CN108136007A - 用于治疗犬癌症的嵌合aav-抗vegf - Google Patents
用于治疗犬癌症的嵌合aav-抗vegf Download PDFInfo
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Abstract
提供了用于治疗受试者的血管肉瘤的组合物和方法。提供了包含衣壳和包含核酸表达盒的载体基因组的重组AAV。表达盒包括编码启动子、可操作地连接至抗VEGF抗体重链免疫球蛋白的第一信号肽、接头序列和可操作地连接至抗VEGF轻链免疫球蛋白的第二信号肽的序列,其中所述表达盒在允许链装配成功能性抗VEGF抗体的条件下在宿主细胞中共表达免疫球蛋白链。在一个实施方案中,抗VEGF抗体是嵌合抗体。
Description
以电子形式提交的材料的引用并入
申请人在此通过引用并入以电子形式随同提交的序列表材料。这个文件被标记为“15-7473_SEQ_LISTING_ST25”。
发明背景
在美国,血管肉瘤(HSA)每年影响超过250,000只狗。HSA是通常位于脾脏或肝脏中的血管肿瘤。目前HSA不能被治愈,而且标准疗法通常是手术,接着是多柔比星(doxorubicin)的化疗方案。这种疗法通常需要花费$6,000+,并且可以延长3-4个月的生存期。虽然任何年龄和品种的狗都容易患血管肉瘤,但它更常见于超过中年(6岁以上)以及如金毛猎犬、德国牧羊犬、葡萄牙水犬、伯尔尼山犬、平毛猎犬、拳师犬和斯凯梗等等品种的狗。根据2000年发表的金毛猎犬健康研究,该品种的血管肉瘤估计终生风险为1/5,说明这个问题的严重性。
在狗中,血管肉瘤的常见原发部位是脾脏、右心房以及皮下组织,即皮肤下面的组织。这些肿瘤的生长模式涉及肿瘤周围的正常组织浸润以及转移。
HSA肿瘤还表达血管内皮生长因子(VEGF)和VEGF受体,其通过血管生成生长帮助肿瘤血管化并增殖。目前没有用于狗或其它伴侣动物的VEGF靶向疗法。
由于其安全性和体内长期基因表达的能力,腺相关病毒(AAV)是用于递送治疗性基因的理想载体。重组AAV载体(rAAV)先前已用于体内表达单链和全长抗体。由于AAV的转基因包装能力有限,所以使严格调控的***使用单一AAV载体表达抗体的重链和轻链以产生全长抗体一直是技术挑战。
因此,需要可用于在受试者,特别是伴侣动物中靶向VEGF的组合物。
发明概要
提供了新的工程化嵌合犬抗VEGF抗体构建体。这些构建体可以通过许多途径递送给需要其的受试者,并且特别是通过重组载体如重组腺相关病毒(rAAV)载体介导的体内表达。在一个实施方案中,受试者是伴侣动物,例如狗或猫。
在一个方面,提供了病毒载体。在一个实施方案中,所述病毒载体包括至少一个核酸表达盒,所述核酸表达盒包含编码嵌合犬血管内皮生长因子(VEGF)抗体的序列,所述序列可操作地连接至指导VEGF抗体在宿主细胞中表达的表达控制序列。
在另一个实施方案中,病毒载体包括至少一个核酸表达盒,所述核酸表达盒包含编码以下各项的序列:启动子、可操作地连接至嵌合犬抗VEGF抗体重链免疫球蛋白的第一信号肽、接头序列以及可操作地连接至嵌合犬抗VEGF轻链免疫球蛋白的第二信号肽,其中所述表达盒在允许链装配成功能性嵌合犬抗VEGF抗体的条件下在宿主细胞中共表达免疫球蛋白链。
另一方面,病毒载体包含至少一个核酸表达盒,所述核酸表达盒包含编码结合犬VEGF的功能性抗VEGF抗体的核酸序列,所述抗体包含SEQ ID NO:15的抗VEGF抗体重链免疫球蛋白和/或SEQ ID NO:14的抗VEGF抗体轻链免疫球蛋白;和在允许链装配成功能性抗体的条件下指导免疫球蛋白链在宿主细胞中表达的表达控制序列。
在另一个实施方案中,病毒载体包括至少一个核酸表达盒,所述核酸表达盒包含编码以下各项的序列:5′AAV反向末端重复序列(ITR)、具有任选增强子的启动子、可操作地连接至嵌合犬抗VEGF抗体重链免疫球蛋白的第一信号肽、接头序列、可操作地连接至抗VEGF轻链免疫球蛋白的第二信号肽和3′AAV ITR,其中所述表达盒在允许链装配成功能性嵌合犬抗VEGF抗体的条件下在宿主细胞中共表达免疫球蛋白链。还提供了由病毒载体产生的嵌合抗VEGF抗体。在一个实施方案中,抗VEGF抗体是鼠可变链与犬恒定域连接的嵌合抗体。在一个实施方案中,病毒载体是腺相关病毒载体。在另一个实施方案中,载体是具有选自AAV8、rh64R1、AAV9、AAVhu.37或rh10及其变体的衣壳的rAAV。在一个实施方案中,衣壳是AAV8衣壳或其变体。
在另一个实施方案中,病毒载体是选自另一种病毒载体。其它合适的载体包括但不限于腺病毒、RNA载体(例如逆转录酶病毒,如莫洛尼鼠肉瘤病毒(Moloney murinesarcoma virus,MoMSV)、哈维鼠肉瘤病毒(Harvey murine sarcoma virus,HaMuSV)、鼠乳腺肿瘤病毒(MuMTV)、长臂猿白血病病毒(GaLV)、猫白血病病毒(FLV)、泡沫病毒、Friend、鼠干细胞病毒(MSCV)和劳氏肉瘤病毒(RSV))。本发明中所用的“逆转录病毒载体”还可以包括来源于人类T细胞白血病病毒HTLV-1和HTLV-2,以及逆转录病毒的慢病毒家族(如人类免疫缺陷病毒HIV-1、HIV-2、猿猴免疫缺陷病毒(SIV)、猫免疫缺陷病毒(FIV)、马免疫缺陷病毒(EIV)和其它类型的逆转录病毒)的载体、脂质体、阳离子脂质、慢病毒载体和转座子。在另一个实施方案中,病毒载体是水疱性口炎病毒。
另一方面,提供了药物组合物,其包含药学上可接受的载剂和如本文所述的病毒载体。在另一个实施方案中,药物组合物是包含病毒载体和载剂、稀释剂、赋形剂和/或佐剂的悬浮液。
另一方面,提供了治疗癌症(例如血管肉瘤)的方法。在一个实施方案中,所述方法包括施用如本文所述的含有病毒载体的组合物。
另一方面,提供了嵌合抗VEGF抗体。在一个实施方案中,嵌合抗体包括鼠和犬免疫球蛋白结构域。另一方面,提供了包含嵌合抗VEGF抗体与药学上可接受的载剂组合的药物组合物。在另一个实施方案中,药物组合物包含嵌合犬抗VEGF抗体和载剂、稀释剂、赋形剂和/或佐剂。
根据下面对本发明的详细描述,本发明的其它方面和优点将是显而易见的。
图式简单说明
图1是显示纯化的嵌合鼠-犬抗VEGF抗体的SDS-PAGE照片。梯子是PagerulerPrestained(Thermo Scientific)。
图2是显示用AAV8载体处理的3只狗中血清抗VEGF抗体浓度的图。
图3是实施例1中所用的表达构建体的草图。
图4是显示图3和实施例1的构建体的表达盒布局的草图。
图5显示了本发明的一个实施方案的嵌合抗VEGF抗体的轻链(顶部;SEQ ID NO:14)和重链(底部;SEQ ID NO:15)。互补决定区(CDR)标有下划线。
实施方式
本文描述了包括至少一个核酸表达盒的病毒载体,所述核酸表达盒包含编码嵌合抗VEGF血管内皮生长因子(VEGF)抗体的序列,所述序列可操作地连接至指导VEGF抗体在宿主细胞中表达的表达控制序列。还提供了使用本文所述构建体产生的含有犬区和鼠区的嵌合抗VEGF抗体。使用由AAV8载体表达的说明性构建体,本发明人已经证明在体内研究中持续110天以上的抗体表达。
在一个实施方案中,病毒载体包括至少一个核酸表达盒,所述核酸表达盒包含编码以下各项的核酸序列:启动子、可操作地连接至嵌合犬抗VEGF抗体重链免疫球蛋白的第一信号肽、接头核酸序列以及可操作地连接至嵌合犬抗VEGF轻链免疫球蛋白的第二信号肽,其中所述表达盒在允许链装配成功能性嵌合抗VEGF抗体的条件下在宿主细胞中共表达免疫球蛋白链(图4)。在另一个实施方案中,病毒载体包括至少一个核酸表达盒,所述核酸表达盒包含编码以下各项的核酸序列:5′AAV反向末端重复序列(ITR)、具有任选增强子的启动子、可操作地连接至嵌合犬抗VEGF抗体重链免疫球蛋白的第一信号肽、接头序列、可操作地连接至嵌合犬抗VEGF轻链免疫球蛋白的第二信号肽和3′AAV ITR,其中所述表达盒在允许链装配成功能性抗VEGF抗体的条件下在宿主细胞中共表达嵌合犬免疫球蛋白链。如本文所用,“功能性抗体”可以是以足够的结合亲和力与选择的靶标(例如VEGF)结合以实现期望的生理效果的抗体或免疫球蛋白,所述生理效果可以是保护性的(例如被动免疫接种)或治疗性的(例如中和VEGF)。
在一个实施方案中,抗VEGF抗体是嵌合体。如本文所用,“嵌合体”是指掺入来自两种或更多种物种的蛋白质的区域以将来自每种“亲本”蛋白质的特性赋予所得嵌合抗体的抗体。在一个实施方案中,抗体含有鼠免疫球蛋白结构域。在一个实施方案中,抗体含有犬免疫球蛋白结构域。在一个实施方案中,抗体含有鼠可变区。在另一个实施方案中,抗体含有来自另一物种的可变链区。在一个实施方案中,抗体含有来自鼠抗体的可变区和来自犬的恒定链区,并且所得抗体被称为“嵌合”。在另一个实施方案中,抗体含有来自抗体最终预期施用的相同受试者物种的恒定链区。在一个实施方案中,Fc区是犬序列。在另一个实施方案中,抗VEGF抗体包含鼠抗VEGF抗体的可变区和犬VEGF IgGA/κ恒定区。在一个实施方案中,鼠可变区来自鼠单克隆抗体a4.6.1(参见Gerber等人,Mice expressing a humanizedform of VEGF-A may provide insights into safety and efficacy of anti-VEGFantibodies,PNAS,104(9):3478-83 2007,其通过引用并入)。在一个实施方案中,抗体包含SEQ ID NO:14和SEQ ID NO:15的序列。在另一个实施方案中,抗体是包含图5中所示的鼠CDR的嵌合犬抗体。在该实施方案中,其余抗体序列来自犬。
本文提供的AAV载体可以含有1或2个表达一个或多个免疫球蛋白结构域的开放阅读框(ORF)。如本文所用,“免疫球蛋白结构域”是指如参照常规全长抗体所定义的抗体重链或轻链的结构域。更具体地说,全长抗体包含含有四个结构域(一个N端可变(VH)区和三个C端恒定(CH1、CH2和CH3)区)的重(H)链多肽和含有两个结构域(一个N端可变(VL)区和一个C端恒定(CL)区)的轻(L)链多肽。对于重链和轻链中的每一个,Fab区可以含有一个恒定结构域和一个可变结构域。
如本文所用,术语“免疫球蛋白”包括如上所述的抗体及其功能片段,包括免疫球蛋白结构域。如本文所述的抗VEGF抗体可以各种形式存在,包括例如多克隆抗体、单克隆抗体、骆驼源化单结构域抗体、胞内抗体(“胞内体”)、重组抗体、多特异性抗体(双特异性)、抗体片段,如Fv、Fab、F(ab)2、F(ab)3、Fab′、Fab′-SH、F(ab′)2、免疫粘附分子、单链可变片段抗体(scFv)、串联/双-scFv、Fc、pFc′、scFvFc(或scFv-Fc)、二硫化物Fv(dsfv)、双特异性抗体(bc-scFv),如BiTE抗体;骆驼抗体、表面重构抗体、人源化抗体、完全人抗体、犬源化抗体、完全犬抗体、单结构域抗体(sdAb,也称为)、嵌合抗体、包含至少一个犬恒定区的嵌合抗体等。“抗体片段”是指结合其靶标(例如VEGF)的免疫球蛋白可变区的至少一部分。在一个实施方案中,免疫球蛋白是IgG。然而,可以选择其它类型的免疫球蛋白。
在一个实施方案中,抗VEGF抗体是嵌合单克隆抗体。在一个实施方案中,抗VEGF抗体重链免疫球蛋白包括可变链序列(VH)。在一个实施方案中,抗VEGF抗体重链免疫球蛋白包括可变链序列(VH)和至少一个犬恒定链序列(CH)。在另一个实施方案中,抗VEGF抗体重链免疫球蛋白包括可变链序列(VH)和全部三个恒定链序列(CH1、CH2和CH3)。在一个实施方案中,抗VEGF抗体可变重链免疫球蛋白氨基酸序列是SEQ ID NO:1。在一个实施方案中,恒定重链氨基酸序列是SEQ ID NO:2。在一个实施方案中,抗VEGF轻链免疫球蛋白包括可变链序列(VL)。在一个实施方案中,抗VEGF轻链免疫球蛋白包括可变链序列(VL)和至少一个犬恒定链序列(CL)。在一个实施方案中,抗VEGF轻链可变免疫球蛋白氨基酸序列是SEQ IDNO:3。在一个实施方案中,抗VEGF轻链恒定免疫球蛋白氨基酸序列是SEQ ID NO:4。在一个实施方案中,嵌合抗VEGF轻链序列是SEQ ID NO:14。在一个实施方案中,嵌合抗VEGF重链序列是SEQ ID NO:15。
当关于蛋白质或核酸使用时,术语“异源”表示蛋白质或核酸包含两种或更多种序列或子序列,这些序列或子序列在自然界中未以彼此相同的关系发现。例如,通常重组产生表达盒,其具有来自不相关基因的两个或更多个序列,以排列成新的功能性核酸。例如,在一个实施方案中,核酸具有来自一个基因的启动子,该启动子被排列以指导来自不同基因的编码序列的表达。因此,相对于免疫球蛋白编码序列,启动子是异源的。同样,相对于AAV衣壳,免疫球蛋白编码序列是异源的。
由包装在载体内的核酸分子携带的一个或多个ORF可以由两个表达盒表达,其中一个或两个可以是双顺反子。因此,当提到表达盒或包含表达盒的载体时,另一个实施方案是可以预期的,其使用多于一个表达盒来表达期望的抗VEGF抗体序列。
另一方面,还提供了编码本文所述的抗体区氨基酸序列的核酸序列。所选免疫球蛋白结构域(例如重链和/或轻链)的编码序列可以在本文中获得和/或合成或描述。对氨基酸进行测序的方法是本领域技术人员熟知的。一旦氨基酸序列已知,就有基于网络和商业可获得的计算机程序以及基于服务的公司将氨基酸序列反向翻译成核酸编码序列。参见例如EMBOSS,http://www.ebi.ac.uk/Tools/st/;Gene Infinity (http:// www.geneinfinity.org/sms/sms_backtranslation.html);ExPasy(http:// www.expasy.org/tools/)的backtranseq。
在一个实施方案中,设计RNA和/或cDNA编码序列以在犬细胞中最佳表达。用于合成核酸的方法是本领域技术人员已知的,并且可以用于本文所述的核酸构建体的全部或部分。在一个实施方案中,编码抗VEGF抗体重链可变区的核酸序列包含SEQ ID NO:6或其密码子优化的变体。在一个实施方案中,编码抗VEGF抗体轻链可变区的核酸序列包含SEQ IDNO:7或其密码子优化的变体。在一个实施方案中,编码抗VEGF抗体重链恒定区的核酸序列包含SEQ ID NO:8或其密码子优化的变体。在一个实施方案中,编码抗VEGF抗体轻链恒定区的核酸序列包含SEQ ID NO:9或其密码子优化的变体。
在另一个实施方案中,编码任何所述免疫球蛋白结构域的核酸序列与本文所述序列(例如,SEQ ID NO:6、7、8或9)具有至少50%的同一性。在另一个实施方案中,编码任何所述免疫球蛋白结构域的核酸序列与本文所述序列(例如,SEQ ID NO:6、7、8或9)具有至少60%的同一性。在另一个实施方案中,编码任何所述免疫球蛋白结构域的核酸序列与本文所述序列(例如,SEQ ID NO:6、7、8或9)具有至少70%的同一性。在另一个实施方案中,编码任何所述免疫球蛋白结构域的核酸序列与本文所述序列(例如,SEQ ID NO:6、7、8或9)具有至少80%的同一性。在另一个实施方案中,编码任何所述免疫球蛋白结构域的核酸序列与本文所述序列(例如,SEQ ID NO:6、7、8或9)具有至少90%的同一性。
在另一个实施方案中,提供了编码SEQ ID NO:1的抗VEGF抗体重链可变区的核酸序列。在另一个实施方案中,提供了编码SEQ ID NO:2的抗VEGF抗体重链恒定区的核酸序列。在另一个实施方案中,提供了编码SEQ ID NO:3的抗VEGF抗体轻链可变区的核酸序列。在另一个实施方案中,提供了编码SEQ ID NO:4的抗VEGF抗体轻链恒定区的核酸序列。意图涵盖编码所述多肽序列的所有核酸,包括已经针对在期望的靶标受试者中表达而优化的核酸序列(例如,通过密码子优化)。
密码子优化的编码区可以通过各种不同的方法来设计。这种优化可以使用在线提供的方法(例如GeneArt)、公开的方法或提供密码子优化服务的公司(例如DNA2.0(MenloPark,CA))进行。例如在国际专利公开No.WO 2015/012924中描述了一种密码子优化算法,其通过引用并入本文。也参见例如美国专利公开No.2014/0032186和美国专利公开No.2006/0136184。产物的开放阅读框(ORF)的整个长度适当地被修改。然而,在一些实施方案中,仅可以改变ORF的片段(例如,一个或多个单独的免疫球蛋白结构域)。通过使用这些方法之一,可以将频率应用于任何给定的多肽序列,并产生编码多肽的密码子优化的编码区的核酸片段。
许多选项可用于对密码子进行实际改变或合成如本文所述设计的密码子优化的编码区。这种修饰或合成可以使用本领域普通技术人员熟知的标准和常规分子生物学操作来进行。在一种方法中,通过标准方法合成长度各自为80-90个核苷酸并跨越所需序列长度的一系列互补寡核苷酸对。合成这些寡核苷酸对,使得它们在退火时形成含有粘性末端的80-90个碱基对的双链片段,例如,合成该对中的每个寡核苷酸以延伸超出与该对中的另一个寡核苷酸互补的区域的3、4、5、6、7、8、9、10个或更多个碱基。每对寡核苷酸的单链末端被设计为与另一对寡核苷酸的单链末端退火。使寡核苷酸对退火,然后使约5-6个这些双链片段经由粘性单链末端退火在一起,然后将它们连接在一起并克隆到标准细菌克隆载体中,例如可从Invitrogen Corporation,Carlsbad,Calif获得的载体。然后通过标准方法对构建体进行测序。制备几个由80至90个碱基对片段连接在一起的5至6个片段(即约500个碱基对的片段)组成的构建体,使得整个所需序列以一系列质粒构建体表示。然后用合适的限制酶切割这些质粒的***物并连接在一起以形成最终构建体。然后将最终的构建体克隆到标准的细菌克隆载体中,并测序。其它方法对于本领域技术人员而言将立即显而易见。另外,基因合成在市场上很容易获得。
任选地,免疫球蛋白结构域核酸或氨基酸序列的取代可以由天然序列或本文提供的序列制备以增强表达、靶向或出于另一原因。用于制备这种比对的方法和计算机程序是可用的,并且是本领域技术人员熟知的。取代还可以写成(由单字母代码标识的氨基酸)-位置#-(由单字母代码标识的氨基酸),其中第一个氨基酸是取代的氨基酸,第二个氨基酸是在指定位置的取代氨基酸。如本文所用,术语“取代”和“氨基酸的取代”和“氨基酸取代”是指氨基酸序列中的氨基酸被另一氨基酸取代,其中后者不同于取代的氨基酸。用于置换氨基酸的方法是本领域技术人员熟知的,并且包括但不限于编码氨基酸序列的核苷酸序列的突变。在IgG中进行氨基酸取代的方法描述在例如WO2013/046704中,其通过引入并入,用于讨论氨基酸修饰技术。
另一方面,提供了嵌合抗VEGF抗体及其结构域。在一个实施方案中,嵌合抗VEGF抗体包括鼠可变区和犬恒定区。在一个实施方案中,抗VEGF抗体重链免疫球蛋白结构域包含可变链序列和至少一个恒定链序列。在另一个实施方案中,抗VEGF抗体重链可变片段免疫球蛋白氨基酸序列是SEQ ID NO:1(CDR标下划线):E I Q L V Q S G P E LK Q P G E T VR I S C K A S G Y T F T N Y G M N W V K Q A P G K G L K W M G W I N T Y T G E P T Y A A D F K R R F T F S L E T S A S T A Y L Q I S N L K N D D T A T Y F CA K Y P H Y Y G S S H WYF D V W G A G T T V T V S S A。在另一个实施方案中,抗VEGF抗体重链可变片段免疫球蛋白具有与SEQ ID NO:1共享80%、85%、90%、95%、96%、97%、98%、99%或更高同一性的序列。在另一个实施方案中,提供了编码抗VEGF抗体重链免疫球蛋白的核酸序列。在另一个实施方案中,抗VEGF抗体包含上面标下划线的CDR。
在另一个实施方案中,抗VEGF抗体重链恒定片段免疫球蛋白氨基酸序列是SEQ IDNO:2:S T T A P S V F P L A P S C G S T S G S T V A L A C L V S G Y F P E P VT V S W N S G S L T S G V H T F P S V L Q S S G L H S L S S M V T V P S S R WP S E T F T C N V V H P A S N T K V D K P V F N E C R C T D T P P C P V P E PL G G P S V L I F P P K P K D I L R I T R T P E V T C V V L D L G R E D P E VQ I S W F V D G K E V H T A K T Q S R E Q Q F N G T Y R V V S V L P I E H Q DW L T G K E F K C R V N H I D L P S P I E R T I S K A R G R A H K P S V Y V LP P S P K E L S S S D T V S I T C L I K D F Y P P D I D V E W Q S N G Q Q E PE R K H R M T P P Q L D E D G S Y F L Y S K L S V D K S R W Q Q G D P F T C AV M H E T L Q N H Y T D L S L S H S P G K。在另一个实施方案中,抗VEGF抗体重链犬恒定区免疫球蛋白具有与SEQ ID NO:2共享80%、85%、90%、95%、96%、97%、98%、99%或更高同一性的序列。在另一个实施方案中,提供了编码抗VEGF抗体犬重链恒定区免疫球蛋白的核酸序列。
在一个实施方案中,抗VEGF抗体轻链免疫球蛋白结构域包含可变链序列和至少一个犬恒定链序列。在一个实施方案中,抗VEGF抗体轻链可变片段免疫球蛋白氨基酸序列是SEQ ID NO:3(CDR标下划线):D I Q M T Q T T S S I S A S L G D R V I I S C S A S O D I S N Y L NW Y Q Q K P D G T V K V L I Y F T S S L H S G V P S R F S G SG S G T D Y S L T I S N L E P E D I A T Y Y C Q Q Y S T V P W T F G G G T K LE I K R。在另一个实施方案中,抗VEGF抗体轻链可变区具有与SEQ ID NO:3共享80%、85%、90%、95%、96%、97%、98%、99%或更高同一性的序列。在另一个实施方案中,提供了编码抗VEGF抗体轻链可变区的核酸序列。在另一个实施方案中,抗VEGF抗体包含上面标下划线的CDR。
在一个实施方案中,抗VEGF抗体轻链犬恒定区免疫球蛋白氨基酸序列是SEQ IDNO:4:N D A Q P A V Y L F Q P S P D Q L H T G S A S V V C L L N S F Y P K D IN V K W K V D G V I Q D T G I Q E S V T E Q D K D S T Y S LS S T L T M S S TE Y L S H E L Y S C E I T H K S L P S T L I K S F Q R S E C。在另一个实施方案中,抗VEGF抗体轻链恒定区具有与SEQ ID NO:4共享80%、85%、90%、95%、96%、97%、98%、99%或更高同一性的序列。在另一个实施方案中,提供了编码抗VEGF抗体轻链恒定区的核酸序列。
在一个实施方案中,嵌合抗VEGF抗体包含SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4中的一个或多个。在另一个实施方案中,嵌合抗VEGF抗体包含与SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4中的一个或多个共享80%、85%、90%、95%、96%、97%、98%、99%或更高同一性的一个或多个序列。
上述术语“氨基酸取代”及其同义词旨在涵盖通过用另一取代氨基酸置换氨基酸来修饰氨基酸序列。取决于期望的结果,取代可以是保守取代或非保守取代。关于两个氨基酸,术语保守意指氨基酸具有本领域技术人员公认的共同特性。参照两个氨基酸,术语非保守是指在本领域技术人员所认识的至少一种特性上具有差异的氨基酸。例如,这些特性可以包括具有疏水性非酸性侧链的氨基酸、具有疏水性侧链的氨基酸(其可以进一步区分为酸性或非酸性)、具有脂肪族疏水性侧链的氨基酸、具有芳香族疏水性侧链的氨基酸、具有极性中性侧链的氨基酸、具有带电侧链的氨基酸、具有带电酸性侧链的氨基酸和具有带电碱性侧链的氨基酸。天然存在的和非天然存在的氨基酸都是本领域已知的,并且可以在实施方案中用作替代氨基酸。因此,保守氨基酸取代可能涉及用具有疏水性侧链的不同氨基酸改变具有疏水性侧链的第一个氨基酸;而非保守氨基酸取代可能涉及用具有不同侧链(例如碱性疏水性侧链或亲水性侧链)的不同氨基酸改变具有酸性疏水性侧链的第一氨基酸。本领域技术人员可以确定其它保守或非保守的改变。在其它实施方案中,给定位置处的取代将是氨基酸或氨基酸组中的一个,这对于本领域技术人员而言是显而易见的,以实现本文所鉴定的目标。如本文所用,术语“%同一性”可以指特定数目的氨基酸取代。例如,对于具有124个氨基酸的SEQ ID NO:1,与天然序列相比共享“至少90%同一性”的序列可能具有1、2、3、4、5、6、7、8、9、10、11或12个氨基酸取代。本文涵盖了这样的定义。
为了表达选定的免疫球蛋白结构域,可以设计一种核酸分子,其包含已经选择用于在所选哺乳动物物种(例如犬)中最佳表达免疫球蛋白结构域多肽的密码子。此外,核酸分子可以包括针对所选抗体的每条重链和轻链的异源前导序列。在一个实施方案中,前导序列编码融合在由可变区和恒定区组成的重链多肽上游的IL-2前导肽和融合在由可变区和恒定区组成的轻链多肽上游的第二前导IL-2前导肽。在一个实施方案中,第一和第二前导序列是相同的。在另一个实施方案中,第一和第二前导序列是不同的。在一个实施方案中,前导序列是SEQ ID NO:5:M Y R M Q L L S C I A L S L A L V T N S。然而,另一种异源前导序列可以取代IL-2信号/前导肽中的一种或两种。信号/前导肽对于重链和轻链免疫球蛋白结构域构建体中的每一个可以是相同或不同的。这些可以是天然存在于免疫球蛋白(例如IgG)中的信号序列,或可以来自异源来源。这样的异源来源可以是细胞因子(例如IL-2、IL12、IL18等)、胰岛素、白蛋白、β-葡糖醛酸糖苷酶、碱性蛋白酶或纤连蛋白分泌信号肽,或来自组织特异性分泌蛋白的序列等。
如本文所用,“表达盒”是指包含免疫球蛋白基因(例如,免疫球蛋白可变区、免疫球蛋白恒定区、全长轻链、全长重链或免疫球蛋白构建体的另一片段)、启动子的核酸分子,并且可以包含其它调节序列,所述盒可以经由遗传元件(例如质粒)递送至包装宿主细胞并包装入病毒载体的衣壳(例如,AAV或其它细小病毒颗粒)或包膜病毒的包膜。通常,用于产生病毒载体的这种表达盒含有本文所述的免疫球蛋白序列,其侧翼是病毒基因组的包装信号和其它表达控制序列。这样的序列一起可以在本文中称为载体基因组。然而,术语“表达盒”和“载体基因组”可以互换使用。在一个实施方案中,表达盒至少包含第一开放阅读框(ORF)和可选的第二ORF。ORF可以含有一个、两个、三个或四个抗体结构域。例如,ORF可以含有全长重链。或者,ORF可以含有一个或两个抗体结构域。例如,ORF可以含有重链可变结构域和单个重链恒定结构域。在另一个实例中,ORF可以含有重链可变结构域和三个重链恒定结构域。在另一个实例中,ORF可以含有轻链可变区和轻链恒定区。因此,表达盒可以设计成双顺反子的,即包含调节序列,其指导来自共享调节序列的ORF的表达。在这种情况下,两个ORF通常由接头隔开。合适的接头,如内部核酶结合位点(IRES)和/或弗林蛋白酶2a自切割肽接头(F2a)[参见例如Radcliffe和Mitrophanous,Gene Therapy(2004),11,1673-1674]在本领域中是已知的。在一个实施方案中,接头是IRES。在另一个实施方案中,接头是F2a。在另一个实施方案中,每个ORF被包含在单独的表达盒内。
合适地,ORF可操作地连接至指导靶细胞表达的调控序列。这种调控序列可以包括polyA、启动子和增强子。为了促进来自AAV载体的共表达,增强子和/或polyA序列中的至少一个可以被第一和第二ORF共享。
除编码至少一个抗VEGF免疫球蛋白结构域(或整个抗VEGF抗体)的序列外,表达盒包括指导VEGF结构域/抗体在宿主细胞中表达的序列。合适的调控序列可以从多种来源中选择和获得。在一个实施方案中,载体包含启动子。在一个实施方案中,启动子是组成型启动子。适用于控制抗体结构域表达的组成型启动子的实例包括但不限于鸡β-肌动蛋白(CB)或来自其它物种的β肌动蛋白启动子、人类巨细胞病毒(CMV)启动子、猿猴病毒40(SV40)的早期和晚期启动子、U6启动子、金属硫蛋白启动子、EF1α启动子、泛素启动子、次黄嘌呤磷酸核糖转移酶(HPRT)启动子、二氢叶酸还原酶(DHFR)启动子(Scharfmann等人,Proc.Natl.Acad.Sci.USA 88:4626-4630(1991)、腺苷脱氨酶启动子、磷酸甘油激酶(PGK)启动子、丙酮酸激酶启动子磷酸甘油变位酶启动子、β-肌动蛋白启动子(Lai等人,Proc.Natl.Acad.Sci.USA 86:10006-10010(1989)、UbB、UbC、莫洛尼氏白血病病毒和其它逆转录病毒的长末端重复序列(LTR)、单纯疱疹病毒的胸苷激酶启动子以及本领域技术人员已知的其它组成型启动子。适用于本发明的组织或细胞特异性启动子的实例包括但不限于对内皮细胞具有特异性的内皮素-I(ET-I)和Flt-I、FoxJ1(其靶向纤毛细胞)。
尽管较不理想,但可利用适合于控制抗体结构域表达的诱导型启动子,包括对外源性试剂(例如药理学试剂)或生理学提示起反应的启动子。这些反应元件包括但不限于结合HIF-Iα和β的缺氧反应元件(HRE)、如Mayo等人(1982,Cell 29:99-108);Brinster等人(1982,Nature 296:39-42)和Searle等人(1985,Mol.Cell.Biol.5:1480-1489)所述的金属离子反应元件;或如由Nouer等人(在Heat Shock Response,编辑Nouer,L.,CRC,BocaRaton,Fla.,第I67-220页,1991)所述的热激反应元件
在一个实施方案中,开放阅读框的表达由对ORF(基因)(例如药理学试剂)的转录提供严格控制的可调节启动子或由药理学试剂或生理学提示(在替代实施方案中)激活的转录因子控制。作为可使用的配体依赖性转录因子复合物的可调节启动子的实例包括但不限于由其各自的配体(例如糖皮质激素、***、孕激素、类视黄醇、蜕皮激素及其类似物和模拟物)激活的核受体超家族的成员和由四环素激活的rTTA。这类***的实例包括但不限于ARGENTTM Transcription al Technology(ARIAD Pharmaceuticals,Cambridge,Mass.)。这种启动子***的实例描述在例如WO 2012/145572中,其通过引用并入本文中。在其它实施方案中,基于小RNA的开关描述在http://www.ncbi.nlm.nih.gov/pubmed/25605380中。
其它启动子可以包括例如人类巨细胞病毒(CMV)立即早期增强子/启动子、SV40早期增强子/启动子、JC多瘤病毒启动子、髓鞘碱性蛋白(MBP)或胶质原纤维酸性蛋白(GFAP)启动子、单纯疱疹病毒(HSV-1)潜伏相关启动子(LAP)、劳氏肉瘤病毒(RSV)长末端重复序列(LTR)启动子、神经元特异性启动子(NSE)、血小板衍生生长因子(PDGF)启动子、hSYN、黑色素浓集激素(MCH)启动子、CBA、胶质原纤维酸性蛋白(GFAP)启动子、基质金属蛋白启动子(MPP)和鸡β-肌动蛋白启动子。每个表达盒的启动子可以相同或不同。
在一个实施方案中,每一个或多个ORF的表达受相同启动子控制(例如,当与如IRES的接头一起使用时)。在另一个实施方案中,每个ORF的表达由单独的启动子控制。基于本文的描述,可以分别选择每个启动子。
在一个实施方案中,可以利用最小启动子和/或最小polyA来保存大小。如本文所用,术语“最小启动子”是指由TATA盒和其它用于指定转录起始位点之序列组成的短DNA序列,向其添加调控元件以控制表达。在一个实施方案中,启动子是指包含最小启动子加上能够控制编码序列或功能性RNA表达的调控元件的核苷酸序列。这种类型的启动子序列由近端和更远端的上游元件组成,后者通常称为增强子。在一个实施方案中,最小启动子是巨细胞病毒(CMV)最小启动子。在另一个实施方案中,最小启动子来源于人类CMV(hCMV),如hCMV立即早期启动子衍生的最小启动子(参见US 20140127749以及Gossen和Bujard(Proc.Natl.Acad.Sci.USA,1992,89:5547-5551),其通过引用并入本文)。在另一个实施方案中,最小启动子来源于病毒来源,例如SV40早期或晚期启动子、巨细胞病毒(CMV)立即早期启动子或劳氏肉瘤病毒(RSV)早期启动子;或来源于真核细胞启动子,例如β肌动蛋白启动子(Ng,Nuc.Acid Res.17:601-615,1989;Quitsche等人,J.Biol.Chem.264:9539-9545,1989)、GADPH启动子(Alexander,M.C.等人,Proc.Nat.Acad.Sci.USA 85:5092-5096,1988,Ercolani,L.等人,J.Biol.Chem.263:15335-15341,1988)、TK-1(胸苷激酶)启动子、HSP(热激蛋白)启动子、UbB或UbC启动子、PGK、Ef1-α启动子或任何含有TATA盒的真核启动子(美国公开申请No.2014/0094392)。在另一个实施方案中,最小启动子包括小启动子,如美国公开申请No.2014/0065666中描述的CLDN5小启动子。在另一个实施方案中,最小启动子是胸苷激酶(TK)启动子。在一个实施方案中,最小启动子是组织特异性的,如肌肉细胞特异性启动子最小TnISlow启动子、最小TnIFast启动子或肌肉肌酸激酶启动子之一(美国公开申请No.2012/0282695)。这些文件中的每一个通过引用并入本文。
在一个实施方案中,包括聚腺苷酸化信号。在一个实施方案中,可以选择野生型或合成polyA。在另一个实施方案中,聚腺苷酸化(poly(A))信号是最小poly(A)信号,即有效聚腺苷酸化所需的最小序列。在一个实施方案中,最小poly(A)是合成poly(A),如Levitt等人,Genes Dev.,1989年7月,3(7):1019-25;和Xia等人,Nat Biotechnol.2002年10月;20(10):1006-10.Epub 2002年9月16日中所描述的。在另一个实施方案中,poly(A)衍生自兔β-球蛋白poly(A)。在一个实施方案中,polyA双向起作用(An等人,2006,PNAS,103(49):18662-18667。在一个实施方案中,poly(A)源自SV40早期poly A信号序列。在一个实施方案中,poly(A)源自SV40晚期poly A信号序列。这些文件中的每一个通过引用并入本文。
任选地,单一增强子或相同增强子可以调节质粒构建体中多个异源基因(即,重链免疫球蛋白和轻链免疫球蛋白)的转录。本领域已知适用于本发明的各种增强子,包括例如CMV早期增强子、Hoxc8增强子、nPE1和nPE2。可用于本文的其它增强子描述在Andersson等人,Nature,2014年3月,507(7493):455-61中,其通过引用并入本文。其它增强子元件可以包括例如载脂蛋白增强子、斑马鱼增强子、GFAP增强子元件和如WO 2013/1555222中所述的组织特异性增强子、土拨鼠肝炎后转录后调控元件。另外或可选地,可以选择其它例如杂合人类巨细胞病毒(HCMV)-立即早期(IE)-PDGR启动子或其它启动子-增强子元件。为了增强表达,其它元件可以是内含子(如promega内含子或嵌合鸡球蛋白-人类免疫球蛋白内含子)。本文可用的其它增强子可以在http://promoter.cdb.riken.jp/上找到的哺乳动物启动子/增强子数据库中找到。
本文所述的构建体可以进一步含有其它表达控制或调节序列,例如合适的转录起始、终止、启动子和增强子序列;内含子;有效的RNA加工信号,如剪接和聚腺苷酸化(polyA)信号;稳定细胞质mRNA的序列;增强翻译效率的序列(即Kozak共有序列);增强蛋白质稳定性的序列;以及必要时,增加编码产物分泌的序列。
这些控制序列“可操作地连接”至免疫球蛋白构建体基因序列。如本文所用,术语“可操作地连接”是指表达控制序列与所关注基因邻接和表达控制序列以反式或相隔一定距离起作用以控制所关注基因。
在一个实施方案中,每个启动子位于增强子序列附近(左侧或右侧(或5′或3′)),并且polyA序列位于ITR附近,其间具有ORF。虽然在一个实施方案中,首先表达重链序列,但ORF的顺序可以变化,由此可以编码免疫球蛋白结构域。例如,轻链恒定序列和可变序列可以位于接头的左侧,并且重链可以由位于接头右侧的ORF编码。或者,重链可以位于接头的左侧,并且接头右侧的ORF可以编码轻链。或者,相反的配置是可能的。在一个实施方案中,表达盒含有编码启动子的序列,接着是编码重链的序列,接着是F2A序列,随后是编码轻链的序列。该构型的说明性实例可以在SEQ ID NO:11和SEQ ID NO:12所示的质粒序列中找到。在另一个实施方案中,表达盒含有编码启动子的序列,接着是编码轻链的序列,接着是IRES序列,随后是编码重链的序列。该构型的说明性实例可以在SEQ ID NO:13所示的质粒序列中找到。在另一个实施方案中,rAAV已经包装在选择的AAV衣壳内,核酸分子包含:5′AAV反向末端重复序列(ITR)、启动子、可操作地连接至鼠VEGF免疫球蛋白可变重链和犬VEGF恒定重链的信号肽、IRES、可操作地连接至鼠VEGF可变轻链的信号肽和3′AAV ITR。在一个实施方案中,AAV衣壳是AAV8。在另一个实施方案中,ITR来自AAV2或不同于AAV衣壳来源的不同来源。
在一个实施方案中,载体是腺相关病毒载体。如本说明书中所述,重组AAV载体(AAV病毒颗粒)可以包含包装在AAV衣壳内的表达功能性抗体的核酸分子。表达盒可以含有用于每个表达盒内的开放阅读框的调控元件,并且核酸分子可以任选地含有额外的调控元件。
AAV载体可以含有全长AAV 5′反向末端重复序列(ITR)和全长3′ITR。已经描述了称为ΔITR的5′ITR的缩短版本,其中删除了D序列和末端决定位点(trs)。缩写“sc”是指自我互补。“自我互补的AAV”是指其中由重组AAV核酸序列携带的编码区已被设计为形成分子内双链DNA模板的构建体。感染后,不是等待细胞介导的第二条链的合成,scAAV的两个互补半部将结合形成一个准备立即复制和转录的双链DNA(dsDNA)单位。参见例如D M McCarty等人,“Self-complementary recombinant adeno-associated virus(scAAV)vectorspromote efficient transduction independently of DNA synthesis”,Gene Therapy,(2001年8月),第8卷,第16期,第1248-1254页。自我互补的AAV描述于例如美国专利No.6,596,535;7,125,717;和7,456,683,其每一个的全部内容通过引用并入本文。在另一个实施方案中,使用自我互补的AAV。
在要产生假型AAV的情况下,ITR是选自与衣壳的AAV来源不同的来源。例如,AAV2ITR可以选择与对选定的细胞受体、靶组织或病毒靶具有特定效率的AAV衣壳一起使用。在一个实施方案中,来自AAV2的ITR序列或其删除版本(ΔITR)出于便利性使用并用于加速调节认可。然而,可能会选择其它AAV来源的ITR。当ITR的来源来自AAV2并且AAV衣壳来自另一个AAV来源时,所得载体可以被称为假型化。但是,也可以使用其它AAV ITR来源。
已经描述了多种AAV衣壳。产生AAV载体的方法已经在文献和专利文件中被广泛地描述,包括例如WO 2003/042397;WO 2005/033321、WO 2006/110689;US 7588772 B2。AAV衣壳的来源可以选自靶向期望组织的AAV。例如,合适的AAV可以包括例如AAV9[US 7,906,111;US 2011-0236353-A1]、rh10[WO 2003/042397]和/或hu37[参见例如US 7,906,111;US2011-0236353-A1]。然而,其它AAV,包括例如AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8[美国专利7790449;美国专利7282199]等,包括其变体。在一个实施方案中,AAV衣壳是AAV8衣壳或其变体。在一个实施方案中,当提及AAV衣壳时,术语“变体”是指与所命名的AAV衣壳共享至少约90%同一性、95%同一性、97%同一性、98%同一性、99%同一性或更高的衣壳。例如,在一个实施方案中,AAV衣壳是由NCBI参考序列:YP_077180.1鉴定的AAV8衣壳或与其共享至少95%同一性的序列。然而,可以选择AAV衣壳和其它病毒元件的其它来源,其它免疫球蛋白构建体和其它载体元件也可以。
提供单链AAV病毒载体。用于产生和分离适合递送至受试者的AAV病毒载体的方法是本领域已知的。参见例如美国专利7790449;美国专利7282199;WO 2003/042397;WO2005/033321,WO 2006/110689;和US 7588772 B2]。在一个***中,生产者细胞系用编码侧翼为ITR的转基因的构建体和编码rep和cap的构建体瞬时转染。在第二个***中,稳定供应rep和cap的包装细胞系用编码侧翼为ITR的转基因的构建体瞬时转染。在这些***中的每一个***中,AAV病毒粒子都是响应于辅助性腺病毒或疱疹病毒感染而产生的,需要将rAAV从污染性病毒中分离出来。最近,已经开发了不需要用辅助病毒感染来恢复AAV的***-所需的辅助功能(即,腺病毒E1、E2a、VA和E4或疱疹病毒UL5、UL8、UL52和UL29以及疱疹病毒聚合酶)也由***以反式提供。在这些较新的***中,辅助功能可以通过用编码所需辅助功能的构建体瞬时转染细胞来提供,或者细胞可以被工程化以稳定地含有编码辅助功能的基因,其表达可以在转录水平或转录后水平加以控制。在另一个***中,通过感染基于杆状病毒的载体将侧翼为ITR和rep/cap基因的转基因导入昆虫细胞中。关于这些生产***的综述,一般参见例如Zhang等人,2009,“Adenovirus-adeno-associated virus hybrid forlarge-scale recombinant adeno-associated virus production,”Human Gene Therapy20:922-929,其中每一个的全部内容通过引用并入本文。在以下美国专利中也描述了制造和使用这些和其它AAV生产***的方法,其全部内容通过引用并入本文:5,139,941;5,741,683;6,057,152;6,204,059;6,268,213;6,491,907;6,660,514;6,951,753;7,094,604;7,172,893;7,201,898;7,229,823;和7,439,065。
为了用于产生AAV病毒载体(例如重组(r)AAV)),可以将表达盒携带在任何合适的载体上,例如质粒,其被递送至包装宿主细胞。可用于本发明的质粒可以工程化,使得它们适合于在原核细胞、哺乳动物细胞或两者中复制和包装。合适的转染技术和包装宿主细胞是已知的和/或可以容易地由本领域技术人员设计。图3和SEQ ID NO:10中显示了用于产生实施例中使用的病毒载体的质粒的实例。
产生和分离适合用作载体的AAV的方法是本领域已知的。一般参见例如Grieger和Samulski,2005,“Adeno-associated virus as a g ene therapy vector:Vectordevelopment,production and clinical app lications,”Adv.Biochem.Engin/Biotechnol.99:119-145;Buning等人,2008,“Recent developments in adeno-associated virus vector te chnology,”J.Gene Med.10:717-733;以及下面引用的参考文献,每篇文献的全部内容通过引用并入本文。为了将转基因包装入病毒粒子中,ITR是与含有表达盒的核酸分子在相同构建体中顺式所需的唯一AAV组分。cap和rep基因可以反式供应。
如上所述,除非另有说明,否则术语“约”用于修饰数值时表示±10%的变化。
在两个或更多个核酸或多肽序列的上下文中,术语“同一”或百分比“同一性”是指两个或更多个序列或子序列在指定区域(例如,当在比较窗口或指定区域上比较和比对以获得最大对应性时,本文提供的任何一个ORF)是相同的或具有特定百分比的氨基酸残基或核苷酸相同(即,约70%同一性,优选75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高的同一性,如使用具有下述默认参数的BLAST或BLAST 2.0序列比较算法所测量,或通过手动对齐和视觉检查(参见例如NCBI网站等)。作为另一个实例,可以使用GCG版本6.1中的程序Fasta比较聚核苷酸序列。Fasta提供查询和搜索序列之间最佳重叠区域的比对和百分比序列同一性。例如,核酸序列之间的百分比序列同一性可以使用Fasta以及其在GCG版本6.1中提供的默认参数(字长6和评分矩阵的NOPAM因子)来确定,其通过引用并入本文。通常,这些程序以默认设置使用,但本领域技术人员可以根据需要改变这些设置。或者,本领域技术人员可以利用另一种算法或计算机程序,其提供至少与参考算法和程序提供一样的同一性或比对水平。该定义也指或可以应用于序列的补码。该定义还包括具有缺失和/或添加的序列,以及具有取代的序列。如下所述,优选的算法可以解决间隙等问题。优选地,同一性存在于至少约25、50、75、100、150、200个氨基酸或核苷酸长度的区域上,并且通常在225、250、300、350、400、450、500个氨基酸或核苷酸长度的区域上或在氨基酸或核酸序列的全长上。
通常,当准备基于氨基酸序列比对时,比对包含相对于参考AAV序列如此鉴定的***和缺失,并且氨基酸残基的编号基于为比对提供的参考标度。然而,任何给定的AAV序列可能具有比参考标度更少的氨基酸残基。在本发明中,当讨论亲本序列时,术语“相同位置”或“对应位置”是指相对于对齐序列的参考标度,在每个序列中位于相同残基编号的氨基酸。然而,当从比对中取出时,每种蛋白质可能具有位于不同残基编号的这些氨基酸。使用各种公共或商业可用的多序列比对程序中的任何一种来进行比对。序列比对程序可用于氨基酸序列,例如“Clustal X”、“MAP”、“PIMA”、“MSA”、“BLOCKMAKER”、“MEME”和“Match-Box”程序。一般,这些程序中的任何一个都以默认设置使用,但本领域的技术人员可以根据需要改变这些设置。或者,本领域技术人员可以利用另外的算法或计算机程序,其提供至少与参考算法和程序提供一样的同一性或比对水平。参见例如J.D.Thomson等人,Nucl.Acids.Res.,“A comprehensive comparison of multiple sequence alignments”,27(13):2682-2690(1999)。
在一个实施方案中,本文所述的表达盒被工程化为将其上携带的免疫球蛋白构建体序列转移至包装宿主细胞以产生病毒载体的遗传元件(例如穿梭质粒)。在一个实施方案中,可以通过包括转染、电穿孔、脂质体递送、膜融合技术、高速DNA包衣小丸、病毒感染和原生质体融合的任何合适的方法将选择的遗传元件递送至AAV包装细胞。也可以制造稳定的AAV包装细胞。或者,表达盒可用于产生除AAV以外的病毒载体,或用于体外产生抗体混合物。用于制造这类构建体的方法对于具有核酸操作技能的人员是已知的,并且包括基因工程、重组工程和合成技术。参见例如Molecular Cloning:A Laboratory Manual,Green和Sambrook编,Cold Spring Harbor Press,Cold Spring Harbor,NY(2012)。
如本文所用,载体可以是转染、转导或感染宿主细胞并表达装配成功能性抗体的免疫球蛋白的任何合适的遗传元件。这种载体可以选自慢病毒载体、杆状病毒载体、细小病毒载体、质粒、修饰的RNA和DNA分子,其中mRNA和DNA可以是纳米颗粒的形式。
载体优选悬浮在生理学相容的载剂中,以便施用于人类或非人类哺乳动物患者。考虑到转移病毒针对的适应症,本领域技术人员可以容易地选择合适的载剂。例如,一种合适的载剂包括盐水,其可以用各种缓冲溶液(例如磷酸盐缓冲盐水)配制。其它示例性的载剂包括无菌盐水、乳糖、蔗糖、麦芽糖和水。任选地,除了rAAV和载剂之外,本发明的组合物可以包含其它常规药物成分,如防腐剂或化学稳定剂。
还提供了包含本文所述的病毒载体构建体的组合物。本文所述的医药组合物被设计用于通过任何合适的途径或不同途径的组合递送至有需要的受试者。可以使用任何合适的方法或途径来施用如本文所述的含AAV的组合物,并任选地与本文所述的AAV介导的抗体一起共同施用其它活性药物或疗法。施用途径包括例如全身、口服、吸入、鼻内、气管内、动脉内、眼内、静脉内、肌内、皮下、真皮内和其它肠胃外施用途径。本文所述的病毒载体可以单一组合物或多种组合物递送。任选地,可以递送两种或更多种不同的AAV或多种病毒[参见例如WO 2011/126808和WO 2013/049493]。在另一个实施方案中,多种病毒可以含有不同的复制缺陷型病毒(例如AAV和腺病毒)。
在AAV病毒载体的情况下,可以使用基因组拷贝(“GC”)的定量作为制剂中所含剂量的量度。本领域已知的任何方法可用于确定本发明的复制缺陷型病毒组合物的基因组拷贝(GC)数量。进行AAV GC数滴定的一种方法如下:纯化的AAV载体样品首先用DNA酶处理以消除生产过程中未包衣壳的AAV基因组DNA或污染性质粒DNA。然后对DNA酶抗性颗粒进行热处理以从衣壳中释放基因组。然后使用靶向病毒基因组特定区(通常是poly A信号)的引物/探针组通过实时PCR对释放的基因组进行定量。其它合适的方法包括数字PCT、数字液滴PCR和优化的qPCR。
此外,复制缺陷型病毒组合物可以剂量单位配制以含有一定量的复制缺陷型病毒,其范围在约1.0×109GC至约1.0×1015GC。在另一个实施方案中,该量的病毒基因组可以分开剂量递送。在一个实施方案中,对于约5kg的平均小型犬受试者,剂量为约1.0×1010GC至约1.0×1012GC。在一个实施方案中,对于约20kg的平均中型犬受试者,剂量为约1.0×1011GC至约5.0×1013GC。在一个实施方案中,对于约50kg的平均大型犬受试者,剂量为约1.0×1012GC至约1.0×1014GC。犬的平均体重范围介于约5至约50kg。在一个实施方案中,剂量为约1×1012GC/kg。在一个实施方案中,受试者的剂量为约1.0×1011GC至1.0×1014GC。在另一个实施方案中,剂量约1×1013GC。例如,AAV病毒的剂量可以是约1×1012GC、约5X1012GC、约1X1013GC、约5X1013GC或约1X1014GC。在另一个实例中,构建体可以每毫升约0.001mg至约10mg的量递送。在一个实施方案中,对于兽医学受试者,构建体可以1μL至约100mL的体积递送。参见例如Dieh1等人,J.Applied Toxicology,21:15-23(2001),以讨论将物质施用于各种兽医学动物的良好实践。该文件通过引用并入本文。如本文所用,术语“剂量”可以指在治疗过程中递送给受试者的总剂量,或单次(多次)施用递送的量。
根据公开的方法可以将上述重组载体递送至宿主细胞。优选悬浮于生理上相容的载剂、载剂、稀释剂、赋形剂和/或佐剂中的rAAV可以施用于期望的受试者,包括但不限于猫、狗或其它非人类哺乳动物受试者。考虑到转移病毒针对的适应症,本领域技术人员可以容易地选择合适的载剂。例如,一种合适的载剂包括盐水,其可以用各种缓冲溶液(例如磷酸盐缓冲盐水)配制。其它示例性的载剂包括无菌盐水、乳糖、蔗糖、磷酸钙、明胶、葡聚糖、琼脂、果胶、花生油、芝麻油和水。载剂的选择不是本发明的限制。
任选地,除了rAAV和/或变体和载剂之外,本发明的组合物可以含有其它常规药物成分,如防腐剂或化学稳定剂。合适的示例性防腐剂包括氯丁醇、山梨酸钾、山梨酸、二氧化硫、没食子酸丙酯、对羟基苯甲酸酯、乙基香兰素、甘油、苯酚和对氯苯酚。合适的化学稳定剂包括明胶和白蛋白。
一方面,当以约3mL或更少、1mL或更少、0.5mL或更少,例如约100μL至250μL的剂量递送时,本文提供的载体表达有效水平的功能性抗体。因此,本文提供的载体在方便计量剂量的剂量或者在含有预先测量的剂量的产品或试剂盒中提供治疗水平的抗体是高度有效的。
本文所述的病毒载体和其它构建体可用于制备用于将嵌合抗VEGF抗体构建体递送至有需要的受试者和/或用于治疗受试者的血管肉瘤的药物。因此,另一方面提供了治疗血管肉瘤的方法。该方法包括将如本文所述的组合物施用于有需要的受试者。在一个实施方案中,组合物包括含有如本文所述的抗VEGF抗体表达盒的病毒载体。在一个实施方案中,受试者是哺乳动物。在另一个实施方案中,受试者是犬。
在另一个实施方案中,提供了用于治疗犬的血管肉瘤的方法。该方法包括向受试者施用包含含有编码嵌合抗VEGF抗体的序列的核酸分子的病毒载体。
在另一个实施方案中,提供了用于治疗受试者的癌症的方法。该方法包括向受试者施用包含含有编码抗VEGF抗体的序列的核酸分子的病毒载体。在一个实施方案中,癌症是其中涉及VEGF(例如上调)的癌症。例如,据信VEGF涉及血管生成、血管渗透性和肿瘤发生。参见例如Goel和Mercurio,VEGF targets the tumor cell,Nature Reviews Cancer,13:871-82(2013),其通过引用并入本文。在另一个实施方案中,癌症是其中显示由VEGF驱动的异常血管生成水平的癌症。在本文所述的方法和组合物的各种实施方案中,癌症可以包括但不限于乳腺癌、肺癌、***癌、结肠直肠癌、脑癌、食管癌、胃癌、膀胱癌、胰腺癌、***、头颈癌、卵巢癌、黑素瘤、急性和慢性淋巴细胞和髓细胞性白血病、骨髓瘤、霍奇金和非霍奇金淋巴瘤以及多药耐药性癌症。在一个实施方案中,癌症是耐药性癌症。在一个实施方案中,受试者是犬。
在另一个实施方案中,提供了用于治疗受试者的黄斑变性的方法。该方法包括向受试者施用包含含有编码抗VEGF抗体的序列的核酸分子的病毒载体。在一个实施方案中,受试者是犬。在一个实施方案中,黄斑变性是X连锁的黄斑变性。在另一个实施方案中,黄斑变性是年龄相关性黄斑变性。
治疗过程可以任选地涉及重复施用表达如本文所述的抗VEGF抗体的相同病毒载体(例如AAV8载体)或不同病毒载体(例如AAV8和AAVrh10)。还可以使用本文所述的病毒载体来选择其它组合。任选地,本文所述的组合物可以在涉及以下一种或多种的方案中组合:癌症药物(包括例如多柔比星、长春新碱+多柔比星+环磷酰胺(VAC)或其它化疗药物、手术去除或减少肿瘤、放射疗法、包括卡洛芬、地拉考昔、多西环素的药物(参见例如Hammer AS,Couto CG,Filppi J等人,Efficacy and toxicity of VAC chemotherapy(vincristine,doxorubicin,and cyclophosphamide)in dogs with hemangiosarcoma.J Vet InternMed;1991;5:160-166.;Sorenmo KU,Jeglum KA,Helfand SC.Chemotherapy of caninehemangiosarcoma with doxorubicin and cyclophosphamide.J Vet Intern Med 1993;7:370-376.;和Ogilvie GK,Powers BE,Mallinckrodt CH等人,Surgery and doxorubicinin dogs with hemangiosarcoma.J Vet Intern Med 1996;10:379-384.,它们通过引用整体并入本文)和多糖肽(PSP)。任选地,本文所述的组合物可以在涉及包括饮食和运动方案的生活方式改变的方案中组合。
应注意,术语“一(a/an)”是指一个或多个。因此,术语“一”、“一个或多个”和“至少一个”在本文中可互换使用。
词语“包含(comprise/comprises/comprising)”应解释为包含性而非排他性的。词语“由......组成(consist/consisting)”及其变体应解释为排他性而非包含性的。尽管本说明书中的各种实施方案是使用“包含”语言来呈现的,但是在其它情况下,相关实施方案也旨在使用“由......组成”或“基本上由......组成”语言来解释和描述。
如本文所用,除非另有说明,否则术语“约”意指与给出的参考值相差10%的变化。
如本文所用,术语“调节”或其变体是指组合物抑制生物学途径的一种或多种组分的能力。
“受试者”是哺乳动物,例如人类、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪或非人类灵长类动物,如猴、黑猩猩、狒狒或大猩猩。在一个实施方案中,受试者是狗。如本文所用,术语“受试者”与“患者”可互换使用。
如本文所用,“疾病”、“病症”和“病况”可互换使用,以指示受试者的异常状态。
除非在本说明书中另外定义,否则本文使用的技术和科学术语具有与本领域普通技术人员通常理解的相同的含义并且通过参考公开文本,其向本领域技术人员提供了对本申请中使用的许多术语的一般指导。
以下实施例仅是说明性的,并不意图限制本发明。
实施例1-VEGF载体的构建
犬IgG亚类A和κ轻链的氨基酸序列从Genbank获得。将鼠抗体A.4.6.1的可变区的氨.基酸序列与犬IgGA/κ恒定区组合以产生靶向VEGF的嵌合犬抗体的氨基酸序列。将氨基酸序列反向翻译并密码子优化,然后加入kozak共有序列、终止密码子和克隆位点。通过GeneArt产生所述序列,并将其克隆到含有CMV或CB启动子的多种表达载体中,通过在多肽链之间包含2A肽序列和弗林蛋白酶切割位点,或通过使用EMCV内部核糖体进入位点表达3′多肽实现重链和轻链的表达。表达构建体侧翼是AAV2 ITR。含有CMV启动子的表达载体的实例显示在图3和SEQ ID NO:10中。通过三重转染和碘克沙醇梯度纯化将构建体包装在AAV血清型8衣壳中,并通过Taqman定量PCR进行滴定。
实施例2-体外表达和抗原结合
使用lipofectamine 2000通过瞬时转染HEK 293细胞体外评估含有CMV启动子,然后是抗体重链、EMCV IRES和抗体轻链的构建体。根据制造商的说明使用蛋白G柱(GE)从上清液中纯化表达的抗体。通过用Sypro红宝石染色还原SDS-PAGE来表征纯化的抗体(图1)。通过ELISA评估抗体与犬VEGF的结合,其中靶抗原是重组犬VEGF(Kingfisher Bio),并且通过HRP缀合的山羊抗狗二级抗体(Peirce)检测结合的抗体。纯化的抗体和转染上清液均通过ELISA显示与犬VEGF的结合。
实施例3-AAV介导的嵌合犬抗VEGF抗体在狗中的表达
通过单次肌内注射1012个基因组拷贝/千克体重(GC/kg)表达嵌合抗体的AAV8处理三只正常的狗。在指定时间收集血清并通过VEGF结合ELISA评估抗体表达,其中纯化的抗体充当定量标准(图2)。
本说明书中引用的所有出版物,以及2015年8月31日提交的美国临时专利申请no.62/212,170,通过引用并入本文。类似地,本文引用的和出现在所附序列表中的SEQ IDNO通过引用并入本文。虽然已经参照特定实施方案描述了本发明,但应理解,可以在不脱离本发明的精神的情况下进行修改。这些修改意图落入所附权利要求的范围内。
SEQUENCE LISTING
<110> 宾夕法尼亚大学的受托人
<120> 用于治疗伴侣动物的癌症的AAV-抗VEGF
<130> UPN-15-7473
<150> US 62/212,170
<151> 2015-08-31
<160> 15
<170> PatentIn版本3.5
<210> 1
<211> 124
<212> PRT
<213> 家犬
<400> 1
Glu Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Gln Pro Gly Glu
1 5 10 15
Thr Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Asp Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala
115 120
<210> 2
<211> 330
<212> PRT
<213> 小家鼠
<400> 2
Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly Ser
1 5 10 15
Thr Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr Phe
20 25 30
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser Gly
35 40 45
Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu His Ser Leu
50 55 60
Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr Phe
65 70 75 80
Thr Cys Asn Val Val His Pro Ala Ser Asn Thr Lys Val Asp Lys Pro
85 90 95
Val Phe Asn Glu Cys Arg Cys Thr Asp Thr Pro Pro Cys Pro Val Pro
100 105 110
Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro Lys Pro Lys
115 120 125
Asp Ile Leu Arg Ile Thr Arg Thr Pro Glu Val Thr Cys Val Val Leu
130 135 140
Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp
145 150 155 160
Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu Gln Gln Phe
165 170 175
Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu His Gln Asp
180 185 190
Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His Ile Asp Leu
195 200 205
Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Arg Ala His
210 215 220
Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser Ser
225 230 235 240
Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe Tyr Pro Pro
245 250 255
Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Arg
260 265 270
Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe
275 280 285
Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly Asp
290 295 300
Pro Phe Thr Cys Ala Val Met His Glu Thr Leu Gln Asn His Tyr Thr
305 310 315 320
Asp Leu Ser Leu Ser His Ser Pro Gly Lys
325 330
<210> 3
<211> 108
<212> PRT
<213> 家犬
<400> 3
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ile Ile Ser Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Val Leu Ile
35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 4
<211> 105
<212> PRT
<213> 小家鼠
<400> 4
Asn Asp Ala Gln Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp Gln
1 5 10 15
Leu His Thr Gly Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe Tyr
20 25 30
Pro Lys Asp Ile Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln Asp
35 40 45
Thr Gly Ile Gln Glu Ser Val Thr Glu Gln Asp Lys Asp Ser Thr Tyr
50 55 60
Ser Leu Ser Ser Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu Ser His
65 70 75 80
Glu Leu Tyr Ser Cys Glu Ile Thr His Lys Ser Leu Pro Ser Thr Leu
85 90 95
Ile Lys Ser Phe Gln Arg Ser Glu Cys
100 105
<210> 5
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> IL-2前导序列
<400> 5
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser
20
<210> 6
<211> 372
<212> DNA
<213> 家犬
<400> 6
gagatccagc tggtgcagtc tggccccgag ctgaagcagc ctggcgagac agtgcggatc 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt caagcaggcc 120
cctggcaagg gcctgaagtg gatgggctgg atcaacacct acaccggcga gcctacctac 180
gccgccgact tcaagcggcg gttcaccttc agcctggaaa ccagcgccag caccgcctac 240
ctgcagatca gcaacctgaa gaacgacgac accgccacct acttttgcgc caagtacccc 300
cactactacg gcagcagcca ctggtacttc gacgtgtggg gagccggcac caccgtgaca 360
gtgtcatctg cg 372
<210> 7
<211> 324
<212> DNA
<213> 家犬
<400> 7
gacatccaga tgacccagac caccagcagc ctgagcgcca gcctgggcga cagagtgatc 60
atcagctgta gcgcctccca ggacatcagc aactacctga actggtatca gcagaaaccc 120
gacggcaccg tgaaggtgct gatctacttc accagctccc tgcacagcgg cgtgcccagc 180
agattttctg gcagcggctc cggcaccgac tacagcctga ccatctccaa cctggaaccc 240
gaggatatcg ccacctacta ctgccagcag tacagcaccg tgccctggac ctttggcgga 300
ggcaccaagc tggaaatcaa gcgg 324
<210> 8
<211> 639
<212> DNA
<213> 小家鼠
<400> 8
gacatccaga tgacccagac caccagcagc ctgagcgcca gcctgggcga cagagtgatc 60
atcagctgta gcgcctccca ggacatcagc aactacctga actggtatca gcagaaaccc 120
gacggcaccg tgaaggtgct gatctacttc accagctccc tgcacagcgg cgtgcccagc 180
agattttctg gcagcggctc cggcaccgac tacagcctga ccatctccaa cctggaaccc 240
gaggatatcg ccacctacta ctgccagcag tacagcaccg tgccctggac ctttggcgga 300
ggcaccaagc tggaaatcaa gcggaatgat gctcagcctg ctgtgtacct ttttcaacca 360
agccctgacc aactgcatac cggcagtgcc tctgtggtct gcctgcttaa tagcttctat 420
cccaaggaca ttaatgtgaa gtggaaggtt gacggcgtga tacaggatac cggaattcag 480
gaaagtgtga cagaacaaga taaggatagc acctatagcc tgtctagcac cctcaccatg 540
agcagcacag agtacttgag tcatgagctg tatagctgtg agattaccca caagagtctg 600
ccaagcaccc ttataaaaag tttccagcga tctgagtgt 639
<210> 9
<211> 315
<212> DNA
<213> 小家鼠
<400> 9
aatgatgctc agcctgctgt gtaccttttt caaccaagcc ctgaccaact gcataccggc 60
agtgcctctg tggtctgcct gcttaatagc ttctatccca aggacattaa tgtgaagtgg 120
aaggttgacg gcgtgataca ggataccgga attcaggaaa gtgtgacaga acaagataag 180
gatagcacct atagcctgtc tagcaccctc accatgagca gcacagagta cttgagtcat 240
gagctgtata gctgtgagat tacccacaag agtctgccaa gcacccttat aaaaagtttc 300
cagcgatctg agtgt 315
<210> 10
<211> 7293
<212> DNA
<213> 人工序列
<220>
<223> 构建的序列
<220>
<221> misc_feature
<222> (12)..(71)
<220>
<221> misc_feature
<222> (72)..(443)
<220>
<221> misc_feature
<222> (444)..(1433)
<220>
<221> 增强子
<222> (1445)..(2032)
<223> IRES
<220>
<221> misc_feature
<222> (2033)..(2092)
<220>
<221> misc_feature
<222> (2093)..(2365)
<220>
<221> misc_feature
<222> (2366)..(2731)
<220>
<221> polyA信号
<222> (2754)..(2985)
<223> SV40\晚期\聚腺苷酸化\信号
<220>
<221> 启动子
<222> (2754)..(2985)
<223> 人类\CMV\I.E.\增强子\和\启动子
<220>
<221> misc_feature
<222> (3050)..(3179)
<223> 3' ITR (互补序列)
<220>
<221> misc_feature
<222> (6001)..(6130)
<223> 5' ITR
<220>
<221> TATA信号
<222> (6897)..(6901)
<220>
<221> 内含子
<222> (7047)..(7179)
<223> Promega\嵌合\内含子
<400> 10
ctagacccac catgtacagg atgcaactcc tgtcttgcat tgcactaagt cttgcacttg 60
tcacaaacag tgagatccag ctggtgcagt ctggccccga gctgaagcag cctggcgaga 120
cagtgcggat cagctgcaag gccagcggct acaccttcac caactacggc atgaactggg 180
tcaagcaggc ccctggcaag ggcctgaagt ggatgggctg gatcaacacc tacaccggcg 240
agcctaccta cgccgccgac ttcaagcggc ggttcacctt cagcctggaa accagcgcca 300
gcaccgccta cctgcagatc agcaacctga agaacgacga caccgccacc tacttttgcg 360
ccaagtaccc ccactactac ggcagcagcc actggtactt cgacgtgtgg ggagccggca 420
ccaccgtgac agtgtcatct gcgtcgacca cagccccctc tgtgttcccc ctggcccctt 480
cctgtgggtc aacctctggc agcacagtgg ccctggcgtg tcttgtgtct ggctacttcc 540
ctgaacctgt gacagtcagc tggaacagcg gaagcctgac ctctggagtg cacaccttcc 600
ccagtgtcct gcaaagctca ggcctgcaca gcctgtcaag tatggtgaca gtgcccagta 660
gcaggtggcc ttctgaaacc tttacctgca acgtggtgca ccctgcatcc aacaccaaag 720
tggataagcc tgttttcaat gagtgcagat gcacagatac acctccctgc cctgtgcctg 780
agcctctggg aggaccatca gtcctgatct tccctccaaa gcctaaggat atcctgcgga 840
tcaccagaac ccccgaggtc acctgtgtcg tcctggatct gggccgggaa gatcctgaag 900
tgcagattag ctggtttgtg gacggcaagg aagtgcacac agctaagacc caatcccggg 960
agcagcagtt caatggcacc taccgggtgg tctctgtcct gcccatcgag caccaagatt 1020
ggctgacagg caaagagttt aagtgccgag tcaaccacat agatcttccc tcccctattg 1080
agcggaccat ctccaaggca cgggggcgag cgcacaaacc ctctgtctat gtgctgcctc 1140
cctctcccaa agaattgagc tctagcgata cagtgtcaat cacctgcctg atcaaggact 1200
tctacccccc tgacattgat gttgaatggc aatcaaatgg gcagcaagaa ccagagagaa 1260
aacacagaat gacccctcca cagctggatg aggacgggtc ctactttctg tactctaaac 1320
tttccgtgga caagagcaga tggcagcagg gagacccttt cacctgtgcg gtcatgcacg 1380
agacactgca aaaccactac acagatctgt ccttgagcca ctcacctggc aagtgataag 1440
gccggcccct ctccctcccc cccccctaac gttactggcc gaagccgctt ggaataaggc 1500
cggtgtgcgt ttgtctatat gttattttcc accatattgc cgtcttttgg caatgtgagg 1560
gcccggaaac ctggccctgt cttcttgacg agcattccta ggggtctttc ccctctcgcc 1620
aaaggaatgc aaggtctgtt gaatgtcgtg aaggaagcag ttcctctgga agcttcttga 1680
agacaaacaa cgtctgtagc gaccctttgc aggcagcgga accccccacc tggcgacagg 1740
tgcctctgcg gccaaaagcc acgtgtataa gatacacctg caaaggcggc acaaccccag 1800
tgccacgttg tgagttggat agttgtggaa agagtcaaat ggctctcctc aagcgtattc 1860
aacaaggggc tgaaggatgc ccagaaggta ccccattgta tgggatctga tctggggcct 1920
cggtacacat gctttacatg tgtttagtcg aggttaaaaa aacgtctagg ccccccgaac 1980
cacggggacg tggttttcct ttgaaaaaca cgatgataat atggccacaa ccatgtaccg 2040
catgcaactc ctgtcttgca ttgcactaag tcttgcactt gtcacaaaca gtgacatcca 2100
gatgacccag accaccagca gcctgagcgc cagcctgggc gacagagtga tcatcagctg 2160
tagcgcctcc caggacatca gcaactacct gaactggtat cagcagaaac ccgacggcac 2220
cgtgaaggtg ctgatctact tcaccagctc cctgcacagc ggcgtgccca gcagattttc 2280
tggcagcggc tccggcaccg actacagcct gaccatctcc aacctggaac ccgaggatat 2340
cgccacctac tactgccagc agtacagcac cgtgccctgg acctttggcg gaggcaccaa 2400
gctggaaatc aagcggaatg atgctcagcc tgctgtgtac ctttttcaac caagccctga 2460
ccaactgcat accggcagtg cctctgtggt ctgcctgctt aatagcttct atcccaagga 2520
cattaatgtg aagtggaagg ttgacggcgt gatacaggat accggaattc aggaaagtgt 2580
gacagaacaa gataaggata gcacctatag cctgtctagc accctcacca tgagcagcac 2640
agagtacttg agtcatgagc tgtatagctg tgagattacc cacaagagtc tgccaagcac 2700
ccttataaaa agtttccagc gatctgagtg ttgatgaaag cttgcggccg cttcgagcag 2760
acatgataag atacattgat gagtttggac aaaccacaac tagaatgcag tgaaaaaaat 2820
gctttatttg tgaaatttgt gatgctattg ctttatttgt aaccattata agctgcaata 2880
aacaagttaa caacaacaat tgcattcatt ttatgtttca ggttcagggg gagatgtggg 2940
aggtttttta aagcaagtaa aacctctaca aatgtggtaa aatcgataag gatcttccta 3000
gagcatggct acgtagataa gtagcatggc gggttaatca ttaactacaa ggaaccccta 3060
gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca 3120
aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcagc 3180
cttaattaac ctaattcact ggccgtcgtt ttacaacgtc gtgactggga aaaccctggc 3240
gttacccaac ttaatcgcct tgcagcacat ccccctttcg ccagctggcg taatagcgaa 3300
gaggcccgca ccgatcgccc ttcccaacag ttgcgcagcc tgaatggcga atgggacgcg 3360
ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt gaccgctaca 3420
cttgccagcg ccctagcgcc cgctcctttc gctttcttcc cttcctttct cgccacgttc 3480
gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg atttagtgct 3540
ttacggcacc tcgaccccaa aaaacttgat tagggtgatg gttcacgtag tgggccatcg 3600
ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa tagtggactc 3660
ttgttccaaa ctggaacaac actcaaccct atctcggtct attcttttga tttataaggg 3720
attttgccga tttcggccta ttggttaaaa aatgagctga tttaacaaaa atttaacgcg 3780
aattttaaca aaatattaac gcttacaatt taggtggcac ttttcgggga aatgtgcgcg 3840
gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc atgagacaat 3900
aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt caacatttcc 3960
gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct cacccagaaa 4020
cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt tacatcgaac 4080
tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt tttccaatga 4140
tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac gccgggcaag 4200
agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca 4260
cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca 4320
tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa 4380
ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc 4440
tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagca atggcaacaa 4500
cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa caattaatag 4560
actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt ccggctggct 4620
ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc attgcagcac 4680
tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg agtcaggcaa 4740
ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt aagcattggt 4800
aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt catttttaat 4860
ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg 4920
agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc 4980
ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg 5040
tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag 5100
cgcagatacc aaatactgtt cttctagtgt agccgtagtt aggccaccac ttcaagaact 5160
ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg 5220
gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc 5280
ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg 5340
aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa gggagaaagg 5400
cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag 5460
ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc 5520
gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc aacgcggcct 5580
ttttacggtt cctggccttt tgctggcctt ttgctcacat gttctttcct gcgttatccc 5640
ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct cgccgcagcc 5700
gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga agagcgccca atacgcaaac 5760
cgcctctccc cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg tttcccgact 5820
ggaaagcggg cagtgagcgc aacgcaatta atgtgagtta gctcactcat taggcacccc 5880
aggctttaca ctttatgctt ccggctcgta tgttgtgtgg aattgtgagc ggataacaat 5940
ttcacacagg aaacagctat gaccatgatt acgccagatt taattaaggc cttaattagg 6000
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 6060
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 6120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 6180
aggaagatct tcaatattgg ccattagcca tattattcat tggttatata gcataaatca 6240
atattggcta ttggccattg catacgttgt atctatatca taatatgtac atttatattg 6300
gctcatgtcc aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat 6360
caattacggg gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg 6420
taaatggccc gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt 6480
atgttcccat agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac 6540
ggtaaactgc ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg 6600
acgtcaatga cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact 6660
ttcctacttg gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt 6720
ggcagtacac caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc 6780
ccattgacgt caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc 6840
gtaataaccc cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata 6900
taagcagagc tcgtttagtg aaccgtcaga tcactagaag ctttattgcg gtagtttatc 6960
acagttaaat tgctaacgca gtcagtgctt ctgacacaac agtctcgaac ttaagctgca 7020
gaagttggtc gtgaggcact gggcaggtaa gtatcaaggt tacaagacag gtttaaggag 7080
accaatagaa actgggcttg tcgagacaga gaagactctt gcgtttctga taggcaccta 7140
ttggtcttac tgacatccac tttgcctttc tctccacagg tgtccactcc cagttcaatt 7200
acagctctta aggctagagt acttaatacg actcactata ggctagcggg gactttgcac 7260
tggaacttac aacacccgag caaggacgcg act 7293
<210> 11
<211> 7584
<212> DNA
<213> 人工序列
<220>
<223> 构建的序列
<220>
<221> polyA信号
<222> (818)..(1049)
<223> SV40\晚期\聚腺苷酸化\信号
<220>
<221> 重复区
<222> (1114)..(1243)
<223> ITR (互补序列)
<220>
<221> rep_origin
<222> (1420)..(1875)
<223> f1 ori (互补序列)
<220>
<221> misc_feature
<222> (2006)..(2863)
<223> Amp R
<220>
<221> misc_feature
<222> (3037)..(3625)
<223> COL\E1\起点
<220>
<221> 重复区
<222> (4065)..(4194)
<223> ITR
<220>
<221> 启动子
<222> (4770)..(5050)
<223> CB启动子
<220>
<221> TATA信号
<222> (5024)..(5027)
<220>
<221> 内含子
<222> (5144)..(6116)
<223> 鸡\β-肌动蛋白\内含子
<400> 11
ctggcaagag aaagcggaga gcccccgtga agcagaccct gaacttcgac ctgctgaagc 60
tggccggcga cgtggaaagc aaccctggcc ctatgtacaa gatgcaactc ctgtcttgca 120
ttgcactaac tcttgtcctt gtcgcaaaca gtgacatcca gatgacccag accaccagca 180
gcctgagcgc cagcctgggc gacagagtga tcatcagctg tagcgcctcc caggacatca 240
gcaactacct gaactggtat cagcagaaac ccgacggcac cgtgaaggtg ctgatctact 300
tcaccagctc cctgcacagc ggcgtgccca gcagattttc tggcagcggc tccggcaccg 360
actacagcct gaccatctcc aacctggaac ccgaggatat cgccacctac tactgccagc 420
agtacagcac cgtgccctgg acctttggcg gaggcaccaa gctggaaatc aagcggaatg 480
atgctcagcc tgctgtgtac ctttttcaac caagccctga ccaactgcat accggcagtg 540
cctctgtggt ctgcctgctt aatagcttct atcccaagga cattaatgtg aagtggaagg 600
ttgacggcgt gatacaggat accgggattc aggaaagtgt gacagaacaa gataaggata 660
gcacctatag cctgtctagc accctcacca tgagcagcac agagtacttg agtcatgagc 720
tgtatagctg tgagattacc cacaagagtc tgccaagcac ccttataaaa agtttccagc 780
gatctgagtg ttgataaggt accgcttgcg gccgcttcga gcagacatga taagatacat 840
tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 900
ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 960
caattgcatt cattttatgt ttcaggttca gggggagatg tgggaggttt tttaaagcaa 1020
gtaaaacctc tacaaatgtg gtaaaatcga taaggatctt cctagagcat ggctacgtag 1080
ataagtagca tggcgggtta atcattaact acaaggaacc cctagtgatg gagttggcca 1140
ctccctctct gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc 1200
cgggctttgc ccgggcggcc tcagtgagcg agcgagcgcg cagccttaat taacctaatt 1260
cactggccgt cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc caacttaatc 1320
gccttgcagc acatccccct ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc 1380
gcccttccca acagttgcgc agcctgaatg gcgaatggga cgcgccctgt agcggcgcat 1440
taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 1500
cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 1560
aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 1620
ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt 1680
ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 1740
caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg 1800
cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat 1860
taacgcttac aatttaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt 1920
atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct 1980
tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc 2040
cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa 2100
agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg 2160
taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt 2220
tctgctatgt ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg 2280
catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac 2340
ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc 2400
ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa 2460
catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc 2520
aaacgacgag cgtgacacca cgatgcctgt agcaatggca acaacgttgc gcaaactatt 2580
aactggcgaa ctacttactc tagcttcccg gcaacaatta atagactgga tggaggcgga 2640
taaagttgca ggaccacttc tgcgctcggc ccttccggct ggctggttta ttgctgataa 2700
atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc cagatggtaa 2760
gccctcccgt atcgtagtta tctacacgac ggggagtcag gcaactatgg atgaacgaaa 2820
tagacagatc gctgagatag gtgcctcact gattaagcat tggtaactgt cagaccaagt 2880
ttactcatat atactttaga ttgatttaaa acttcatttt taatttaaaa ggatctaggt 2940
gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt cgttccactg 3000
agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt ttctgcgcgt 3060
aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt tgccggatca 3120
agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga taccaaatac 3180
tgttcttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag caccgcctac 3240
atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata agtcgtgtct 3300
taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg gctgaacggg 3360
gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga gatacctaca 3420
gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca ggtatccggt 3480
aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa acgcctggta 3540
tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc 3600
gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc 3660
cttttgctgg ccttttgctc acatgttctt tcctgcgtta tcccctgatt ctgtggataa 3720
ccgtattacc gcctttgagt gagctgatac cgctcgccgc agccgaacga ccgagcgcag 3780
cgagtcagtg agcgaggaag cggaagagcg cccaatacgc aaaccgcctc tccccgcgcg 3840
ttggccgatt cattaatgca gctggcacga caggtttccc gactggaaag cgggcagtga 3900
gcgcaacgca attaatgtga gttagctcac tcattaggca ccccaggctt tacactttat 3960
gcttccggct cgtatgttgt gtggaattgt gagcggataa caatttcaca caggaaacag 4020
ctatgaccat gattacgcca gatttaatta aggccttaat taggctgcgc gctcgctcgc 4080
tcactgaggc cgcccgggca aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag 4140
tgagcgagcg agcgcgcaga gagggagtgg ccaactccat cactaggggt tccttgtagt 4200
taatgattaa cccgccatgc tacttatcta cgtagccatg ctctaggaag atcttcaata 4260
ttggccatta gccatattat tcattggtta tatagcataa atcaatattg gctattggcc 4320
attgcatacg ttgtatctat atcataatat gtacatttat attggctcat gtccaatatg 4380
accgccatgt tggcattgat tattgactag ttattaatag taatcaatta cggggtcatt 4440
agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg gcccgcctgg 4500
ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc ccatagtaac 4560
gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa ctgcccactt 4620
ggcagtacat caagtgtatc atatgccaag tacgccccct attgacgtca atgacggtaa 4680
atggcccgcc tggcattatg cccagtacat gaccttatgg gactttccta cttggcagta 4740
catctacgta ttagtcatcg ctattaccat ggtcgaggtg agccccacgt tctgcttcac 4800
tctccccatc tcccccccct ccccaccccc aattttgtat ttatttattt tttaattatt 4860
ttgtgcagcg atgggggcgg gggggggggg ggggcgcgcg ccaggcgggg cggggcgggg 4920
cgaggggcgg ggcggggcga ggcggagagg tgcggcggca gccaatcaga gcggcgcgct 4980
ccgaaagttt ccttttatgg cgaggcggcg gcggcggcgg ccctataaaa agcgaagcgc 5040
gcggcgggcg ggagtcgctg cgcgctgcct tcgccccgtg ccccgctccg ccgccgcctc 5100
gcgccgcccg ccccggctct gactgaccgc gttactccca caggtgagcg ggcgggacgg 5160
cccttctcct ccgggctgta attagcgctt ggtttaatga cggcttgttt cttttctgtg 5220
gctgcgtgaa agccttgagg ggctccggga gggccctttg tgcgggggga gcggctcggg 5280
gggtgcgtgc gtgtgtgtgt gcgtggggag cgccgcgtgc ggctccgcgc tgcccggcgg 5340
ctgtgagcgc tgcgggcgcg gcgcggggct ttgtgcgctc cgcagtgtgc gcgaggggag 5400
cgcggccggg ggcggtgccc cgcggtgcgg ggggggctgc gaggggaaca aaggctgcgt 5460
gcggggtgtg tgcgtggggg ggtgagcagg gggtgtgggc gcgtcggtcg ggctgcaacc 5520
ccccctgcac ccccctcccc gagttgctga gcacggcccg gcttcgggtg cggggctccg 5580
tacggggcgt ggcgcggggc tcgccgtgcc gggcgggggg tggcggcagg tgggggtgcc 5640
gggcggggcg gggccgcctc gggccgggga gggctcgggg gaggggcgcg gcggcccccg 5700
gagcgccggc ggctgtcgag gcgcggcgag ccgcagccat tgccttttat ggtaatcgtg 5760
cgagagggcg cagggacttc ctttgtccca aatctgtgcg gagccgaaat ctgggaggcg 5820
ccgccgcacc ccctctagcg ggcgcggggc gaagcggtgc ggcgccggca ggaaggaaat 5880
gggcggggag ggccttcgtg cgtcgccgcg ccgccgtccc cttctccctc tccagcctcg 5940
gggctgtccg cggggggacg gctgccttcg ggggggacgg ggcagggcgg ggttcggctt 6000
ctggcgtgtg accggcggct ctagagcctc tgctaaccat gttcatgcct tcttcttttt 6060
cctacagctc ctgggcaacg tgctggttat tgtgctgtct catcattttg gcaaagaatt 6120
cgctagcggg gactttgcac tggaacttac aacacccgag caaggccacc atgtacaaga 6180
tgcaactcct gtcttgcatt gcactaactc ttgtccttgt cgcaaacagt gagatccagc 6240
tggtgcagtc tggccccgag ctgaagcagc ctggcgagac agtgcggatc agctgcaagg 6300
ccagcggcta caccttcacc aactacggca tgaactgggt caagcaggcc cctggcaagg 6360
gcctgaagtg gatgggctgg atcaacacct acaccggcga gcctacctac gccgccgact 6420
tcaagcggcg gttcaccttc agcctggaaa ccagcgccag caccgcctac ctgcagatca 6480
gcaacctgaa gaacgacgac accgccacct acttttgcgc caagtacccc cactactacg 6540
gcagcagcca ctggtacttc gacgtgtggg gagccggcac caccgtgaca gtgtcatctg 6600
cgtcgaccac agccccctct gtgttccccc tggccccttc ctgtgggtca acctctggca 6660
gcacagtggc cctggcgtgt cttgtgtctg gctacttccc tgaacctgtg acagtcagct 6720
ggaacagcgg aagcctgacc tctggagtgc acaccttccc cagtgtcctg caaagctcag 6780
gcctgcacag cctgtcaagt atggtgacag tgcccagtag caggtggcct tctgaaacct 6840
ttacctgcaa cgtggtgcac cctgcatcca acaccaaagt ggataagcct gttttcaatg 6900
agtgcagatg cacagataca cctccctgcc ctgtgcctga gcctctggga ggaccatcag 6960
tcctgatctt ccctccaaag cctaaggata tcctgcggat caccagaacc cccgaggtca 7020
cctgtgtcgt cctggatctg ggccgggaag atcctgaagt gcagattagc tggtttgtgg 7080
acggcaagga agtgcacaca gctaagaccc aatcccggga gcagcagttc aatggcacct 7140
accgggtggt ctctgtcctg cccatcgagc accaagattg gctgacaggc aaagagttta 7200
agtgccgagt caaccacata gatcttccct cccctattga gcggaccatc tccaaggcac 7260
gggggcgagc gcacaaaccc tctgtctatg tgctgcctcc ctctcccaaa gaattgagct 7320
ctagcgatac agtgtcaatc acctgcctga tcaaggactt ctacccccct gacattgatg 7380
ttgaatggca atcaaatggg cagcaagaac cagagagaaa acacagaatg acccctccac 7440
agctggatga ggacgggtcc tactttctgt actctaaact ttccgtggac aagagcagat 7500
ggcagcaggg agaccctttc acctgtgcgg tcatgcacga gacactgcaa aaccactaca 7560
cagatctgtc cttgagccac tcac 7584
<210> 12
<211> 7584
<212> DNA
<213> 人工序列
<220>
<223> 构建的序列
<400> 12
ctggcaagag aaagcggaga gcccccgtga agcagaccct gaacttcgac ctgctgaagc 60
tggccggcga cgtggaaagc aaccctggcc ctatgtacaa gatgcaactc ctgtcttgca 120
ttgcactaac tcttgtcctt gtcgcaaaca gtgacatcca gatgacccag accaccagca 180
gcctgagcgc cagcctgggc gacagagtga tcatcagctg tagcgcctcc caggacatca 240
gcaactacct gaactggtat cagcagaaac ccgacggcac cgtgaaggtg ctgatctact 300
tcaccagctc cctgcacagc ggcgtgccca gcagattttc tggcagcggc tccggcaccg 360
actacagcct gaccatctcc aacctggaac ccgaggatat cgccacctac tactgccagc 420
agtacagcac cgtgccctgg acctttggcg gaggcaccaa gctggaaatc aagcggaatg 480
atgctcagcc tgctgtgtac ctttttcaac caagccctga ccaactgcat accggcagtg 540
cctctgtggt ctgcctgctt aatagcttct atcccaagga cattaatgtg aagtggaagg 600
ttgacggcgt gatacaggat accgggattc aggaaagtgt gacagaacaa gataaggata 660
gcacctatag cctgtctagc accctcacca tgagcagcac agagtacttg agtcatgagc 720
tgtatagctg tgagattacc cacaagagtc tgccaagcac ccttataaaa agtttccagc 780
gatctgagtg ttgataaggt accgcttgcg gccgcttcga gcagacatga taagatacat 840
tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta tttgtgaaat 900
ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag ttaacaacaa 960
caattgcatt cattttatgt ttcaggttca gggggagatg tgggaggttt tttaaagcaa 1020
gtaaaacctc tacaaatgtg gtaaaatcga taaggatctt cctagagcat ggctacgtag 1080
ataagtagca tggcgggtta atcattaact acaaggaacc cctagtgatg gagttggcca 1140
ctccctctct gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc 1200
cgggctttgc ccgggcggcc tcagtgagcg agcgagcgcg cagccttaat taacctaatt 1260
cactggccgt cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc caacttaatc 1320
gccttgcagc acatccccct ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc 1380
gcccttccca acagttgcgc agcctgaatg gcgaatggga cgcgccctgt agcggcgcat 1440
taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag 1500
cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc 1560
aagctctaaa tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc 1620
ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt 1680
ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa 1740
caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg 1800
cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat 1860
taacgcttac aatttaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt 1920
atttttctaa atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct 1980
tcaataatat tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc 2040
cttttttgcg gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa 2100
agatgctgaa gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg 2160
taagatcctt gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt 2220
tctgctatgt ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg 2280
catacactat tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac 2340
ggatggcatg acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc 2400
ggccaactta cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa 2460
catgggggat catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc 2520
aaacgacgag cgtgacacca cgatgcctgt agcaatggca acaacgttgc gcaaactatt 2580
aactggcgaa ctacttactc tagcttcccg gcaacaatta atagactgga tggaggcgga 2640
taaagttgca ggaccacttc tgcgctcggc ccttccggct ggctggttta ttgctgataa 2700
atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc cagatggtaa 2760
gccctcccgt atcgtagtta tctacacgac ggggagtcag gcaactatgg atgaacgaaa 2820
tagacagatc gctgagatag gtgcctcact gattaagcat tggtaactgt cagaccaagt 2880
ttactcatat atactttaga ttgatttaaa acttcatttt taatttaaaa ggatctaggt 2940
gaagatcctt tttgataatc tcatgaccaa aatcccttaa cgtgagtttt cgttccactg 3000
agcgtcagac cccgtagaaa agatcaaagg atcttcttga gatccttttt ttctgcgcgt 3060
aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt tgccggatca 3120
agagctacca actctttttc cgaaggtaac tggcttcagc agagcgcaga taccaaatac 3180
tgttcttcta gtgtagccgt agttaggcca ccacttcaag aactctgtag caccgcctac 3240
atacctcgct ctgctaatcc tgttaccagt ggctgctgcc agtggcgata agtcgtgtct 3300
taccgggttg gactcaagac gatagttacc ggataaggcg cagcggtcgg gctgaacggg 3360
gggttcgtgc acacagccca gcttggagcg aacgacctac accgaactga gatacctaca 3420
gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca ggtatccggt 3480
aagcggcagg gtcggaacag gagagcgcac gagggagctt ccagggggaa acgcctggta 3540
tctttatagt cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc 3600
gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc 3660
cttttgctgg ccttttgctc acatgttctt tcctgcgtta tcccctgatt ctgtggataa 3720
ccgtattacc gcctttgagt gagctgatac cgctcgccgc agccgaacga ccgagcgcag 3780
cgagtcagtg agcgaggaag cggaagagcg cccaatacgc aaaccgcctc tccccgcgcg 3840
ttggccgatt cattaatgca gctggcacga caggtttccc gactggaaag cgggcagtga 3900
gcgcaacgca attaatgtga gttagctcac tcattaggca ccccaggctt tacactttat 3960
gcttccggct cgtatgttgt gtggaattgt gagcggataa caatttcaca caggaaacag 4020
ctatgaccat gattacgcca gatttaatta aggccttaat taggctgcgc gctcgctcgc 4080
tcactgaggc cgcccgggca aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag 4140
tgagcgagcg agcgcgcaga gagggagtgg ccaactccat cactaggggt tccttgtagt 4200
taatgattaa cccgccatgc tacttatcta cgtagccatg ctctaggaag atcttcaata 4260
ttggccatta gccatattat tcattggtta tatagcataa atcaatattg gctattggcc 4320
attgcatacg ttgtatctat atcataatat gtacatttat attggctcat gtccaatatg 4380
accgccatgt tggcattgat tattgactag ttattaatag taatcaatta cggggtcatt 4440
agttcatagc ccatatatgg agttccgcgt tacataactt acggtaaatg gcccgcctgg 4500
ctgaccgccc aacgaccccc gcccattgac gtcaataatg acgtatgttc ccatagtaac 4560
gccaataggg actttccatt gacgtcaatg ggtggagtat ttacggtaaa ctgcccactt 4620
ggcagtacat caagtgtatc atatgccaag tacgccccct attgacgtca atgacggtaa 4680
atggcccgcc tggcattatg cccagtacat gaccttatgg gactttccta cttggcagta 4740
catctacgta ttagtcatcg ctattaccat ggtcgaggtg agccccacgt tctgcttcac 4800
tctccccatc tcccccccct ccccaccccc aattttgtat ttatttattt tttaattatt 4860
ttgtgcagcg atgggggcgg gggggggggg ggggcgcgcg ccaggcgggg cggggcgggg 4920
cgaggggcgg ggcggggcga ggcggagagg tgcggcggca gccaatcaga gcggcgcgct 4980
ccgaaagttt ccttttatgg cgaggcggcg gcggcggcgg ccctataaaa agcgaagcgc 5040
gcggcgggcg ggagtcgctg cgcgctgcct tcgccccgtg ccccgctccg ccgccgcctc 5100
gcgccgcccg ccccggctct gactgaccgc gttactccca caggtgagcg ggcgggacgg 5160
cccttctcct ccgggctgta attagcgctt ggtttaatga cggcttgttt cttttctgtg 5220
gctgcgtgaa agccttgagg ggctccggga gggccctttg tgcgggggga gcggctcggg 5280
gggtgcgtgc gtgtgtgtgt gcgtggggag cgccgcgtgc ggctccgcgc tgcccggcgg 5340
ctgtgagcgc tgcgggcgcg gcgcggggct ttgtgcgctc cgcagtgtgc gcgaggggag 5400
cgcggccggg ggcggtgccc cgcggtgcgg ggggggctgc gaggggaaca aaggctgcgt 5460
gcggggtgtg tgcgtggggg ggtgagcagg gggtgtgggc gcgtcggtcg ggctgcaacc 5520
ccccctgcac ccccctcccc gagttgctga gcacggcccg gcttcgggtg cggggctccg 5580
tacggggcgt ggcgcggggc tcgccgtgcc gggcgggggg tggcggcagg tgggggtgcc 5640
gggcggggcg gggccgcctc gggccgggga gggctcgggg gaggggcgcg gcggcccccg 5700
gagcgccggc ggctgtcgag gcgcggcgag ccgcagccat tgccttttat ggtaatcgtg 5760
cgagagggcg cagggacttc ctttgtccca aatctgtgcg gagccgaaat ctgggaggcg 5820
ccgccgcacc ccctctagcg ggcgcggggc gaagcggtgc ggcgccggca ggaaggaaat 5880
gggcggggag ggccttcgtg cgtcgccgcg ccgccgtccc cttctccctc tccagcctcg 5940
gggctgtccg cggggggacg gctgccttcg ggggggacgg ggcagggcgg ggttcggctt 6000
ctggcgtgtg accggcggct ctagagcctc tgctaaccat gttcatgcct tcttcttttt 6060
cctacagctc ctgggcaacg tgctggttat tgtgctgtct catcattttg gcaaagaatt 6120
cgctagcggg gactttgcac tggaacttac aacacccgag caaggccacc atgtacaaga 6180
tgcaactcct gtcttgcatt gcactaactc ttgtccttgt cgcaaacagt gagatccagc 6240
tggtgcagtc tggccccgag ctgaagcagc ctggcgagac agtgcggatc agctgcaagg 6300
ccagcggcta caccttcacc aactacggca tgaactgggt caagcaggcc cctggcaagg 6360
gcctgaagtg gatgggctgg atcaacacct acaccggcga gcctacctac gccgccgact 6420
tcaagcggcg gttcaccttc agcctggaaa ccagcgccag caccgcctac ctgcagatca 6480
gcaacctgaa gaacgacgac accgccacct acttttgcgc caagtacccc cactactacg 6540
gcagcagcca ctggtacttc gacgtgtggg gagccggcac caccgtgaca gtgtcatctg 6600
cgtcgaccac agccccctct gtgttccccc tggccccttc ctgtgggtca acctctggca 6660
gcacagtggc cctggcgtgt cttgtgtctg gctacttccc tgaacctgtg acagtcagct 6720
ggaacagcgg aagcctgacc tctggagtgc acaccttccc cagtgtcctg caaagctcag 6780
gcctgcacag cctgtcaagt atggtgacag tgcccagtag caggtggcct tctgaaacct 6840
ttacctgcaa cgtggtgcac cctgcatcca acaccaaagt ggataagcct gttttcaatg 6900
agtgcagatg cacagataca cctccctgcc ctgtgcctga gcctctggga ggaccatcag 6960
tcctgatctt ccctccaaag cctaaggata tcctgcggat caccagaacc cccgaggtca 7020
cctgtgtcgt cctggatctg ggccgggaag atcctgaagt gcagattagc tggtttgtgg 7080
acggcaagga agtgcacaca gctaagaccc aatcccggga gcagcagttc aatggcacct 7140
accgggtggt ctctgtcctg cccatcgagc accaagattg gctgacaggc aaagagttta 7200
agtgccgagt caaccacata gatcttccct cccctattga gcggaccatc tccaaggcac 7260
gggggcgagc gcacaaaccc tctgtctatg tgctgcctcc ctctcccaaa gaattgagct 7320
ctagcgatac agtgtcaatc acctgcctga tcaaggactt ctacccccct gacattgatg 7380
ttgaatggca atcaaatggg cagcaagaac cagagagaaa acacagaatg acccctccac 7440
agctggatga ggacgggtcc tactttctgt actctaaact ttccgtggac aagagcagat 7500
ggcagcaggg agaccctttc acctgtgcgg tcatgcacga gacactgcaa aaccactaca 7560
cagatctgtc cttgagccac tcac 7584
<210> 13
<211> 7241
<212> DNA
<213> 人工序列
<220>
<223> 构建的序列
<400> 13
ccccgcggcc gcttcgagca gacatgataa gatacattga tgagtttgga caaaccacaa 60
ctagaatgca gtgaaaaaaa tgctttattt gtgaaatttg tgatgctatt gctttatttg 120
taaccattat aagctgcaat aaacaagtta acaacaacaa ttgcattcat tttatgtttc 180
aggttcaggg ggagatgtgg gaggtttttt aaagcaagta aaacctctac aaatgtggta 240
aaatcgataa ggatcttcct agagcatggc tacgtagata agtagcatgg cgggttaatc 300
attaactaca aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg 360
ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca 420
gtgagcgagc gagcgcgcag ccttaattaa cctaattcac tggccgtcgt tttacaacgt 480
cgtgactggg aaaaccctgg cgttacccaa cttaatcgcc ttgcagcaca tccccctttc 540
gccagctggc gtaatagcga agaggcccgc accgatcgcc cttcccaaca gttgcgcagc 600
ctgaatggcg aatgggacgc gccctgtagc ggcgcattaa gcgcggcggg tgtggtggtt 660
acgcgcagcg tgaccgctac acttgccagc gccctagcgc ccgctccttt cgctttcttc 720
ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag ctctaaatcg ggggctccct 780
ttagggttcc gatttagtgc tttacggcac ctcgacccca aaaaacttga ttagggtgat 840
ggttcacgta gtgggccatc gccctgatag acggtttttc gccctttgac gttggagtcc 900
acgttcttta atagtggact cttgttccaa actggaacaa cactcaaccc tatctcggtc 960
tattcttttg atttataagg gattttgccg atttcggcct attggttaaa aaatgagctg 1020
atttaacaaa aatttaacgc gaattttaac aaaatattaa cgcttacaat ttaggtggca 1080
cttttcgggg aaatgtgcgc ggaaccccta tttgtttatt tttctaaata cattcaaata 1140
tgtatccgct catgagacaa taaccctgat aaatgcttca ataatattga aaaaggaaga 1200
gtatgagtat tcaacatttc cgtgtcgccc ttattccctt ttttgcggca ttttgccttc 1260
ctgtttttgc tcacccagaa acgctggtga aagtaaaaga tgctgaagat cagttgggtg 1320
cacgagtggg ttacatcgaa ctggatctca acagcggtaa gatccttgag agttttcgcc 1380
ccgaagaacg ttttccaatg atgagcactt ttaaagttct gctatgtggc gcggtattat 1440
cccgtattga cgccgggcaa gagcaactcg gtcgccgcat acactattct cagaatgact 1500
tggttgagta ctcaccagtc acagaaaagc atcttacgga tggcatgaca gtaagagaat 1560
tatgcagtgc tgccataacc atgagtgata acactgcggc caacttactt ctgacaacga 1620
tcggaggacc gaaggagcta accgcttttt tgcacaacat gggggatcat gtaactcgcc 1680
ttgatcgttg ggaaccggag ctgaatgaag ccataccaaa cgacgagcgt gacaccacga 1740
tgcctgtagc aatggcaaca acgttgcgca aactattaac tggcgaacta cttactctag 1800
cttcccggca acaattaata gactggatgg aggcggataa agttgcagga ccacttctgc 1860
gctcggccct tccggctggc tggtttattg ctgataaatc tggagccggt gagcgtgggt 1920
ctcgcggtat cattgcagca ctggggccag atggtaagcc ctcccgtatc gtagttatct 1980
acacgacggg gagtcaggca actatggatg aacgaaatag acagatcgct gagataggtg 2040
cctcactgat taagcattgg taactgtcag accaagttta ctcatatata ctttagattg 2100
atttaaaact tcatttttaa tttaaaagga tctaggtgaa gatccttttt gataatctca 2160
tgaccaaaat cccttaacgt gagttttcgt tccactgagc gtcagacccc gtagaaaaga 2220
tcaaaggatc ttcttgagat cctttttttc tgcgcgtaat ctgctgcttg caaacaaaaa 2280
aaccaccgct accagcggtg gtttgtttgc cggatcaaga gctaccaact ctttttccga 2340
aggtaactgg cttcagcaga gcgcagatac caaatactgt tcttctagtg tagccgtagt 2400
taggccacca cttcaagaac tctgtagcac cgcctacata cctcgctctg ctaatcctgt 2460
taccagtggc tgctgccagt ggcgataagt cgtgtcttac cgggttggac tcaagacgat 2520
agttaccgga taaggcgcag cggtcgggct gaacgggggg ttcgtgcaca cagcccagct 2580
tggagcgaac gacctacacc gaactgagat acctacagcg tgagctatga gaaagcgcca 2640
cgcttcccga agggagaaag gcggacaggt atccggtaag cggcagggtc ggaacaggag 2700
agcgcacgag ggagcttcca gggggaaacg cctggtatct ttatagtcct gtcgggtttc 2760
gccacctctg acttgagcgt cgatttttgt gatgctcgtc aggggggcgg agcctatgga 2820
aaaacgccag caacgcggcc tttttacggt tcctggcctt ttgctggcct tttgctcaca 2880
tgttctttcc tgcgttatcc cctgattctg tggataaccg tattaccgcc tttgagtgag 2940
ctgataccgc tcgccgcagc cgaacgaccg agcgcagcga gtcagtgagc gaggaagcgg 3000
aagagcgccc aatacgcaaa ccgcctctcc ccgcgcgttg gccgattcat taatgcagct 3060
ggcacgacag gtttcccgac tggaaagcgg gcagtgagcg caacgcaatt aatgtgagtt 3120
agctcactca ttaggcaccc caggctttac actttatgct tccggctcgt atgttgtgtg 3180
gaattgtgag cggataacaa tttcacacag gaaacagcta tgaccatgat tacgccagat 3240
ttaattaagg ccttaattag gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag 3300
cccgggcgtc gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag 3360
ggagtggcca actccatcac taggggttcc ttgtagttaa tgattaaccc gccatgctac 3420
ttatctacgt agccatgctc taggaagatc ttcaatattg gccattagcc atattattca 3480
ttggttatat agcataaatc aatattggct attggccatt gcatacgttg tatctatatc 3540
ataatatgta catttatatt ggctcatgtc caatatgacc gccatgttgg cattgattat 3600
tgactagtta ttaatagtaa tcaattacgg ggtcattagt tcatagccca tatatggagt 3660
tccgcgttac ataacttacg gtaaatggcc cgcctggctg accgcccaac gacccccgcc 3720
cattgacgtc aataatgacg tatgttccca tagtaacgcc aatagggact ttccattgac 3780
gtcaatgggt ggagtattta cggtaaactg cccacttggc agtacatcaa gtgtatcata 3840
tgccaagtcc gccccctatt gacgtcaatg acggtaaatg gcccgcctgg cattatgccc 3900
agtacatgac cttacgggac tttcctactt ggcagtacat ctacgtatta gtcatcgcta 3960
ttaccatggt gatgcggttt tggcagtaca ccaatgggcg tggatagcgg tttgactcac 4020
ggggatttcc aagtctccac cccattgacg tcaatgggag tttgttttgg caccaaaatc 4080
aacgggactt tccaaaatgt cgtaataacc ccgccccgtt gacgcaaatg ggcggtaggc 4140
gtgtacggtg ggaggtctat ataagcagag ctcgtttagt gaaccgtcag atcactagaa 4200
gctttattgc ggtagtttat cacagttaaa ttgctaacgc agtcagtgct tctgacacaa 4260
cagtctcgaa cttaagctgc agaagttggt cgtgaggcac tgggcaggta agtatcaagg 4320
ttacaagaca ggtttaagga gaccaataga aactgggctt gtcgagacag agaagactct 4380
tgcgtttctg ataggcacct attggtctta ctgacatcca ctttgccttt ctctccacag 4440
gtgtccactc ccagttcaat tacagctctt aaggctagag tacttaatac gactcactat 4500
aggctagcgc caccatgtac aagatgcaac tcctgtcttg cattgcacta actcttgtcc 4560
ttgtcgcaaa cagtgacatc cagatgaccc agaccaccag cagcctgagc gccagcctgg 4620
gcgacagagt gatcatcagc tgtagcgcct cccaggacat cagcaactac ctgaactggt 4680
atcagcagaa acccgacggc accgtgaagg tgctgatcta cttcaccagc tccctgcaca 4740
gcggcgtgcc cagcagattt tctggcagcg gctccggcac cgactacagc ctgaccatct 4800
ccaacctgga acccgaggat atcgccacct actactgcca gcagtacagc accgtgccct 4860
ggacctttgg cggaggcacc aagctggaaa tcaagcggaa tgatgctcag cctgctgtgt 4920
acctttttca accaagccct gaccaactgc ataccggcag tgcctctgtg gtctgcctgc 4980
ttaatagctt ctatcccaag gacattaatg tgaagtggaa ggttgacggc gtgatacagg 5040
ataccgggat tcaggaaagt gtgacagaac aagataagga tagcacctat agcctgtcta 5100
gcaccctcac catgagcagc acagagtact tgagtcatga gctgtatagc tgtgagatta 5160
cccacaagag tctgccaagc acccttataa aaagtttcca gcgatctgag tgttgataag 5220
cccctctccc tccccccccc ctaacgttac tggccgaagc cgcttggaat aaggccggtg 5280
tgcgtttgtc tatatgttat tttccaccat attgccgtct tttggcaatg tgagggcccg 5340
gaaacctggc cctgtcttct tgacgagcat tcctaggggt ctttcccctc tcgccaaagg 5400
aatgcaaggt ctgttgaatg tcgtgaagga agcagttcct ctggaagctt cttgaagaca 5460
aacaacgtct gtagcgaccc tttgcaggca gcggaacccc ccacctggcg acaggtgcct 5520
ctgcggccaa aagccacgtg tataagatac acctgcaaag gcggcacaac cccagtgcca 5580
cgttgtgagt tggatagttg tggaaagagt caaatggctc tcctcaagcg tattcaacaa 5640
ggggctgaag gatgcccaga aggtacccca ttgtatggga tctgatctgg ggcctcggta 5700
cacatgcttt acatgtgttt agtcgaggtt aaaaaaacgt ctaggccccc cgaaccacgg 5760
ggacgtggtt ttcctttgaa aaacacgatg ataatatggc cacaaccatg tacaagatgc 5820
aactcctgtc ttgcattgca ctaactcttg tccttgtcgc aaacagtgag atccagctgg 5880
tgcagtctgg ccccgagctg aagcagcctg gcgagacagt gcggatcagc tgcaaggcca 5940
gcggctacac cttcaccaac tacggcatga actgggtcaa gcaggcccct ggcaagggcc 6000
tgaagtggat gggctggatc aacacctaca ccggcgagcc tacctacgcc gccgacttca 6060
agcggcggtt caccttcagc ctggaaacca gcgccagcac cgcctacctg cagatcagca 6120
acctgaagaa cgacgacacc gccacctact tttgcgccaa gtacccccac tactacggca 6180
gcagccactg gtacttcgac gtgtggggag ccggcaccac cgtgacagtg tcatctgcgt 6240
cgaccacagc cccctctgtg ttccccctgg ccccttcctg tgggtcaacc tctggcagca 6300
cagtggccct ggcgtgtctt gtgtctggct acttccctga acctgtgaca gtcagctgga 6360
acagcggaag cctgacctct ggagtgcaca ccttccccag tgtcctgcaa agctcaggcc 6420
tgcacagcct gtcaagtatg gtgacagtgc ccagtagcag gtggccttct gaaaccttta 6480
cctgcaacgt ggtgcaccct gcatccaaca ccaaagtgga taagcctgtt ttcaatgagt 6540
gcagatgcac agatacacct ccctgccctg tgcctgagcc tctgggagga ccatcagtcc 6600
tgatcttccc tccaaagcct aaggatatcc tgcggatcac cagaaccccc gaggtcacct 6660
gtgtcgtcct ggatctgggc cgggaagatc ctgaagtgca gattagctgg tttgtggacg 6720
gcaaggaagt gcacacagct aagacccaat cccgggagca gcagttcaat ggcacctacc 6780
gggtggtctc tgtcctgccc atcgagcacc aagattggct gacaggcaaa gagtttaagt 6840
gccgagtcaa ccacatagat cttccctccc ctattgagcg gaccatctcc aaggcacggg 6900
ggcgagcgca caaaccctct gtctatgtgc tgcctccctc tcccaaagaa ttgagctcta 6960
gcgatacagt gtcaatcacc tgcctgatca aggacttcta cccccctgac attgatgttg 7020
aatggcaatc aaatgggcag caagaaccag agagaaaaca cagaatgacc cctccacagc 7080
tggatgagga cgggtcctac tttctgtact ctaaactttc cgtggacaag agcagatggc 7140
agcagggaga ccctttcacc tgtgcggtca tgcacgagac actgcaaaac cactacacag 7200
atctgtcctt gagccactca cctggcaagt gataaggccg g 7241
<210> 14
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 嵌合序列
<400> 14
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ile Ile Ser Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Val Leu Ile
35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Asn Asp Ala Gln
100 105 110
Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp Gln Leu His Thr Gly
115 120 125
Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln Asp Thr Gly Ile Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu Ser His Glu Leu Tyr Ser
180 185 190
Cys Glu Ile Thr His Lys Ser Leu Pro Ser Thr Leu Ile Lys Ser Phe
195 200 205
Gln Arg Ser Glu Cys
210
<210> 15
<211> 454
<212> PRT
<213> 人工序列
<220>
<223> 嵌合序列
<400> 15
Glu Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Gln Pro Gly Glu
1 5 10 15
Thr Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Asp Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Thr Ala
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly Ser Thr Ser Gly Ser
130 135 140
Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ser Val Leu Gln Ser Ser Gly Leu His Ser Leu Ser Ser Met Val
180 185 190
Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr Phe Thr Cys Asn Val
195 200 205
Val His Pro Ala Ser Asn Thr Lys Val Asp Lys Pro Val Phe Asn Glu
210 215 220
Cys Arg Cys Thr Asp Thr Pro Pro Cys Pro Val Pro Glu Pro Leu Gly
225 230 235 240
Gly Pro Ser Val Leu Ile Phe Pro Pro Lys Pro Lys Asp Ile Leu Arg
245 250 255
Ile Thr Arg Thr Pro Glu Val Thr Cys Val Val Leu Asp Leu Gly Arg
260 265 270
Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Glu Val
275 280 285
His Thr Ala Lys Thr Gln Ser Arg Glu Gln Gln Phe Asn Gly Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Pro Ile Glu His Gln Asp Trp Leu Thr Gly
305 310 315 320
Lys Glu Phe Lys Cys Arg Val Asn His Ile Asp Leu Pro Ser Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Ala Arg Gly Arg Ala His Lys Pro Ser Val
340 345 350
Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser Ser Ser Asp Thr Val
355 360 365
Ser Ile Thr Cys Leu Ile Lys Asp Phe Tyr Pro Pro Asp Ile Asp Val
370 375 380
Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Arg Lys His Arg Met
385 390 395 400
Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys
405 410 415
Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly Asp Pro Phe Thr Cys
420 425 430
Ala Val Met His Glu Thr Leu Gln Asn His Tyr Thr Asp Leu Ser Leu
435 440 445
Ser His Ser Pro Gly Lys
450
Claims (22)
1.一种包含至少一个核酸表达盒的病毒载体,所述核酸表达盒包含编码结合犬VEGF的功能性抗VEGF抗体的核酸序列,所述抗体包含SEQ ID NO:15的抗VEGF抗体重链免疫球蛋白和/或SEQ ID NO:14的抗VEGF抗体轻链免疫球蛋白;和在允许所述链装配成所述功能性抗体的条件下指导所述免疫球蛋白链在宿主细胞中表达的表达控制序列。
2.一种包含至少一个核酸表达盒的病毒载体,所述核酸表达盒包含编码以下各项的核酸序列:启动子、可操作地连接至抗VEGF抗体重链免疫球蛋白的第一信号肽、接头序列和可操作性地连接至抗VEGF轻链免疫球蛋白的第二信号肽,其中所述表达盒在允许所述链装配成包含SEQ ID NO:14和/或SEQ ID NO:15的功能性嵌合抗VEGF抗体的条件下在宿主细胞中共表达所述免疫球蛋白链。
3.如权利要求1或权利要求2所述的病毒载体,其中所述病毒载体是腺相关病毒载体。
4.如权利要求3所述的病毒载体,其中所述载体具有AAV8衣壳。
5.如权利要求2所述的病毒载体,其中所述接头序列包含IRES序列、2A肽序列和弗林蛋白酶位点中的一个或多个。
6.根据权利要求1至4中任一项所述的病毒载体,其中所述嵌合抗VEGF抗体是选自单克隆抗体、Fv、Fab、F(ab)2、F(ab)3、Fab’、Fab’-SH、F(ab’)2、免疫粘附素或单链可变片段抗体。
7.如权利要求5所述的病毒载体,其中所述抗体是嵌合单克隆抗体。
8.根据权利要求1至4中任一项所述的病毒载体,其中所述编码抗VEGF抗体重链可变区的核酸序列包含SEQ ID NO:6或其密码子优化的变体。
9.根据权利要求1至4中任一项所述的病毒载体,其中所述编码抗VEGF抗体重链恒定区的核酸序列包含SEQ ID NO:8或其密码子优化的变体。
10.根据权利要求1至4中任一项所述的病毒载体,其中所述编码抗VEGF抗体轻链可变区的核酸序列包含SEQ ID NO:7或其密码子优化的变体。
11.根据权利要求1至4中任一项所述的病毒载体,其中所述编码抗VEGF抗体轻链恒定区的核酸序列包含SEQ ID NO:9或其密码子优化的变体。
12.根据权利要求1至4中任一项所述的病毒载体,其中所述启动子是CMV启动子。
13.如权利要求1所述的病毒载体,其中所述表达控制序列包含组成型启动子。
14.根据权利要求1至4中任一项所述的病毒载体,还包含内含子、Kozak序列、polyA和转录后调控元件中的一种或多种。
15.根据权利要求1所述的病毒载体,其中AAV衣壳是选自AAV8、rh64R1、AAV9、AAVhu.37或rh10及其变体。
16.一种药物组合物,其包含药学上可接受的载剂和根据权利要求1至15中任一项所述的rAAV。
17.一种治疗癌症的方法,所述方法包括将如权利要求16所述的组合物施用于有需要的受试者。
18.根据权利要求17所述的方法,其中所述组合物以约1×1012GC/kg的剂量施用。
19.一种嵌合抗VEGF抗体,其包含SEQ ID NO:14和SEQ ID NO:15。
20.如权利要求19所述的嵌合抗体,其中编码所述抗体的核酸序列包含SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8或SEQ ID NO:9中的至少一个,或其密码子优化的变体。
21.一种根据权利要求1至15中任一项所述的病毒载体的用途,其用于治疗有需要的受试者的癌症。
22.根据权利要求1至15中任一项所述的病毒载体,其用于治疗有需要的受试者的癌症。
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PCT/US2016/049492 WO2017040528A1 (en) | 2015-08-31 | 2016-08-30 | Chimeric aav-anti-vegf for treating cancer in canines |
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US (1) | US20190292250A1 (zh) |
EP (1) | EP3344294A4 (zh) |
JP (1) | JP2018526003A (zh) |
KR (1) | KR20180057637A (zh) |
CN (1) | CN108136007A (zh) |
AU (1) | AU2016315703A1 (zh) |
CA (1) | CA2995849A1 (zh) |
HK (1) | HK1257490A1 (zh) |
WO (1) | WO2017040528A1 (zh) |
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EP3452103A1 (en) | 2016-04-15 | 2019-03-13 | The Trustees Of The University Of Pennsylvania | Compositions for treatment of wet age-related macular degeneration |
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CN117467016A (zh) * | 2023-12-27 | 2024-01-30 | 北京索莱宝科技有限公司 | 人IgA的抗体、抗体组合及其应用 |
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HK1257490A1 (zh) | 2019-10-25 |
KR20180057637A (ko) | 2018-05-30 |
EP3344294A1 (en) | 2018-07-11 |
JP2018526003A (ja) | 2018-09-13 |
WO2017040528A1 (en) | 2017-03-09 |
AU2016315703A1 (en) | 2018-03-08 |
EP3344294A4 (en) | 2019-03-20 |
US20190292250A1 (en) | 2019-09-26 |
CA2995849A1 (en) | 2017-03-09 |
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