CN108697779A - 癌症疫苗和递送方法 - Google Patents
癌症疫苗和递送方法 Download PDFInfo
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Abstract
公开了用于治疗癌症或前期癌的组合物、方法和试剂盒。具体来说,本发明一般涉及癌症疫苗以及递送所述疫苗的方法。还考虑了包括所述疫苗与免疫调节剂的组合的组合治疗。
Description
关于联邦资助研究的声明
本发明是在由美国国防部拨款号BC113107授予的美国政府支持下完成的。美国政府享有本发明的某些权利。
相关专利申请的交叉参考
本申请要求2016年1月7日提交的美国临时专利申请号62/275,952的优先权,其内容以全文引用的方式并入本文中。
序列表
本申请通过EFS-Web以电子方式提交,并且包括采用.txt格式的以电子方式提交的序列表。txt文件包含2017年1月9日创建的名为“2017-01-09_5667-00376_ST25_Sequence_Listing.txt”的序列表,大小为151,883字节。包括在该.txt文件中的序列表是说明书的一部分,并且其通过全文引用的方式并入本文中。
引言
癌症疫苗靶向由肿瘤表达的抗原,但由于在不存在共刺激分子的情况下被靶向蛋白的慢性过表达诱导了免疫耐受以及诱导了免疫调节环境,因此这些疫苗的应用并不像曾经希望的那样有效。预防性癌症疫苗可能更有希望,但癌症变化很大,有多种遗传变化,但很少有真正的普遍变化。因此,很难预测哪些抗原会在任何特定癌症上过表达,或者是否应该对个体接种疫苗,如果接种疫苗的话,应该接种哪些抗原以及使用什么样的疫苗接种策略。相比之下,本文提出了一种策略,其中使用针对一种或多种可预见将响应于治疗而被过表达的一种或多种抗原进行疫苗接种,所述疫苗接种在癌细胞过表达所述抗原之前进行,以诱导强大的抗癌免疫应答。
本申请一般涉及癌症疫苗和递送方法。更具体地,疫苗可以针对抗原,例如HER2、HER3和ESR1同种型,所述抗原在癌细胞上表达或响应于对癌症(或前期癌)的治疗性干预产生抗性而表达。还提供了递送疫苗的方法和包括疫苗与免疫调节剂的组合的组合治疗。
发明内容
在一个方面,提供了包含可操作地连接至编码第一抗原多肽的第一多核苷酸的异源启动子的多核苷酸构建体。多核苷酸构建体可以是环状的和/或可以缺乏细菌复制起点和/或抗生素抗性基因。
在另一方面,提供了治疗癌症或前期癌的方法或降低癌症对受试者中的癌症治疗剂或预防剂产生抗性的可能性的方法。这些方法可以包括给受试者施用治疗有效量的DNA疫苗,并给受试者施用治疗有效量的疫苗载体组合物。优选地,DNA疫苗包括编码第一抗原多肽的第一多核苷酸,并且疫苗载体组合物包括第二抗原多肽。
在另一方面,提供了癌症疫苗试剂盒。癌症疫苗试剂盒可以包括DNA疫苗组分和疫苗载体组分,所述DNA疫苗组分包括编码第一抗原多肽的第一多核苷酸,所述疫苗载体组分包括第二抗原多肽。合适地,DNA疫苗组分包括本文所述的多核苷酸构建体中的任一种。
附图说明
图1显示了pAdCMV/HER3/Δpp载体的构建。
图2显示了IFN-γELISPOT数据。通过足垫注射Ad-hHER3/ECD-C1C2,或肌内注射小环DNA-hHER3/ECD-C1C2,然后进行活体电穿孔(50V,5个脉冲,脉冲长度60ms,间隔时间200ms)而对HER3转基因小鼠进行疫苗接种。疫苗接种进行3次,间隔2周。最后一次疫苗接种后两周,处死小鼠并用脾细胞进行IFN-γELISPOT测定。HER3 ECD肽混合物和/或HER3ICD肽混合物用作刺激抗原。每个条形显示每个试验组(arm)的平均值。误差棒:标准差。
图3A显示了基于细胞的ELISA数据。最后一次疫苗接种后两周,对小鼠实施安乐死并单独收集血液。使用涂布4T1细胞和涂布4T1-HER3细胞的平板对个体小鼠血清进行基于细胞的ELISA。从1:50至1:6400滴定血清,加入到4T1或4T1-HER3细胞上并孵育。显示OD 450值的差异。
图3B显示了IFN-γELISPOT测定数据。用Ad-HER3/ECD-C1C2接种小鼠3次,或用异源初次免疫-加强免疫(heterologous prime-boost)(mcDNA-HER3/ECD-C1C2两次,随后用Ad-HER3,或者pDNA-HER3/ECD-C1C2两次,随后用Ad-HER3)接种小鼠。在最后一次疫苗接种7天后收集脾脏,并使用HER3 ECD和ICD肽混合物作为刺激抗原进行IFN-γELISPOT测定。HER3 ECD肽混合物和/或HER3 ICD肽混合物用作刺激抗原。
图4显示了抗HER3抗体(在疫苗接种后)的基于细胞的ELISA数据。用Ad-HER3/ECD-C1C2接种小鼠3次,或用异源初次免疫-加强免疫(mcDNA-HER3/ECD-C1C2两次,随后用Ad-HER3,或者pDNA-HER3/ECD-C1C2两次,随后用Ad-HER3)接种小鼠。在最后一次疫苗接种7天后处死小鼠,收集血液并用血清进行基于细胞的ELISA。
图5显示了HER3疫苗接种小鼠中的4T1-HER3肿瘤生长。用Ad-HER3/ECD-C1C2接种小鼠3次,或用异源初次免疫-加强免疫(mcDNA-HER3/ECD-C1C2两次,随后用Ad-HER3,或者pDNA-HER3/ECD-C1C2两次,随后用Ad-HER3)接种小鼠。最后一次疫苗接种7天后,将4T1-HER3细胞(0.3M细胞/小鼠)植入小鼠的侧腹,并且每周测量肿瘤大小两次。在第28天处死小鼠。
图6显示了实验结束时的IFN-γELISPOT测定数据。在用Ad-HER3/ECD-C1C2接种小鼠3次后,或用异源初次免疫-加强免疫接种小鼠后,将4T1-HER3细胞(0.3M细胞/小鼠)植入小鼠的侧腹,并在第25天处死小鼠。收集脾脏并使用HER3 ECD和ICD肽混合物作为刺激抗原进行IFN-γELISPOT测定。
图7是用于产生实施例中使用的小环DNA的质粒的示意图,包括能够产生HER3ECD-C1C2融合蛋白的pCMV-hHER3ECD-C1C2构建体。
图8显示了通过不同疫苗策略在HER3转基因小鼠中诱导的细胞免疫应答。通过肌内注射质粒DNA-hHER3/ECDC1C2(25μg/小鼠)、小环DNA-hHER3/ECDC1C2(12.5μg/小鼠)或盐水,然后进行活体电穿孔(50V,5次脉冲,脉冲长度60ms,间隔时间200ms),从而对雌性HER3转基因小鼠进行疫苗接种。对每只小鼠重复电穿孔两次,将电极从第一位置垂直放置。将Ad[E1-]-hHER3(2.6×10E10vp/小鼠)注射到足垫中作为阳性对照。疫苗接种两周后,处死小鼠并进行ELISPOT测定。每组有3只小鼠。
图9显示了通过不同疫苗策略在HER3转基因小鼠中诱导的细胞免疫应答。通过肌内注射质粒DNA-hHER3/ECDC1C2(25μg/小鼠)、小环DNA-hHER3/ECDC1C2(12.5μg/小鼠)或盐水,然后进行活体电穿孔(50V,5次脉冲,脉冲长度60ms,间隔时间200ms),从而对雌性HER3转基因小鼠进行疫苗接种。对每只小鼠重复电穿孔两次,将电极从第一位置垂直放置。将Ad[E1-]-hHER3(2.6×10E10vp/小鼠)注射到足垫中作为阳性对照。疫苗接种两周后,处死小鼠并进行ELISPOT测定。每组有3只小鼠。显示了具有小环DNA疫苗的小鼠的数据。
图10显示了通过不同疫苗策略在HER3转基因小鼠中诱导的细胞免疫应答。通过肌内注射质粒DNA-hHER3/ECDC1C2(25μg/小鼠)、小环DNA-hHER3/ECDC1C2(12.5μg/小鼠)或盐水,然后进行活体电穿孔(50V,5次脉冲,脉冲长度60ms,间隔时间200ms),从而对雌性HER3转基因小鼠进行疫苗接种。对每只小鼠重复电穿孔两次,将电极从第一位置垂直放置。将Ad[E1-]-hHER3(2.6×10E10vp/小鼠)注射到足垫中作为阳性对照。疫苗接种两周后,处死小鼠并进行ELISPOT测定。每组有3只小鼠。显示了HER3抗原(ECD+ICD肽混合物)的数据。
图11显示了不同疫苗接种策略的直方图叠加(4T1-HER3与4T1)。
图12显示了IFN-γELISPOT测定数据。在第0天和第14天用小环DNA(mcDNA-hHER3/ECD-mC1C2,25μg)、质粒DNA(pDNA-hHER3/ECD-mC1C2,25μg)或腺病毒载体(Ad-hHER3,2.6×10E10vp)对小鼠进行两次疫苗接种。在第21天,对小鼠实施安乐死,并使用脾细胞进行IFN-γELISPOT测定。HER3肽混合物(ECD、ICD或ECD+ICD)或HIV肽混合物用作刺激抗原。
图13显示了IFN-γELISPOT测定数据。在第0天和第14天用小环DNA(mcDNA-hHER3/ECD-mC1C2,25μg)、质粒DNA(pDNA-hHER3/ECD-mC1C2,25μg)或腺病毒载体(Ad-hHER3,2.6×10E10vp)对小鼠进行两次疫苗接种。在第21天,对小鼠实施安乐死,并使用脾细胞进行IFN-γELISPOT测定。HER3肽混合物(ECD、ICD或ECD+ICD)或HIV肽混合物用作刺激抗原。显示了小环DNA(mcDNA-hHER3/ECD-C1C2)的代表性案例。
图14显示了抗HER3抗体的基于细胞的ELISA数据。在第0天和第14天用小环DNA(mcDNA-hHER3/ECD-mC1C2,25μg)、质粒DNA(pDNA-hHER3/ECD-mC1C2,25μg)或腺病毒载体(Ad-hHER3,2.6×10E10vp)对小鼠进行两次疫苗接种。在第21天,对小鼠实施安乐死并收集血清。使用4T1-HER3细胞和4T1细胞,通过基于细胞的ELISA评估抗HER3抗体的水平。进行血清滴定并加入到孔中,然后加入HRP缀合的二抗小鼠IgG抗体。通过TMB显色,并在用H2SO4停止反应后在450nm下读取板。
具体实施方式
所有乳腺癌中约有70%被归类为雌激素受体阳性(ER+),其依赖于组成型雌激素受体信号传导。虽然不同类别的内分泌(抗雌激素)疗法(包括选择性雌激素受体调节剂(SERMS)、下调剂和芳香酶抑制剂(AI))是辅助方案中这些癌症的有效治疗,但大约50%的女性最终会复发并死于转移性ER+疾病。因此,尽管出现了新疗法(例如AI),但ER+乳腺癌仍然存在无情的复发率,特别是在发生转移的情况下。值得注意的是,所有发生转移性ER+疾病的患者都将发展为内分泌治疗抗性疾病。在这个阶段,没有治愈ER+乳腺癌的方法。由于补偿机制似乎可以解释相当大百分比的经过抗雌激素治疗的患者出现的耐药性,因此我们提出了一种新颖方法,该方法有可能在患者的一生中靶向关键的驱动突变(drivermutation)。本文描述了针对特异性抗性驱动因子(resistance driver)的特异性靶向的基于免疫疗法的疫苗和疫苗策略,预期所述特异性抗性驱动因子可通过补偿性抗性机制产生。
作为靶向确定的肿瘤抗原的疫苗的新型替代品,我们假设通过靶向在暴露于癌症治疗剂或预防剂后所诱导的肿瘤抗原(作为产生治疗抗性的机制),可以避免对常规肿瘤相关抗原的抗原特异性免疫无应答性。尽管可能存在许多响应于癌症治疗剂或预防剂而过表达的潜在抗原,但那些可能是特定治疗抗性机制的关键组分的抗原将是有吸引力的靶标,因为表达此类抗原的克隆的免疫消融应该消除治疗抗性肿瘤细胞的临床复发。被认为对治疗抗性必不可少的抗原包括受体酪氨酸激酶(RTK)的HER家族的成员HER2、HER3以及雌激素受体α(ESR1)。
HER2是与其形成异二聚体的其他HER蛋白例如HER3的优选二聚化配偶体。与HER2的二聚化导致受体细胞质结构域内酪氨酸残基的自磷酸化,并启动多种信号传导途径。HER2在一些癌症中具有肿瘤促进功能,并且HER2的扩增或过表达与疾病复发增加和预后不良有关。用HER2靶向酪氨酸激酶抑制剂(TKI)治疗HER2扩增的乳腺癌导致HER3表达和下游信号传导的增加,从而产生治疗抗性。
例如,抗HER2单克隆抗体帕妥珠单抗破坏神经调节蛋白诱导的HER2-HER3二聚化和信号传导;然而,它在破坏HER2过表达肿瘤细胞中不依赖配体的HER2-HER3相互作用和信号传导的升高的基础状态方面效果较差。正在开发的其他HER3特异性抗体与HER3结合并导致HER3内化,从而抑制下游信号传导。作为单克隆抗体的替代品,我们最近证明了通过针对例如HER2和HER3等受体的疫苗接种所诱导的多克隆抗体可以介导深度的受活体化和降解,从而在体外和活体提供治疗效果(Ren等人,Breast cancer Research 2012 14:R89和国际专利申请号WO 2013/110030,两者皆以全文引用的方式并入本文)。
本文提供了旨在通过引发针对HER3、HER2或ESR1中的至少一种的免疫应答来靶向治疗抗性的常见形式的疫苗策略。疫苗可以是疫苗载体或DNA疫苗,其由缺失外显子16(从核苷酸1899开始的48bp缺失或其部分)的HER2基因的一种或多种形式、包含全长HER3或其部分的HER3基因、或编码ESR1的突变形式(例如WO 2016/007504中描述的那些)的ESR1基因构成。这些多核苷酸可以包括在平台中,例如DNA疫苗,或疫苗载体,例如脂质体、细菌、酵母或病毒载体,其将引发对从这些遗传构建体表达的表位的免疫应答。作为所描述的遗传构建体的替代或补充,由这些基因或遗传构建体编码的多肽可用于如下所述的疫苗制剂中以引发免疫应答。我们预期本文公开的选择性靶向与抗癌疗法抗性相关的抗原的疫苗接种策略可以阻断抗性发展。
本文所述的疫苗载体、DNA构建体或基于多肽的疫苗制剂可包括编码任何抗原多肽的多核苷酸或抗原多肽。抗原多肽可选自由HER2d16(SEQ ID NO:3)、Her2d16Ki(SEQ IDNO:4)、HER2d16TM(SEQ ID NO:5)、ESR1 Y537N(SEQ ID NO:6)、ESR1 Y537S(SEQ ID NO:7)、ESR1 D538G(SEQ ID NO:8)、ESR1 K303R(SEQ ID NO:9)、HER3(SEQ ID NO:1)、HER3(SEQ IDNO:2)和HER3表位(SEQ ID NO:13-30)或其部分或组合组成的组。包括在疫苗中的HER2d16的部分应包括各种同种型中的外显子16中的缺失的连接。外显子16的缺失始于SEQ ID NO:3的氨基酸序列中的氨基酸633。本领域技术人员预期表位的长度为6、8、10、12、14、16、18或20个氨基酸。因此,所提到的部分应该至少足够长以含有表位。实施例中使用的疫苗涵盖较大的多肽,但疫苗也可包括比本文提供的多肽更小的多肽部分。疫苗可包括侧接SEQ IDNO:3的氨基酸633处的缺失的区域或侧接ESR1的537、538或303位的突变的区域。疫苗和疫苗制剂可包括编码多肽的多核苷酸或长度为至少8、10、12、14、16、18、20或更多个氨基酸的多肽。
编码HER2d16、ESR1或HER3多肽的多核苷酸可包涵在疫苗载体中。例如,SEQ IDNO:31-33(HER2d16的核酸序列)或其部分可包含在疫苗中。合适的疫苗载体包括但不限于病毒载体,例如腺病毒、禽痘、牛痘、VEE等,以及基于DNA的疫苗接种载体。使用蛋白质/肽疫苗接种策略的疫苗制剂也可以被使用,并且例如可以包括包含SEQ ID NO:3、4和/或5的制剂。脂质体、酵母或细菌疫苗载体也可以是合适的。这种免疫治疗平台可以在发展或鉴定依赖于HER2介导的信号传导的癌症类型之前使用,在内分泌抗性发展之前,可以在前线或辅助设置中用作这些癌症的治疗,并且还可以用作预防措施,以防止这种信号传导路径发展和演变成抗性路径。
疫苗或疫苗载体可包括编码另外的多肽的多核苷酸,所述多肽例如是其他鉴定的HER2、HER3、ESR1多肽或包含突变的其他多肽,例如SEQ ID NO:34-39、SEQ ID NO:40-44中提供的那些,或国际公开号WO2013/110030中提供的任何表位,所述国际公开以全文引用的方式并入本文。包括编码多肽的多核苷酸的疫苗载体还可以包括可操作地连接至多核苷酸的启动子,使得多核苷酸能够由疫苗载体表达。启动子可以是异源启动子。本领域技术人员能够选择合适的启动子,并且许多启动子是本领域已知的。疫苗或疫苗载体还可以包括检查点抑制性免疫调节剂或与检查点抑制性免疫调节剂联合给药。检查点抑制性免疫调节剂可以是对选自CTLA-4、PD1、PD-L1、A2AR、B7-H3(CD276)、B7-H4、BTLA、IDO、KIR、LAG3、TIM-3和VISTA的抑制性检查点分子具有拮抗作用的抗体。PD1抗体可以从BioXCell获得,称为RMP1-14,并且CTLA-4抗体可以来自BioXCell,称为9D9。其他类似的抗体可商购或处于临床试验中,例如伊匹单抗(ipilimumab)、派姆单抗(pembrolizumab)和尼沃单抗(nivolumab)。
对癌症治疗剂或预防剂的抗性的产生是癌症或前期癌治疗中的常见问题,并且在一些情况下,对治疗剂的抗性机制是已知的。抗性通常是由基因表达的变化(蛋白质的过表达或阻断表达)、突变所致的基因变化、或通过细胞中蛋白质的改变的剪接或易位改变的序列或改变的激活(蛋白质的过度激活或阻断激活)而引起的。
在蛋白质过表达或过度活化或蛋白质中的新序列导致增加癌症或前期癌细胞对治疗剂或预防剂的抗性的那些情况下,我们报道了一种用于减少癌症或前期癌对癌症治疗剂或预防剂产生抗性的可能性的方法。如本文所用,对癌症治疗剂或预防剂的抗性表明癌症治疗剂或预防剂在响应于癌症治疗剂或预防剂时不能有效抑制癌症或前期癌细胞的生长或杀死癌症或前期癌细胞。该方法甚至可以阻止对癌症治疗剂或预防剂的抗性的产生,或者可以在对癌症治疗剂或预防剂的抗性产生之后逆转该抗性。这些方法包括向需要癌症治疗的受试者施用癌症治疗剂或预防剂,并施用至少一种疫苗制剂。本文所述的疫苗制剂包含编码多肽的多核苷酸或多肽,所述多肽的表达或活化与癌症或前期癌对癌症治疗剂或预防剂的抗性的产生相关或导致所述抗性的产生。本文提供的疫苗包括HER2多肽、HER3多肽或ESR1多肽,或编码HER2多肽如HER2d16多肽、HER3多肽或ESR1多肽的多核苷酸。
疫苗制剂可以在用癌症治疗剂或预防剂治疗之前、期间或之后施用,或者可以与癌症治疗剂或预防剂同时施用。如实施例中所证明的,可以向受试者施用一种以上的疫苗制剂,并且可以在一段时间内施用一种以上的疫苗制剂。与患有类似癌症或前期癌但未施用疫苗制剂的对照受试者相比,或者与患有癌症或前期癌的受试者群体的普遍可能性相比,向受试者施用疫苗制剂和癌症治疗剂或预防剂降低了受试者的癌症或前期癌对治疗剂或预防剂产生抗性的可能性。在一些实施方案中,施用疫苗制剂和治疗剂或预防剂的个体中的癌症或前期癌未对癌症治疗剂或预防剂产生抗性并得到治疗。或者,可以抑制癌症或前期癌的生长或降低生长速度。如果癌症或前期癌已经对癌症治疗剂或预防剂具有抗性,则疫苗制剂和癌症治疗剂或预防剂的施用还可以逆转对癌症治疗剂或预防剂的抗性。在一些实施方案中,疫苗制剂的施用足以治疗癌症或抑制癌症的生长或杀死癌症。在其他实施方案中,疫苗制剂必须与癌症治疗剂或预防剂联合施用,或者在癌症对癌症治疗剂或预防剂产生抗性之前施用。
疫苗制剂可以包括编码HER2、HER3或ESR1多肽的多核苷酸或基于肽的疫苗制剂中列出的多肽之一。HER2d16蛋白质序列在SEQ ID NO:3中提供。疫苗可以包含全长HER2d16或其部分,例如SEQ ID NO:4和SEQ ID NO:5中所示。例如,疫苗可以仅包含HER2多肽的细胞外结构域或细胞外结构域加上跨膜结构域或其他部分。疫苗可以包括编码ESR1多肽的多核苷酸。与对癌症治疗剂的抗性相关的ESR1的三个点突变(4种突变形式)作为SEQ ID NO:6-9提供。疫苗可以包含全长ESR1或其部分。例如,疫苗可以仅包含WO 2016/007504的实施例中鉴定的表位,或包含与抗性相关的突变或缺失的肽。疫苗可以包括编码如SEQ ID NO:1或2中所定义的全长HER3多肽的多核苷酸或其部分或HER3多肽本身或其部分,例如SEQ ID NO:13-30中定义的那些。
合适地,疫苗能够在施用过疫苗的受试者中引发对疫苗制剂中包含的多核苷酸或多肽的免疫应答。免疫应答可以是B细胞或T细胞应答。合适地,免疫应答包括针对疫苗中包括的多肽的抗体应答。免疫应答可以针对侧接或重叠突变位点的表位,或者可以针对多肽的天然部分。免疫应答可以是多克隆抗体应答,其中多肽的多个表位被抗体识别。
HER2d16在HER2的外显子16中含有缺失。该缺失产生肽中的独特连接区段,并且可以使用本文所述的疫苗产生跨越该连接的表位。本领域技术人员将理解,包括仅编码全长HER2的部分(即抗原表位)的多核苷酸的疫苗可用于本文所述的疫苗中。在缺失点处包括接合位点的HER2部分可以包括在疫苗中。SEQ ID NO:6-9中公开的ESR1多肽序列还含有与治疗抗性相关的突变。突变产生肽中的独特序列,并且可以鉴定跨越这些突变的表位并使用本文所述的疫苗产生抗体。本领域技术人员将理解,包括仅编码全长ESR1的部分(即抗原表位)的多核苷酸或这些肽本身的疫苗可用于本文所述的疫苗中。一些潜在的表位在WO2016/007504的表1和WO2016/007499中鉴定。包括突变位点的HER2或ESR1的部分、或HER3的部分可以包括在疫苗中。
疫苗制剂可包括疫苗载体。疫苗载体可以是细菌、酵母、病毒或脂质体疫苗载体。疫苗载体可以是腺病毒、腺相关病毒、禽痘、牛痘、病毒马脑炎病毒、委内瑞拉马脑炎病毒或其他病毒疫苗载体。产生腺病毒载体的一种方法在Luo等人,Nature Protocols,(2007)2:1236-1247中提供,该文献通过引用并入本文。疫苗载体可含有HER2、HER3或ESR1多核苷酸或其部分。疫苗载体可含有HER2、HER3或ESR1多肽或其部分。疫苗载体可以表达HER2、HER3或ESR1多肽或其部分。HER2、HER3或ESR1多肽或其部分可以在疫苗载体的表面或内部表达。HER2、HER3或ESR1多核苷酸或其部分可以在疫苗载活体携带,并且HER2、HER3或ESR1多肽或其部分可以仅在疫苗接种后表达。HER2、HER3或ESR1多肽或其部分可以表达为融合蛋白或与佐剂或其他免疫刺激分子联合表达,以进一步增强对多肽的免疫应答。
疫苗制剂还包括DNA疫苗和基于肽的疫苗,因此可以包括或不包括疫苗载体。DNA疫苗包括质粒和基于小环的多核苷酸构建体。例如,提供了包含异源启动子的多核苷酸构建体,所述异源启动子可操作地连接至编码第一抗原多肽的第一多核苷酸。多核苷酸构建体本质上可以是线性的或环状的。如本文所用,“异源启动子”是指与其可操作连接的多核苷酸不天然连接的任何启动子。合适的启动子包括能够在真核宿主细胞中表达多核苷酸的任何启动子。尽管在实施例的质粒和小环构建体中使用的真核启动子是CMV或EF1a启动子,但也可以使用许多其他真核启动子。其他示例性性真核启动子包括但不限于人基因启动子或病毒启动子,例如SV40晚期启动子、HSVITK启动子、腺病毒启动子和小鼠肉瘤病毒启动子。
在一些实施方案中,多核苷酸构建体是环状的并且缺乏细菌复制起点和抗生素抗性基因。例如,在说明性实施例中,发明人开发了小环构建体。小环构建体是附加型DNA载体,其作为不含任何细菌质粒DNA骨架的环状表达盒而产生。参见例如SystemBiosciences,Mountain View CA,MN501A-1。与仅仅工作几天的标准质粒载体相比,小环构建体较小的分子大小能够实现更有效的转染并在数周内提供持续表达。小环构建体可以衍生自具有细菌复制起点和任选地侧接att位点的抗生素抗性基因的质粒,以允许在att位点之间的DNA重组和排除并形成小环DNA。图7描绘此类构建体。
本文所述的抗原多核苷酸和抗原多肽还可以与为抗原载运体(antigenic cargo)提供额外的功能的融合配偶体(例如融合多核苷酸或多肽)连接。在一些实施方案中,本文所述的多核苷酸构建体包括第一多核苷酸,其在框内与编码乳凝集素多肽或其部分的第二多核苷酸融合。乳凝集素是一种蛋白质,通过其C1C2结构域(一种脂质结合结构域)被输送到外泌体中。在一些实施方案中,乳凝集素多肽包括SEQ ID NO:10(小鼠乳凝集素的C1C2结构域)或其同源物。在实施例中,HER3细胞外结构域与乳凝集素C1C2融合,如SEQ ID NO:11和12(核酸和氨基酸序列)所示。在另一个实施方案中,多核苷酸构建体或编码的多肽可以与多核苷酸或其编码的多肽融合,以允许递送至细胞和/或与细胞融合。例如,与单纯疱疹病毒VP16融合可以允许抗原多肽的细胞递送。其他潜在的融合蛋白配偶体是在靶细胞上发现的受体的配体,使得肽将通过受体介导的内吞作用被细胞摄取。
还可以改变肽以使它们更稳定地递送。肽也可以使用本领域技术人员已知的任何其他方法进行环化或二聚化。在本文提供的肽的N-末端添加甲硫氨酸可以用作使用Tam和Xu的方法产生环化肽的靶标(Biopolymers(1998)《甲状旁腺激素仿生合成中的甲硫氨酸连接策略(Methionine ligation strategy in the biomimetic synthesis ofparathyroid hormones)》46:319-329)。肽可具有与肽的任一末端键合的取代基。例如,肽可以在N-末端具有乙酰基或氨基甲酰基添加,和/或在C-末端具有酰胺添加。此外,肽可以多聚化成超过二聚体,或使用标准化学环化以提供药理学稳定性。多聚体可以含有本文公开的肽之一的超过一个拷贝,或者可以含有单个肽或多于一个本文公开的肽的反向拷贝。本领域技术人员将理解,可以对本文提供的肽进行各种其他修饰以增加施用后培养物或受试者中肽的稳定性或半衰期。例如,可以向N-末端添加脂肪酸或其他修饰,包括但不限于甲酰化、肉豆蔻酰化或聚二乙醇化。肽可以与载体蛋白连接以增加肽的稳定性。载体蛋白-肽可以是融合蛋白,并且可以使用本领域技术人员可获得的技术表达为重组蛋白。可以改变连接肽的氨基酸的肽键,或可以改变至少一个肽键以使肽更耐降解,例如可以添加甲基。氨基酸可以被与天然氨基酸具有相似侧链的功能相关的非天然氨基酸取代,例如用高半胱氨酸或α-甲基-半胱氨酸取代半胱氨酸。
递送粒子可用于递送DNA疫苗或基于肽的疫苗。递送粒子可包括本文公开的任何一种组合物。适于递送多核苷酸和/或蛋白质的递送粒子是本领域已知的,并且可包括但不限于聚合物纳米粒子、脂质体纳米粒子和包括脂质和至少一种类型的聚合物的纳米粒子。
聚合物纳米粒子
本领域已经描述了聚合物纳米粒子。(参见例如Reis等人,Nanomedicine 2(I)(2006)8-21;Kumari等人,Colloids and Surfaces B:Biointerfaces 75(2010)1-18;和美国专利公开20140066388,其内容以全文引用的方式并入本文)。聚合物纳米粒子可包括可生物降解的聚合物分子或可由可生物降解的聚合物分子形成,在一些实施方案中,其可包括树枝状大分子。合适的树枝状大分子可包括但不限于聚酰胺-胺(PAMAM)树枝状大分子。聚酰胺-胺树枝状大分子已经在本领域中用作细胞内递送治疗剂的载体。(参见Esfand等人,Drug Discov.Today(2001)6(8):427-436;和Bharali,International Journal ofNanomedicine(2009)4:1-7,其内容以全文引用的方式并入本文)。适用于制备当前公开的纳米粒子的聚酰胺-胺树枝状大分子可包括第3代、第4代、第5代或优选至少第6代树枝状大分子。
聚合物纳米粒子还可以包括其他可生物降解的聚合物分子或可以由其他可生物降解的聚合物分子形成,所述可生物降解的聚合物分子可以包括但不限于聚乳酸(PLA)、聚乙醇酸(PGA)、PLA和PGA的共聚物(即聚乳酸-共-乙醇酸(PLGA))、聚-ε-己内酯(PCL)、聚乙二醇(PEG)、聚(3-羟基丁酸酯)、聚(对二氧杂环己酮)、聚富马酸丙二醇酯、聚(原酸酯)、多元醇/双烯酮缩醛加成聚合物、聚-烷基-氰基-丙烯酸酯(PAC)、聚(癸二酸酐)(PSA)、聚(羧基双羧基苯氧基苯氧基)己酮(PCPP)、聚[双(对羧基苯氧基)甲烷](PCPM)、PSA、PCPP和PCPM的共聚物、聚(氨基酸)、聚(假氨基酸)、聚磷腈、聚[(二氯)磷腈]和聚[(有机)磷腈]的衍生物、聚羟基丁酸或S-己酸、弹性蛋白、凝胶和壳聚糖。(参见例如Kumari等人,Colloids andSurfaces B:Biointerfaces 75(2010)1-18;和美国专利号6,913,767;6,884,435;6,565,777;6,534,092;6,528,087;6,379,704;6,309,569;6,264,987;6,210,707;6,090,925;6,022,564;5,981,719;5,871,747;5,723,269;5,603,960;和5,578,709;和美国公开申请号2007/0081972;和国际申请公开号WO 2012/115806;和WO 2012/054425,其内容以全文引用的方式并入本文)。在一些实施方案中,纳米粒子可包括PLGA和PAMAM的混合物。
聚合物纳米粒子可通过本领域已知的方法制备。(参见例如Nagavarma等人,AsianJ.of Pharma.And Clin.Res.,第5卷,增刊3,2012,第16-23页;Cismaru等人,Rev.Roum.Chim.,2010,55(8),433-442;和国际申请公开号WO 2012/115806;和WO 2012/054425,其内容以全文引用的方式并入本文。制备纳米粒子的合适方法可包括利用预形成聚合物的分散体的方法,其可包括但不限于溶剂蒸发、纳米沉淀、乳化/溶剂扩散、盐析、透析和超临界流体技术。在一些实施方案中,纳米粒子可以通过形成双重乳液(例如,水包油包水)并随后进行溶剂蒸发来制备。通过所公开的方法获得的纳米粒子可以根据需要进行进一步的处理步骤,例如洗涤和冻干。任选地,纳米粒子可以与防腐剂(例如海藻糖)组合。
胶束和脂质体纳米粒子
胶束和基于脂质体的纳米粒子也可以用作合适的递送粒子。参见例如美国专利8,252,324,其内容通过全文引用的方式并入本文。胶束是由两亲分子形成的自组装球形胶体纳米粒子。胶束也被描述为在液体胶体中分布的聚集表面活性剂分子。胶束的核心在水性环境中被隔离,能够包封多核苷酸和/或蛋白质,保护它们免受破坏和不受生物环境影响,同时改善它们的药代动力学和生物分布。胶束的直径通常为约5-50nm,因此由于增强的渗透性和保留效应,从而能够在具有渗漏脉管系统的病理区域(例如梗塞区和肿瘤)中积聚。胶束还能够逃避颗粒系统的药物靶向中的主要障碍:网状内皮系统的非特异性摄取和肾分泌。
胶束可以由任何通常已知的表面活性剂形成,例如十二烷基硫酸钠或磷脂,但是与由特别设计的嵌段共聚物组成的胶束(如Kataoka等人,同上,和Torchilin等人,同上(2003)所述)相比,这类表面活性剂作为药物递送系统的性能较低。用作聚合物胶束的壳形成区段的柔性亲水聚合物组装成致密的栅栏壳,其由许多水分子交联以实现囊泡的有效稳定化。因此,聚合物胶束比未改性的表面活性剂胶束解离得慢得多,使加载的药物保留更长的时间并更有效地在靶位点积聚药物。此外,聚合物胶束易于设计成具有几十纳米的范围内的大小和窄的尺寸分布,这在调节生物分布方面是一个很大的优点。
与胶束相反,脂质体是直径约50至1,000nm的双层磷脂囊泡。脂质体具有生物惰性并且完全具有生物相容性;它们几乎不会引起毒性或抗原反应。脂质体中包括的多核苷酸和/或蛋白质被脂质体保护免受外部介质的破坏作用。因此,脂质体能够将其内容物递送到细胞内,甚至递送到不同的细胞区室内。通常,脂质体被认为是具有显著治疗潜力的有前景的载体,如在许多实验室测试和临床试验中所证明的,例如Torchilin,Nat.Rev.Drugdiscov.4,145-160(2005)。
已知脂质体和胶束可以通过用水溶性聚合物如聚乙二醇(PEG)增强最外层疏水壳来稳定。在这些载体粒子的疏水表面上存在亲水聚合物会吸引水壳,导致调理素对载体粒子的吸附减少。这反过来导致单核吞噬细胞摄取载体粒子的速率和程度的降低。长循环脂质体改善了药物的治疗指数并将药物包封在其中。目前,基于长循环脂质体的若干制剂是可商购的,例如即含有聚乙二醇化(PEG化)脂质体的多柔比星(doxorubicin),Sharp等人,Drugs 62 2089-2126(2002)。Doxil由Bridgewater,N.J.,USA的ortho biotechproducts公司制造。O'Shaughnessy,Clin.Breast cancer 4,318-328,(2003)证明了通过将药物包封到聚乙二醇化脂质体中来实现将多柔比星选择性递送到患有乳腺癌转移的患者的实体瘤中,这导致随后的存活改善。通过将脂质体多柔比星与紫杉醇(paclitaxel)(可作为获得,美国纽约州纽约市的百时美施贵宝公司(Bristol-Meyers SquibbCompany,New York,N.Y.,USA))、caelyx(美国新泽西州凯尼尔沃思的先灵葆雅公司(Schering-Plough corporation,Kenilworth,N.J.,USA))和卡铂(以购自百时美施贵宝公司)组合也证实了功效。已经批准了几种脂质体制剂用于临床应用或正在接受临床评估(Torchilin,同上,(2005))。
示例性的递送粒子也已在例如美国专利公开号20150232883和WO专利公开号2014/093635和2015/089351中公开,其内容通过全文引用的方式并入本文。在一些实施方案中,递送粒子包含1,2-二油酰基-3-三甲基铵-丙烷(DOTAP)、1,2-二(十四烷酰基)-sn-甘油基-3-磷酸胆碱(DMPC)、聚乙二醇(PEG)、胆固醇或其任何组合。
包括脂质和聚合物的纳米粒子
递送粒子还可以包括纳米粒子,包括脂质和聚合物组分。例如,已经开发了包括磷脂双层和聚(β-氨基酯)(PBAE)的纳米粒子用于活体递送多核苷酸。参见例如Su等人,Molecular Pharmaceutics,8(3):774-787(2011),其内容通过全文引用的方式并入本文。
递送粒子的一般性质
递送粒子可包括表面活性剂,其可包括阳离子表面活性剂。合适的阳离子表面活性剂可包括但不限于季铵化合物,例如具有式(X)3N+(CH2)n(CH3)的季铵化合物或其盐,其中X为C1-6烷基或芳基,并且n=(9,11,13,15或17)。合适的季铵化合物的盐可包括卤化物盐(例如Cl-或Br-盐),例如十六烷基三甲基溴化铵(CTAB)。
递送粒子优选具有促进靶向细胞摄取的物理性质。例如,优选地,纳米粒子具有促进靶向细胞摄取的大小和电荷。典型地,纳米粒子的平均有效直径小于1微米,优选地纳米粒子的平均有效直径为约25nm至约500nm,更优选约50nm至约250nm,最优选约100nm至约150nm。粒子的大小(例如平均有效直径)可以通过本领域已知的方法评估,所述方法可以包括但不限于透射电子显微镜(TEM)、扫描电子显微镜(SEM)、原子力显微镜(AFM)、光子相关光谱法(PCS)、纳米粒子表面积监测(NSAM)、凝聚粒子计数器(CPC)、差分迁移率分析仪(DMA)、扫描迁移粒度分析仪(SMPS)、纳米粒子跟踪分析(NTA)、X射线衍射(XRD)、气溶胶飞行时间质谱(ATFMS)和气溶胶粒子质量分析仪(APM)。
所公开的递送粒子优选具有促进靶细胞摄取的ζ电位。典型地,纳米粒子具有大于0的ζ电位。在一些实施方案中,纳米粒子具有约5mV至约45mV、约15mV至约35mV或约20mV至约30mV的ζ电位。ζ电位可以通过包括电泳迁移率或动态电泳迁移率的特性进行实验确定。可以利用电动学现象和电声现象来计算ζ电位。
即使粒子在其表面上不包括特异性配体,递送粒子也将被细胞非特异性地吸收。然而,所公开的递送粒子可以配置成还包括特异性地靶向特定细胞类型的配体。为了实现递送粒子的更特异的靶向,可以使用预先缀合程序用各种配体修饰这些粒子。例如,抗体和小肽已连接到聚乙二醇链的水暴露尖端(Blume等人Biomembranes 1149,180-184(1993))。抗体和小肽也通过反应性对硝基苯基羰基、N-苯并三唑羰基或马来酰亚胺封端的PEG-磷脂酰乙醇胺缀合(Moreira,Pharm.Res.19,265-269(2002);Torchilin等人,同上(2001);Xiong等人,J.Pharm.Sci.94,1782-1793(2005))。
本文所述的疫苗制剂可与佐剂组合以增加疫苗的免疫原性并衍生出药物组合物。在一些实施方案中,这些组合物包含矿物质佐剂、基于凝胶的佐剂、张力活性剂(tensoactive agent)、细菌产物、油乳剂、颗粒状佐剂、融合蛋白和脂肽(lipopeptide)中的一种或多种。矿物盐佐剂包括铝佐剂、钙盐(例如磷酸钙)、铁盐和锆盐。基于凝胶的佐剂包括基于铝凝胶的佐剂和乙酰化甘露聚糖(acemannan)。张力活性剂包括Quil A,它是从来自皂树(Quillaja saponaria)树皮的水提取物衍生的皂苷;皂苷,这是含有三萜结构的疏水核的张力活性糖苷,所述三萜结构具有与核连接的碳水化合物链;和QS-21。细菌产物包括革兰氏阴性细菌(例如来自分枝杆菌属(Mycobacterium spp.)、小棒状杆菌(Corynebacterium parvum)、肉芽肿棒状杆菌(C.granulosum)、百日咳博德特氏菌(Bordetella pertussis)和脑膜炎奈瑟氏菌(Neisseria meningitidis))的细胞壁肽聚糖或脂多糖、N-乙酰胞壁酰-L-丙氨酰-D-异谷氨酰胺(MDP)、衍生自MDP的不同化合物(例如苏氨酰-MDM)、脂多糖(LPS)(例如来自革兰氏阴性细菌的细胞壁)、海藻糖二霉菌酸酯(TDM)、霍乱毒素或其他细菌毒素,以及含有CpG基序的DNA。油乳剂包括FIA、Montanide、Adjuvant65、Lipovant、montanide家族的油基佐剂和各种脂质体。在颗粒状系统和聚合物系统中,聚(DL-丙交酯-共-乙交酯)微球已经被广泛研究并可在本文中使用。值得注意的是,上面提到的几种递送粒子也可以作为佐剂。
在一些实施方案中,组合物还包含细胞因子(例如IFN-γ、粒细胞-巨噬细胞集落刺激因子(GM-CSF)IL-2或IL-12)或免疫刺激分子,例如FasL、CD40配体或toll样受体激动剂,或碳水化合物佐剂(例如菊粉衍生的佐剂,例如γ菊粉、algammulin和基于葡萄糖和甘露糖的多糖,例如葡聚糖(glucan)、右旋糖酐(dextran)、香菇多糖、葡甘露聚糖(glucomannan)和半乳甘露聚糖(galactomannan))。在一些实施方案中,佐剂制剂可用于本发明,并且包括明矾盐和其他佐剂组合,例如脂质A、algammulin、免疫刺激复合物(ISCOMS)(其为30-40nm的病毒样粒子)和由Quil A、脂质和胆固醇构成的十二面体结构。
在一些实施方案中,另外的佐剂描述于Jennings等人《用于病毒疫苗机制和潜力的佐剂和递送系统(Adjuvants and Delivery Systems for Viral Vaccines-Mechanismsand Potential.)》收录于Brown F,Haaheim LR,(编).《调节针对免疫抗原的免疫应答(Modulation of the Immune Response to Vaccine Antigens.)》Dev.Biol.Stand,Vol.92.Basel:Karger 1998;19–28和/或Sayers等人J Biomed Biotechnol.2012;2012:831486,和/或Petrovsky and Aguilar,Immunology and Cell Biology(2004)82,488–496,其内容通过全文引用的方式并入本文。
在一些实施方案中,佐剂是铝凝胶或盐,例如氢氧化铝、磷酸铝和硫酸铝钾、AS04(其由铝盐和MPL组成)和ALHYDROGEL。在一些实施方案中,铝凝胶或盐是与本文所述的任何其他佐剂形成的制剂或混合物。
在一些实施方案中,组合物包含水包油乳液制剂、皂苷佐剂、卵清蛋白、弗氏佐剂、细胞因子和/或壳聚糖。说明性组合物包含以下一种或多种。
(1)卵清蛋白(例如ENDOFIT);
(2)含有或不含其他特异性免疫刺激剂的水包油乳液制剂,例如:(a)MF59(PCT公开号WO 90/14837),其可含有配制成亚微米粒子的5%角鲨烯、0.5%Tween 80和0.5%Span85(任选地含有各种量的MTP-PE),(b)SAF,其含有10%角鲨烷、0.4%Tween 80、5%普洛尼克(pluronic)封闭聚合物L121和thr-MDP,被微流化成亚微米乳液或涡旋以产生更大粒径的乳液,(c)RIBI佐剂系统(RAS)(RIBI IMMUNOCHEM,Hamilton,MO),其含有2%角鲨烯、0.2%Tween 80和任选地一种或多种来自单磷酰脂质A(MPL)、海藻糖二霉菌酸酯(TDM)和细胞壁骨架(CWS)的群组的细菌细胞壁组分,包括MPL+CWS(DETOXTM);和(d)ADDAVAX(英杰(Invitrogen));
(3)皂苷佐剂,例如STIMULON(Cambridge Bioscience,Worcester,Mass.);
(4)完全弗氏佐剂(CFA)和不完全弗氏佐剂(IFA);
(5)细胞因子,例如白细胞介素(作为非限制性实例IL-1、IL-2、IL-4、IL-5、IL-6、IL-7、IL-12等)、干扰素(例如γ干扰素)、巨噬细胞集落刺激因子(M-CSF)、肿瘤坏死因子(TNF)等;
(6)壳聚糖和甲壳质的其他衍生物,或聚-N-乙酰基-D-葡糖胺,其中通过水解除去了更大比例的N-乙酰基;和
(7)作为免疫刺激剂起作用以增强组合物有效性的其他物质,例如单磷酰脂质A。
在其他实施方案中,佐剂包括基于鞭毛蛋白的试剂、铝盐或凝胶、模式识别受体(PRR)激动剂、CpG ODN和咪唑喹啉。在一些实施方案中,佐剂包括TLR激动剂(例如TLR1、和/或TLR2、和/或TLR3、和/或TLR4、和/或TLR5、和/或TLR6、和/或TLR7、和/或TLR8、和/或TLR9、和/或TLR10、和/或TLR11、和/或TLR12、和/或TLR13)、核苷酸结合寡聚化结构域(NOD)激动剂、干扰素基因刺激物(STING)配体或相关试剂。
还提供了治疗癌症或前期癌、或降低癌症或前期癌对癌症治疗剂或预防剂产生抗性的可能性的方法。这些方法包括将如上所述的疫苗制剂施用给患有癌症或前期癌的受试者。受试者可以是任何哺乳动物,合适地是人、驯养动物,例如狗、猫、马、牛、猪或小鼠或大鼠。癌症治疗剂或预防剂可以在施用疫苗的同时、之前或之后施用。
这些方法还可包括向受试者施用治疗有效量的DNA疫苗,并向受试者施用治疗有效量的疫苗载体组合物。优选地,DNA疫苗包括编码第一抗原多肽的第一多核苷酸,并且疫苗载体组合物包括第二抗原多肽。第一抗原多肽和第二抗原多肽可以是相同的多肽或融合多肽,或者可以是不同的多肽或融合多肽。DNA疫苗可以在施用疫苗载体组合物之前、期间或之后施用。在一些实施方案中,在施用疫苗载体组合物之前施用DNA疫苗至少2、3、4、5次或更多次。施用DNA疫苗和疫苗载体组合物之间的时间间隔可以是至少1、2、3、4、5周或更长。
癌症治疗剂或预防剂可以是能够治疗癌症或抑制癌细胞生长的任何药剂。合适的药剂包括靶向HER2、HER1/EGFR、HER3、雌激素受体或IGF1R的那些药剂。治疗剂可以是曲妥珠单抗(trastuzumab)(赫赛汀(Herceptin))、曲妥珠单抗-美坦新偶联物(ado-trastuzumab emtansine)、拉帕替尼(lapatinib)、帕妥珠单抗(pertuzumab)或另一种HER2靶向治疗剂,或者它可以是EGFR靶向治疗剂,例如西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、帕尼单抗(panitumumab)或埃罗替尼(erlotanib),或者它可以是抗-雌激素,或防止雌激素合成的药剂,如芳香酶抑制剂。ER阳性癌症也可用帕布昔利布(Palbociclib)或依维莫司(Everolimus)治疗。我们先前已经证明HER3疫苗当与靶向HER2的治疗剂组合使用时可以治疗HER2阳性癌症。癌细胞通常对HER2靶向治疗剂产生抗性。添加用HER2、HER3或ESR1疫苗进行接种或被动转移的对HER2、HER3或ESR1特异的多克隆抗体导致抗阻断性(blocking resistance),抑制癌细胞生长并导致癌症的治疗。
适合地,接种疫苗的受试者响应于疫苗的施用而对疫苗制剂中使用的抗原多肽产生免疫应答。免疫应答可以是抗体免疫应答或T细胞免疫应答。例如,免疫应答可包括抗体依赖性细胞的细胞毒性、多克隆抗体应答、补体依赖性细胞的细胞毒性、细胞的细胞毒性、配体结合破坏、二聚化破坏、模拟配体结合从而导致靶抗原内化、或靶抗原降解。免疫应答可包括针对至少一部分靶抗原的抗体应答,合适地是包括突变位点的部分或抗原的过表达和可接近部分。免疫应答可以对侧接或包含SEQ ID NO:3的氨基酸633处外显子16的缺失的T细胞或B细胞表位具有特异性、或对侧接HER2d16中外显子16的缺失的区域具有特异性。
可以通过几种方式测量抗性产生的减少。在实施例中,可以将接种疫苗的受试者的抗性与未接种疫苗的类似受试者进行比较。或者,可以基于所产生的统计数据来测量减少,所述统计数据是关于用治疗剂治疗的个体产生抗性的可能性与用治疗剂治疗并用本文提供的一种或多种疫苗制剂接种的个体产生抗性的可能性。还可以通过测量癌细胞表面上抗原表达的水平来测量癌症抗性的可能性的降低。在有效施用疫苗后,HER2、HER3和ESR1在癌细胞上表达减少。可以通过跟踪肿瘤的生长或肿瘤或癌细胞的生长速率来测量疫苗在治疗癌症或降低抗性可能性方面的有效性。肿瘤大小或肿瘤生长速率的降低表明癌症得到治疗。
癌症可以选自能够通过增加癌细胞的蛋白质表达或活化而对治疗剂产生抗性的任何癌症。具体来说,癌症可以是能够对靶向HER家族酪氨酸激酶(合适地是HER2、HER3或EGFR)或雌激素受体(合适地是抗雌激素)的治疗剂产生抗性的任何癌症。癌症可通过增加HER2、HER3或ESR1的表达,缺失HER2的一部分或突变ESR1以避免对治疗剂的敏感性而产生抗性。合适地,癌症选自乳腺、前列腺、肺、卵巢、结肠、直肠、胰腺、膀胱、头颈或肝的癌症或前期癌。抗性可能是由于单个或多个变化引起,并且疫苗制剂或疫苗接种方案可以靶向这些变化中的一种或多种,和/或包括可能在抗性细胞中、但不一定在所有抗性细胞中发现的多种抗原。
治疗癌症包括但不限于降低受试者中癌细胞的数量或肿瘤的大小,将癌症的进展降低为更具侵袭性的形式(即以对治疗剂敏感的形式维持癌症),减少癌细胞的增殖或降低肿瘤生长的速度,杀死癌细胞,减少癌细胞的转移或降低受试者中癌症复发的可能性。如本文所用,治疗受试者是指对患有癌症或处于患上癌症或面临癌症复发的风险下的受试者赋予益处的任何类型的治疗。治疗包括改善受试者的状况(例如,在一种或多种症状方面),延迟疾病发展,延迟症状发作或减缓症状的发展等。
向受试者共同施用或施用多于一种组合物(即多于一种疫苗制剂、治疗剂和/或检查点抑制性免疫调节剂)表明所述组合物可以按任何顺序、同时或作为单位组合物的一部分施用。可以施用组合物使得一种在另一种之前施用,施用时间差异为1小时、2小时、4小时、8小时、12小时、16小时、20小时、1天、2天、4天、7天、2周、4周或更长时间。在实施例中,两种疫苗制剂以两周间隔施用,总共接种两次或三次,并且可以与检查点抑制性免疫调节剂组合。
如本文所用,有效量或治疗有效量意指当施用于受试者以治疗状态、病症或病况时足以实现治疗(如上所定义)的组合物的量。治疗有效量将根据化合物、制剂或组合物、疾病及其严重程度以及待治疗的受试者的年龄、体重、身体状况和反应性而变化。
本文所述的组合物(即,包括递送粒子和治疗剂或检查点抑制剂的疫苗制剂)可以通过本领域技术人员已知的任何方式施用,包括但不限于口服、局部、鼻内、腹膜内、肠胃外、静脉内、肌肉内、皮下、鞘内、经皮、鼻咽、病变内、肿瘤内、皮内或经粘膜吸收。因此,组合物可以配制成可摄取、可注射、局部或栓剂制剂。组合物还可以与脂质体或延时释放(time-release)运载体一起递送。DNA疫苗和多肽疫苗还可包括电刺激或电穿孔步骤,以帮助DNA疫苗或基于肽的疫苗进入细胞内空间。根据本发明将组合物施用于受试者似乎以剂量依赖性方式表现出有益效果。因此,在广泛的限度内,预期施用较大量的组合物比施用较小量的组合物实现增加的有益生物学效果。此外,还考虑了在低于观察到毒性的水平的剂量下的功效。
应当理解,在任何给定情况下施用的具体剂量将根据所施用的一种或多种组合物、待治疗或抑制的疾病、受试者的状况以及可能改变组合物的活性或受试者的应答的其他相关医学因素进行调整,如本领域技术人员所熟知的。例如,用于特定受试者的具体剂量取决于年龄、体重、一般健康状况、饮食、给药时间和模式、排泄速率、组合使用的药物和应用治疗的特定病症的严重程度。用于给定患者的剂量可以使用常规考虑因素来确定,例如通过借助于适当的常规药理学或预防方案来常规比较本文所述的组合物和已知药剂的差异活性。
用于受试者的最大剂量是不会引起不良或不可耐受的副作用的最高剂量。关于个体预防或治疗方案的变量的数量很大,并且预期相当大的剂量范围。给药途径也会影响剂量要求。与未经过治疗或只用治疗剂治疗的癌症相比,预计组合物的剂量将使癌症的生长减少至少10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或更多。特别考虑的是,药物制剂和组合物可以减轻与癌症相关的症状,阻止与癌症相关的症状的进一步生长或缓解与癌症相关的症状而不提供治愈,或者在一些实施方案中,可以用于治愈癌症并使受试者摆脱疾病。
本文所述的有效剂量的量是指施用的总量,即,如果施用多于一种组合物,则有效剂量的量对应于施用的总量。组合物可以单剂量或分剂量施用。例如,组合物可以4小时、6小时、8小时、12小时、一天、两天、三天、四天、一周、两周或三周或更长时间间隔施用两次或更多次。
疫苗制剂可以向受试者施用一次或多于一次,以有效地增强针对抗原多肽的免疫应答。如果疫苗制剂作为疫苗载体提供,则疫苗载体可以基于递送至受试者的粒子(即噬斑形成单位、集落形成单位、脂质体或其他粒子)的数量施用。受试者可以被施用1012、1011、1010、109、108、107或106个粒子。在基于递送粒子的肽疫苗制剂或DNA疫苗中递送的抗原多肽的量将变化。合适的剂量范围是每次疫苗接种约数百微克有效成分(抗原性多核苷酸或多肽),其范围为约0.01至10mg/kg/天,优选约0.1至1mg/kg/天。用于初始给药和加强注射(booster shots)的合适方案也是可变的,但典型的是先进行初始给药,随后再进行接种或其他给药,给药之间间隔一段时间。需要施用的有效成分的精确量取决于从业者的判断,并且对于每个受试者可能都是独特的。对于本领域技术人员显而易见的是,本文所述的表达抗原多肽的DNA构建体或抗原肽的治疗有效量将尤其取决于给药方案、施用的抗原的单位剂量、疫苗制剂是否是与其他治疗剂组合施用、接受体的免疫状态和健康以及特定疫苗制剂的治疗活性。
组合物可以以单剂量方案给予,或优选地以多剂量方案给予。多剂量方案是这样一种方案,其中接种疫苗的主要过程可以包括1至10次单独的剂量,然后是以维持和/或加强免疫应答所需的随后时间间隔给予其他剂量,例如,第二剂在1至4周或数月后给予,并且如果需要,在另外的几周或数月之后给予一个或多个后续剂量。可能需要间隔1至5个月至数年的定期加强剂以维持所需的免疫应答水平。
还提供癌症疫苗试剂盒。癌症疫苗试剂盒可以包括DNA疫苗组分和疫苗载体组分,所述DNA疫苗组分包括编码第一抗原多肽的第一多核苷酸,所述疫苗载体组分包括第二抗原多肽。合适地,DNA疫苗组分包括本文所述的多核苷酸构建体中的任一种。第一抗原多肽和第二抗原多肽可以是相同的多肽或融合多肽,或者可以是不同的多肽或融合多肽。
本公开不限于本文所述的构建、组件布置或方法步骤的具体细节。本文公开的组合物和方法能够以各种方式制备、实践、使用、实施和/或形成,这些方式对于本领域技术人员而言根据以下公开内容是显而易见的。这里使用的措辞和术语仅用于描述的目的,不应视为限制权利要求的范围。在说明书和权利要求中使用的涉及各种结构或方法步骤的顺序指示词(ordinal indicator)(诸如第一、第二和第三)并不意味着被解释为指示任何特定结构或步骤,或关于这些结构或步骤的任何特定顺序或配置。除非本文中另外指定或上下文明显矛盾,否则本文所述的所有方法都可按任何合适次序进行。除非另外声明,否则本文提供的任何和所有实例或示例性语言(例如,“诸如”)的使用仅旨在促进本公开,并不意味着对本公开的范围构成任何限制。说明书中的语言和附图中示出的结构都不应被解释为表示任何未要求保护的要素对于所公开的主题的实践是必不可少的。本文中术语“包括”、“包含”或“具有”及其变体的使用旨在涵盖其后列出的要素及其等同物,以及其他要素。被叙述为“包括”、“包含”或“具有”某些要素的实施方案也被认为是“基本上由所述某些要素组成”和“由所述某些要素组成”。
除非本文另外指定,否则本文叙述的值的范围仅打算用作个别地提及落在所述范围内的每一单独值的简化方法,且每一单独值都被纳入说明书中,就如同其在本文中个别地叙述一样。例如,如果浓度范围表示为1%至50%,则意图在本说明书中明确列举诸如2%至40%、10%至30%或1%至3%等的值。这些仅是具体意图的实例,并且在所列举的最低值和最高值之间并且包括所列举的最高值和最高值的数值的所有可能组合都被认为在本公开中明确陈述。使用词语“约”来描述特定的所述量或量的范围意味着表示非常接近所述量的值被包括在该量中,例如由于制造公差、仪器和形成测量中的人为错误等而可能或自然会被考虑的值。除非另有说明,否则所有涉及量的百分比均以重量计。
不承认任何参考文献(包括本说明书中引用的任何非专利或专利文献)构成现有技术。特别地,应理解,除非另有说明,否则本文中对任何文件的引用并不构成承认任何这些文件形成美国或任何其他国家的本领域公知常识的一部分。对参考文献的任何讨论均陈述其作者的主张,并且申请人保留质疑本文引用的任何文献的准确性和相关性的权利。除非另有明确说明,否则本文引用的所有参考文献均通过引用的方式完全并入。如果在引用的参考文献中找到的任何定义和/或描述之间存在任何差异,则将以本公开为准。
以下实施例仅用于说明,并不意味着对本发明或所附权利要求的范围构成限制。
实施例
材料和方法
试剂
含有15聚体肽(15mer peptide)(各自与后一个重叠11个氨基酸,跨越HER3蛋白的细胞外结构域和跨膜区段(ECD-TM)和HER3蛋白的细胞内结构域(ICD))的HER3肽的混合物购自JPT Peptide Technologies(Berlin,Germany),并用于IFN-γELISPOT测定。代表HIVgag蛋白的HIV肽的混合物购自BD Biosciences(San Jose,CA)并用作阴性对照。
hHER3ECDC1C2小环DNA的构建和生产
将通过PCR技术从人HER3 cDNA(OriGene,Rockville,MD)获得的人HER3的细胞外结构域插入小鼠乳凝集素表达质粒p6MLC1C2(1)中,以产生含有框内融合的小鼠乳凝集素的C1C2结构域的外泌体盒(hHER3ECDmC1C2)。将hHER3ECDmC1C2 DNA(SEQ ID NO:11和SEQID NO:12,分别为核酸和氨基酸序列)亚克隆到小环亲本质粒(MN501A-1,SystemBiosciences,Mountain View CA)中。图7提供了质粒的图谱。将得到的质粒在Top10大肠杆菌感受态细胞中进一步繁殖并筛选。通过限制酶以及DNA测序确认阳性克隆,并转化到ZYCY10P3S2T大肠杆菌小环生产菌株(MN900A-1,SBI)中。将100ml(OD600 6-8)来自单个质粒转化的ZYCY10P3S2T菌落的过夜细菌生长物加入到含有1%L-阿拉伯糖(Sigma ChemicalCo.,St.Louis,MO)的200ml新鲜培养基中,然后在30℃和250rpm振荡下孵育5小时。使用来自Qiagen(Germantown MD)的质粒纯化试剂盒从细菌制备小环DNA。通过运行琼脂糖凝胶检查小环的质量,通过Minicircle-safe DNase(MN912A-1,SBI)除去基因组和亲本质粒DNA污染物。
pINGhHER3FL/pING-hHER3ECDC1C2的构建和生产
将人HER3全长cDNA(OriGene,Rockville,MD)或hHER3ECDmC1C2 DNA克隆到pING-DNA疫苗载体中,该载体被设计成用强病毒启动子驱动HER3全长或人HER3ECDC1C2融合蛋白表达(2)。pING亲本载体含有以下成分:(i)来自CMV的Towne菌株的真核启动子和增强子;(ii)促进克隆的多接头区(polylinker region);(iii)供体和受体剪接位点和源自牛生长激素基因的多腺苷酸化信号序列;(iv)ColE1复制起点和(v)赋予卡那霉素抗性的基因。将得到的质粒进一步繁殖并在Df5α大肠杆菌感受态细胞中筛选。通过限制酶和DNA测序确认阳性克隆。来自单个菌落的过夜细菌生长物用于提取质粒。使用来自Qiagen的质粒纯化试剂盒从细菌制备质粒DNA。
Ad-hHER3FL/Ad-hHER3ECDC1C2的构建和生产
将人HER3全长和hHER3ECDC1C2 DNA亚克隆并定向连接到pShuttle CMV质粒多克隆位点(参见例如图1)。因此,得到的质粒将CMV-HER3FL/HER3ECDC1C2-polyA小基因盒置于Ad5基因组的E1区内。在卡那霉素选择下与pAdEASYΔpol,ΔpTP质粒的同源重组导致质粒pAdCMV/HER3FL/Δpp的分离。所述质粒含有缺失E1的Ad5基因组、聚合酶、pTP和E3基因。pAdCMV/HER3FL/Δpp质粒的PacI消化从细菌质粒序列中释放载体基因组,并且该~33kb质粒转染到C7细胞系中会产生最终病毒:Ad5[E1-,E2b-]-HER3FL或Ad5[E1-,E2b-]-HER3ECDC1C2。
小鼠
将雌性野生型BALB/c小鼠(Jackson Laboratory,Bar Harbor,ME,USA)在杜克大学医学中心无病原体动物研究设施中饲养和维持,并在6至8周龄时使用。具有FVB背景的人HER3转基因小鼠(MMTV-neu/MMTV-hHER3)是来自凯斯西储大学(Case Western ReserveUniversity)的Stan Gerson博士的捐赠物。HER3基因纯合的FVB小鼠是在杜克大学创建,并与BALB/c小鼠杂交以产生F1杂交HER3转基因小鼠(FVB x BALB/c),用于肿瘤植入实验。所描述的所有动物研究均由杜克大学医学中心机构动物护理和使用委员会(DukeUniversity Medical Center Institutional Animal Care&Use Committee)根据美国国家研究委员会生命科学委员会(Commission on Life Sciences of the NationalResearch Council)发布的指南进行批准。
IFN-γ酶联免疫吸附斑(ELISpot)测定
根据制造商的说明书进行小鼠IFN-γELISPOT测定(Mabtech Inc.,Cincinnati,OH)。在小鼠实验结束时,收集它们的脾脏并通过切碎和穿过40μm细胞筛网(CellStrainer)收获淋巴细胞。用红细胞裂解缓冲液(Sigma)裂解红细胞。将脾细胞(500,000个细胞/孔)在补充有10%马血清的RPMI-1640培养基(英杰)中孵育,并将HER3 ECD-TM肽混合物和/或HER3 ICD肽混合物(1.3μg/ml)用作刺激抗原。HIV肽混合物用作阴性对照,并且PMA(50ng/ml)和离子霉素(Ionomycin)(1μg/ml)的混合物用作测定的阳性对照。使用KSELISpot版本4.2软件,用高分辨率自动ELISpot读取器系统(Carl Zeiss,Inc.,Thornwood,NY,USA)读取膜。
抗HER3抗体的流式细胞术分析
当对小鼠实施安乐死时,收集血液并将分离的血清冷冻保存在-80℃直至测定时为止。通过慢病毒载体用HER3基因转导4T1细胞,以在细胞表面(4T1-HER3细胞)上表达人HER3。将4T1亲本细胞和4T1-HER3细胞都与稀释的小鼠血清(1:100)在冰上孵育30分钟,用PBS洗涤,然后与PE缀合的抗小鼠IgG二抗(1:200)在冰上共同孵育30分钟。用PBS洗涤两次后,通过LSRII机器(BD Biosciences,San Jose,CA)获得细胞以分析血清中HER3特异性抗体的存在。
用于抗HER3抗体的基于细胞的ELISA
通过慢病毒载体用HER3基因转导4T1细胞,以在细胞表面(4T1-HER3细胞)上表达人HER3。在测定前一天将4T1和4T1-HER3细胞置于96孔平底板(3×10E4个细胞/100μL培养基/孔)中,并在37℃孵育过夜。通过用DMEM培养基稀释(最终滴定1:50~1:6,400)制备小鼠血清,并向孔中加入50μl含有小鼠血清的培养基,并在冰上孵育1小时。将平板用PBS轻轻洗涤两次,然后用稀释的福尔马林(在PBS中的1%BSA中的福尔马林1:10稀释液)固定细胞,并在室温下孵育20分钟。用PBS洗涤三次后,向孔中加入50μL的1:2000稀释的HRP缀合山羊抗小鼠IgG,并在室温下孵育1小时。用PBS洗涤三次后,将TMB底物加入孔中(50μL/孔)并孵育约20分钟。通过加入50μL的1M H2SO4缓冲液来停止显色。使用BioRad平板读出器(PlateReader)(型号680)读取450nm处的吸光度。作为检测抗体的替代方法,使用近红外红(nIR)染料缀合的抗小鼠IgG(IRDye 800CW,LI-COR Biosciences,Lincoln,NE)作为二抗,并通过LI-COR Odyssey成像仪在800nm通道处检测nIR信号,并使用Image Studio软件(LI-COR)分析。
用小环DNA和质粒DNA接种小鼠
用氯胺酮/赛拉嗪/阿托品(ketamine/xylatine/atropine)麻醉小鼠,并将50μl盐水中的小环DNA(mcDNA-HER3/ECD-mC1C2,mcDNA-HER3-FL)或质粒DNA(pDNA-HER3/ECD-mC1C2,pDAN-HER3-FL)注入胫骨前肌。注射后不久,使用BTX ECM830电穿孔仪(HarvardApparatus,Holliston,MA)对腿进行活体电穿孔(50V,5个脉冲,脉冲长度60ms,间隔时间200ms)。通过将镊子型电极从第一位置垂直放置,对每只小鼠重复进行电穿孔。
用腺病毒载体接种小鼠
在全身麻醉下,将编码hHER3/ECD-C1C2的腺病毒(2.6×10E10个病毒粒子/40μl/注射)注射到小鼠的双侧足垫(每个足垫20μl,总共40μl/小鼠)中。
HER3转基因小鼠中的预防性抗肿瘤模型
通过肌内注射小环DNA(mcDNA-HER3/ECD-mC1C2)或质粒DNA(pDNA-HER3/ECD-mC1C2),然后使用BTX ECM830进行电穿孔,免疫HER3转基因F1杂交小鼠。通过将Ad[E1-,E2b-]-HER3/ECD-mC1C2(在40μL盐水中的2.6×1010个粒子)注射到双侧足垫进行腺病毒免疫。最后一次疫苗接种后一周,将小鼠用100μL盐水中的5×105个JC-HER3细胞(实验1)或3×105个4T1-HER3细胞(实验2)皮下接种到侧腹中。连续测量肿瘤尺寸,并使用下式计算肿瘤体积:长轴×(短轴)2×0.5。
结果
免疫原性测试:同源疫苗与具有mcDNA和编码hHER3/ECD-C1C2的腺病毒的异源初次免疫-加强免疫疫苗的比较。
在第0天,HER3转基因小鼠通过将编码hHER3/ECD-C1C2的小环DNA(25μg/小鼠)肌内注射到胫骨前肌来接受疫苗接种。很快,进行活体电穿孔。作为阴性对照,将盐水施用至肌肉中。为了与基于mcDNA的疫苗比较,通过足垫注射(2.6×10E10vp/小鼠)给小鼠接种Ad-HER3病毒。在第0、14和28天(2周间隔)对小鼠接种疫苗一次或三次,如下表1所示。最后一次疫苗接种后两周,对小鼠实施安乐死,并从个体小鼠收集脾脏和血液。通过IFN-γELISPOT测定(参见图2)和基于细胞的ELISA(参见图3)分别测试针对HER3抗原的细胞免疫应答和体液免疫应答。
表1:疫苗时间表:Ad:Ad-HER3/ECD-C1C2(2.6×10E10vp/注射),mcDNA:小环DNA-HER3/ECD-C1C2(25μg/注射)
重要的是,先用小环DNA-HER3/ECD-C1C2,后用Ad-HER3/ECD-C1C2重复接种会诱导针对HER3 ECD抗原的显著更强的细胞免疫应答(图2)。单独Ad-HER3的重复或单独小环DNA-HER3/ECD-C1C2的重复诱导抗HER3细胞应答,但基于ELISPOT测定结果与Ad-HER3单次疫苗接种的水平相似。为了产生体液免疫应答,基于细胞的ELISA(图3A)显示小环DNA-HER3/ECD-C1C2和随后的Ad-HER3/ECD-C1C2可以诱导最强的抗HER3抗体产生,然后重复Ad-HER3疫苗3次,或重复mcDNA-HER3/ECD-C1C2疫苗然后重复Ad-HER3疫苗。因此,基于这个免疫原性测试,接种mcDNA-HER3/ECD-C1C2疫苗两次和随后接种Ad-HER3/ECD-C1C2似乎诱导了大大增强的抗HER3细胞免疫应答和体液免疫应答。
为了证实通过HER3靶向异源初次免疫-加强免疫疫苗诱导的强抗肿瘤效果,我们在此证明了这种策略比如下所示的同源初次免疫-加强免疫疫苗具有更强的抗肿瘤效果。我们还利用编码HER3/ECD-C1C2的质粒DNA和腺病毒测试了异源初次免疫-加强免疫疫苗。
免疫原性和抗肿瘤功效测试:具有编码hHER3/ECD-C1C2的mcDNA/pDNA和腺病毒的异源初次免疫-加强免疫疫苗。
在第0天,HER3转基因小鼠通过将编码hHER3/ECD-C1C2的小环DNA或质粒DNA(25μg/小鼠,50μg/小鼠)肌内注射到胫骨前肌来接受疫苗接种。很快,进行活体电穿孔。作为阴性对照,将Ad-GFP载体(2.6×10E10vp/小鼠)施用于足垫。为了与基于mcDNA或pDNA的疫苗进行比较,通过足垫注射(2.6×10E10vp/小鼠)对小鼠接种Ad-HER3病毒。在第0、14和28天(2周间隔)对小鼠接种疫苗一次或三次,如下表2所示。
表2.疫苗时间表将Ad-HER3/ECD-C1C2或Ad-GFP(2.6×10E10vp/注射)注射到双侧足垫中。将mcDNA-HER3/ECD-C1C2(25μg/注射)或pDNA-HER3/ECD-C1C2肌内注射到右胫骨前肌,然后进行活体电穿孔。对左胫骨前肌进行加强免疫。
基于ELISPOT测定,先用pDNA的mcDNA后用Ad-HER3进行异源初次免疫-加强免疫诱导了强得多的抗HER3细胞免疫应答(图3B)。特别地,先接种pDNA疫苗后接种Ad诱导了最有效的抗HER3应答,比先接种mcDNA疫苗后接种Ad更强。在诱导的抗HER3体液免疫应答中证实了类似的趋势(图4)。如图4所示,先接种pDNA疫苗后接种Ad诱导了针对HER3的最强抗体应答,并且先接种mcDNA疫苗后接种Ad对于抗HER3抗体产生显示出相似或稍差的效果。最后一次疫苗接种后7天,将4T1-HER3细胞植入小鼠的侧腹,并监测肿瘤大小直至人道终点。小鼠在第28天全部安乐死,因为Ad-GFP疫苗组中的一些小鼠达到人道终点。每组的平均肿瘤体积如图5所示。与重复的Ad-HER3疫苗接种相比,具有mcDNA或质粒DNA的异源初次免疫-加强免疫疫苗更显著地抑制肿瘤生长(图5)。因为这些不同治疗的免疫原性和抗肿瘤效果之间存在一些差异,所以进行IFN-γELISPOT测定以确定实验结束时的细胞免疫应答(参见图6)。有趣的是,在实验结束时,与pDNA相比,mcDNA疫苗接种组显示出更强的抗HER3细胞免疫应答,这可能表明在活体电穿孔中mcDNA的抗原表达的持续时间更长,因此疫苗效果更持久。
pDNA/mcDNA/Ad载体的比较
如表3所总结,通过肌内注射质粒DNA-hHER3/ECDC1C2(25μg/小鼠)、小环DNA-hHER3/ECDC1C2(12.5μg/小鼠)或盐水对雌性HER3转基因小鼠进行疫苗接种,然后进行活体电穿孔(50V,5个脉冲,脉冲长度60ms,间隔时间200ms)。对每只小鼠重复电穿孔两次,将电极从第一位置垂直放置。将Ad[E1-]-hHER3(2.6×10E10vp/小鼠)注射到足垫中作为阳性对照。每组包括三只小鼠。疫苗接种两周后,处死小鼠并进行ELISPOT测定。每组有3只小鼠。
表3
将等摩尔量的小环DNA-hHER3/ECDC1C2和质粒DNA-hHER3/ECDC1C2肌内施用于小鼠,然后进行活体电穿孔。如IFN-γELISPOT测定所示,两种DNA疫苗均诱导HER3特异性细胞免疫应答(图8)。每个DNA疫苗组中的小鼠之间没有显着差异(图9和10),并且与接受mcDNA的小鼠相比,在接受pDNA疫苗的小鼠中观察到更强的细胞应答。Ad[E1-]-hHER3疫苗在单次疫苗接种后至少2周时间点时在这3种疫苗策略中诱导最强的T细胞应答。因此,为了与Ad疫苗具有相当的细胞免疫应答,可能需要更高剂量的或重复接种pDNA或mcDNA。pDNA疫苗在小鼠血清中诱导较弱至中等抗HER3抗体水平,而mcDNA在疫苗接种后2周时未诱导可检测水平的抗HER3抗体(图11)。pDNA疫苗和mcDNA疫苗可能不会在相对较短的时间段(2周)内诱导很强的抗体产生,但可能逐渐增加HER3特异性抗体产生的水平。
pDNA/mcDNA/Ad载体的比较实验2
如表4所总结,在第0天,通过肌内注射质粒DNA-hHER3/ECDC1C2(25μg/小鼠)、小环DNA-hHER3/ECDC1C2(25μg/小鼠)或盐水对雌性HER3转基因小鼠进行疫苗接种,接着进行活体电穿孔(50V,5个脉冲,脉冲长度60ms,间隔时间200ms)。对每只小鼠重复电穿孔两次,将电极从第一位置垂直放置。将Ad[E1-]-hHER3(2.6×10E10vp/小鼠)注射到足垫中作为阳性对照。每组包括两只或3只小鼠。在第14天(初次免疫疫苗接种后两周),对小鼠重复相同的疫苗接种。在第21天(加强疫苗(boosting vaccine)后一周),处死小鼠并进行ELISPOT测定。
表4
基于IFN-γELISPOT测定的结果(图12),与用质粒DNA-hHER3/ECDC1C2接种两次的小鼠相比,当施加等量的DNA时,在用小环DNA-hHER3/ECDC1C2接种两次的小鼠中观察到更强的抗HER3细胞免疫应答。正如预期的那样,只有细胞外结构域才能看到应答,但细胞内结构域却看不到应答。图13显示了ELISPOT测定的代表性情况,其中用来自接种有小环DNA-hHER3/ECDC1C2的小鼠的脾细胞产生IFN-γ阳性斑点。作为刺激性抗原,使用HER3蛋白的ECD、ICD或ECD加ICD,并且HIV肽混合物用作阴性对照。重要的是,与在免疫测定之前仅对小鼠进行一次免疫接种的比较实验1(图8-10)相反,重复接种mcDNA比重复接种pDNA疫苗更有效地诱导抗原特异性细胞免疫应答,可能是因为通过mcDNA活体电穿孔的抗原表达持续时间更长,因此疫苗效果更持久。此外,如ELISPOT测定所示,重复的Ad[E1-]-hHER3疫苗不再具有比mcDNA或pDNA疫苗更强的抗HER3细胞应答,可能是因为第一次疫苗接种后产生的抗Ad抗体的中和作用。根据基于细胞的ELISA检测小鼠中的抗HER3抗体水平的结果,mcDNA和pDNA对于抗HER3抗体产生显示出类似作用(图14)。因此,已经提出,与重复的pDNA疫苗相比,用mcDNA疫苗重复接种疫苗在诱导抗原特异性T细胞应答方面更有效,而这两种疫苗接种策略具有相似的诱导体液免疫应答的效力。
参考文献
1.Delcayre A,Estelles A,Sperinde J,Roulon T,Paz P,Aguilar B,Villanueva J,Khine S和Le Pecq JB.《外泌体展示技术:对于新颖诊断剂和治疗剂的开发的应用(Exosome Display technology:applications to the development of newdiagnostics and therapeutics.)》Blood cells,molecules&diseases.2005;35(2):158-68.
2.Tiriveedhi V,Tucker N,Herndon J,Li L,Sturmoski M,Ellis M,Ma C,Naughton M,Lockhart AC,Gao F等人《乳腺珠蛋白-DNA疫苗在稳定转移性乳腺癌患者中的生物学功效的安全性和初步证据(Safety and preliminary evidence of biologicefficacy of a mammaglobin-a DNA vaccine in patients with stable metastaticbreast cancer.)》Clinical cancer research:an official journal of the AmericanAssociation for Cancer Research.2014;20(23):5964-75.
序列表
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H·K·莱尔利(Nationality: US)
T·长田
Z·C·哈特曼
<120> 癌症疫苗和递送方法
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Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
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Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
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Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
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His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
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Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
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Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
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Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
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Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
945 950 955 960
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
965 970 975
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
980 985 990
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu
995 1000 1005
Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly Ala
1010 1015 1020
Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg Ser
1025 1030 1035
Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu Glu
1040 1045 1050
Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser Asp
1055 1060 1065
Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu Gln
1070 1075 1080
Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser Glu
1085 1090 1095
Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val Ala
1100 1105 1110
Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro Asp
1115 1120 1125
Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro Ala
1130 1135 1140
Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Ala Lys Thr Leu Ser
1145 1150 1155
Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly Gly
1160 1165 1170
Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala Ala
1175 1180 1185
Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp Asn
1190 1195 1200
Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro Pro
1205 1210 1215
Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr Leu
1220 1225 1230
Gly Leu Asp Val Pro Val
1235
<210> 4
<211> 111
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(111)
<223> 智人HER2多肽
<400> 4
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn
100 105 110
<210> 5
<211> 668
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(668)
<223> 智人HER2多肽
<400> 5
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Pro Leu Thr Ser Ile Val Ser
625 630 635 640
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
645 650 655
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys
660 665
<210> 6
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人ESR1多肽
<400> 6
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Asn Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 7
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人ESR1多肽
<400> 7
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Ser Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 8
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人ESR1多肽
<400> 8
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Tyr Gly Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 9
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人ESR1多肽
<400> 9
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Arg Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Tyr Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 10
<211> 315
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(315)
<223> 乳凝集素C1C2
<400> 10
Ser Thr Gln Leu Gly Met Glu Gly Gly Ala Ile Ala Asp Ser Gln Ile
1 5 10 15
Ser Ala Ser Ser Val Tyr Met Gly Phe Met Gly Leu Gln Arg Trp Gly
20 25 30
Pro Glu Leu Ala Arg Leu Tyr Arg Thr Gly Ile Val Asn Ala Trp Thr
35 40 45
Ala Ser Asn Tyr Asp Ser Lys Pro Trp Ile Gln Val Asn Leu Leu Arg
50 55 60
Lys Met Arg Val Ser Gly Val Met Thr Gln Gly Ala Ser Arg Ala Gly
65 70 75 80
Arg Ala Glu Tyr Leu Lys Thr Phe Lys Val Ala Tyr Ser Leu Asp Gly
85 90 95
Arg Lys Phe Glu Phe Ile Gln Asp Glu Ser Gly Gly Asp Lys Glu Phe
100 105 110
Leu Gly Asn Leu Asp Asn Asn Ser Leu Lys Val Asn Met Phe Asn Pro
115 120 125
Thr Leu Glu Ala Gln Tyr Ile Lys Leu Tyr Pro Val Ser Cys His Arg
130 135 140
Gly Cys Thr Leu Arg Phe Glu Leu Leu Gly Cys Glu Leu His Gly Cys
145 150 155 160
Ser Glu Pro Leu Gly Leu Lys Asn Asn Thr Ile Pro Asp Ser Gln Met
165 170 175
Ser Ala Ser Ser Ser Tyr Lys Thr Trp Asn Leu Arg Ala Phe Gly Trp
180 185 190
Tyr Pro His Leu Gly Arg Leu Asp Asn Gln Gly Lys Ile Asn Ala Trp
195 200 205
Thr Ala Gln Ser Asn Ser Ala Lys Glu Trp Leu Gln Val Asp Leu Gly
210 215 220
Thr Gln Arg Gln Val Thr Gly Ile Ile Thr Gln Gly Ala Arg Asp Phe
225 230 235 240
Gly His Ile Gln Tyr Val Ala Ser Tyr Lys Val Ala His Ser Asp Asp
245 250 255
Gly Val Gln Trp Thr Val Tyr Glu Glu Gln Gly Ser Ser Lys Val Phe
260 265 270
Gln Gly Asn Leu Asp Asn Asn Ser His Lys Lys Asn Ile Phe Glu Lys
275 280 285
Pro Phe Met Ala Arg Tyr Val Arg Val Leu Pro Val Ser Trp His Asn
290 295 300
Arg Ile Thr Leu Arg Leu Glu Leu Leu Gly Cys
305 310 315
<210> 11
<211> 2880
<212> DNA
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(2880)
<223> 人Her3ECDC1C2的DNA序列
<400> 11
accatgaggg cgaacgacgc tctgcaggtg ctgggcttgc ttttcagcct ggcccggggc 60
tccgaggtgg gcaactctca ggcagtgtgt cctgggactc tgaatggcct gagtgtgacc 120
ggcgatgctg agaaccaata ccagacactg tacaagctct acgagaggtg tgaggtggtg 180
atggggaacc ttgagattgt gctcacggga cacaatgccg acctctcctt cctgcagtgg 240
attcgagaag tgacaggcta tgtcctcgtg gccatgaatg aattctctac tctaccattg 300
cccaacctcc gcgtggtgcg agggacccag gtctacgatg ggaagtttgc catcttcgtc 360
atgttgaact ataacaccaa ctccagccac gctctgcgcc agctccgctt gactcagctc 420
accgagattc tgtcaggggg tgtttatatt gagaagaacg ataagctttg tcacatggac 480
acaattgact ggagggacat cgtgagggac cgagatgctg agatagtggt gaaggacaat 540
ggcagaagct gtcccccctg tcatgaggtt tgcaaggggc gatgctgggg tcctggatca 600
gaagactgcc agacattgac caagaccatc tgtgctcctc agtgtaatgg tcactgcttt 660
gggcccaacc ccaaccagtg ctgccatgat gagtgtgccg ggggctgctc aggccctcag 720
gacacagact gctttgcctg ccggcacttc aatgacagtg gagcctgtgt acctcgctgt 780
ccacagcctc ttgtctacaa caagctaact ttccagctgg aacccaatcc ccacaccaag 840
tatcagtatg gaggagtttg tgtagccagc tgtccccata actttgtggt ggatcaaaca 900
tcctgtgtca gggcctgtcc tcctgacaag atggaagtag ataaaaatgg gctcaagatg 960
tgtgagcctt gtgggggact atgtcccaaa gcctgtgagg gaacaggctc tgggagccgc 1020
ttccagactg tggactcgag caacattgat ggatttgtga actgcaccaa gatcctgggc 1080
aacctggact ttctgatcac cggcctcaat ggagacccct ggcacaagat ccctgccctg 1140
gacccagaga agctcaatgt cttccggaca gtacgggaga tcacaggtta cctgaacatc 1200
cagtcctggc cgccccacat gcacaacttc agtgtttttt ccaatttgac aaccattgga 1260
ggcagaagcc tctacaaccg gggcttctca ttgttgatca tgaagaactt gaatgtcaca 1320
tctctgggct tccgatccct gaaggaaatt agtgctgggc gtatctatat aagtgccaat 1380
aggcagctct gctaccacca ctctttgaac tggaccaagg tgcttcgggg gcctacggaa 1440
gagcgactag acatcaagca taatcggccg cgcagagact gcgtggcaga gggcaaagtg 1500
tgtgacccac tgtgctcctc tgggggatgc tggggcccag gccctggtca gtgcttgtcc 1560
tgtcgaaatt atagccgagg aggtgtctgt gtgacccact gcaactttct gaatggggag 1620
cctcgagaat ttgcccatga ggccgaatgc ttctcctgcc acccggaatg ccaacccatg 1680
gagggcactg ccacatgcaa tggctcgggc tctgatactt gtgctcaatg tgcccatttt 1740
cgagatgggc cccactgtgt gagcagctgc ccccatggag tcctaggtgc caagggccca 1800
atctacaagt acccagatgt tcagaatgaa tgtcggccct gccatgagaa ctgcacccag 1860
gggtgtaaag gaccagagct tcaagactgt ttaggacaaa cactggtgct gatcggcaaa 1920
acccatctga catctacaca gctgggcatg gaagggggcg ccattgctga ttcacagatt 1980
tccgcctcgt ctgtgtatat gggtttcatg ggcttgcagc gctggggccc ggagctggct 2040
cgtctgtacc gcacagggat cgtcaatgcc tggacagcca gcaactatga tagcaagccc 2100
tggatccagg tgaaccttct gcggaagatg cgggtatcag gtgtgatgac gcagggtgcc 2160
agccgtgccg ggagggcgga gtacctgaag accttcaagg tggcttacag cctcgacgga 2220
cgcaagtttg agttcatcca ggatgaaagc ggtggagaca aggagttttt gggtaacctg 2280
gacaacaaca gcctgaaggt taacatgttc aacccgactc tggaggcaca gtacataaag 2340
ctgtaccctg tttcgtgcca ccgcggctgc accctccgct tcgagctcct gggctgtgag 2400
ttgcacggat gttctgagcc cctgggcctg aagaataaca caattcctga cagccagatg 2460
tcagcctcca gcagctacaa gacatggaac ctgcgtgctt ttggctggta cccccacttg 2520
ggaaggctgg ataatcaggg caagatcaat gcctggacgg ctcagagcaa cagtgccaag 2580
gaatggctgc aggttgacct gggcactcag aggcaagtga caggaatcat cacccagggg 2640
gcccgtgact ttggccacat ccagtatgtg gcgtcctaca aggtagccca cagtgatgat 2700
ggtgtgcagt ggactgtata tgaggagcaa ggaagcagca aggtcttcca gggcaacttg 2760
gacaacaact cccacaagaa gaacatcttc gagaaaccct tcatggctcg ctacgtgcgt 2820
gtccttccag tgtcctggca taaccgcatc accctgcgcc tggagctgct gggctgttaa 2880
<210> 12
<211> 958
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(958)
<223> HER3C1C2-乳凝集素蛋白(多肽)序列
<400> 12
Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
1 5 10 15
Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30
Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
35 40 45
Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
50 55 60
Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95
Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
100 105 110
Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
115 120 125
His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
145 150 155 160
Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
165 170 175
Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
180 185 190
Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
210 215 220
Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
225 230 235 240
Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
245 250 255
Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270
Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
275 280 285
Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
290 295 300
Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
305 310 315 320
Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
325 330 335
Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
340 345 350
Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu
355 360 365
Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu
370 375 380
Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln
385 390 395 400
Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr
405 410 415
Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile
420 425 430
Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu
435 440 445
Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr
450 455 460
His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
465 470 475 480
Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu
485 490 495
Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro
500 505 510
Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val
515 520 525
Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala
530 535 540
His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu
545 550 555 560
Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
565 570 575
Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly
580 585 590
Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn
595 600 605
Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro
610 615 620
Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr
625 630 635 640
His Leu Thr Ser Thr Gln Leu Gly Met Glu Gly Gly Ala Ile Ala Asp
645 650 655
Ser Gln Ile Ser Ala Ser Ser Val Tyr Met Gly Phe Met Gly Leu Gln
660 665 670
Arg Trp Gly Pro Glu Leu Ala Arg Leu Tyr Arg Thr Gly Ile Val Asn
675 680 685
Ala Trp Thr Ala Ser Asn Tyr Asp Ser Lys Pro Trp Ile Gln Val Asn
690 695 700
Leu Leu Arg Lys Met Arg Val Ser Gly Val Met Thr Gln Gly Ala Ser
705 710 715 720
Arg Ala Gly Arg Ala Glu Tyr Leu Lys Thr Phe Lys Val Ala Tyr Ser
725 730 735
Leu Asp Gly Arg Lys Phe Glu Phe Ile Gln Asp Glu Ser Gly Gly Asp
740 745 750
Lys Glu Phe Leu Gly Asn Leu Asp Asn Asn Ser Leu Lys Val Asn Met
755 760 765
Phe Asn Pro Thr Leu Glu Ala Gln Tyr Ile Lys Leu Tyr Pro Val Ser
770 775 780
Cys His Arg Gly Cys Thr Leu Arg Phe Glu Leu Leu Gly Cys Glu Leu
785 790 795 800
His Gly Cys Ser Glu Pro Leu Gly Leu Lys Asn Asn Thr Ile Pro Asp
805 810 815
Ser Gln Met Ser Ala Ser Ser Ser Tyr Lys Thr Trp Asn Leu Arg Ala
820 825 830
Phe Gly Trp Tyr Pro His Leu Gly Arg Leu Asp Asn Gln Gly Lys Ile
835 840 845
Asn Ala Trp Thr Ala Gln Ser Asn Ser Ala Lys Glu Trp Leu Gln Val
850 855 860
Asp Leu Gly Thr Gln Arg Gln Val Thr Gly Ile Ile Thr Gln Gly Ala
865 870 875 880
Arg Asp Phe Gly His Ile Gln Tyr Val Ala Ser Tyr Lys Val Ala His
885 890 895
Ser Asp Asp Gly Val Gln Trp Thr Val Tyr Glu Glu Gln Gly Ser Ser
900 905 910
Lys Val Phe Gln Gly Asn Leu Asp Asn Asn Ser His Lys Lys Asn Ile
915 920 925
Phe Glu Lys Pro Phe Met Ala Arg Tyr Val Arg Val Leu Pro Val Ser
930 935 940
Trp His Asn Arg Ile Thr Leu Arg Leu Glu Leu Leu Gly Cys
945 950 955
<210> 13
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 13
Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr
1 5 10
<210> 14
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 14
Asp Lys Leu Cys His Met Asp Thr Ile Asp Trp Arg Asp Ile Val
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 15
Pro Cys His Glu Val Cys Lys
1 5
<210> 16
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 16
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro
1 5 10 15
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 17
Asn Gly Asp Pro Trp His Lys
1 5
<210> 18
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 18
Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly
1 5 10
<210> 19
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 19
Cys Pro His Gly Val Leu Gly Ala Lys Gly Pro
1 5 10
<210> 20
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 20
Ile Ala Gly Leu Val Val Ile Phe Met Met Leu Gly Gly Thr Phe
1 5 10 15
<210> 21
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 21
Leu Glu Arg Gly Glu Ser Ile Glu Pro Leu Asp
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 22
Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile
1 5 10
<210> 23
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 23
Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp
1 5 10 15
<210> 24
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 24
Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr Ala Gly Leu
1 5 10 15
<210> 25
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 25
Glu Ser Gly Pro Gly Ile Ala Pro
1 5
<210> 26
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 26
Thr Leu Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser
1 5 10 15
<210> 27
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 27
Glu Ala Glu Leu Gln Glu Lys Val Ser Met Cys Arg Ser Arg Ser
1 5 10 15
<210> 28
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 28
Glu Glu Asp Val Asn Gly Tyr Val Met Pro Asp
1 5 10
<210> 29
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 29
Met Pro Thr Ala Gly Thr Thr
1 5
<210> 30
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 衍生自HER3蛋白序列的合成肽
<400> 30
Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala Met
1 5 10
<210> 31
<211> 3720
<212> DNA
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(3720)
<223> 智人HER2多核苷酸
<400> 31
atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc 60
gcgagcaccc aagtgtgcac cggcacagac atgaagctgc ggctccctgc cagtcccgag 120
acccacctgg acatgctccg ccacctctac cagggctgcc aggtggtgca gggaaacctg 180
gaactcacct acctgcccac caatgccagc ctgtccttcc tgcaggatat ccaggaggtg 240
cagggctacg tgctcatcgc tcacaaccaa gtgaggcagg tcccactgca gaggctgcgg 300
attgtgcgag gcacccagct ctttgaggac aactatgccc tggccgtgct agacaatgga 360
gacccgctga acaataccac ccctgtcaca ggggcctccc caggaggcct gcgggagctg 420
cagcttcgaa gcctcacaga gatcttgaaa ggaggggtct tgatccagcg gaacccccag 480
ctctgctacc aggacacgat tttgtggaag gacatcttcc acaagaacaa ccagctggct 540
ctcacactga tagacaccaa ccgctctcgg gcctgccacc cctgttctcc gatgtgtaag 600
ggctcccgct gctggggaga gagttctgag gattgtcaga gcctgacgcg cactgtctgt 660
gccggtggct gtgcccgctg caaggggcca ctgcccactg actgctgcca tgagcagtgt 720
gctgccggct gcacgggccc caagcactct gactgcctgg cctgcctcca cttcaaccac 780
agtggcatct gtgagctgca ctgcccagcc ctggtcacct acaacacaga cacgtttgag 840
tccatgccca atcccgaggg ccggtataca ttcggcgcca gctgtgtgac tgcctgtccc 900
tacaactacc tttctacgga cgtgggatcc tgcaccctcg tctgccccct gcacaaccaa 960
gaggtgacag cagaggatgg aacacagcgg tgtgagaagt gcagcaagcc ctgtgcccga 1020
gtgtgctatg gtctgggcat ggagcacttg cgagaggtga gggcagttac cagtgccaat 1080
atccaggagt ttgctggctg caagaagatc tttgggagcc tggcatttct gccggagagc 1140
tttgatgggg acccagcctc caacactgcc ccgctccagc cagagcagct ccaagtgttt 1200
gagactctgg aagagatcac aggttaccta tacatctcag catggccgga cagcctgcct 1260
gacctcagcg tcttccagaa cctgcaagta atccggggac gaattctgca caatggcgcc 1320
tactcgctga ccctgcaagg gctgggcatc agctggctgg ggctgcgctc actgagggaa 1380
ctgggcagtg gactggccct catccaccat aacacccacc tctgcttcgt gcacacggtg 1440
ccctgggacc agctctttcg gaacccgcac caagctctgc tccacactgc caaccggcca 1500
gaggacgagt gtgtgggcga gggcctggcc tgccaccagc tgtgcgcccg agggcactgc 1560
tggggtccag ggcccaccca gtgtgtcaac tgcagccagt tccttcgggg ccaggagtgc 1620
gtggaggaat gccgagtact gcaggggctc cccagggagt atgtgaatgc caggcactgt 1680
ttgccgtgcc accctgagtg tcagccccag aatggctcag tgacctgttt tggaccggag 1740
gctgaccagt gtgtggcctg tgcccactat aaggaccctc ccttctgcgt ggcccgctgc 1800
cccagcggtg tgaaacctga cctctcctac atgcccatct ggaagtttcc agatgaggag 1860
ggcgcatgcc agccttgccc catcaactgc acccactccc ctctgacgtc catcgtctct 1920
gcggtggttg gcattctgct ggtcgtggtc ttgggggtgg tctttgggat cctcatcaag 1980
cgacggcagc agaagatccg gaagtacacg atgcggagac tgctgcagga aacggagctg 2040
gtggagccgc tgacacctag cggagcgatg cccaaccagg cgcagatgcg gatcctgaaa 2100
gagacggagc tgaggaaggt gaaggtgctt ggatctggcg cttttggcac agtctacaag 2160
ggcatctgga tccctgatgg ggagaatgtg aaaattccag tggccatcaa agtgttgagg 2220
gaaaacacat cccccaaagc caacaaagaa atcttagacg aagcatacgt gatggctggt 2280
gtgggctccc catatgtctc ccgccttctg gggatctgcc tgacatccac ggtgcagctg 2340
gtgacacagc ttatgcccta tggctgcctc ttagaccatg tccgggaaaa ccgcggacgc 2400
ctgggctccc aggacctgct gaactggtgt atgcagattg ccaaggggat gagctacctg 2460
gaggatgtgc ggctcgtaca cagggacttg gccgctcgga acgtgctggt caagagtccc 2520
aaccatgtca aaattacaga cttcgggctg gctcggctgc tggacattga cgagacagag 2580
taccatgcag atgggggcaa ggtgcccatc aagtggatgg cgctggagtc cattctccgc 2640
cggcggttca cccaccagag tgatgtgtgg agttatggtg tgactgtgtg ggagctgatg 2700
acttttgggg ccaaacctta cgatgggatc ccagcccggg agatccctga cctgctggaa 2760
aagggggagc ggctgcccca gccccccatc tgcaccattg atgtctacat gatcatggtc 2820
aaatgttgga tgattgactc tgaatgtcgg ccaagattcc gggagttggt gtctgaattc 2880
tcccgcatgg ccagggaccc ccagcgcttt gtggtcatcc agaatgagga cttgggccca 2940
gccagtccct tggacagcac cttctaccgc tcactgctgg aggacgatga catgggggac 3000
ctggtggatg ctgaggagta tctggtaccc cagcagggct tcttctgtcc agaccctgcc 3060
ccgggcgctg ggggcatggt ccaccacagg caccgcagct catctaccag gagtggcggt 3120
ggggacctga cactagggct ggagccctct gaagaggagg cccccaggtc tccactggca 3180
ccctccgaag gggctggctc cgatgtattt gatggtgacc tgggaatggg ggcagccaag 3240
gggctgcaaa gcctccccac acatgacccc agccctctac agcggtacag tgaggacccc 3300
acagtacccc tgccctctga gactgatggc tacgttgccc ccctgacctg cagcccccag 3360
cctgaatatg tgaaccagcc agatgttcgg ccccagcccc cttcgccccg agagggccct 3420
ctgcctgctg cccgacctgc tggtgccact ctggaaaggg ccaagactct ctccccaggg 3480
aagaatgggg tcgtcaaaga cgtttttgcc tttgggggtg ccgtggagaa ccccgagtac 3540
ttgacacccc agggaggagc tgcccctcag ccccaccctc ctcctgcctt cagcccagcc 3600
ttcgacaacc tctattactg ggaccaggac ccaccagagc ggggggctcc acccagcacc 3660
ttcaaaggga cacctacggc agagaaccca gagtacctgg gtctggacgt gccagtgtga 3720
<210> 32
<211> 335
<212> DNA
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(335)
<223> 智人HER2多核苷酸
<400> 32
atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc 60
gcgagcaccc aagtgtgcac cggcacagac atgaagctgc ggctccctgc cagtcccgag 120
acccacctgg acatgctccg ccacctctac cagggctgcc aggtggtgca gggaaacctg 180
gaactcacct acctgcccac caatgccagc ctgtccttcc tgcaggatat ccaggaggtg 240
cagggctacg tgctcatcgc tcacaaccaa gtgaggcagg tcccactgca gaggctgcgg 300
attgtgcgag gcacccagct ctttgaggac aacta 335
<210> 33
<211> 3720
<212> DNA
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(3720)
<223> 智人HER2多核苷酸
<400> 33
atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc 60
gcgagcaccc aagtgtgcac cggcacagac atgaagctgc ggctccctgc cagtcccgag 120
acccacctgg acatgctccg ccacctctac cagggctgcc aggtggtgca gggaaacctg 180
gaactcacct acctgcccac caatgccagc ctgtccttcc tgcaggatat ccaggaggtg 240
cagggctacg tgctcatcgc tcacaaccaa gtgaggcagg tcccactgca gaggctgcgg 300
attgtgcgag gcacccagct ctttgaggac aactatgccc tggccgtgct agacaatgga 360
gacccgctga acaataccac ccctgtcaca ggggcctccc caggaggcct gcgggagctg 420
cagcttcgaa gcctcacaga gatcttgaaa ggaggggtct tgatccagcg gaacccccag 480
ctctgctacc aggacacgat tttgtggaag gacatcttcc acaagaacaa ccagctggct 540
ctcacactga tagacaccaa ccgctctcgg gcctgccacc cctgttctcc gatgtgtaag 600
ggctcccgct gctggggaga gagttctgag gattgtcaga gcctgacgcg cactgtctgt 660
gccggtggct gtgcccgctg caaggggcca ctgcccactg actgctgcca tgagcagtgt 720
gctgccggct gcacgggccc caagcactct gactgcctgg cctgcctcca cttcaaccac 780
agtggcatct gtgagctgca ctgcccagcc ctggtcacct acaacacaga cacgtttgag 840
tccatgccca atcccgaggg ccggtataca ttcggcgcca gctgtgtgac tgcctgtccc 900
tacaactacc tttctacgga cgtgggatcc tgcaccctcg tctgccccct gcacaaccaa 960
gaggtgacag cagaggatgg aacacagcgg tgtgagaagt gcagcaagcc ctgtgcccga 1020
gtgtgctatg gtctgggcat ggagcacttg cgagaggtga gggcagttac cagtgccaat 1080
atccaggagt ttgctggctg caagaagatc tttgggagcc tggcatttct gccggagagc 1140
tttgatgggg acccagcctc caacactgcc ccgctccagc cagagcagct ccaagtgttt 1200
gagactctgg aagagatcac aggttaccta tacatctcag catggccgga cagcctgcct 1260
gacctcagcg tcttccagaa cctgcaagta atccggggac gaattctgca caatggcgcc 1320
tactcgctga ccctgcaagg gctgggcatc agctggctgg ggctgcgctc actgagggaa 1380
ctgggcagtg gactggccct catccaccat aacacccacc tctgcttcgt gcacacggtg 1440
ccctgggacc agctctttcg gaacccgcac caagctctgc tccacactgc caaccggcca 1500
gaggacgagt gtgtgggcga gggcctggcc tgccaccagc tgtgcgcccg agggcactgc 1560
tggggtccag ggcccaccca gtgtgtcaac tgcagccagt tccttcgggg ccaggagtgc 1620
gtggaggaat gccgagtact gcaggggctc cccagggagt atgtgaatgc caggcactgt 1680
ttgccgtgcc accctgagtg tcagccccag aatggctcag tgacctgttt tggaccggag 1740
gctgaccagt gtgtggcctg tgcccactat aaggaccctc ccttctgcgt ggcccgctgc 1800
cccagcggtg tgaaacctga cctctcctac atgcccatct ggaagtttcc agatgaggag 1860
ggcgcatgcc agccttgccc catcaactgc acccactccc ctctgacgtc catcgtctct 1920
gcggtggttg gcattctgct ggtcgtggtc ttgggggtgg tctttgggat cctcatcaag 1980
cgacggcagc agaagatccg gaagtagacg atgcggagac tgctgcagga aacggagctg 2040
gtggagccgc tgacacctag cggagcgatg cccaaccagg cgcagatgcg gatcctgaaa 2100
gagacggagc tgaggaaggt gaaggtgctt ggatctggcg cttttggcac agtctacaag 2160
ggcatctgga tccctgatgg ggagaatgtg aaaattccag tggccatcaa agtgttgagg 2220
gaaaacacat cccccaaagc caacaaagaa atcttagacg aagcatacgt gatggctggt 2280
gtgggctccc catatgtctc ccgccttctg gggatctgcc tgacatccac ggtgcagctg 2340
gtgacacagc ttatgcccta tggctgcctc ttagaccatg tccgggaaaa ccgcggacgc 2400
ctgggctccc aggacctgct gaactggtgt atgcagattg ccaaggggat gagctacctg 2460
gaggatgtgc ggctcgtaca cagggacttg gccgctcgga acgtgctggt caagagtccc 2520
aaccatgtca aaattacaga cttcgggctg gctcggctgc tggacattga cgagacagag 2580
taccatgcag atgggggcaa ggtgcccatc aagtggatgg cgctggagtc cattctccgc 2640
cggcggttca cccaccagag tgatgtgtgg agttatggtg tgactgtgtg ggagctgatg 2700
acttttgggg ccaaacctta cgatgggatc ccagcccggg agatccctga cctgctggaa 2760
aagggggagc ggctgcccca gccccccatc tgcaccattg atgtctacat gatcatggtc 2820
aaatgttgga tgattgactc tgaatgtcgg ccaagattcc gggagttggt gtctgaattc 2880
tcccgcatgg ccagggaccc ccagcgcttt gtggtcatcc agaatgagga cttgggccca 2940
gccagtccct tggacagcac cttctaccgc tcactgctgg aggacgatga catgggggac 3000
ctggtggatg ctgaggagta tctggtaccc cagcagggct tcttctgtcc agaccctgcc 3060
ccgggcgctg ggggcatggt ccaccacagg caccgcagct catctaccag gagtggcggt 3120
ggggacctga cactagggct ggagccctct gaagaggagg cccccaggtc tccactggca 3180
ccctccgaag gggctggctc cgatgtattt gatggtgacc tgggaatggg ggcagccaag 3240
gggctgcaaa gcctccccac acatgacccc agccctctac agcggtacag tgaggacccc 3300
acagtacccc tgccctctga gactgatggc tacgttgccc ccctgacctg cagcccccag 3360
cctgaatatg tgaaccagcc agatgttcgg ccccagcccc cttcgccccg agagggccct 3420
ctgcctgctg cccgacctgc tggtgccact ctggaaaggg ccaagactct ctccccaggg 3480
aagaatgggg tcgtcaaaga cgtttttgcc tttgggggtg ccgtggagaa ccccgagtac 3540
ttgacacccc agggaggagc tgcccctcag ccccaccctc ctcctgcctt cagcccagcc 3600
ttcgacaacc tctattactg ggaccaggac ccaccagagc ggggggctcc acccagcacc 3660
ttcaaaggga cacctacggc agagaaccca gagtacctgg gtctggacgt gccagtgtga 3720
<210> 34
<211> 331
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(331)
<223> 智人HER2多肽
<400> 34
Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
1 5 10 15
Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30
Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
35 40 45
Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
50 55 60
Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95
Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
100 105 110
Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
115 120 125
His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
145 150 155 160
Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
165 170 175
Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
180 185 190
Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
210 215 220
Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
225 230 235 240
Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
245 250 255
Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270
Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
275 280 285
Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
290 295 300
Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
305 310 315 320
Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Phe
325 330
<210> 35
<211> 1342
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(1342)
<223> 智人HER2多肽
<400> 35
Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
1 5 10 15
Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30
Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
35 40 45
Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
50 55 60
Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95
Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
100 105 110
Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
115 120 125
His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
145 150 155 160
Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
165 170 175
Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
180 185 190
Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
210 215 220
Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
225 230 235 240
Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
245 250 255
Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270
Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
275 280 285
Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
290 295 300
Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
305 310 315 320
Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
325 330 335
Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
340 345 350
Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu
355 360 365
Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu
370 375 380
Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln
385 390 395 400
Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr
405 410 415
Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile
420 425 430
Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu
435 440 445
Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr
450 455 460
His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
465 470 475 480
Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu
485 490 495
Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro
500 505 510
Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val
515 520 525
Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala
530 535 540
His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Gly
545 550 555 560
Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
565 570 575
Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly
580 585 590
Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn
595 600 605
Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro
610 615 620
Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr
625 630 635 640
His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe
645 650 655
Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln
660 665 670
Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu
675 680 685
Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe
690 695 700
Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe
705 710 715 720
Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys
725 730 735
Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser
740 745 750
Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His
755 760 765
Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln
770 775 780
Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg
785 790 795 800
Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val
805 810 815
Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His
820 825 830
Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val
835 840 845
Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys
850 855 860
Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu
865 870 875 880
Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser
885 890 895
Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr
900 905 910
Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu
915 920 925
Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met
930 935 940
Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu
945 950 955 960
Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu
965 970 975
Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro
980 985 990
His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu
995 1000 1005
Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala
1010 1015 1020
Thr Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu
1025 1030 1035
Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly
1040 1045 1050
Tyr Met Pro Met Asn Gln Gly Asn Leu Gly Gly Ser Cys Gln Glu
1055 1060 1065
Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser
1070 1075 1080
Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu
1085 1090 1095
Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu Lys Val Ser
1100 1105 1110
Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly
1115 1120 1125
Asp Ser Ala Tyr His Ser Gln Arg His Ser Leu Leu Thr Pro Val
1130 1135 1140
Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly
1145 1150 1155
Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg
1160 1165 1170
Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr
1175 1180 1185
Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg
1190 1195 1200
Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu
1205 1210 1215
Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala
1220 1225 1230
Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile
1235 1240 1245
Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met
1250 1255 1260
Asn Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala
1265 1270 1275
Met Gly Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg
1280 1285 1290
Ala Phe Gln Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala
1295 1300 1305
Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe
1310 1315 1320
Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn
1325 1330 1335
Ala Gln Arg Thr
1340
<210> 36
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人HER2多肽
<400> 36
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Asn Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 37
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人HER2多肽
<400> 37
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Ser Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 38
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人HER多肽
<400> 38
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Lys Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Tyr Gly Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 39
<211> 595
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(595)
<223> 智人HER2多肽
<400> 39
Met Thr Met Thr Leu His Thr Lys Ala Ser Gly Met Ala Leu Leu His
1 5 10 15
Gln Ile Gln Gly Asn Glu Leu Glu Pro Leu Asn Arg Pro Gln Leu Lys
20 25 30
Ile Pro Leu Glu Arg Pro Leu Gly Glu Val Tyr Leu Asp Ser Ser Lys
35 40 45
Pro Ala Val Tyr Asn Tyr Pro Glu Gly Ala Ala Tyr Glu Phe Asn Ala
50 55 60
Ala Ala Ala Ala Asn Ala Gln Val Tyr Gly Gln Thr Gly Leu Pro Tyr
65 70 75 80
Gly Pro Gly Ser Glu Ala Ala Ala Phe Gly Ser Asn Gly Leu Gly Gly
85 90 95
Phe Pro Pro Leu Asn Ser Val Ser Pro Ser Pro Leu Met Leu Leu His
100 105 110
Pro Pro Pro Gln Leu Ser Pro Phe Leu Gln Pro His Gly Gln Gln Val
115 120 125
Pro Tyr Tyr Leu Glu Asn Glu Pro Ser Gly Tyr Thr Val Arg Glu Ala
130 135 140
Gly Pro Pro Ala Phe Tyr Arg Pro Asn Ser Asp Asn Arg Arg Gln Gly
145 150 155 160
Gly Arg Glu Arg Leu Ala Ser Thr Asn Asp Lys Gly Ser Met Ala Met
165 170 175
Glu Ser Ala Lys Glu Thr Arg Tyr Cys Ala Val Cys Asn Asp Tyr Ala
180 185 190
Ser Gly Tyr His Tyr Gly Val Trp Ser Cys Glu Gly Cys Lys Ala Phe
195 200 205
Phe Lys Arg Ser Ile Gln Gly His Asn Asp Tyr Met Cys Pro Ala Thr
210 215 220
Asn Gln Cys Thr Ile Asp Lys Asn Arg Arg Lys Ser Cys Gln Ala Cys
225 230 235 240
Arg Leu Arg Lys Cys Tyr Glu Val Gly Met Met Lys Gly Gly Ile Arg
245 250 255
Lys Asp Arg Arg Gly Gly Arg Met Leu Lys His Lys Arg Gln Arg Asp
260 265 270
Asp Gly Glu Gly Arg Gly Glu Val Gly Ser Ala Gly Asp Met Arg Ala
275 280 285
Ala Asn Leu Trp Pro Ser Pro Leu Met Ile Lys Arg Ser Lys Arg Asn
290 295 300
Ser Leu Ala Leu Ser Leu Thr Ala Asp Gln Met Val Ser Ala Leu Leu
305 310 315 320
Asp Ala Glu Pro Pro Ile Leu Tyr Ser Glu Tyr Asp Pro Thr Arg Pro
325 330 335
Phe Ser Glu Ala Ser Met Met Gly Leu Leu Thr Asn Leu Ala Asp Arg
340 345 350
Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val
355 360 365
Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp Leu
370 375 380
Glu Ile Leu Met Ile Gly Leu Val Trp Arg Ser Met Glu His Pro Gly
385 390 395 400
Lys Leu Leu Phe Ala Pro Asn Leu Leu Leu Asp Arg Asn Gln Gly Lys
405 410 415
Cys Val Glu Gly Met Val Glu Ile Phe Asp Met Leu Leu Ala Thr Ser
420 425 430
Ser Arg Phe Arg Met Met Asn Leu Gln Gly Glu Glu Phe Val Cys Leu
435 440 445
Lys Ser Ile Ile Leu Leu Asn Ser Gly Val Tyr Thr Phe Leu Ser Ser
450 455 460
Thr Leu Lys Ser Leu Glu Glu Lys Asp His Ile His Arg Val Leu Asp
465 470 475 480
Lys Ile Thr Asp Thr Leu Ile His Leu Met Ala Lys Ala Gly Leu Thr
485 490 495
Leu Gln Gln Gln His Gln Arg Leu Ala Gln Leu Leu Leu Ile Leu Ser
500 505 510
His Ile Arg His Met Ser Asn Lys Gly Met Glu His Leu Tyr Ser Met
515 520 525
Lys Cys Lys Asn Val Val Pro Leu Tyr Asp Leu Leu Leu Glu Met Leu
530 535 540
Asp Ala His Arg Leu His Ala Pro Thr Ser Arg Gly Gly Ala Ser Val
545 550 555 560
Glu Glu Thr Asp Gln Ser His Leu Ala Thr Ala Gly Ser Thr Ser Ser
565 570 575
His Ser Leu Gln Lys Tyr Tyr Ile Thr Gly Glu Ala Glu Gly Phe Pro
580 585 590
Ala Thr Val
595
<210> 40
<211> 1239
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(1239)
<223> 智人ESR1多肽
<400> 40
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Pro Leu Thr Ser Ile Val Ser
625 630 635 640
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
645 650 655
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
660 665 670
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
675 680 685
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
690 695 700
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
705 710 715 720
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
725 730 735
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
740 745 750
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
755 760 765
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
770 775 780
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
785 790 795 800
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
805 810 815
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
820 825 830
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
835 840 845
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
850 855 860
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
865 870 875 880
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
885 890 895
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
900 905 910
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
915 920 925
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
930 935 940
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
945 950 955 960
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
965 970 975
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
980 985 990
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu
995 1000 1005
Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly Ala
1010 1015 1020
Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg Ser
1025 1030 1035
Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu Glu
1040 1045 1050
Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser Asp
1055 1060 1065
Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu Gln
1070 1075 1080
Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser Glu
1085 1090 1095
Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val Ala
1100 1105 1110
Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro Asp
1115 1120 1125
Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro Ala
1130 1135 1140
Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Ala Lys Thr Leu Ser
1145 1150 1155
Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly Gly
1160 1165 1170
Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala Ala
1175 1180 1185
Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp Asn
1190 1195 1200
Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro Pro
1205 1210 1215
Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr Leu
1220 1225 1230
Gly Leu Asp Val Pro Val
1235
<210> 41
<211> 111
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(111)
<223> 智人ESR1多肽
<400> 41
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn
100 105 110
<210> 42
<211> 668
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(668)
<223> 智人ESR1多肽
<400> 42
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Pro Leu Thr Ser Ile Val Ser
625 630 635 640
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
645 650 655
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys
660 665
<210> 43
<211> 331
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(331)
<223> 智人ESR1多肽
<400> 43
Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
1 5 10 15
Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30
Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
35 40 45
Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
50 55 60
Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95
Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
100 105 110
Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
115 120 125
His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
145 150 155 160
Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
165 170 175
Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
180 185 190
Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
210 215 220
Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
225 230 235 240
Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
245 250 255
Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270
Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
275 280 285
Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
290 295 300
Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
305 310 315 320
Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Phe
325 330
<210> 44
<211> 1342
<212> PRT
<213> 智人
<220>
<221> 未归类的特征
<222> (1)..(1342)
<223> 智人ESR1多肽
<400> 44
Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu
1 5 10 15
Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30
Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr
35 40 45
Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu
50 55 60
Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile
65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95
Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp
100 105 110
Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser
115 120 125
His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser
130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr
145 150 155 160
Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val
165 170 175
Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly
180 185 190
Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr
195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn
210 215 220
Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp
225 230 235 240
Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val
245 250 255
Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270
Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala
275 280 285
Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala
290 295 300
Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys
305 310 315 320
Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
325 330 335
Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
340 345 350
Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu
355 360 365
Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu
370 375 380
Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln
385 390 395 400
Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr
405 410 415
Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile
420 425 430
Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu
435 440 445
Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr
450 455 460
His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
465 470 475 480
Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu
485 490 495
Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro
500 505 510
Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val
515 520 525
Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala
530 535 540
His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Gly
545 550 555 560
Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
565 570 575
Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly
580 585 590
Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn
595 600 605
Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro
610 615 620
Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr
625 630 635 640
His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe
645 650 655
Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln
660 665 670
Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu
675 680 685
Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe
690 695 700
Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe
705 710 715 720
Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys
725 730 735
Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser
740 745 750
Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His
755 760 765
Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln
770 775 780
Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg
785 790 795 800
Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val
805 810 815
Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His
820 825 830
Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val
835 840 845
Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys
850 855 860
Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu
865 870 875 880
Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser
885 890 895
Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr
900 905 910
Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu
915 920 925
Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met
930 935 940
Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu
945 950 955 960
Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu
965 970 975
Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro
980 985 990
His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu
995 1000 1005
Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala
1010 1015 1020
Thr Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu
1025 1030 1035
Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly
1040 1045 1050
Tyr Met Pro Met Asn Gln Gly Asn Leu Gly Gly Ser Cys Gln Glu
1055 1060 1065
Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser
1070 1075 1080
Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu
1085 1090 1095
Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu Lys Val Ser
1100 1105 1110
Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly
1115 1120 1125
Asp Ser Ala Tyr His Ser Gln Arg His Ser Leu Leu Thr Pro Val
1130 1135 1140
Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly
1145 1150 1155
Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg
1160 1165 1170
Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr
1175 1180 1185
Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg
1190 1195 1200
Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu
1205 1210 1215
Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala
1220 1225 1230
Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile
1235 1240 1245
Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met
1250 1255 1260
Asn Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala
1265 1270 1275
Met Gly Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg
1280 1285 1290
Ala Phe Gln Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala
1295 1300 1305
Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe
1310 1315 1320
Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn
1325 1330 1335
Ala Gln Arg Thr
1340
Claims (39)
1.一种多核苷酸构建体,其包含可操作地连接至编码第一抗原多肽的第一多核苷酸的异源启动子,其中所述多核苷酸构建体是环状的并且缺乏细菌复制起点和抗生素抗性基因。
2.根据权利要求1所述的多核苷酸构建体,其中所述第一抗原多肽选自由以下组成的组:ESR1多肽、其突变体或部分;HER3多肽、其突变体或部分;突变的HER2多肽或其部分;及其组合。
3.根据权利要求2所述的多核苷酸构建体,其中所述第一抗原多肽包含HER3多肽并且包含SEQ ID NO:1、SEQ ID NO:2或其部分。
4.根据权利要求2所述的多核苷酸构建体,其中所述第一抗原多肽包含HER2多肽并且包含SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或其部分。
5.根据权利要求4所述的多核苷酸构建体,其中所述HER2多肽的部分包含被鉴定为HER2d16(SEQ ID NO:3)的缺失或突变。
6.根据权利要求4至5中任一项所述的多核苷酸构建体,其中所述第一抗原多肽由SEQID NO:3或其部分组成。
7.根据权利要求2所述的多核苷酸构建体,其中所述第一抗原多肽包含ESR1多肽并且包含SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9,或SEQ ID NO:6-9中的任一个的部分。
8.根据权利要求7所述的多核苷酸构建体,其中所述ESR1多肽由SEQ ID NO:6、SEQ IDNO:7、SEQ ID NO:8或SEQ ID NO:9中的至少一个组成。
9.根据权利要求7至8中任一项所述的多核苷酸构建体,其中所述ESR1多肽的部分包含ESR1中的突变。
10.根据前述权利要求中任一项所述的多核苷酸构建体,其中所述第一多核苷酸与编码乳凝集素多肽或其部分的第二多核苷酸框内融合。
11.根据权利要求10所述的多核苷酸构建体,其中所述乳凝集素多肽包含SEQ ID NO:10(小鼠乳凝集素的C1C2结构域)或其同源物。
12.一种治疗受试者中癌症或前期癌或降低受试者中所述癌症对癌症治疗剂或预防剂产生抗性的可能性的方法,其包括:
给所述受试者施用治疗有效量的DNA疫苗,所述DNA疫苗包含编码第一抗原多肽的第一多核苷酸,和
给所述受试者施用治疗有效量的疫苗载体组合物,所述疫苗载体组合物包含第二抗原多肽。
13.根据权利要求12所述的方法,其中所述第一抗原多肽和第二抗原多肽选自由已下组成的组:ESR1多肽、其突变体或部分;HER3多肽、其突变体或部分;突变HER2多肽或其部分;及其组合。
14.根据权利要求12至13中任一项所述的方法,其中所述DNA疫苗包含权利要求1至11的多核苷酸构建体中的任一种。
15.根据权利要求12至14中任一项所述的方法,其中所述第一抗原多肽和所述第二抗原多肽是相同的多肽或融合多肽。
16.根据权利要求12至15中任一项所述的方法,其中所述疫苗载体组合物包含腺病毒。
17.根据权利要求12至16中任一项所述的方法,其中在施用所述疫苗载体组合物之前施用所述DNA疫苗。
18.根据权利要求12至17中任一项所述的方法,其中在施用所述疫苗载体组合物之前施用所述DNA疫苗至少两次。
19.根据权利要求12至18中任一项所述的方法,其中施用所述DNA疫苗和所述疫苗载体组合物之间的时间段为至少1周。
20.根据权利要求13至19中任一项所述的方法,其中所述癌症对ESR1、HER3、HER2,或其突变体呈阳性。
21.根据权利要求12至20中任一项所述的方法,其中在所述癌症治疗剂或预防剂的施用的同时、之前或之后施用所述DNA疫苗和所述疫苗载体组合物。
22.根据权利要求12至21中任一项所述的方法,其中所述癌症治疗剂或预防剂是靶向HER2、HER1、雌激素受体、EGFR或IGF1R的药剂。
23.根据权利要求12至22中任一项所述的方法,其中所述癌症治疗剂或预防剂选自曲妥珠单抗、拉帕替尼、西妥昔单抗、帕妥珠单抗和埃罗替尼。
24.根据权利要求12至23中任一项所述的方法,其中在检查点抑制剂免疫调节剂的施用的同时、之前或之后施用所述DNA疫苗和所述疫苗载体组合物。
25.根据权利要求24所述的方法,其中所述检查点抑制剂免疫调节剂是CTLA-4拮抗性抗体或PD1拮抗性抗体。
26.根据权利要求12至25中任一项所述的方法,其中所述癌症或前期癌选自乳腺、前列腺、肺、卵巢、结肠、直肠、胰腺、膀胱、头颈或肝的癌症或前期癌。
27.根据权利要求12至26中任一项所述的方法,其中所述受试者是人。
28.根据权利要求13至27中任一项所述的方法,其中在施用后所述受试者对ESR1、HER2或HER3产生免疫应答。
29.根据权利要求28所述的方法,其中所述免疫应答包括抗体应答或T细胞介导的应答。
30.根据权利要求28所述的方法,其中所述免疫应答包括以下中的至少一种:抗体依赖性细胞的细胞毒性;多克隆抗体应答;补体依赖性细胞毒性;细胞的细胞毒性;配体结合破坏;二聚化破坏;导致ESR1、HER2或HER3的内化的模拟配体结合;或ESR1、HER2或HER3的降解。
31.根据权利要求28所述的方法,其中所述免疫应答包括针对以下的至少一部分的抗体应答:SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8或SEQ ID NO:9。
32.根据权利要求28至31中任一项所述的方法,其中所述免疫应答对于侧接或包含处于以下位置的突变的T细胞表位或B细胞表位是特异性的:SEQ ID NO:6或7的位置537、SEQID NO:8的位置538或SEQ ID NO:9的位置303。
33.根据权利要求28所述的方法,其中所述免疫应答包括针对SEQ ID NO:3、4或5的至少一部分的抗体应答。
34.根据权利要求33所述的方法,其中所述免疫应答对于侧接或包含处于SEQ ID NO:3的氨基酸633处的外显子16缺失的T细胞表位或B细胞表位是特异性的。
35.根据权利要求28所述的方法,其中所述免疫应答包括针对SEQ ID NO:1或SEQ IDNO:2的至少一部分的抗体应答。
36.一种癌症疫苗试剂盒,其包括:
DNA疫苗组分,所述DNA疫苗组分包含权利要求1至11的多核苷酸构建体中的任一种,和
疫苗载体组分,所述疫苗载体组分包含第二抗原多肽。
37.根据权利要求36所述的试剂盒,其中所述第二抗原多肽选自由以下组成的组:ESR1多肽、其突变体或部分;HER3多肽、其突变体或部分;突变HER2多肽或其部分;及其组合。
38.根据权利要求36至37中任一项所述的试剂盒,其中所述疫苗载体组分是腺病毒。
39.根据权利要求36至38中任一项所述的试剂盒,其中所述第一抗原多肽和所述第二抗原多肽是相同的多肽或融合多肽。
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