CN109890425B - 包含CFLIP SIRNA的用于治疗或致敏干扰素β抗性癌症疾病的组合物 - Google Patents
包含CFLIP SIRNA的用于治疗或致敏干扰素β抗性癌症疾病的组合物 Download PDFInfo
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Abstract
本发明涉及包含cFLIP siRNA的治疗或致敏干扰素β抗性癌症疾病的组合物,更具体涉及治疗干扰素β抗性癌症疾病的药物组合物,包含以下作为活性成分:(a)与cFLIP基因的mRNA互补结合的siRNA;和(b)人干扰素β突变体,其在SEQ ID NO:1所示的人天然干扰素β氨基酸序列中的C末端包含甘氨酸‑天冬酰胺‑异亮氨酸‑苏氨酸‑缬氨酸序列(GNITV),或已用苏氨酸或丝氨酸取代第27位置的精氨酸氨基酸,且涉及包含cFLIP siRNA作为活性成分的用于致敏干扰素β抗性癌症细胞的组合物。通过降低在显示对干扰素β抗性的癌症或对干扰素β变得抗性的癌症中的cFLIP蛋白质的表达水平,本发明的组合物可有效用于开发具有促进细胞凋亡的新机制并有效地致敏细胞以用于治疗的抗癌药剂或抗癌佐剂。
Description
技术领域
本发明涉及包含cFLIP siRNA的组合物,其用于治疗或致敏干扰素-β-抗性癌症疾病,更具体地,涉及用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物包含以下作为活性成分:(a)与cFLIP基因的mRNA结合的siRNA;和(b)人干扰素-β突变体,其在由SEQ IDNO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸,并且涉及包含cFLIP siRNA作为用于致敏干扰素-β-抗性癌细胞的活性成分的组合物。
背景技术
本申请要求于2016年7月29日向韩国知识产权局(KIPO)提交的韩国专利申请号10-2016-0097516的优先权,其公开内容通过引用整体并入本文。
干扰素(IFN)属于一类细胞因子,具有抗病毒活性,抑制细胞增殖和调节天然免疫反应。在干扰素中,属于1型干扰素的干扰素-β(IFNβ或IFN-β)是具有5个α-螺旋的22kDa球形蛋白,并且在去除聚糖后其大小为18kDa(Arduini等人,Protein Science,8:1867-1877,1999)。
干扰素-β的临床应用已被广泛和积极地研究。已据报道,干扰素-β通过各种免疫活性例如抗病毒活性,细胞生长抑制或抗生长活性,淋巴细胞毒性增加活性,免疫调节活性,靶细胞分化诱导或抑制活性,巨噬细胞活化活性,细胞因子产生增加活性,细胞毒性T细胞效应增加活性和自然杀伤细胞增加活性有效地治疗多发性硬化症,癌症,自身免疫性疾病,病毒感染,HIV相关疾病,丙型肝炎和类风湿性关节炎等。(Pilling等人,EuropeanJournal of Immunology,29:1041-1050,1999;Young等人,Neurology 51:682-689,1998,Cirelli等人,Clin Immunother 3:27-87,1995)。
特别地,美国食品和药物管理局于1988年批准了1型干扰素作为各种类型癌症的药物,例如慢性粒细胞白血病,黑色素瘤和肾细胞癌,但最近由于其不良副作用的发展,无反应性和耐受性等而已被减少用作抗癌药物。直到最近,干扰素-β已被证明通过许多研究具有抗癌作用,并且已被证实与干扰素-α相比显示出优异的抗癌效力。然而,干扰素-β尚未被批准作为抗癌药物。因此,为了克服现有干扰素-β的副作用,更重要的是,为了最大化干扰素-β的抗癌作用,迫切需要开发能够增加干扰素抗性癌症对化疗的敏感性的致敏剂。
发明内容
技术问题
因此,本发明人证实,抑制癌细胞中cFLIP的表达水平可以致敏癌细胞并改善干扰素-β的抗癌作用,从而完成了本发明。
本发明的一个方面是提供用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物包含以下作为活性成分:
(a)以互补方式与cFLIP基因的mRNA结合的siRNA;和
(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
本发明的另一方面是提供(a)siRNA和(b)人干扰素-β突变体在制备用于治疗干扰素-β-抗性癌症疾病的药剂中的用途,
其中,siRNA(a)以互补方式结合cFLIP基因的mRNA,并且
其中,人干扰素-β突变体(b)在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
本发明的另一方面是提供用于治疗干扰素-β-抗性癌症疾病的方法,该方法包括将有效量的组合物施用于有此需要的受试者,
其中,组合物包含以下作为活性成分:(a)以互补方式与cFLIP基因的mRNA结合的siRNA;(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
本发明的另一方面是提供用于致敏干扰素-β-抗性癌细胞的组合物,该组合物包含作为活性成分的siRNA,其以互补方式与cFLIP基因的mRNA结合。
本发明的又一方面是提供siRNA在制备用于致敏干扰素-β-抗性癌细胞的试剂中的用途,其中siRNA以互补方式与cFLIP基因的mRNA结合。
本发明的又一方面是提供用于致敏干扰素-β-抗性癌细胞的方法,该方法包括将有效量的组合物施用于有此需要的受试者,其中该组合物包含作为活性成分的siRNA,其以互补方式与cFLIP基因的mRNA结合。
技术方案
根据本发明的一个方面,提供了用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物包含以下作为活性成分:
(a)以互补方式与cFLIP基因的mRNA结合的siRNA;和
(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
此外,提供了用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物包含:
(a)以互补方式与cFLIP基因的mRNA结合的siRNA;和
(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
此外,提供了用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物基本上由以下组成:
(a)以互补方式与cFLIP基因的mRNA结合的siRNA;和
(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
根据本发明的另一方面,提供了(a)siRNA和(b)人干扰素-β突变体在制备用于治疗干扰素-β-抗性癌症疾病的药剂中的用途,
其中,siRNA(a)以互补方式结合cFLIP基因的mRNA,并且
其中,人干扰素-β突变体(b)在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
根据本发明的另一方面,提供了用于治疗干扰素-β-抗性癌症疾病的方法,该方法包括向有此需要的受试者施用有效量的组合物,
其中,该组合物包含以下作为活性成分:(a)以互补方式与cFLIP基因的mRNA结合的siRNA;(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
此外,提供了用于治疗干扰素-β-抗性癌症疾病的方法,该方法包括向有此需要的受试者施用有效量的组合物,
其中,该组合物由以下组成:(a)以互补方式与cFLIP基因的mRNA结合的siRNA;(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
此外,提供了用于治疗干扰素-β-抗性癌症疾病的方法,该方法包括向有此需要的受试者施用有效量的组合物,
其中,该组合物基本上由以下组成:(a)以互补方式与cFLIP基因的mRNA结合的siRNA;(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
根据本发明的另一方面,提供了用于致敏干扰素-β-抗性癌细胞的组合物,其中该组合物包含以互补方式与cFLIP基因的mRNA结合的siRNA作为活性成分。
此外,提供了用于致敏干扰素-β-抗性癌细胞的组合物,其中该组合物由以互补方式与cFLIP基因的mRNA结合的siRNA组成。
此外,提供了用于致敏干扰素-β-抗性癌细胞的组合物,其中该组合物基本上由以互补方式与cFLIP基因的mRNA结合的siRNA组成。
根据本发明的另一方面,提供了siRNA在制备用于致敏干扰素-β-抗性癌细胞的试剂中的用途,其中siRNA以互补方式与cFLIP基因的mRNA结合。
根据本发明的另一方面,提供了用于致敏干扰素-β-抗性癌细胞的方法,该方法包括将有效量的组合物给予有需要的受试者,其中该组合物包含作为活性成分的siRNA,其以互补方式与cFLIP基因的mRNA结合。
此外,提供了用于致敏干扰素-β-抗性癌细胞的方法,该方法包括向有此需要的受试者施用有效量的组合物,其中该组合物由以互补方式与cFLIP基因的mRNA结合的siRNA组成。
此外,提供了用于致敏干扰素-β-抗性癌细胞敏感的方法,该方法包括向有此需要的受试者施用有效量的组合物,其中该组合物基本上由以互补方式与cFLIP基因的mRNA结合的siRNA组成。
在下文中,将详细描述本发明。
本发明提供了用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物包含以下作为活性成分:
(a)以互补方式与cFLIP基因的mRNA结合的siRNA;和
(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
本发明人发现,作为比较癌细胞后与细胞凋亡和死亡受体信号传导相关的蛋白质的表达模式的结果,其中细胞凋亡响应于干扰素-β(IFNβ或IFN-β)而发生,并且用Carbiferon处理IFNβ抗性癌细胞作为IFNβ突变体,在IFNβ抗性癌细胞中通过IFNβ处理增加cFLIP的表达率。此外,本发明人证实,当在IFNβ抗性癌细胞中使用siRNA抑制cFLIP的表达时,对于细胞凋亡重要的半胱天冬酶-8等在响应于Carbiferon的IFNβ抗性癌细胞中被激活,从而大大降低了细胞活力,从而发挥了Carbiferon的癌细胞凋亡作用。因此,本发明提供了包含cFLIP siRNA作为致敏活性成分的组合物,该组合物允许IFNβ抗性癌细胞响应IFNβ诱导其细胞凋亡。此外,本发明提供了通过共同施用IFNβ或其突变体和cFLIP siRNA有效治疗IFNβ抗性癌症疾病的药物组合物。
如本文所用,“多核苷酸”或“核酸”是指单链或双链脱氧核糖核酸(DNA)或核糖核酸(RNA)。除非另有限制,否则多核苷酸或核酸包括天然核苷酸的已知类似物,其以与天然存在的核苷酸类似的方式与核酸杂交。通常,DNA由四种类型的碱基组成,包括腺嘌呤(A),鸟嘌呤(G),胞嘧啶(C)和胸腺嘧啶(T),而RNA具有尿嘧啶(U)而不是胸腺嘧啶(T)。在双链核酸中,碱基A与碱基T或U形成氢键,而碱基C与碱基G形成氢键。碱基之间的这种关系被称为“互补”。
这里,“信使RNA(mRNA)”通过在蛋白质合成期间将特定基因的核苷酸序列的遗传信息转移至核糖体而充当用于多肽合成(蛋白质翻译)的蓝图RNA。使用该基因作为模板,通过转录过程合成单链mRNA。
如本文所用,“蛋白质”可与“多肽”或“肽”互换使用,并且是指例如氨基酸残基的聚合物,如通常在自然界中的蛋白质中发现的。
如本文所用,氨基酸的单字母(三字母)代码是指根据生物化学中的标准缩写的以下氨基酸:A(Ala):丙氨酸;C(Cys);半胱氨酸;D(Asp):天冬氨酸;E(Glu):谷氨酸;F(Phe):苯丙氨酸;G(Gly):甘氨酸;H(His):组氨酸;I(Ile):异亮氨酸;K(Lys):赖氨酸;L(Leu):亮氨酸;M(Met):甲硫氨酸;N(Asn):天冬酰胺;O(Ply)吡咯酸;P(Pro):脯氨酸;Q(Gln):谷氨酰胺;R(Arg):精氨酸;S(Ser):丝氨酸;T(Thr):苏氨酸;U(Sec):硒代半胱氨酸,V(Val):缬氨酸;W(Trp):色氨酸;Y(Tyr):酪氨酸。
如本文所示,(氨基酸单字母代码)(氨基酸位置)(氨基酸单字母代码)是指在野生型蛋白(在本文中,由SEQ ID NO:1定义的野生型人干扰素-β蛋白质)中的相应氨基酸位置用后面的氨基酸取代前面的氨基酸。例如,R27T意指用苏氨酸取代精氨酸,其对应于正常类型蛋白质中的第27个氨基酸残基。
如本文所用,“表达”是指在细胞中产生蛋白质或核酸。
“细胞FLICE样抑制蛋白(cFLIP)”是一种基因,也称为CASH,FLIP,MRIT,CLARP,FLAME,Casper,FLAME1,FLAME-1,I-FLICE或CASP8AP1等,官方名称其为“CASP8和FADD样凋亡调节剂(CFLAR)”。cFLIP在结构上与半胱天冬酶-8相似,但没有蛋白水解活性,并通过典型的死亡受体和模式识别受体调节细胞凋亡。
如本文所用,cFLIP基因源自人,并且位于染色体2q33-34上。人cFLIP基因具有编码各种同种型蛋白的转录变体,而其三种代表性同种型是cFLIPL,cFLIPR和cFLIPS。如本文所用,cFLIP优选指cFLIPL或cFLIPS。cFLIPL是一种约55kDa的蛋白质,其在N-末端具有两个死亡效应结构域(DED)且在C-末端具有半胱天冬酶样结构域,而cFLIPS是约27kDa的蛋白质,其具有两个没有半胱天冬酶样结构域的DED。
更具体地,根据本发明的cFLIP基因的mRNA编码cFLIPL或cFLIPS,并且可以包括但不限于选自由SEQ ID NO:7和SEQ ID NO:8组成的组中的任一种核苷酸序列。
“siRNA(小干扰RNA,短干扰RNA或沉默RNA)”是一种短的双链RNA,人工引入细胞以诱导特定基因mRNA的降解,从而阻止蛋白质翻译并导致RNA抑制基因表达的干扰。siRNA由与靶mRNA的特定位点互补的20-25个核苷酸组成。在细胞中,siRNA的双链中与靶mRNA(反义链)互补的链通过与RNA诱导的沉默复合物(RISC)蛋白复合物结合而与靶mRNA结合,并且RISC复合物中的argonaute蛋白降解通过切割靶向mRNA,或阻止蛋白质翻译中重要的蛋白质和核糖体与mRNA结合,从而抑制特定基因的表达。
因此,作为本发明药物组合物的活性成分的cFLIP siRNA是指20bp至25bp的短RNA,其以互补方式结合cFLIP基因的mRNA上的特定核苷酸序列,从而导致cFLIP mRNA降解,从而降低cFLIP基因的表达水平。cFLIP siRNA可以特别是选自由SEQ ID NO:9至SEQ IDNO:13组成的组中的任一个,并且最优选地是SEQ ID NO:11或SEQ ID NO:12。根据本发明的cFLIP mRNA上的cFLIPsiRNA的靶位点显示于图5中。在本发明的药物组合物中,cFLIPsiRNA激活干扰素-β-抗性癌细胞中的细胞凋亡或死亡受体相关信号传导途径,因此充当能够敏感地响应抗癌药物的抗癌作用的致敏剂,最优选地,干扰素-β或其突变体。
根据本发明的siRNA可以通过向寡核苷酸应用各种修饰来获得,所述修饰用于改善寡核苷酸的体内稳定性,提供对核酸酶的抗性和减少非特异性免疫应答。寡核苷酸的修饰可以是选自以下的一种或多种的组合:通过在至少一个核苷酸的糖结构上的2'碳位置处用-CH3(甲基),-OCH3(甲氧基),-NH2,-F,-O-2-甲氧基乙基,-O-丙基,-O-2-甲硫基乙基,-O-3-氨基丙基,-O-3-二甲基氨基丙基,-O-N-甲基乙酰氨基或-O-二甲基酰胺基乙基取代OH基团的修饰;通过在核苷酸的糖结构中用硫取代氧的修饰;或通过用硫代磷酸酯键,硼烷磷酸酯键或甲基膦酸酯键取代核苷酸键的修饰。还可以使用对肽核酸(PNA),锁核酸(LNA)或解锁核酸(UNA)形式的修饰。
本发明药物组合物的另一种活性成分是具有抗癌活性的人干扰素-β突变体,其中突变体在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸序列(GNITV),或者苏氨酸(R27T)或丝氨酸(R27S)在第27个氨基酸处取代精氨酸。人干扰素-β突变体通过添加至少一个N-连接的聚糖到野生型人干扰素-β中而获得。
其中GNITV序列在野生型干扰素-β多肽(SEQ ID NO:1)的C-末端添加,使得N-连接的糖基化发生在其天冬酰胺的位置,或者
通过将氨基酸取代R27T或R27S引入野生型干扰素-β多肽(SEQ ID NO:1),相应位点的氨基酸序列即第25至28个氨基酸的序列将转变为天冬酰胺-甘氨酸-苏氨酸/丝氨酸-亮氨酸(NG(T/S)L)以在其位置诱导N-连接的糖基化。
与其野生型相比,干扰素突变体具有改善的抗病毒活性,细胞生长抑制活性,免疫调节功能,体内半衰期和稳定性,这在韩国专利号10-0781666和PCT申请号PCT/KR2016/002129中更详细地公开。
特别地,人干扰素-β突变体可包括选自由SEQ ID NO:2至SEQ ID NO:6组成的组中的任一种氨基酸序列。
本发明的干扰素-β突变体还包括含有SEQ ID NO:2至SEQ ID NO:6中任一个所定义的氨基酸序列的多肽的功能等同物。“功能等同物”是指与由上述序列号定义的氨基酸序列具有至少70%,优选至少80%,更优选至少90%的序列同源性(即同一性)的多核苷酸。例如,功能等同物包括具有70%,71%,72%,73%,74%,75%,76%,77%,78%,79%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%和100%序列同源性的多肽,并且是指与由上述序列号定义的多肽显示出基本相同的生理活性的多肽。这里,“基本上相同的生理活性”是指通过保留与包含SEQID NO:2至SEQ ID NO:6中任一个所定义的氨基酸序列的多肽相同的N-连接糖基化而具有与野生型(WT)人干扰素-β相当或更高的活性。
人干扰素-β的这种活性的各种实例可包括多种硬化-缓解,-改善或-治疗活性,抗病毒活性,细胞生长抑制活性,抗生长活性,抗增殖活性,淋巴细胞增加毒性,免疫调节活性,靶细胞分化诱导或抑制活性,细胞因子产生增加活性,细胞毒性T细胞效应增加活性,巨噬细胞效应增加活性,自然杀伤细胞增加活性,癌症预防或治疗活性,自身免疫疾病预防或治疗活性,病毒感染预防或治疗活性,HIV相关疾病预防或治疗活性,丙型肝炎预防或治疗活性以及类风湿性关节炎预防或治疗活性等。出于本发明的目的,“人干扰素-β的活性”是指抑制癌细胞增殖并诱导细胞凋亡的抗癌活性。
干扰素-β通过抑制癌细胞的增殖和通过各种机制诱导细胞凋亡而具有抗癌活性。干扰素-β通过抑制肿瘤细胞血管生成抑制肿瘤细胞的生长,或通过在肿瘤部位周围的环境中诱导先天或获得性免疫应答诱导肿瘤细胞凋亡,从而表现出抗癌作用。此外,干扰素-β直接作用于癌细胞以调节主要细胞凋亡相关信号传导,例如外在死亡受体途径和内在线粒体途径,以响应细胞外刺激(Parker B等人,Nat.Rev.Cancer.,16:131-144,2016)。
功能等同物可以由SEQ ID NO:2至SEQ ID NO:6中任一个所定义的氨基酸序列的一部分的添加、取代或缺失而产生。在上文中,取代氨基酸优选为保守取代。天然存在的氨基酸的保守取代的实例如下:脂肪族氨基酸(Gly,Ala,Pro),疏水性氨基酸(Ile,Leu,Val),芳香族氨基酸(Phe,Tyr,Trp),酸性氨基酸酸(Asp,Glu),碱性氨基酸(His,Lys,Arg,Gln,Asn)和含硫氨基酸(Cys,Met)。功能等同物还包括其中一些氨基酸在本发明的干扰素-β突变体多肽的氨基酸序列上缺失的突变体。氨基酸的缺失或取代优选位于与本发明多肽的生理活性不直接相关的区域。此外,氨基酸的缺失优选位于不直接参与由上述序列号定义的氨基酸序列的多肽的生理活性的区域。功能等同物还包括其中一些氨基酸被添加到多肽的氨基酸序列的两个末端或其氨基酸序列内的变体。此外,本发明的功能等同物还涵盖了对根据本发明的多肽的化学结构进行一些修饰同时保持其基本骨架和生理活性的多肽衍生物。例如,本发明的功能等同物还包括用于改变本发明多肽的稳定性,可储存性,挥发性或溶解性的结构修饰。
此外,根据本发明的人干扰素-β突变体可以是融合蛋白,其中结合有抗体或其抗体片段。由于干扰素-β在各种组织和细胞中表达,干扰素-β突变体(其中蛋白质或聚合物质在癌细胞中特异性表达,从而允许干扰素-β的抗增殖活性和细胞凋亡活性专注于癌细胞,即特异性识别肿瘤抗原的抗体被结合)可以预期降低副作用并且作为癌症靶向药物具有更好的治疗效果。具体地,根据本发明的人干扰素-β突变体可包含选自由SEQ ID NO:18至SEQID NO:21组成的组中的任一种氨基酸序列。
肿瘤抗原是由肿瘤细胞产生的蛋白质,其引发免疫应答,尤其是T细胞介导的免疫应答。肿瘤抗原是本领域公知的,其实例包括神经胶质瘤相关抗原,癌胚抗原(CEA),β-人绒毛膜促性腺激素,甲胎蛋白(AFP),凝集素反应性AFP,甲状腺球蛋白,RAGE-1,MN-CA IX,人端粒酶逆转录酶,RU1,RU2(AS),肠道羧基酯酶,mut hsp70-2,M-CSF,前列腺素酶,前列腺特异性抗原(PSA),PAP,NY-ESO-1,LAGE-Ια,p53,prostein,PSMA,Her2/neu,survivin和端粒酶,前列腺癌肿瘤抗原-1(PCTA-1),MAGE,ELF2M,中性粒细胞弹性蛋白酶,ephrin-B2,CD22,胰岛素生长因子(IGF)-I,IGF-II,IGF-I受体或间皮素。
本文指定的肿瘤抗原的类型也可以是肿瘤特异性抗原(TSA)或肿瘤相关抗原(TAA)。TSA是肿瘤细胞独有的,不会在身体的其它细胞中产生。TAA相关抗原不是肿瘤细胞独有的,而是在不诱导对抗原的免疫耐受状态的条件下在正常细胞中表达。肿瘤中抗原的表达可以在允许免疫系统响应抗原的条件下发生。当免疫系统不成熟且无法应答时,TAA可能是在胎儿发育期间在正常细胞中表达的抗原,或者可能是正常细胞中通常以极低水平存在但在肿瘤细胞中以显著高水平表达的抗原。
TSA或TAA的非限制性实例包括:分化抗原,例如MART-1/MelanA(MART-1),gp100(Pmel17),酪氨酸酶,TRP-1和TRP-2,以及肿瘤特异性多谱系抗原,如MAGE-1,MAGE-3,BAGE,GAGE-1,GAGE-2和p15;过表达的胚胎抗原,如CEA;过表达的癌基因和突变的肿瘤抑制基因,如p53,Ras和HER-2/neu;由染色体易位引起的独特肿瘤抗原,如BCR-ABL,E2A-PRL,H4-RET,IGH-IGK,MYL-RAR;和病毒抗原,如Epstein Barr病毒抗原EBVA和人乳头瘤病毒(HPV)抗原E6和E7。其它大的蛋白质类抗原包括:TSP-180,MAGE-4,MAGE-5,MAGE-6,RAGE,NY-ESO,p185erbB2,p180erbB-3,c-met,nm-23H1,PSA,TAG-72,CA 19-9,CA 72-4,CAM 17.1,NuMa,K-ras,β-连环蛋白,CDK4,Mum-1,p15,p16,43-9F,5T4,791Tgp72,甲胎蛋白,β-HCG,BCA225,BTAA,CA 125,CA 15-3\CA 27.29\BCAA,CA 195,CA 242,CA-50,CAM43,CD68,P1,CO-029,FGF-5,G250,Ga733,EpCAM,HTgp-175,M344,MA-50,MG7-Ag,MOV18,NB/70K,NY-CO-1,RCAS1,SDCCAG16,TA-90,Mac-2结合蛋白,胞嘧啶C-相关蛋白,TAAL6,TAG72,TLP和TPS。
特异性识别肿瘤抗原的抗体的实例可包括但不限于HuM195(例如Kossman等人,Clin.Cancer Res.,5:2748-2755,1999),CMA-676(例如Sievers等人,Blood,93:3678-3684,1999),AT13/5(例如Ellis等人,J.Immunol.155:925-937,1995),HB7,曲妥珠单抗(例如赫赛汀;Fornier等人,Oncology(Huntingt),13:647-58,1999),TAB-250(Rosenblum等人,Clin.Cancer Res.,5:865-874,1999),BACH-250,TA1(Maier等人,Cancer Res.,51:5361-5369,1991)和美国专利号5,772,997;美国专利号5,770,195中描述的mAb(mAb 4D5;ATCC CRL10463);和美国专利号5,677,171中描述的mAb,Mc5(例如Peterson等人,CancerRes.,57:1103-1108,1997;Ozzello等人,Breast Cancer Res.Treat.,25:265-276,1993),hCTMO1(例如Van YM等人,Cancer Res.,56:5179-5185,1996),CC49(例如Pavlinkova等人,Clin.Cancer Res.,5:2613-2619,1999),B72.3(例如Divgi等人,Nucl.Med.Biol.,21:9-15,1994),小鼠克隆抗HM1.24 IgG2a/κ,人源化抗HM1.24 IgG1/κ抗体(例如Ono等人,Mol.Immuno.,36:387-395,1999),利妥昔单抗,替伊莫单抗和托西莫单抗,AME-133v(应用分子进化),奥瑞单抗(Roche),奥法木单抗(Genmab),TRU-015(Trubion)和IMMU-106(Immunomedics)等。
本发明的抗体可以是人抗体,嵌合抗体和/或人源化抗体,但不限于此。嵌合抗体是指由鼠免疫球蛋白的可变区和人免疫球蛋白的恒定区组成的抗体。这种交替简单地构建为用鼠恒定区取代人抗体恒定区,从而产生能够具有足够低免疫原性的人/鼠嵌合体,以允许药物使用。
“人源化抗体”是指通过修饰具有非人互补决定区(CDR)的抗体的序列,由衍生自人抗体种系的氨基酸序列组成的抗体(全部或部分)。抗体可变区和CDR的人源化通过本领域熟知的技术进行。这种抗体是Fc依赖性效应子功能所必需的,但保留了人恒定区,其显著不太可能诱导针对抗体的免疫应答。作为实例,可变区的框架区被相应的人框架区取代,使得非人CDR基本上完整,或者甚至用衍生自人基因组的序列替换CDR(参见例如专利申请US2006/25885)。在转基因小鼠中产生完全人抗体,其免疫系统已被改变以对应于人免疫系统。人源化抗体还指包含人框架的抗体,来自非人抗体的至少一个CDR,其中存在的任何恒定区与人免疫球蛋白恒定区基本相同,即至少约85%或90%,优选至少95%相同。因此,人源化抗体的所有部分(可能除CDR之外)与至少一种天然人免疫球蛋白序列的相应部分基本相同。
如本文所用,“抗体片段”是指能够响应与其抗体对应物相同的抗原的抗体片段。此类片段可以由本领域技术人员简单地鉴定,并且可以包括例如Fab片段(例如,通过木瓜蛋白酶消化的片段),Fab'片段(例如,通过胃蛋白酶消化和部分还原的片段),F(ab')2片段(例如,通过胃蛋白酶消化的片段),Facb片段(例如,通过纤溶酶消化的片段),Fd片段(例如,通过胃蛋白酶消化,部分还原和再聚集的片段)和scFv片段(单链Fv;例如,通过分子生物学技术的片段)片段。此类片段可以通过酶促切割,合成或重组技术产生,如本领域已知和/或如本文所述。
如本文所用,术语“治疗”是指抑制疾病的发生或复发,减轻症状,减少疾病的直接或间接病理后果,降低疾病进展率,改善、优化或缓解疾病状况,或改善预后。本发明中待治疗的疾病是干扰素-β-抗性癌症疾病。
用于治疗干扰素-β-抗性癌症疾病的药物组合物不限于癌症疾病的类型,只要癌症的类型不响应干扰素的抗癌作用即可。干扰素-β-抗性癌症疾病的实例可以是选自乳腺癌,胃癌,卵巢癌,肺癌,结肠癌,肛门癌,星形细胞瘤,白血病,淋巴瘤,头颈癌,肝癌,睾丸癌,宫颈癌,肉瘤,血管瘤,食道癌,眼癌,喉癌,口腔癌,间皮瘤,骨髓瘤,口腔癌,直肠癌,咽喉癌,膀胱癌,子宫癌,前列腺癌,大肠癌,胰腺癌,肾癌,皮肤癌,基底细胞癌,黑素瘤,鳞状细胞癌,口腔鳞状细胞癌,结肠直肠癌,胶质母细胞瘤,子宫内膜癌和恶性胶质瘤中的任一种。
根据施用途径,根据本发明的药物组合物可以与药学上可接受的载体一起配制,用于抗癌作用或癌细胞致敏。载体包括各种溶剂,分散介质,水包油或油包水乳液,含水组合物,脂质体,微珠和微粒体。
根据本发明的药物组合物可以以药学有效量施用于患者,即足以致敏干扰素-β-抗性癌症并且当与人干扰素-β或其突变体组合施用时表现出抗癌作用的量。例如,一般日剂量可以在约0.01-1000mg/kg的范围内,并且优选在约1-100mg/kg的范围内。本发明的药物组合物可以在优选的剂量范围内以分剂量施用一次或数次。根据本发明的药物组合物的剂量可以由本领域技术人员根据施用途径,施用方式,年龄,性别,体重,个体差异和疾病状态适当地确定。
施用途径可以是口服或肠胃外途径。肠胃外施用方法包括但不限于静脉内,肌肉内,动脉内,髓内,皮内,心内,透皮,皮下,腹膜内,鼻内,肠内,局部,舌下或直肠施用。
当口服施用时,当本发明的药物组合物以粉末,颗粒,片剂,丸剂,糖衣片,胶囊,液体,凝胶,糖浆,悬浮液或晶片等形式口服施用时,可以通过本领域已知的方法与合适载体一起配制。合适的载体的实例可包括:糖类,包括乳糖,右旋糖,蔗糖,山梨糖醇,甘露糖醇,木糖醇,赤藓糖醇和麦芽糖醇;淀粉,包括玉米淀粉,小麦淀粉,大米淀粉和马铃薯淀粉;纤维素,包括纤维素,甲基纤维素,羧甲基纤维素钠和羟丙基甲基纤维素;和填料,如明胶和聚乙烯吡咯烷酮。在一些情况下,可以加入交联聚乙烯吡咯烷酮,琼脂,海藻酸或海藻酸钠等作为崩解剂。此外,药物组合物还可包含抗凝血剂,润滑剂,润湿剂,香料,乳化剂和防腐剂等。
至于肠胃外施用,本发明的药物组合物可以通过本领域已知的方法配制成注射剂,透皮施用制剂和鼻吸入剂以及合适的肠胃外载体。注射剂需要基本上进行灭菌,并且需要保护其免受微生物(例如细菌和真菌)的污染。用于注射的合适载体的实例可以是含有水,乙醇,多元醇(例如甘油,丙二醇,液体聚乙二醇等),其混合物和/或植物油的溶剂或分散介质,但是不限于此。更优选地,合适的载体可以是等渗溶液,例如Hank溶液,林格氏溶液,含有三乙醇胺的磷酸盐缓冲盐水(PBS)或注射用无菌水,10%乙醇,40%丙二醇和5%右旋糖。为了保护注射免受微生物污染,注射剂可以进一步含有各种抗微生物剂和抗真菌剂,例如对羟基苯甲酸酯,氯丁醇,苯酚,山梨酸和硫柳汞。在大多数情况下,注射剂可进一步含有糖或等渗剂,例如氯化钠。
透皮施用制剂的剂型包括软膏,乳膏,洗剂,凝胶,外用溶液,糊剂,搽剂和气雾剂。“透皮施用”是指通过将药物组合物局部施用到皮肤中,将药物组合物中含有的有效量的活性成分递送到皮肤中。例如,可以将本发明的药物组合物制备成注射制剂,然后通过使用30号针头轻微刺破皮肤或直接施用于皮肤来施用。这些制剂描述于文献中,这是药物化学中通常已知的处方(Remington's Pharmaceutical Science,第15版,1975,Mack PublishingCompany,Easton,Pennsylvania)。
对于吸入施用制剂,根据本发明使用的化合物可以通过使用合适的推进剂(例如二氯氟甲烷,三氯氟甲烷,二氯四氟乙烷或二氧化碳)或其它合适的气体从加压包装或喷雾器以气溶胶喷雾的形式方便地递送。对于加压气溶胶,可以通过提供递送计量的阀来确定剂量。例如,可以将明胶胶囊和用于吸入器或吹入器的药筒配制成含有化合物和合适的粉末基质材料如乳糖或淀粉的粉末混合物。
其它药学上可接受的载体参考以下文献(Remington's PharmaceuticalSciences,第19版,Mack Publishing Company,Easton,PA,1995)。
根据本发明的药物组合物可以进一步含有至少一种缓冲液(例如盐水溶液或PBS),碳水化合物(例如葡萄糖,甘露糖,蔗糖或葡聚糖),抗氧化剂,抑菌剂,螯合剂(例如EDTA或谷胱甘肽),助剂(例如氢氧化铝),悬浮剂,增稠剂和/或防腐剂。
本发明的药物组合物还可以通过本领域已知的方法配制,以便在施用于哺乳动物后提供活性成分的快速,连续或延迟释放。
此外,本发明的药物组合物可以单独施用或与已知的具有抗癌作用或致敏干扰素-β-抗性癌症的作用的化合物联合施用。
此外,本发明提供了用于致敏干扰素-β-抗性癌细胞的组合物,该组合物包含作为活性成分的siRNA,其以互补方式结合cFLIP基因的mRNA。
“致敏干扰素-β-抗性癌细胞的组合物”是指增加对癌细胞的细胞凋亡的敏感性的组合物,其不响应干扰素-β的刺激,从而允许干扰素-β或其突变体展示其抗癌治疗效果。抑制本发明人发现的cFLIP基因表达的siRNA对干扰素-β-抗性癌细胞敏感的机制如上所述。
以互补方式与cFLIP基因的mRNA结合的siRNA通过有效抑制人cFLIP基因的表达来防止cFLIP的所有各种同种型的表达。具体地,siRNA可包含选自由SEQ ID NO:9至SEQ IDNO:13组成的组中的任一种核苷酸序列。
此外,根据本发明的致敏组合物可以同时或依次与抗癌药一起施用。也就是说,根据本发明的致敏组合物可以在抗癌药物之前或之后分开施用,其间具有时间间隔。施用方法和施用途径如关于本发明的药物组合物所述。
为了本发明的目的,抗癌药物是指人干扰素-β或其突变体,优选包含选自由SEQID NO:2至SEQ ID NO:6组成的组中的任一种氨基酸序列的干扰素-β突变体。此外,人干扰素-β突变体可以是一种蛋白质,形式为其中结合癌症特异性标记物或其片段的抗体融合或结合,使得人干扰素-β突变体可以选择性地集中于体内的癌细胞组织。具体地,形式为其中抗体或其片段融合或结合的干扰素-β突变体可包含选自由SEQ ID NO:18至SEQ ID NO:21组成的组中的任一种氨基酸序列。
根据本发明的致敏组合物制备成优化用于致敏干扰素抗性癌细胞的制剂,其可以是与人干扰素-β突变体相同的制剂,或者可以根据情况制备成不同的制剂。
可以应用本发明的致敏组合物的癌症疾病的类型不受限制,只要癌症疾病是干扰素-β-抗性癌症疾病即可。具体类型的癌症疾病如关于本发明的药物组合物所述。
此外,本发明提供了(a)siRNA和(b)人干扰素-β突变体在制备用于治疗干扰素-β-抗性癌症疾病的药剂中的用途,其中siRNA(a)以互补方式与cFLIP基因的mRNA结合;并且其中人干扰素-β突变体(b)在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
此外,本发明提供了用于治疗干扰素-β-抗性癌症疾病的方法,该方法包括向有此需要的受试者施用有效量的组合物,该组合物包含以下作为活性成分:(a)siRNA,其以互补方式与cFLIP基因的mRNA结合;(b)人干扰素-β突变体,其在由SEQ ID NO:1定义的野生型人干扰素-β氨基酸序列中的C-末端包含甘氨酸-天冬酰胺-异亮氨酸-苏氨酸-缬氨酸(GNITV)序列,或者其中苏氨酸或丝氨酸在第27个氨基酸处取代精氨酸。
此外,本发明提供了siRNA在制备用于致敏干扰素-β-抗性癌细胞的试剂中的用途,其中siRNA以互补方式结合cFLIP基因的mRNA。
此外,本发明提供了用于致敏干扰素-β-抗性癌细胞的方法,该方法包括向有此需要的受试者施用有效量的组合物,其中该组合物包含作为活性成分的siRNA,其以互补方式结合cFLIP基因的mRNA。
如本文所用,“有效量”是指当将组合物施用于受试者时显示出治疗干扰素-β-抗性癌症疾病或致敏干扰素-β-抗性癌细胞效果的量。“受试者”可以是动物,优选哺乳动物,尤其是包括人的动物,并且可以是源自动物的细胞、组织和器官等。受试者可以是需要该效果的患者。
如本文所用,“药剂或组合物”可以是食品组合物,化妆品组合物和药物组合物等的形式,并且可以优选地意指本发明中的药物组合物,其如上所述。
如本文所用,术语“包含”与“含有”或“特征在于”同义使用,并且不排除组合物或方法中未提及的其它成分或步骤。术语“由......组成”是指排除未另外指定的其它要素、步骤或成分。术语“基本上由......组成”是指包括所提及的要素或步骤以及在组合物或方法的范围内基本上不影响其基本特征的任何要素或步骤。
有益效果
因此,本发明提供了用于治疗干扰素-β-抗性癌症疾病的药物组合物,该组合物包含以下作为活性成分:以互补方式与cFLIP基因的mRNA结合的siRNA,和干扰素-β突变体;并且提供了用于致敏干扰素-β-抗性癌细胞的组合物,该组合物包含cFLIP siRNA作为活性成分。本发明的组合物具有通过降低癌细胞中cFLIP的表达水平来促进癌细胞的细胞凋亡的作用,所述癌细胞显示出对干扰素-β的抗性或对干扰素-β不响应的耐受性。
附图说明
图1显示了证实Carbiferon在作为IFNβ响应性癌症细胞的OVCAR-3细胞系中的作用的测试结果。
图1A显示了根据Carbiferon的浓度和处理时间的细胞活力(柱形图;上图)和显微细胞图像(下图)。图1B显示了证实Carbiferon(100ng/ml)对死亡受体相关基因表达水平作用的qPCR结果。图1C显示了证实Carbiferon(100ng/ml)对死亡受体相关基因表达水平作用的蛋白质印迹结果。
图2显示了证实Carbiferon在作为IFNβ非响应性癌症细胞的HeLa细胞系中的作用的测试结果。
图2A显示了根据Carbiferon的浓度和处理时间的细胞活力(柱形图;上图)和显微镜细胞图像(下图)。图2B显示了证实Carbiferon(100ng/ml)对死亡受体相关基因表达水平作用的qPCR结果。图2C显示了证实Carbiferon(100ng/ml)对死亡受体相关基因表达水平作用的蛋白质印迹结果。
图3显示了证实在IFNβ响应性癌症细胞或非响应性癌症细胞中由于Carbiferon(100ng/ml)的cFLIP表达水平变化的测试结果。
图3A显示了OVCAR-3细胞系的蛋白质印迹结果。图3B显示了HeLa细胞系的蛋白质印迹结果。
图4显示了证实抑制cFLIP基因表达对Carbiferon在HeLa细胞系中的抗癌作用的效果的测试结果。
图4A显示了具有混合的四种类型的核苷酸序列的cFLIP siRNA(总共10nM)对细胞活力的作用。图4B显示了证实混合的cFLIP siRNA对半胱天冬酶-8水平作用的蛋白质印迹结果。
图5显示了用于抑制cFLIP基因表达的siRNA设计。
图5A是显示用于抑制cFLIP长形(cFLIPL)和短形(cFLIPS)表达的siRNA靶标位点的示意图。图5B显示了相应siRNA的核苷酸序列。
图6显示了证实HeLa细胞系中cFLIP siRNA表达抑制能力的测试结果。
图6A显示了显示出用各种类型的siRNA(10nM)处理48小时后观察到的cFLIP蛋白质水平的蛋白质印迹结果。图6B显示了证实用各种类型的siRNA(20nM)处理48小时后的cFLIP mRNA水平的qPCR结果。由蓝色虚线标记的siRNA代表了首次选择的siRNA。NC表示阴性对照siRNA。
图7显示了证实首次选择的siRNA在HeLa细胞系中的作用的测试结果。
图7A显示了单独用相应的siRNA(10nM)处理的细胞活力。图7B显示了用相应的siRNA(10nM)和Carbiferon(100ng/ml)共同处理的细胞活力。由蓝色虚线标记的siRNA代表了二次选择的siRNA。NC表示阴性对照siRNA。
图8显示了证实单独或与抗癌药物一起施用二次选择的siRNA(10nM)对各种癌症细胞系中的细胞活力作用的测试结果。
图8A显示了作为卵巢癌细胞的SK-OV-3细胞系的结果;图8B显示了作为胃癌细胞的SNU-216细胞系的结果;和图8C显示了作为胃癌细胞的NCI-N487细胞系的结果。NC表示阴性对照siRNA。抗体-细胞因子融合蛋白ACFP是指其中将Carbiferon融合到赫赛汀重链末端的融合蛋白。
具体实施方式
在下文中,将详细描述本发明。
然而,以下实施例仅用于说明本发明,而不旨在限制本发明的范围。
<实施例1>
根据癌症细胞的IFNβ抗性的Carbiferon的不同作用
在IFNβ响应性癌症细胞和IFNβ非响应性抗性癌细胞中比较了Carbiferon(R27T等)的抗癌作用(图1和2)。
为了研究Carbiferon的细胞毒性,将OVCAR-3细胞(1×104个细胞/孔)或HeLa细胞(5×103个细胞/孔)分配到96孔板的每个孔中,然后在37.5℃、5%CO2气氛中温育24小时。24小时后,除去细胞培养物,用浓度为10-1000ng/ml的Carbiferon处理细胞,然后温育24-72小时。此后,除去培养物,然后用PBS洗涤三次。以每孔100μl添加稀释至1∶10的WST试剂,然后将细胞在37.5℃、5%CO2气氛中放置2小时。在430nm的波长下测量吸光度。
[表1]
qPCR中所用的引物
正向 | 反向 | |
DR4 | gggtccacaagaccttcaagt(SEQ ID No:22) | tgcagctgagctaggtacga(SEQ ID No:23) |
DR5 | agacccttgtgctcgttgtc(SEQ ID NO:24) | ttgttgggtgatcagagcag(SEQ ID NO:25) |
FASL | cagtccaccccctgaaaaa(SEQ ID NO:26) | ggaccttgagttggacttgc(SEQ ID NO:27) |
FAS | atggccaattctgccataag(SEQ ID NO:28) | tgactgtgcagtccctagctt(SEQ ID NO:29) |
TNF-α | gacaagcctgtagcccatgt(SEQ ID NO:30) | tctcagctccacgccatt(SEQ ID NO:31) |
Trail | cctcagagagtagcagctcaca(SEQ ID No:32) | cagagccttttcattcttgga(SEQ ID NO:33) |
为了测量基因表达,用浓度为100ng/ml的Carbiferon处理OVCAR-3或HeLa细胞,然后温育24-72小时。此后,除去培养物,并进行三次PBS洗涤。收集细胞,然后利用Trizol提取RNA,然后在此基础上合成cDNA。此后,使用合成的cDNA作为模板进行利用Taqman探针的qPCR。qPCR中所用的引物核苷酸序列示于表1中。
为了研究由于Carbiferon的死亡受体信号分子的表达模式,用100ng/mlCarbiferon处理OVCAR-3或HeLa细胞系,然后以与上述相同的方式温育。用PBS将细胞培养物洗涤三次,用100μl含有蛋白酶抑制剂和磷酸酶抑制剂的RIPA缓冲液处理,并置于冰上30分钟以裂解细胞。将经裂解的细胞置于1.5mL管中,并在4℃以13000rpm离心。然后,仅取上清液(裂解物),并收集在新管中。通过BCA测定定量裂解物的蛋白质浓度,然后取30μg裂解物,与5x样品缓冲液混合,并在100℃煮沸10分钟以诱导足够的蛋白质变性。将制得的样品与标记物一起加载到10%SDS-PAGE凝胶上,并使其在70V流动30分钟,并在120V流动1小时。此后,小心地分离凝胶,并将其置于3M纸上,然后在其上设置聚偏二氟乙烯(PVDF)膜,并再次用3M纸覆盖。此后,将膜浸入1×转移缓冲液中,然后在100V蛋白质转移90分钟。将膜在含有5%BSA的tris缓冲盐水-吐温20(TBS-T,0.1%Tween 20)中封闭1小时30分钟,然后通过在TBS-T中以1:1000稀释来制备每种抗体。将膜浸入抗体稀释的溶液中,然后在室温下振荡温育2小时。在该程序后,用TBS-T将膜洗涤三次10分钟,并向其中添加辣根过氧化物酶(HRP)-缀合的二抗,然后反应1小时。再次洗涤膜,用经增强的化学发光(ECL,内含子)试剂处理,然后在膜上显影。在图1C、图2C和图3中,泳道1代表对照,泳道2、3和4分别代表24小时、48小时和72小时的Carbiferon 100ng/ml处理组。
由于研究了用1、10、100或1000ng/ml浓度的作为IFNβ突变体的Carbiferon处理作为IFNβ响应性癌症细胞的OVCAR-3细胞系,然后温育24-72小时后的细胞活力,因此,观察到OVCAR-3细胞的细胞活力显著降低,这取决于Carbiferon的浓度和更长的温育时间(图1A)。此外,由于通过qPCR(图1B)和蛋白质印迹(图1C)研究了参与死亡受体信号的DR4、DR5、FASL、FAS、TNF-α和TRAIL的表达水平,这些受体信号在细胞凋亡中很重要,因此,它们的表达水平显著增加。
相反,由于研究了当将作为IFNβ非响应性和抗性癌细胞的HeLa细胞系以相同方式温育时Carbiferon的作用,因此,观察到即使在最高浓度下细胞活力也没有显著改变(图2A),但是死亡受体信号相关基因甚至在HeLa细胞系中也显示出增加的表达(图2B和图2C)。
同时,由于研究了IFNβ响应性OVCAR-3细胞系和IFNβ非响应性HeLa细胞系中cFLIP(一种抑制细胞凋亡的蛋白质)的表达,因此,观察到仅用Carbiferon(100ng/ml)刺激的HeLa细胞系中cFLIP蛋白质水平的增加(图3)。这些结果表明了cFLIP蛋白质表达的抑制可用作治疗IFNβ非响应性癌症疾病的致敏剂。
<实施例2>
cFLIP表达抑制对Carbiferon活性的作用
使用cFLIP siRNA研究了抑制cFLIP蛋白质表达对癌症细胞中Carbiferon的抗癌作用的作用(图4)。
为了研究通过抑制cFLIP改善Carbiferon细胞毒性的能力,将1×104个细胞/孔的HeLa细胞分配到24孔板中,并在37.5℃、5%CO2气氛中温育24小时。24小时后,除去细胞培养物,然后将10nM cFLIP siRNA(Dharmacon,分类号LU-003772-00-0002)与Dharmafect转染试剂混合,在室温下温育15分钟后,用混合物处理细胞。处理24小时后,除去培养物,用100ng/ml的Carbiferon处理细胞,另外温育48小时。此后,除去培养物,然后用PBS洗涤三次,然后测量细胞活力(图4A)或检查蛋白质表达(图4B)。
为了测量细胞活力,将WST试剂与培养物以1:10混合,然后用混合物处理每个孔,并在37.5℃、5%CO2气氛中温育2小时。在430nm的波长下测量吸光度。
对于用于研究蛋白质表达的蛋白质印迹,用100μl含有蛋白酶抑制剂和磷酸酶抑制剂的RIPA缓冲液处理每个孔,并置于冰上30分钟以裂解细胞。将经裂解的细胞置于1.5mL管中,并在4℃以13000rpm离心,然后,仅取上清液(裂解物),并收集在新管中。通过BCA测定定量裂解物的蛋白质浓度,然后取30μg裂解物,与5x样品缓冲液混合,并在100℃煮沸10分钟以诱导足够的蛋白质变性。将制得的样品与标记物一起加载到10%SDS-PAGE凝胶上,并在70V进行电泳30分钟,且在120V进行电泳1小时。此后,小心地分离凝胶,并将其置于3M纸上,然后在其上设置聚偏二氟乙烯(PVDF)膜,并再次用3M纸覆盖。此后,将膜浸入1×转移缓冲液中,然后在100V蛋白质转移90分钟。将膜在含有5%BSA的tris缓冲盐水-吐温20(TBS-T,0.1%Tween 20)中封闭1小时30分钟,然后通过在TBS-T中以1:1000稀释来制备每种抗体。将膜浸入抗体稀释的溶液中,然后在室温下振荡反应2小时。在该程序后,用TBS-T将膜洗涤三次10分钟,并向其中添加辣根过氧化物酶(HRP)-缀合的二抗,然后在室温下反应1小时。再次洗涤膜,用经增强的化学发光(ECL,内含子)试剂处理,然后在膜上显影。在图4B中,泳道1代表对照,泳道2代表单独的Carbiferon处理组,泳道3代表单独的siRNA处理组,泳道4代表Carbiferon和cFLIP siRNA共同处理组。
IFNβ突变体Carbiferon可活化癌症细胞中的死亡受体信号系统,导致半胱天冬酶-3引起细胞凋亡。为了抑制cFLIP蛋白质的表达,将市售的四种类型cFLIP siRNA(Dharmacon,分类号LU-003772-00-0002)混合,并用该混合物处理HeLa细胞。然后,在存在或不存在Carbiferon的情况下测量细胞活力(图4A)。通过蛋白质印迹证实了cFLIP siRNA几乎完全抑制了长形cFLIP和短形cFLIP的表达(图4B,cFLIPL和cFLIPS)。因此,仅用Carbiferon(100ng/ml)或仅用cFLIP siRNA(10nM)处理的细胞活力与对照组的细胞活力无显著差异,但与对照组的细胞活力相比,用Carbiferon和cFLIP siRNA共同处理的细胞活力降低了约50%。此外,蛋白质印迹结果证实了仅在用Carbiferon和cFLIP siRNA的共处理组中存在经活化的裂解的半胱天冬酶-8,该半胱天冬酶-8在细胞凋亡中很重要。上述结果表明了由cFLIP siRNA抑制cFLIP表达可有效促进IFNβ非响应性细胞中由于Carbiferon的细胞凋亡。
<实施例3>
用于致敏IFNβ抗性癌细胞的cFLIP siRNA的选择
设计并选择用于在IFNβ非响应性癌症细胞中致敏IFNβ或Carbiferon的细胞凋亡作用的最佳siRNA。
由于长形cFLIP和短形cFLIP在细胞凋亡方面执行相同的功能,因此,最优选能够抑制两种类型cFLIP表达的siRNA,因此,确定了cFLIP的合适靶标序列的位置和序列(图5)。首先,使用siDirect 2.0版程序选择7种类型siRNA,另外还包括市售的两种类型siRNA(Dharmacon)。
为了研究设计的cFLIP siRNA的cFLIP抑制能力,分配HeLa细胞,并在37.5℃、5%CO2环境中温育24小时。24小时后,除去细胞培养物,将10nM siRNA与Dharmafect转染试剂混合,在室温下温育15分钟后,用混合物处理细胞。48小时后,除去培养物,通过与上述实施例相同的方法进行蛋白质印迹。在图6A中,泳道1代表Mock,泳道2代表阴性对照siRNA(NCsiRNA),泳道3至11代表设计的cFLIP siRNA处理组。利用Trizol从细胞中提取RNA,该细胞通过用20nM siRNA转化并以相同方式温育获得,然后基于提取的RNA合成cDNA。另外,使用合成的cDNA作为模板进行利用Taqman探针的qPCR(图6B)。
用选择的siRNA处理作为IFNβ非响应性细胞的HeLa细胞系48小时,然后,通过蛋白质印迹研究了cFLIP长形(cFLIPL)和cFLIP短形(cFLIPS)的蛋白质水平(图6A)。在用作为分析靶标的九(9)种类型siRNA处理的所有细胞中均未检测到cFLIPL和cFLIPS蛋白质。此外,观察到与对照组相比,用siRNA处理的细胞中通过qPCR测量的cFLIP mRNA水平降低了约50%或更多。首次选择了五种类型siRNA,即D-513、211、262、404和480,基于qPCR和蛋白质印迹结果证实了其具有优异的cFLIP表达抑制能力。
使用HeLa细胞系进一步研究了首次选择的cFLIP siRNA对Carbiferon的细胞凋亡作用的作用。首先,为了研究每种siRNA对细胞凋亡的作用,在没有Carbiferon的情况下,用每个siRNA单独处理细胞,并以与前述实施例相同的方式测量细胞活力(图7A)。将HeLa细胞接种在板上,24小时后用siRNA(终浓度:10nM)处理,并在另外24小时后进行WST测定。因此,观察到细胞活力降低,因此甚至单独的siRNA也显示出细胞毒性,即细胞凋亡诱导作用。
接下来,研究了用cFLIP siRNA和Carbiferon共同处理的作用(图7B)。在接种后24小时用siRNA(终浓度:10nM)处理HeLa细胞系,并在另外24小时后用Carbiferon(100ng/ml)处理,然后测量24小时后的细胞活力。观察到与仅用siRNA处理相比,用Carbiferon和siRNA共同处理在降低HeLa细胞系的细胞活力方面具有协同作用。在分析了用Carbiferon共同处理作用的siRNA中,二次选择了具有最佳作用的404 cFLIP siRNA和480 cFLIP siRNA。
<实施例4>
各种癌症细胞系中用cFLIP siRNA和Carbiferon共同处理的作用
使用各种癌症细胞系研究了最终选择的404 cFLIP siRNA和480 cFLIP siRNA对IFNβ非响应性癌症细胞的致敏作用(图8)。
为了通过选择的cFLIP siRNA和Carbiferon或ACFP的共同处理来研究细胞凋亡能力,将SK-OV-3、SNU-216和NCI-N87细胞以1×104个细胞/孔分配在24孔板中,在37.5℃、5%CO2环境中温育24小时。ACFP是其中将Carbiferon(R27T)融合到赫赛汀重链末端的融合蛋白。24小时后,除去细胞培养物,将10nM siRNA与Dharmafect转染试剂混合,在室温下温育15分钟后,用混合物处理细胞。处理24小时后,除去培养物,用100ng/ml的Carbiferon、ACFP和赫赛汀处理细胞,并另外温育48小时。此后,除去培养物,然后用PBS洗涤三次。然后,将WST试剂与培养物以1:10混合,并用混合物处理每个孔,在37.5℃、5%CO2气氛中温育2小时。在430nm的波长下测量吸光度。与通常对IFNβ有响应的细胞相比,本实施例中所用的细胞系被证实了它们对IFNβ(SNU-216)完全没有响应或对IFNβ(SK-OV-3或NCI-N87)的敏感性非常低(数据未显示)。
通过测量细胞活力研究了cFLIP siRNA在作为卵巢癌细胞的SK-OV-3细胞系(图8A),作为胃癌细胞的SNU-216细胞系(图8B)和作为胃癌细胞的NCI-N87细胞系(图8C)中的作用。在未用siRNA处理细胞的情况下,ACFP(一种其中结合有Carbiferon和Herceptin的融合蛋白)比单独的Herceptin能更有效地降低癌症细胞活力。此外,观察到当用cFLIP siRNA和ACPF或Carbiferon处理细胞时,进一步增强了ACFP和Carbiferon的细胞凋亡作用。
工业应用
如上所述,本发明的组合物可以有利地用于开发抗癌药物或佐剂的新机制,其通过降低显示对干扰素-β-抗性的癌症或对干扰素-β具有抗性的癌症中cFLIP蛋白质的表达水平而获得有效的致敏和治疗,从而有效地致敏癌症。
<110> 首尔大学校产学协力团
瑷备恩有限公司
<120> 包含CFLIP SIRNA的用于治疗或致敏干扰素β抗性癌症疾病的组合物
<130> OP19-0020/PCT/CN
<150> KR 10-2016-0097516
<151> 2016-07-29
<150> PCT/KR2017/008239
<151> 2017-07-31
<160> 33
<170> KopatentIn 2.0
<210> 1
<211> 166
<212> PRT
<213> 人工序列
<220>
<223> 人干扰素-β
<400> 1
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
115 120 125
Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
130 135 140
Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn
165
<210> 2
<211> 166
<212> PRT
<213> 人工序列
<220>
<223> 人干扰素-β突变体R27T
<400> 2
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
115 120 125
Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
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Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn
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<210> 3
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Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
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Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Ser Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
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His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
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Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
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Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn
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<210> 4
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<212> PRT
<213> 人工序列
<220>
<223> 人干扰素-β突变体GNITV
<400> 4
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu
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Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
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Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
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Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
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Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
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His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
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Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
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Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
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Thr Gly Tyr Leu Arg Asn Gly Asn Ile Thr Val
165 170
<210> 5
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<212> PRT
<213> 人工序列
<220>
<223> 人干扰素-β双突变体(GNITV+R27T)
<400> 5
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
35 40 45
Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
50 55 60
Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
65 70 75 80
Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
85 90 95
His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
100 105 110
Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
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Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
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Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
145 150 155 160
Thr Gly Tyr Leu Arg Asn Gly Asn Ile Thr Val
165 170
<210> 6
<211> 171
<212> PRT
<213> 人工序列
<220>
<223> 人干扰素-β双突变体(GNITV+R27S)
<400> 6
Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln
1 5 10 15
Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Ser Leu Glu Tyr Cys Leu
20 25 30
Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln
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Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln
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Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn
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Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn
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His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr
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Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg
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Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr
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Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu
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Thr Gly Tyr Leu Arg Asn Gly Asn Ile Thr Val
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<210> 7
<211> 1443
<212> DNA
<213> 人工序列
<220>
<223> 人cFLIP L mRNA (CASP8和FADD样细胞凋亡调节剂
(CFLAR), 转录变体2; NM_001127183.2)
<400> 7
atgtctgctg aagtcatcca tcaggttgaa gaagcacttg atacagatga gaaggagatg 60
ctgctctttt tgtgccggga tgttgctata gatgtggttc cacctaatgt cagggacctt 120
ctggatattt tacgggaaag aggtaagctg tctgtcgggg acttggctga actgctctac 180
agagtgaggc gatttgacct gctcaaacgt atcttgaaga tggacagaaa agctgtggag 240
acccacctgc tcaggaaccc tcaccttgtt tcggactata gagtgctgat ggcagagatt 300
ggtgaggatt tggataaatc tgatgtgtcc tcattaattt tcctcatgaa ggattacatg 360
ggccgaggca agataagcaa ggagaagagt ttcttggacc ttgtggttga gttggagaaa 420
ctaaatctgg ttgccccaga tcaactggat ttattagaaa aatgcctaaa gaacatccac 480
agaatagacc tgaagacaaa aatccagaag tacaagcagt ctgttcaagg agcagggaca 540
agttacagga atgttctcca agcagcaatc caaaagagtc tcaaggatcc ttcaaataac 600
ttcaggctcc ataatgggag aagtaaagaa caaagactta aggaacagct tggcgctcaa 660
caagaaccag tgaagaaatc cattcaggaa tcagaagctt ttttgcctca gagcatacct 720
gaagagagat acaagatgaa gagcaagccc ctaggaatct gcctgataat cgattgcatt 780
ggcaatgaga cagagcttct tcgagacacc ttcacttccc tgggctatga agtccagaaa 840
ttcttgcatc tcagtatgca tggtatatcc cagattcttg gccaatttgc ctgtatgccc 900
gagcaccgag actacgacag ctttgtgtgt gtcctggtga gccgaggagg ctcccagagt 960
gtgtatggtg tggatcagac tcactcaggg ctccccctgc atcacatcag gaggatgttc 1020
atgggagatt catgccctta tctagcaggg aagccaaaga tgttttttat tcagaactat 1080
gtggtgtcag agggccagct ggaggacagc agcctcttgg aggtggatgg gccagcgatg 1140
aagaatgtgg aattcaaggc tcagaagcga gggctgtgca cagttcaccg agaagctgac 1200
ttcttctgga gcctgtgtac tgcggacatg tccctgctgg agcagtctca cagctcacca 1260
tccctgtacc tgcagtgcct ctcccagaaa ctgagacaag aaagaaaacg cccactcctg 1320
gatcttcaca ttgaactcaa tggctacatg tatgattgga acagcagagt ttctgccaag 1380
gagaaatatt atgtctggct gcagcacact ctgagaaaga aacttatcct ctcctacaca 1440
taa 1443
<210> 8
<211> 666
<212> DNA
<213> 人工序列
<220>
<223> 人cFLIP S mRNA (CASP8和FADD样细胞凋亡调节剂
(CFLAR), 转录变体3; NM_001127184.2)
<400> 8
atgtctgctg aagtcatcca tcaggttgaa gaagcacttg atacagatga gaaggagatg 60
ctgctctttt tgtgccggga tgttgctata gatgtggttc cacctaatgt cagggacctt 120
ctggatattt tacgggaaag aggtaagctg tctgtcgggg acttggctga actgctctac 180
agagtgaggc gatttgacct gctcaaacgt atcttgaaga tggacagaaa agctgtggag 240
acccacctgc tcaggaaccc tcaccttgtt tcggactata gagtgctgat ggcagagatt 300
ggtgaggatt tggataaatc tgatgtgtcc tcattaattt tcctcatgaa ggattacatg 360
ggccgaggca agataagcaa ggagaagagt ttcttggacc ttgtggttga gttggagaaa 420
ctaaatctgg ttgccccaga tcaactggat ttattagaaa aatgcctaaa gaacatccac 480
agaatagacc tgaagacaaa aatccagaag tacaagcagt ctgttcaagg agcagggaca 540
agttacagga atgttctcca agcagcaatc caaaagagtc tcaaggatcc ttcaaataac 600
ttcaggatga taacacccta tgcccattgt cctgatctga aaattcttgg aaattgttcc 660
atgtga 666
<210> 9
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 211-Flip
<400> 9
cuugaagaug gacagaaaag c 21
<210> 10
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 262-Flip
<400> 10
ccuuguuucg gacuauagag u 21
<210> 11
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 404-Flip
<400> 11
guugaguugg agaaacuaaa u 21
<210> 12
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 480-Flip
<400> 12
gaauagaccu gaagacaaaa a 21
<210> 13
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 513-Flip
<400> 13
caagcagucu guucaagga 19
<210> 14
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 23-Flip
<400> 14
guugaagaag cacuugauac a 21
<210> 15
<211> 19
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 72-Flip
<400> 15
gugccgggau guugcuaua 19
<210> 16
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 435-Flip
<400> 16
cagaucaacu ggauuuauua g 21
<210> 17
<211> 21
<212> RNA
<213> 人工序列
<220>
<223> cFLIP siRNA 495-Flip
<400> 17
caaaaaucca gaaguacaag c 21
<210> 18
<211> 627
<212> PRT
<213> 人工序列
<220>
<223> 干扰素-β突变体-抗体融合蛋白(免疫因子1)
<400> 18
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Ser His Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Ala Arg Val Cys Thr Pro Lys Arg Cys Tyr Ser Tyr Asp
100 105 110
Ala Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
115 120 125
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
130 135 140
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
145 150 155 160
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
165 170 175
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
180 185 190
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
195 200 205
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
210 215 220
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
225 230 235 240
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
245 250 255
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
260 265 270
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
275 280 285
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
290 295 300
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
305 310 315 320
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
325 330 335
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
340 345 350
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
355 360 365
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
370 375 380
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
385 390 395 400
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
405 410 415
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
420 425 430
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
435 440 445
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Ser Tyr
450 455 460
Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys
465 470 475 480
Leu Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu Lys Asp Arg
485 490 495
Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln
500 505 510
Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe
515 520 525
Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile
530 535 540
Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys
545 550 555 560
Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys
565 570 575
Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His
580 585 590
Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg
595 600 605
Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr
610 615 620
Leu Arg Asn
625
<210> 19
<211> 386
<212> PRT
<213> 人工序列
<220>
<223> 干扰素-β突变体-抗体融合蛋白(免疫因子2)
<400> 19
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ala Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp Asp Ser Leu
85 90 95
Asn Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Lys Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Ala Glu Cys Ser Gly Gly Gly Gly Ser Ser Tyr Asn
210 215 220
Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu
225 230 235 240
Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr Cys Leu Lys Asp Arg Met
245 250 255
Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys
260 265 270
Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala
275 280 285
Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn Glu Thr Ile Val
290 295 300
Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn His Leu Lys Thr
305 310 315 320
Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu
325 330 335
Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr
340 345 350
Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr Ile Val Arg Val
355 360 365
Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu
370 375 380
Arg Asn
385
<210> 20
<211> 648
<212> PRT
<213> 人工序列
<220>
<223> 干扰素-β突变体-抗体融合蛋白(抗c-Met
干扰素-β突变蛋白)
<400> 20
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Trp Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Ser Gly Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ser Ala Ile Ser His Ser Gly Gly Ser Thr Tyr Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
85 90 95
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ala Lys Trp Gly Pro Ala Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
130 135 140
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
145 150 155 160
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
165 170 175
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
210 215 220
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
465 470 475 480
Ala Lys Ala Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn
485 490 495
Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Thr Leu Glu Tyr
500 505 510
Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln
515 520 525
Leu Gln Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met
530 535 540
Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly
545 550 555 560
Trp Asn Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln
565 570 575
Ile Asn His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp
580 585 590
Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr
595 600 605
Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala
610 615 620
Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn
625 630 635 640
Arg Leu Thr Gly Tyr Leu Arg Asn
645
<210> 21
<211> 652
<212> PRT
<213> 人工序列
<220>
<223> 干扰素-β突变体-抗体融合蛋白(抗ERBB2
干扰素-β突变蛋白)
<400> 21
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn
35 40 45
Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys
85 90 95
Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
145 150 155 160
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
210 215 220
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
225 230 235 240
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala
465 470 475 480
Lys Glu Ala Ala Ala Lys Ala Ser Tyr Asn Leu Leu Gly Phe Leu Gln
485 490 495
Arg Ser Ser Asn Phe Gln Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly
500 505 510
Thr Leu Glu Tyr Cys Leu Lys Asp Arg Met Asn Phe Asp Ile Pro Glu
515 520 525
Glu Ile Lys Gln Leu Gln Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr
530 535 540
Ile Tyr Glu Met Leu Gln Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser
545 550 555 560
Ser Ser Thr Gly Trp Asn Glu Thr Ile Val Glu Asn Leu Leu Ala Asn
565 570 575
Val Tyr His Gln Ile Asn His Leu Lys Thr Val Leu Glu Glu Lys Leu
580 585 590
Glu Lys Glu Asp Phe Thr Arg Gly Lys Leu Met Ser Ser Leu His Leu
595 600 605
Lys Arg Tyr Tyr Gly Arg Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr
610 615 620
Ser His Cys Ala Trp Thr Ile Val Arg Val Glu Ile Leu Arg Asn Phe
625 630 635 640
Tyr Phe Ile Asn Arg Leu Thr Gly Tyr Leu Arg Asn
645 650
<210> 22
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> DR4正向引物
<400> 22
gggtccacaa gaccttcaag t 21
<210> 23
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> DR4反向引物
<400> 23
tgcagctgag ctaggtacga 20
<210> 24
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> DR5正向引物
<400> 24
agacccttgt gctcgttgtc 20
<210> 25
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> DR5反向引物
<400> 25
ttgttgggtg atcagagcag 20
<210> 26
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> FASL正向引物
<400> 26
cagtccaccc cctgaaaaa 19
<210> 27
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> FASL反向引物
<400> 27
ggaccttgag ttggacttgc 20
<210> 28
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> FAS正向引物
<400> 28
atggccaatt ctgccataag 20
<210> 29
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> FAS反向引物
<400> 29
tgactgtgca gtccctagct t 21
<210> 30
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> TNF-a正向引物
<400> 30
gacaagcctg tagcccatgt 20
<210> 31
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> TNF-a反向引物
<400> 31
tctcagctcc acgccatt 18
<210> 32
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> Trail正向引物
<400> 32
cctcagagag tagcagctca ca 22
<210> 33
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> Trail反向引物
<400> 33
cagagccttt tcattcttgg a 21
Claims (5)
1.(a)siRNA和(b)人干扰素-β突变体在制备用于治疗干扰素-β-抗性癌症疾病的药剂中的用途,
其中,所述siRNA(a)以互补方式与cFLIP基因的mRNA结合,并且
其中,所述人干扰素-β突变体的氨基酸序列如选自由SEQ ID NO:2至SEQ ID NO:6组成的组中的任一种氨基酸序列所示,
其中,所述siRNA的核苷酸序列如选自由SEQ ID NO:9至SEQ ID NO:13组成的组中的任一种核苷酸序列所示。
2.根据权利要求1所述的用途,其中,所述cFLIP基因的mRNA的核苷酸序列如选自由SEQID NO:7和SEQ ID NO:8组成的组中的任一种核苷酸序列所示。
3.根据权利要求1所述的用途,其中,所述干扰素-β突变体是其中结合有抗体或其抗体片段的融合蛋白,所述融合蛋白的氨基酸序列如选自由SEQ IDNO:18至SEQ ID NO:21组成的组中的任一种氨基酸序列所示。
4.根据权利要求1所述的用途,其中,所述癌症疾病是选自由乳腺癌、胃癌、卵巢癌、肺癌、结肠癌、肛门癌、星形细胞瘤、白血病、淋巴瘤、头颈癌、肝癌、睾丸癌、宫颈癌、肉瘤、血管瘤、食道癌、眼癌、喉癌症、口癌、间皮瘤、骨髓瘤、口腔癌、直肠癌、咽喉癌、膀胱癌、子宫癌、前列腺癌、大肠癌、胰腺癌、肾癌、皮肤癌、基底细胞癌、黑色素瘤、鳞状细胞癌、口鳞状细胞癌、结直肠癌、胶质母细胞瘤、子宫内膜癌和恶性神经胶质瘤组成的组中的任一种。
5.siRNA在制备用于致敏干扰素-β-抗性癌细胞的药剂中的用途,其中,所述siRNA以互补方式与cFLIP基因的mRNA结合,
其中,所述siRNA的核苷酸序列如选自由SEQ ID NO:9至SEQ ID NO:13组成的组中的任一种核苷酸序列所示。
Applications Claiming Priority (3)
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KR1020160097516A KR102666000B1 (ko) | 2016-07-29 | 2016-07-29 | cFLIP siRNA를 포함하는 인터페론 베타 저항성 암 질환 치료용 또는 감작용 조성물 |
KR10-2016-0097516 | 2016-07-29 | ||
PCT/KR2017/008239 WO2018021892A1 (ko) | 2016-07-29 | 2017-07-31 | cFLIP siRNA를 포함하는 인터페론 베타 저항성 암 질환 치료용 또는 감작용 조성물 |
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CN1287430C (zh) | 2001-06-15 | 2006-11-29 | 东京毅力科创株式会社 | 干蚀刻方法 |
CN1604783A (zh) | 2001-10-26 | 2005-04-06 | 里伯药品公司 | 通过rna干扰治疗纤维化疾病的药物 |
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EP3492107A1 (en) | 2019-06-05 |
EP3492107B1 (en) | 2022-12-21 |
US11464832B2 (en) | 2022-10-11 |
JP6853921B2 (ja) | 2021-04-07 |
EP3492107A4 (en) | 2020-03-11 |
WO2018021892A1 (ko) | 2018-02-01 |
CN109890425A (zh) | 2019-06-14 |
JP2019530731A (ja) | 2019-10-24 |
KR102666000B1 (ko) | 2024-05-14 |
US20230241176A1 (en) | 2023-08-03 |
KR20180013587A (ko) | 2018-02-07 |
EP4012030A1 (en) | 2022-06-15 |
ES2941669T3 (es) | 2023-05-24 |
US20210299225A1 (en) | 2021-09-30 |
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