cctgagcagc accttcgtgt acaatagcat aggaaccatc aaccagcagg 480
ctatggacca actgtactat gtgacagagc tgacacatag aatccgatca aaatcctcac 540
ctgatgagaa tgagaatgag gttgaggatt cagctgactt tgtgagcttc ttcccagact 600
ttgtgtggac actgagagat ttctccctgg acttggaagc agatggacaa cccctcacac 660
cagatgagta cctgacatac tccctgaagc tgaagaaagg taccagtcaa aaagatgaaa 720
cttttaacct gcccagactc tgtatccgga aattcttccc aaagaaaaaa tgctttgtct 780
ttgatcggcc cgttcaccgc aggaagcttg cccagctcga gaaactacaa gatgaagagc 840
tggaccccga atttgtgcaa caagtagcag acttctgttc ctacatcttt agtaattcca 900
aaactaaaac tctttcagga ggcatccagg tcaacgggcc tcgtctagag agcctggtgc 960
tgacctacgt caatgccatc agcagtgggg atctgccgtg catggagaac gcagtcctgg 1020
ccttggccca gatagagaac tcagctgcag tgcaaaaggc tattgcccac tatgaacagc 1080
agatgggcca gaaggtgcag ctgcccacag aaagcctcca ggagctgctg gacctgcaca 1140
gggacagtga gagagaggcc attgaagtct tcatcaggag ttccttcaaa gatgtggacc 1200
atctatttca aaaggagtta gcggcccagc tagaaaaaaa gcgggatgac ttttgtaaac 1260
agaatcagga agcatcatca gatcgttgct caggtttact tcaggtcatt ttcagtcctc 1320
tagaagaaga agtgaaggcg ggaatttatt cgaaaccagg gggctatcgt ctctttgttc 1380
agaagctaca agacctgaag aaaaagtact atgaggaacc gaggaagggg atacaggctg 1440
aagagattct gcagacatac ttgaaatcca aggagtctat gactgatgca attctccaga 1500
cagaccagac tctcacagaa aaagaaaagg agattgaagt ggaacgtgtg aaagctgagt 1560
ctgcacaggc ttcagcaaaa atgttgcagg aaatgcaaag aaagaatgag cagatgatgg 1620
aacagaagga gaggagttat caggaacact tgaaacaact gactgagaag atggagaacg 1680
acagggtcca gttgctgaaa gagcaagaga ggaccctcgc tcttaaactt caggaacagg 1740
agcaactact aaaagaggga tttcaaaaag aaagcagaat aatgaaaaat gagatacagg 1800
atctccagac gaaaatgaga cgacgaaagg catgtaccat aagctaaaga ccagagcctt 1860
cctgtcaccc ctaaccaagg cataattgaa acaattttag aatttggaac aagcgtcact 1920
acatttgata ataattagat cttgcatcat aacaccaaaa gtttataaag gcatgtggta 1980
caatgatcaa aatcatgttt tttcttaaaa aaaaaaaaaa gactgtaaat tgtgcaacaa 2040
agatgcattt acctctgtat caactcagga aatctcataa gctggtacca ctcaggagaa 2100
gtttattctt ccagatgacc agcagtagac aaatggatac tgagcagagt cttaggtaaa 2160
agtcttggga aatatttggg cattggtctg gccaagtcta caatgtccca atatcaagga 2220
caaccaccct agcttcttag tgaagacaat gtacagttat ccattagatc aagactacac 2280
ggtctatgag caataatgtg atttctggac attgcccatg tataatcctc actgatgatt 2340
tcaagctaaa gcaaaccacc ttatacagag atctagaatc tctttatgtt ctccagagga 2400
aggtggaaga aaccatgggc aggagtagga attgagtgat aaacaattgg gctaatgaag 2460
aaaacttctc ttattgttca gttcatccag attataactt caatgggaca ctttagacca 2520
ttagacaatt gacactggat taaacaaatt cacataatgc caaatacaca atgtatttat 2580
agcaacgtat aatttgcaaa gatggacttt aaaagatgct gtgtaactaa actgaaataa 2640
ttcaattact tattatttag aatgttaaag cttatgatag tcttttctaa ttcttaacac 2700
tcatacttga aatctttccg agtttcccca gaagagaata tgggattttt tttgacattt 2760
ttgacccatt taataatgct cttgtgttta cctagtatat gtagactttg tcttatgtgt 2820
caaaagtcct aggaaagtgg ttgatgtttc ttatagcaat taaaaattat ttttgaactg 2880
a 2881
<210>36
<211>592
<212>PRT
<213>智人
<400>36
Met Ala Ser Glu Ile His Met Thr Gly Pro Met Cys Leu Ile Glu Asn
1 5 10 15
Thr Asn Gly Arg Leu Met Ala Asn Pro Glu Ala Leu Lys Ile Leu Ser
20 25 30
Ala Ile Thr Gln Pro Met Val Val Val Ala Ile Val Gly Leu Tyr Arg
35 40 45
Thr Gly Lys Ser Tyr Leu Met Asn Lys Leu Ala Gly Lys Lys Lys Gly
50 55 60
Phe Ser Leu Gly Ser Thr Val Gln Ser His Thr Lys Gly Ile Trp Met
65 70 75 80
Trp Cys Val Pro His Pro Lys Lys Pro Gly His Ile Leu Val Leu Leu
85 90 95
Asp Thr Glu Gly Leu Gly Asp Val Glu Lys Gly Asp Asn Gln Asn Asp
100 105 110
Ser Trp Ile Phe Ala Leu Ala Val Leu Leu Ser Ser Thr Phe Val Tyr
115 120 125
Asn Ser Ile Gly Thr Ile Asn Gln Gln Ala Met Asp Gln Leu Tyr Tyr
130 135 140
Val Thr Glu Leu Thr His Arg Ile Arg Ser Lys Ser Ser Pro Asp Glu
145 150 155 160
Asn Glu Asn Glu Val Glu Asp Ser Ala Asp Phe Val Ser Phe Phe Pro
165 170 175
Asp Phe Val Trp Thr Leu Arg Asp Phe Ser Leu Asp Leu Glu Ala Asp
180 185 190
Gly Gln Pro Leu Thr Pro Asp Glu Tyr Leu Thr Tyr Ser Leu Lys Leu
195 200 205
Lys Lys Gly Thr Ser Gln Lys Asp Glu Thr Phe Asn Leu Pro Arg Leu
210 215 220
Cys Ile Arg Lys Phe Phe Pro Lys Lys Lys Cys Phe Val Phe Asp Arg
225 230 235 240
Pro Val His Arg Arg Lys Leu Ala Gln Leu Glu Lys Leu Gln Asp Glu
245 250 255
Glu Leu Asp Pro Glu Phe Val Gln Gln Val Ala Asp Phe Cys Ser Tyr
260 265 270
Ile Phe Ser Asn Ser Lys Thr Lys Thr Leu Ser Gly Gly Ile Gln Val
275 280 285
Asn Gly Pro Arg Leu Glu Ser Leu Val Leu Thr Tyr Val Asn Ala Ile
290 295 300
Ser Ser Gly Asp Leu Pro Cys Met Glu Asn Ala Val Leu Ala Leu Ala
305 310 315 320
Gln Ile Glu Asn Ser Ala Ala Val Gln Lys Ala Ile Ala His Tyr Glu
325 330 335
Gln Gln Met Gly Gln Lys Val Gln Leu Pro Thr Glu Ser Leu Gln Glu
340 345 350
Leu Leu Asp Leu His Arg Asp Ser Glu Arg Glu Ala Ile Glu Val Phe
355 360 365
Ile Arg Ser Ser Phe Lys Asp Val Asp His Leu Phe Gln Lys Glu Leu
370 375 380
Ala Ala Gln Leu Glu Lys Lys Arg Asp Asp Phe Cys Lys Gln Asn Gln
385 390 395 400
Glu Ala Ser Ser Asp Arg Cys Ser Gly Leu Leu Gln Val Ile Phe Ser
405 410 415
Pro Leu Glu Glu Glu Val Lys Ala Gly Ile Tyr Ser Lys Pro Gly Gly
420 425 430
Tyr Arg Leu Phe Val Gln Lys Leu Gln Asp Leu Lys Lys Lys Tyr Tyr
435 440 445
Glu Glu Pro Arg Lys Gly Ile Gln Ala Glu Glu Ile Leu Gln Thr Tyr
450 455 460
Leu Lys Ser Lys Glu Ser Met Thr Asp Ala Ile Leu Gln Thr Asp Gln
465 470 475 480
Thr Leu Thr Glu Lys Glu Lys Glu Ile Glu Val Glu Arg Val Lys Ala
485 490 495
Glu Ser Ala Gln Ala Ser Ala Lys Met Leu Gln Glu Met Gln Arg Lys
500 505 510
Asn Glu Gln Met Met Glu Gln Lys Glu Arg Ser Tyr Gln Glu His Leu
515 520 525
Lys Gln Leu Thr Glu Lys Met Glu Asn Asp Arg Val Gln Leu Leu Lys
530 535 540
Glu Gln Glu Arg Thr Leu Ala Leu Lys Leu Gln Glu Gln Glu Gln Leu
545 550 555 560
Leu Lys Glu Gly Phe Gln Lys Glu Ser Arg Ile Met Lys Asn Glu Ile
565 570 575
Gln Asp Leu Gln Thr Lys Met Arg Arg Arg Lys Ala Cys Thr Ile Ser
580 585 590
<210>37
<211>18
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400> 37
aggagattga agtggaac 18
<210>38
<211>16
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>38
ttgctcctgt tcctga 16
<210>39
<211>2380
<212>DNA
<213>智人
<400>39
ctccaggctg tggaaccttt gttctttcac tctttgcaat aaatcttgct gctgctcact 60
ctttgggtcc acactgcctt tatgagctgt aacactcact gggaatgtct gcagcttcac 120
tcctgaagcc agcgagacca cgaacccacc aggaggaaca aacaactcca gacgcgcagc 180
cttaagagct gtaacactca ccgcgaaggt ctgcagcttc actcctgagc cagccagacc 240
acgaacccac cagaaggaag aaactccaaa cacatccgaa catcagaagg agcaaactcc 300
tgacacgcca cctttaagaa ccgtgacact caacgctagg gtccgcggct tcattcttga 360
agtcagtgag accaagaacc caccaattcc ggacacgcta attgttgtag atcatcactt 420
caaggtgccc atatctttct agtggaaaaa ttattctggc ctccgctgca tacaaatcag 480
gcaaccagaa ttctacatat ataaggcaaa gtaacatcct agacatggct ttagagatcc 540
acatgtcaga ccccatgtgc ctcatcgaga actttaatga gcagctgaag gttaatcagg 600
aagctttgga gatcctgtct gccattacgc aacctgtagt tgtggtagcg attgtgggcc 660
tctatcgcac tggcaaatcc tacctgatga acaagctggc tgggaagaac aagggcttct 720
ctgttgcatc tacggtgcag tctcacacca agggaatttg gatatggtgt gtgcctcatc 780
ccaactggcc aaatcacaca ttagttctgc ttgacaccga gggcctggga gatgtagaga 840
aggctgacaa caagaatgat atccagatct ttgcactggc actcttactg agcagcacct 900
ttgtgtacaa tactgtgaac aaaattgatc agggtgctat cgacctactg cacaatgtga 960
cagaactgac agatctgctc aaggcaagaa actcacccga ccttgacagg gttgaagatc 1020
ctgctgactc tgcgagcttc ttcccagact tagtgtggac tctgagagat ttctgcttag 1080
gcctggaaat agatgggcaa cttgtcacac cagatgaata cctggagaat tccctaaggc 1140
caaagcaagg tagtgatcaa agagttcaaa atttcaattt gccccgtctg tgtatacaga 1200
agttctttcc aaaaaagaaa tgctttatct ttgacttacc tgctcaccaa aaaaagcttg 1260
cccaacttga aacactgcct gatgatgagc tagagcctga atttgtgcaa caagtgacag 1320
aattctgttc ctacatcttt agccattcta tgaccaagac tcttccaggt ggcatcatgg 1380
tcaatggatc tcgtctaaag aacctggtgc tgacctatgt caatgccatc agcagtgggg 1440
atctgccttg catagagaat gcagtcctgg ccttggctca gagagagaac tcagctgcag 1500
tgcaaaaggc cattgcccac tatgaccagc aaatgggcca gaaagtgcag ctgcccatgg 1560
aaaccctcca ggagctgctg gacctgcaca ggaccagtga gagggaggcc attgaagtct 1620
tcatgaaaaa ctctttcaag gatgtagacc aaagtttcca gaaagaattg gagactctac 1680
tagatgcaaa acagaatgac atttgtaaac ggaacctgga agcatcctcg gattattgct 1740
cggctttact taaggatatt tttggtcctc tagaagaagc agtgaagcag ggaatttatt 1800
ctaagccagg aggccataat ctcttcattc agaaaacaga agaactgaag gcaaagtact 1860
atcgggagcc tcggaaagga atacaggctg aagaagttct gcagaaatat ttaaagtcca 1920
aggagtctgt gagtcatgca atattacaga ctgaccaggc tctcacagag acggaaaaaa 1980
agaagaaaga ggcacaagtg aaagcagaag ctgaaaaggc tgaagcgcaa aggttggcgg 2040
cgattcaaag gcagaacgag caaatgatgc aggagaggga gagactccat caggaacaag 2100
tgagacaaat ggagatagcc aaacaaaatt ggctggcaga gcaacagaaa atgcaggaac 2160
aacagatgca ggaacaggct gcacagctca gcacaacatt ccaagctcaa aatagaagcc 2220
ttctcagtga gctccagcac gcccagagga ctgttaataa cgatgatcca tgtgttttac 2280
tctaaagtgc taaatatggg agtttccttt ttttactctt tgtcactgat gacacaacag 2340
aaaagaaact gtagaccttg ggacaatcaa catttaaata 2380
<210>40
<211>586
<212>PRT
<213>智人
<400>40
Met Ala Leu Glu Ile His Met Ser Asp Pro Met Cys Leu Ile Glu Asn
1 5 10 15
Phe Asn Glu Gln Leu Lys Val Asn Gln Glu Ala Leu Glu Ile Leu Ser
20 25 30
Ala Ile Thr Gln Pro Val Val Val Val Ala Ile Val Gly Leu Tyr Arg
35 40 45
Thr Gly Lys Ser Tyr Leu Met Asn Lys Leu Ala Gly Lys Asn Lys Gly
50 55 60
Phe Ser Val Ala Ser Thr Val Gln Ser His Thr Lys Gly Ile Trp Ile
65 70 75 80
Trp Cys Val Pro His Pro Asn Trp Pro Asn His Thr Leu Val Leu Leu
85 90 95
Asp Thr Glu Gly Leu Gly Asp Val Glu Lys Ala Asp Asn Lys Asn Asp
100 105 110
Ile Gln Ile Phe Ala Leu Ala Leu Leu Leu Ser Ser Thr Phe Val Tyr
115 120 125
Asn Thr Val Asn Lys Ile Asp Gln Gly Ala Ile Asp Leu Leu His Asn
130 135 140
Val Thr Glu Leu Thr Asp Leu Leu Lys Ala Arg Asn Ser Pro Asp Leu
145 150 155 160
Asp Arg Val Glu Asp Pro Ala Asp Ser Ala Ser Phe Phe Pro Asp Leu
165 170 175
Val Trp Thr Leu Arg Asp Phe Cys Leu Gly Leu Glu Ile Asp Gly Gln
180 185 190
Leu Val Thr Pro Asp Glu Tyr Leu Glu Asn Ser Leu Arg Pro Lys Gln
195 200 205
Gly Ser Asp Gln Arg Val Gln Asn Phe Asn Leu Pro Arg Leu Cys Ile
210 215 220
Gln Lys Phe Phe Pro Lys Lys Lys Cys Phe Ile Phe Asp Leu Pro Ala
225 230 235 240
His Gln Lys Lys Leu Ala Gln Leu Glu Thr Leu Pro Asp Asp Glu Leu
245 250 255
Glu Pro Glu Phe Val Gln Gln Val Thr Glu Phe Cys Ser Tyr Ile Phe
260 265 270
Ser His Ser Met Thr Lys Thr Leu Pro Gly Gly Ile Met Val Asn Gly
275 280 285
Ser Arg Leu Lys Asn Leu Val Leu Thr Tyr Val Asn Ala Ile Ser Ser
290 295 300
Gly Asp Leu Pro Cys Ile Glu Asn Ala Val Leu Ala Leu Ala Gln Arg
305 310 315 320
Glu Asn Ser Ala Ala Val Gln Lys Ala Ile Ala His Tyr Asp Gln Gln
325 330 335
Met Gly Gln Lys Val Gln Leu Pro Met Glu Thr Leu Gln Glu Leu Leu
340 345 350
Asp Leu His Arg Thr Ser Glu Arg Glu Ala Ile Glu Val Phe Met Lys
355 360 365
Asn Ser Phe Lys Asp Val Asp Gln Ser Phe Gln Lys Glu Leu Glu Thr
370 375 380
Leu Leu Asp Ala Lys Gln Asn Asp Ile Cys Lys Arg Asn Leu Glu Ala
385 390 395 400
Ser Ser Asp Tyr Cys Ser Ala Leu Leu Lys Asp Ile Phe Gly Pro Leu
405 410 415
Glu Glu Ala Val Lys Gln Gly Ile Tyr Ser Lys Pro Gly Gly His Asn
420 425 430
Leu Phe Ile Gln Lys Thr Glu Glu Leu Lys Ala Lys Tyr Tyr Arg Glu
435 440 445
Pro Arg Lys Gly Ile Gln Ala Glu Glu Val Leu Gln Lys Tyr Leu Lys
450 455 460
Ser Lys Glu Ser Val Ser His Ala Ile Leu Gln Thr Asp Gln Ala Leu
465 470 475 480
Thr Glu Thr Glu Lys Lys Lys Lys Glu Ala Gln Val Lys Ala Glu Ala
485 490 495
Glu Lys Ala Glu Ala Gln Arg Leu Ala Ala Ile Gln Arg Gln Asn Glu
500 505 510
Gln Met Met Gln Glu Arg Glu Arg Leu His Gln Glu Gln Val Arg Gln
515 520 525
Met Glu Ile Ala Lys Gln Asn Trp Leu Ala Glu Gln Gln Lys Met Gln
530 535 540
Glu Gln Gln Met Gln Glu Gln Ala Ala Gln Leu Ser Thr Thr Phe Gln
545 550 555 560
Ala Gln Asn Arg Ser Leu Leu Ser Glu Leu Gln His Ala Gln Arg Thr
565 570 575
Val Asn Asn Asp Asp Pro Cys Val Leu Leu
580 585
<210>41
<211>1051
<212>DNA
<213>智人
<400>41
ggaccgccgc ctggttaaag gcgcttattt cccaggcagc cgctgcagtc gccacacctt 60
tgcccctgct gcgatgaccc tgtcgccact tctgctgttc ctgccaccgc tgctgctgct 120
gctggacgtc cccacggcgg cggtgcaggc gtcccctctg caagcgttag acttctttgg 180
gaatgggcca ccagttaact acaagacagg caatctatac ctgcgggggc ccctgaagaa 240
gtccaatgca ccgcttgtca atgtgaccct ctactatgaa gcactgtgcg gtggctgccg 300
agccttcctg atccgggagc tcttcccaac atggctgttg gtcatggaga tcctcaatgt 360
cacgctggtg ccctacggaa acgcacagga acaaaatgtc agtggcaggt gggagttcaa 420
gtgccagcat ggagaagagg agtgcaaatt caacaaggtg gaggcctgcg tgttggatga 480
acttgacatg gagctagcct tcctgaccat tgtctgcatg gaagagtttg aggacatgga 540
gagaagtctg ccactatgcc tgcagctcta cgccccaggg ctgtcgccag acactatcat 600
ggagtgtgca atgggggacc gcggcatgca gctcatgcac gccaacgccc agcggacaga 660
tgctctccag ccaccacacg agtatgtgcc ctgggtcacc gtcaatggga aacccttgga 720
agatcagacc cagctcctta cccttgtctg ccagttgtac cagggcaaga agccggatgt 780
ctgcccttcc tcaaccagct ccctcaggag tgtttgcttc aagtgatggc cggtgagctg 840
cggagagctc atggaaggcg agtgggaacc cggctgcctg cctttttttc tgatccagac 900
cctcggcacc tgctacttac caactggaaa attttatgca tcccatgaag cccagataca 960
caaaattcca ccccatgatc aagaatcctg ctccactaag aatggtgcta aagtaaaact 1020
agtttaataa gcaaaaaaaa aaaaaaaaaa a 1051
<210>42
<211>250
<212>PRT
<213>智人
<400>42
Met Thr Leu Ser Pro Leu Leu Leu Phe Leu Pro Pro Leu Leu Leu Leu
1 5 10 15
Leu Asp Val Pro Thr Ala Ala Val Gln Ala Ser Pro Leu Gln Ala Leu
20 25 30
Asp Phe Phe Gly Asn Gly Pro Pro Val Asn Tyr Lys Thr Gly Asn Leu
35 40 45
Tyr Leu Arg Gly Pro Leu Lys Lys Ser Asn Ala Pro Leu Val Asn Val
50 55 60
Thr Leu Tyr Tyr Glu Ala Leu Cys Gly Gly Cys Arg Ala Phe Leu Ile
65 70 75 80
Arg Glu Leu Phe Pro Thr Trp Leu Leu Val Met Glu Ile Leu Asn Val
85 90 95
Thr Leu Val Pro Tyr Gly Asn Ala Gln Glu Gln Asn Val Ser Gly Arg
100 105 110
Trp Glu Phe Lys Cys Gln His Gly Glu Glu Glu Cys Lys Phe Asn Lys
115 120 125
Val Glu Ala Cys Val Leu Asp Glu Leu Asp Met Glu Leu Ala Phe Leu
130 135 140
Thr Ile Val Cys Met Glu Glu Phe Glu Asp Met Glu Arg Ser Leu Pro
145 150 155 160
Leu Cys Leu Gln Leu Tyr Ala Pro Gly Leu Ser Pro Asp Thr Ile Met
165 170 175
Glu Cys Ala Met Gly Asp Arg Gly Met Gln Leu Met His Ala Asn Ala
180 185 190
Gln Arg Thr Asp Ala Leu Gln Pro Pro His Glu Tyr Val Pro Trp Val
195 200 205
Thr Val Asn Gly Lys Pro Leu Glu Asp Gln Thr Gln Leu Leu Thr Leu
210 215 220
Val Cys Gln Leu Tyr Gln Gly Lys Lys Pro Asp Val Cys Pro Ser Ser
225 230 235 240
Thr Ser Ser Leu Arg Ser Val Cys Phe Lys
245 250
<210>43
<211>17
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>43
ctacaagaca ggcaatc 17
<210>44
<211>17
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>44
ttcatccaac acgcagg 17
<210>45
<211>875
<212>DNA
<213>智人
<400>45
ggttgctaag gagtgggtgc ctcagaatca ggctgcaatg ggcattgtct gtgcacaatg 60
ttcctttatt ctgctgctgt ccataataag ggctcgtcca cctcccttcc tcttctgccc 120
attgagcagt caaagaactg aaagtcctta taagcctgtg cacctgggcc tgggccctac 180
agataaggta gctgctattg ctatggcccg catcattgac ctggtgccct gggacgatgg 240
ctccacacat gtgtatgcct ccccggccat cctgcttccc atggagcggc agcgcaacca 300
gctggcgggc gtgaagcagc agctctacca cccagccctg cccaccctgc gccacatgga 360
cagggacacc gtcaaggcct gccttcctga tgagcactgc cagtccacca cctactgccg 420
caaagatgaa tttgacaacg cccattttac actccttggg gtccccaaca aacccctgca 480
gtgtttggac atcaccgcca caggccagaa gcttcgcaac aggtaccacg agggaaagct 540
ggcgcccatc gcgccaggca tcaaccgagt ggactggccc tgcttcacgc gcgccatcga 600
ggactggtcc cacttcgtgt cctcggccgg ggagttcaag ctgccttgcc tgaggaagcg 660
agcggagggt ctcagcggct acgcggtgcg gtacttgaag cccgacgtga cccagacctg 720
gcggtactgc ctcaaccaga accccagcct ggaccgctac ggacagaagc ccctgccttt 780
cgactccctg aacactttcc gaagcttcgg ctccagctac agtcgtgtca actacctgac 840
cccctggcat taatctctgg aaaggaggct gactc 875
<210>46
<211>271
<212>PRT
<213>智人
<400>46
Met Gly Ile Val Cys Ala Gln Cys Ser Phe Ile Leu Leu Leu Ser Ile
1 5 10 15
Ile Arg Ala Arg Pro Pro Pro Phe Leu Phe Cys Pro Leu Ser Ser Gln
20 25 30
Arg Thr Glu Ser Pro Tyr Lys Pro Val His Leu Gly Leu Gly Pro Thr
35 40 45
Asp Lys Val Ala Ala Ile Ala Met Ala Arg Ile Ile Asp Leu Val Pro
50 55 60
Trp Asp Asp Gly Ser Thr His Val Tyr Ala Ser Pro Ala Ile Leu Leu
65 70 75 80
Pro Met Glu Arg Gln Arg Asn Gln Leu Ala Gly Val Lys Gln Gln Leu
85 90 95
Tyr His Pro Ala Leu Pro Thr Leu Arg His Met Asp Arg Asp Thr Val
100 105 110
Lys Ala Cys Leu Pro Asp Glu His Cys Gln Ser Thr Thr Tyr Cys Arg
115 120 125
Lys Asp Glu Phe Asp Asn Ala His Phe Thr Leu Leu Gly Val Pro Asn
130 135 140
Lys Pro Leu Gln Cys Leu Asp Ile Thr Ala Thr Gly Gln Lys Leu Arg
145 150 155 160
Asn Arg Tyr His Glu Gly Lys Leu Ala Pro Ile Ala Pro Gly Ile Asn
165 170 175
Arg Val Asp Trp Pro Cys Phe Thr Arg Ala Ile Glu Asp Trp Ser His
180 185 190
Phe Val Ser Ser Ala Gly Glu Phe Lys Leu Pro Cys Leu Arg Lys Arg
195 200 205
Ala Glu Gly Leu Ser Gly Tyr Ala Val Arg Tyr Leu Lys Pro Asp Val
210 215 220
Thr Gln Thr Trp Arg Tyr Cys Leu Asn Gln Asn Pro Ser Leu Asp Arg
225 230 235 240
Tyr Gly Gln Lys Pro Leu Pro Phe Asp Ser Leu Asn Thr Phe Arg Ser
245 250 255
Phe Gly Ser Ser Tyr Ser Arg Val Asn Tyr Leu Thr Pro Trp His
260 265 270
<210>47
<211>22
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>47
tccaccacct actgccgcaa ag 22
<210>48
<211>20
<212>DNA
<213>人工序列
<220>
<223>人工序列的描述:寡核苷酸
<400>48
accctccgct cgcttcctca 20
<210>49
<211>956
<212>DNA
<213>智人
<400>49
ggttgctaag gagtgggtgc ctcagaatca ggctgcaatg ggcattgtct gtgcacaatg 60
ttcctttatt ctgctgctgt ccataataag ggctcgtcca cctcccttcc tcttctgccc 120
attgagcagt caaagaactg aaagtcctta taagcctgtg cacctgggcc tgggccctac 180
agataaggta gctgctattg ctatggcccg catcattgac ctggtgccct gggacgatgg 240
ctccacacat gtgtatgcct ccccggccat cctgcttccc atggagcggc agcgcaacca 300
gctggcgggc gtgaagcagc agctctacca cccagccctg cccaccctgc gccacatgga 360
cagggacacc gtcaaggcct gccttcctga tgagcactgc cagtccacca cctactgccg 420
caaagatgaa tttgacaacg cccattttac actccttggg gtccccaaca aacccctgca 480
gtgtttggac atcaccgcca caggccagaa gcttcgcaac aggtaccacg agggaaagct 540
ggcgcccatc gcgccaggca tcaaccgagt ggactggccc tgcttcacgc gcgccatcga 600
ggactggtcc cacttcgtgt cctcggccgg ggagttcaag ctgccttgcc tgaggaagcg 660
agcggagggt ctcagcggct acgcggtgcg gtacttgaag cccgacgtga cccagacctg 720
gcggcaggaa gccctgtgtg gggcgtgggc agggcgtccg tgctcccccg actcaccgcg 780
cccctatccc tgctgcccgc ctcagtactg cctcaaccag aaccccagcc tggaccgcta 840
cggacagaag cccctgcctt tcgactccct gaacactttc cgaagcttcg gctccagcta 900
cagtcgtgtc aactacctga ccccctggca ttaatctctg gaaaggaggc tgactc 956
<210>50
<211>298
<212>PRT
<213>智人
<400>50
Met Gly Ile Val Cys Ala Gln Cys Ser Phe Ile Leu Leu Leu Ser Ile
1 5 10 15
Ile Arg Ala Arg Pro Pro Pro Phe Leu Phe Cys Pro Leu Ser Ser Gln
20 25 30
Arg Thr Glu Ser Pro Tyr Lys Pro Val His Leu Gly Leu Gly Pro Thr
35 40 45
Asp Lys Val Ala Ala Ile Ala Met Ala Arg Ile Ile Asp Leu Val Pro
50 55 60
Trp Asp Asp Gly Ser Thr His Val Tyr Ala Ser Pro Ala Ile Leu Leu
65 70 75 80
Pro Met Glu Arg Gln Arg Asn Gln Leu Ala Gly Val Lys Gln Gln Leu
85 90 95
Tyr His Pro Ala Leu Pro Thr Leu Arg His Met Asp Arg Asp Thr Val
100 105 110
Lys Ala Cys Leu Pro Asp Glu His Cys Gln Ser Thr Thr Tyr Cys Arg
115 120 125
Lys Asp Glu Phe Asp Asn Ala His Phe Thr Leu Leu Gly Val Pro Asn
130 135 140
Lys Pro Leu Gln Cys Leu Asp Ile Thr Ala Thr Gly Gln Lys Leu Arg
145 150 155 160
Asn Arg Tyr His Glu Gly Lys Leu Ala Pro Ile Ala Pro Gly Ile Asn
165 170 175
Arg Val Asp Trp Pro Cys Phe Thr Arg Ala Ile Glu Asp Trp Ser His
180 185 190
Phe Val Ser Ser Ala Gly Glu Phe Lys Leu Pro Cys Leu Arg Lys Arg
195 200 205
Ala Glu Gly Leu Ser Gly Tyr Ala Val Arg Tyr Leu Lys Pro Asp Val
210 215 220
Thr Gln Thr Trp Arg Gln Glu Ala Leu Cys Gly Ala Trp Ala Gly Arg
225 230 235 240
Pro Cys Ser Pro Asp Ser Pro Arg Pro Tyr Pro Cys Cys Pro Pro Gln
245 250 255
Tyr Cys Leu Asn Gln Asn Pro Ser Leu Asp Arg Tyr Gly Gln Lys Pro
260 265 270
Leu Pro Phe Asp Ser Leu Asn Thr Phe Arg Ser Phe Gly Ser Ser Tyr
275 280 285
Ser Arg Val Asn Tyr Leu Thr Pro Trp His
290 295
<210>51
<211>16
<212>PRT
<213>智人
<400>51
Cys Ser Lys Asp Ser Arg Gly Ile Ala Asp Pro Asn Gln Ser Ala Lys
1 5 10 15
<210>52
<211>13
<212>PRT
<213>智人
<400>52
Cys Glu Glu Asp Ser Lys Ile Lys Gly Ile His Asp Glu
1 5 10
<210>53
<211>12
<212>PRT
<213>智人
<400>53
Cys Lys Leu Arg Asn Arg Ile Trp Gly Met Val Asn
1 5 10
<210>54
<211>64
<212>PRT
<213>智人
<400>54
Arg Tyr Arg Lys Cys Ile Lys Leu Lys Gln Val Gln Ser Pro Pro Thr
1 5 10 15
Glu Thr Leu Gly Val Glu Asn Lys Gly Tyr Phe Gly Asp Glu Gln Gln
20 25 30
Ile Arg Thr Glu Pro Ile Leu Pro Glu Ile His Phe Leu Asn Lys Pro
35 40 45
Ala Ser Lys Asp Ser Arg Gly Ile Ala Asp Pro Asn Gln Ser Ala Lys
50 55 60
<210>55
<211>667
<212>PRT
<213>智人
<400>55
Met Leu Pro Gly Cys Ile Phe Leu Met Ile Leu Leu Ile Pro Gln Val
1 5 10 15
Lys Glu Lys Phe Ile Leu Gly Val Glu Gly Gln Gln Leu Val Arg Pro
20 25 30
Lys Lys Leu Pro Leu Ile Gln Lys Arg Asp Thr Gly His Thr His Asp
35 40 45
Asp Asp Ile Leu Lys Thr Tyr Glu Glu Glu Leu Leu Tyr Glu Ile Lys
50 55 60
Leu Asn Arg Lys Thr Leu Val Leu His Leu Leu Arg Ser Arg Glu Phe
65 70 75 80
Leu Gly Ser Asn Tyr Ser Glu Thr Phe Tyr Ser Met Lys Gly Glu Ala
85 90 95
Phe Thr Arg His Pro Gln Ile Met Asp His Cys Phe Tyr Gln Gly Ser
100 105 110
Ile Val His Glu Tyr Asp Ser Ala Ala Ser Ile Ser Thr Cys Asn Gly
115 120 125
Leu Arg Gly Phe Phe Arg Ile Asn Asp Gln Arg Tyr Leu Ile Glu Pro
130 135 140
Val Lys Tyr Ser Asp Glu Gly Glu His Leu Val Phe Lys Tyr Asn Leu
145 150 155 160
Arg Val Pro Tyr Gly Ala Asn Tyr Ser Cys Thr Glu Leu Asn Phe Thr
165 170 175
Arg Lys Thr Val Pro Gly Asp Asn Glu Ser Glu Glu Asp Ser Lys Ile
180 185 190
Lys Gly Ile His Asp Glu Lys Tyr Val Glu Leu Phe Ile Val Ala Asp
195 200 205
Asp Thr Val Tyr Arg Arg Asn Gly His Pro His Asn Lys Leu Arg Asn
210 215 220
Arg Ile Trp Gly Met Val Asn Phe Val Asn Met Ile Tyr Lys Thr Leu
225 230 235 240
Asn Ile His Val Thr Leu Val Gly Ile Glu Ile Trp Thr His Glu Asp
245 250 255
Lys Ile Glu Leu Tyr Ser Asn Ile Glu Thr Thr Leu Leu Arg Phe Ser
260 265 270
Phe Trp Gln Glu Lys Ile Leu Lys Thr Arg Lys Asp Phe Asp His Val
275 280 285
Val Leu Leu Ser Gly Lys Trp Leu Tyr Ser His Val Gln Gly Ile Ser
290 295 300
Tyr Pro Gly Gly Met Cys Leu Pro Tyr Tyr Ser Thr Ser Ile Ile Lys
305 310 315 320
Asp Leu Leu Pro Asp Thr Asn Ile Ile Ala Asn Arg Met Ala His Gln
325 330 335
Leu Gly His Asn Leu Gly Met Gln His Asp Glu Phe Pro Cys Thr Cys
340 345 350
Pro Ser Gly Lys Cys Val Met Asp Ser Asp Gly Ser Ile Pro Ala Leu
355 360 365
Lys Phe Ser Lys Cys Ser Gln Asn Gln Tyr His Gln Tyr Leu Lys Asp
370 375 380
Tyr Lys Pro Thr Cys Met Leu Asn Ile Pro Phe Pro Tyr Asn Phe His
385 390 395 400
Asp Phe Gln Phe Cys Gly Asn Lys Lys Leu Asp Glu Gly Glu Glu Cys
405 410 415
Asp Cys Gly Pro Ala Gln Glu Cys Thr Asn Pro Cys Cys Asp Ala His
420 425 430
Thr Cys Val Leu Lys Pro Gly Phe Thr Cys Ala Glu Gly Glu Cys Cys
435 440 445
Glu Ser Cys Gln Ile Lys Lys Ala Gly Ser Ile Cys Arg Pro Ala Lys
450 455 460
Asp Glu Cys Asp Phe Pro Glu Met Cys Thr Gly His Ser Pro Ala Cys
465 470 475 480
Pro Lys Asp Gln Phe Arg Val Asn Gly Phe Pro Cys Lys Asn Ser Glu
485 490 495
Gly Tyr Cys Phe Met Gly Lys Cys Pro Thr Arg Glu Asp Gln Cys Ser
500 505 510
Glu Leu Phe Asp Asp Asp Ala Ile Glu Ser His Asp Ile Cys Tyr Lys
515 520 525
Met Asn Thr Lys Gly Asn Lys Phe Gly Tyr Cys Lys Asn Lys Glu Asn
530 535 540
Arg Phe Leu Pro Cys Glu Glu Lys Asp Val Arg Cys Gly Lys Ile Tyr
545 550 555 560
Cys Thr Gly Gly Glu Leu Ser Ser Leu Leu Gly Glu Asp Lys Thr Tyr
565 570 575
His Leu Lys Asp Pro Gln Lys Asn Ala Thr Val Lys Cys Lys Thr Ile
580 585 590
Phe Leu Tyr His Asp Ser Thr Asp Ile Gly Leu Val Ala Ser Gly Thr
595 600 605
Lys Cys Gly Glu Gly Met Val Cys Asn Asn Gly Glu Cys Leu Asn Met
610 615 620
Glu Lys Val Tyr Ile Ser Thr Asn Cys Pro Ser Gln Cys Asn Glu Asn
625 630 635 640
Pro Val Asp Gly His Gly Leu Gln Cys His Cys Glu Glu Gly Gln Ala
645 650 655
Pro Val Ala Cys Glu Glu Thr Leu His Val Thr
660 665
<210>56
<211>39
<212>PRT
<213>智人
<400>56
Ile Ser Thr Asn Cys Pro Ser Gln Cys Asn Glu Asn Pro Val Asp Gly
1 5 10 15
His Gly Leu Gln Cys His Cys Glu Glu Gly Gln Ala Pro Val Ala Cys
20 25 30
Glu Glu Thr Leu His Val Thr
35
<210>57
<211>62
<212>PRT
<213>智人
<400>57
Ile Ser Thr Asn Cys Pro Ser Gln Cys Asn Glu Asn Pro Val Asp Gly
1 5 10 15
His Gly Leu Gln Cys His Cys Glu Glu Gly Gln Ala Pro Val Ala Cys
20 25 30
Glu Glu Thr Leu His Val Thr Asn Ile Thr Ile Leu Val Val Val Leu
35 40 45
Val Leu Val Ile Val Gly Ile Gly Val Leu Ile Leu Leu Val
50 55 60
<210>58
<211>12
<212>PRT
<213>智人
<400>58
Ala Pro Gln Lys Ser Pro Trp Leu Thr Lys Pro Cys
1 5 10
<210>59
<211>14
<212>PRT
<213>智人
<400>59
Cys Pro Leu Gln Pro Ser His Phe Leu Asp Ile Ser Glu Asp
1 5 10
<210>60
<211>12
<212>PRT
<213>智人
<400>60
Cys Ile Tyr Ser Thr Glu Ile His Tyr Ser Ser Lys
1 5 10
<210>61
<211>500
<212>DNA
<213>智人
<400>61
gcagcctcac tgtcctgtct tgaacatcct ccaccaaagt gtgaacacag gtggcatggg 60
cttcgtaacg aataagagcg ccttcaaagc aggagattcc ctgtacctgc gaagggcctt 120
cgtgaacaac cttggagagg aaaggagaac caggattcag atccaaagca tccagaaggc 180
tttagacatc cagatcaggg agattgatag agaaaaagca gccctgaaga gatttttggt 240
aaagcttcac aagacaactg gctattttcc tcaaaagcca ttgtggtgac tgatgctgtg 300
ccaccatagg ggacgagttc atctgaaaca tccaatacag acagaacaca cctgggtctc 360
cttctgtatc tctctgtgac ccaagaaagc agtagaagtg gctactggga caagccaaaa 420
aagaaaaaaa aggactagat aattgaggac acaaatggac tgcctctaaa ataataaaca 480
aaacctccta caaaagagag 500
<210>62
<211>2256
<212>DNA
<213>智人
<400>62
atgcggctga tgggccccct gagcctgaga gtagggatga ccctggaagc ggcgctagtg 60
ctgatccgca ggtccccgcg ctcccgccag agccgcgacc cggcttgtgc cacccagctt 120
cggggcctgc agggagcgct gcttcttctg agcctgagtc tgggaccctc tttgcagtgt 180
ggctgtgggg gcgctggtcc catcacggcc tttttcataa agcacatggt gccaactgtt 240
agtggatcta ccatcctgga ggatgatagc cctcttctaa cagctccact aggcagtgcc 300
ccagtaggga ctctgtgtag gcgccctcac cccacatttc ccttccacac tgccctagca 360
gaggttctcc atgagggcgc tgcccctgca gcaaacttct gcctggacat ccaggaaccg 420
ccccagtggt cagctgccgc gctgttgcta ggcaacagcg tgcgagctca gatcagcgtg 480
gggtggagga gaagtggagt ttggaagttc aggggcacag gggcacaggc ccacgactgc 540
agcgggatgg accagtactg catcctgggc cgcatcgggg agggcgccca cggcatcgtc 600
ttcaaggcca agcacgtgga gccgagggtg ggctggcagt gtctgccttc tatcctgcag 660
actggcgaga tagttgccct caagaaggtg gccctaaggc ggttggagga cggcttccct 720
aaccaggccc tgcgggagat taaggctctg caggagatgg aggacaatca gtatgtggta 780
caactgaagg ctgtgttccc acacggtgga ggctttgtgc tggcctttga gttcatgctg 840
tcggatctgg ccgaggtggt gcgccatgcc cagaggccac tagcccaggc acaggtcaag 900
agctacctgc agatgctgct caagggtgtc gccttctgcc atgccaacaa cattgtacat 960
cgggacctga aacctgccaa cctgctcatc agcgcctcag gccagctcaa gatagcggac 1020
tttggcctgg ctcgagtctt ttccccagac ggcagccgcc tctacacaca ccaggtggcc 1080
accaggtggt accgagcccc cgagctcctg tatggtgccc gccagtatga ccagggcgtc 1140
gatctgtggt ctgtgggctg catcatgggg gagctgttga atgggtcccc ccttttcccg 1200
ggcaagaacg atattgaaca gctttgctat gtgcttcgca tcttgggcac cccaaaccct 1260
caagtctggc cggagctcac tgagctgccg gactacaaca agatctcctt taaggagcag 1320
gtgcccatgc ccctggagga ggtgctgcct gacgtctctc cccaggcatt ggatctgctg 1380
ggtcaattcc ttctctaccc tcctcaccag cgcatcgcag cttccaagct gtgggagccc 1440
caggagagag gcaaggccga ctttggggtc aagcaaagct tcctggtgga gggcaggttt 1500
aagcatgaga tgtttgagga ggtgttcgct gaagagagaa atgctcccct gcctgcccat 1560
ccatctgagc tgccgattcc tcagcgtcta gggggacctg cccccaaggc ccatccaggg 1620
cccccccaca tccatgactt ccacgtggac cggcctcttg aggagtcgct gttgaaccca 1680
gagctgattc ggcccttcat cctggagggc ccttgcgagg gttggtctcg aggcagaggt 1740
catgttccca gccaagagta tgagaacatc cagtcgagca gaggagattc atggcctgtg 1800
ctcgtttcac tgacctgcat gttctggaag gagccaggac agcagcctac cccgcaagct 1860
gcccagaagc cccggatggc ccctcagcca gctgaaacca ccgtccactg ggaagatggc 1920
tacttggagg cctctggagg ggagggggtt gttcacgaag gcccttcgca ggtacaggga 1980
atctcctgct ttgaaggcgc tcttattcgt tacgaagccc atgccacctg tgttcacact 2040
ttggtggagg atgttcaaga caggacacat ctactggccc ctcctaaagc ctttgcctgg 2100
ctgctcctgc aagagcatgc acaaagcaca gcctccactg ccttgcctgg gaacactttg 2160
gctcccccag cacagccaat gctcaactca acaggacaaa gctgcaggcc cagtcccaaa 2220
ccgccagggt gtgagaatat agctcaggag tattga 2256
<210>63
<211>751
<212>PRT
<213>智人
<400>63
Met Arg Leu Met Gly Pro Leu Ser Leu Arg Val Gly Met Thr Leu Glu
1 5 10 15
Ala Ala Leu Val Leu Ile Arg Arg Ser Pro Arg Ser Arg Gln Ser Arg
20 25 30
Asp Pro Ala Cys Ala Thr Gln Leu Arg Gly Leu Gln Gly Ala Leu Leu
35 40 45
Leu Leu Ser Leu Ser Leu Gly Pro Ser Leu Gln Cys Gly Cys Gly Gly
50 55 60
Ala Gly Pro Ile Thr Ala Phe Phe Ile Lys His Met Val Pro Thr Val
65 70 75 80
Ser Gly Ser Thr Ile Leu Glu Asp Asp Ser Pro Leu Leu Thr Ala Pro
85 90 95
Leu Gly Ser Ala Pro Val Gly Thr Leu Cys Arg Arg Pro His Pro Thr
100 105 110
Phe Pro Phe His Thr Ala Leu Ala Glu Val Leu His Glu Gly Ala Ala
115 120 125
Pro Ala Ala Asn Phe Cys Leu Asp Ile Gln Glu Pro Pro Gln Trp Ser
130 135 140
Ala Ala Ala Leu Leu Leu Gly Asn Ser Val Arg Ala Gln Ile Ser Val
145 150 155 160
Gly Trp Arg Arg Ser Gly Val Trp Lys Phe Arg Gly Thr Gly Ala Gln
165 170 175
Ala His Asp Cys Ser Gly Met Asp Gln Tyr Cys Ile Leu Gly Arg Ile
180 185 190
Gly Glu Gly Ala His Gly Ile Val Phe Lys Ala Lys His Val Glu Pro
195 200 205
Arg Val Gly Trp Gln Cys Leu Pro Ser Ile Leu Gln Thr Gly Glu Ile
210 215 220
Val Ala Leu Lys Lys Val Ala Leu Arg Arg Leu Glu Asp Gly Phe Pro
225 230 235 240
Asn Gln Ala Leu Arg Glu Ile Lys Ala Leu Gln Glu Met Glu Asp Asn
245 250 255
Gln Tyr Val Val Gln Leu Lys Ala Val Phe Pro His Gly Gly Gly Phe
260 265 270
Val Leu Ala Phe Glu Phe Met Leu Ser Asp Leu Ala Glu Val Val Arg
275 280 285
His Ala Gln Arg Pro Leu Ala Gln Ala Gln Val Lys Ser Tyr Leu Gln
290 295 300
Met Leu Leu Lys Gly Val Ala Phe Cys His Ala Asn Asn Ile Val His
305 310 315 320
Arg Asp Leu Lys Pro Ala Asn Leu Leu Ile Ser Ala Ser Gly Gln Leu
325 330 335
Lys Ile Ala Asp Phe Gly Leu Ala Arg Val Phe Ser Pro Asp Gly Ser
340 345 350
Arg Leu Tyr Thr His Gln Val Ala Thr Arg Trp Tyr Arg Ala Pro Glu
355 360 365
Leu Leu Tyr Gly Ala Arg Gln Tyr Asp Gln Gly Val Asp Leu Trp Ser
370 375 380
Val Gly Cys Ile Met Gly Glu Leu Leu Asn Gly Ser Pro Leu Phe Pro
385 390 395 400
Gly Lys Asn Asp Ile Glu Gln Leu Cys Tyr Val Leu Arg Ile Leu Gly
405 410 415
Thr Pro Asn Pro Gln Val Trp Pro Glu Leu Thr Glu Leu Pro Asp Tyr
420 425 430
Asn Lys Ile Ser Phe Lys Glu Gln Val Pro Met Pro Leu Glu Glu Val
435 440 445
Leu Pro Asp Val Ser Pro Gln Ala Leu Asp Leu Leu Gly Gln Phe Leu
450 455 460
Leu Tyr Pro Pro His Gln Arg Ile Ala Ala Ser Lys Leu Trp Glu Pro
465 470 475 480
Gln Glu Arg Gly Lys Ala Asp Phe Gly Val Lys Gln Ser Phe Leu Val
485 490 495
Glu Gly Arg Phe Lys His Glu Met Phe Glu Glu Val Phe Ala Glu Glu
500 505 510
Arg Asn Ala Pro Leu Pro Ala His Pro Ser Glu Leu Pro Ile Pro Gln
515 520 525
Arg Leu Gly Gly Pro Ala Pro Lys Ala His Pro Gly Pro Pro His Ile
530 535 540
His Asp Phe His Val Asp Arg Pro Leu Glu Glu Ser Leu Leu Asn Pro
545 550 555 560
Glu Leu Ile Arg Pro Phe Ile Leu Glu Gly Pro Cys Glu Gly Trp Ser
565 570 575
Arg Gly Arg Gly His Val Pro Ser Gln Glu Tyr Glu Asn Ile Gln Ser
580 585 590
Ser Arg Gly Asp Ser Trp Pro Val Leu Val Ser Leu Thr Cys Met Phe
595 600 605
Trp Lys Glu Pro Gly Gln Gln Pro Thr Pro Gln Ala Ala Gln Lys Pro
610 615 620
Arg Met Ala Pro Gln Pro Ala Glu Thr Thr Val His Trp Glu Asp Gly
625 630 635 640
Tyr Leu Glu Ala Ser Gly Gly Glu Gly Val Val His Glu Gly Pro Ser
645 650 655
Gln Val Gln Gly Ile Ser Cys Phe Glu Gly Ala Leu Ile Arg Tyr Glu
660 665 670
Ala His Ala Thr Cys Val His Thr Leu Val Glu Asp Val Gln Asp Arg
675 680 685
Thr His Leu Leu Ala Pro Pro Lys Ala Phe Ala Trp Leu Leu Leu Gln
690 695 700
Glu His Ala Gln Ser Thr Ala Ser Thr Ala Leu Pro Gly Asn Thr Leu
705 710 715 720
Ala Pro Pro Ala Gln Pro Met Leu Asn Ser Thr Gly Gln Ser Cys Arg
725 730 735
Pro Ser Pro Lys Pro Pro Gly Cys Glu Asn Ile Ala Gln Glu Tyr
740 745 750
<210>64
<211>455
<212>DNA
<213>智人
<400>64
tcagaccgac agtcaggcag aagcagggcc cccggtctgt ctaggcttca ggatgcctaa 60
gaagctctcg gtgggcagcc agtgctccag aaccaggggg ttgttgtggg caggtctctg 120
gggaggcctg aggggccaca cggtgtcctg ggtgtggggt ctgcatctac atacgactca 180
taggcacctg ccattggggc gatttgtgat ggtttaggga aacagggtct gcccttggat 240
gggctggcct acagtcaggg gccttccttg tctgtcttac tttccccgct ctgccagagt 300
gaacccaagg atgccgccag cctcacccca gtgggtggca gttacgccgg catggaactc 360
agactcaccg gcacgcatga cttccaaccg tccacacatc tttgcaccca cagtatctgc 420
ttcagagaat gtattctaaa taataaaaat cataa 455
<210>65
<211>746
<212>DNA
<213>智人
<400>65
cccactttgc tggatgaagc tctgtgaact cttcctggtt cttagtactg cctaattcat 60
gaatccttct ttgctcaaat gaactcaaag ttaatttaaa gtttttattc taacatgaga 120
ctctttctcc catgagactt tgcatgaggg agaacagtcg ctaattaaca gccagttctt 180
gaaatcacgc agtcctgaaa tccagctgat gctgctcagc agagaagcag atgtttggag 240
gttaaaacaa agtcacaagt ctgacccaca ctcaaaggga gaagattatg caagagcaaa 300
agcacgagat ggaaaccatg gggccatctt atagtctgtc tgccggagaa agatgaacac 360
aaatcctcgt gcagaaaagt gtgacactaa aagaaccaac ctgatactac tatccttaga 420
aaagcctgca tacaaggttg gctgtcatct gggaatgtag gtgatcaaga gttctctcca 480
ctgacataaa ctttgtttaa ataataagga tgactcattg tgactagact atgcaaataa 540
tgggatgtgt gttaaacatc tcctttcctt ctgggagtct ggaattttgg tgtatgctaa 600
acagtgggtg cctgcaagac cagcctcaaa taaaaaccct gggcactgag tctctaaaaa 660
gactcccagt aggcaatatt tcacacgtgt tctcacaaac ttactgctgg aggaattatg 720
cacgccttgc atgactctat tggaaa 746
<210>66
<211>782
<212>DNA
<213>智人
<400>66
gcacgagaga tgttataata attttcaaaa gaaggtaaaa tcatgactca tatggatata 60
aaaatgaaca ccttgttatg gattgaactg tgtgccccta aaagatatgt tgaagcctga 120
actcccagta cctgagaatg tgaccatgtt tggaaatagt gtctttgcag gtttaatcaa 180
gttaagatga ggtcattaga tgggacctaa tttaatatgg ctgatgccct tataagaaga 240
gggaattttg gacacagaca tacaaggagg acgccatgtg aagacacagt tggaaaagca 300
gggaagagat ggccttgtgt ataaggaggc agagactgga gttatgctgc cacaagccaa 360
ggaacaactg gggctacctg agctggaaga ggcgaggaag gattctcccc tagagggttc 420
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gaaataggtg aggtgttaca accaattcaa aaaagaagtg aaaaataagc ccaaatgtat 660
atagagtaaa ggaatgttga aatgaatgtg caaatggaag caaaactaga ttctcctaca 720
atgggacaga aaagtcaatt gaacctctac tggacagaac ataatttgca tgtgtataga 780
aa 782
<210>67
<211>525
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gcaccaggtt tctggtaagg ggcaattttg tgtttgcctg ttctttggga atatcacctg 60
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ttattagaat tgagtatatc tcaggtcctc tttcattact acaacacaaa ataaatctgg 180
gggccaggaa cggtggctca cacctgtaat cccagagtgc taggattaca agcaacaagc 240
atgagctacc acgctcggcc tatgcatctc agtcttaaat tttcttctag gtggatttag 300
gggtttgtgc tcgtggccct aaaaatgaac atgagaaagg cagggagtac ctgcttagtt 360
gcaataggcc ttgtttaggc taaaaataag ctcgatacct gtattttata tactgtaaag 420
agcattaacc ataacctgcc tgcaacagcc tctgtaggta gaaacaatta tggaggtgtc 480
aagtaagaat aaagagctga taacatcaaa aaaaaaaaaa aaaaa 525
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<222>(1)..(19)
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uugcuggcua cucucaugga g 21
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<220>
<223>siRNA有义链
<220>
<221>misc_feature
<222>(1)..(19)
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<210>73
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Claims (37)
1.药物组合物,其包含选自下述的一种或多种组分:
(i)肿瘤相关抗原或其部分,
(ii)编码肿瘤相关抗原或其部分的核酸,
(iii)与肿瘤相关抗原结合的抗体,
(iv)与编码肿瘤相关抗原的核酸选择性地杂交的反义核酸,
(v)针对编码肿瘤相关抗原的核酸的siRNA,和
(vi)表达肿瘤相关抗原或其部分的宿主细胞,
其中,所述肿瘤相关抗原由由核酸编码的序列组成,所述核酸由SEQID NO:1的核酸序列组成,
其中,所述部分由选自SEQ ID NO:58、68和69的氨基酸序列组成。
2.权利要求1的药物组合物,其中(ii)的所述核酸存在于表达载体中。
3.权利要求1的药物组合物,其中所述宿主细胞分泌所述肿瘤相关抗原或其部分。
4.权利要求1的药物组合物,其中所述宿主细胞另外表达与所述肿瘤相关抗原或其部分结合的MHC分子。
5.权利要求4的药物组合物,其中所述宿主细胞以重组方式表达所述MHC分子和/或所述肿瘤相关抗原或其部分。
6.权利要求4的药物组合物,其中所述宿主细胞内源性地表达所述MHC分子。
7.权利要求1、4或6的药物组合物,其中所述宿主细胞是抗原呈递细胞。
8.权利要求1的药物组合物,其中所述抗体是单克隆、嵌合或人源化抗体,或者是抗体片段。
9.权利要求1或8的药物组合物,其中所述抗体与治疗或诊断剂偶联。
10.权利要求1-6和8中任一项的药物组合物,其可以用于治疗或预防癌症。
11.权利要求10的药物组合物,其中所述癌症是肺肿瘤、乳腺肿瘤、前列腺肿瘤、黑素瘤、结肠肿瘤、胃肿瘤、胰腺肿瘤、ENT肿瘤、肾细胞癌或子宫颈癌、结肠癌或乳房癌。
12.权利要求1-6和8中任一项的药物组合物,其中所述肿瘤相关抗原由SEQ ID NO:2的氨基酸序列组成。
13.权利要求1-6和8中任一项的药物组合物,其以疫苗的形式存在。
14.权利要求13的药物组合物,其用于治疗和/或预防用途。
15.用于检测或测定下述物质的量的试剂在制备用于诊断或监控特征在于肿瘤相关抗原的表达或异常表达的疾病的药物组合物中的用途:
(i)编码所述肿瘤相关抗原的核酸,和/或
(ii)所述肿瘤相关抗原,和/或
(iii)针对所述肿瘤相关抗原的抗体,和/或
(iv)对于在从患者中分离的生物样品中的所述肿瘤相关抗原或其部分特异的T淋巴细胞,
其中,所述肿瘤相关抗原由由核酸编码的序列组成,所述核酸由SEQID NO:1的核酸序列组成,
其中,所述部分由选自SEQ ID NO:58、68和69的氨基酸序列组成。
16.权利要求15的用途,其中所述量的检测或测定包括
(i)使所述生物样品与试剂接触,所述试剂与编码所述肿瘤相关抗原的核酸、所述肿瘤相关抗原、所述抗体或所述T淋巴细胞特异性地结合,和
(ii)检测所述试剂与所述核酸、所述肿瘤相关抗原、所述抗体或所述T淋巴细胞之间的复合物的形成,或测定所述复合物的量。
17.权利要求16的用途,其中与编码所述肿瘤相关抗原的核酸特异性地结合的所述试剂是与所述核酸特异性地杂交的寡核苷酸或多核苷酸。
18.权利要求16的用途,其中与所述肿瘤相关抗原特异性地结合的所述试剂是与所述肿瘤相关抗原特异性地结合的抗体。
19.权利要求16的用途,其中与所述抗体特异性地结合的所述试剂是与所述抗体特异性地结合的蛋白质或肽。
20.权利要求16的用途,其中与所述T淋巴细胞特异性地结合的所述试剂是呈递所述肿瘤相关抗原或其部分与MHC分子之间的复合物的细胞。
21.权利要求15-20中任一项的用途,其中所述疾病的所述监控包括测定来自患者的样品中所述疾病的消退、进程或发作,所述患者具有所述疾病或怀疑因所述疾病而生病。
22.权利要求21的用途,其包括在第一个时间点上检测或测定第一个样品中的量和在第二个时间点上检测或测定另一样品中的量,以及比较所述2个样品。
23.权利要求16-20中任一项的用途,其中所述试剂以可检测的方式进行标记。
24.权利要求15-20中任一项的用途,其中所述样品包括体液和/或身体组织。
25.权利要求1-14中任一项的药物组合物在制备用于治疗或预防特征在于肿瘤相关抗原的表达或异常表达的疾病的药物中的用途,
其中,所述肿瘤相关抗原由由核酸编码的序列组成,所述核酸由SEQID NO:1的核酸序列组成。
26.与肿瘤相关抗原结合并且与治疗或诊断剂偶联的抗体在制备用于治疗、预防、诊断或监控特征在于肿瘤相关抗原的表达或异常表达的疾病的药物组合物中的用途,
其中,所述肿瘤相关抗原由由核酸编码的序列组成,所述核酸由SEQID NO:1的核酸序列组成。
27.权利要求18或26的用途,其中所述抗体是单克隆、嵌合或人源化抗体,或者是抗体片段。
28.溶细胞性或细胞因子释放性T细胞在制备用于治疗具有特征在于肿瘤相关抗原的表达或异常表达的疾病的患者的药物组合物中的用途,其中所述溶细胞性或细胞因子释放性T细胞通过下述方式产生:
(i)提供包含免疫反应性细胞的样品,和
(ii)在有利于产生针对所述肿瘤相关抗原或其部分的溶细胞性或细胞因子释放性T细胞的条件下,使所述样品与表达所述肿瘤相关抗原或其部分的宿主细胞接触,
其中,所述肿瘤相关抗原由由核酸编码的序列组成,所述核酸由SEQID NO:1的核酸序列组成,
其中,所述部分由选自SEQ ID NO:58、68和69的氨基酸序列组成。
其中,所述药物组合物用于以适合于使表达所述肿瘤相关抗原的细胞裂解的量将所述溶细胞性或细胞因子释放性T细胞引入所述患者内。
29.权利要求28的用途,其中所述宿主细胞重组地表达与所述肿瘤相关抗原或其部分结合的MHC分子。
30.权利要求28的用途,其中所述宿主细胞内源性地表达与所述肿瘤相关抗原或其部分结合的MHC分子。
31.权利要求1-14中任一项的药物组合物在制备用于抑制患者中的癌症发展的药物中的用途。
32.权利要求15-20、25-26和28-31中任一项的用途,其中所述肿瘤相关抗原由SEQ ID NO:2的氨基酸序列组成。
33.抗体,其与蛋白质或多肽特异性地结合,所述蛋白质或多肽由由SEQ ID NO:1的核酸序列组成的核酸编码,或者由选自SEQ ID NO:2、58、68和69的氨基酸序列组成。
34.权利要求33的抗体,其中所述抗体是单克隆、嵌合或人源化抗体,或者是抗体片段。
35.权利要求33-34中任一项的抗体与治疗或诊断剂之间的缀合物。
36.权利要求35的缀合物,其中所述治疗或诊断剂是毒素。
37.用于检测肿瘤相关抗原的表达或异常表达的试剂盒,所述试剂盒包含用于检测或测定下述物质的量的试剂:
(i)编码所述肿瘤相关抗原的核酸,和/或
(ii)所述肿瘤相关抗原,和/或
(iii)与所述肿瘤相关抗原结合的抗体,
其中,所述肿瘤相关抗原由由核酸编码的序列组成,所述核酸由SEQID NO:1的核酸序列组成。
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EP20050019786 EP1762575A1 (en) | 2005-09-12 | 2005-09-12 | Identification of tumor-associated antigens for diagnosis and therapy |
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PCT/EP2006/008695 WO2007031222A2 (en) | 2005-09-12 | 2006-09-06 | Identification of tumor-associated antigens for diagnosis and therapy |
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