CN1300222A - 策略性修饰的乙肝核心蛋白及其衍生物 - Google Patents
策略性修饰的乙肝核心蛋白及其衍生物 Download PDFInfo
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Abstract
公开了一种策略性修饰的乙肝蛋白核心抗原,其中提供了一种***片段,其优选位于核衣壳蛋白的免疫显性区,含有一化学反应性氨基酸残基。修饰的乙肝核心蛋白或其聚集的核衣壳蛋白颗粒可悬垂连接到半抗原上以形成一修饰的核衣壳偶联物。该偶联物可用以制备废品或抗体、修饰的乙肝核心蛋白亦可被修饰成包括一个T细胞表位。
Description
技术领域
本发明涉及免疫学和蛋白工程学的交叉领域,尤其是涉及载体蛋白,更具体而言涉及通过***具有化学反应活性的氨基酸残基进行策略性修饰的嗜肝DNA病毒核衣壳蛋白、上述嗜肝DNA病毒核衣壳蛋白的悬垂连接(pendently linked)半抗原偶联物,以及涉及由这些偶联物组成的免疫原性颗粒。
发明背景
已知通过利用大的免疫原性蛋白分子作为载体,可以产生针对小分子的抗体。通过和载体连接而免疫原性得以增强的小分子被称为半抗原。在本领域中相对较大的分子增强小分子实体免疫原性的现象被称为“载体效应”。
免疫原上被辅助T细胞(Th细胞)识别的部分是T细胞决定簇或表位。免疫原上被抗体结合的部分是B细胞决定簇或表位。载体效应可被定义为针对多决定簇免疫原的一种决定簇,“辅助”或T(Th)细胞决定簇,的免疫性增强了针对另一种决定簇,B细胞决定簇,的免疫应答。
现在已经确认大多数免疫原需要T细胞辅助以诱导B细胞产生抗体。因此,Th细胞通过辨认免疫原上的辅助决定簇辅助B细胞产生针对免疫原的抗体。
由T辅助细胞(Th)和B细胞识别的抗原性决定簇必须连接形成单一的分子实体,但是它们不一定要共价连接。参见,Russel et al.,Nature,280:147(1979),Lamb et al.,J.Immunol.,129:1465(1982),Scherle et al.,J.Exp.Med.,164:1114(1986)andLake et al.,Cold Spring Harbor Symp.Quant.Biol.,41:589(1976)。一些免疫原诱导抗体的形成不需要T细胞的辅助,这些是不依赖T细胞的抗原。
通过产生序列和病原体的决定簇相应的合成多肽可在免疫学上模仿病原体相关的蛋白。这样的多肽免疫原已有报道:Sutcliffe etal.,Nature,287:801(1980),and Lerner et al.,Proc.Natl.Acad.Sci USA,78:3403(1981)。
Gerin et al.,Proc.Natl.Acad.Sci.USA 80:2365(1983)报道用氨基酸残基序列和HBsAg决定簇部分,尤其是“S”(表面)区域的残基110-137,的序列相应的合成多肽结合载体免疫后能有限地增强黑猩猩对乙肝的抵抗力。但是,这些研究中用的载体蛋白是匙孔血蓝蛋白(KLH),一种T细胞依赖载体,它不适合于对人的医学用途,因为它是一种导致严重炎症的刺激源。
能增强半抗原免疫原性并且在人类受试者中不产生不可接受的副作用的,并且能刺激T细胞的载体蛋白通常为免疫原性的天然蛋白。例如,当需要适用于人类施用的载体时经常使用破伤风类毒素(TT)。但是由于剂量限制以及对该类毒素自身的致敏的风险等问题破伤风类毒素作为载体的应用受到了限制。并且,在已经产生了针对破伤风的免疫力的个体中可能产生应答于其所携带的半抗原的表位特异性抑制。
已经有人提出将乙肝表面蛋白作为异源表位的载体。Delpeyrouxet al.,Science,233:472-475(1986),报道了将HBV表面蛋白(S蛋白)用作脊髓灰质炎病毒多肽半抗原的载体。这些研究者构建了一种重组脱氧核糖核酸(DNA)蛋白表达载体,该载体产生名为HBsPolioAg的融合蛋白,该融合蛋白能形成和真正的22纳米HBsAg颗粒非常相似的颗粒。HBsPolioAg由***了11个氨基酸残基序列的HBV S蛋白组成,上述11氨基酸残基序列与脊髓灰质炎病毒1型(Mahoney株)的衣壳蛋白VPI的氨基酸残基93-103相对应。
嗜肝DNA病毒核衣壳蛋白已经被用作半抗原载体。***到乙肝核心内部,并以融合颗粒形式表达的异源免疫原性多肽序列在没有佐剂存在的情况下能在被免疫的动物中诱导非常高的免疫应答。B.E.Clarke et al.Vaccines 91:313-318(1991);F.Schodel et al.J.Virol.66(1):106-114(1992)。公开内容在此引入作为参考的美国专利号4,818,527,4,882,145和5,143,726,中描述了通过乙肝病毒核衣壳蛋白的载体效应增强可操作连接的多肽半抗原的免疫原性。这些专利描述了通过天然存在于乙肝核衣壳蛋白序列中的一个氨基酸残基的侧链将多肽半抗原连接到乙肝病毒核衣壳蛋白上。
嗜肝DNA病毒核衣壳蛋白得到了较好的研究。SEQ ID NO:1和2是人乙肝核心蛋白(HBc),ayw亚型的DNA和核酸序列,如美国专利号4,818,527 4,882,145和5,143,726中所描述。其它嗜肝DNA病毒核衣壳蛋白的序列在本领域中也是已知的,参见,例如,SEQ IDNO:3-13。
选择嗜肝DNA病毒核衣壳蛋白而非其它本领域中使用的载体,如匙孔血蓝蛋白(KLH),BCG,破伤风类毒素和白喉类毒素是有很多理由的。KLH、BCG、破伤风类毒素和白喉类毒素是非颗粒状的,而嗜肝DNA病毒核衣壳蛋白倾向于聚集形成“颗粒”。HBc颗粒倾向于具有比乙肝表面抗原(HBsAg)颗粒更高的免疫原性。D.R.Milich et al.,Science,234:1398-1401(1986)。HBc同时是T细胞依赖性免疫原和非T细胞依赖性免疫原。出处同上HBc是已知的免疫原性最强的蛋白之一。几乎所有感染乙肝的人都产生很强的抗核心的免疫应答。J.H.Hoofnagle,Semin.Liver Dis.,1(1):7-14(1981)。不管遗传背景如何,HBc都能产生广泛的反应性。出处同上。HBc直接激活T细胞。HBc诱导很强的Th细胞应答。HBc被抗原呈递细胞有效地加工和呈递。由于HBc内在的强免疫原性,通常不需要复合佐剂,例如,常用和便宜的铝就足够了。
hepadnaviridae是具有DNA核心和衣壳的动物病毒的一个科,它们在人类中产生乙型肝炎。hepadnaviridae不导致人类甲肝(单链RNA肠道病毒)人类丙肝(Flaviridae科的单链RNA病毒)或人类丁肝(闭合环状反义RNA卫星病毒,“delta病毒”,需要乙肝病毒进行复制)。Hepadnaviridae科包括除了人类和猿猴的乙肝外其它种类的肝炎病毒,例如,花白旱獭、鸭子、地松鼠、苍鹭。下文所用的乙肝(HB)指hepadnaviridae科,除非讨论指的是特定的例子。
乙肝核心蛋白单体自我组装成稳定的聚集体,称为乙肝核心蛋白颗粒(HBc颗粒)。例如,人HBc颗粒直径为27纳米。Conway et al.,Nature,386:91-94(1997),描述了从冷冻电镜图象得到的9埃分辨率的人HBc颗粒的结构。Bottcher et al.,Nature,386:88-91(1997)描述了人HBc单体多肽的折叠并给出了形成α螺旋区域和它们的连接环区域的氨基酸残基的近似编号示意图。Bottcher et al.提出了在乙肝核心蛋白的大约残基78到82有一环(loop)。
利用合成多肽和单克隆抗体将HBc的免疫显性环区域定位在大约氨基酸残基75到83之间。G.Colucci et al.,J.Immunol.,141:4376-4380(1988)。其它研究者报道了两个免疫显性线性表位,位于氨基酸残基75至85和130至140。Salfeld et al.,J.Virol.63:798(1989)。
当外源表位被克隆到HBc免疫显性环区域时乙肝核心蛋白***突变体仍然能形成核心颗粒。P.Pumpens et al.,Intervirology,38:63-74(1995)。该HBc融合蛋白在原核和真核表达***中形成颗粒。出处同上。
一种蛋白用作悬垂连接半抗原的载体的能力依赖于几个因素,关于HBc的这些因素已被研究。具有化学反应活性的氨基酸侧链,如赖氨酸(K),天冬氨酸(D),谷氨酸(E)和还原型的半胱氨酸残基(C)提供了可被用于修饰多肽的功能性基团。
在天然序列中乙肝核心蛋白序列具有几个化学反应活性的氨基酸侧链。核心具有三个伯氨基,一个位于氨基末端,和两个赖氨酸残基(K5和K96),以及4个半胱氨酸残基(C48,C61,C107和C183)。还有几个羧基基团,D(2,4,22,29,32,78,83)和E(8,14,40,43,46,64,77,113,117,145,179)和羧基末端。
但是在天然的未修饰的乙肝核心蛋白颗粒的天然序列中氨基酸侧链并不表现出明显的化学反应性。蛋白中氨基酸侧链的化学反应性依赖于氨基酸侧链的特性以及它在折叠蛋白中的环境。
如此后所详细描述,现在发现可通过在HBc蛋白序列中***一个化学反应活性氨基酸侧链而克服天然乙肝核衣壳蛋白氨基酸侧链的低反应性。相对于带有化学连接的半抗原的HBc颗粒的衍生物,本发明的策略性修饰的嗜肝DNA病毒核心蛋白颗粒表现出显著增强的反应性。
这些修饰的HBc蛋白和它们的悬垂连接半抗原的偶联衍生物在随后的公开内容中进行讨论。
发明简述
本发明涉及一种策略性修饰的乙肝核心(HBc)蛋白,上述蛋白通过***到HBc序列的化学反应活性氨基酸残基连接到悬垂半抗原上。预期的HBc的策略性修饰是HBc蛋白的一种***突变。预期***的长度是1至约40氨基酸残基,优选1至10个氨基酸残基,并且包括一个化学反应活性氨基酸残基。
***区域大约相应于SEQ ID NO:2中所示的乙肝核心蛋白序列中的氨基酸残基大约50至大约100。优选的***区域相应于乙肝核心蛋白免疫显性环区域,大约在氨基酸残基70至大约90,更为优选环尖端区域,大约在氨基酸78至大约82,最优选在氨基酸78至氨基酸80。
这样一个引入的化学反应活性氨基酸残基的特征在于其化学反应活性侧链提供了一个化学基团以将半抗原悬垂连接到策略性修饰的HBc上。通常该化学反应活性氨基酸残基是赖氨酸、半胱氨酸或组氨酸残基或含羧基的残基如天冬氨酸或谷氨酸,优选赖氨酸或含羧基的残基,最为优选的为赖氨酸。
结合到化学反应活性氨基酸残基上的半抗原是任何用于产生免疫应答的感兴趣的化合物,并通常是B细胞决定簇。优选地,该半抗原是多肽半抗原,碳水化合物半抗原或非肽/非糖类(化学)半抗原。在本发明的一个实施方案中该半抗原是病原体相关的半抗原,如病原体的B细胞决定簇。
在策略性修饰的乙肝核心蛋白偶联物的另一个实施方案中策略性修饰的乙肝核心蛋白也含有可操作地连接到乙肝核心氨基酸序列C末端的T细胞刺激性氨基酸残基序列。优选地,上述半抗原和T细胞刺激性氨基酸残基序列都是病原体相关的,最为优选的是,两者都是和同一种病原体相关的,或来自同一病原体。
在本发明的上述实施方案中,通过提供T辅助(Th)细胞决定簇促进了对B细胞表位的应答。在本发明的这个优选实施方案中,这样的Th细胞决定簇和悬垂连接到策略性修饰乙肝核心蛋白上的B细胞决定簇半抗原是来自同一病原体的,以便除了在乙肝核心蛋白抗原特异的T细胞记忆外还提供病原体特异的T细胞记忆。
策略性修饰的乙肝核心蛋白偶联物含有半抗原,该半抗原悬垂连接到策略性修饰的乙肝核心蛋白上。换个角度看,上述策略性修饰的乙肝核心蛋白可被认为具有三个肽连接区域,Ⅰ,Ⅱ和Ⅲ(从氨基端开始依次编号)。区域Ⅰ包括大约相应于SEQ ID NO:2中的乙肝核心蛋白氨基酸序列的氨基酸残基10到50,优选相应于该序列的氨基酸残基号1到50。区域Ⅱ与区域Ⅰ的羧基端残基相结合。区域Ⅱ相应于SEQ ID NO:2中的乙肝核心蛋白氨基酸序列的残基号50至100。区域Ⅲ包括连接到区域Ⅱ的羧基端残基的一段序列。区域Ⅲ相应于乙肝核心蛋白氨基酸序列的残基100至大约140,优选相应于该序列的残基100至大约149。
在以上所讨论的本发明的实施方案中,策略性修饰的乙肝核心蛋白进而具有一个相对于HBc为外源性的区域Ⅳ,该区域连接到区域Ⅲ的羧基端残基以得到融合蛋白的肽。区域Ⅳ是T细胞表位。
本发明的策略性修饰的乙肝核心蛋白颗粒是由乙肝核心蛋白装配而成的,其中多个亚基是策略性修饰的乙肝核心蛋白亚基。同时还预期了一种由策略性修饰的乙肝核心蛋白亚基以及其它乙肝核心蛋白亚基组成的混合物构成的颗粒。
一种预期的策略性修饰的乙肝核心蛋白颗粒偶联物是由装配的乙肝核心蛋白亚基组成的,其中多个亚基是策略性修饰的乙肝核心蛋白亚基。在此实施方案中半抗原是悬垂连接到乙肝核心蛋白亚基上的。优选的是,半抗原是病原体相关的。和以上相同,一段T细胞刺激性氨基酸残基序列可通过肽键被连接到和乙肝核心蛋白相应的序列的羧基端上。优选该病原体相关的T细胞决定簇和病原体相关的半抗原所相关的是同一病原体。
本发明的策略性修饰的乙肝核心蛋白颗粒偶联物具有悬垂连接的半抗原。在该颗粒偶联物的一个预期实施方案中,该颗粒是由具有悬垂连接的半抗原的策略性修饰乙肝核心蛋白亚基以及其它乙肝核心蛋白亚基的混合物组成的。在一个实施方案中大约0.1至0.5的策略性修饰的乙肝核心蛋白亚基和半抗原形成悬垂连接。还预期了一种由策略性修饰的乙肝核心蛋白亚基和其它乙肝核心蛋白亚基的混合物组成的颗粒偶联物。
上文描述的一种本发明的策略性修饰乙肝核心蛋白包括一段含有化学反应活性氨基酸残基的***的肽。该***的肽可以是B细胞抗原决定簇,但通常其自身不是单独的B细胞抗原决定簇,尽管该***物的一些B细胞免疫原性仅仅因为该***物被置于HBc蛋白或颗粒中就能得以表现。这样的***物可以是,并且在一些实施例中是,T细胞表位。将一个***物置于HBc环区域大大降低了得到的分子的HBc免疫原性和抗原性。
本发明的接种物包含免疫原性剂量的本发明的策略性修饰的乙肝核心蛋白偶联物。当悬垂连接的半抗原是病原体相关的半抗原时该接种物可被用作疫苗以帮助用该接种物处理的动物抵抗该病原体。这样,在本发明的一个实施方案中,策略性修饰的乙肝核心蛋白偶联物被用作疫苗以提供针对病原体的保护作用,上述病原体为半抗原所来自的病原体。更为优选地是,该接种物由作为免疫原的策略性修饰的乙肝核心蛋白颗粒偶联物组成。
本发明具有几个优点和长处。
预期的修饰的HBc蛋白的优点之一是该蛋白能够在HBc颗粒的聚合体形式下进行衍生化。
本发明的一个优点是修饰的HBc蛋白在衍生化时表现出略可估计的增强的化学反应性,例如,与使用N末端伯胺相比。
预期的HBc修饰蛋白的另一个优点是这样侧链的衍生化的化学已经得到了很好的研究,是直接并且相对可预测的。
预期的HBc修饰蛋白的另一个优点是它增强了和它偶联形成衍生物的半抗原的免疫应答。
预期的HBc修饰蛋白的另一个优点是它不太可能在人类中产生不所期望的的免疫副作用。
在以下的讨论中本发明进一步的优点和长处对于技术人员将是显而易见的。
附图简述
在形成本说明书一部分的图中,图解1示明了通过1-羧酸硫代(smlpno)-琥珀酰亚氨基4-(N-马来酸亚氨酰基)环己烷酯(硫代-SMCC)将半抗原悬垂地连接到策略性修饰乙肝核心蛋白(sm-HBc)颗粒上的反应顺序。sm-HBc颗粒被画成具有一个悬垂氨基的方框(为了使图示清楚)。
发明详述
定义
术语“抗体”指一种能特异性地结合抗原的分子,该分子是被称为免疫球蛋白的糖蛋白家族的一员。
“抗原”这个词历史上被用来指抗体结合的实体,也用来指诱导产生抗体的实体。在更现代的用法中将抗体的意思限制为被抗体结合的实体,而“免疫原”这个词被用于指诱导产生抗体的实体。此处所讨论的实体同时具有免疫原性和抗原性,称其为免疫原或抗原通常是根据其预期的用途而定的。
“半抗原”这个词用于描述和蛋白质载体化学偶联时能刺激免疫应答(例如产生抗体)的分子。本领域中这个词通常用于指无抗原性的小分子,但是在这里它仅仅指被悬垂地连接到载体蛋白上的分子,尽管它可能具有抗原性并且不小。
“抗原决定簇”指抗原上真正和抗体结合位点或T细胞受体免疫结合的结构部分。该术语可以和“表位”互换使用。
名词“偶联物”在此用于指半抗原通过氨基酸残基侧链和载体悬垂连接形成的分子。
此处所用的术语“保守替换”表示一个氨基酸残基被生物学上相似的残基替代。保守替换的例子包括用一个疏水残基,如异亮氨酸、丙氨酸、亮氨酸或甲硫氨酸替换另一个,或用一个极性氨基酸替换另一个,例如精氨酸和赖氨酸之间的替换,谷氨酸和天冬氨酸之间的替换或谷氨酰胺和天冬酰胺之间的替换等等。术语“保守替换”还包括以下情况:用替换氨基酸取代未替换的原氨基酸,抗这样替换多肽的抗体也和相应的具有未替换氨基酸的多肽发生免疫反应。
涉及肽序列时所用的各种语法形式的术语“相应”的意思为在该描述的肽序列的氨基或羧基端的之一或两端加上或减去多达三个氨基酸残基,并且在多肽序列上的特定氨基酸残基上只有保守替换。
“表位”指一个分子的该部分为T细胞抗原受体或抗体结合位点所特异性结合。“表位”和“决定簇”可以互换使用。
此处所用的术语“融合蛋白”指两个在天然状况下通常不连接在一起的至少两个氨基酸残基序列在它们各自的末端氨基酸残基通过肽键可操作地末端和末端相连(头尾相连)。
在此所用的“乙肝”是在其最广泛的意义上指hepadnaviridae科,一个能导致人类乙型肝炎的含包被DNA的动物病毒科,的任何成员。
此处所用的术语“HBc”指氨基酸序列相应于乙肝病毒(HBV)核衣壳蛋白基因编码的氨基酸残基序列的T细胞刺激性蛋白。作为例子,由人HBV核衣壳基因编码的一种众所周知的天然存在的蛋白是“核心”蛋白,ayw亚型,该蛋白具有SEQ ID NO:1和2的生物学序列。Galibert,et al.,Nature 281:646(1979)。HBeAg蛋白,HBc的前体,包含乙肝核心蛋白的序列及其氨基端的“前核心”序列,如地松鼠乙肝核衣壳基因的例子中的SEQ ID NO:8和9所示。核心蛋白序列在其中的第31位氨基酸残基开始,因此相应于SEQ ID NO:2中的氨基酸残基1。其它乙肝核心蛋白的序列在本领域中是已知的。人乙肝病毒核心蛋白亚型adr在SEQ ID NO:3和4中给出,亚型adw在SEQ ID NO:5和6中给出。Ono et al.,Nucl.Acids Res.11.1747(1983)。花白旱獭乙肝核心蛋白的序列在SEQ ID NO:7(Schodelet al.,Adv.Viral Oncol.8:73-102(1989))中给出,地松鼠的在SEQ ID NO:8和9中给出,苍鹭的在SEQ ID NO:10和11中给出,鸭子的在SEQ ID NO:12和13中给出。为了清楚起见,SEQ IDNO:1和2中相应于人乙肝核心蛋白亚型ayw的氨基酸编号***被用作基准。利用常规的生物学序列对比程序和方法可将其它HBc序列和该序列进行对比,以确定和“SEQ ID NO:2中的乙肝核心蛋白相应的”氨基酸残基。参见,例如,Schodel et al.,Adv.Viral Oncol.8:73-102(1989)。
当提及以上描述的任何天然HBV核衣壳基因编码蛋白一个多肽部分时,通过陈述,例如,所指的特定蛋白的T细胞刺激部分,或通过示明所包括的氨基酸残基位置指出该序列的特定部分,所提及的部分是清晰明白的。
不同形式的“免疫反应”的意思为作为配体的抗原和含有抗体结合部位的分子如全抗体的Fab部分之间的结合。
此处所用的短语“可操作连接”的意思为连接不干扰参与连接的任一基团按照所描述的方式发挥功能;例如作为T或B细胞决定簇发挥功能。
短语“悬垂连接”指从HBc蛋白与另一分子间,直接或桥联的,位于氨基端或羧基端之外的单键。该短语在此用于描述策略性修饰乙肝核心蛋白的化学反应活性氨基酸侧链和半抗原之间的连接。
“大分子装配体”指非共价键连接的蛋白亚基聚合体。在本发明中上述蛋白亚基通常为策略性修饰的乙肝核心蛋白单体。如下文所详细描述,这些核心蛋白单体通常自我组装成具有90或120个核心蛋白双体的球形“核心颗粒”(总共为180或240个核心蛋白亚基)。球形核心颗粒是大分子装配体的一个例子。
此处所用的短语“病原体相关的”指能诱导产生能和天然形式的病原体发生免疫反应的抗体的B细胞或T细胞免疫原。病原体相关的B细胞或T细胞免疫原的例子将在此后加以阐述。
在本说明书的全文中“多肽”和“肽”可互换使用,指氨基酸残基的线性系列,氨基酸残基彼此之间通过α氨基和相邻氨基酸的羧基基团形成的肽键连接。多肽可以是不同的长度,可以是中性(不带电荷)形式或盐的形式,可以带有或不带有修饰,如糖基化、侧链氧化或磷酸化。在本领域中众所周知氨基酸残基序列含有酸性和碱性基团,当蛋白在溶液中时肽所表现出的特定离子化状态依赖于周围介质的pH值,或者当蛋白处于固体形式时则依赖于它所来自的介质。本定义中还包括被连接到氨基酸侧链上的其它取代物,如糖基、脂或无机离子如磷酸根,所修饰的蛋白,以及包括涉及对链的化学转化的修饰,如对巯基的氧化。因此,“多肽”或其对等术语是用来包括所提及的适当氨基酸残基序列,这些氨基酸残基序列受到上述的那些并不破坏其功能特性的修饰。用作半抗原的肽或多肽通常含有少于70个氨基酸残基,更典型地含有5至约40个氨基酸残基的线性链,并且更为优选地为约10到约25个残基。应当指出,预期的多肽半抗原可以长于70残基,但这样的多肽短于共有其序列的天然存在的蛋白质。
“蛋白质”这个词指具有70或更多氨基酸残基并且是天然存在的实体的多肽。
在本领域中涉及抗体分子所来自的细胞时“分泌”和“产生’’这两个词经常可互换使用。但是,产生抗体的细胞可以不将这些分子分泌到其环境中.在此,抗体分子是分泌的并且从血流中得到的(体液抗体)。但是当提及抗体时通常用“产生”以和本领域中所用的短语保持一致。
所有此处所鉴定的氨基酸残基都是天然的或L构型的。为了和标准的多肽命名相一致, (J.Bi01.chem.,243,3557,59(1969)),氨基酸残基的缩写在下文的表1. 对应表中列出。
表1. | 符号对应表 | |
单字母 | 三字母 | 氨基酸 |
YGFMASILTVPKHQEZW | TyrGlyPheMetAlaSerIleLeuThrValProLysHisGlnGluGlxTrp | L-赖氨酸甘氨酸L-苯丙氨酸L-甲硫氨酸L-丙氨酸L-丝氨酸L-异亮氨酸L-亮氨酸L-苏氨酸L-缬氨酸L-脯氨酸L-赖氨酸L-组氨酸L-谷酰胺L-谷氨酸L-谷氨酰胺或L-谷氨酸L-色氨酸 |
RDNBC | ArgAspAsnAsxCys | L-精氨酸L-天冬氨酸L-天冬酰胺L-天冬酰胺或L-天冬氨酸L-半胱氨酸 |
B.策略性修饰的乙肝核心蛋白
本发明预期一种策略性修饰的嗜肝DNA病毒(hepadnaviridae)核心(“HBc”)蛋白,该蛋白有一个***的化学反应活性氨基酸残基,该残基用于和半抗原,如多肽和碳水化合物,悬垂连接.本发明的策略性修饰是在乙肝核心蛋白序列中***包含一个化学反应活性氨基酸残基的大约1到40个氨基酸残基,***位点相应于SEQ IDNO:2的HBc序列氨基酸残基50到100的区域。这样引入的化学反应活性氨基酸残基有一个侧链,该侧链提供一个功能基团将半抗原悬垂连接到策略性修饰的载体上。
嗜肝DNA病毒有被含有表面蛋白的脂类衣壳包围着的核衣壳或核心。该核衣壳是核心蛋白(“核心抗原”HBcAg)二聚体的普通球形聚合体。在体外, 乙肝核心蛋白自我组装成“颗粒”,二十面体对称的球形外壳由90或120个乙肝核心蛋白二聚体,即180或240个蛋白亚基,组成。这些颗粒的直径分别为大约280或310埃。B.Bottcheret al.,Nature,386:88-91(1997):J.F.Conway et al.Nature386:91-94(1997)。
预期的策略性修饰的乙肝核心蛋白也形成大分子装配体。这样的颗粒呈现为180或240蛋白亚基的形式,尽管它不一定是90或120个二聚体。
有人报道,在氨基酸残基80附近的区域带有***的外源氨基酸残基的杂交核心蛋白也装配成规则的外壳,甚至在***长度达到46氨基酸时也是如此。A.I.Brown et al.,Vaccine,9:595-601(1991):F.Schodel et al.,J.virol,66:106-114(1992)。
在此用作基准序列的嗜肝Dnal病毒核心蛋白序列是人乙肝核心蛋白,亚型ayw,如SEQ ID NO:1和2所示。其它亚型的人乙肝病毒是已知的。SEQ ID NO:3和4是人HBc亚型adr,SEQ ID NO:5和6是HBc亚型adw。各种动物肝炎核心蛋白的序列也已经发表。此处SEQ ID NO:12和13公开了鸭子的肝炎核心蛋白的生物学序列;地松鼠肝炎核衣壳基因的一部分见SEQ ID NO:8和9;花白旱獭肝炎核心蛋白见SEQ ID NO:7,苍鹭肝炎核心见SEQ ID NO:10和11。F.Schodel et al.,Adv.Viral Oncology 8:73-102(1989)将动物乙肝核心蛋白的例子和人乙肝核心蛋白进行了序列对比。1.核心蛋白的策略性修饰
本发明预期一种含有一个半抗原的策略性修饰的乙肝核心蛋白偶联物,该半抗原和策略性修饰的乙肝核心蛋白(HBc)悬垂连接。策略性修饰的乙肝核心蛋白自身包含的氨基酸序列相应于SEQ IDNO:2中乙肝核心蛋白氨基酸序列的包括氨基酸残基大约10至140的序列。该HBc氨基酸残基序列进而含有***的外源氨基酸残基,***的区域相应于从HBc氨基端算起约50到约100的位置,其中***的外源***序列(ⅰ)长度为1至约40个氨基酸残基,和(ⅱ)含有化学反应活性氨基酸残基。半抗原是通过***序列中的化学反应活性氨基酸残基悬垂地连接到策略性修饰的乙肝核心蛋白上的。
SEQ ID NO:2中的残基1至10出现在策略性修饰的HBc蛋白分子中是优选的。当任何残基缺席或从位置1至10中被缺失时这些残基被从序列中缺失而剩下的残基出现在序列中,这是更为优选的。因此,如果预期5个残基的缺失,那么缺失残基将被编号为1-5,剩下从残基6到所需的HBc羧基端存在,加上***序列。
SEQ ID NO:2中位置140到149的残基出现在策略性修饰的HBc蛋白分子中也是同样优选的。如本文中别处所提及,HBc中从150到羧基端的区域含有多个精氨酸残基。表达后纯化HBc颗粒时这些残基结合核酸,在策略性修饰的HBc蛋白分子中含有这些残基的序列优选地被省略了。和残基1至10中的情况相似,位置约为140至149中的残基以连续的方式出现以及相应地缺席。这样,当羧基端残基相应于146位的残基时141-145位的残基也存在,而147至149位的残基缺席。最为优选地,预期的HBc序列为SEQ ID NO:2中所示的1位至149位的序列加上***的序列。
如上文已经提及,***序列可被置于HBc序列中的编号为从50到100的区域。优选地是,***序列出现在相应于氨基酸残基编号70至90的区域。更为优选地是,***序列出现在相应于氨基酸残基编号78至82的区域。最为优选地是,***序列位于相应于氨基酸残基编号78至80的区域。
本发明的策略性修饰乙肝核心蛋白含有1至约40个氨基酸氨基的***序列。优选地是***序列的长度为1至10个氨基酸残基。该***序列含有化学反应活性氨基酸残基。还预期了***一个以上的化学反应活性氨基酸残基。
预期在策略性修饰乙肝蛋白基因构建体中所期望的的***区域位置附近提供限制性核酸内切酶位点。表达时限制性核酸内切酶的核苷酸将被翻译成氨基酸,这种效应关系到核酸内切酶的选择。几种限制性核酸内切酶是可由商业途径获得的(例如,从Promega Corp.,Madison,Wisconsin),它们的识别位点序列和剪切位点在本领域中是广为人知的。实施例1描述了这样一个策略性修饰乙肝核心蛋白的构建体。
在一个优选的实施方案中***序列是单一残基,即作为化学反应活性残基加入。在另一个优选的实施方案中利用限制性酶和它们的识别位点导致了***3至大约5个残基,包括所期望的的化学反应残基在内。
包含化学反应活性氨基酸残基的一个***序列被***到天然的乙肝核心蛋白中,***位点大约相应于氨基酸残基50到100。***乙肝核心蛋白的优选区域是免疫显性环区域(大约为氨基酸残基70到90),更优选地***位点为大约相应于天然乙肝核心蛋白氨基酸残基78到大约82的环区域。最优选地是,***序列被置于SEQ ID NO:2中残基78到80。
此处提及***序列“位于一个位置”时的意思是***序列的氨基端通过肽键连接到具有该氨基酸残基编号的相应乙肝核心蛋白序列氨基酸残基的羧基端。换句话说,***序列紧接在所说的那个位置的残基之后。
***可通过本领域中常用的方法实现。实施例1和5中阐明了通过以PCR为基础的方法进行的遣传操作。进而,如J.Sambrook et al.,Molecular Cloning:a laboratory manual,2nd ed.,Cold SpringHarbor Laboratory Press,15.51-ff.(1989)中所讨论的寡聚核苷酸介导的定点突变可被用于加入一个密码子,密码子的加入可通过将所期望的的DNA序列和添加了单一残基的密码子的模板杂交,然后填充剩下的核酸序列。Dawson et al.,Science 266:776-779(1994)描述了一种方法将多肽链在它们的肽骨架上连接起来,使得可通过肽片段构建融合蛋白。
上述化学反应活性氨基酸残基可位于***序列的任何位置。优选地,化学反应活性氨基酸残基所处的位置相应于天然(野生型)核心的氨基酸70至90之间,最为优选地位于78至82之间。例如,当10个氨基酸残基长度的***序列被***到相应于天然核心蛋白残基73的位置时,化学反应活性氨基酸残基优选地位于***序列的5至9位。当30个氨基酸残基长度的***序列被***到相应于天然核心蛋白残基58的位置时,化学反应活性氨基酸残基优选地位于***序列的22至24位。
引入的化学反应活性氨基酸残基具有化学反应活性的侧链,该侧链提供了衍生策略性修饰的HBc(i.e.将一半抗原偶联到修饰的HBc上)的功能性基团。有用的侧链功能性基团包括ε-氨基,β或γ羧基,巯基(-SH)和芳香环(例如酪氨酸和组氨酸)。化学反应活性氨基酸残基通常为赖氨酸、半胱氨酸或组氨酸残基或含羧基的残基如天冬氨酸或谷氨酸。赖氨酸是尤其优选的化学反应活性氨基酸残基。
特别指出SEQ ID NO:1和2分别示明和编码的乙肝核心蛋白的氨基酸残基序列具有两个连续的内源的含羧基的残基,存在于77和78位的谷氨酸(glu,E)和天冬氨酸(asp,D)。但是,本发明考虑引入至少一个另加的外源的化学反应活性氨基酸残基。欧洲专利第385610号报道尝试将多肽半抗原化学偶联到HBc颗粒上时达到的结果并不理想。应当指出这些偶联的尝试是针对氨基而非氨基酸侧链的羧基。
除了在***中使用单独的化学反应活性氨基酸残基如天冬氨酸或赖氨酸外基本上任何所期望的的长度并含有化学反应活性氨基酸残基的序列都可以使用。大于单一残基的***序列的例子包括B.E.Clarke et al.Vaccines 91:313-318(1991)中所讨论的B细胞HRV-2 VP2表位和F.Schodel et al.J.virol.66(1):106-114(1992)中所讨论的HBsAg Pre-S(1)27-53序列和在F.Sch_del等,Vaccines90:193-198(1990)中所讨论的HbsAg Pre-S(2)133-143序列。下文所讨论的作为半抗原的适当T细胞表位也可用作***序列。序列的例子包括这些:SEQ ID NO:28,32,33,34,47,48,49,50和55。
ⅱ.核心蛋白的其它修饰
还考虑到按照以上描述进行策略性修饰的乙肝核心蛋白还有其它修饰。预期的策略性修饰核心的其它修饰包括含有化学反应活性氨基酸残基的***序列的特性,氨基端的截断,羧基端的截断,羧基端的融合,羧基端区域的悬垂连接。
含有半抗原偶联到其上的化学反应活性氨基酸残基的***序列除了提供化学反应活性氨基酸残基外还可以具有其它用途。预期一种含有化学反应活性氨基酸残基的***序列是T细胞刺激性氨基酸序列。这样的T细胞刺激性氨基酸序列优选是和将成为偶联抗原的B细胞表位来自同一来源的T细胞表位,例如,都来自结核分支杆菌Mycobacterium tuberculosis。作为例子的表位将在以后讨论。
还可选择含有化学反应活性氨基酸残基的***序列使之具有其它所期望的的特性,如增强稳定性或增强溶解性的特征。
可利用本领域中众所周知的方法对策略性修饰的乙肝核心蛋白进行化学修饰。Roger L.Lundblad,Techniques in ProteinModification,CRC Press(Ann Arbor,Michigan:1994)中公开了多个这样的技术。进行这样的化学修饰是为了增强或减弱一些特征,例如,赖氨酸氨基可被封闭以改变蛋白的等电点,使其在离子交换树脂色谱上被差异分离。
还考虑到核心蛋白序列的羧基端可以被截短,优选地截短到约氨基酸残基位置140。SEQ ID NO:2中从150位残基开始的富含精氨酸的序列和核酸结合,会妨碍表达的核心蛋白的纯化和处理。在SEQ IDNO:2中富含精氨酸的片段从150位开始。一种优选的策略性修饰HBc蛋白具有149位残基的羧基端残基缬氨酸。
ⅲ.策略性修饰核心蛋白的制备
乙肝核心蛋白的策略性修饰通常是在DNA的水平上通过本领域中已知的方法进行的,例如通过***相应于待***氨基酸序列的密码子。然后在本领域中已知的方便的***中表达操作后的基因,例如在受感染的永生化细胞的病毒培养物中表达。
总体上制备HBcAg蛋白的方法和具体上制备前核心、核心和HBeAg蛋白的方法在本领域中是广为人知的。同样的方法很容易被改造成分离本发明的修饰的核心蛋白颗粒的方法。此外,可通过多种众所周知重组DNA技术生产HBcAg和HBeAg。参见,如,授予Itakura的美国专利第4,356,270号和授予Murray等的第4,563,423号。这些重组DNA技术很容易被改造成生产本发明的修饰核心颗粒的方法。修饰的核心蛋白可在形成颗粒之前或之后和半抗原偶联,优选地是在形成核心颗粒和纯化之后偶联。
C.修饰的乙肝核心蛋白偶联物
任何所对应的抗体是所期望的的半抗原都可以被连接到策略性修饰的乙肝核心蛋白上以形成本发明的免疫原性策略性修饰乙肝核心蛋白。感兴趣的半抗原通常为B细胞决定簇。该半抗原可以是多肽、碳水化合物(糖类)或非多肽、非碳水化合物,如2,4-二硝基苯。
将单一半抗原通过蛋白或多肽的氨基酸残基侧链可操作地连接到蛋白或多肽上以形成悬垂连接的免疫原性偶联物,即分支链多肽多聚物,的方法在本领域中是广为人知的。这些方法包括通过各种侧链上的一种或多种功能性基团连接,得到的载体蛋白的多肽骨架被悬垂连接-共价连接(偶联)到半抗原上,但与之分开至少一个侧链。
Erlanger,Method of Enzymology,70:85(1980),Aurameas,et al.,Scand.J.Immunol.,Vol.8,Suppl.7,7-23(1978)和授予Nestor et al.的美国专利第4,493,795号中描述了利用上述的各种功能性基团将载体蛋白连接到半抗原上的方法。此外,可进行Rodwell et al.,Biotech.,3,889-894(1985)中所描述的定点偶联反应,使得多肽的生物学活性基本上不会减小。
进而,如本领域中所广为人知的,HBcAg蛋白和多肽半抗原可以用它们的天然形式,或者可通过赖氨酸残基的琥珀酰化或通过半胱氨酸-巯基丙酮反应改变它们功能基团的含量。也可通过氨基和2-亚氨基硫烷(iminothiolane)或3-(3-巯基吡啶)丙酸-N-羟基琥珀酰亚胺酯的反应将巯基基团掺入到载体蛋白中或偶联物中。
也可修饰HBc蛋白或半抗原以掺入一个间隔臂,如己二胺或其它类似大小的双功能分子,以促进悬垂连接。
多肽半抗原。共价连接多肽半抗原的方法之间差别很大,这些方法在免疫学领域的技术人员之中是广为人知的。例如,按照美国专利第4,818,527号,m-顺丁烯二酰亚胺苯甲酰-N-羟基琥珀酰胺酯(ICNBiochemical,Inc)或sucinimidyl 4-(N-maleidomythyl)cyclohexane-1-carboxylate(SMCC,Pierce)和策略性修饰的乙肝核心蛋白反应以形成激活的载体。然后该激活载体和含末端半胱氨酸的多肽,或者和加入另加的氨基端或羧基端半胱氨酸残基的多肽反应以形成共价连接的策略性修饰乙肝核心蛋白交联物。作为替代的例子,多肽半抗原的氨基基团可以先和N-succinimidyl 3-(2-pyridylthio)propionate(SPDP,Phamacia)反应,然后含硫的多肽可以在还原后和激活的载体反应。当然,含硫的部分和含双键的Michael受体可以被反转。这些反应在供应商的参考文献里和Kitagawa,et al.,J.Biochem.,79:233(1976)和Lachmann et al.,in 1986 Synthetic Peptides as Antigens,(Ciba FoundationSymposium 119)PP.25-40(Wiley,Chichester:1986)中都有所描述。
美国专利第4,767,842号中教导了几种载体和多肽之间共价连接的一些方法,这些方法在此是有用的。在一种方法中,二异氰酸苯甲酸酯和载体在二氧六环缓冲溶液中0℃反应形成激活载体。然后加入一种多肽半抗原混合并和激活载体反应形成共价连接的策略性修饰乙肝核心蛋白偶联物。
尤其有用的是大量的异双功能试剂,它们在一个功能基团的一端形成二硫键连接,在另一端形成肽键连接,包括N-Succidimidyl-3-(2-pyridyldithio)propionate(SPDP)。这种试剂在其自身和策略性修饰的乙肝核心蛋白或半抗原的巯基之间,形成二硫键,例如和多肽半抗原的半胱氨酸残基,并且在偶联的配偶体之间形成酰胺键,例如和载体蛋白的赖氨酸的氨基或其它自由氨基。多个这样的二硫键/酰胺键形成试剂是已知的。例子参见Immun.Rev.(1982)62:185。其它双功能偶联试剂形成硫酯键而非二硫键。多个这样的硫酯形成试剂可由商业途径获得,包括6-马来酰亚氨丙酸(maleimidocaproicacid),2-溴乙酸,2-碘乙酸,4-(N-maleimido-methyl)cyclohexane-1-carboxylic acid等等的活性酯。羧基可经过将它们与琥珀酰亚胺或1-羟基-2-硝基-4-磺酸,钠盐结合而被激活。本发明的方法中尤其优选的偶联试剂是从Pierce Company,Rockford,I11得到的succinimidyl 4-(N-maleimidomethyl)环己烷-1-羧酸酯(SMCC)。以上列出的试剂并不是全部,指出的化合物的修饰显然是可以用的,例如,在图中所画的硫代-SMCC。
可以通过本领域中众所周知的多个方法得到多肽半抗原。可以很简单地使用通常的肽段合成技术。例如,利用重组和基于PCR的技术来产生较长的肽是有用的。因为所需的序列通常相对较短,所以固相化学合成技术是有用的。
如下文所讨论,编码多个多肽半抗原的DNA序列在本领域中是已知的。此处所预期长度的肽段的编码序列很容易通过化学技术合成,例如Matteucci et al.,J.Am.Chem.Soc.103:3185(1981)中的磷酸三酯方法。当然,通过化学合成编码序列可简单地通过替换天然肽段编码序列的适当的碱基进行所期望的的改动。然后可为编码序列提供适当的连接序列并连接到本领域中可得到的普通表达载体上,并且然后该调控载体可用于转化适当的宿主以产生所需的蛋白。
多个这样的载体和适当的宿主都可以得到。例如,在含有便利的限制性位点以***所需的编码序列的质粒中提供了和细菌宿主兼容的启动子序列。这样质粒的典型为,例如,可从University ofMinnesota的J.Messing那里得到的pUC8,和pUC13(参见,如,Messing et al.,Nucleic Acids Res.9:309(1981))或可从NewEngland Biolabs得到的pBR322。适当的启动子包括,例如,β-内酰胺酶(青霉素酶)和半乳糖(lac)启动子***(Chang.et al.,Nature 198:1056(1977))和色氨酸(trp)启动子***(Goeddelet al.,Nucleic Acids Res.8:4057(1980))。得到的表达载体并用Cohen,et al.,Proc.Natl.Acad.Sci U.S.A.69:2110(1972)所描述的氯化钙方法转化到适当的细菌宿主中。成功的转化体可产生所需的多肽片段,多肽片段表达的水平比在通常产生完整菌毛的菌株中要高。当然,使用适当的载体和调控序列也可使用哺乳动物细胞或酵母。
表2
多肽半抗原
生物 | 抗原 | T或B细胞表位 | 序列 | SEQ IDNO |
肺炎链球菌 | PspA | B | KLEELSDKIDELDAE | 25 |
肺炎链球菌 | PspA | B | SQKKYDEDQKKTEEKAALEKAASEEMDKAVAAVQQA | 26 |
白喉棒状杆菌 | P23 | B | QDKPADAPAAEAPAAEPAAQQDKPADA | 27 |
HIV | P24 | T | GPKEPFRDYVDRFYKC | 28 |
HIV | GP120 | B | RKRIHIGPGRAFYITKN | 29 |
***病毒 | VP1 | B | YNGECRYNRNAVPNLRGDLQVLAQKVARTLP | 30 |
白喉棒状杆菌 | 毒素 | T | FQVVHNSYNRPAYSPGC | 31 |
Borreliaburgdorferi | OspA | T | VEIKEGTVTLKREIDKNGKVTVSLC | 32 |
Borreliaburgdorferi | OspA | T | TLSKNISKSGEVSVELNDC | 33 |
InfluenzaA8/PR8 | HA | T | SSVSSFERFEC | 34 |
InfluenzaA8/PR8 | HA | B | YRNLLWLTEK | 35 |
Yersiniapestis | V Ag | B | DILKVIVDSMNHHGDARSKLREELAELTAELKIYSVIQAEINKHLSSSGTINIHDKSINLMDKNLYGYTDEEIFKASAEYKILEKMPQTTIQVDGSEKKIVSIKDFLGSENKRTGALGNLKNSYSYNKDNNELSHFATTCSD | 36 |
流感嗜血杆菌 | pBOMP | B | CSSSNNDAAGNGAAQFGGY | 37 |
流感嗜血杆菌 | pBOMP | B | NKLGTVSYGEE | 38 |
流感嗜血杆菌 | pBOMP | B | NDEAAYSKNRRAVLAY | 39 |
Moraxellacatarrhalis | copB | B | LDIEKDKKKRTDEQLQAELDDKYAGKGY | 40 |
Moraxellacatarrhalis | copB | B | NDEAAYSKNRRAVLAY | 39 |
Moraxellacatarrhalis | copB | B | IDIEKKGKIRTEAELLAELNKDYPGQGY | 42 |
Porphyromonasgingivalis | HA | B | GVSPKVCKDVTVEGSNEFAPVQNLT | 43 |
Porphyromonasgingivalis | HA | B | RIQSTWRQKTVDLPAGTKYV | 44 |
Trypanosomacruzi | T | SHNFTLVASVIIEEAPSGNTC | 45 | |
Trypanosomacruzi | B | KAAIAPAKAAAAPAKAATAPA | 46 |
Plasmodiumfalciparum | MSP1 | T | SVQIPKVPYPNGIVYC | 47 |
Plasmodiumfalciparum | MSP1 | T | DFNHYYTLKTGLEADC | 48 |
Streptococcussobrinus | AgⅠ/Ⅱ | B&T | KPRPIYEAKLAQNQKC | 49 |
Streptococcussobrinus | AgⅠ/Ⅱ | B&T | AKADYEAKLAQYEKDLC | 50 |
淋巴细胞绒毛脑膜炎病毒 | NP | T | RPQASGVYMGNLTAQC | 51 |
Shigellaflexneri | 扩散因子 | B | KDRTLIEQK | 52 |
呼吸道合胞病毒 | G | B | CSICSNNPTCWAICK | 53 |
Plasmodiumvivax | CS | B | GDRADGQPAGDRADGQPAG | 54 |
Clostridiumtetani | tox | T | QYIKANSKFIGITELC | 55 |
Entamoebahistolytica | 凝集素 | B | VECASTVCQNDNSCPIIADVEKCNQ | 56 |
Schistosomajaponicum | para | B | DLQSEISLSLENGELIRRAKSAESLASELQRRVD | 57 |
Schistosomamansoni | para | B | DLQSEISLSLENSELIRRAKAAESLASDLQRRVD | 58 |
Plasmodiumvivax | B | DRAAGQPAGDRADGQPAG | 83 | |
流感病毒 | Infl | B | CNNPHRIL | 84 |
流感病毒 | Infl | T | CPKYVKQNTLKLATGMRNVPEKQTR | 85 |
流感病毒 | Infl | B | SIMRSDAPIGTCSSECITPNGSIPNDKPQNVNKITY | 14 |
流感病毒 | B | RGIFGAIAGFIENGWEGMI | 15 |
DGWYGFRHQN | ||||
流感病毒 | B | EKQTRGIFGA | 16 | |
Mycobacteriumtuberculosis | T | AVLEDPYILLVSSKV | 86 | |
Mycobacteriumtuberculosis | T | LLVSSKVSTVKDLLP | 87 | |
Mycobacteriumtuberculosis | T | LLPLLEKVIGAGKPL | 88 | |
Mycobacteriumtuberculosis | T | AILTGGQVISEEVGL | 89 | |
Mycobacteriumtuberculosis | T | IAFNSGLEPGVVAEK | 90 | |
Mycobacteriumtuberculosis | T | ARRGLERGLNALADAVKV | 91 | |
Mycobacteriumtuberculosis | T | EKIGAELVKEVAKK | 92 | |
Mycobacteriumtuberculosis | T | GLKRGIEKAVEKVTETL | 93 | |
Mycobacteriumtuberculosis | T | IEDAVRNAKAAVEEG | 94 | |
猫白血病毒 | Felv | B | CDIIGNTWNPSDQEPFPGYG | 95 |
猫白血病毒 | Felv | B | CIGTVPKTHQALCNETQQGHT | 96 |
猫白血病毒 | Felv | B | GNYSNQTNPPPSC | 97 |
猫白血病毒 | Felv | B | TDIQALEESISALEKSLTSLSE | 98 |
猫白血病毒 | Felv | AKLRERLKQRQQLF | 99 | |
猫白血病毒 | Felv | DSQQGWFEGWFNKSPWFTTLISS | 100 | |
猫白血病毒 | Felv | QVMTITPPQAMGPNLVLP | 101 |
猫白血病毒 | Felv | DQKPPSRQSQIESRVTP | 102 | |
猫白血病毒 | Felv | RRGLDILFLQEGGLC | 103 | |
猫白血病毒 | Felv | QEGGLCAALEECQIGGLCAALKEEC | 104 | |
Plasmodiumfalciparum | B | NANPNANPNANP | 105 | |
Cirumpsporozoite | QAQGDGANAGQP | 113 |
化学半抗原。相关的化学被用于将化学化合物偶联到载体蛋白上。通常在化学化合物上设计了适当的偶联功能基团。
针对化合物6-O-磷酸胆碱羟基己酸的抗体帮助抵抗肺炎链球菌。Randy T.Fisher et al.J.Immunol.154:3373-3382(1995)
表3
化学半抗原
化学半抗原 | 引用自 |
哌啶N-氧化物 | 美国专利第5,304,252号 |
磷酸内酯或内酰胺 | 美国专利第5,248,611号 |
金属离子复合物 | 美国专利第5,236,825号 |
[2.2.1]或[7.2.2]双环化合物 | 美国专利第5,208,152号 |
带电荷的含羟基化合物 | 美国专利第5,187,086号 |
羧酸酯的膦酸类似物 | 美国专利第5,126,258号 |
***类似物 | Carrera et al.,Nature 378:725(1995) |
碳水化合物半抗原。本领域中有多个方法将载体蛋白偶联到多糖上。可以在寡聚糖或相对较小的多糖的还原端[Anderson,Infect.Immun.,39:233-238(1983);Jennings,et al.,J.Immunol.,127:1011-1018(1981);Poren et al.,Mol.Immunol.,22:907-919(1985)]或末端产生醛基[Anderson et al.,J.Immunol.,137:1181-1186(1986);Beuvery et al.,Dev.Bio.Scand.,65:197-204(1986)],酸酐基团可通过还原型氨基化连接到载体蛋白上。
大的多糖可通过末端激活[Anderson et al.,J.Immunol.,137:1181-1186(1986)]或随机激活[Chu et al.,Infect.Immun.,40:245-256(1983);Gordon,美国专利第4,619,828号(1986);Marbug美国专利第4,882,317号(1989)]多糖链上的几个功能基团而偶联。随机激活多糖链上的几个功能基团可能由于多糖链上的随机连接产生导致高度交联的偶联物。多糖对载体蛋白的最优比率依赖于具体多糖、载体蛋白和所用的偶联物。
多糖和载体蛋白偶联方法的详细综述参见Dick et al.,inContributions to Microbiology and Immunology,Vol.10,Cruseet al.,eds.,(S.Karger:1989),pp.48-114;Jennings et al.,in Neoglycoconjugates:Preparation and Applications,Lee etal.,eds.,(Academic Press:1994),pp.325-371;Aplin et al.,CRC Crit.Rev.Biochem.,10:259-306(1981);and Stowell etal.,Adv.Carbohydr.Chem.Biochem.,37:225-281(1980)。
碳水化合物本身可以通过本领域已知的方法合成,例如通过Witte et al.,J.Am.Chem.Soc.,119:2114-2118(1997)所描述的糖蛋白酶合成方法。
下面的段落中讨论了一些合成的,半合成的,和天然的寡聚糖作为预期用于制备本发明的策略性修饰的核心蛋白偶联物的半抗原的寡聚糖例子。
适合制备用于治疗b型流感嗜血杆菌(Hib)的疫苗的寡聚糖半抗原由2到20个重复的D-核糖-D-核醣醇-磷酸盐(Ⅰ,下图),D-核糖醇-磷酸盐-D-核糖(Ⅱ,下图),或磷酸-D-核糖-D-核糖醇(Ⅲ,下图)组成。Eduard C.Beuvery et al.,欧洲专利0 276516-B1。
美国专利第4,220,717号也公开了用于b型流感嗜血杆菌的多聚核糖核糖醇磷酸盐(PRP)半抗原。
Ellena M.Peterson et al.,Infection and Immunity,66(8):3848-3855(1998)公开了一种三糖半抗原,αKdo(28)αKdo(24)αKdo,该半抗原提供了对Chlamydia pneumoniae的抵抗力。Chlamydia pneumoniae是从咽炎到致命肺炎的人类呼吸道感染的原因之一。kdo是3-脱氧-D-甘露糖-八-2-ulosonic acid
Bengt Anderson等,在欧洲专利0 126 043-A1中公开了能够用来治疗,预防或诊断由Streptococci pneumoniae引起的细菌感染的糖类。其中一类有用的糖类是从二糖GlcNAcβ1 3Gal得到的。Andersson等还发现neolactotetraosylceramide,即Galβ14GlcNAcβ1 3 Galβ1 4Glc-Cer,是有用的。
公开内容在此引入作为参考的欧洲专利第0 157 899-B1号中公开了在本发明中有用的肺炎球菌多糖的分离。下表列出了产生的荚膜多糖在本发明中可用作半抗原的肺炎球菌培养物的类型。
表4.多糖半抗原来源
丹麦典型命名 | 美国命名 | 1978 ATCC目录号 |
1 | 1 | 6301 |
2 | 2 | 6302 |
3 | 3 | 6303 |
4 | 4 | 6304 |
5 | 5 | |
6A | 6 | 6306 |
6B | 26 | 6326 |
7F | 51 | 10351 |
8 | 8 | 6308 |
9N | 9 | 6309 |
9V | 68 | |
10A | 34 | |
11A | 43 | |
12F | 12 | 6312 |
14 | 14 | 6314 |
15B | 54 | |
17F | 17 | |
18C | 56 | 10356 |
19A | 57 | |
19F | 19 | 6319 |
20 | 20 | 6320 |
22F | 22 | |
23F | 23 | 6323 |
25 | 25 | 6325 |
33F | 70 |
已知Moraxella(Branhamella)catarrhalis是儿童中耳炎和鼻窦炎以及成人下呼吸道感染的一种病因。细菌的脂多糖表面抗原(LOS)的脂类A部分是在3-脱氧-D-甘露糖-辛酮糖酸-葡糖胺的连接处被切开的。用温和的碱处理该切割产物以除去酯键连接的脂肪酸而保留酰胺键连接的脂肪酸,以产生来自M.Catarrhalis的去毒脂多糖(dLOS)。DLOS不具有免疫原性,直到它附着到蛋白质载体上。Xin-Xing Gu等,Infection and Immunity 66(5):1891-1897(1998)。
B组链球菌(GBS)是人类脓毒,脑膜炎和有关神经学疾病的病因。已知类膜多糖特异性的抗体保护人类婴儿免受感染。Jennings等,US 5,795,580。GBS荚膜多糖Ⅱ型的重复单元是:4)-β-D-GlcpNAc-(1,3)-[β-D-Galp(16)]-β-D-Galp(14)-β-D-Glop-(13)-β-D-Glcp-(12)-[α-D-NeupNAc(23)]-β-D-Galp-(1,其中加括号的部分是紧接下面未加括号的亚基的支链。GBS荚膜多糖V型重复单元是:4)-[-α-D-NeupNAc-(23)-β-D-Galp-(14)-β-D-GlcpNAc-(16)]-α-D-Glcp-(14)-[β-D-Glcp-(13)]-β-D-Galp-(14)-β-D-Glcp-(1。
Helmut Brade博士的欧洲专利申请号EU-0641568-A1公开了从Chlamydia trachomatis,pneumoniae和psittaci获得梯状结合型抗原的方法。
D.与修饰的HBc偶联的病原体相关性偶联物
在本发明的一个实施方案中,偶联到策略性修饰的HBc蛋白上的半抗原是病原体的B细胞决定簇。多个病原体的B细胞决定簇在本领域中是定已知的,在前面的多肽和碳水化合物半抗原的讨论中描述了一些病原体的B细胞决定簇。
在优选的实施方案中,半抗原是病原体相关的半抗原。和暴露于真正的病原体相比,应用病原体蛋白序列的一部分或碳水化合物序列作为半抗原有明显的优势,甚至优于钝化或“灭活”的病原体形式。
特别重要的病原体相关半抗原的例子来自细菌,如B.pertussis,S.typosa,S.Paratyphoid A和B,C.diptheriae,C.tetani,C.botulinum,C.perfringens,B.anthracis,P.pestis,P.multocida,V.cholerae,N.meningitides,N.gonorrhea,H.infuenzae,T.palladium,等等。
其它特别重要的病原体相关半抗原来源的例子是病毒,如脊髓灰质炎病毒,腺病毒,副流感病毒,麻疹病毒,腮腺炎病毒呼吸道合胞病毒,流感病毒,马脑脊髓炎病毒,猪霍乱病毒,新城疫病毒,禽痘病毒,狂犬病毒,猫和狗温热病毒,***病毒(FMDV),人和猿猴免疫缺陷病毒等等。其它病原体相关半抗原的重要来源包括发疹伤寒,流行性和地方性的斑疹伤寒症,斑疹热等等。
病原体相关的多肽半抗原在本领域中是广为人知的,并且多个公开内容中都有讨论,如美国专利第3,149,036和3,983,228以及4,069,313号;Essential Immunology,3rd Ed.,by Roit,BlackwellScientific Publications出版;Fundamentals of ClinicalImmunology,by Alexander and Good,W.B.Saunders出版;Immunology,by Bellanti,W.B.Saunders出版。
尤其优选的病原体相关半抗原是美国专利第4,625,015号,第4,544,500号,第4,545,931号,第4,663,436号,第4,631,191号,第4,629,783号中所描述的半抗原以及专利合作条约国际公开号WO87/02775和WO87/02892中所描述的半抗原,所有的这些公开内容都在此引入作为参考。
通过将相应于HBsAg决定簇部分序列的多肽半抗原,尤其是相应于Gerin et al.,Proc.Natl.Acad Sci.USA,80:2365(1983)中所描述的“S”(表面)区域的残基110-137的多肽半抗原偶联到修饰的HBc上可得到和乙肝病毒免疫反应的抗体。
另一偶联物相应于1型脊髓灰质炎病毒(PV1,Mahoney株)衣壳蛋白VPI的氨基酸93-103,类似于Delpeyroux et al.,Science,233:472-475(1986)的工作。这样修饰的HBc交联物提供和脊髓灰质炎病毒免疫反应的抗体。其它源自1型脊髓灰质炎病毒,Mahoney和Sabin株的潜在半抗原在欧洲专利385610中有所描述。
在优选的实施方案中,半抗原是病原体相关的半抗原,它们和该病原体诱导的抗体发生免疫反应,即,它们和该病原体诱导的抗体发生免疫学意义上的结合。更为优选地是,病原体相关的半抗原诱导一种提供防止被该病原体感染的抗体应答。
在一个受免疫动物的身体样品中确定是否存在针对一种免疫原的抗体的方法在本领域中是广为人知的。确定是否存在交叉反应抗体和保护性抗体的方法在本领域中是广为人知的。
在本发明的另一实施方案中,还通过提供T细胞决定簇加强对B细胞的决定簇的免疫反应。
例如,美国专利第4,882,145号描述了源自HBV核衣壳蛋白的T细胞刺激性多肽。其它T细胞决定簇在本领域中是已知的并在预期的修饰HBc蛋白或颗粒中可被用作可操作连接的决定簇。
在本发明的一个尤其优选的实施方案中这样的T细胞决定簇和偶联到修饰HBc上的B细胞决定簇源自同一病原体。本领域中报道了多种病原体的T细胞决定簇。
尽管T细胞和B细胞决定簇源自相同的病原体是优选的,但它们不一定要源自该病原体的同一蛋白。例如,源自***病毒(FMDV)VP1蛋白的B细胞决定簇可被交联到一个修饰的HBc颗粒上,其中HBc蛋白进而受源自FMDV的VP4蛋白的T细胞决定簇的修饰。
利用众所周知的方法可在基因水平上将另加的T细胞决定簇引入到修饰的HBc蛋白的HBc蛋白序列之内或末端(氨基或羧基端)之上,包括作为引入化学反应活性氨基酸残基的***DNA序列的一部分,但优选地是作为羧基端的融合蛋白。替代地,另加的T细胞决定簇可以和偶联的B细胞决定簇或策略性修饰的HBc蛋白可操作地连接。
可用于产生本发明的融合蛋白的DNA序列的遗传操作技术,描述这些技术的公开内容的例子参见授予Galibert等,的美国专利第4,428,941号,授予Cohen等,的第4,237,224号,授予Manis的第4,273,875号,授予Riggs的第4,431,739号,授予Goodman等的第4,363,877号以及Rodriguez&Tait,Recombinant DNATechniques;An Introduction,The Benjamin-Cumming PublishingCo.,Inc.Menlo Park,Calif.(1983),这些公开内容在此引入作为参考。
E.接种物和疫苗
在本发明的另一个实施例中偶联一种半抗原的修饰HBc蛋白或颗粒(HBc偶联物)被用作一种接种物的免疫原,该接种物用于诱导产生和该半抗原免疫反应的抗体,或作为疫苗提供针对该半抗原所源自的病原体的抵抗力。
预期的接种物或疫苗含有HbcAg偶联物,上述偶联物溶解于或分散于药用上可接受的稀释剂组合物中,上述组合物通常含有水。当免疫原性有效量的接种物被施用到动物如哺乳动物(如,小鼠,狗,山羊,绵羊,马,牛,猴子,猿,或人类)或鸟类(如,鸡,火鸡,鸭子或鹅)时诱导出能和偶联(悬垂连接)半抗原免疫反应的抗体。疫苗是这样一种接种物,它的半抗原是病原体相关的,并且诱导出的抗体不仅和半抗原免疫反应,还和病原体或死亡细胞免疫反应,并且中和和它们发生免疫反应的病原体和死亡细胞。
含有蛋白类物质作为活性成分的接种物和疫苗的制备在本领域中也是广为人知的。通常,这样的接种物或疫苗是制备成非肠道施用形式的,为液体溶液或悬浮液;也可制备适于在注射前用液体溶解或悬浮的固体形式。上述制备物也可被乳化。免疫原性活性成分经常与药用上可接受的并且和活性成分兼容的赋形剂混合。适当的赋形剂为,如,水、盐溶液、葡萄糖、甘油、乙醇或它们的类似物以及它们的组合物。另外,如果需要的话接种物或疫苗可含有少量增强组合物的免疫原性效力的辅助物质如润湿剂或乳化剂,pH缓冲剂或佐剂。
佐剂的范例包括不在人类上使用的完全Freund’s佐剂(CFA)、不完全Freund’s佐剂(IFA)和矾,这些是本领域中众所周知的物质,并且可通过商业途径从几个来源得到。在此还考虑了小分子佐剂的应用。
一组小分子佐剂例子是美国专利第4,767,842号中所描述的所谓的胞壁酰二肽类似物(muramyl dipetide analogues)。另一种在美国专利第4,787,482号中所描述的小分子佐剂是鲨烯或鲨烷与AracelTM(mannide monooleate)体积比为4∶1的混合物,这种佐剂在此也是有用的。
在此有用的另一类小分子佐剂是美国专利第4,539,205号,第4,643,992号,第5,011,828号,第5,093,318号中所描述的7-取代-8-氧代(7-substituted-8-oxo)或8-硫代-鸟苷衍生物,以上这些专利的公开内容在此引入作为参考。这些物质中7-烯丙基-8-氧鸟苷(loxoribine)是尤其优选的。在诱导抗原-(免疫原)特异的应答上该分子表现得特别有效。
接种物和疫苗通常是通过非肠道施用的,例如通过注射,通过皮下注射或肌肉注射。适用于其它施用形式的其它配方包括栓剂和,在一些情况下,口服配方或通过鼻腔喷用。对于栓剂,传统的结合剂和载体包括,例如,polyalkalene glycols或甘油三酯;这样的栓剂可从含有0.5%-10%,优选地1-2%活性物质混合物得到。口服配方包括诸如这样的常用赋形剂,如药用级别的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等等。
一种接种物或疫苗组合物的形式为溶液、悬浮液、片剂、丸剂、胶囊、持久释放配方或粉剂,并含有免疫原性剂量的作为活性成分的策略性修饰HBc蛋白偶联物或策略性修饰HBc蛋白颗粒偶联物。在典型的组合物中免疫原性剂量的策略性修饰的HBc蛋白偶联物或策略性修饰的HBc蛋白颗粒偶联物为每剂50μg至2mg活性成分,更优选大约每剂100μg到大约1mg。
颗粒和蛋白偶联物可被配制成中性的或盐形式的疫苗。药用上可接受的盐包括和无机酸,如盐酸或磷酸,或和有机酸,如乙酸,草酸,酒石酸,扁桃酸等等,形成的加酸的盐(和肽的自由氨基形成盐)。也可从无机碱如氢氧化钠,钾,铵,钙或铁或有机碱如异丙胺、三甲基胺,2-乙基氨基乙醇,组胺,普鲁卡因等等得到自由羧基的盐。
接种物或疫苗的施用方式和药剂的配制方式是一致的,施用的剂量在药用上是有效的并且具有免疫原性的。施用的量依赖于待治疗的客体、客体免疫***合成抗体的能力以及所需的保护程度。所需施用的活性物质的精确量依赖于实践者的判断并且对于每个个体而言是特定的。但是,适当剂量的范围为约几百毫克活性物质每个个体。初次施用和加强注射(booster shot)的适当疗法也是不尽相同的,但通常为初次施用之后间隔地(通常为几个星期或几个月)进行随后的注射或其它形式的施用。
本发明的另一实施例是一种在动物宿主中诱导抗体的方法,该方法包括用接种物接种上述动物宿主的步骤。该方法中所用的接种物包含免疫原性剂量的策略性修饰乙肝核心蛋白偶联物,上述偶联物溶解或扩散于药用上可接受的稀释液中。本方法中所用的策略性修饰乙肝核心蛋白偶联物含有一个悬垂连接到策略性修饰乙肝核心蛋白上的半抗原。优选的策略性修饰的乙肝核心蛋白是颗粒的形式。策略性修饰的乙肝核心蛋白包含一个氨基酸序列,该序列相应于SEQ ID NO:2中包括氨基酸残基编号为大约10到140的乙肝核心蛋白氨基酸序列,并且此外在相应于氨基酸残基大约50到100的区域有一个***序列,上述***序列(ⅰ)长度为大约1到40个氨基酸残基,并且(ⅱ)包含化学反应活性氨基酸残基。半抗原是通过上述化学反应活性氨基酸残基悬垂连接到策略性修饰乙肝核心蛋白上的。优选的半抗原是病原体相关的。将动物饲养足够的时间以诱导抗体的产生。
下文的非限制性实施例对本发明进行了阐述。
实施例1:修饰乙肝核心蛋白表达载体的构建。
利用定点突变在HBc基因的氨基酸D78和P79之间引入了赖氨酸密码子(TTT),还引入了EcoRⅠ(GAATTC)和SacⅠ(GAGCTC)限制性内切酶位点以便于遗传***其它密码子以产生策略性修饰的杂交HBc颗粒。这样的***序列的氨基酸残基序列为GIQKEL,其中GIQ是EcoRⅠ位点的产物,而EL是SacⅠ位点的产物。因此策略性修饰的乙肝核心蛋白的长度为155个氨基酸残基。pKK322-HBc155-K81表达质粒的构建在下文描述。
用寡聚核苷酸引物P1F(SEQ ID NO:17)和P1R(SEQ ID NO:18,互补链上)扩增了HBc基因的5’端(碱基1-234,氨基酸1-78)并同时在扩增产物的5’端引入了NcoⅠ限制性位点(CCATGG),在3’端引入了EcoRⅠ限制性位点(GAATTC)。用寡聚核苷酸引物P2F(SEQID NO:19)和P2R(SEQ ID NO:20,互补链上)扩增了HBc基因的3’端(碱基232-450,氨基酸79-149)并同时在扩增产物的5’端引入了EcoRⅠ限制性位点(GAATTC)、与之相邻的SacⅠ限制性位点(GAGCTC)并在两个限制性位点之间***了赖氨酸密码子(AAA),在3’端引入了HindⅢ限制性位点(AAGCTT)。
用EcoRⅠ水解两个PCR产物(编码氨基酸1-78和氨基酸79-149),在它们共同的EcoRⅠ粘性端连接,然后用NcoⅠ和HindⅢ水解并用常规技术克隆到表达质粒pKK332(Pharmacia)上。得到的质粒称为pKK332-HBc-K81。该质粒可用于表达在免疫显性环区域带有赖氨酸的策略性修饰的HBc蛋白。表达的策略性修饰的HBc蛋白自动形成颗粒。本实施例的策略性修饰的HBc蛋白在相应于SEQ ID NO:2中HBc的78位***了一段序列,在相应于SEQ ID NO:2中HBc的82位有一个化学反应活性的赖氨酸残基,并且在相应于SEQ ID NO:2中HBc的149位被截断。
实施例2:修饰的乙肝核心蛋白颗粒的纯化
在E.coli中,通常是Novagen(Madison,Wisconsin)的E.coliBLR或BL21或Amersham(Arlington Heights,Illinois)的E.coliTB11,表达实施例1的策略性修饰的HBc蛋白。转染E.coli的HBc155-K81为表达的质粒pKK332-HBc155-K81。利用SepharoseCL-4B色谱通过已经建立的方法纯化了策略性修饰的HBc颗粒。由于颗粒是以可预测的方式纯化的,用简单的分光光度法(OD280)加上在收集前用SDS-PAGE检测各个级分的纯度来监测颗粒洗脱足以使得常规纯化能得到高产量的电泳纯颗粒(5-120mg/L细胞培养物)。在电子显微镜下能清楚地看到纯化的策略性修饰的乙肝核心颗粒的球形结构。
实施例3:合成多肽和修饰乙肝核心颗粒的化学偶联
检测了实施例中表达质粒pKK332-HBc155-K81的策略性修饰乙肝核心颗粒产物的化学反应活性,并和类似表达和纯化的截短的“野生型”乙肝核心颗粒HBc149进行了比较,上述“野生型”颗粒除了缺少引入的赖氨酸残基和赖氨酸侧翼的5个氨基酸外和HBc155-K81相同。
合成肽(半抗原)是通过succinimidyl 4-(N-maleimido-methyl)cyclohexane 1-carboxylate(SMCC),一种水溶性的异双功能交联剂化学偶联到HBc颗粒上的。SMCC对于巯基和伯胺基都具有反应活性,使得它能依次将合成多肽与HBc颗粒连接,上述HBc颗粒的伯胺基已经预先用SMCC修饰。进而,SMCC提供的11.6埃的间隔臂能辅助减小半抗原和HBc载体之间的空间位阻,因此使得高效的偶联效率成为可能。
简言之,HBc155-K81与HBc149颗粒分别和比所有氨基(天然氨基或天然氨基加上***序列中的一个赖氨酸的氨基)3倍过量的SMCC在50mM磷酸钠,pH7.5中室温反应2小时以形成马来酰亚胺激活的HBc颗粒。通过对50mM磷酸钠,pH7.0的反复透析除去未反应的SMCC。SDS-PAGE未能检测到HBc颗粒的SMCC衍生反应后引起的很小的分子量的增加。但是,PAGE检测确实确认了在进行肽偶联之前HBc蛋白的完整性。
和HBc颗粒偶联的合成多肽在N末端设计了半胱氨酸残基,使得多肽半抗原能够通过半抗原的半胱氨酸巯基直接连接到引入的赖氨酸的侧链的伯胺上
表5示明了化学交联到HBc颗粒上的源自人类细胞色素P450酶的合成多肽。合成多肽溶于50mM磷酸钠,pH7.0中使得浓度达到10mg/ml。然后合成肽被逐滴加入到马来酰亚胺激活的策略性修饰HBc155-K81颗粒中,加入的量比总氨基基团过量5倍,让它们在室温反应2小时。马来酰亚胺激活的HBc149颗粒和两段2D6(206和206-C)肽段反应作为对照。
表5细胞色素P-450半抗原
肽段名称 | 序列 | SEQ ID NO: |
1A1(289-302) | CQEKQLDENANVQL | 21 |
1A2(291-302) | CSKKGPRASGNLI | 22 |
2D6(263-277) | CLTEHRMTWDPAQPRDLT | 23 |
3A4(253-273) | CVKRMKESRLEDTQKHRVDFLQ | 24 |
1A1-c | CMQLRS | 106 |
1A2-c | CRFSIN | 107 |
2D6-c | CAVPR | 108 |
2E1-c | CIPRS | 109 |
2C-c | CFIPV | 110 |
3A3/4/7-c | CTVSGA | 111 |
3A5-c | CTLSGE | 112 |
实施例4:修饰核心颗粒偶联物的检测
用SDS-PAGE和免疫印迹法检测了实施例3中和细胞色素P-450决定簇半抗原悬垂连接的策略性修饰HBc颗粒以确定合成肽段是否成功地偶联到HBc上。电泳的变性条件使得颗粒解聚成它们的组成亚基,HBc单体。因为HBc单体的分子量为大约16,000Da,分辨和1A1(289-302),1A2(291-302),2D6(263-277)或3A4(253-273)肽段化学偶联的HBc155-K81颗粒是很简单的,因为这些肽段的相对分子量大约为2,000Da,因此它们导致的HBc蛋白单体分子量的增加可以观察到。SDS-PAGE上的偶联和非偶联条带的相对强度表明大约百分50的HBc155-K81单体和半抗原可操作地连接,而只有百分5的“野生型”HBc149颗粒和半抗原连接。观察到的策略性修饰乙肝核心蛋白悬垂连接到半抗原上的成功率显著增加支持了以下结论:观察到的连接是通过***的赖氨酸而不是通过“野生型”中也存在的赖氨酸残基。
和较长的抑制性肽段相比,与源自P450C末端的较短肽段(5或6肽)偶联的HBc颗粒在SDS-PAGE上迁移性的变化不那么明显,但是在成功偶联的HBc155-K81单体上显然有约700Da的变化。策略性修饰HBc155-K81蛋白表现出的和半抗原悬垂连接的能力明显比“野生型”HBc149颗粒强,HBc149表现出极小的偶联能力。
在Conway等人提出的核心颗粒的模型中;由180个或240个核心蛋白单体结合成二十面体颗粒[Nature,386:91-94(1997)],核心单体相对暴露的免疫显性环区域的二聚体从组装的核心颗粒中伸出到溶液中,象狼牙棒上的长钉子。在HBc颗粒上这些钉子是紧密分布的。引入的赖氨酸残基策略性地位于钉子的尖端上,使得半抗原和组装的核心颗粒偶联反应的空间位阻最小。最多达百分之50的策略性修饰HBc单体和Cyt P-450的合成肽段成功偶联。悬垂连接的量相当于每个核心颗粒的钉子平均附着一个半抗原。半变性条件下的PAGE结果支持了这种半抗原和策略性修饰HBc颗粒连接的分布的提议,在上述半变性的条件下颗粒解聚但却保持了二聚体的结构。
利用免疫印迹法检测了通过肽偶联制备的HBc-2D6颗粒以确认2D6表位的存在。当用抗HBc抗血清探测时化学交联的颗粒得到两种不同的单体,分别代表含有和不含有2D6肽段。只有上边的那条带抗2D6肽抗血清产生印迹,从而确认了迁移性改变和2D6肽连接之间的关系。
实施例6:策略性赖氨酸***
为了构建在免疫显性表面暴露环区域(氨基酸75-85)的每个位置都具有***的赖氨酸残基的HBc颗粒,用PCR扩增了HBc基因的5’和3’端片段并通过寡聚核苷酸引物引入了一个单一的赖氨酸密码子。寡聚核苷酸引物和得到的氨基酸序列在SEQ ID NO:61-82中示明。野生型的序列在SEQ ID NO:59-60示明。
为了在位置75-84产生赖氨酸***序列(HBc-K75到HBc-K84),用识别序列AATT的限制性内切酶MseⅠ消化了一对PCR片段。在位于核苷酸221-224的MseⅠ限制性位点将寡聚核苷酸引物(含有赖氨酸)连接在一起,从而恢复了修饰的基因。对于HBc-K85(SEQ ID NO:85-86)需要产生两个片段,两个片段在共有的XhoⅠ限制性位点(CTCGAG)连接;XhoⅠ限制性位点在野生型基因中并不存在,但可在239-244位引入而不改变任何氨基酸。
表6
HBc免疫显性环中的赖氨酸***突变体
名称 | 序列 | SEQ ID NO: |
野生型HBc | TWVGVNLEDPASRDLVVSYV | 60 |
K75 | TWVGVKNLEDPASRDLVVSYV | 62 |
K76 | TWVGVNKLEDPASRDLVVSYV | 64 |
K77 | TWVGVNLKEDPASRDLVVSYV | 66 |
K78 | TWVGVNLEKDPASRDLVVSYV | 68 |
K79 | TWVGVNLEDKPASRDLVVSYV | 70 |
K80 | TWVGVNLEDPKASRDLVVSYV | 72 |
K81 | TWVGVNLEDPAKSRDLVVSYV | 74 |
K82 | TWVGVNLEDPASKRDLVVSYV | 76 |
K83 | TWVGVNLEDPASRKDLVVSYV | 78 |
K84 | TWVGVNLEDPASRDKLVVSYV | 80 |
K85 | TWVGVNLEDPASRDLKVVSYV | 82 |
为了纯化策略性修饰的HBc蛋白,用45%硫酸铵沉淀了从1L发酵液得到的澄清细胞裂解液,然后利用Sepharose CL-4B层析(2.5×100cm)将得到的沉淀进行凝胶过滤。用这种类型的柱子进行分析时颗粒状的HBc具有特征性的洗脱位置,该洗脱位置与***颗粒的氨基酸无关。用这种方法分析了11种为本研究而制备的策略性修饰HBc颗粒,用分光光度法检测在280nm下的吸光度测量洗脱曲线。
构建体中的3种(HBc-K75,HBc-K77,HBc-K79)生产的水平大约在50到100mg/L之间,和野生型的未修饰的HBc颗粒,如,HBc 149颗粒,的典型产量是可比的。构建体中的4种(HBc-K76,HBc-K78,HBc-K81,HBc-K82)生产的水平相当低大约在1到20mg/L之间。最后,这些颗粒中的4种(HBc-K80,HBc-K83,HBc-K84,HBc-K85)生产的水平似乎几乎不能检测到(<1mg/L)。
表7
从1L发酵液中纯化含赖氨酸的HBc颗粒的产量
颗粒 | 产量(mg/L) |
HBc-150(K75) | 77 |
HBc-150(K76) | 5 |
HBc-150(K77) | 74 |
HBc-150(K78) | 10 |
HBc-150(K79) | 94 |
HBc-150(K80) | 0 |
HBc-150(K81) | 17 |
HBc-150(K82) | 1 |
HBc-150(K83) | 0 |
HBc-150(K84) | 0 |
HBc-150(K85) | 0 |
以上对本发明的描述,包括特定的实施方案和实施例是用于阐述本发明的,并不应被认为是对本发明的限制。可以进行多个其它的变化和修改而不偏离本发明的真正精神和范围。
序列表<110>Birkett,Ashley J.
Immune Complex Inc.<120>策略性修饰的乙肝核心蛋白及其衍生物<130>SYN-101 4564/69529<140>PCT/US99/<141>1999-02-11<150>60/074537<151>1998-02-12<160>113<170>PatentIn Ver.2.0<210>1<211>553<212>DNA<213>乙肝病毒<220><221>CDS<222>(1)..(549)<300><303>天然<304>281<306>646-<307>1979<400>1atg gac atc gac cct tat aaa gaa ttt gga gct act gtg gag tta ctc 48Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu1 5 10 15tcg ttt ttg cct tct gac ttc ttt cct tca gta cga gat ctt cta gat 96Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30acc gcc tca gct ctg tat cgg gaa gcc tta gag tct cct gag cat tgt 144Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45tca cct cac cat act gca ctc agg caa gca att ctt tgc tgg ggg gaa 192Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60cta atg act cta gct acc tgg gtg ggt gtt aat ttg gaa gat cca gcgLeu Met Thr Leu Ala Thr Trp Val Gly Val Asn Leu Glu Asp Pro Ala 24065 70 75 80tct aga gac cta gta gtc agt tat gtc aac act aat atg ggc cta aag 288Ser Arg Asp Leu Val Val Ser Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95ttc agg caa ctc ttg tgg ttt cac att tct tgt ctc act ttt gga aga 336Phe Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110gaa aca gtt ata gag tat ttg gtg tct ttc gga gtg tgg att cgc act 384Glu Thr Val Ile Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125cct cca gct tat aga cca cca aat gcc cct atc cta tca aca ctt ccg 432Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Set Thr Leu Pro
130 135 140gag act act gtt gtt aga cga cga ggc agg tcc cct aga aga aga act 480Glu Thr Thr Val Val Arg Arg Arg Gly Arg Ser Pro Arg Arg Arg Thr145 150 155 160ccc tcg cct cgc aga cga agg tct caa tcg ccg cgt cgc aga aga tct 528Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg Arg Ser
165 170 175caa tct cgg gaa tct caa tgt tagt 553Gln Ser Arg Glu Ser Gln Cys
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20 25 30Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60Leu Met Thr Leu Ala Thr Trp Val Gly Val Asn Leu Glu Asp Pro Ala65 70 75 80Ser Arg Asp Leu Val Val Ser Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95Phe Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110Glu Thr Val Ile Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140Glu Thr Thr Val Val Arg Arg Arg Gly Arg Ser Pro Arg Arg Arg Thr145 150 155 160Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg Arg Ser
165 170 175Gln Ser Arg Glu Ser Gln Cys
180<210>3<211>552<212>DNA<213>乙肝病毒<220><221>CDS<222>(1)..(549)<300><303>(核酸研究)<304>11<306>1747-<307>1983<400>3atg gac att gac ccg tat aaa gaa ttt gga gca tct gtg gag tta ctc 48Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Ser Val Glu Leu Leu1 5 10 15tct ttt ttg cct tct gac ttc ttt ccg tct att cga gat ctc ctt gac 96Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Ile Arg Asp Leu Leu Asp
20 25 30acc gcc tct gct ctg tat cgg gag gcc tta gag tct ccg gaa cat tgt 144Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45tca cct cac cat aca gca ctc agg caa gct att ctg tgt tgg ggt gag 192Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60tta atg aat ctg gcc acc tgg gtg gga agt aat ttg gaa gac cca gca 240Leu Met Asn Leu Ala Thr Trp Val Gly Ser Asn Leu Glu Asp Pro Ala65 70 75 80tcc agg gaa tta gta gtc agc tat gtc aat gtt aat atg ggc cta aaa 288Ser Arg Glu Leu Val Val Ser Tyr Val Asn Val Asn Met Gly Leu Lys
85 90 95atc aga caa cta ttg tgg ttt cac att tcc tgc ctt act ttt gga aga 336Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110gaa act gtt ttg gag tat ttg gta tct ttt gga gtg tgg att cgc act 384Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125cct ccc gct tac aga cca cca aat gcc cct atc tta tca aca ctt ccg 432Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140gaa act act gtt gtt aga cga cga ggc agg tcc cct aga aga aga act 480Glu Thr Thr Val Val Arg Arg Arg Gly Arg Ser Pro Arg Arg Arg Thr145 150 155 160ccc tcg cct cgc aga cga agg tct caa tcg ccg cgt cgc aga aga tct 528Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg Arg Ser
165 170 175caa tct cgg gaa tct caa tgt tag 552Gln Ser Arg Glu Ser Gln Cys
180<210>4<211>183<212>PRT<213>乙肝病毒<400>4Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Ser Val Glu Leu Leu1 5 10 15Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Ile Arg Asp Leu Leu Asp
20 25 30Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60Leu Met Asn Leu Ala Thr Trp Val Gly Ser Asn Leu Glu Asp Pro Ala65 70 75 80Ser Arg Glu Leu Val Val Ser Tyr Val Asn Val Asn Met Gly Leu Lys
85 90 95Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140Glu Thr Thr Val Val Arg Arg Arg Gly Arg Ser Pro Arg Arg Arg Thr145 150 155 160Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg Arg Ser
165 170 175Gln Ser Arg Glu Ser Gln Cys
180<210>5<211>558<212>DNA<213>乙肝病毒<220><221>CDS<222>(1)..(555)<300><303>核酸研究<304>11<306>1747-<307>1983<400>5atg gac att gac cct tat aaa gaa ttt gga gct act gtg gag tta ctc 48Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu1 5 10 15tcg ttt ttg cct tct gac ttc ttt cct tcc gta cga gat ctc cta gac 96Ser Phe Leu Pro Ser Asp Phe Phe Pro Ger Val Arg Asp Leu Leu Asp
20 25 30acc gcc tca gct ctg tat cga gaa gcc tta gag tct cct gag cat tgc 144Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45tca cct cac cat act gca ctc agg caa gcc att ctc tgc tgg ggg gaa 192Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60ttg atg act cta gct acc tgg gtg ggt aat aat ttg caa gat cca gca 240Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Gln Asp Pro Ala65 70 75 80tcc aga gat cta gta gtc aat tat gtt aat act aac atg ggt tta aag 288Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95atc agg caa cta ttg tgg ttt cat ata tct tgc ctt act ttt gga aga 336Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110gag act gta ctt gaa tat ttg gtc tct ttc gga gtg tgg att cgc act 384Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125cct cca gcc tat aga cca cca aat gcc cct atc tta tca aca ctt ccg 432Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140gaa act act gtt gtt aga cga cgg gac cga ggc agg tcc cct aga aga 480Glu Thr Thr Val Val Arg Arg Arg Asp Arg Gly Arg Ser Pro Arg Arg145 150 155 160aga act ccc tcg cct cgc aga cgc aga tct caa tcg ccg cgt cgc aga 528Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175aga tct caa tct cgg gaa tct caa tgt tag 558Arg Ser Gln Ser Arg Glu Ser Gln Cys
180 185<210>6<211>185<212>PRT<213>乙肝病毒<400>6Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu1 5 10 15Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Gln Asp Pro Ala65 70 75 80Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140Glu Thr Thr Val Val Arg Arg Arg Asp Arg Gly Arg Ser Pro Arg Arg145 150 155 160Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175Arg Ser Gln Ser Arg Glu Ser Gln Cys
180 185<210>7<211>188<212>PRT<213>乙肝病毒<300><301>Schodel,Florian
et al.,<302>动物乙肝病毒<303>Adv.Viral Oncol.<304>8<306>73-102<307>1989<400>7Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ser Ser Tyr Gln Leu Leu1 5 10 15Asn Phe Leu Pro Leu Asp Phe Phe Pro Asp Leu Asn Ala Leu Val Asp
20 25 30Thr Ala Ala Ala Leu Tyr Glu Glu Glu Leu Thr Gly Arg Glu His Cys
35 40 45Ser Pro His His Thr Ala Ile Arg Gln Ala Leu Val Cys Trp Asp Glu
50 55 60Leu Thr Lys Leu Ile Ala Trp Met Ser Ser Asn Ile Thr Ser Glu Gln65 70 75 80Val Arg Thr Ile Ile Val Asn His Val Asn Asp Thr Trp Gly Leu Lys
85 90 95Val Arg Gln Ser Leu Trp Phe His Leu Ser Cys Leu Thr Phe Gly Gln
100 105 110His Thr Val Gln Glu Phe Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125Pro Ala Pro Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140Glu His Thr Val Ile Arg Arg Arg Gly Gly Ala Arg Ala Ser Arg Ser145 150 155 160Pro Arg Arg Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro
165 170 175Arg Arg Arg Arg Ser Gln Ser Pro Ser Ala Asn Cys
180 185<210>8<211>654<212>DNA<213>乙肝病毒<220><221>CDS<222>(1)..(651)<300><302>动物乙肝病毒<303>Adv.Viral Oncol.<304>8<306>73-102<307>1989<400>8atg tat ctt ttt cac ctg tgc ctt gtt ttt gcc tgt gtt cca tgt cct 48Met Tyr Leu Phe His Leu Cys Leu Val Phe Ala Cys Val Pro Cys Pro1 5 10 15act gtt caa gcc tcc aag ctg tgc ctt gga tgg ctt tgg gac atg gac 96Thr Val Gln Ala Set Lys Leu Cys Leu Gly Trp Leu Trp Asp Met Asp
20 25 30ata gat ccc tat aaa gaa ttt ggt tct tct tat cag ttg ttg aat ttt 144Ile Asp Pro Tyr Lys Glu Phe Gly Ser Ser Tyr Gln Leu Leu Asn Phe
35 40 45ctt cct ttg gac ttt ttt cct gat ctc aat gca ttg gtg gac act gct 192Leu Pro Leu Asp Phe Phe Pro Asp Leu Asn Ala Leu val Asp Thr Ala
50 55 60gct gct ctt tat gaa gaa gaa tta aca ggt agg gag cat tgt tct cct 240Ala Ala Leu Tyr Glu Glu Glu Leu Thr Gly Arg Glu His Cys Ser Pro65 70 75 80cat cat act gct att aga cag gcc tta gtg tgt tgg gaa gaa tta act 288His His Thr Ala Ile Arg Gln Ala Leu Val Cys Trp Glu Glu Leu Thr
85 90 95aga tta att aca tgg atg agt gaa aat aca aca gaa gaa gtt aga aga 336Arg Leu Ile Thr Trp Met Ser Glu Asn Thr Thr Glu Glu Val Arg Arg
100 105 110att att gtt gat cat gtc aat aat act tgg gga ctt aaa gta aga cag 384Ile Ile Val Asp His Val Asn Asn Thr Trp Gly Leu Lys Val Arg Gln
115 120 125act tta tgg ttt cat tta tca tgt ctt act ttt gga caa cac aca gtt 432Thr Leu Trp Phe His Leu Ser Cys Leu Thr Phe Gly Gln His Thr Val
130 135 140caa gaa ttt ttg gtt agt ttt gga gta tgg att aga act cca gct cct 480Gln Glu Phe Leu Val Ser Phe Gly Val Trp Ile Arg Thr Pro Ala Pro145 150 155 160tat aga cca cct aat gca ccc att tta tca act ctt ccg gaa cat aca 528Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro Glu His Thr
165 170 175gtc att agg aga aga gga ggt tca aga gct gct agg tcc ccc cga aga 576Val Ile Arg Arg Arg Gly Gly Ser Arg Ala Ala Arg Ser Pro Arg Arg
180 185 190cgc act ccc tct cct cgc agg aga agg tct caa tca ccg cgt cgc aga 624Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
195 200 205cgc tct caa tct cca gct tcc aac tgc tga 654Arg Ser Gln Ser Pro Ala Ser Asn Cys
210 215<210>9<211>217<212>PRT<213>乙肝病毒<400>9Met Tyr Leu Phe His Leu Cys Leu Val Phe Ala Cys Val Pro Cys Pro1 5 10 15Thr Val Gln Ala Ser Lys Leu Cys Leu Gly Trp Leu Trp Asp Met Asp
20 25 30Ile Asp Pro Tyr Lys Glu Phe Gly Ser Ser Tyr Gln Leu Leu Asn Phe
35 40 45Leu Pro Leu Asp Phe Phe Pro Asp Leu Asn Ala Leu Val Asp Thr Ala
50 55 60Ala Ala Leu Tyr Glu Glu Glu Leu Thr Gly Arg Glu His Cys Ser Pro65 70 75 80His His Thr Ala Ile Arg Gln Ala Leu Val Cys Trp Glu Glu Leu Thr
85 90 95Arg Leu Ile Thr Trp Met Ser Glu Asn Thr Thr Glu Glu Val Arg Arg
100 105 110Ile Ile Val Asp His Val Asn Asn Thr Trp Gly Leu Lys Val Arg Gln
115 120 125Thr Leu Trp Phe His Leu Ser Cys Leu Thr Phe Gly Gln His Thr Val
130 135 140Gln Glu Phe Leu Val Ser Phe Gly Val Trp Ile Arg Thr Pro Ala Pro145 150 155 160Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro Glu His Thr
165 170 175Val Ile Arg Arg Arg Gly Gly Ser Arg Ala Ala Arg Ser Pro Arg Arg
180 185 190Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
195 200 205Arg Ser Gln Ser Pro Ala Ser Asn Cys
210 215<210>10<211>918<212>DNA<213>乙肝病毒<220><221>CDS<222>(1)..(915)<400>10atg tgg tct cta aga tta cac ccc tct cca ttc gga gct gcg tgc caa 48Met Trp Ser Leu Arg Leu His Pro Ser Pro Phe Gly Ala Ala Cys Gln1 5 10 15ggt atc ttt acg tcg acc tcg ctg ttg ttc ctt gtg act gta cct ttg 96Gly Ile Phe Thr Ser Thr Ser Leu Leu Phe Leu Val Thr Val Pro Leu
20 25 30gta tgt acc att gtt tat gat tct tgc tta tat atg gat gtc aat gct 144Val Cys Thr Ile Val Tyr Asp Ser Cys Leu Tyr Met Asp Val Asn Ala
35 40 45tca aga gct tta gca aat gta tat gat ctg cca gat gat ttc ttt cct 192Ser Arg Ala Leu Ala Asn Val Tyr Asp Leu Pro Asp Asp Phe Phe Pro
50 55 60cag att gat gat ctt gtt aga gat gct aag gat gct tta gaa cct tat 240Gln Ile Asp Asp Leu Val Arg Asp Ala Lys Asp Ala Leu Glu Pro Tyr65 70 75 80tgg aaa gcc gaa aca ata aag aaa cat gtt tta att gct act cac ttt 288Trp Lys Ala Glu Thr Ile Lys Lys His Val Leu Ile Ala Thr His Phe
85 90 95gtg gat ttg att gag gac ttc tgg cag acc act cag ggt atg agc caa 336Val Asp Leu Ile Glu Asp Phe Trp Gln Thr Thr Gln Gly Met Ser Gln
100 105 110att gca gac gcc ctc cga gca gta att cca cct act acc gta cca gta 384Ile Ala Asp Ala Leu Arg Ala Val Ile Pro Pro Thr Thr Val Pro Val
115 120 125ccg gag ggt ttt ctc att act cat agt gag gca gaa gag atc ccc ttg 432Pro Glu Gly Phe Leu Ile Thr His Ser Glu Ala Glu Glu Ile Pro Leu
130 135 140aac gat ctc ttt tca aat caa gag gag agg ata gtc aat ttc caa cct 480Asn Asp Leu Phe Ser Asn Gln Glu Glu Arg Ile Val Asn Phe Gln Pro145 150 155 160gac tat ccc att aca gct aga att cat acc cac tta cgt gtt tat act 528Asp Tyr Pro Ile Thr Ala Arg Ile His Thr His Leu Arg Val Tyr Thr
165 170 175aaa ttg aat gaa caa gct ttg gac aaa gct cgc aga ttg ctt tgg tgg 576Lys Leu Asn Glu Gln Ala Leu Asp Lys Ala Arg Arg Leu Leu Trp Trp
180 185 190cat tac aat tgc ctc ctc tgg gga gaa gcc act gtt aca aat tat att 624His Tyr Asn Cys Leu Leu Trp Gly Glu Ale Thr Val Thr Asn Tyr Ile
195 200 205tct cgc ctc cgt act tgg ctt tct act ccc gaa aaa tat cga ggc aag 672Ser Arg Leu Arg Thr Trp Leu Ser Thr Pro Glu Lys Tyr Arg Gly Lys
210 215 220gat gcc cca acc att gaa gca atc act aga cca atc cag gtg gct caa 720Asp Ala Pro Thr Ile Glu Ala Ile Thr Arg Pro Ile Gln Val Ala Gln225 230 235 240gga ggc aga aat caa act aag gga act aga aaa cct cgt gga ctc gaa 768Gly Gly Arg Asn Gln Thr Lys Gly Thr Arg Lys Pro Arg Gly Leu Glu
245 250 255cct aga aga cga aag gtt aaa acc aca gtt gtc tat ggg aga aga cgt 816Pro Arg Arg Arg Lys Val Lys Thr Thr Val Val Tyr Gly Arg Arg Arg
260 265 270tct aag tcc cga ggc agg aga tcc tct cca tcc caa cgt gcg ggc tcc 864Ser Lya Ser Arg Gly Arg Arg Ser Ser Pro Ser Gln Arg Ala Gly Ser
275 280 285cct ctc cca cgt aat cgg gga aac cag aca cga tcc ccc tca cct agg 912Pro Leu Pro Arg Asn Arg Gly Asn Gln Thr Arg Ser Pro Ser Pro Arg
290 295 300gaa tag 918Glu305<210>11<211>305<212>PRT<213>乙肝病毒<400>11Met Trp Ser Leu Arg Leu His Pro Ser Pro Phe Gly Ala Ala Cys Gln1 5 10 15Gly Ile Phe Thr Ser Thr Ser Leu Leu Phe Leu Val Thr Val Pro Leu
20 25 30Val Cys Thr Ile Val Tyr Asp Ser Cys Leu Tyr Met Asp Val Asn Ala
35 40 45Ser Arg Ala Leu Ala Asn Val Tyr Asp Leu Pro Asp Asp Phe Phe Pro
50 55 60Gln Ile Asp Asp Leu Val Arg Asp Ala Lys Asp Ala Leu Glu Pro Tyr65 70 75 80Trp Lys Ala Glu Thr Ile Lys Lys His Val Leu Ile Ala Thr His Phe
85 90 95Val Asp Leu Ile Glu Asp Phe Trp Gln Thr Thr Gln Gly Met Ser Gln
100 105 110Ile Ala Asp Ala Leu Arg Ala Val Ile Pro Pro Thr Thr Val Pro Val
115 120 125Pro Glu Gly Phe Leu Ile Thr His Ser Glu Ala Glu Glu Ile Pro Leu
130 135 140Asn Asp Leu Phe Ser Asn Gln Glu Glu Arg Ile Val Asn Phe Gln Pro145 150 155 160Asp Tyr Pro Ile Thr Ala Arg Ile His Thr His Leu Arg Val Tyr Thr
165 170 175Lys Leu Asn Glu Gln Ala Leu Asp Lys Ala Arg Arg Leu Leu Trp Trp
180 185 190His Tyr Asn Cys Leu Leu Trp Gly Glu Ala Thr Val Thr Asn Tyr Ile
195 200 205Ser Arg Leu Arg Thr Trp Leu Ser Thr Pro Glu Lys Tyr Arg Gly Lys
210 215 220Asp Ala Pro Thr Ile Glu Ala Ile Thr Arg Pro Ile Gln Val Ala Gln225 230 235 240Gly Gly Arg Asn Gln Thr Lys Gly Thr Arg Lys Pro Arg Gly Leu Glu
245 250 255Pro Arg Arg Arg Lys Val Lys Thr Thr Val Val Tyr Gly Arg Arg Arg
260 265 270Ser Lys Ser Arg Gly Arg Arg Ser Ser Pro Ser Gln Arg Ala Gly Ser
275 280 285Pro Leu Pro Arg Asn Arg Gly Asn Gln Thr Arg Ser Pro Ser Pro Arg
290 295 300Glu305<210>12<211>918<212>DNA<213>乙肝病毒<220><221>CDS<222>(1)..(915)<400>12atg tgg aac tta aga att aca ccc ctc tcc ttc gga gct gct tgc caa 48Met Trp Asn Leu Arg Ile Thr Pro Leu Ser Phe Gly Ala Ala Cys Gln1 5 10 15ggt atc ttt acg tct aca ttg ctg ttg tcg tgt gtg act gta cct ttg 96Gly Ile Phe Thr Ser Thr Leu Leu Leu Ser Cys Val Thr Val Pro Leu
20 25 30gta tgt acc att gtt tat gat tct tgc tta tat atg gat atc aat gct 144Val Cys Thr Ile Val Tyr Asp Ser Cys Leu Tyr Met Asp Ile Asn Ala
35 40 45tct aga gcc tta gcc aat gtg tat gat cta cca gat gat ttc ttt cca 192Ser Arg Ala Leu Ala Asn Val Tyr Asp Leu Pro Asp Asp Phe Phe Pro
50 55 60aaa ata gat gat ctt gtt aga gat gct aaa gac gct tta gag cct tat 240Lys Ile Asp Asp Leu Val Arg Asp Ala Lys Asp Ala Leu Glu Pro Tyr65 70 75 80tgg aaa tca gat tca ata aag aaa cat gtt ttg att gca act cac ttt 288Trp Lys Ser Asp Ser Ile Lys Lys His Val Leu Ile Ala Thr His Phe
85 90 95gtg gat ctc att gaa gac ttc tgg cag act aca cag ggc atg cat gaa 336Val Asp Leu Ile Glu Asp Phe Trp Gln Thr Thr Gln Gly Met His Glu
100 105 110ata gcc gaa tca tta aga gct gtt ata cct ccc act act act cct gtt 384Ile Ala Glu Ser Leu Arg Ala Val Ile Pro Pro Thr Thr Thr Pro Val
115 120 125cca ccg ggt tat ctt att cag cac gag gaa gct gaa gag ata cct ttg 432Pro Pro Gly Tyr Leu Ile Gln His Glu Glu Ala Glu Glu Ile Pro Leu
130 135 140gga gat tta ttt aaa cac caa gaa gaa agg ata gta agt ttc caa ccc 480Gly Asp Leu Phe Lys His Gln Glu Glu Arg Ile Val Ser Phe Gln Pro145 150 155 160gac tat ccg att acg gct aga att cat gct cat ttg aaa gct tat gca 528Asp Tyr Pro Ile Thr Ala Arg Ile His Ala His Leu Lys Ala Tyr Ala
165 170 175aaa att aac gag gaa tca ctg gat agg gct agg aga ttg ctt tgg tgg 576Lys Ile Asn Glu Glu Ser Leu Asp Arg Ala Arg Arg Leu Leu Trp Trp
180 185 190cat tac aac tgt tta ctg tgg gga gaa gct caa gtt act aac tat att 624His Tyr Asn Cys Leu Leu Trp Gly Glu Ala Gln Val Thr Asn Tyr Ile
195 200 205tct cgt ttg cgt act tgg ttg tca act cct gag aaa tat aga ggt aga 672Ser Arg Leu Arg Thr Trp Leu Ser Thr Pro Glu Lys Tyr Arg Gly Arg
210 215 220gat gcc ccg acc att gaa gca atc act aga cca atc cag gtg gct cag 720Asp Ala Pro Thr Ile Glu Ala Ile Tht Arg Pro Ile Gln Val Ala Gln225 230 235 240gga ggc aga aaa aca act acg ggt act aga aaa cct cgt gga ctc gaa 768Gly Gly Arg Lys Thr Thr Thr Gly Thr Arg Lys Pro Arg Gly Leu Glu
245 250 255cct aga aga aga aaa gtt aaa acc aca gtt gtc tat ggg aga aga cgt 816Pro Arg Arg Arg Lys Val Lys Thr Thr Val Val Tyr Gly Arg Arg Arg
260 265 270tca aag tcc cgg gaa agg aga gcc cct aca ccc caa cgt gcg ggc tcc 864Ser Lys Ser Arg Glu Arg Arg Ala Pro Thr Pro Gln Arg Ala Gly Ser
275 280 285cct ctc cca cgt agt tcg agc agc cac cat aga tct ccc tcg cct agg 912Pro Leu Pro Arg Ser Ser Ser Ser His His Arg Ser Pro Ser Pro Arg
290 295 300aaa taa 918Lys305<210>13<211>305<212>PRT<213>乙肝病毒<400>13Met Trp Asn Leu Arg Ile Thr Pro Leu Ser Phe Gly Ala Ala Cys Gln1 5 10 15Gly Ile Phe Thr Ser Thr Leu Leu Leu Ser Cys Val Thr Val Pro Leu
20 25 30Val Cys Thr Ile Val Tyr Asp Ser Cys Leu Tyr Met Asp Ile Asn Ala
35 40 45Ser Arg Ala Leu Ala Asn Val Tyr Asp Leu Pro Asp Asp Phe Phe Pro
50 55 60Lys Ile Asp Asp Leu Val Arg Asp Ala Lys Asp Ala Leu Glu Pro Tyr65 70 75 80Trp Lys Ser Asp Ser Ile Lys Lys His Val Leu Ile Ala Thr His Phe
85 90 95Val Asp Leu Ile Glu Asp Phe Trp Gln Thr Thr Gln Gly Met His Glu
100 105 110Ile Ala Glu Ser Leu Arg Ala Val Ile Pro Pro Thr Thr Thr Pro Val
115 120 125Pro Pro Gly Tyr Leu Ile Gln His Glu Glu Ala Glu Glu Ile Pro Leu
130 135 140Gly Asp Leu Phe Lys His Gln Glu Glu Arg Ile Val Ser Phe Gln Pro145 150 155 160Asp Tyr Pro Ile Thr Ala Arg Ile His Ala His Leu Lys Ala Tyr Ala
165 170 175Lys Ile Asn Glu Glu Ser Leu Asp Arg Ala Arg Arg Leu Leu Trp Trp
180 185 190His Tyr Asn Cys Leu Leu Trp Gly Glu Alu Gln Val Thr Asn Tyr Ile
195 200 205Ser Arg Leu Arg Thr Trp Leu Ser Thr Pro Glu Lys Tyr Arg Gly Arg
210 215 220Asp Ala Pro Thr Ile Glu Ala Ile Thr Arg Pro Ile Gln Val Ala Gln225 230 235 240Gly Gly Arg Lys Thr Thr Thr Gly Thr Arg Lys Pro Arg Gly Leu Glu
245 250 255Pro Arg Arg Arg Lys Val Lys Thr Thr Val Val Tyr Gly Arg Arg Arg
260 265 270Ser Lys Ser Arg Glu Arg Arg Ala Pro Thr Pro Gln Arg Ala Gly Ser
275 280 285Pro Leu Pro Arg Ser Ser Ser Ser His His Arg Ser Pro Ser Pro Arg
290 295 300Lys305<210>14<211>37<212>PRT<213>流感病毒<400>14Ser Ile Met Arg Ser Asp Ala Pro Ile Gly Thr Cys Ser Ser Glu Cys1 5 10 15Ile Thr Pro Asn Gly Ser Ile Pro Asn Asp Lys Pro Phe Gln Asn Val
20 25 30Asn Lys Ile Thr Tyr
35<210>15<211>29<212>PRT<213>流感病毒<400>15Arg Gly Ile Phe Gly Ala Ile Ala Gly Phe Ile Glu Asn Gly Trp Glu1 5 10 15Gly Met lle Asp Gly Trp Tyr Gly Phe Arg His Gln Asn
20 25<210>16<211>10<212>PRT<213>流感病毒 引<400>16Glu Lys Gln Thr Arg Gly Ile Phe Gly Ala1 5 10<210>17<211>23<212>DNA<213>人工序列<220><223>人工序列的描述:带有EcoⅠ限制性位点的乙肝病毒PCR引物。<400>17ttgggccatg gacatcgacc tta 23<210>18<211>31<212>DNA<213>人工序列<220><223>人工序列的描述:带确EcoⅠ限制性位点的乙肝病毒PCR引物。<400>18gcggaattcc atcttccaaa ttaacaccca c 31<210>19<211>41<212>DNA<213>人工序列<220><223>人工序列的描述:带有EcoⅠ限制性位点的乙肝病毒PCR引物。<400>19cgcgaattca aaaagagctc ccagcgtcta gagagaccta g 41<210>20<211>31<212>DNA<213>人工序列<220><223>人工序列的描述:带有Hind Ⅲ限制性位点的乙肝病毒PCR引物。<400>20cgcaagctta aacaacagta gtctccggaa g 31<210>21<211>14<212>乙肝病毒<400>21Cys Gln Glu Lys Gln Leu Asp Glu Asn Ala Asn Val Gln Leu1 5 10<210>22<211>13<212>PRT<213>乙肝病毒<400>22Cys Ser Lys Lys Gly Pro Arg Ala Ser Gly Asn Leu Ile1 5 10<210>23<211>19<212>PRT<213>乙肝病毒<400>23Cys Leu Thr Glu His Arg Met Thr Trp Asp Pro Ala Gln Pro Pro Arg1 5 10 15Asp Leu Thr<210>24<211>22<212>PRT<213>乙肝病毒<400>24Cys Val Lys Arg Met Lys Glu Ser Arg Leu Glu Asp Thr Gln Lys His1 5 10 15Arg Val Asp Phe Leu Gln
20<210>25<211>15<212>PRT<213>Streptococcus pneumoniae<300><310>EP-0 786 521-A<400>25Lys Leu Glu Glu Leu Ser Asp Lys Ile Asp Glu Leu Asp Ala Glu1 5 10 15<210>26<211>35<212>PRT<213>Streptococcus pneumoniae<300><310>EP-0 786 521-A<400>26Gln Lys Lys Tyr Asp Glu Asp Gln Lys Lys Thr Glu Glu Lys Ala Ala1 5 10 15Leu Glu Lys Ala Ala Ser Glu Glu Met Asp Lys Ala Val Ala Ala Val
20 25 30Gln Gln Ala
35<210>27<211>31<212>PRT<213>Cryptosporidium parvum<300><310>WO 98/07320<400>27Gln Asp Lys Pro Ala Asp Ala Pro Ala Ala Glu Ala Pro Ala Ala Glu1 5 10 15Pro Ala Ala Glu Pro Ala Ala Gln Gln Asp Lys Pro Ala Asp Ala
20 25 30<210>28<211>16<212>PRT<213>人类免疫缺陷病毒<300><310>US 5,639,854<400>28Gly Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Cys1 5 10 15<210>29<211>17<212>PRT<213>人类免疫缺陷病毒<300><310>WO 98/07320<400>29Arg Lys Arg Ile His Ile Gly Pro Gly Arg Ala Phe Tyr Ile Thr Lys1 5 10 15Asn<210>30<211>31<212>PRT<213>***病毒<300><310>US 4,544,500<400>30Tyr Asn Gly Glu Cys Arg Tyr Asn Arg Asn Ala Val Pro Asn Leu Arg1 5 10 15Gly Asp Leu Gln Val Leu Ala Gln Lys Val Ala Arg Thr Leu Pro
20 25 30<210>31<211>17<212>PRT<213>白喉棒杆菌<300><310>EP-0 399 011-B1<400>31Phe Gln Val Val His Asn Ser Tyr Asn Arg Pro Ala Tyr Ser Pro Gly1 5 10 15Cys<210>32<211>25<212>PRT<213>Borrelia burgdorferi<300><301>Bockenstedt,L.K.
et al.,<303>J.Immunol.<304>157<305>12<306>5496-<307>(1966)<400>32Val Glu Ile Lys Glu Gly Thr Val Thr Leu Lys Arg Glu Ile Asp Lys1 5 10 15Asn Gly Lys Val Thr Val Ser Leu Cys
20 25<210>33<211>19<212>PRT<213>Borrelia burgdorferi<300><301>Zhong,W.
et al.,<303>Bur.J.Immunol.<304>26<305>11<306>2749-<307>1996<400>33Thr Leu Ser Lys Asn Ile Ser Lys Ser Gly Glu Val Ser Val Glu Leu1 5 10 15Asn Asp Cys<210>34<211>11<212>PRT<213>Influenza A virus<300><301>Brumeanu,T.D.<303>Immunotechnology<304>2<305>2<306>85-<307>(1996)<400>34Ser Ser Val Ser Ser Phe Glu Arg Phe Glu Cys1 5 10<210>35<211>10<212>PRT<213>Influenza A virus<300><301>Brumeanu,T.D.<303>Immunotechnology<304>2<305>2<306>85-<307>(1996)<400>35Tyr Arg Asn Leu Leu Trp Leu Thr Glu Lys1 5 10<210>36<211>142<212>PRT<213>Yersinia pestis<300><301>Hill,J.
et al.,<303>Infect.Immun.<304>65<305>11<306>4476-<307>(1997)<400>36Asp Ile Leu Lys Val Ile Val Asp Ser Met Asn His His Gly Asp Ala1 5 10 15Arg Ser Lys Leu Arg Glu Glu Leu Ala Glu Leu Thr Ala Glu Leu Lys
20 25 30Ile Tyr Ser Val Ile Gln Ala Glu Ile Asn Lys His Leu Ser Ser Ser
35 40 45Gly Thr Ile Asn Ile His Asp Lys Ser Ile Asn Leu Met Asp Lys Asn
50 55 60Leu Tyr Gly Tyr Thr Asp Glu Glu Ile Phe Lys Ala Ser Ala Glu Tyr65 70 75 80Lys Ile Leu Glu Lys Met Pro Gln Thr Thr Ile Gln Val Asp Gly Ser
85 90 95Glu Lys Lys Ile Val Ser Ile Lys Asp Phe Leu Gly Ser Glu Asn Lys
100 105 110Arg Thr Gly Ala Leu Gly Asn Leu Lys Asn Ser Tyr Ser Tyr Asn Lys
115 120 125Asp Asn Asn Glu Leu Ser His Phe Ala Thr Thr Cys Ser Asp
130 135 140<210>37<211>19<212>PRT<213>流感嗜血菌<300><310>EP-0 432 220-B1<400>37Cys Ser Ser Ser Asn Asn Asp Ala Ala Gly Asn Gly Ala Ala Gln Phe1 5 10 15Gly Gly Tyr<210>38<211>11<212>PRT<2>流感嗜血菌<300><310>EP-0 432 220-B1<400>38Asn Lys Leu Glg Thr Val Ser Tyr Gly Glu Glu1 5 10<210>39<211>16<212>PRT<213>流感嗜血菌<300><310>EP-0 432 220-B1<400>39Asn Asp Glu Ala Ala Tyr Ser Lys Asn Arg Arg Ala Val Leu Ala Tyr1 5 10 15<210>40<211>28<212>PRT<213>Moraxella catarrhalis<300><310>WO 98/06851<400>40Leu Asp Ile Glu Lys Asp Lys Lys Lye Arg Thr Asp Glu Gln Leu Gln1 5 10 15Ala Glu Leu Asp Asp Lys Tyr Ala Gly Lys Gly Tyr
20 25<210>41<211>28<212>PRT<213>Moraxella catarrhalis<300><310>WO 98/06851<400>41Leu Asp Ile Glu Lys Asn Lys Lys Lys Arg Thr Glu Ala Glu Leu Gln1 5 10 15Ala Glu Leu Asp Asp Lys Tyr Ala Gly Lys Gly Tyr
20 25<210>42<211>28<212>PRT<213>Moraxella catarrhalis<300><310>WO 98/06851<400>42Ile Asp Ile Glu Lys Lys Gly Lys Ile Arg Thr Glu Ala Glu Leu Leu1 5 10 15Ala Glu Leu Asn Lys Asp Tyr Pro Gly Gln Gly Tyr
20 25<210>43<211>25<212>PRT<213>Porphyromonas gingivalis<300><304>110<305>2<306>285-<307>1997<400>43Gly Val Ser Pro Lys Val Cys Lys Asp Val Thr Val Glu Gly Ser Asn1 5 10 15Glu Phe Ala Pro Val Gln Asn Leu Thr
20 25<210>44<211>20<212>PRT<213>Porphyromonas gingivalis<300><304>110<305>2<306>285-<307>1997<400>44Arg Ile Gln Ser Thr Trp Arg Gln Lys Thr Val Asp Leu Pro Ala Gly1 5 10 15Thr Lys Tyr Val
20<210>45<211>20<212>PRT<213>Trypanosoma cruzi<300><304>159<305>9<306>4444-<307>(1997)<400>45Ser His Asn Phe Thr Leu Val Ala Ser Val Ile Ile Glu Ala Pro Ser1 5 10 15Gly Asn Thr Cys
20<210>46<211>21<212>PRT<213>Trypanosoma cruzi<300><310>WO 97/18475<400>46Lys Ala Ala Ile Ala Pro Ala Lys Ala Ala Ala Ala Pro Ala Lys Ala1 5 10 15Ala Thr Ala Pro Ala
20<210>47<211>16<212>PRT<213>Plasmocdium falciparum<300><303>Int.Arch.Allergy APPl.Immunol.<304>114<305>1<306>15-<400>47Ser Val Gln Ile Pro Lys Val Pro Tyr Pro Asn Gly Ile Val Tyr Cys1 5 10 15<210>48<211>16<212>PRT<213>Plasmodium falciparum<300><303>Int.Arch.Allergy Appl.Immunol.<304>114<305>1<306>15-<400>48Asp Phe Asn His Tyr Tyr Thr Leu Lya Thr Gly Leu Glu Ala Asp Cys1 5 10 15<210>49<211>16<212>PRT<213>Streptococcus sobrinus<300><303>Arch.Oral Biol.<304>35<306>Suppl.475-<307>(1990)<400>49Lys Pro Arg Pro Ile Tyr Glu Ala Lys Leu Ala Gln Asn Gln Lys Cys1 5 10 15<210>50<211>17<212>PRT<213>Streptococcus sobrinus<300><303>Arch.Oral Biol.<304>35<306>Suppl.475-<307>(1990)<400>50Ala Lys Ala Asp Tyr Glu Ala Lys Leu Ala Gln Tyr Glu Lys Asp Leu1 5 10 15Cys<210>51<211>16<212>PRT<213>淋巴细胞性脉络丛膜膜炎病毒<300><303>Proc.Natl.Acad.Sci.U.S.A.<304>94<305>7<306>3314-<307>(1997)<400>51Arg Pro Gln Ala Ser Gly Val Tyr Met Gly Asn Leu Thr Ala Gln Cys1 5 10 15<210>52<211>9<212>PRT<213>Shigella flexneri<300><303>J.Biol.Chem.<304>271<305>52<306>33670-<307>(1996)<400>52Lys Asp Arg Thr Leu Ile Glu Gln Lys1 5<210>53<211>15<212>PRT<213>呼吸道合胞病毒<300><304>234<305>1<306>118-<307>1997<400>53Cys Ser Ile Cys Ser Asn Asn Pro Thr Cys Trp Ala Ile Cys Lys1 5 10 15<210>54<211>19<212>PRT<213>Plasmodium vivax<300><303>Vaccine<304>15<305>4<306>377-<307>1997<400>54Gly Asp Arg Ala Asp Gly Gln Pro Ala Gly Asp Arg Ala Asp Gly Gln1 5 10 15Pro Ala Gly<210>55<211>16<212>PRT<213>Clostridium tetani<300><303>Vaccine<304>15<305>4<306>377-<307>1997<400>55Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Thr Glu Leu Cys1 5 10 15<210>56<211>25<212>PRT<213>Entamoeba histolytica<300><303>J.Exp.Med.<304>185<305>10<306>1793-<307>1997<400>56Val Glu Cys Ala Ser Thr Val Cys Gln Asn Asp Asn Ser Cya Pro Ile1 5 10 15Ile Ala Asp Val Glu Lys Cys Asn Gln
20 25<210>57<211>34<212>PRT<213>Schistosoma japonicum<300><303>Vaccine<304>15<305>1<306>79-<307>1997<400>57Asp Leu Gln Ser Glu Ile Ser Leu Ser Leu Glu Asn Gly Glu Leu Ile1 5 10 15Arg Arg Ala Lys Ser Ala Glu Ser Leu Ala Ser Glu Leu Gln Arg Arg
20 25 30Val Asp<210>58<211>34<212>PRT<213>Schistosoema mansoni<300><303>Vaccine<304>15<305>1<306>79-<307>1997<400>58Asp Leu Gln Ser Glu Ile Ser Leu Ser Leu Glu Asn Ser Glu Leu Ile1 5 10 15Arg Arg Ala Lys Ala Ala Glu Ser Leu Ala Ser Asp Leu Gln Arg Arg
20 25 30Val Asp<210>59<211>63<212>DNA<213>人工序列<220><223>人工序列的描述:在75位***到野生型乙肝序列的MseⅠ限制性内切酶位点。<220><221>CDS<222>(1)..(63)<400>59gct acc tgg gtg ggt gtt aat ttg gaa gat cca gcg tct aga gac cta 48Ala Thr Trp Val Gly Val Asn Leu Glu Asp Pro Ala Ser Arg Asp Leu1 5 10 15gta gtc agt tat gtc 63Val Val Ser Tyr Val
20<210>60<211>21<212>PRT<213>人工序列<400>60Ala Thr Trp Val Gly Val Asn Leu Glu Asp Pro Ala Ser Arg Asp Leu1 5 10 15Val Val Ser Tyr Val
20<210>61<211>41<212>DNA<213>人工序列<220>人工序列的描述:在乙肝核心序列的75位氨基酸***的K。<223>
sequence<220><221>CDS<222>(1)..(39)<400>61gct acc tgg gtg ggt gtt aaa aat ttg gaa gat cca gcg tc 41Ala Thr Trp Val Gly Val Lys Asn Leu Glu Asp Pro Ala1 5 10<210>62<211>13<212>PRT<213>人工序列<400>62Ala Thr Trp Val Gly Val Lys Asn Leu Glu Asp Pro Ala1 5 10<210>63<211>27<212>DNA<213>人工序列<220><223>人工序列的描述:在乙肝核心的76位氨基酸***的K。<220><221>CPS<222>(3)..(26)<400>63tt aat aaa ttg gaa gat cca gcg tct a 27Asn Lys Leu Glu Asp Pro Ala Ser
1 5<210>64<211>8<212>PRT<213>人工序列<400>64Asn Lys Leu Glu Asp Pro Ala Ser 1 5<210>65<211>27<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第77位氨基酸***的K<220><221>CDS<222>(3)..(26)<400>65tt aat ttg aaa gaa gat cca gcg tct a 27Asn Leu Lys Glu Asp Pro Ala Ser
1 5<210>66<211>8<212>PRT<213>人工序列<400>66Asn Leu Lys Glu Asp Pro Ala Ser1 5<210>67<211>32<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第78位氨基酸***的K<220><221>CDS<222>(3)..(32)<400>67tt aat ttg gaa aaa gat cca gcg tct aga gac 32Aen Leu Glu Lys Asp Pro Ala Ser Arg Asp
1 5 10<210>68<211>10<212>PRT<213>人工序列<400>68Asn Leu Glu Lys Asp Pro Ala Ser Arg Asp1 5 10<210>69<211>36<212>DNA<213>Artificial Sequence<220><223>人工序列描述:在乙肝核心的第79位氨基酸***的K<220><221>CDS<222>(3)..(35)<400>69tt aat ttg gaa gat aaa cca gcg tct aga gac cta g 36Asn Leu Glu Asp Lys Pro Ala Ser Arg Asp Leu
1 5 10<210>70<211>11<212>PRT<213>人工序列<400>70Asn Leu Glu Asp Lys Pro Ala Ser Arg Asp Leu1 5 10<210>71<211>39<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第80位氨基酸***的K<220><221>CDS<222>(3)..(38)<400>71tt aat ttg gaa gat cca aaa gcg tct aga gac cta gta g 39Asn Leu Glu Asp Pro Lys Ala Ser Arg Asp Leu Val
1 5 10<210>72<211>12<212>PRT<213>人工序列<400>72Asn Leu Glu Asp Pro Lys Ala Ser Arg Asp Leu Val1 5 10<210>73<211>43<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第81位氨基酸***的K<220><221>CDS<222>(3)..(41)<400>73tt aat ttg gaa gat cca gcg aaa tct aga gac cta gta gtc ag 43Asn Leu Glu Asp Pro Ala Lys Ser Arg Asp Leu Val Val
1 5 10<210>74<211>13<212>PRT<213>人工序列<400>74Asn Leu Glu Asp Pro Ala Lys Ser Arg Asp Leu Val Val1 5 10<210>75<211>45<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第82位氨基酸的***K<220><221>CDS<222>(3)..(44)<400>75tt aat ttg gaa gat cca gcg tct aaa aga gac cta gta gtc agt t 45Asn Leu Glu Asp Pro Ala Ser Lys Arg Asp Leu Val Val Ser
1 5 10<210>76<211>14<212>PRT<213>人工序列<400>76Asn Leu Glu Asp Pro Ala Ser Lys Arg Asp Leu Val Val Ser1 5 10<210>77<211>50<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第83位氨基酸***的K<220><221>CDS<222>(3)..(50)<400>77tt aat ttg gaa gat cca gcg tct aga aaa gac cta gta gtc agt tat 47 Asn Leu Glu Asp Pro Ala Ser Arg Lys Asp Leu Val Val Ser Tyr
1 5 10 15gtc 50Val<210>78<211>16<212>PRT<213>人工序列<400>78Asn Leu Glu Asp Pro Ala Ser Arg Lys Asp Leu Val Val Ser Tyr Val1 5 10 15<210>79<211>50<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第84位氨基酸***的K<220><221>CDS<222>(3)..(50)<400>79tt aat ttg gaa gat cca gcg tct aga gac aaa cta gta gtc agt tat 47Asn Leu Glu Asp Pro Ala Ser Arg Asp Lys Leu Val Val ger Tyr
1 5 10 15gtc 50Val<210>80<211>16<212>PRT<213>人工序列<400>80Asn Leu Glu Asp Pro Ala Ser Arg Asp Lys Leu Val Val Ser Tyr Vel1 5 10 15<210>81<211>31<212>DNA<213>人工序列<220><223>人工序列描述:在乙肝核心的第85位氨基酸***的K<220><221>CDS<222>(2)..(31)<400>81c tcg aga gac cta aaa gta gtc agt tat gtc 31Ser Arg Asp Leu Lys Val Val Ser Tyr Val
1 5 10<210>82<211>10<212>PRT<213>人工序列<400>82Ser Arg Asp Leu Lys Val Val Ser Tyr Val1 5 10<210>83<211>18<212>PRT<213>Plasmodium vivax<400>83Asp Arg Ala Ala Gly Gln Pro Ala Gly Asp Arg Ala Asp Gly Gln Pro1 5 10 15Ala Gly<210>84<211>8<212>PRT<213>流感病毒<400>84Cys Asn Asn Pro His Arg Ile Leu1 5<210>85<211>25<212>PRT<213>流感病毒<400>85Cys Pro Lys Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr Gly Met1 5 10 15Arg Asn Val Pro Glu Lys Gln Thr Arg
20 25<210>86<211>15<212>PRT<213>Mycobacterium tuberculosis<400>86Als Val Leu Glu Asp Pro Tyr Ile Leu Leu Val Ser Ser Lys Val1 5 10 15<210>87<211>15<212>PRT<213>Mycobacterium tuberculosis<400>87Leu Leu Val Ser Ser Lys Val Ser Thr Val Lys Asp Leu Leu Pro1 5 10 15<210>88<211>15<212>PRT<213>Mycobacterium tuberculosis<400>88Leu Leu Pro Leu Leu Glu Lys Val Ile Gly Ala Gly Lys Pro Leu1 5 10 15<210>89<211>15<212>PAT<213>Mycobacterium tuberculoeis<400>89Ala Ile Leu Thr Gly Gly Gln Val Ile Ser Glu Glu Val Gly Leu1 5 10 15<210>90<211>15<212>PRT<213>Mycobacterium tuberculosis<400>90Ile Ala Phe Asn Ser Gly Leu Glu Pro Gly Val Val Ala Glu Lys1 5 10 15<210>91<211>18<212>PRT<213>Mycobacterium tuberculosis<400>91Ala Arg Arg Gly Leu Glu Arg Gly Leu Asn Ala Leu Ala Asp Ala Val1 5 10 15Lys Val<210>92<211>14<212>PRT<213>Mycobacterium tuberculosis<400>92Glu Lys Ile Gly Ala Glu Leu Val Lys Glu Val Ala Lys Lys1 5 10<210>93<211>17<212>PRT<213>Mycobacterium tuberculosis<400> 93Gly Leu Lys Arg Gly Ile Glu Lys Ala Val Glu Lys Val Thr Glu Thr1 5 10 15Leu<210>94<211>15<212>PRT<213>Mycobacterium tuberculosis<400>94Ile Glu Asp Ala Val Arg Asn Ala Lys Ala Ala Val Glu Glu Gly1 5 10 15<210>95<211>20<212>PRT<213>猫白血病病毒<400>95Cys Asp Ile Ile Gly Asn Thr Trp Asn Pro Ser Asp Gln Glu Pro Phe1 5 10 15Pro Gly Tyr Gly
20<210>96<211>21<212>PRT<213>猫白血病病毒<400>96Cys Ile Gly Thr Val Pro Lys Thr His Gln Ala Leu Cys Asn Glu Thr1 5 10 15Gln Gln Gly His Thr
20<210>97<211>13<212>PRT<213>猫白血病病毒<400>97Gly Asn Tyr Ser Asn Gln Thr Asn Pro Pro Pro Ser Cys1 5 10<210>98<211>22<212>PRT<213>猫白血病病毒<400>98Thr Asp Ile Gln Ala Leu Glu Glu Ser Ile Ser Ala Leu Glu Lys Ser1 5 10 15Leu Thr Ser Leu Ser Glu
20<210>99<211>14<212>PRT<213>猫白血病病毒<400>99Ala Lys Leu Arg Glu Arg Leu Lys Gln Arg Gln Gln Leu Phe1 5 10<210>100<211>23<212>PRT<213>猫白血病病毒<400>100Asp Ser Gln Gln Gly Trp Phe Glu Gly Trp Phe Asn Lys Ser Pro Trp1 5 10 15Phe Thr Thr Leu Ile Ser Ser
20<210>101<211>18<212>PRT<213>猫白血病病毒<400>101Gln Val Met Thr Ile Thr Pro Pro Gln Ala Met Gly Pro Asn Leu Val1 5 10 15Leu Pro<210>102<211>17<212>PRT<213>猫白血病病毒<400>102Asp Gln Lys Pro Pro Ser Arg Gln Ser Gln Ile Glu Ser Arg Val Thr1 5 10 15Pro<210>103<211>15<212>PRT<213>猫白血病病毒<400>103Arg Arg Gly Leu Asp Ile Leu Phe Leu Gln Glu Gly Gly Leu Cys1 5 10 15<210>104<211>25<212>PRT<213>猫白血病病毒<400>104Gln Glu Gly Gly Leu Cys Ala Ala Leu Glu Glu Cys Gln Ile Gly Gly1 5 10 15Leu Cys Ala Ala Leu Lys Glu Glu Cys
20 25<210>105<211>12<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P450片段<300><303>Science<304>228<306>1436-1440<307>1985<400>105Asn Ala Asn Pro Asn Ala Asn Pro Asn Ala Asn Pro1 5 10<210>106<211>6<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P-450片段<400>106Cys Met Gln Leu Arg Ser1 5<210>107<211>6<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P-450片段<400>107Cys Arg Phe Ser Ile Asn1 5<210>108<211>5<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P-450片段<400>108Cys Ala Val Pro Arg1 5<210>109<211>5<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P-450片段<400>109Cys Ile Pro Arg Ser1 5<210>110<211>5<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P-450片段<400>110Cys Phe Ile Pro Val1 5<210>111<211>6<212>PRT<213>人工序列<220><223>人工序列描述:细胞色素P-450片段<400>111Cys Thr Val Ser Gly Ala<210>112<211>6<212>PRT<213>Plasmodium knowlesi<400>112Cys Thr Leu Ser Gly Glu1 5<210>113<211>12<212>PRT<213>Plasmodium knowlesi<400>113Gln Ala Gln Gly Asp Gly Ala Asn Ala Gly Gln Pro1 5 10
Claims (22)
1.一种策略性修饰的乙肝核心蛋白偶联物,包括一种和半抗原悬垂连接的策略性修饰的嗜肝DNA病毒核衣壳蛋白,其中策略性修饰的乙肝核心蛋白包含的氨基酸序列相应于SEQ ID NO:2中包括氨基酸残基编号为大约10到大约140的乙肝核心蛋白氨基酸序列,并且此外在相应于氨基酸残基大约50到大约100的区域有一个***序列,上述***序列(ⅰ)长度为1到大约40个氨基酸残基,并且(ⅱ)包含化学反应活性氨基酸残基,上述半抗原和上述化学反应活性氨基酸残基悬垂连接。
2.根据权利要求1的策略性修饰的乙肝核心蛋白偶联物,其中***序列是在相应于氨基酸残基编号大约70至90的区域。
3.根据权利要求1的策略性修饰的乙肝核心蛋白偶联物,其中***序列是在相应于氨基酸残基编号78至82的区域。
4.根据权利要求1的策略性修饰的乙肝核心蛋白偶联物,其中半抗原是多肽半抗原,化学半抗原或碳水化合物半抗原。
5.根据权利要求1的策略性修饰的乙肝核心蛋白偶联物,其中半抗原是病原体相关的半抗原。
6.根据权利要求5的策略性修饰的乙肝核心蛋白偶联物,其中策略性修饰的乙肝核心蛋白进而包括和上述乙肝氨基酸序列的羧基端可操作连接的T细胞刺激性氨基酸残基序列。
7.根据权利要求6的策略性修饰的乙肝核心蛋白偶联物,其中所说的T细胞刺激性氨基酸残基序列和悬垂连接的病原体相关半抗原相关于是同一病原体。
8.策略性修饰的乙肝核心蛋白颗粒,包括具有***序列的策略性修饰的乙肝核心蛋白亚基,上述***序列含化学反应活性氨基酸侧链,并且该***序列本身不是抗原决定簇。
9.策略性修饰的乙肝核心蛋白颗粒偶联物,含有多个和半抗原悬垂连接的策略性修饰的乙肝核心蛋白亚基。
10.根据权利要求9的策略性修饰的乙肝核心蛋白颗粒偶联物,其中大约0.1至大约0.5的策略性修饰的乙肝核心蛋白亚基和半抗原悬垂连接。
11.根据权利要求9的策略性修饰的乙肝核心蛋白颗粒偶联物,含有多个和不同半抗原悬垂连接的策略性修饰的乙肝核心蛋白亚基。
12.根据权利要求9的策略性修饰的乙肝核心蛋白颗粒偶联物,其中策略性修饰的乙肝核心蛋白亚基进而包括和上述乙肝氨基酸序列相应的氨基酸序列的羧基端以肽键结合的T细胞刺激性氨基酸残基序列。
13.根据权利要求12的策略性修饰的乙肝核心蛋白颗粒偶联物,其中T细胞刺激性氨基酸残基和悬垂连接的半抗原来自同一病原体。
14.免疫原性融合蛋白偶联物,包括和策略性修饰的乙肝核心蛋白悬垂连接的多肽半抗原,其中上述策略性修饰的乙肝核心蛋白从N末端开始包括三个肽键连接的区域,Ⅰ,Ⅱ,Ⅲ,其中:
(a)区域Ⅰ相应于SEQ ID NO:2中乙肝核心蛋白氨基酸序列大约10到50的残基
(b)区域Ⅱ和区域Ⅰ的羧基端残基连接并相应于上述乙肝核心蛋白氨基酸序列的残基50-100,并且进而含有长度为1至大约40氨基酸残基且含有化学反应活性氨基酸残基的外源***序列;
(c)区域Ⅲ和区域Ⅱ的羧基端残基连接并相应于上述乙肝核心蛋白氨基酸序列的残基100至大约140
15.根据权利要求14的免疫原性融合蛋白偶联物,其中策略性修饰的乙肝核心蛋白进而含有第四个肽键连接的区域,区域Ⅳ,其中
(d)区域Ⅳ是连接到区域Ⅲ的羧基端残基上并且包括T细胞表位。
16.策略性修饰的乙肝核心蛋白包括一段氨基酸序列,该序列大约相应于SEQ ID NO:2中乙肝氨基酸序列的氨基酸残基10至氨基酸残基140,并且在相应于乙肝残基大约50至残基大约100的区域有一段***的氨基酸序列,其中上述***序列含有化学反应活性的氨基酸残基并且该***序列自身不是抗原决定簇。
17.一种接种物,包括溶于或分散于药用上可接受的稀释液中的免疫原性剂量的策略性修饰的乙肝核心蛋白偶联物,上述策略性修饰的乙肝核心蛋白偶联物包括和策略性修饰的乙肝核心蛋白悬垂连接的半抗原,其中策略性修饰的乙肝核心蛋白包括一段氨基酸序列,该序列相应于SEQ ID NO:2中包括氨基酸残基编号为大约10到大约140的乙肝核心蛋白氨基酸序列,并且此外在相应于氨基酸残基大约50到100的区域有一个***序列,上述***序列(ⅰ)长度为大约1到40个氨基酸残基,并且(ⅱ)包含化学反应活性氨基酸残基,所说的半抗原悬垂连接到所说的化学反应活性氨基酸残基上。
18.根据权利要求17的接种物,其中所述的策略性修饰的乙肝核心蛋白偶联物以颗粒的形式出现。
19.根据权利要求18的接种物,其中所述的半抗原是源自病原体的,并且其中所述接种物应用于哺乳动物宿主,保护所述哺乳动物宿主,抵抗所述病原体。
20.在动物宿主中诱导抗体的方法,包括用一种接种物接种所述动物宿主的步骤,所述接种物包含溶于或分散于药用上可接受的稀释剂中的免疫原性剂量的策略性修饰的乙肝核心蛋白偶联物,所述策略性修饰的乙肝核心蛋白偶联物包括和策略性修饰的乙肝核心蛋白悬垂连接的半抗原,其中策略性修饰的乙肝核心蛋白包括一段氨基酸序列,该序列相应于SEQ ID NO:2中包括氨基酸残基编号为大约10到大约140的乙肝核心蛋白氨基酸序列,并且此外在相应于氨基酸残基大约50到大约100的区域有一个***序列,上述***序列(ⅰ)长度为1到大约40个氨基酸残基,并且(ⅱ)包含化学反应活性氨基酸残基,上述半抗原是通过所述化学反应活性氨基酸残基悬垂连接到上述策略性修饰的乙肝核心蛋白上的,并且将上述动物饲养足够长的时间以诱导抗体。
21.根据权利要求20的方法,其中所述的策略性修饰的乙肝核心蛋白偶联物是以颗粒的形式出现的。
22.根据权利要求21的方法,其中所述的半抗原是源自病原体的,并且其中在上述哺乳动物宿主中诱导的抗体保护上述哺乳动物宿主抵抗上述病原体。
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Cited By (7)
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CN1305527C (zh) * | 2003-11-21 | 2007-03-21 | 薛平 | 乙型肝炎治疗疫苗及其制备方法 |
CN104208670A (zh) * | 2014-09-09 | 2014-12-17 | 韩自勤 | 一种***的药物组合物 |
CN104208670B (zh) * | 2014-09-09 | 2017-07-28 | 韩自勤 | 一种***的药物组合物 |
CN107624117A (zh) * | 2015-03-25 | 2018-01-23 | Iqur有限公司 | 基于乙型肝炎核心抗原的疫苗 |
CN111132692A (zh) * | 2017-06-23 | 2020-05-08 | 美国菌种保藏中心 | 包含寨卡病毒抗原的病毒样颗粒 |
CN110804097A (zh) * | 2019-10-30 | 2020-02-18 | 云南沃森生物技术股份有限公司 | 一种同时制备两种单克隆抗体的方法 |
CN110804097B (zh) * | 2019-10-30 | 2021-02-26 | 云南沃森生物技术股份有限公司 | 一种同时制备两种单克隆抗体的方法 |
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TR200002338T2 (tr) | 2002-06-21 |
KR100581991B1 (ko) | 2006-05-23 |
EP1054689B1 (en) | 2003-09-10 |
PT1054689E (pt) | 2003-11-28 |
EP1054689A4 (en) | 2002-02-13 |
US6231864B1 (en) | 2001-05-15 |
EP1054689A1 (en) | 2000-11-29 |
KR20010052165A (ko) | 2001-06-25 |
IL137766A0 (en) | 2001-10-31 |
DE69911175T2 (de) | 2004-07-29 |
ES2207177T3 (es) | 2004-05-16 |
CA2320488A1 (en) | 1999-08-19 |
CZ302092B6 (cs) | 2010-10-06 |
NZ506245A (en) | 2003-08-29 |
AU767144B2 (en) | 2003-10-30 |
DK1054689T3 (da) | 2004-01-26 |
ATE249240T1 (de) | 2003-09-15 |
WO1999040934A1 (en) | 1999-08-19 |
CN100387622C (zh) | 2008-05-14 |
JP4480268B2 (ja) | 2010-06-16 |
IL137766A (en) | 2007-12-03 |
AU2675399A (en) | 1999-08-30 |
CZ20002819A3 (en) | 2001-06-13 |
CA2320488C (en) | 2007-03-06 |
DE69911175D1 (de) | 2003-10-16 |
ID26669A (id) | 2001-01-25 |
JP2002509700A (ja) | 2002-04-02 |
BR9907855A (pt) | 2001-04-24 |
HK1038306A1 (en) | 2002-03-15 |
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