CN101184997B - 用于检测抗猪繁殖呼吸综合征病毒抗体的肽 - Google Patents
用于检测抗猪繁殖呼吸综合征病毒抗体的肽 Download PDFInfo
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Abstract
本发明提供了采用多肽检测和定量PRRSV抗体和抗体片段的组合物和方法。
Description
优先权
本申请要求2005年2月25日递交的美国申请NO.60/656,348的权益,将其整体通过参考并入本文。
发明领域
本发明涉及采用PRRSV多肽检测和定量猪繁殖呼吸综合征病毒(PRRSV)抗体和抗体片段的方法和组合物。
发明背景
猪繁殖和呼吸综合征病毒(PRRSV)属于动脉炎病毒属(RNA包膜病毒),它引起猪繁殖和呼吸综合征(PRRS)。该病毒可在成年猪中引起较多的繁殖问题,导致流产。在生长猪中,该症状包括死亡率增加、食欲减退、发热、呼吸问题、肺炎、继发细菌感染以及萎缩性鼻炎增加。在新生猪中,该病毒可导致呼吸窘迫、生长停滞以及继发细菌感染增加。该病毒主要在猪之间传播。该病毒也可通过感染的粪便、尿和乳汁传至缺乏初乳抗体的幼猪。此外,通过针头、昆虫和空气的传播也是可能的。
现有技术中需要检测PRRSV的方法。PRRS抗体检测试剂盒例如HerdChekPRRSAntibody 2XR Test Kit(IDEXX Labs,Inc.,Westbrook,ME)是可购得的。
发明概述
本发明的一个实施方案提供了物质组合物,包含基本上由SEQ IDNO:1或SEQ IDNO:12组成的纯化多肽。所述纯化多肽还可在任一端包含一个或多个不与PRRSV ORF7天然邻接的氨基酸。所述纯化多肽可为多聚体形式。所述组合物还可包含载体。所述纯化多肽可被连接到指示剂、氨基酸间隔物、氨基酸接头、信号序列、终止转移序列、跨膜结构域、蛋白纯化配体或其组合。所述纯化多肽可基本上由SEQ ID NO:2或SEQ ID NO:13以及一种或多种不与SEQ ID NO:1、SEQ ID NO:2、SEQID NO:18、或SEQ ID NO:13天然邻接的多肽组成。所述一种或多种不 与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18、或SEQ ID NO:13天然邻接的多肽可为非PRRSV多肽。
本发明的另一实施方案提供了纯化的融合多肽,所述融合多肽包含基本上由SEQID NO:1或SEQ ID NO:18以及一种或多种不与SEQ IDNO:1或SEQ ID NO:18天然邻接的多肽组成的多肽。所述一种或多种不与SEQ ID NO:1或SEQ ID NO:18天然邻接的多肽可为非PRRSV多肽。SEQ ID NO:1或SEQ ID NO:18可为多聚体形式。所述纯化的融合多肽可包含指示剂、氨基酸间隔物、氨基酸接头、信号序列、终止转移序列、跨膜结构域、蛋白纯化配体或其组合。所述纯化多肽可基本上由SEQ IDNO:2或SEQ ID NO:13组成。
本发明的又一实施方案提供了编码本发明所述纯化多肽和纯化的融合多肽的纯化的多核苷酸。
本发明的再一实施方案提供了检测特异性结合繁殖呼吸综合征病毒(PRRSV)或PRRSV多肽的抗体的方法。所述方法包括:在允许形成多肽/抗体复合物的条件下使基本上由SEQ ID NO:1、SEQ ID NO:2、SEQID NO:18、SEQ ID NO:13或其组合组成的纯化多肽与怀疑包含有PRRSV特异性抗体的测试样品接触,并且检测多肽/抗体复合物。检测到多肽/抗体复合物表明PRRSV特异性抗体存在于所述测试样品中,而不存在多肽/抗体复合物则表明PRRSV特异性抗体不存在于所述测试样品中。所述方法还包括在检测所述多肽/抗体复合物之前使它们与指示剂接触。所述抗体可为抗体片段。可确定所述抗体在测试样品中的量。所述多肽可被附着到基质。所述多肽可为多聚体形式。所述多肽可为包含SEQ ID NO:1、SEQID NO:2、SEQ ID NO:18或SEQ ID NO:13或其组合以及一种或多种不与SEQ ID NO:1、SEQID NO:2、SEQ ID NO:18或SEQ ID NO:13天然邻接的多肽的融合蛋白。所述一种或多种不与SEQID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13天然邻接的多肽可为非PRRSV多肽。所述测试样品可包括来自哺乳动物的生物样品。所述方法可包括选自逆流层析结合测定、酶联免疫吸附测定、放射免疫测定、血细胞凝集测定、western印迹测定、荧光偏振免疫测定以及间接的免疫荧光测定的测定。
本发明的另一实施方案提供了在哺乳动物中检测PRRSV感染的方法。所述方法包括:从怀疑具有PRRSV感染的哺乳动物获得生物样品; 在允许多肽/抗体复合物形成的条件下使基本上由SEQ ID NO:1、SEQ IDNO:2、SEQ ID NO:18或SEQ ID NO:13或其组合组成的纯化多肽与所述生物样品接触;以及检测多肽/抗体复合物。检测到多肽/抗体复合物表明所述哺乳动物具有PRSSV感染,而不存在多肽/抗体复合物表明所述哺乳动物不具有PRSSV感染。所述方法还包括在检测之前使所述多肽/抗体复合物与产生可测量信号的指示剂接触。所述多肽可为基本上由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13或其组合以及一种或多种不与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13天然邻接的多肽组成的融合蛋白。
本发明的另一实施方案提供了特异性结合PRRSV多肽至少一个表位的抗体,其中所述多肽为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13。所述抗体可单克隆抗体、多克隆抗体或抗体片段。
本发明的另一实施方案提供了检测样品中PRRSV多肽或PRRSV的方法。所述方法包括:在允许形成多肽/抗体复合物的条件下,使一种或多种特异性结合PRRSV多肽至少一个表位的抗体与所述样品接触,其中所述多肽包括SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ IDNO:13;检测多肽/抗体复合物。检测到多肽/抗体复合物表明PRRSV或PRRSV多肽存在于所述样品中,而不存在多肽/抗体复合物表明PRRSV或PRRSV多肽不存在于所述样品中。所述一种或多种抗体为单克隆抗体、多克隆抗体或抗体片段。所述样品可为血清、全血、痰、乳、肉汁、肺灌洗液、肺组织、扁桃体组织或淋巴结组织。
本发明的另一实施方案提供了在检测PRRSV ORF 7特异性PRRSV抗体的诊断测定中减少假阳性出现率的方法。所述方法包括在所述诊断测定中采用包含约19至约28个N末端氨基酸缺失的PRRSV ORF 7多肽作为抗体捕获抗原。所述PRRSV ORF7多肽可为SEQ IDNO:1或SEQID NO:18。所述多肽还可在任一端包含一个或多个不与PRRSV ORF7天然邻接的氨基酸。
因此,本发明提供了采用多肽可灵敏和特异地检测PRRSV抗体和抗体片段的方法和组合物。
发明的详细说明
PRRSV多肽
多肽是三个或更多个通过酰胺键共价连接的氨基酸的聚合物。多肽可以是被翻译后修饰的。纯化多肽为这样的多肽制剂,它基本上无细胞物质、其它类型的多肽、化学前体、用于合成该多肽的化学品或它们的组合。基本上无细胞物质、培养基、化学前体、用于合成该多肽的化学品的多肽制剂含有少于约30%、20%、10%、5%、1%或更少的其它多肽、培养基、化学前体和/或用在合成中的其它化学品。因此,纯化多肽的纯度为约70%、80%、90%、95%、99%或更高。
本发明纯化多肽可以为全长多肽或多肽的片段。
表1中比较了PRRSV的三种US ORF 7毒株的序列:VR-2332(黑体)(美国专利号5,998,601)(SEQ ID NO:8);ISU-12(下划线)(SEQ IDNO:9);以及US-A(斜体)(SEQ ID NO:10)。
表1
表2中显示了这三个病毒株的相对同一性。
表2
VR-2332 | ISU-12 | US-A | |
VR-2332 | 100 | 95.9 | 96.7 |
ISU-12 | 95.9 | 100 | 96.7 |
US-A | 96.7 | 96.7 | 100 |
共有序列显示在SEQ ID NO:11中:
MPNNXGKQXX EKKGDGQPVN QLCQMLGKII AXQNQSRGKG 40
PGKKNKKKNP EKPHFPLATE DDVRHHFTPS ERQLCLSSIQ 80
TAFNQGAGTC TLSDSGRISY TVEFSLPTHH TVRLIRVTAX PSA 123
5位的X可为N或T。在另一实施方案中,5位的X可为任何氨基酸。9位的X可为Q或T。在另一实施方案中,9位的X可为任何氨基酸。10位的X可为E或K。在另一实施方案中,10位的X可为任何氨基酸。11位的X可为E、R或K。在另一实施方案中,11位的X可为任何氨基酸。32位的X可为Q或H。在另一实施方案中,32位的X可为任何氨基酸。120位的X可为S或P。在另一实施方案中,120位的X可为任何氨基酸。
在本发明的一个实施方案中,多肽包含U.S.血清型PKRSV ORF7的一部分:
LCQXLGKIIAXQNQSRGKGPGKKNKKKNPEKPHFPLATEDDVRHHFTPSERQLCLSSIQTAFNQGAGTCTLSDSGRISYTVEFSLPTHHTVRLIRVTAXPSA(SEQID NO:1).
11位的X可为任何氨基酸。在另一实施方案中,11位的X可为Q或H。99位的X可为任何氨基酸。在另一实施方案中,99位的X可为P或S。4位的X可为任何氨基酸。
在本发明的另一实施方案中,多肽包含U.S.血清型PRRSV ORF7的一部分和组氨酸标签:
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGSLCQXLGKIIAXQNQSRGKGPGKKNKKKNPEKPHFPLATEDDVRHHFTPSERQLCLSSIQTAFNQGAGTCTLSDSGRISYTVEFSLPTHHTVRLIRVTAXPSA(SEQ ID NO:2).
42位的X代表任何氨基酸。在某些实施方案中,42位的X可为M或I。49位的X代表任何氨基酸。在某些实施方案中,49位的X代表Q或H。137位的X代表任何氨基酸。在某些实施方案中,137位的X代表P或S。
另一实施方案提供了N末端截短的PRRSV Lelystad ORF7多肽。
CQLLGAXIKSQRQQPRGGQAKKKKPEKPHFPLAAEDDIRHHLTQTERSLCLQSIQTAFNQGAGTASLSSSGEVSFQVEFMLPVAHTVRLIRVTSTSASQGAS(SEQ IDNO:12).
7位的X代表任何氨基酸。在某些实施方案中,7位的X可为M或I。另一实施方案为
CQLLGAXIKSQRQQPRGGQAKKKKPEKPHFPLAAEDDIRHHLTQTERSLCLQSIQTAFNQGAGTASLSSSGEVSFQVEFMLPVAHTVRLIRVTSTSASQGAS(SEQ ID NO:18).
7位的X可为任何氨基酸。在优选的实施方案中,7位的X为M或I。
另一实施方案提供了带有His标签的N末端截短的PRRSV LelystadORF7多肽:
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGSCQLLGAXIKSQRQQPRGGQAKKKKPEKPHFPLAAEDDIRHHLTQTERSLCLQSIQTAFNQGAGTASLSSSGEVSFQVEFMLPVAHTVRLIRVTSTSASQGAS(SEQ ID NO:13).
45位的X代表任何氨基酸。在某些实施方案中,45位的X可以为M或I。
在本发明的一个实施方案中,SEQ ID NO:1、SEQ ID NO:2、SEQ IDNO:12和/或SEQID NO:13比包含全长PRRSV ORF7的多肽更易溶解。此外,本发明的多肽特异性结合PRRSV特异性抗体。因此,本发明多肽的基本的和新的特征在于它们比全长PRRSV ORF7更易溶解,在PRRSV检测测定中它们比全长PRRSV ORF7有更好的特异性,以及它们特异性结合抗PRRSV抗体。
本发明的一个实施方案提供小于全长PRRSV ORF7的多肽。具体地,该PRRSV ORF7多肽在N末端截短。即,该多肽从N末端移除约1、 2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、或43个氨基酸。在本发明优选的实施方案中,PRRSV ORF7多肽从N末端移除了约15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31或32个氨基酸。在其它实施方案中,PRRSV ORP 7多肽在N末端移除了约16至约31个氨基酸;在N末端移除了约17至约30个氨基酸;在N末端移除了约18至约29个氨基酸;在N末端移除了约19至约28个氨基酸;在N末端移除了约20至约27个氨基酸;或在N末端移除了约21至约26个氨基酸。如果存在的话,在USPRRSV ORF 7中出现在约25位和LelystadPRRSV约33位的M可被另一氨基酸所置换。参见,例如SEQ ID NO:1和SEQ ID NO.18。
本发明多肽的片段可包含本发明多肽的约5、10、15、20、30、40、50、60、70、80或更多的氨基酸。变体多肽与显示在SEQ ID NO:1、SEQID NO:2、SEQ ID NO:12或SEQ ID NO:13中的多肽序列有至少约80或约90、96、98或99%的同一性,并且也为本发明的多肽。变体多肽具有一个或多个保守氨基酸改变或其它小的修饰并保留生物学活性,即为生物功能等同物。在与相应的野生型多肽相比较时,生物活性等同物具有基本上相同的功能。
同一性百分比具有本领域公认的含义,有很多测定两个多肽或多核苷酸序列之间同一性的方法。参见,例如Lesk,Ed.,ComputationalMolecular Biology,OxfordUniversity Press,New York,(1988);Smith,Ed.,Biocomputing:Informatics AndGenome Projects,Academic Press,NewYork,(1993);Griffin & Griffin,Eds.,ComputerAnalysis Of Sequence Data,Part I,Humana Press,NeW Jersey,(1994);von Heinje,Sequence AnalysisinMolecular Biology,Academic Press,(1987);以及Gribskov &Devereux,Eds.,Sequence Analysis Primer,M Stockton Press,New York,(1991)。比对多核苷酸或多肽的方法在计算机程序中系统化,包括GCG程序包(Devereux等人,Nuc.AcidsRes.12:387(1984))、BLASTP、BLASTN、FASTA(Atschul等人,J.Molec.Biol 215:403(1990))、以及采用Smith和Waterman的局部同源性算法的Bestfit程序(Wisconsin序列分析包,Version 8 for Unix,Genetics Computer Group,University Research Park, 575Science Drive,Madison,WI 53711)。例如,可采用利用FASTA算法的计算机程序ALIGN,仿射空位查询(affine gap search)中空位开放罚分(gap open penalty)为-12,空位延伸罚分(gap extension penalty)为-2。
例如,当采用任何序列比对程序确定特定序列是否与参比序列有约95%同一性时,设置参数以使得在参比多核苷酸的全长基础上计算同一性百分比并且同一性中的空位允许多至参比多核苷酸中总核苷酸数量的5%。
通常可通过如下方式来鉴别变体以确定其是否为生物学等同物:修饰本发明多肽序列之一并且评估修饰的多肽的特性。如果变体在诸如免疫组化测定、酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)、免疫酶测定或western印迹测定的测定法中与本发明的多肽基本相同地反应,例如具有原始多肽90-110%的活性,则该变体为生物学等同物。在一个实施方案中,该测定为竞争测定,其中生物学上等同的多肽能够将本发明的多肽与对应的反应性抗原或抗体的结合减少约80、95、99、或100%。特异结合对应的野生型多肽的抗体也特异结合该变体多肽。本发明的变体多肽可包含约1、2、3、4、5或6个保守氨基酸置换。
保守置换为这样的置换:其中某个氨基酸由另一具有类似特性的氨基酸所置换,使得肽化学领域技术人员可预料该多肽的二级结构和亲水性基本无变化。通常,以下的氨基酸组代表了保守改变:(1)ala,pro,gly,glu,asp,gln,asn,ser,thr;(2)cys,ser,tyr,thr;(3)val,ile,leu,met,ala,phe;(4)lys,arg,his;以及(5)phe,tyr,tip,his。
本发明的多肽还可包含在翻译时或翻译后指导蛋白质转移的信号(或前导)序列。该多肽还可包含接头或其它序列(如多聚His),以方便合成、纯化或鉴定该多肽,或增强该多肽与固体支持物的结合。例如,多肽可被缀合到免疫球蛋白Fc区或牛血清白蛋白。
多肽可被共价或非共价连接到该多肽并非通常天然连接的氨基酸序列。此外,多肽可共价或非共价连接到化合物或分子而非氨基酸。例如,多肽可连接到指示剂、氨基酸间隔物、氨基酸接头、信号序列、终止转移序列、跨膜结构域、蛋白纯化配体或其组合。氨基酸接头是通常不与本发明的多肽天然地邻接结合的氨基酸序列。氨基酸接头可包含约1、5、10、20、100、1,000个或更多的氨基酸。
如果需要,多肽可为融合蛋白,它还可含有其它氨基酸序列,例如 氨基酸接头、氨基酸间隔物、信号序列、TMR终止转移序列、跨膜结构域以及可用于蛋白纯化的配体,如谷胱甘肽-S-转移酶、组氨酸标签和葡萄球菌蛋白A,或其组合。不止一种本发明的多肽可存在于融合蛋白中。本发明的多肽片段可存在于本发明的融合蛋白中。本发明的融合蛋白可包含SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:12、SEQ ID NO:13中的一个或多个,其片段或其组合。
本发明的多肽可以以多聚体的形式存在。即,多肽可包含SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:12和/或SEQ ID NO:13的一个或多个拷贝。多聚体多肽可为多抗原肽(MAP)。参见,例如Tarn,J.Immunol.Methods,196:17-32(1996)。
本发明的多肽可包含由与PRRSV有反应性的抗体识别的抗原。该抗原可包含一个或多个表位(即抗原决定簇)。表位可为线性表位、顺序表位或构象表位。本发明多肽中的表位可用几种方法鉴别。参见,例如美国专利4,554,101;Jameson & Wolf,CABIOS 4:181-186(1988)。例如,本发明的多肽可被分离和筛选。可通过蛋白水解切割制备一系列的短肽,它们合起来跨越整个多肽序列。例如,从20-mer多肽片段开始,可对每一片段是否存在在ELISA中被识别的表位进行测试。例如,在ELISA测定中,诸如20-mer多肽片段的PRRSV多肽被连接到固体支持物,例如塑料多孔板的孔。将抗体群标记、添加至固体支持物并使其与未标记的抗原在非特异性吸附被阻断的条件下结合,将任何未结合的抗体和其它蛋白洗涤除去。例如通过将无色底物转化为有颜色的反应产物的反应来检测抗体结合。逐渐地,接着从已鉴定的20-mer测试更小和交叠的片段来定位目的表位。
本发明的多肽可通过重组产生。编码本发明多肽的多核苷酸可被引入到重组表达载体中,采用本领域公知的技术该表达载体可在适合的表达宿主细胞体系中表达。本领域中可获得多种细菌、酵母、植物、哺乳动物和昆虫表达系统,并且任何这样的表达系统都可使用。任选地,编码多肽的多核苷酸可在无细胞翻译系统中翻译。多肽也可化学合成或从PRRSV培养物中获得。
PRRSV多核苷酸
本发明的多核苷酸含有小于整个微生物基因组,可为单链或多链核 酸。多核苷酸可为RNA、DNA、cDNA、基因组DNA、化学合成的RNA或DNA或其组合。该多核苷酸可被纯化,无其它组分,如蛋白、脂质和其它多核苷酸。例如,多核苷酸的纯度可为50%、75%、90%、95%、96%、97%、98%、99%或100%。本发明的多核苷酸编码以上描述的多肽。在本发明的一个实施方案中,该多核苷酸编码SEQ ID NO.1、SEQ IDNO:2、SEQ ID NO:12、SEQ ID NO:13或其组合所示的多肽。本发明的多肽可包含其它核苷酸序列,例如编码连接物、间隔物、信号序列、TMP终止转移序列、跨膜结构域或可用于蛋白纯化的配体如谷胱甘肽-S-转移酶、组氨酸标签和葡萄球菌蛋白A的序列。
本发明的多核苷酸可被分离。分离的多核苷酸为天然存在的多核苷酸,它不与其天然连接的5’和3’侧翼基因组序列中的一个或两个紧接。分离的多核苷酸例如可为任何长度的重组DNA分子,前提是天然地紧接该重组DNA分子侧翼的核酸序列被移除或不存在。分离的多核苷酸还可包括非天然存在的核酸分子。存在于数百至数百万其它核酸分子中的核酸分子,例如存在于cDNA或基因组文库或含有基因组DNA限制性酶切产物的凝胶块中的核酸分子,不被认为是分离的多核苷酸。
本发明的多核苷酸还可包含编码免疫原性多肽的片段。本发明的多核苷酸可编码全长多肽、多肽片段和变体或融合多肽。
编码本发明多肽的简并核苷酸序列以及与本发明的多核苷酸序列及其互补序列有至少约80或约90、96、98或99%同一性的同源核苷酸序列也是本发明的多核苷酸。序列同一性百分比可以按描述在“多肽”部分的方法计算。简并核苷酸序列为编码本发明多肽或其片段的多核苷酸,但由于遗传密码的简并性而与野生型多核苷酸序列在核酸序列上不同。编码生物学上有功能的PRRSV多肽的PRRSV多核苷酸的互补DNA(cDNA)分子、种间同源物或变体也为PRRSV多核苷酸。本发明的多核苷酸可从存在于例如生物样品,如唾液、血、乳、肉汁、血清、肺灌洗液、痰、肺、扁桃体、淋巴结或其它组织样品、尿、粪便、脑脊液、羊水、或伤口渗出物中的核酸序列分离。多核苷酸也可在实验室合成,例如采用自动合成仪。诸如PCR的扩增方法可用于从编码多肽的基因组DNA或cDNA扩增多核苷酸。
本发明的多核苷酸可包含天然存在的多肽的编码序列或可编码非天然存在的经改变的序列。如果需要,多核苷酸可被克隆进包含表达控 制元件的表达载体中,所述表达控制元件例如包括复制起点、启动子、增强子或其它促进本发明的多核苷酸在宿主细胞中表达的调节元件。表达载体例如可为质粒,例如pBR322、pUC、或ColE1,或腺病毒载体,例如2型或5型腺病毒载体。任选地,可使用其它载体,包括但不限于Sindbis病毒、猿猴病毒40、α病毒载体、痘病毒载体以及巨细胞病毒和逆转录病毒载体,如鼠肉瘤病毒、小鼠乳腺瘤病毒、Moloney鼠白血病病毒以及Rous肉瘤病毒。还可以使用诸如MC和MC1的微型染色体、噬菌体、噬菌粒、酵母人工染色体、细菌人工染色体、病毒颗粒、病毒样颗粒、粘粒(插入了噬菌体λcos位点的质粒)以及复制子(在细胞中在它们自身控制下能复制的遗传元件)。
制备可操作地连接到表达控制序列的多核苷酸并在宿主细胞中表达它们的方法在本领域是公知的。参见,例如美国专利4,366,246。当本发明的多核苷酸被置于临近或接近一个或多个指导该多核苷酸的转录和/或翻译的表达控制元件时,它是被可操作地连接的。
本发明的多核苷酸例如可用作探针或引物(如PCR引物),以检测PRRSV多核苷酸在诸如生物样品的样品中的存在。这类探针和引物特异性杂交PRRSV多核苷酸序列的能力使得它们可用于在给定的样品中检测互补序列的存在。本发明的多核苷酸探针和引物可杂交至诸如生物样品的样品中的互补序列,这些样品包括唾液、血、血清、乳、肉汁、肺灌洗液、痰、肺、扁桃体、淋巴结或其它组织样品、尿、粪便、脑脊液、羊水、或伤口渗出物。来自该样品的多核苷酸可例如接受凝胶电泳或其它尺寸分离技术,或在无尺寸分离情况下被固定。多核苷酸探针或引物可被标记。适合的标记物和标记探针和引物的方法在本领域是已知的,例如包括通过缺口平移或激酶并入的放射性标记物,或生物素标记物、荧光标记物、化学发光标记物、生物发光标记物、金属螯合标记物和酶标记物。来自样品的多核苷酸在适当严紧的杂交条件下与探针或引物接触。
根据应用情况,不同的杂交条件可用于获得探针或引物与靶序列不同程度的选择性。对于需要高选择性的应用,可使用相对严紧的条件,例如由低盐和/或高温度条件,例如约0.02M至约0.15M盐的盐浓度和约50℃至约70℃的温度所提供的严紧条件。对于需要较小选择性的应用,可使用较不严紧的杂交条件。例如,约0.14M至约0.9M盐的盐浓 度和约20℃至约50℃的温度。包含探针或引物和测试样品中互补多核苷酸的杂交复合物的存在表明样品中存在PRRSV或PRRSV多核苷酸序列。
抗体
本发明的抗体为特异并稳定结合本发明的PRRSV多肽或其片段的抗体分子。本发明的抗体可为多克隆抗体、单克隆抗体、单链抗体(scFv)或抗体片段。抗体片段为包含抗原结合位点或完整抗体可变区的完整抗体的一部分,其中该部分无完整抗体Fc区的恒定重链结构域。抗体片段的实例包括Fab、Fab’、Fab’-SH、F(ab’)2和Fv片段。
本发明的抗体可为任何抗体种类,例如包括IgG、IgM、IgA、IgD和IgE。抗体或其片段结合本发明多肽的表位。可在适合的实验室动物体内或在体外采用重组DNA技术制备抗体。制备和表征抗体的手段在本领域是公知的。参见,例如Dean,Methods Mol.Biol.80:23-37(1998);Dean,Methods Mol.Biol.32:361-79(1994);Baileg,Methods Mol.Biol.32:381-88(1994);Gullick,Methods Mol.Biol.32:389-99(1994);Drenckhahn etal.Methods Cell.Biol.37:7-56(1993);Morrison,Ann.Rev.Immunol.10:239-65(1992);Wright et al.Crit.Rev.Immunol.12:125-68(1992)。例如,多克隆抗体可通过将本发明的多肽给予诸如人或其它灵长类、小鼠、大鼠、兔、豚鼠、山羊、猪、狗、牛、绵羊、驴或马的动物而产生。收集来自经免疫的动物的血清,并从血清中通过用例如硫酸铵沉淀以及随后的层析(如亲和层析)纯化该抗体。产生和加工多克隆抗体的技术在现有技术中是已知的。
“特异性结合”或“特异性”指第一抗原(例如多肽)识别并以比与其它非特异性分子更大的亲和力结合本发明的抗体。非特异性分子是与该第一抗原无共同表位的抗原。例如,针对抗原(例如多肽)产生的抗体与该抗原较与非特异性抗原结合更为有效可被描述为特异性结合该抗原。在优选的实施方案中,当抗体或其抗原结合部分以1071/mol或更高Ka的结合亲和力结合时,则该抗体或其抗原结合部分特异性结合由SEQ ID NO:1、2、12或13(或本发明的其它序列)组成的多肽。特异结合可利用本领域熟知的方法通过采用例如酶联免疫测定(ELISA)、反射免疫测定(RIA)或western印迹测定来测试。
此外,针对存在于本发明多肽上的表位的单克隆抗体也可容易地产生。例如,来自诸如小鼠的哺乳动物(经本发明的多肽免疫)的正常B细胞可与例如HAT敏感的小鼠骨髓瘤细胞融合产生杂交瘤细胞。可采用RIA或ELISA鉴别产生PRRSV特异性抗体的杂交瘤细胞并通过在半固体琼脂中克隆或通过有限稀释来分离。通过另一轮的筛选来分离产生PRRSV特异性抗体的克隆。可采用标准技术,例如通过将本发明的多肽结合到微量滴定板并通过ELISA测定法测定该单克隆抗体的结合,来筛选单克隆抗体。产生和加工单克隆抗体的技术在现有技术中是已知的。参见,例如Kohler & Milstein,Nature,256:495(1975)。单克隆抗体的特定同种型可直接通过从最初的融合物选择来制备,或间接通过采用同胞选择技术从分泌不同同种型单克隆抗体的亲本杂交瘤细胞来制备,以分离类别转换变体来准备。参见Steplewski等人,P.N.A.S.U.S.A.82:86531985;Spria et al.,J.Immunolog.Meth.74:307,1984。本发明的单克隆抗体也可为重组单克隆抗体。参见,例如美国专利4,474,893;美国专利4,816,567。本发明的抗体也可在化学上构建。参见,例如美国专利4,676,980。
本发明的抗体可为嵌合抗体(参见,例如美国专利5,482,856)、人源化抗体(参见,例如Jones等人,Nature 321:522(1986);Reichmann等人,Nature 332:323(1988);Presta,Curr.Op.Struct.Biol.2:593(1992))或人抗体。可通过例如直接永生化、噬菌体展示、转基因小鼠或Trimera方法制备人抗体,参见,例如Reisener等人,Trends Biotechnol.16:242-246(1998)。
特异性结合PRRSV抗原(例如PRRSV多肽)的抗体在检测PRRSV或PRRSV抗原是否存在于样品中尤其有用,该样品例如为来自PRRSV感染的动物如猪的唾液、血、血清、乳、肉汁、肺灌洗液、痰、肺、扁桃体、淋巴结或其它组织样品、尿、粪便、脑脊液、羊水、或伤口渗出物样品。PRRSV或PRRSV抗原的免疫测定可采用一种抗体或几种抗体。PRRSV或PRRSV抗原的免疫测定例如可使用针对PRRSV表位的单克隆抗体、针对一种PRRSV多肽的一些表位的单克隆抗体组合、针对不同PRRSV多肽的表位的单克隆抗体、针对相同PRRSV抗原的多克隆抗体、针对不同PRRSV抗原的多克隆抗体、或单克隆抗体和多克隆抗体的组合。免疫测定方案可例如基于竞争、直接反应或采用例如标记 抗体的夹心测定法。本发明的抗体可标记有本领域中已知的任何标记物类型,例如包括荧光、化学发光、放射性、酶、胶体金属、放射性同位素以及生物发光的标记物。
本发明的抗体或其片段可被结合到支持物并用于检测PRRSV或PRRSV抗原是否存在。支持物包括例如玻璃、聚苯乙烯、聚丙烯、聚乙烯、葡聚糖、尼龙、淀粉酶、天然和改性纤维素、聚丙烯酰胺、琼脂糖和magletite。
本发明的抗体还可用于通过免疫亲和柱分离PRRSV或PRRSV抗原。通过例如吸附或共价连接使抗体附着到固体支持物,以使得抗体保留它们的免疫选择活性。任选地,可包括进间隔物基团以便使抗体的抗原结合位点可接近。该固定的抗体随后可用于结合诸如生物样品的样品中的PRRSV或PRRSV抗原,该样品包括唾液、血、血清、乳、肉汁、肺灌洗液、痰、肺、扁桃体、淋巴结或其它组织样品、尿、粪便、脑脊液、羊水、或伤口渗出物。结合的PRRSV或PRRSV抗原通过例如改变pH从柱基质上回收。
本发明的抗体也可用在免疫定位研究中,以分析多种细胞事件或生理条件中本发明多肽的存在和分布。抗体也可用于鉴别参与被动免疫的分子和鉴别参与非蛋白抗原的生物合成的分子。对这类分子的鉴别可用于疫苗开发。包括例如单克隆抗体和单链抗体在内的本发明抗体可用于监测PRRSV引起的疾病的改善进程。通过测量动物测试样品中针对PRRSV抗原的PRRSV抗体的增加或减少,可确定旨在改善该病症的特定治疗方案是否有效。采用例如直接结合测定法如RIA、ELISA、或western测定可检测和/或定量抗体。
检测方法
本发明的方法可用于检测测试样品中PRRSV特异性抗体或抗体片段,该样品例如为生物样品、环境样品或实验室样品。生物样品例如可包括来自诸如马、猫、狗、猪或人的唾液、血、血清、乳、肉汁、肺灌洗液、痰、肺、扁桃体、淋巴结或其它组织样品、尿、粪便、脑脊液、羊水或伤口渗出物。测试样品在与本发明的多肽混合前可以是未经处理的、经沉淀的、经分级的、经分离的、经稀释的、经浓缩的或经纯化的。
该方法包括使本发明的多肽与测试样品在允许多肽/抗体复合物形 成的条件下接触。即,本发明的多肽特异性结合样品中的PRRSV特异性抗体。在该实施方案中,本发明的多肽用作抗体捕获剂。本领域技术人员熟悉用于检测抗体/多肽复合物结合的测定法和条件。检测多肽与样品中抗PRRSV抗体复合物的形成。
本发明的抗体可用在通过获得怀疑具有PRRSV感染的人或动物的测试样品的PRRSV诊断方法中。使该测试样品与本发明的抗体在能形成抗体-抗原复合物(即免疫复合物)的条件下接触。可通过现有技术中已知的方法来确定抗体-抗原复合物的量。比对照样品中形成的水平高表明具有PRRSV感染。或者,使本发明的多肽与测试样品接触。阳性身体样品中的PRRSV抗体将在适合的条件下形抗原-抗体复合物。可通过现有技术中已知的方法来确定抗体-抗原复合物的量。
在本发明的一个实施方案中,当结合到抗体的指示剂如酶催化可检测的反应时,多肽/抗体复合物被检测。任选地,将包含信号生成化合物的指示剂在允许形成多肽/抗体/指示剂复合物的条件下应用到多肽/抗体复合物。检测多肽/抗体/指示剂复合物。任选地,多肽或抗体可在形成多肽/抗体复合物之前被标记有指示剂。该方法可任选地包含阳性或阴性对照。
本发明的测定法包括但不限于基于竞争、直接反应或夹心型测定法的那些测试法,包括但不限于酶联免疫吸附测定法(ELISA)、western印迹、IFA、放射免疫测定法(RIA)、血细胞凝集(HA)以及荧光偏振免疫测定法(FPIA)。本发明的一个测定法包括逆流层析测定法,例如 测定。参见美国专利5,726,010。
测定可采用固相或基质或通过免疫沉淀或不使用固相的任何其它方法进行。当使用固相或基质时,使本发明的多肽直接或间接附着到固体支持物或基质,例如微量滴定孔、磁珠、无磁珠、柱、基质(matrix)、膜、由合成或天然纤维(例如,玻璃或基于纤维素的材料或热塑性聚合物如聚乙烯、聚丙烯或聚酯)构成的纤维、由颗粒物质构成的烧结结构(例如玻璃或各种热塑性聚合物)、或由硝酸纤维素尼龙、聚砜等构成的浇铸膜片(通常本质上是合成的)。在一个实施方案中,基质是聚乙烯的烧结的细颗粒,通常称为多孔聚乙烯,例如来自Chromex Corporation(Albuquerque,NM)的10-15微米多孔聚乙烯。所有这些基质材料可以以诸如膜、片或板的适合形状使用,或者它们被包被或键合或层压在适合 的惰性载体上,这载体例如为纸、玻璃、塑料膜或织物。适合的使肽固定在固相上的方法包括离子、疏水、共价相互作用等。
在一种类型的测定方式中,将一种或多种多肽包被在固相或基质上。使怀疑含有抗PRRSV抗体或其片段的测试样品与缀合到PRRSV特异性抗体或抗体片段的指示剂(包含信号产生化合物)在足以形成抗原/抗体复合物的条件下孵育一段时间,所述抗原/抗体复合物为测试样品的抗体与所述固相上的多肽的复合物,或者为缀合有PRRSV特异性抗体的指示剂化合物与所述固相上的多肽的复合物。缀合有抗PRRSV抗体的指示剂对固相结合的减少可被定量测定。相对于经确认的阴性PRRSV测试样品所形成的信号,信号的可测量的减少表明在测试样品中存在抗PRRSV抗体。这种类型的测定可对样品中的抗PRRSV抗体的量进行量化。
在另一类型的测定形式中,使一种或多种本发明的多肽包被到支持物或基质上。本发明的多肽与指示剂缀合并加入至测试样品中。将该混合物加至支持物或基质。如果PRRSV抗体存在于测试样品中,则它们将结合缀合有指示剂的多肽以及固定在支持物上的多肽。然后可检测多肽/抗体/指示剂复合物。这种类型的测定可定量测试样品中的抗PRRSV抗体的量。
在另一类型的测定形式中,本发明的一种或多种多肽被包被在支持物或基质上。将测试样品加至支持物或基质并孵育。通过用洗涤溶液洗涤固体支持物将未结合的组分从样品中洗去。如果PRRSV抗体存在于测试样品中,则它们可结合包被到固相上的多肽。这种多肽/抗体复合物可采用缀合有指示剂的物种特异性第二抗体来检测。然后可检测该多肽/抗体/抗物种抗体指示剂复合物。这种类型的测定可在测试样品中定量抗PRRSV抗体的量。
多肽/抗体复合物或多肽/抗体/指示剂复合物的形成可通过辐射测量法、比色法、荧光测量法、尺寸分离法或沉淀方法检测。任选地,对多肽/抗体复合物的检测是通过添加偶联有包含信号生成化合物的指示剂的第二抗体来完成的。与多肽/抗体复合物结合的包含信号生成化合物(标记物)的指示剂可采用以上描述的方法检测,并包括显色剂、催化剂如酶、荧光化合物如荧光素和罗丹明、化学发光化合物如二氧杂环丁烷(dioxetane)、吖啶(acridinium)、菲啶(phenanthridiniums)、 钌(ruthenium)和鲁米诺(luminol)、放射元素、直接视觉标记物,以及辅因子、抑制剂、磁性颗粒等。酶的实例包括碱性磷酸酶、辣根过氧化物酶、β-半乳糖苷酶等。选择具体标记物并不重要,但是它应能够自己产生信号或联合一种或多种其它物质产生信号。
复合物的形成表明在测试样品中存在抗PRRSV抗体。因此,本发明的方法可用于诊断患者中的PRRSV感染。
本发明的方法也可用于指示存在于测试样品中的抗PRRSV抗体的量。对于很多指示剂如酶来说,所存在的抗体的量与产生的信号成比例。根据测试样品的类型,它可由适合的缓冲试剂稀释、浓缩、或不经任何处理而与固相接触。例如,通常优选测试之前被稀释的血清或血浆样品或诸如尿的浓缩样品,以便确定抗体是否存在和/或抗体的量。
本发明进一步包括用于检测样品中抗PRRSV抗体或抗体片段或PRRSV多肽的测定试剂盒(例如制品)。试剂盒包括一种或多种本发明多肽以及用于确定该多肽与样品中抗PRRSV抗体或抗体片段结合的工具。试剂盒或制品也可包括一种或多种本发明的抗体或抗体片段以及用于确定该抗体或抗体片段与样品中PRRSV或PRRSV多肽结合的工具。试剂盒可包含含有一种或多种本发明的多肽或抗体的装置和一种或多种多肽或抗体在例如鉴定哺乳动物中的PRRSV感染的使用说明书。该试剂盒还可包含含有标签的包装材料,该标签标明该试剂盒的一种或多种多肽或抗体可用于鉴定PRRSV感染。本领域普通技术人员已知的其它组分,如缓冲剂、对照等可包括在这类测试试剂盒中。本发明的多肽、抗体、测定法和试剂盒例如可用于诊断患者中的PRRSV感染个例,并可用于PRRSV爆发的流行病学研究。本发明的多肽和测定法可与其它的多肽或测定法联合以检测PRRSV以及其它有机体的存在。
这里描述的本发明可在缺乏未在本文中明确公开的任何一个或多个元件、一种或多种限制下合适地实施。因此,例如在本文的各实例中,术语“包含”、“主要由......组成”以及“由......组成”中的任一个可被其它两个术语中的任一个替换。所使用的术语和表达仅用作说明而非限制,使用这类术语和表达并不排除所显示和描述的特征或其部分的任何等同物,而是应意识到在本发明所要求保护的范围内作出各种修改是可能的。因此,应理解尽管本发明已经通过优选的实施方案明确地进行了说明,但是本领域技术人员可采用任选的特征、这里公开的概念的修 改和变化,并且这些修改和变化被认为是落入说明书和所附的权利要求书所定义的本发明的范围内。
此外,当本发明的特征或各个方面是按马库什组或其它的可选择组描述时,本领域技术人员应意识到本发明也因此是以马库什组或其它组的任何个体成员或部分成员的方式描述的。
以下提供的内容仅是出于举例说明的目的,无意限制以上在广义上描述的本发明的范围。将在本公开中引用的所有参考文献都通过引用并入本文。
实施例
实施例1
按以前的描述(EMBO J.1984,3:1429-1434)表达和纯化PEXUSorf7。采用制造商(EMD Biosciences,Ind.,Madison,WI 53719)描述的方法,采用Studier pET表达系统表达重组全长U.S.ORF7、U.S.ORF7的N末端缺失衍生物和U.S.ORF7的羧基末端缺失衍生物蛋白。采用制造商描述的方法将以下描述的编码蛋白的核酸克隆进pET200表达系统。重组蛋白表达为在氨基未端具有组氨酸标签,所述组氨酸标签是该载体编码的,使得能快速亲和纯化。采用制造商(EMD Biosciences)描述的方法从E.coli菌株BL21(star)表达和纯化所述蛋白。采用SDS-PAGE凝胶分离E.coli的粗裂解物,分离的蛋白被转印至硝酸纤维素,并采用本领域普通技术人员已知的标准技术封闭硝酸纤维素印迹。参见,例如Sambrook andRussell,″Molecular Cloning:A Laboratory Manual″(3rd Edition,Cold Spring HarborLaboratory Press,Cold Spring Harbor,NY,2001)。采用本领域普通技术人员已知的标准技术以山羊抗猪IgG HRP缀合物(Jackson ImmunoResearch Laboratories Inc.,WestGrove,PA,19390)检测猪抗体是否存在。
PRSSV(U.S.血清型)开放阅读框7(ORF7)的序列长123个氨基酸,并显示如下:猪繁殖与呼吸综合征病毒,U.S.血清型
MPNNNGKQQKKKKGDGQPVNQLCQMLGKIIAQQNQSRGKGPGKKNKKKNPEKPHFPLATEDDVRHHFTPSERQLCLSSIQTAFNQGAGTCTLSDSGRISYTVEFSLPTHHTVRLIRVTAPPSA(SEQ ID NO:3)
PEXUSorf7的氨基酸序列显示在SEQ ID NO:4中。来自PRRS ORF7,U.S.血清型的氨基酸为黑体和下划线表示。ORF7的全部123个氨基酸都存在。
MEQRITLKEAWDRSGAWLLPVSLVKRKTTLAPNTQTASPRALADSLMQLARQVSRLNRLAAHPPFASWRNSEEARTDRPSQQLRSLNGEWRFAWFPAPEAVPESWLECDLPEADTVVVPSNWQMHGYDAPIYTNVTYPITVNPPFVPTENPTGCYSLTFNVDESWLQEGQTRIIFDGVNSAFHLWCNGRWVGYGQDSRLPSEFDLSAFLRAGENRLAVMVLRWSDGSYLEDQDMWRMSGIFRDVSLLHKPTTQISDFHVATRFNDDFSRAVLEAEVQMCGELRDYLRVTVSLWQGETQVASGTAPFGGEIIDERGGYADRVTLRLNVENPKLWSAEIPNLYRAVVELHTADGTLIEAEACDVGFREVRIENGLLLLNGKPLLIRGVNRHEHHPLHGQVMDEQTMVQDGDP SEQ ID NO:4.
U.S.血清型ORF7的第2至123个氨基酸存在于SEQ ID NO:5中并以黑体和下划线表示。该重组蛋白采用来自Novagen的pET200表达载体表达。37个氨基酸的融合物标签被连接到蛋白的氨基末端。
MRGSHHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGSL SEQ ID NO:5.
从ORF7氨基末端除去21个氨基酸。第22至123个氨基酸(U.S.血清型ORF7的氨基酸)存在于SEQ ID NO:6中并以黑体和下划线表示。采用来自Novagen的pET200表达载体表达重组蛋白。(全长PRRS蛋白)的第25位氨基酸甲硫氨酸(M)被转化为异亮氨酸(I)以除去非正常的转录起始位点。该蛋白具有连接到蛋白氨基末端的相同的37个氨基酸融合物标签。
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGS SEQIDNO:6.
从U.S.ORF7的羧基端除去30个氨基酸。U.S.ORF7的第2至93个氨基酸存在于SEQID NO:7中并以黑体和下划线表示。采用来自Novagen的pET200表达载体表达重组蛋白。该蛋白具有连接到蛋白氨基末端的相同的37个氨基酸融合物标签。该蛋白还具有连接到羧基端的另一30个氨基酸的标签,所述标签由载体编码,而不是来自PRRS病毒。
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGSL LESLEKGELNDPAANKARKEAELAAATAEQ SEQ IDNO:7
实施例2
Western印迹中的反应性:
该数据证实U.S.ORF7的C末端缺失衍生物(SEQ ID NO:7)在Western印迹中不与阳性猪血清反应,然而全长U.S.ORF7和U.S.ORF 7的N末端(a.k.a氨基末端)缺失衍生物二者都和阳性猪血清反应。
表3
阳性猪血清 | 阴性猪血清 | |
PEXUSorf7(SEQ ID NO:4) | 阳性 | 阴性 |
全长U.S.ORF7(SEQ ID NO:5) | 阳性 | 阴性 |
U.S.ORF7 N末端衍生物(SEQ ID NO:6) | 阳性 | 阴性 |
U.S.ORF7 C末端衍生物(SEQ ID NO:7) | 阴性 | 阴性 |
实施例3
在ELISA中的反应性
按照制造商(EMD Biosciences,Ind.,Madison,WI 53719)描述的方法 采用Studier pET表达系统表达重组蛋白。按照制造商描述的方法将编码上述蛋白的基因克隆进pET200表达系统。重组蛋白表达为在氨基末端带有组氨酸标签,该组氨酸标签由载体编码,使得能快速亲和纯化。采用制造商(EMD Biosciences)描述的方法从E.coli菌株BL21(star)表达和纯化所述蛋白。
Immulon 1板在4℃用溶于碳酸盐缓冲液(pH9.5)、浓度为1μg/ml的纯化重组蛋白包被。通过“轻弹”和拍打干来将板空干。采用含有2.5%BSA的PBS过夜封闭板。将板“轻弹”和拍打干,并用含有2.5%蔗糖的10mM Tris缓冲液(pH7.5)重复包被(over-coated)。在轻弹和拍打干后,将板真空干燥4小时并在干燥剂存在下保存。
采用来自“猪繁殖与呼吸综合征病毒抗体测试试剂盒”(IDEXXLaboratoriesInc.,Westbrook ME,分类号06-04404-00)的商购试剂以及方法在这些ELISA板上测试样品。结果显示U.S.ORF7蛋白的N末端缺失衍生物(SEQ ID NO:6)在ELISA测定中以类似于全长蛋白(SEQ ID NO:5)的方式反应。
实施例4
采用现有技术中已知的技术来制备以下的Lelystad PRRSV ORF 7多肽。来自Lelystad ORF7蛋白的序列以黑体和下划线表示。其它氨基酸为添加到这些重组蛋白中的融合伙伴/标签。
βgal-ORF7 Lelystad的序列通过pEX4载体表达:
MEQRITLKEAWDRSGAWLLPVSLVKRKTTLAPNTQTASPRALADSLMQLARQVSRLNRLAAHPPFASWRNSEEARTDRPSQQLRSLNGEWRFAWFPAPEAVPESWLECDLPEADTVVVPSNWQMHGYDAPIYTNVTYPITVNPPFVPTENPTGCYSLTFNVDESWLQEGQTRIIFDGVNSAFHLWCNGRWVGYGQDSRLPSEFDLSAFLRAGENRLAVMVLRWSDGSYLEDQDMWRMSGIFRDVSLLHKPTTQISDFHVATRFNDDFSRAVLEAEVQMCGELRDYLRVTVSLWQGETQVASGTAPFGGEIIDERGGYADRVTLRLNVENPKLWSAEIPNLYRAVVELHTADGTLIEAEACDVGFREVRIENGLLLLNGKPLLIRGVNRHEHHPLHGQVMDEQTMVQDGDPKGFEFELGTL RDPLE(SEQ ID NO:14)
His-orf7 Lelystad的序列由pET200载体表达。
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGL
His-N末端截短的ORF7 Lelystad序列由pET200载体表达。这种N末端缺失的肽在氨基末端去除了26个氨基酸:
MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDHPFTGS (SEQ ID NO:16)
His羧基截短的ORF7 Lelystad序列由pET200载体表达。这种C末端缺失的肽在羧基末端去除了34个氨基酸:
MGSHHHHHHGMASMTGGQQMGRDDDDKDHPFTGL
采用Western印迹测试了这些多肽的反应性。结果显示在表4中。
表4
阳性猪血清 | 阴性猪血清 | |
PEXLorf7(SEQ 14) | 阳性 | 阴性 |
全长Lelystad ORF7(SEQ 15) | 阳性 | 阴性 |
Lelystad ORF7 N末端缺失衍生物(SEQ 16) | 阳性 | 阴性 |
Lelystad ORF7 C末端缺失衍生物(SEQ 17) | 阴性 | 阴性 |
该数据显示Lelystad ORF7的C末端缺失衍生物在Western印迹中不与阳性猪血清反应,而全长Lelystad ORF7和Lelystad ORF 7的N末端缺失衍生物二者都与阳性猪血清反应。
实施例5
在ELISA中的反应性
按照制造商(EMD Biosciences,Ind.,Madison,WI 53719)描述的方法采用Studier pET表达系统表达重组蛋白。按照制造商描述的方法将编码上述多肽的核酸克隆进pET200表达系统。重组蛋白表达为在氨基末端带有组氨酸标签,所述组氨酸标签由载体编码,使得能快速亲和纯化。采用制造商(EMD Biosciences)描述的方法从E.coli菌株BL21(star)表达和纯化所述蛋白。Immulon 1板在4℃用溶于碳酸盐缓冲液(pH9.5)、浓度为1μg/ml的纯化重组蛋白包被。通过“轻弹”和拍打干来将板空干。采用含有2.5%BSA的PBS封闭板。将板“轻弹”和拍打干,并用含有2.5%蔗糖的10 mM Tris缓冲液(pH7.5)重复包被。在轻弹和拍打干后,将板真空干燥4小时并在干燥剂存在下保存。采用来自“猪繁殖与呼吸综合征病毒抗体测试试剂盒”(IDEXX Laboratories Inc.,WestbrookME,catalog number 06-04404-00)的商购试剂以及方法在这些ELISA板上测试样品。该数据表明Lelystad ORF7蛋白的N末端缺失衍生物在ELISA测定中的反应性与全长蛋白的相似。
实施例6
采用截短的U.S.orf7抗原改善抗体检测的特异性
以ELISA方式中测试通过重组蛋白表达产生的US Orf7 N末端截短的多肽(SEQ IDNO:6)的反应性,并与全长US Orf7(SEQ ID NO:5)进行比较。SEQ ID NO:5和6的重组蛋白按之前的描述(实施例3)表达和纯化。ImmulonI板按之前的描述(实施例3)用所述多肽包被。优化板的包被和第二抗体的稀释度以产生与采用阳性对照猪血清的IDEXXHerdCheck2XR ELISA测定基本相等的特异性信号。通过ELISA评估对所选的猪血清的反应性(参见表7)。
筛选的血清样品被包括IFA和PCR在内的其它方法指定为PRRSV阴性,然而在IDEXXHerdCheck2XR ELISA上显示出反应性。这暗示在2XR板上存在非特异性信号。具有这些特征的血清样品在IDEXXHerdCheck2XR ELISA上为假阳性,通常被PRRS诊断领域技术人员称为“singleton”。从US Orf7除去N末端的26个氨基酸得到了免疫反应性抗原,与全长USOrf7相比,所述免疫反应性抗原显示出反应性减 弱和特异性增强(分别为79%特异性和69%特异性)。≤0.200的OD650值被确定为截断值,因为以采用阳性和阴性对照标准品对IDEXXHerdCheck2XR优化为基础,则认为该样本为阴性。U.S.orf7抗原氨基末端部分的截短导致猪血清非特异性信号的显著降低。
表5
实施例7
采用截短的Lelystad orf7抗原改善抗体检测的特异性
来自PRRS病毒Lelystad株的全长Orf7(SEQ ID NO:15)以及N末端截短形式(SEQID NO:16)在E.coli中被表达,并且按之前的描述(实施例5)分离,用于针对所选的猪血清的ELISA分析。优化板的包被和第二抗体(偶联物)的稀释度以产生与采用阳性对照血清的IDEXXHerdCheck2XR ELISA测定基本相等的特异性信号。筛选的血清样品被包括IFA和PCR在内的其它方法指定为PRRSV阴性,然而在IDEXXHerdCheck2XR ELISA上显示出反应性。
与全长Lelystad orf7蛋白相比,N末端截短的Lelystad orf7蛋白显示出反应性减弱和特异性增强(分别为62%特异性对42%特异性)。≤0.200的OD650值被确定为截断值,因为以采用阳性和阴性对照标准品对IDEXX HerdCheck2XR优化为基础,则认为该样本为阴性。Lelystadorf7抗原N末端部分的截短导致猪血清非特异性信号的显著降低。
表6
表7“singleton”血清样品与全长和截短的orf7多肽在ELIsA中的反应性。示出全长(FL)和N末端截短(Trn)多肽的OD650值。OD>0.2为阳性(加粗的值)。
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<212>PRT
<213>人工
<220>
<223>带有His标签的5′截短的PRRSV Lelystad ORF7多肽
<220>
<221>MISC_FEATURE
<222>(45)..(45)
<223>X代表任何氨基酸。
<400>13
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<210>14
<211>551
<212>PRT
<213>人工
<220>
<223>由pEX4载体表达的βgal-ORF7Lelystad
<400>14
Met Glu Gln Arg Ile Thr Leu Lys Glu Ala Trp Asp Arg Ser Gly Ala
1 5 10 15
Trp Leu Leu Pro Val Ser Leu Val Lys Arg Lys Thr Thr Leu Ala Pro
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Asn Thr Gln Thr Ala Ser Pro Arg Ala Leu Ala Asp Ser Leu Met Gln
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Leu Ala Arg Gln Val Ser Arg Leu Asn Arg Leu Ala Ala His Pro Pro
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Gln Gln Leu Arg Ser Leu Asn Gly Glu Trp Arg Phe Ala Trp Phe Pro
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Ala Pro Glu Ala Val Pro Glu Ser Trp Leu Glu Cys Asp Leu Pro Glu
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Ala Asp Thr Val Val Val Pro Ser Asn Trp Gln Met His Gly Tyr Asp
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Ala Pro Ile Tyr Thr Asn Val Thr Tyr Pro Ile Thr Val Asn Pro Pro
130 135 140
Phe Val Pro Thr Glu Asn Pro Thr Gly Cys Tyr Ser Leu Thr Phe Asn
145 150 155 160
Val Asp Glu Ser Trp Leu Gln Glu Gly Gln Thr Arg Ile Ile Phe Asp
165 170 175
Gly Val Asn Ser Ala Phe His Leu Trp Cys Asn Gly Arg Trp Val Gly
180 185 190
Tyr Gly Gln Asp Ser Arg Leu Pro Ser Glu Phe Asp Leu Ser Ala Phe
195 200 205
Leu Arg Ala Gly Glu Asn Arg Leu Ala Val Met Val Leu Arg Trp Ser
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Asp Gly Ser Tyr Leu Glu Asp Gln Asp Met Trp Arg Met Ser Gly Ile
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Phe Arg Asp Val Ser Leu Leu His Lys Pro Thr Thr Gln Ile Ser Asp
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Pro Phe Gly Gly Glu Ile Ile Asp Glu Arg Gly Gly Tyr Ala Asp Arg
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Val Thr Leu Arg Leu Asn Val Glu Asn Pro Lys Leu Trp Ser Ala Glu
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Thr Leu Ile Glu Ala Glu Ala Cys Asp Val Gly Phe Arg Glu Val Arg
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Ser Ser Ser Gly Lys Val Ser Phe Gln Val Glu Phe Met Leu Pro Val
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Ala His Thr Val Arg Leu Ile Arg Val Thr Ser Thr Ser Ala Ser Gln
530 535 540
Gly Ala Arg Asp Pro Leu Glu
545 550
<210>15
<211>165
<212>PRT
<213>人工
<220>
<223>由pET200载体表达的His-orf7Lelystad PRRSV
<400>15
Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr
1 5 10 15
Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp
20 25 30
His Pro Phe Thr Gly Leu Ala Gly Lys Asn Gln Ser Gln Lys Lys Lys
35 40 45
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Gln Leu Leu Gly Ala Met Ile Lys Ser Gln Arg Gln Gln Pro Arg Gly
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Ser Gln Gly Ala Ser
165
<210>16
<211>140
<212>PRT
<213>人工
<220>
<223>由pET200载体表达的His-5′截短的PRF7Lelystad PRRSV
<400>16
Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr
1 5 10 15
Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp
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115 120 125
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<210>17
<211>127
<212>PRT
<213>人工
<220>
<223>由pET200载体表达的His-3′截短的PRF7Lelystad PRRSV
<400>17
Met Gly Ser His His His His His His Gly Met Ala Ser Met Thr Gly
1 5 10 15
Gly Gln Gln Met Gly Arg Asp Asp Asp Asp Lys Asp His Pro Phe Thr
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<210>18
<211>102
<212>PRT
<213>猪繁殖和呼吸综合征病毒
<220>
<221>MISC_FEATURE
<222>(7)..(7)
<223>X代表任何氨基酸。
<400>18
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Gly Gly Gln Ala Lys Lys Lys Lys Pro Glu Lys Pro His Phe Pro Leu
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35 40 45
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Ala Ser Leu Ser Ser Ser Gly Glu Val Ser Phe Gln Val Glu Phe Met
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Leu Pro Val Ala His Thr Val Arg Leu Ile Arg Val Thr Ser Thr Ser
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Ala Ser Gln Gly Ala Ser
100
Claims (31)
1.一种物质组合物,包含由SEQ ID NO:1或SEQ ID NO:18组成的纯化多肽,其中SEQ IDNO:1的11位的X可为Q或H,SEQ ID NO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,且SEQ ID NO:18的7位的X可为I。
2.如权利要求1的物质组合物,其中所述纯化多肽为多聚体形式。
3.如权利要求1的物质组合物,还包含载体。
4.如权利要求1的物质组合物,其中所述纯化多肽被连接到指示剂、氨基酸间隔物、氨基酸接头、信号序列、终止转移序列、跨膜结构域、蛋白纯化配体或其组合。
5.如权利要求4的物质组合物,其中所述纯化多肽由SEQ ID NO:2或SEQ ID NO:13组成,其中SEQ ID NO:2的42位的X可为M或I,SEQ ID NO:2的49位的X可为Q或H,SEQ ID NO:2的137位的X可为P或S,且SEQ ID NO:13的45位的X可为I。
6.一种纯化的融合蛋白,由SEQ ID NO:1或SEQ ID NO:18以及一种或多种不与SEQ IDNO:1或SEQ ID NO:18天然邻接的多肽组成,其中SEQ ID NO:1的11位的X可为Q或H,SEQ IDNO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,且SEQ ID NO:18的7位的X可为I。
7.如权利要求6的纯化的融合蛋白,其中SEQ ID NO:1或SEQ ID NO:18为多聚体形式。
8.如权利要求6的纯化的融合蛋白,其中所述纯化的融合蛋白包含指示剂、氨基酸间隔物、氨基酸接头、信号序列、终止转移序列、跨膜结构域、蛋白纯化配体或其组合。
9.如权利要求6的纯化的融合蛋白,其中所述纯化多肽由SEQ ID NO:2或SEQ ID NO:13组成,其中SEQ ID NO:2的42位的X可为M或I,SEQ ID NO:2的49位的X可为Q或H,SEQ ID NO:2的137位的X可为P或S,且SEQ ID NO:13的45位的X可为I。
10.一种纯化的多核苷酸,编码权利要求1所述的纯化多肽。
11.一种纯化的多核苷酸,编码权利要求6所述的纯化的融合多肽。
12.由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18、SEQ ID NO:13或其组合组成的纯化多肽在制备用于检测测试样品中特异性结合繁殖呼吸综合征病毒(PRRSV)或PRRSV多肽的抗体的试剂盒中的用途,其中所述检测包括:
(a)在允许形成多肽/抗体复合物的条件下,使由SEQ ID NO:1、SEQ ID NO:2、SEQ IDNO:18、SEQ ID NO:13或其组合组成的纯化多肽与怀疑包含有PRRSV特异性抗体的测试样品接触;
(b)检测多肽/抗体复合物;
其中检测到多肽/抗体复合物表明PRRSV特异性抗体存在于所述测试样品中,并且其中不存在多肽/抗体复合物表明PRRSV特异性抗体不存在于所述测试样品中,且
其中SEQ ID NO:1的11位的X可为Q或H,SEQ ID NO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,SEQ ID NO:2的42位的X可为M或I,SEQ ID NO:2的49位的X可为Q或H,SEQ ID NO:2的137位的X可为P或S,SEQ ID NO:13的45位的X可为I,且SEQ ID NO:18的7位的X可为I。
13.如权利要求12的用途,其中所述检测还包括在进行(b)之前使(a)的复合物与包含的指示剂接触。
14.如权利要求12的用途,其中所述抗体为抗体片段。
15.如权利要求12的用途,其中确定所述测试样品中所述抗体的量。
16.如权利要求12的用途,其中所述多肽被附着到基质。
17.如权利要求12的用途,其中所述多肽为多聚体形式。
18.如权利要求12的用途,其中所述多肽为由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18、SEQ ID NO:13或其组合以及一种或多种不与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13天然邻接的多肽组成的融合蛋白。
19.如权利要求12的用途,其中所述测试样品包括从哺乳动物获得的生物样品。
20.如权利要求12的用途,其中所述检测包括选自逆流层析结合测定、酶联免疫吸附测定、放射免疫测定、血细胞凝集测定、western印迹测定、荧光偏振免疫测定以及间接的免疫荧光测定的测定。
21.由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18、SEQ ID NO:13或其组合组成的纯化多肽在制备用于在哺乳动物中检测PRRSV感染的试剂盒中的用途,其中所述检测包括:
(a)从怀疑具有PRRSV感染的哺乳动物获得生物样品;
(b)在允许形成多肽/抗体复合物的条件下,使由SEQ ID NO:1、SEQ ID NO:2、SEQ IDNO:18或SEQ ID NO:13或其组合组成的纯化多肽与所述生物样品接触;
(c)检测多肽/抗体复合物;
其中检测到多肽/抗体复合物表明所述哺乳动物具有PRRSV感染,并且其中不存在多肽/抗体复合物表明所述哺乳动物不具有PRRSV感染,且
其中SEQ ID NO:1的11位的X可为Q或H,SEQ ID NO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,SEQ ID NO:2的42位的X可为M或I,SEQ ID NO:2的49位的X可为Q或H,SEQ ID NO:2的137位的X可为P或S,SEQ ID NO:13的45位的X可为I,且SEQ ID NO:18的7位的X可为I。
22.如权利要求21的用途,其中所述检测还包括在进行(c)之前使(b)的多肽/抗体复合物与形成可测量信号的指示剂接触。
23.如权利要求22的用途,其中所述多肽为由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18、SEQ ID NO:13或其组合以及一种或多种不与SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13天然邻接的多肽组成的融合多肽。
24.一种特异性结合PRRSV多肽的至少一个表位的抗体,其中所述多肽为SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ IDNO:13,且其中SEQ ID NO:1的11位的X可为Q或H,SEQID NO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,SEQ ID NO:2的42位的X可为M或I,SEQ ID NO:2的49位的X可为Q或H,SEQ ID NO:2的137位的X可为P或S,SEQ ID NO:13的45位的X可为I,且SEQ ID NO:18的7位的X可为I。
25.如权利要求24的抗体,其中所述抗体为单克隆抗体、多克隆抗体或抗体片段。
26.一种或多种特异性结合PRRSV多肽至少一个表位的抗体在制备用于检测样品中PRRSV多肽或PRRSV的试剂盒中的用途,其中所述多肽由SEQ ID NO:1、SEQ ID NO:2、SEQ IDNO:18或SEQ ID NO:13组成,其中所述检测包括:
(a)在允许形成多肽/抗体复合物的条件下,使一种或多种特异性结合PRRSV多肽至少一个表位的抗体与所述样品接触,其中所述多肽由SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:18或SEQ ID NO:13组成;
(b)检测多肽/抗体复合物;
其中检测到多肽/抗体复合物表明PRRSV或PRRSV多肽存在于所述样品中,并且不存在多肽/抗体复合物表明PRRSV或PRRSV多肽不存在于所述样品中,且
其中SEQ ID NO:1的11位的X可为Q或H,SEQ ID NO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,SEQ ID NO:2的42位的X可为M或I,SEQ ID NO:2的49位的X可为Q或H,SEQ ID NO:2的137位的X可为P或S,SEQ ID NO:13的45位的X可为I,且SEQ ID NO:18的7位的X可为I。
27.如权利要求26的用途,其中所述一种或多种抗体为单克隆抗体、多克隆抗体或抗体片段。
28.如权利要求26的用途,其中所述样品为血清、全血、乳、肉汁、痰、肺灌洗液、肺组织、扁桃体组织或淋巴结组织。
29.包含SEQ ID NO:1或SEQ ID NO:18的PRRSV ORF 7多肽在制备用于在检测PRRSVORF 7特异性PRRSV抗体的诊断测定中减少假阳性出现率的试剂盒中的用途,其中SEQ IDNO:1的11位的X可为Q或H,SEQ ID NO:1的99位的X可为P或S,SEQ ID NO:1的4位的X可为I或L,且SEQ ID NO:18的7位的X可为I。
30.如权利要求29的用途,其中所述PRRSV ORF7多肽还在任一端包含一个或多个不与SEQ ID NO:8、SEQ ID NO:9或SEQ ID NO:10的PRRSV ORF7天然邻接的氨基酸。
31.如权利要求1的物质组合物,其中所述纯化多肽还在任一端包含一个或多个不与SEQ ID NO:8、SEQ ID NO:9或SEQ ID NO:10的PRRSV ORF7天然邻接的氨基酸。
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BR9809221A (pt) * | 1997-05-06 | 2000-07-04 | Stichting Dienst Landbouwkundi | Peptìdeo gerador de anticorpos, composição imunogênica, vacina para profilaxia de infecções de prrs, uso da mesma, anticorpo sintético, kit de teste de diagnóstico,uso do mesmo, e, processo para testar a ocorrência de prrs em um porco ou em uma vara de porcos |
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JP5580967B2 (ja) * | 2005-02-25 | 2014-08-27 | アイデックス ラボラトリーズ インコーポレイテッド | ブタ繁殖性呼吸器症候群ウイルスに対する抗体を検出するためのペプチド |
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Also Published As
Publication number | Publication date |
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ES2581211T3 (es) | 2016-09-02 |
KR20080005192A (ko) | 2008-01-10 |
AU2006216590A1 (en) | 2006-08-31 |
KR101329696B1 (ko) | 2013-11-25 |
MX2007010220A (es) | 2007-11-06 |
PL1856534T3 (pl) | 2017-08-31 |
JP5580967B2 (ja) | 2014-08-27 |
CA2601932A1 (en) | 2006-08-31 |
US20060234211A1 (en) | 2006-10-19 |
CN101184997A (zh) | 2008-05-21 |
JP2008538175A (ja) | 2008-10-16 |
AU2006216590B2 (en) | 2012-03-01 |
WO2006091824A3 (en) | 2006-10-19 |
EP1856534B1 (en) | 2016-06-29 |
WO2006091824A2 (en) | 2006-08-31 |
BRPI0607692A2 (pt) | 2009-09-22 |
CA2601932C (en) | 2017-03-21 |
KR20130105750A (ko) | 2013-09-25 |
EP1856534A2 (en) | 2007-11-21 |
US20090305232A1 (en) | 2009-12-10 |
US7572445B2 (en) | 2009-08-11 |
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