CN1918176A - 用于诱导针对金黄色葡萄球菌的保护性免疫反应的多肽 - Google Patents
用于诱导针对金黄色葡萄球菌的保护性免疫反应的多肽 Download PDFInfo
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- CN1918176A CN1918176A CNA2005800050692A CN200580005069A CN1918176A CN 1918176 A CN1918176 A CN 1918176A CN A2005800050692 A CNA2005800050692 A CN A2005800050692A CN 200580005069 A CN200580005069 A CN 200580005069A CN 1918176 A CN1918176 A CN 1918176A
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- lys
- thr
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Abstract
本发明表征了包含结构上与SEQ ID NO:1有关的氨基酸序列的多肽和这样的多肽的用途。SEQ ID NO:1是全长金黄色葡萄球菌多肽的截短的衍生物。该全长多肽在本文中称作全长“sai-1”。发现SEQ ID NO:1的His-标记的衍生物能产生针对金黄色葡萄球菌的保护性免疫反应。
Description
与相关申请的交叉参考
本申请要求享有2004年2月18日提交的美国临时申请号60/545,447的利益,其在这里引作参考。
发明背景
在贯穿本申请中引用的文献不能视作要求保护的发明的现有技术。
金黄色葡萄球菌(Staphylococcus aureus)是负责广泛的疾病和状况的病原体。由金黄色葡萄球菌造成的疾病和状况的实例包括菌血症、感染性心内膜炎、毛囊炎、疖、痈、脓疱病、大疱性脓疱病、蜂窝织炎、botryomyosis、中毒性休克综合征、皮肤烫伤综合征、中枢神经系统感染、传染性和炎性眼病、osteomyletitis和关节和骨的其它感染和呼吸道感染。(The Staphylococci in Human Disease,Crossley和Archer(编),Churchill Livingstone Inc.1997.)
可以采用基于免疫学的策略,来控制金黄色葡萄球菌感染和金黄色葡萄球菌的传播。基于免疫学的策略包括被动和自动免疫接种。被动免疫接种采用靶向金黄色葡萄球菌的免疫球蛋白。自动免疫接种能诱导针对金黄色葡萄球菌的免疫反应。
潜在的金黄色葡萄球菌疫苗靶向金黄色葡萄球菌多糖和多肽。使用合适的金黄色葡萄球菌多糖或多肽作为疫苗组分,可以实现靶向。可以用作可能的疫苗组分的多糖的实例包括金黄色葡萄球菌5型和8型荚膜多糖。(Shinefield等,N.Eng.J.Med.346:491-496,2002)。可以用作可能的疫苗组分的多肽的实例包括胶原粘附素、血纤蛋白原结合蛋白和聚集因子。(Mamo等,FEMS Immunology and MedicalMicrobiology 10:47-54,1994,Nilsson等,J.Clin.Invest.101:2640-2649,1998,Josefsson等,The Journal of Infectious Diseases 184:1572-1580,2001.)
已经从对金黄色葡萄球菌基因组测序得到了关于金黄色葡萄球菌多肽序列的信息。(Kuroda等,Lancet 357:1225-1240,2001,Baba等,Lancet 359:1819-1827,2000,Kunsch等,欧洲专利公开EP 0 786519,1997年7月30日公开)。在一定程度上,已经在表征从基因组测序得到的多肽序列的努力中采用了生物信息学。(Kunsch等,欧洲专利公开EP 0 786 519,1997年7月30日公开)
在鉴别能编码潜在抗原的基因的努力中,已经使用了多种技术,例如包含展示技术和来自感染的患者的血清的技术。(Foster等,国际公开号WO 01/98499,2001年12月27日公开,Meinke等,国际公开号WO 02/059148,2002年8月1日公开,Etz等,PNAS 99:6573-6578,2002.)
发明概述
本发明表征了包含结构上与SEQ ID NO:1有关的氨基酸序列的多肽和这样的多肽的用途。SEQ ID NO:1是全长金黄色葡萄球菌多肽的截短的衍生物。该全长多肽在本文中称作全长“sai-1”。发现SEQID NO:1的His-标记的衍生物能产生针对金黄色葡萄球菌的保护性免疫反应。
“保护性的”免疫或免疫反应指可检测水平的针对金黄色葡萄球菌感染的保护。使用动物模型,例如本文所述的那些,可以估计保护水平。
因而,本发明的第一个方面描述了多肽免疫原,其包含与SEQ IDNO:1至少85%相同的氨基酸序列,其中该多肽不含有由SEQ ID NO:7的氨基酸261-294提供的羧基末端,且该多肽能提供针对金黄色葡萄球菌的保护性免疫。SEQ ID NO:7提供了全长sai-1多肽,其中氨基酸261-294提供了从LPXTG基序开始的羧基末端结构域。
“免疫原”指产生保护性免疫反应的能力。
“包含与SEQ ID NO:1至少85%相同的氨基酸序列”指,存在SEQ ID NO:1有关的区域,且可存在其它的多肽区域。如果存在其它的多肽区域,则该多肽不具有如SEQ ID NO:7的氨基酸261-294提供的羧基LPXTG基序。
通过比对多肽序列与参照序列,并确定在对应区域中的相同氨基酸的数目,可以确定与参照序列的百分比同一性(也称作百分比相同的)。将该数目除以参照序列(例如,SEQ ID NO:1)中的氨基酸总数,然后乘以100,并四舍五入到最接近的整数。
本发明的另一个方面描述了包含多肽的免疫原,该多肽能提供针对金黄色葡萄球菌的保护性免疫。免疫原由多肽和一个或多个在羧基末端或氨基末端共价连接到该多肽上的其它的区域或部分组成,其中每个区域或部分独立地选自具有至少一种下述性质的区域或部分:增强免疫反应、促进纯化或促进多肽稳定性。
“其它的区域或部分”指不同于sai-1区域的区域或部分。其它的区域或部分可以是,例如,其它的多肽区域或非肽区域。
本发明的另一个方面描述了组合物,其能在患者中诱导针对金黄色葡萄球菌的保护性免疫。该组合物包含药学上可接受的载体和免疫有效量的免疫原,其能提供针对金黄色葡萄球菌的保护性免疫。
免疫有效量是足以提供针对金黄色葡萄球菌感染的保护性免疫的量。该量应当足以显著预防金黄色葡萄球菌感染的可能性或严重性。
本发明的另一个方面描述了包含能编码多肽的重组基因的核酸,该多肽能提供针对金黄色葡萄球菌的保护性免疫。重组基因含有能编码多肽的重组核酸,以及正确的转录和加工的调节元件(其可以包括翻译和翻译后元件)。重组基因可以独立于宿主基因组存在,或作为宿主基因组的一部分。
重组核酸是由于它的序列和/或形式,不能天然产生的核酸。重组核酸的实例包括纯化的核酸,结合到一起的2或更多个核酸区域,其能提供与天然发现的核酸不同的核酸,以及缺少一个或多个天然地彼此结合的核酸区域(例如,上游或下游区域)。
本发明的另一个方面描述了重组细胞。该细胞包含重组基因,其能编码提供针对金黄色葡萄球菌的保护性免疫的多肽。
本发明的另一个方面描述了制备多肽的方法,该多肽能提供针对金黄色葡萄球菌的保护性免疫。该方法包含使含有能编码多肽的重组核酸的重组细胞生长,和纯化多肽。
本发明的另一个方面描述了通过包含下述步骤的方法生产的能提供针对金黄色葡萄球菌的保护性免疫的多肽:在宿主中使含有能编码多肽的重组核酸的重组细胞生长,和纯化多肽。可以采用不同的宿主细胞。
本发明的另一个方面描述了在患者中诱导针对金黄色葡萄球菌的保护性免疫反应的方法。该方法包含下述步骤:给患者施用免疫有效量的免疫原,其能提供针对金黄色葡萄球菌的保护性免疫。
除非特定术语是相互排斥的,“或”指一种或两种可能性。有时,使用诸如“和/或”的短语来强调一种或两种可能性。
诸如“包含”的开放式术语允许其它的元件或步骤。有时,与或不与开放式术语一起,使用诸如“一个或多个”的短语来强调其它元件或步骤的可能性。
除非明确地说明,诸如“一个(a)”或“一个(an)”的术语不限于一个。例如,“一个细胞”不排除“多个细胞”。有时,使用诸如“一个或多个”的短语来强调可能存在复数。
从本文提供的其它描述,包括不同的实施例,可以明白本发明的其它特征和优点。提供的实施例解释用于实现本发明的不同的组分和方法。实施例不限制要求保护的发明。基于本发明的公开内容,熟练的技术人员能鉴别和采用可用于实现本发明的其它组分和方法。
附图简述
图1解释了SEQ ID NO:1的氨基酸序列。
图2解释了SEQ ID NO:2的氨基酸序列。
图3解释了SEQ ID NO:3(SEQ 3)、SEQ ID NO:4(SEQ 4)、SEQID NO:5(SEQ 5)、SEQ ID NO:6(SEQ 6)、SEQ ID NO:7(SEQ 7)、SEQ ID NO:8(SEQ 8)和SEQ ID NO:9(SEQ 9)之间的序列对比。SEQ ID NO:3是SEQ ID NO:1的氨基His-标记的构建体。SEQ IDNO:4是SEQ ID NO:2的氨基His-标记的构建体。SEQ ID NO:5是SEQ ID NO:1的羧基His-标记的构建体。SEQ ID NO:6是SEQ ID NO:7的氨基His-标记的构建体。SEQ ID NO:7是全长COL sai-1序列。SEQ ID NO:8是sai-1ATTC#ABO42826。SEQ ID NO:9是SEQ ID
NO:7的羧基His-标记的构建体。
图4解释了能编码SEQ ID NO:3的核酸序列。粗体显示了能编码SEQ ID NO:1的氨基酸3-260的区域。
图5解释了能编码SEQ ID NO:4的核酸序列。粗体显示了能编码SEQ ID NO:2的氨基酸3-264的区域。
图6A和6B分别显示了SDS-PAGE凝胶和蛋白印迹的示例性的考马斯染色,对比了能编码SEQ ID NO:1有关的蛋白的核酸的细胞内表达。使用抗-his抗体,探测了蛋白印迹。泳道-1,纯化的SEQ IDNO:3(100ng);2,SEQ ID NO:3大肠杆菌(E.coli)粗裂解物(有诱导);3,SEQ ID NO:3大肠杆菌粗裂解物(无诱导);4,SEQ ID NO:5大肠杆菌粗裂解物(有诱导);5,SEQ ID NO:5大肠杆菌粗裂解物(无诱导);6,SEQ ID NO:6大肠杆菌粗裂解物(有诱导);7,SEQ ID NO:6大肠杆菌粗裂解物(无诱导);8,SEQ ID NO:9大肠杆菌粗裂解物(有诱导);9,SEQ ID NO:9大肠杆菌粗裂解物(无诱导);10,标准。
图7A和7B解释了使用在羟基磷酸铝佐剂(AHP)中的SEQ ID NO:3多肽,从分开的实验得到的存活数据。多肽在图7A中称作“SEQ3”,且在图7B中称作“疫苗”。
发明详述
SEQ ID NO:1是金黄色葡萄球菌运铁蛋白结合蛋白的截短的衍生物。发现SEQ ID NO:1的氨基His-标记的衍生物能在大肠杆菌中较好地表达,且提供针对金黄色葡萄球菌感染的保护性免疫(见下文的实施例)。
通过修饰编码核酸以去除氨基信号序列、去除羧基疏水区域、添加氨基末端甲硫氨酸和向氨基末端添加限制位点,在全长运铁蛋白结合蛋白基础上生成了SEQ ID NO:1。去除的疏水区域位于LPXTG基序后。氨基末端限制位点的添加导致丝氨酸至甘氨酸的取代。
使用SEQ ID NO:3的多肽,解释了结构上与SEQ ID NO:1有关的多肽提供保护性免疫的能力。SEQ ID NO:3是SEQ ID NO:1的氨基His-标记衍生物。His-标记能促进多肽纯化和鉴别。
结构上与SEQ ID NO:1有关的多肽包括含有存在于不同金黄色葡萄球菌菌株中的对应区域和天然发生的区域的衍生物的多肽。图1解释了SEQ ID NO:1的氨基酸序列。图2(SEQ ID NO:2)解释了在以与SEQ ID NO:1类似的方式修饰的不同的金黄色葡萄球菌菌株中发现的对应区域的实例。
SEQ ID NO:1和SEQ ID NO:2是基于不同的天然产生的全长金黄色葡萄球菌sai-1序列(SEQ ID NO:7和8)的。图3提供了序列对比,其包括SEQ ID NO:7和8和基于SEQ ID NO:1、2和7的不同的His-标记的构建体。
Sai-1序列
在不同的文献中,为Sai-1序列给出了不同的命名。不同的命名的实例提供在Kuroda等,Lancet 357:1225-1240,2001(SAV1130和SA0977);Baba等,Lancet 359:1819-1827,2002(MW1012);Mazmanian等Molecular Microbiology 40(5):1049-1057,2001(SasE);Taylor和Heinrichs Mol.Microbiol.43(6):1603-1614(StbA),2002;和Mazmanian等,PNAS 99(4):2293-2298,2002和Mazmanian等,Scienee 299:906-909,2003(IsdA)。
与sai-1蛋白序列相对应的多肽序列似乎提供在不同的专利出版物中(Meinke等,2002年8月1日公开的国际公开号WO02/059148,,Masignani等,2002年11月28日公开的国际公开号WO02/094868,Foster等,2002年12月27日公开的国际公开号WO 02/102829,和Foster等,2003年2月13日公开的国际公开号WO 03/011899)。
不同的sai-1序列可以存在于金黄色葡萄球菌的不同菌株中。SEQID NO:7和8提供了sai-1序列的2个实例。基于与已知的sai-1序列相比存在高度的序列相似性或邻接的氨基酸,可以鉴别其它天然产生的sai-1序列。邻接的氨基酸能提供特征标记。在不同的实施方案中,天然产生的sai-1序列是在葡萄球菌、优选金黄色葡萄球菌中发现的序列,其具有SEQ ID NO:1中的至少20,至少30,或至少50个邻接的氨基酸;和/或与SEQ ID NO:1具有至少85%序列相似性或同一性。
通过本领域众所周知的不同的算法和技术,可以确定序列相似性。通常,通过下述技术,确定序列相似性:比对2个序列,以得到最大氨基酸同一性,允许一个序列中的缺口、添加和取代。
可以确定序列相似性,例如,使用局部比对工具,其使用程序lalign(由Huang和Miller开发,Adv.Appl.Math.12:337-357,1991,用于《sim》程序)。选项和环境变量是:-f#缺口中的第一个残基的罚分(默认为-14);-g#缺口中的每个其它残基的罚分(默认为-4)-s str(SMATRIX)可选择的评分矩阵文件的文件名。对于蛋白序列,默认使用PAM250,-w#(LINLEN)序列比对的输出线长度(60)。
SEO ID NO:1有关的多肽
SEQ ID NO:1有关的多肽含有与SEQ ID NO:1至少85%相同的氨基酸序列。“多肽”不提供最小或最大尺寸限制。
与SEQ ID NO:1相比,与SEQ ID NO:1至少85%相同的多肽含有最多26个氨基酸改变。SEQ ID NO:2是结构上与SEQ ID NO:1有关的多肽的实例。在不同的实施方案中,SEQ ID NO:1有关的多肽与SEQ ID NO:1至少90%,至少94%,或至少99%相同;与SEQID NO:2至少94%或99%相同;与SEQ ID NO:1或SEQ ID NO:2的差别为0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个氨基酸改变;或基本上由SEQ ID NO:1的氨基酸3-260或SEQ ID NO:2的3-264组成。每个氨基酸改变独立地是添加、缺失或取代。
“基本上由指定的氨基酸组成”指,存在提及的氨基酸,且可能存在其它的氨基酸。其它的氨基酸可以在羧基或氨基末端。在不同的实施方案中,存在1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个其它的氨基酸。优选的其它的氨基酸是氨基末端甲硫氨酸。
可以改变SEQ ID NO:1或2,以得到可以诱导针对金黄色葡萄球菌的保护性免疫的衍生物。可以进行改变,例如,以得到衍生物,其能保留诱导针对金黄色葡萄球菌的保护性免疫的能力,或得到衍生物,其除了能提供保护性免疫外,还另外具有可以实现特定目的的区域。
图2提供了序列对比,其包括全长sai-1序列(SEQ ID NO:7和8)。对比解释了金黄色葡萄球菌分离物之间的氨基酸差异,所述分离物可以用于指导设计对SEQ ID NO:1或2的潜在改变。另外,可以考虑氨基酸的已知性质,进行改变。
通常,在取代不同的氨基酸以保留活性时,优选地交换具有类似性质的氨基酸。可以为氨基酸取代考虑的因素包括氨基酸大小、电荷、极性和疏水性。不同的氨基酸R-基团对氨基酸性质的作用是本领域众所周知的(见,例如,Ausubel,Current Protocols in MolecularBiology,John Wiley,1987-2002,附录1C.)
在交换氨基酸以维持活性时,取代氨基酸应当具有一种或多种类似的性质,例如大约相同的电荷和/或大小和/或极性和/或疏水性。例如,用缬氨酸取代亮氨酸、用精氨酸取代赖氨酸和用天冬酰胺取代谷氨酰胺,是不会造成多肽功能变化的良好候选方案。
能达到特定目的的改变包括,设计用于促进多肽的生产或功效;或编码的核酸的克隆的改变。通过使用适于重组表达的起始密码子(例如,编码甲硫氨酸),可以促进多肽生产。在以后的细胞加工过程中,可以去除甲硫氨酸。通过例如导入限制位点,其可以伴有氨基酸添加或变化,可以促进克隆。
通过表位增强,可以增强多肽诱导免疫反应的功效。使用不同的技术,例如包含改变锚着残基以提高肽对MHC分子的亲和力的那些,和能增加肽-MHC复合物对T-细胞受体的亲和力的那些,可以进行表位增强(Berzofsky等,Nature Review 1:209-219,2001.)
优选地,多肽是纯化的多肽。“纯化的多肽”存在于缺少它天然伴随的一种或多种其它多肽的环境中,和/或由至少约10%的存在的总蛋白代表。在不同的实施方案中,纯化的多肽代表着样品或制剂中的至少约50%,至少约75%,或至少约95%总蛋白。
在一个实施方案中,该多肽是“基本上纯化的”。基本上纯化的多肽存在于缺少该多肽天然伴随的所有或大多数其它多肽的环境中。例如,基本上纯化的金黄色葡萄球菌多肽存在于缺少所有或大多数其它金黄色葡萄球菌多肽的环境中。环境可以是,例如,样品或制剂。
“纯化的”或“基本上纯化的”不需要多肽经历任何纯化,且可以包括,例如,尚未纯化的化学合成的多肽。
通过修饰多肽羧基或氨基末端,可以增强多肽稳定性。可能的修饰的实例包括氨基末端保护基,例如乙酰基、丙基、琥珀酰基、苄基、苄氧基羰基或叔丁氧基羰基;和羧基末端保护基,例如酰胺、甲酰胺和乙酰胺。
通过向羧基或氨基末端添加基团来促进纯化,可以增强多肽纯化。可以用于促进纯化的基团的实例包括能提供亲和标记的多肽。亲和标记的实例包括六组氨酸标记、trpE、谷胱甘肽和麦芽糖-结合蛋白。
使用通常能增强免疫反应的基团,可以增强多肽产生免疫反应的能力。可以连接到多肽上来增强针对多肽的免疫反应的基团的实例包括细胞因子,例如IL-2.(Buchan等,2000.Molecular Immunology 37:545-552.)
多肽生产
使用标准技术,包括包含化学合成的那些和包含从生产多肽的细胞纯化的那些,可以生产多肽。化学合成多肽的技术,是本领域众所周知的(见例如,Vincent,Peptide and Protein Drug Delivery,NewYork,N.Y.,Decker,1990.)
在下面提供的实施例中,解释了从细胞纯化多肽的技术。纯化技术的其它实例是本领域众所周知的(见例如,Ausubel,CurrentProtocols in Molecular Biology,John Wiley,1987-2002.)
使用重组核酸技术来生产多肽,能促进从细胞得到多肽。生产多肽的重组核酸技术包含向细胞中导入或生产能编码多肽的重组基因,并表达多肽。
重组基因含有能编码多肽的核酸和多肽表达的调节元件。重组基因可以存在于细胞基因组中,或可以是表达载体的一部分。
可以作为重组基因的一部分存在的调节元件包括,天然与多肽编码序列结合的那些,和非天然地与多肽编码序列结合的外源调节元件。外源调节元件例如外源启动子可以用于在特定宿主中表达重组基因,或增加表达水平。通常,存在于重组基因中的调节元件包括转录启动子、核糖体结合位点、终止子和任选地存在的操纵基因。用于在真核细胞中加工的优选元件是多腺苷酸化信号。
通过使用表达载体,可以促进重组基因在细胞中的表达。优选地,除了重组基因外,表达载体还含有在宿主细胞中自主复制的复制起点、选择标记、有限数目的有用的限制酶位点和高拷贝数的潜力。表达载体的实例是克隆载体、修饰的克隆载体、特别设计的质粒和病毒。
由于遗传密码的简并性,可以使用大量不同的编码核酸序列来编码特定多肽。因为几乎所有的氨基酸都由核苷酸三联体或“密码子”的不同组合来编码,所以产生遗传密码的简并性。氨基酸由如下的密码子编码:
A=Ala=丙氨酸:密码子GCA、GCC、GCG、GCU
C=Cys=半胱氨酸:密码子UGC、UGU
D=Asp=天冬氨酸:密码子GAC、GAU
E=Glu=谷氨酸:密码子GAA、GAG
F=Phe=苯丙氨酸:密码子UUC、UUU
G=Gly=甘氨酸:密码子GGA、GGC、GGG、GGU
H=His=组氨酸:密码子CAC、CAU
I=Ile=异亮氨酸:密码子AUA、AUC、AUU
K=Lys=赖氨酸:密码子AAA、AAG
L=Leu=亮氨酸:密码子UUA、UUG、CUA、CUC、CUG、CUU
M=Met=甲硫氨酸:密码子AUG
N=Asn=天冬酰胺:密码子AAC、AAU
P=Pro=脯氨酸:密码子CCA、CCC、CCG、CCU
Q=Gln=谷氨酰胺:密码子CAA、CAG
R=Arg=精氨酸:密码子AGA、AGG、CGA、CGC、CGG、CGU
S=Ser=丝氨酸:密码子AGC、AGU、UCA、UCC、UCG、UCU
T=Thr=苏氨酸:密码子ACA、ACC、ACG、ACU
V=Val=缬氨酸:密码子GUA、GUC、GUG、GUU
W=Trp=色氨酸:密码子UGG
Y=Tyr=酪氨酸:密码子UAC、UAU
用于sai-1有关的多肽的重组核酸表达的合适的细胞是原核细胞和真核细胞。原核细胞的实例包括大肠杆菌;葡萄球菌属的成员,例如金黄色葡萄球菌;乳杆菌属(Lactobacillus)的成员,例如植物乳杆菌(L.plantarum);乳球菌属(Lactococcus)的成员,例如乳酸乳球菌(L.lactis);和芽胞杆菌属(Bacillus)的成员,例如枯草芽胞杆菌(B.subtilis)。真核细胞的实例包括哺乳动物细胞;昆虫细胞;酵母细胞例如糖酵母属(Saccharomyces)的成员(例如,啤酒糖酵母(S.cerevisiae))、毕赤氏酵母属(Pichia)的成员(例如,巴斯德毕赤氏酵母(P.pastoris))、汉逊氏酵母属(Hansenula)的成员(例如,多形汉逊氏酵母(H.polymorpha))、克鲁维氏酵母属(Kluyveromyces)的成员(例如,乳克鲁维氏酵母(K.lactis)或脆壁克鲁维氏酵母(K.fragilis)和裂殖糖酵母属(Schizosaccharomyces)的成员(例如,粟酒裂殖糖酵母(S.pombe))。
重组基因生产、导入细胞和重组基因表达的技术,是本领域众所周知的。这样的技术的实例提供在文献中,例如Ausubel,CurrentProtocols in Molecular Biology,John Wiley,1987-2002,和Sambrook等,Molecular Cloning,A Laboratory Manual,2nd Edition,ColdSpring Harbor Laboratory Press,1989。
如果需要,通过密码子最优化,可以增强在特定宿主中的表达。密码子最优化包括使用更优选的密码子。在不同的宿主中进行密码子最优化的技术,是本领域众所周知的。
依赖于用于表达的宿主,sai-1有关的多肽可以含有翻译后的修饰。“多肽”或多肽的“氨基酸”序列包括含有一个或多个氨基酸的多肽,其具有从宿主细胞(例如酵母宿主)进行翻译后修饰的结构。
例如,在啤酒糖酵母中,倒数第二个氨基酸的性质似乎能决定是否去除N-末端甲硫氨酸。此外,倒数第二个氨基酸的性质还决定N-末端氨基酸是否被Nα-乙酰化(Huang等,Biochemistry 26:(1987),8242-8246,1987)。因而,在本发明的范围内,依赖于哪个氨基酸位于倒数第二个位置,sai-1有关的多肽可以具有Nα-乙酰化的N-末端,且可以去除N末端甲硫氨酸。
另外,如果由于分泌前导序列(例如,信号肽)的存在,sai-1有关的多肽被靶向分泌,则该蛋白可以被N-连接的或O-连接的糖基化修饰(Kukuruzinska等,Ann.Rev.Biochem.56:915-944,1987.)
佐剂
佐剂是能辅助免疫原产生免疫反应的物质。佐剂可以通过不同的机理起作用,例如下述的一个或多个机理:增加抗原生物学或免疫学半衰期;提高向抗原呈递细胞的抗原送递;改良抗原加工和抗原-呈递细胞的呈递;和诱导免疫调制细胞因子的生产(Vogel,ClinicalInfectious Diseases 30(suppl.3):S266-270,2000.)
可以采用许多不同类型的佐剂,来辅助产生免疫反应。具体佐剂的实例包括氢氧化铝、磷酸铝或其它铝盐、磷酸钙、DNA CpG基序、单磷酰脂质A、霍乱毒素、大肠杆菌不耐热毒素、百日咳毒素、胞壁酰二肽、弗氏不完全佐剂、MF59、SAF、免疫刺激复合物、脂质体、生物可降解的小球体、皂甙、非离子型嵌段共聚物、胞壁酰肽类似物、聚磷腈、合成的多核苷酸、IFN-γ、IL-2和IL-12。(Vogel ClinicalInfectious Diseases 30(suppl 3):S266-270,2000,Klein等,Journal ofPharmaceutical Sciences 89:311-321,2000.)
诱导保护性免疫的患者
“患者”指能被金黄色葡萄球菌感染的哺乳动物。可以预防性地或治疗性地治疗患者。预防性治疗能提供足够的保护性免疫,以减少金黄色葡萄球菌感染的可能性或严重性。可以进行治疗性治疗,以减少金黄色葡萄球菌感染的严重性。
使用含有本文所述的免疫原的疫苗,可以进行预防性治疗。优选地在人类进行这样的治疗。可以将疫苗施用给普通人群或处于金黄色葡萄球菌感染的高风险中的那些人。
具有金黄色葡萄球菌感染的高风险的人包括,卫生保健工作者;医院患者;具有减弱的免疫系统的患者;接受手术的患者;接受异物植入(例如导管或血管装置)的患者;面临会导致减弱的免疫的治疗的患者;和具有烧伤或伤口损害的高风险职业的人员(TheStaphylococci in Human Disease,Crossley和Archer(编),ChurchillLivingstone Inc.1997.)
可以被金黄色葡萄球菌感染的非人患者包括母牛、猪、绵羊、山羊、兔子、马、狗、猫和小鼠。非人患者的治疗,可以用于保护宠物和家畜,和评价特定治疗的功效。
组合疫苗
可以单独地或与其它免疫原一起使用SEQ ID NO:1有关的多肽,以诱导免疫反应。可以存在的其它免疫原包括:一种或多种其它的金黄色葡萄球菌免疫原,例如在上文的发明背景中提及的那些;靶向一种或多种其它葡萄球菌生物(例如表皮葡萄球菌(Staphylococcusepidermidis)、溶血葡萄球菌(S.haemolyticus)、沃氏葡萄球菌(S.warneri)或S.lugunensis)的一种或多种免疫原;和靶向其它感染生物的一种或多种免疫原。
动物模型系统
动物模型系统用于评价免疫原产生针对葡萄球菌的保护性免疫反应的功效。在建立保护性的动物模型时遇到的2个障碍是:(1)需要非常高的攻击剂量来克服先天免疫,和(2)死亡速度太快,以致于不能检测保护性的反应。具体地,细菌攻击后,小鼠会在24小时内死于感染,这不能提供足够的时间进行特异性的免疫反应,以消除感染。如果降低剂量,则对照和免疫的小鼠都能在感染下存活。
通过开发慢动力学致死率模型,其包含从稳定期的细胞制备的金黄色葡萄球菌,适当地滴定,和静脉内施用,解决了这些障碍。该慢的死亡动力学能提供足够的时间进行特异性的免疫防御,以对抗细菌感染(例如,10天而不是24小时)。
可以从在固体培养基上生长的细胞,得到在稳定期的金黄色葡萄球菌细胞。它们也可以从液体得到,但是用在固体培养基上生长的细胞得到的结果是更可再现的。可以使细胞方便地在固体培养基上生长过夜。例如,金黄色葡萄球菌可以在倍增时间为约20-30分钟的条件下生长约18至约24小时。
使用标准的技术,可以从固体或液体培养基分离金黄色葡萄球菌,以维持葡萄球菌效价。可以将分离的葡萄球菌保藏在例如-70℃,作为在含有甘油的磷酸缓冲盐水中的洗涤的高密度悬浮液(>109菌落形成单位(CFU)/mL)。
金黄色葡萄球菌攻击应当具有这样的效价,其能在从第一天或第二天开始的约7-10天的时间段内,在动物模型中提供约80-90%死亡。可以使用动物模型进行滴定实验,以监控保藏的葡萄球菌接种物的效价。可以在接种实验前约1-2周,进行滴定实验。
滴定实验的初始效价可以基于以前的实验。对于金黄色葡萄球菌和动物模型菌株Becker,发现合适的效价通常在5×108至8×108CFU/ml的范围内。
施用
使用本文提供的指导和本领域众所周知的技术,可以配制免疫原,并施用给患者。药物施用的指南通常记载在,例如,Vaccines Eds.Plotkin和Orenstein,W.B.Sanders Company,1999;Remington′sPharmaceutical Sciences第20版,Ed。Gennaro,Mack Publishing,2000;和Moden Pharmaceutics第2版,Eds.Banker和Rhodes,Marcel Dekker,Inc.,1990,它们每一篇都在本文引作参考。
药学上可接受的载体有助于保藏和将免疫原施用给患者。药学上可接受的载体可以含有不同的组分,例如缓冲液、无菌的注射用水、生理盐水或磷酸缓冲盐水、蔗糖、组氨酸、盐和聚山梨醇酯。
可以通过不同的途径施用免疫原,例如皮下的、肌内的或粘膜的。使用例如针或喷射-注射器,可以进行皮下和肌内施用。
优选地,考虑本领域众所周知的因素,包括患者的年龄、体重、性别和医学状况;施用途径;希望的效果;和采用的特定化合物,来确定合适的给药方案。可以以多剂疫苗形式使用免疫原。预期剂量由1.0μg-1.0mg总多肽组成,在本发明的不同实施方案中,该范围是0.01mg-1.0mg和0.1mg-1.0mg。
给药的时间选择取决于本领域众所周知的因素。初次施用后,可以随后施用一次或多次加强剂量,以维持或加强抗体效价。给药方案的实例是第1天、1个月、在第4、6或12个月进行第三次给药,以及根据需要,在远时间进行其它加强剂量。
抗体的产生
SEQ ID NO:1有关的多肽可以用于产生抗体和抗体片段,其能结合多肽或金黄色葡萄球菌。这样的抗体和抗体片段具有不同的用途,包括用于多肽纯化、金黄色葡萄球菌鉴别或针对金黄色葡萄球菌感染的治疗性或预防性治疗。
抗体可以是多克隆的或单克隆的。生产和使用抗体的技术是本领域众所周知的。这样的技术的实例,记载在Ausubel,CurrentProtocols in Molecular Biology,John Wiley,1987-2002,Harlow等,Antibodies,A Laboratory Manual,Cold Spring Harbor Laboratory,1988,和Kohler等,Nature 256:495-497,1975。
实施例
下面提供的实施例进一步解释了本发明的不同特征。实施例还解释了有用的实现本发明的方法。这些实施例不会限制要求保护的发明。
实施例1:SEQ ID NO:3提供保护性免疫的用途
该实施例解释了SEQ ID NO:1有关的多肽在模型中提供保护性免疫的能力。使用SEQ ID NO:3(SEQ ID NO:1的His-标记的衍生物)来提供保护性免疫。
Sai-1克隆和表达
使用Vector NTI软件翻译sai-1DNA序列,并分析得到的355氨基酸序列。设计PCR引物,以扩增从第一个天冬酰胺残基开始并在末端天冬酰胺残基终止密码子之前结束的基因。这些PCR引物也具有其它的NcoI(正向引物)和XhoI(反向引物)位点,以促进向表达载体中的克隆。
将蛋白设计成从pET28载体表达,其中该载体编码末端His残基和终止密码子。另外,在Sai-N的甲硫氨酸起始密码子后面,将甘氨酸残基添加到蛋白上。Sai-C具有羧基末端His-标记,且由350氨基酸sai-1蛋白和在羧基末端的其它的8氨基酸组成,所述羧基末端包含多His尾巴和载体序列。Sai-N具有氨基末端His-标记,且由351氨基酸sai-1蛋白(包括甘氨酸插入物)与包含多His尾巴和载体序列的其它的46氨基酸组成。
使用已经工程改造进PCR引物的NcoI/XhoI位点,将PCR扩增的序列连接进pET28载体(Novagen),并通过热激,导入大肠杆菌DH5α(Invitrogen)。使用已经工程改造进PCR引物的NcoI/XhoI位点,将PCR扩增的序列连接进pET28载体(Novagen),并通过热激,导入大肠杆菌DH5α(Invitrogen)。选择菌落,在含有30μg/mL卡那霉素的LB中生长,进行DNA小量制备(Promega),并通过限制酶切消化和PCR,确定插入片段完整性。使用表1列出的引物,对4个具有正确的插入片段大小的小量制备进行测序。选择不含有相对于所需序列的DNA变化的克隆。
表1
SEQ ID NO: | 描述 | 序列 |
12 | Sail-CF | GAGATATACCATGGGCACAAAACATTATTTAAACAGT |
13 | Sail-CR | CCGGCGGCCCTCGAGTTTAGATTCTTTTCTTTTGAA |
14 | Sail-NF | GAGATATACCATGGGCACAAAACATTATTTAAACAGT |
15 | Sail-NR | CCGGCGGCCCTCGAGTTATTTAGATTCTTTTCTTTTGAA |
16 | Sail-C2F | GAGATATACCATGGGCACACAAGTTTCTCAAGCAACATCAC |
17 | Sail-C2R | GGTGGTGCTCGAGAGTTTTTGGTAATTCTTTAGCTT |
18 | Sail-N2F | GAGATATCATATGGGCACACAAGTTTCTCAAGCAACATCAC |
19 | Sail-N2R | GGTGGTGCTCGAGTCAAGTTTTTGGTAATTCTTTAGCTT |
转化大肠杆菌HMS174(DE3)细胞(Novagen),并在含有卡那霉素(30μg/ml)的LB平板上生长;选择3个菌落进行表达测试。在37℃、250rpm温育液体LB(卡那霉素)培养物,直到A600为0.6-1.0,然后通过添加IPTG至1mM终浓度进行诱导,然后进一步温育3小时。通过在4℃、在5000xg离心5分钟,收获培养物。将细胞重新悬浮在500μl裂解缓冲液(Bug Buster,含有蛋白酶抑制剂,Novagen)中。加入等体积的加样缓冲液(补充β-mecapto ethanol至5%终体积),然后将样品在70℃加热5分钟。将提取物在Novex 4-20%Tris-甘氨酸凝胶上运行,并测定蛋白(考马斯蓝染色),并在硝酸纤维素上印迹,且用抗-HIS6抗体(Zymedd)探测。观察到的表达极其低。
重新分析蛋白;去除推定的信号序列,也去除LPXTG基序的下游区域。这些PCR引物也具有其它的NdeI(正向引物)和XhoI(反向引物)位点,以促进向表达载体中的克隆。
将蛋白设计成从pET28载体表达,该pET28载体编码末端His残基和终止密码子。另外,将甘氨酸残基添加到蛋白的甲硫氨酸起始密码子后。Sai-N2(SEQ ID NO:3)含有氨基His-标记。Sai-C2(SEQID NO:5)含有羧基末端His-标记。
使用已经工程改造进PCR引物中的NdeI/XhoI位点,将PCR扩增的序列连接进pET28载体(Novagen),并通过热激导入大肠杆菌DH5α(Invitrogen)。使用已经工程改造进PCR引物中的NdeI/XhoI位点,将PCR扩增的序列连接进pET28载体(Novagen),并通过热激导入大肠杆菌DH5α(Invitrogen)。选择菌落,在含有30μg/mL卡那霉素的LB中生长,进行DNA小量制备(Promega),并通过限制酶切消化和PCR,确定插入片段完整性。使用表1列出的引物,对4个具有正确的插入片段大小的小量制备进行测序。选择不含有相对于所需序列的DNA变化的克隆。
转化大肠杆菌HMS174(DE3)细胞(Novagen),并在含有卡那霉素(30μg/ml)的LB平板上生长;选择3个菌落进行表达测试。在37℃、250rpm温育液体LB(卡那霉素)培养物,直到A600为0.6-1.0,然后通过添加IPTG至1mM终浓度进行诱导,然后进一步温育3小时。通过在4℃、在5000xg离心5分钟,收获培养物。将细胞重新悬浮在500μl裂解缓冲液(Bug Buster,含有蛋白酶抑制剂,Novagen)中。加入等体积的加样缓冲液(补充β-mecapto ethanol至5%终体积),然后将样品在70℃加热5分钟。将提取物在Novex 4-20%Tris-甘氨酸凝胶上运行,并测定蛋白(考马斯蓝染色),并在硝酸纤维素上印迹,且用抗-HIS6抗体(Zymedd)探测。
SEQ ID NO:3纯化
以3ml/g细胞湿重,将重组大肠杆菌细胞(46g湿细胞重)悬浮于裂解缓冲液(50mM磷酸钠,pH8.0,0.15M NaCl,2mM MgCl2,10mM咪唑,0.1%TweenTM-80,和0.02%叠氮化钠)。以1片/15g细胞浆,将与多-(组氨酸)-标记的蛋白(Roche#1873580)一起使用的蛋白酶抑制剂混合物加入悬浮液。加入BenzonaseTM(EM Ind.)至1μL/mL。通过使悬浮液在14,000 PSI穿过微型流化床装置(microfluidizer)(Microfluidics Model 110S)3次,完成细胞裂解。在每次穿过之间,在冰上冷却细胞悬浮液,从而使温度保持低于25℃。在4℃,在11,000xg沉淀细胞碎片30分钟,并保留上清液。
从上清液纯化携带His-标记的蛋白。轻柔翻转18小时,在4℃混合上清液与12mL Ni+-NTA琼脂糖(Qiagen)。将混合物倒入空心柱(1.5cm×20cm),并将未结合的级分收集到一起。用洗涤缓冲液(50mM磷酸钠,pH8.0,0.3M NaCl,20mM咪唑,和0.1%TweenTM-80)洗涤柱子。用300mM咪唑,20mM Tris-HCl,pH8,0.3M NaCl,0.1%TweenTM-80的阶梯梯度,洗脱His-标记的蛋白。
通过考马斯染色的SDS-PAGE,检测含有SEQ ID NO:3多肽的级分,并合并。通过0.2微米滤器过滤合并的级分,以去除微粒材料,并应用到尺寸排阻柱(Sephacryl S-300 26/60柱,AmershamBiosciences),且以1mL/分钟,用30mM MOPS pH7.0,0.3M NaCl,和10%甘油洗脱。通过考马斯染色的SDS-PAGE和蛋白印迹(抗-四His Mab,Qiagen),检测含有SEQ ID NO:3多肽的级分。通过BCA(Pierce)测定蛋白。通过考马斯染色的凝胶的光密度分析法,测定纯度。
金黄色葡萄球菌攻击的制备
使金黄色葡萄球菌在TSA平板上在37℃生长过夜。通过加入5mlPBS到平板上,并用无菌涂布器轻柔地重新悬浮细菌,从TSA平板洗涤细菌。使用Sorvall RC-5B离心机(DuPont Instruments),在6000rpm离心细菌悬浮液20分钟。将沉淀重新悬浮于16%甘油,且在-70℃冷冻保藏等分试样。
使用前,解冻接种物,适当稀释,并用于感染。将每份原液滴定至少3次,以测定在首次用于试验的小鼠中诱导慢死亡动力学的适当剂量。经常监控细菌接种物的效价(80-90%致死率),以确保模型的再现性。在每个攻击实验前10天,攻击一组10只对照动物(用单独的佐剂免疫),并监控。
SEQ ID NO:3多肽的保护研究
用3剂在羟基磷酸铝佐剂(450μg/剂)上的SEQ ID NO:3多肽(20μg/剂),免疫20只BALB/c小鼠。Klein等,Journal ofPharmaceutical Sciences 89,311-321,2000描述了羟基磷酸铝佐剂(AHP)。在第0、7和21天,作为2次50μl注射施用剂量。在第28天,取小鼠的血,并通过ELSIA,筛选它们的血清对SEQ ID NO:3多肽的反应性。
在实验的第35天,通过静脉内注射在一定剂量(8.0×108CFU ml)生长的金黄色葡萄球菌来攻击小鼠。在10天时间段监控小鼠的存活。在实验结束时,与含有30只小鼠的AHP对照组存活2只相比,SEQ ID NO:3多肽免疫组存活5只小鼠。使用20只免疫的小鼠和20只对照小鼠,重复实验。图7A和7B显示了2次实验的结果。
实施例2:能编码SEQ ID NO:1有关的蛋白的核酸的细胞内表达
图6A和6B分别显示了SDS-PAGE凝胶和蛋白印迹的示例性的考马斯染色,从而对比了能编码SEQ ID NO:1有关的蛋白的核酸的细胞内表达。使用抗-his抗体,探测蛋白印迹。泳道-1,纯化的SEQ IDNO:3(100ng);2,SEQ ID NO:3大肠杆菌粗裂解物(有诱导);3,SEQID NO:3大肠杆菌粗裂解物(无诱导);4,SEQ ID NO:5大肠杆菌粗裂解物(有诱导);5,SEQ ID NO:5大肠杆菌粗裂解物(无诱导);6,SEQ ID NO:6大肠杆菌粗裂解物(有诱导);7,SEQ ID NO:6大肠杆菌粗裂解物(无诱导);8,SEQ ID NO:9大肠杆菌粗裂解物(有诱导);9,SEQ ID NO:9大肠杆菌粗裂解物(无诱导);10,标准。
其它实施方案在下面的权利要求内。尽管已经显示和描述了几个实施方案,但可以进行各种修饰,而不脱离本发明的精神和范围。
序列表
序列表
<110>Merck & Co.,Inc.
<120>用于诱导针对金黄色葡萄球菌的保护性免疫反应的多肽
<130>21490Y PCT
<150>60/545,447
<151>2004-02-18
<160>19
<170>FastSEQ for Windows Version 4.0
<210>1
<211>260
<212>PRT
<213>人工序列
<220>
<223>sai-1的截短的衍生物
<400>1
Met Gly Thr Gln Val Ser Gln Ala Thr Ser Gln Pro Ile Asn Phe Gln
1 5 10 15
Val Gln Lys Asp Gly Ser Ser Glu Lys Ser His Met Asp Asp Tyr Met
20 25 30
Gln His Pro Gly Lys Val Ile Lys Gln Asn Asn Lys Tyr Tyr Phe Gln
35 40 45
Thr Val Leu Asn Asn Ala Ser Phe Trp Lys Glu Tyr Lys Phe Tyr Asn
50 55 60
Ala Asn Asn Gln Glu Leu Ala Thr Thr Val Val Asn Asp Asn Lys Lys
65 70 75 80
Ala Asp Thr Arg Thr Ile Asn Val Ala Val Glu Pro Gly Tyr Lys Ser
85 90 95
Leu Thr Thr Lys Val His Ile Val Val Pro Gln Ile Asn Tyr Asn His
100 105 110
Arg Tyr Thr Thr His Leu Glu Phe Glu Lys Ala Ile Pro Thr Leu Ala
115 120 125
Asp Ala Ala Lys Pro Asn Asn Val Lys Pro Val Gln Pro Lys Pro Ala
130 135 140
Gln Pro Lys Thr Pro Thr Glu Gln Thr Lys Pro Val Gln Pro Lys Val
145 150 155 160
Glu Lys Val Lys Pro Thr Val Thr Thr Thr Ser Lys Val Glu Asp Asn
165 170 175
His Ser Thr Lys Val Val Ser Thr Asp Thr Thr Lys Asp Gln Thr Lys
180 185 190
Thr Gln Thr Ala His Thr Val Lys Thr Ala Gln Thr Ala Gln Glu Gln
195 200 205
Asn Lys Val Gln Thr Pro Val Lys Asp Val Ala Thr Ala Lys Ser Glu
210 215 220
Ser Asn Ash Gln Ala Val Ser Asp Asn Lys Ser Gln Gln Thr Asn Lys
225 230 235 240
Val Thr Lys His Asn Glu Thr Pro Lys Gln Ala Ser Lys Ala Lys Glu
245 250 255
Leu Pro Lys Thr
260
<210>2
<211>264
<212>PRT
<213>金黄色葡萄球菌(S.aureus)
<220>
<400>2
Met Gly Thr Gln Val Ser Gln Ala Thr Ser Gln Pro Ile Asn Phe Gln
1 5 10 15
Val Gln Lys Asp Gly Ser Ser Glu Lys Ser His Met Asp Asp Tyr Met
20 25 30
Gln His Pro Gly Lys Val Ile Lys Gln Asn Asn Lys Tyr Tyr Phe Gln
35 40 45
Ala Val Leu Asn Asn Ala Ser Phe Trp Lys Glu Tyr Lys Phe Tyr Asn
50 55 60
Ala Asn Asn Gln Glu Leu Ala Thr Thr Val Val Asn Asp Asp Lys Lys
65 70 75 80
Ala Asp Thr Arg Thr Ile Asn Val Ala Val Glu Pro Gly Tyr Lys Ser
85 90 95
Leu Thr Thr Lys Val His Ile Val Val Pro Gln Ile Asn Tyr Asn His
100 105 110
Arg Tyr Thr Thr His Leu Glu Phe Glu Lys Ala Ile Pro Thr Leu Ala
115 120 125
Asp Ala Ala Lys Pro Asn Asn Val Lys Pro Val Gln Pro Lys Pro Ala
130 135 140
Gln Pro Lys Thr Pro Thr Glu Gln Thr Lys Pro Val Gln Pro Lys Val
145 150 155 160
Glu Lys Val Lys Pro Ala Val Thr Ala Pro Ser Lys Asn Glu Asn Arg
165 170 175
Gln Thr Thr Lys Val Val Ser Ser Glu Ala Thr Lys Asp Gln Ser Gln
180 185 190
Thr Gln Ser Ala Arg Thr Val Lys Thr Thr Gln Thr Ala Gln Asp Gln
195 200 205
Asn Lys Val Gln Thr Pro Val Lys Asp Val Ala Thr Ala Lys Ser Glu
210 215 220
Ser Asn Asn Gln Ala Val Ser Asp Asn Lys Ser Gln Gln Thr Asn Lys
225 230 235 240
Val Thr Lys Gln Asn Glu Val His Lys Gln Gly Pro Ser Lys Asp Ser
245 250 255
Lys Ala Lys Glu Leu Pro Lys Thr
260
<210>3
<211>280
<212>PRT
<213>人工序列
<220>
<223>SEQ ID NO:1的氨基His-标记的构建体
<400>3
Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro
1 5 10 15
Arg Gly Ser His Met Gly Thr Gln Val Ser Gln Ala Thr Ser Gln Pro
20 25 30
Ile Asn Phe Gln Val Gln Lys Asp Gly Ser Ser Glu Lys Ser His Met
35 40 45
Asp Asp Tyr Met Gln His Pro Gly Lys Val Ile Lys Gln Asn Asn Lys
50 55 60
Tyr Tyr Phe Gln Thr Val Leu Asn Asn Ala Ser Phe Trp Lys Glu Tyr
65 70 75 80
Lys Phe Tyr Asn Ala Asn Asn Gln Glu Leu Ala Thr Thr Val Val Asn
85 90 95
Asp Asn Lys Lys Ala Asp Thr Arg Thr Ile Asn Val Ala Val Glu Pro
100 105 110
Gly Tyr Lys Ser Leu Thr Thr Lys Val His Ile Val Val Pro Gln Ile
115 120 125
Asn Tyr Asn His Arg Tyr Thr Thr His Leu Glu Phe Glu Lys Ala Ile
130 135 140
Pro Thr Leu Ala Asp Ala Ala Lys Pro Asn Asn Val Lys Pro Val Gln
145 150 155 160
Pro Lys Pro Ala Gln Pro Lys Thr Pro Thr Glu Gln Thr Lys Pro Val
165 170 175
Gln Pro Lys Val Glu Lys Val Lys Pro Thr Val Thr Thr Thr Ser Lys
180 185 190
Val Glu Asp Asn His Ser Thr Lys Val Val Ser Thr Asp Thr Thr Lys
195 200 205
Asp Gln Thr Lys Thr Gln Thr Ala His Thr Val Lys Thr Ala Gln Thr
210 215 220
Ala Gln Glu Gln Asn Lys Val Gln Thr Pro Val Lys Asp Val Ala Thr
225 230 235 240
Ala Lys Ser Glu Ser Asn Asn Gln Ala Val Ser Asp Asn Lys Ser Gln
245 250 255
Gln Thr Asn Lys Val Thr Lys His Asn Glu Thr Pro Lys Gln Ala Ser
260 265 270
Lys Ala Lys Glu Leu Pro Lys Thr
275 280
<210>4
<211>284
<212>PRT
<213>人工序列
<220>
<223>SEQ ID NO:2的氨基His-标记的构建体
<400>4
Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro
1 5 10 15
Arg Gly Ser His Met Gly Thr Gln Val Ser Gln Ala Thr Ser Gln Pro
20 25 30
Ile Asn Phe Gln Val Gln Lys Asp Gly Ser Ser Glu Lys Ser His Met
35 40 45
Asp Asp Tyr Met Gln His Pro Gly Lys Val Ile Lys Gln Asn Asn Lys
50 55 60
Tyr Tyr Phe Gln Ala Val Leu Asn Asn Ala Ser Phe Trp Lys Glu Tyr
65 70 75 80
Lys Phe Tyr Asn Ala Asn Asn Gln Glu Leu Ala Thr Thr Val Val Asn
85 90 95
Asp Asp Lys Lys Ala Asp Thr Arg Thr Ile Asn Val Ala Val Glu Pro
100 105 110
Gly Tyr Lys Ser Leu Thr Thr Lys Val His Ile Val Mal Pro Gln Ile
115 120 125
Asn Tyr Asn His Arg Tyr Thr Thr His Leu Glu Phe Glu Lys Ala Ile
130 135 140
Pro Thr Leu Ala Asp Ala Ala Lys Pro Asn Asn Val Lys Pro Val Gln
145 150 155 160
Pro Lys Pro Ala Gln Pro Lys Thr Pro Thr Glu Gln Thr Lys Pro Val
165 170 175
Gln Pro Lys Val Glu Lys Val Lys Pro Ala Val Thr Ala Pro Ser Lys
180 185 190
Asn Glu Asn Arg Gln Thr Thr Lys Val Val Ser Ser Glu Ala Thr Lys
195 200 205
Asp Gln Ser Gln Thr Gln Ser Ala Arg Thr Val Lys Thr Thr Gln Thr
210 215 220
Ala Gln Asp Gln Asn Lys Val Gln Thr Pro Val Lys Asp Val Ala Thr
225 230 235 240
Ala Lys Ser Glu Ser Asn Asn Gln Ala Val Ser Asp Asn Lys Ser Gln
245 250 255
Gln Thr Asn Lys Val Thr Lys Gln Asn Glu Val His Lys Gln Gly Pro
260 265 270
Ser Lys Asp Ser Lys Ala Lys Glu Leu Pro Lys Thr
275 280
<210>5
<211>268
<212>PRT
<213>人工序列
<220>
<223>SEQ ID NO:1的羧基His-标记的构建体
<400>5
Met Gly Thr Gln Val Ser Gln Ala Thr Ser Gln Pro Ile Asn Phe Gln
1 5 10 15
Val Gln Lys Asp Gly Ser Ser Glu Lys Ser His Met Asp Asp Tyr Met
20 25 30
Gln His Pro Gly Lys Val Ile Lys Gln Asn Asn Lys Tyr Tyr Phe Gln
35 40 45
Thr Val Leu Asn Asn Ala Ser Phe Trp Lys Glu Tyr Lys Phe Tyr Asn
50 55 60
Ala Asn Asn Gln Glu Leu Ala Thr Thr Val Val Asn Asp Asn Lys Lys
65 70 75 80
Ala Asp Thr Arg Thr Ile Asn Val Ala Val Glu Pro Gly Tyr Lys Ser
85 90 95
Leu Thr Thr Lys Val His Ile Val Val Pro Gln Ile Asn Tyr Asn His
100 105 110
Arg Tyr Thr Thr His Leu Glu Phe Glu Lys Ala Ile Pro Thr Leu Ala
115 120 125
Asp Ala Ala Lys Pro Asn Asn Val Lys Pro Val Gln Pro Lys Pro Ala
130 135 140
Gln Pro Lys Thr Pro Thr Glu Gln Thr Lys Pro Val Gln Pro Lys Val
145 150 155 160
Glu Lys Val Lys Pro Thr Val Thr Thr Thr Ser Lys Val Glu Asp Asn
165 170 175
His Ser Thr Lys Val Val Ser Thr Asp Thr Thr Lys Asp Gln Thr Lys
180 185 190
Thr Gln Thr Ala His Thr Val Lys Thr Ala Gln Thr Ala Gln Glu Gln
195 200 205
Asn Lys Val Gln Thr Pro Val Lys Asp Val Ala Thr Ala Lys Ser Glu
210 215 220
Ser Asn Asn Gln Ala Val Ser Asp Asn Lys Ser Gln Gln Thr Asn Lys
225 230 235 240
Val Thr Lys His Asn Glu Thr Pro Lys Gln Ala Ser Lys Ala Lys Glu
245 250 255
Leu Pro Lys Thr Leu Glu His His His His His His
260 265
<210>6
<211>395
<212>PRT
<213>人工序列
<220>
<223>SEQ ID NO:7的氨基His-标记的构建体
<400>6
Met His His His His His His Ser Ser Gly Leu Val Pro Arg Gly Ser
1 5 10 15
Gly Met Lys Glu Thr Ala Ala Ala Lys Phe Glu Arg Gln His Met Asp
20 25 30
Ser Pro Asp Leu Gly Thr Asp Asp Asp Asp Lys Ala Met Gly Thr Lys
35 40 45
His Tyr Leu Asn Ser Lys Tyr Gln Ser Glu Gln Arg Ser Ser Ala Met
50 55 60
Lys Lys Ile Thr Met Gly Thr Ala Ser Ile Ile Leu Gly Ser Leu Val
65 70 75 80
Tyr Ile Gly Ala Asp Ser Gln Gln Val Asn Ala Ala Thr Glu Ala Thr
85 90 95
Asn Ala Thr Asn Asn Gln Ser Thr Gln Val Ser Gln Ala Thr Ser Gln
100 105 110
Pro Ile Asn Phe Gln Val Gln Lys Asp Gly Ser Ser Glu Lys Ser His
115 120 125
Met Asp Asp Tyr Met Gln His Pro Gly Lys Val Ile Lys Gln Asn Asn
130 135 140
Lys Tyr Tyr Phe Gln Thr Val Leu Asn Asn Ala Ser Phe Trp Lys Glu
145 150 155 160
Tyr Lys Phe Tyr Asn Ala Asn Asn Gln Glu Leu Ala Thr Thr Val Val
165 170 175
Asn Asp Asn Lys Lys Ala Asp Thr Arg Thr Ile Asn Val Ala Val Glu
180 185 190
Pro Gly Tyr Lys Ser Leu Thr Thr Lys Val His Ile Val Val Pro Gln
195 200 205
Ile Asn Tyr Asn His Arg Tyr Thr Thr His Leu Glu Phe Glu Lys Ala
210 215 220
Ile Pro Thr Leu Ala Asp Ala Ala Lys Pro Asn Asn Val Lys Pro Val
225 230 235 240
Gln Pro Lys Pro Ala Gln Pro Lys Thr Pro Thr Glu Gln Thr Lys Pro
245 250 255
Val Gln Pro Lys Val Glu Lys Val Lys Pro Thr Val Thr Thr Thr Ser
260 265 270
Lys Val Glu Asp Asn His Ser Thr Lys Val Val Ser Thr Asp Thr Thr
275 280 285
Lys Asp Gln Thr Lys Thr Gln Thr Ala His Thr Val Lys Thr Ala Gln
290 295 300
Thr Ala Gln Glu Gln Asn Lys Val Gln Thr Pro Val Lys Asp Val Ala
305 310 315 320
Thr Ala Lys Ser Glu Ser Asn Asn Gln Ala Val Ser Asp Asn Lys Ser
325 330 335
Gln Gln Thr Asn Lys Val Thr Lys His Asn Glu Thr Pro Lys Gln Ala
340 345 350
Ser Lys Ala Lys Glu Leu Pro Lys Thr Gly Leu Thr Ser Val Asp Asn
355 360 365
Phe Ile Ser Thr Val Ala Phe Ala Thr Leu Ala Leu Leu Gly Ser Leu
370 375 380
Ser Leu Leu Leu Phe Lys Arg Lys Glu Ser Lys
385 390 395
<210>7
<211>350
<212>PRT
<213>金黄色葡萄球菌(S.aureus)
<400>7
Met Thr Lys His Tyr Leu Asn Ser Lys Tyr Gln Ser Glu Gln Arg Ser
1 5 10 15
Ser Ala Met Lys Lys Ile Thr Met Gly Thr Ala Ser Ile Ile Leu Gly
20 25 30
Ser Leu Val Tyr Ile Gly Ala Asp Ser Gln Gln Val Asn Ala Ala Thr
35 40 45
Glu Ala Thr Asn Ala Thr Asn Asn Gln Ser Thr Gln Val Ser Gln Ala
50 55 60
Thr Ser Gln Pro Ile Asn Phe Gln Val Gln Lys Asp Gly Ser Ser Glu
65 70 75 80
Lys Ser His Met Asp Asp Tyr Met Gln His Pro Gly Lys Val Ile Lys
85 90 95
Gln Asn Asn Lys Tyr Tyr Phe Gln Thr Val Leu Asn Asn Ala Ser Phe
100 105 110
Trp Lys Glu Tyr Lys Phe Tyr Asn Ala Asn Asn Gln Glu Leu Ala Thr
115 120 125
Thr Val Val Asn Asp Asn Lys Lys Ala Asp Thr Arg Thr Ile Asn Val
130 135 140
Ala Val Glu Pro Gly Tyr Lys Ser Leu Thr Thr Lys Val His Ile Val
145 150 155 160
Val Pro Gln Ile Asn Tyr Asn His Arg Tyr Thr Thr His Leu Glu Phe
165 170 175
Glu Lys Ala Ile Pro Thr Leu Ala Asp Ala Ala Lys Pro Asn Asn Val
180 185 190
Lys Pro Val Gln Pro Lys Pro Ala Gln Pro Lys Thr Pro Thr Glu Gln
195 200 205
Thr Lys Pro Val Gln Pro Lys Val Glu Lys Val Lys Pro Thr Val Thr
210 215 220
Thr Thr Ser Lys Val Glu Asp Asn His Ser Thr Lys Val Val Ser Thr
225 230 235 240
Asp Thr Thr Lys Asp Gln Thr Lys Thr Gln Thr Ala His Thr Val Lys
245 250 255
Thr Ala Gln Thr Ala Gln Glu Gln Asn Lys Val Gln Thr Pro Val Lys
260 265 270
Asp Val Ala Thr Ala Lys Ser Glu Ser Asn Asn Gln Ala Val Ser Asp
275 280 285
Asn Lys Ser Gln Gln Thr Asn Lys Val Thr Lys His Asn Glu Thr Pro
290 295 300
Lys Gln Ala Ser Lys Ala Lys Glu Leu Pro Lys Thr Gly Leu Thr Ser
305 310 315 320
Val Asp Asn Phe Ile Ser Thr Val Ala Phe Ala Thr Leu Ala Leu Leu
325 330 335
Gly Ser Leu Ser Leu Leu Leu Phe Lys Arg Lys Glu Ser Lys
340 345 350
<210>8
<211>354
<212>PRT
<213>金黄色葡萄球菌(S.aureus)
<400>8
Met Thr Lys His Tyr Leu Asn Ser Lys Tyr Gln Ser Glu Gln Arg Ser
1 5 10 15
Ser Ala Met Lys Lys Ile Thr Met Gly Thr Ala Ser Ile Ile Leu Gly
20 25 30
Ser Leu Val Tyr Ile Gly Ala Asp Ser Gln Gln Val Asn Ala Ala Thr
35 40 45
Glu Ala Thr Asn Ala Thr Asn Asn Gln Ser Thr Gln Val Ser Gln Ala
50 55 60
Thr Ser Gln Pro Ile Asn Phe Gln Val Gln Lys Asp Gly Ser Ser Glu
65 70 75 80
Lys Ser His Met Asp Asp Tyr Met Gln His Pro Gly Lys Val Ile Lys
85 90 95
Gln Asn Asn Lys Tyr Tyr Phe Gln Ala Val Leu Asn Asn Ala Ser Phe
100 105 110
Trp Lys Glu Tyr Lys Phe Tyr Asn Ala Asn Asn Gln Glu Leu Ala Thr
115 120 125
Thr Val Val Asn Asp Asp Lys Lys Ala Asp Thr Arg Thr Ile Asn Val
130 135 140
Ala Val Glu Pro Gly Tyr Lys Ser Leu Thr Thr Lys Val His Ile Val
145 150 155 160
Val Pro Gln Ile Asn Tyr Asn His Arg Tyr Thr Thr His Leu Glu Phe
165 170 175
Glu Lys Ala Ile Pro Thr Leu Ala Asp Ala Ala Lys Pro Asn Asn Val
180 185 190
Lys Pro Val Gln Pro Lys Pro Ala Gln Pro Lys Thr Pro Thr Glu Gln
195 200 205
Thr Lys Pro Val Gln Pro Lys Val Glu Lys Val Lys Pro Ala Val Thr
210 215 220
Ala Pro Ser Lys Asn Glu Asn Arg Gln Thr Thr Lys Val Val Ser Ser
225 230 235 240
Glu Ala Thr Lys Asp Gln Ser Gln Thr Gln Ser Ala Arg Thr Val Lys
245 250 255
Thr Thr Gln Thr Ala Gln Asp Gln Asn Lys Val Gln Thr Pro Val Lys
260 265 270
Asp Val Ala Thr Ala Lys Ser Glu Ser Asn Asn Gln Ala Val Ser Asp
275 280 285
Asn Lys Ser Gln Gln Thr Asn Lys Val Thr Lys Gln Asn Glu Val His
290 295 300
Lys Gln Gly Pro Ser Lys Asp Ser Lys Ala Lys Glu Leu Pro Lys Thr
305 310 315 320
Gly Leu Thr Ser Val Asp Asn Phe Ile Ser Thr Val Ala Phe Ala Thr
325 330 335
Leu Ala Leu Leu Gly Ser Leu Ser Leu Leu Leu Phe Lys Arg Lys Glu
340 345 350
Ser Lys
<210>9
<211>358
<212>PRT
<213>人工序列
<220>
<223>SEQ ID NO:7的羧基His-标记的构建体
<400>9
Met Thr Lys His Tyr Leu Asn Ser Lys Tyr Gln Ser Glu Gln Arg Ser
1 5 10 15
Ser Ala Met Lys Lys Ile Thr Met Gly Thr Ala Ser Ile Ile Leu Gly
20 25 30
Ser Leu Val Tyr Ile Gly Ala Asp Ser Gln Gln Val Asn Ala Ala Thr
35 40 45
Glu Ala Thr Asn Ala Thr Asn Asn Gln Ser Thr Gln Val Ser Gln Ala
50 55 60
Thr Ser Gln Pro Ile Asn Phe Gln Val Gln Lys Asp Gly Ser Ser Glu
65 70 75 80
Lys Ser His Met Asp Asp Tyr Met Gln His Pro Gly Lys Val Ile Lys
85 90 95
Gln Ash Asn Lys Tyr Tyr Phe Gln Thr Val Leu Asn Asn Ala Ser Phe
100 105 110
Trp Lys Glu Tyr Lys Phe Tyr Asn Ala Asn Asn Gln Glu Leu Ala Thr
115 120 125
Thr Val Val Asn Asp Asn Lys Lys Ala Asp Thr Arg Thr Ile Asn Val
130 135 140
Ala Val Glu Pro Gly Tyr Lys Ser Leu Thr Thr Lys Val His Ile Val
145 150 155 160
Val Pro Gln Ile Asn Tyr Asn His Arg Tyr Thr Thr His Leu Glu Phe
165 170 175
Glu Lys Ala Ile Pro Thr Leu Ala Asp Ala Ala Lys Pro Asn Asn Val
180 185 190
Lys Pro Val Gln Pro Lys Pro Ala Gln Pro Lys Thr Pro Thr Glu Gln
195 200 205
Thr Lys Pro Val Gln Pro Lys Val Glu Lys Val Lys Pro Thr Val Thr
210 215 220
Thr Thr Ser Lys Val Glu Asp Asn His Ser Thr Lys Val Val Ser Thr
225 230 235 240
Asp Thr Thr Lys Asp Gln Thr Lys Thr Gln Thr Ala His Thr Val Lys
245 250 255
Thr Ala Gln Thr Ala Gln Glu Gln Asn Lys Val Gln Thr Pro Val Lys
260 265 270
Asp Val Ala Thr Ala Lys Ser Glu Ser Asn Asn Gln Ala Val Ser Asp
275 280 285
Asn Lys Ser Gln Gln Thr Asn Lys Val Thr Lys His Asn Glu Thr Pro
290 295 300
Lys Gln Ala Ser Lys Ala Lys Glu Leu Pro Lys Thr Gly Leu Thr Ser
305 310 315 320
Val Asp Asn Phe Ile Ser Thr Val Ala Phe Ala Thr Leu Ala Leu Leu
325 330 335
Gly Ser Leu Ser Leu Leu Leu Phe Lys Arg Lys Glu Ser Lys Leu Glu
340 345 350
His His His His His His
355
<210>10
<211>843
<212>DNA
<213>人工序列
<220>
<223>编码SEQ ID NO:3的核酸序列
<400>10
atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60
atgggcacac aagtttctca agcaacatca caaccaatta atttccaagt gcaaaaagat 120
ggctcttcag agaagtcaca catggatgac tatatgcaac accctggtaa agtaattaaa 180
caaaataata aatattattt ccaaaccgtg ttaaacaatg catcattctg gaaagaatac 240
aaattttaca atgcaaacaa tcaagaatta gcaacaactg ttgttaacga taataaaaaa 300
gcggatacta gaacaatcaa tgttgcagtt gaacctggat ataagagctt aactactaaa 360
gtacatattg tcgtgccaca aattaattac aatcatagat atactacgca tttggaattt 420
gaaaaagcaa ttcctacatt agctgacgca gcaaaaccaa acaatgttaa accggttcaa 480
ccaaaaccag ctcaacctaa aacacctact gagcaaacta aaccagttca acctaaagtt 540
gaaaaagtta aacctactgt aactacaaca agcaaagttg aagacaatca ctctactaaa 600
gttgtaagta ctgacacaac aaaagatcaa actaaaacac aaactgctca tacagttaaa 660
acagcacaaa ctgctcaaga acaaaataaa gttcaaacac ctgttaaaga tgttgcaaca 720
gcgaaatctg aaagcaacaa tcaagctgta agtgataata aatcacaaca aactaacaaa 780
gttacaaaac ataacgaaac gcctaaacaa gcatctaaag ctaaagaatt accaaaaact 840
tga 843
<210>11
<211>855
<212>DNA
<213>人工序列
<220>
<223>编码SEQ ID NO:4的核酸序列
<400>11
atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60
atgggcacac aagtttctca agcaacatca caaccaatta atttccaagt gcaaaaagat 120
ggctcttcag agaagtcaca catggatgac tatatgcaac accctggtaa agtgattaaa 180
caaaataata aatattattt ccaagctgta ttgaacaacg catcattctg gaaagaatac 240
aaattttaca atgcaaacaa tcaagaatta gcaacaactg ttgttaacga tgataaaaaa 300
gctgacacta gaacaatcaa tgttgctgtt gaacctgggt ataagagttt aactacaaaa 360
gtacatattg tcgtgccaca aattaattat aatcatagat atactacgca tttagaattt 420
gaaaaagcaa ttcctacatt agctgacgca gcaaaaccaa acaatgttaa accggttcaa 480
ccaaaacctg ctcaacctaa aacacctact gagcaaacga aaccagttca acctaaagtt 540
gaaaaagtta aacctgctgt aactgcacca agcaaaaatg aaaacagaca aactacaaaa 600
gttgtaagta gtgaagctac aaaagatcaa agtcaaacac aaagtgctcg tacagtgaaa 660
acaacacaaa cagctcaaga tcaaaataaa gttcaaacac ctgttaaaga tgttgcaaca 720
gcgaaatctg aaagcaacaa tcaagctgta agtgacaata aatcacaaca aactaacaaa 780
gttacaaaac aaaacgaagt tcataaacaa ggaccttcaa aagattctaa agctaaagaa 840
ttaccaaaaa cttga 855
<210>12
<211>37
<212>DNA
<213>人工序列
<220>
<223>引物
<400>12
gagatatacc atgggcacaa aacattattt aaacagt 37
<210>13
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物
<400>13
ccggcggccc tcgagtttag attcttttct tttgaa 36
<210>14
<211>37
<212>DNA
<213>人工序列
<220>
<223>引物
<400>14
gagatatacc atgggcacaa aacattattt aaacagt 37
<210>15
<211>39
<212>DNA
<213>人工序列
<220>
<223>引物
<400>15
ccggcggccc tcgagttatt tagattcttt tcttttgaa 39
<210>16
<211>41
<212>DNA
<213>人工序列
<220>
<223>引物
<400>16
gagatatacc atgggcacac aagtttctca agcaacatca c 41
<210>17
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物
<400>17
ggtggtgctc gagagttttt ggtaattctt tagctt 36
<210>18
<211>41
<212>DNA
<213>人工序列
<220>
<223>引物
<400>18
gagatatcat atgggcacac aagtttctca agcaacatca c 41
<210>19
<211>39
<212>DNA
<213>人工序列
<220>
<223>引物
<400>19
ggtggtgctc gagtcaagtt tttggtaatt ctttagctt 39
Claims (15)
1.多肽免疫原,其包含与SEQ ID NO:1至少85%相同的氨基酸序列,其中所述多肽能提供针对金黄色葡萄球菌的保护性免疫,且其中如果存在一个或多个其它的多肽区域,则所述其它的区域不能提供含有SEQ ID NO:7的氨基酸261-294的羧基末端。
2.权利要求1的多肽,其中所述多肽由与SEQ ID NO:1或SEQID NO:2至少94%相同的氨基酸序列组成。
3.权利要求1的多肽,其中所述多肽基本上由SEQ ID NO:1的氨基酸3-260或SEQ ID NO:2的3-264组成。
4.权利要求3的多肽,其中所述多肽由SEQ ID NO:1的氨基酸序列组成。
5.包含权利要求1的多肽的免疫原,其中所述免疫原由所述多肽和一个或多个在羧基末端或氨基末端共价连接到所述多肽上的其它的区域部分组成,其中每个区域或部分独立地选自具有至少一种下述性质的区域或部分:增强免疫反应、促进纯化或促进多肽稳定性。
6.能在患者中诱导保护性免疫反应的组合物,其包含免疫有效量的权利要求1-5中的任一项的免疫原和药学上可接受的载体。
7.权利要求6的组合物,其中所述组合物还包含佐剂。
8.核酸,其包含重组基因,后者包含能编码权利要求1-4中的任一项的多肽的核苷酸序列。
9.权利要求8的核酸,其中所述核酸是表达载体。
10.重组细胞,其包含重组基因,后者包含能编码权利要求1-4中的任一项的多肽的核苷酸序列。
11.制备能提供保护性免疫的金黄色葡萄球菌多肽的方法,其包含下述步骤:
(a)在能表达多肽的条件下,使权利要求10的重组细胞生长;和
(b)纯化所述多肽。
12.在患者中诱导保护性免疫反应的方法,其包含下述步骤:向所述患者施用免疫有效量的多肽免疫原,后者包含与SEQ ID NO:1至少85%相同的氨基酸。
13.权利要求12的方法,其中所述患者是人。
14.权利要求13的方法,其中针对金黄色葡萄球菌感染预防性地治疗所述患者。
15.权利要求12的方法,其中所述免疫原是权利要求1、2、3、4或5中任一项的免疫原。
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US54544704P | 2004-02-18 | 2004-02-18 | |
US60/545,447 | 2004-02-18 |
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CNA2005800050692A Pending CN1918176A (zh) | 2004-02-18 | 2005-02-14 | 用于诱导针对金黄色葡萄球菌的保护性免疫反应的多肽 |
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US (1) | US20070134263A1 (zh) |
EP (1) | EP1725575B1 (zh) |
JP (1) | JP2007528217A (zh) |
CN (1) | CN1918176A (zh) |
AU (1) | AU2005214061B2 (zh) |
CA (1) | CA2555342A1 (zh) |
WO (1) | WO2005079315A2 (zh) |
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CN102292105A (zh) * | 2008-11-26 | 2011-12-21 | 默沙东公司 | 用于诱导抗金黄色葡萄球菌的保护性免疫应答的多肽 |
CN102844047A (zh) * | 2009-09-02 | 2012-12-26 | 诺华有限公司 | 含tlr活性调节剂的免疫原性组合物 |
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BR112020016314A2 (pt) | 2018-02-12 | 2020-12-15 | Inimmune Corporation | Compostos ou um sais farmaceuticamente aceitáveis, composição farmacêutica, kit, e, métodos para elicitar, intensificar ou modificar uma resposta imunológica, para tratar, prevenir ou reduzir a suscetibilidade a câncer, para tratar, prevenir ou reduzir a suscetibilidade a uma doença infecciosa, para tratar, prevenir ou reduzir a suscetibilidade a uma alergia, para tratar, prevenir ou reduzir a suscetibilidade a uma afecção autoimune, para tratar, prevenir ou reduzir a suscetibilidade em um sujeito à infecção bacteriana, viral, priônica, autoimunidade, câncer ou alergia, para tratar, prevenir ou reduzir a suscetibilidade à autoimunidade, alergia, reperfusão de isquemia ou sepse, para tratar, prevenir ou reduzir a gravidade de ataques epiléticos e para tratar, prevenir ou reduzir a suscetibilidade a doenças oculares como degeneração macular, hipertensão ocular e infecção ocular |
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GB0107661D0 (en) * | 2001-03-27 | 2001-05-16 | Chiron Spa | Staphylococcus aureus |
IL158328A0 (en) * | 2001-04-13 | 2004-05-12 | Wyeth Corp | Surface proteins of streptococcus pyogenes |
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JP4404627B2 (ja) * | 2001-08-02 | 2010-01-27 | ユニヴァーシティー オヴ シェフィールド | 抗原性ポリペプチド |
NZ570750A (en) * | 2003-07-24 | 2009-12-24 | Merck & Co Inc | Polypeptides for inducing a protective immune response against staphylococcus aureus |
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- 2005-02-14 US US10/589,381 patent/US20070134263A1/en not_active Abandoned
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- 2005-02-14 WO PCT/US2005/004431 patent/WO2005079315A2/en active Application Filing
- 2005-02-14 EP EP05713397A patent/EP1725575B1/en active Active
- 2005-02-14 JP JP2006554143A patent/JP2007528217A/ja active Pending
- 2005-02-14 CN CNA2005800050692A patent/CN1918176A/zh active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102292105A (zh) * | 2008-11-26 | 2011-12-21 | 默沙东公司 | 用于诱导抗金黄色葡萄球菌的保护性免疫应答的多肽 |
CN102844047A (zh) * | 2009-09-02 | 2012-12-26 | 诺华有限公司 | 含tlr活性调节剂的免疫原性组合物 |
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WO2005079315A2 (en) | 2005-09-01 |
EP1725575A4 (en) | 2009-04-22 |
JP2007528217A (ja) | 2007-10-11 |
EP1725575B1 (en) | 2012-11-28 |
EP1725575A2 (en) | 2006-11-29 |
US20070134263A1 (en) | 2007-06-14 |
CA2555342A1 (en) | 2005-09-01 |
WO2005079315A3 (en) | 2006-01-19 |
AU2005214061A1 (en) | 2005-09-01 |
AU2005214061B2 (en) | 2010-02-04 |
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