CN1612935A - 编码靶相关抗原表位的表达载体及其设计方法 - Google Patents
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Abstract
此处公开的本发明涉及鉴定适于表位释放的多肽的方法，其包括例如，鉴定目的表位的步骤；提供包括表位的底物多肽序列，其中所述底物多肽允许被蛋白酶体加工；在支持底物多肽被蛋白酶体加工的条件下，将所述底物多肽与包括蛋白酶体的组合物接触；测定表位的释放。本发明还涉及包括管家表位表达盒的载体。管家表位可以衍生自靶相关抗原，并且管家表位可以是可释放的，即通过免疫蛋白酶体加工能够丛盒的翻译产物释放。本发明还涉及激活T细胞的方法，其包含将底物多肽与APC接触和将APC与T细胞接触。
Description
发明背景
发明领域
本发明此处公开的是涉及用于组合物的表位编码载体的设计方法，所述组合物包括，例如能够在施用了该组合物的受试者中诱发免疫应答的药物组合物。本发明还涉及载体自身。使用这些载体表达的表位能够激发针对展示这些表位的靶细胞的细胞免疫应答。
相关领域的描述
免疫系统可以分成两个不同的效应分支。一个是先天性免疫，包括应答所有感染刺激的许多细胞成分和可溶因子。另一个是适应性免疫应答，它专门的特异应答来自感染剂的精确表位。适应性免疫应答还可分成两个效应分支，称为体液和细胞免疫系统。体液分支集中于由B淋巴细胞生成抗体，而细胞分支涉及细胞毒性T淋巴细胞的杀伤细胞活性。
细胞毒性T淋巴细胞(CTL)自身不能识别感染剂上的表位。然而，CTL能够检测受感染细胞表面展示的由感染剂衍生的抗原片段。因此，抗原只有在经过受感染细胞加工并因此展示于细胞表面之后才能得到CTL的识别。
细胞表面上的抗原加工和展示系统已经得到了建立。CTL识别通过与I类主要组织相容性复合物分子(MHC)的非共价关联而展示在表面上的短肽抗原。这些I类肽是由胞质蛋白的降解依次衍生的。
发明概述
本发明的实施方案提供了例如用于免疫载体的表达盒以及用于设计和测试这些表达盒的方法，所述表达盒编码一种或多种嵌入的管家表位。可以通过消化性抗原呈递细胞(pAPC)的免疫蛋白酶体的蛋白酶解加工这些盒的翻译产物释放管家表位。在本发明的一个实施方案中，可以改变管家表位的侧翼序列以促进免疫蛋白酶体在预定部位的切割。于2000年4月28日提交的题目分别为EPITOPE SYNCHRONIZATION IN ANTIGENPRESENTING CELLS和METHOD OF EPITOPE DISCOVERY的美国专利申请编号09/560,465和09/561,074描述了管家表位及其用途和鉴定。
于2001年4月6日提交的题为EPITOPE SEQUENCE，编号60/282,211；于2001年11月7日提交的编号60/337,017；于3/7/02提交的编号60/363,210和于2002年9月5日提交的编号60/409,123的临时美国专利申请；和于2002年4月4日提交的题目同样为EPITOPE SEQUENCE的美国申请编号10/117,937公开了管家表位的实例。
在本发明的其它实施方案中，管家表位的侧翼可以是已知有助于免疫蛋白酶体切割位点的任意序列或序列掺入残基。在用于本文时，术语“任意序列”指不涉及表位的天然序列环境(context)，促进加工的能力，或免疫学功能而选择的序列。在本发明的其它实施方案中，可以以头尾相连的方式排列多个表位。这些排列可以完全由管家表位组成。同样，这些排列可以包括交替的管家和免疫表位。或者，这些排列可以包括侧翼为完整或末端截短的免疫表位的管家表位。另外，这些排列可以是任何其它类似排列。对于将管家表位置于排列的末端位置没有任何限制。载体还可以包含真实蛋白质编码序列或其片段，它们包含表位簇作为免疫表位源。术语“真实”指天然蛋白质序列。
于2000年4月28日提交的题为EPITOPE CLUSTERS的美国专利申请号09/561,571，于2001年11月7日提交的题为EPITOPESYNCHRONIZATION IN ANTIGEN PRESENTING CELLS的美国专利申请号10/005,905，和于2001年12月7日提交的标题同样为EPITOPESYNCHRONIZATION IN ANTIGEN PRESENTING CELLS的美国专利申请号10/026,066描述了表位簇及其用途。
本发明的实施方案可以包括筛选构建体以测定是否释放了管家表位。在包含多个管家表位的构建体中，实施方案可以包括筛选以测定释放了哪个表位。在一个优选的实施方案中，包含嵌入表位的载体可以用于免疫HLA转基因小鼠，而且可以对由此产生的CTL测试它们识别呈递成熟表位的靶细胞的能力。在另一个实施方案中，可以用载体转化表达免疫蛋白酶体的靶细胞。例如，可以通过干扰素(IFN)处理或基因操作而使靶细胞组成性表达免疫蛋白酶体。可以对识别成熟表位的CTL测试它们识别这些靶细胞的能力。在还有一个实施方案中，可以作为合成肽来制备嵌入的表位。然后可以在体外用免疫蛋白酶体制剂对合成肽进行消化，并分析由此产生的片段以测定切割位点。还可以将能够成功释放嵌入表位的这些重组或合成多肽掺入免疫原性组合物。
本文公开的发明涉及适用于表位释放的多肽的鉴定。本发明的一个实施方案涉及适用于表位释放的多肽鉴定方法，包括例如下列步骤：鉴定目的表位；提供包含表位的底物多肽序列，其中底物多肽容许蛋白酶体的加工；在支持蛋白酶体加工底物多肽的条件下将底物多肽接触包含蛋白酶体的组合物；和测定表位释放。
可以将表位嵌入底物多肽，而且在有些方面底物多肽可以包含例如超过一个表位。还有，表位可以是管家表位。
一方面，底物多肽可以是合成肽。任选的是，可以在促进蛋白质转移的制剂中包含底物多肽。或者，底物多肽可以是融合蛋白。融合蛋白还可以包含具有蛋白质转移活性的蛋白质结构域。另外，接触步骤可以包括使用底物多肽进行免疫。
另一方面，可以由多核苷酸编码底物多肽。例如，接触步骤可以包括使用包含多核苷酸的载体进行免疫。例如，可以对HLA转基因小鼠或任何其它合适动物进行免疫。或者，接触步骤可以包括用包含多核苷酸的载体转化细胞。在有些实施方案中，转化细胞可以是为了测定正确表位释放而由CTL靶向的靶细胞。
蛋白酶体加工可以发生于细胞内，或体外或体内。另外，蛋白酶体加工可以发生于非细胞体系。
测定步骤可以包括选自但不限于下组的技术：质谱，N端混合测序，HPLC，等等。同样，测定步骤可以包括T细胞靶识别测定。T细胞靶识别测定可以选自但不限于下组：溶细胞活性测定，铬释放测定，细胞因子测定，ELISPOT测定，四聚物分析，等等。
还有一个方面，包含表位的底物多肽的氨基酸序列可以是任意的。同样，嵌入了表位的底物多肽可以衍生自靶相关抗原的真实序列。另外，可以使嵌入了表位的底物多肽符合优选的免疫蛋白酶体切割位点侧翼序列。
另一方面，底物多肽可以包含额外表位的排列。排列成员可以以例如头尾相连的方式排列。排列可以包含超过一个管家表位。超过一个管家表位可以包括相同表位的拷贝。例如，排列可以包含一个管家表位和一个免疫表位，或者交替的管家和免疫表位。同样，在一个表位组中排列可以包括位于两个免疫表位之间的一个管家表位。排列可以包括多表位组，使得排列内部每个管家表位之间有两个免疫表位。任选的是，至少一个表位可以在与相邻表位接合的末端截短。例如，截短的表位可以是免疫表位。截短的表位可以具有选自但不限于下组的长度：9，8，7，6，5，4个氨基酸等。
还有一个方面，底物多肽可以包含表位排列和表位簇。排列成员可以以例如头尾相连的方式排列。
还有一个方面，蛋白酶体可以是免疫蛋白酶体。
公开的本发明的另一个实施方案涉及包含管家表位表达盒的载体。管家表位可以衍生自靶相关抗原，而且管家表位是通过免疫蛋白酶体加工可以由盒的翻译产物可释放的，即能够释放的。
在本发明的一个方面中，表达盒可以编码两个或多个表位的排列，或者至少一个表位和至少一个表位簇。排列成员可以以例如头尾相连的方式排列。还有，例如，排列成员可以以由间隔序列相隔的头尾相连的方式排列。另外，排列可以包含多个管家表位。例如，多个管家表位可以包括超过一个拷贝的相同表位或单个拷贝的不同表位。排列可以包含至少一个管家表位和至少一个免疫表位。还有，排列可以包括交替的管家和免疫表位。另外，排列包括夹在两个免疫表位中间的管家表位，使得排列内部的每个管家表位之间有两个免疫表位。免疫表位可以在与相邻管家表位接合的末端截短。
另一方面，表达盒还编码包含至少一个免疫表位的真实蛋白质序列或其片段。任选的是，片段可以包含至少一个表位簇。例如，包含至少一个免疫表位的管家表位表达盒和真实序列可以在单一读码框中编码或者转录成单一mRNA种类。同样，包含至少一个免疫表位的管家表位表达盒和真实序列可能不转录成单一mRNA种类。
在另一个方面，载体可以包括DNA分子或RNA分子。载体可以编码例如SEQ ID NO.4，SEQ ID NO.17，SEQ ID NO.20，SEQ ID NO.26，SEQ ID NO.27，SEQ ID NO.29，SEQ ID NO.33，等等。同样，载体可以包含SEQ ID NO.9，SEQ ID NO.19，SEQ ID NO.21，SEQ ID NO.30，SEQ ID NO.34，等等。同样，载体可以编码例如SEQ ID NO.5或SEQ IDNO.18。
在另一个方面，靶相关抗原可以是由肿瘤或胞内寄生物衍生或与其相关的抗原，而胞内寄生物可以是例如病毒，细菌，原生动物等。
本发明的另一个实施方案涉及包含依照本文公开的任何方法鉴定，要求或其它方面的管家表位的载体。例如，实施方案可以涉及编码底物多肽的载体，所述底物多肽包含通过本文描述的任何方法得到的管家表位。
一方面，可以通过免疫蛋白酶体加工由表达盒的翻译产物释放管家表位。
公开的本发明的另一个实施方案涉及激活T细胞的方法。所述方法包括例如将包含管家表位表达盒的载体接触APC的步骤。管家表位可以衍生自例如靶相关抗原，而且管家表位可以通过免疫蛋白酶体加工由盒的翻译产物释放。所述方法还可以包括将APC接触T细胞。载体与APC的接触可以发生于体外或体内。
公开的本发明的另一个实施方案涉及包含管家表位的底物多肽，其中管家表位可以在pAPC中通过免疫蛋白酶体加工而释放。
公开的本发明的另一个实施方案涉及激活T细胞的方法，包括将包含管家表位的底物多肽接触APC，其中管家表位可以通过免疫蛋白酶体加工而释放，和将APC接触T细胞。
附图简述
图1.描述pMA2M的图解。
图2.显示通过模拟免疫的CTL对经过或未经ELAGIGILTV脉冲的T2靶细胞的特异溶解百分比的测定结果。
图3.显示通过pVAXM3免疫的CTL对经过或未经ELAGIGILTV脉冲的T2靶细胞的特异溶解百分比的测定结果。
图4.显示通过pVAXM2免疫的CTL对经过或未经ELAGIGILTV脉冲的T2靶细胞的特异溶解百分比的测定结果。
图5.显示通过pVAXM1免疫的CTL对经过或未经ELAGIGILTV脉冲的T2靶细胞的特异溶解百分比的测定结果。
图6.例示了通过免疫蛋白酶体加工而释放NY-ESO-I157-165表位的SEQ ID NO.22的序列。
图7.显示了免疫蛋白酶体和管家蛋白酶体对SLLMWITQC表位(SEQ ID NO.12)在其天然环境中的不同加工，其中由管家蛋白酶体产生的C后面的切割比免疫蛋白酶体更有效。
图8.8A：显示了SEQ ID NO.31的人免疫蛋白酶体消化结果。8B：显示了SEQ ID NO.31的小鼠与人免疫蛋白酶体消化的比较结果。
图9.显示了管家和免疫蛋白酶体对SSX-231-68的不同加工。
优选实施方案的详述
定义
除非另外不同于本文使用术语的内容，下列术语在用于本文描述时一般具有指定的含义。
消化性抗原呈递细胞(pAPC)-具有T细胞共刺激分子且能够诱发T细胞应答的细胞。充分表征的pAPC包括树突细胞，B细胞，和巨噬细胞。
外周细胞-pAPC以外的细胞。
管家蛋白酶体-在外周细胞中通常有活性，而在pAPC中通常不存在或活性不强的蛋白酶体。
免疫蛋白酶体-在pAPC中通常有活性的蛋白酶体；免疫蛋白酶体在受感染组织中或在暴露于干扰素后在有些外周细胞中也有活性。
表位-能够激发免疫应答的分子或物质。在优选的实施方案中，依照此定义的表位包括但不必限于多肽和编码多肽的核酸，其中多肽能够激发免疫应答。在其它优选的实施方案中，依照此定义的表位包括但不必限于展示在细胞表面的肽，所述肽非共价结合I类MHC结合缝从而能够与T细胞受体(TCR)相互作用。由I类MHC展示的表位可以是未成熟或成熟形式。“成熟”指与可能包含或基本由管家表位组成，而且在初级翻译产物中还包含通过加工消除的其它序列的任何前体(未成熟)不同的MHC表位，所述加工包括但不限于下列单项或任意组合：蛋白酶体消化，N端修剪，或外源酶活性的作用。因此，可以分别通过嵌入稍长多肽来提供成熟表位，所述多肽的免疫学潜力至少部分归咎于嵌入的表位；或者处于能够在MHC结合缝中结合从而得到TCR识别的最终形式。
MHC表位-对哺乳动物I类或II类主要组织相容性复合物(MHC)分子具有已知或预测结合亲和力的多肽。
管家表位-在一个优选的实施方案中，管家表位定义为作为MHC表位且展示在细胞上的多肽片段，在所述细胞中管家蛋白酶体有显著活性。在另一个优选的实施方案中，管家表位定义为包含依照上述定义的管家表位且侧翼为一个至几个额外氨基酸的多肽。在另一个优选的实施方案中，管家表位定义为编码依照上述定义的管家表位的核酸。于2002年4月4日提交的美国申请号10/117,937；以及于2001年4月6日提交的美国临时申请号60/282,211；于2001年11月7日提交的60/337,017；于3/7/02提交的60/363,210；和于2002年9月5日提交的60/409,123，均题为EPITOPESEQUENCES中提供了例示性管家表位。
免疫表位-在一个优选的实施方案中，免疫表位定义为作为MHC表位且展示在细胞上的多肽片段，在所述细胞中免疫蛋白酶体有显著活性。在另一个优选的实施方案中，免疫表位定义为包含依照上述定义的免疫表位且侧翼为一个至几个额外氨基酸的多肽。在另一个优选的实施方案中，免疫表位定义为包含表位簇序列的多肽，所述序列具有的至少两个多肽序列对I类MHC具有已知或预测的亲和力。在还有一个优选的实施方案中，免疫表位定义为编码依照任何上述定义的免疫表位的核酸。
靶细胞-由本发明的疫苗和方法靶向的细胞。依照此定义的靶细胞的实例包括但不必限于：肿瘤细胞和具有胞内寄生物诸如例如病毒，细菌，或原生动物的细胞。靶细胞还可以包括作为测定的一部分以测定或确认正确表位释放的由CTL靶向并由表达免疫蛋白酶体的细胞加工以对预期表位测定T细胞特异性或免疫原性的细胞。可以转化这些细胞以表达底物或释放序列，或者可以仅仅用肽/表位对细胞进行脉冲。
靶相关抗原(TAA)-靶细胞中存在的蛋白质或多肽。
肿瘤相关抗原(TuAA)-靶细胞是肿瘤细胞时的TAA。
HLA表位-对人I类或II类HLA复合物分子具有已知或预测结合亲和力的多肽。
抗体-天然免疫球蛋白(Ig)，多克隆或单克隆，或者完全或部分由Ig结合结构域构成的任何分子，无论是通过生化方法或是使用重组DNA衍生的。实例包括尤其是F(ab)，单链Fv，和Ig可变区-噬菌体外壳蛋白融合体等。
编码-一个不受限制的术语，使得编码独特氨基酸序列的核酸可以是由指定该(多)肽的密码子组成的，但也可以包含额外序列，或是可翻译的，或是用于控制转录，翻译，或复制，或是促进某些宿主核酸构建体的操作。
实质相似性-此术语用于指通过检查序列而判断得出在无关紧要的方面与参考序列不同的序列。编码相同氨基酸序列的核酸序列是实质相似的，尽管简并位置有差异，或者任何非编码区的长度或组成有适度差异。只是因保守替代或较少长度变化而不同的氨基酸序列是实质相似的。另外，包含N端侧翼残基数目不同的管家表位，或者两端侧翼残基数目不同的免疫表位或表位簇的氨基酸序列是实质相似的。编码实质相似的氨基酸序列的核酸自身也是实质相似的。
功能相似性-该术语用于指通过检查生物学或生化特性而判断得出在无关紧要的方面与参考序列不同的序列，尽管序列可能不是实质相似的。例如，两种核酸都可用作相同序列的杂交探针，但是编码不同的氨基酸序列。诱发交叉反应的CTL应答的两种肽是功能相似的，即使它们因非保守氨基酸替代而不同(并因而未满足实质相似性定义)。识别相同表位的成对抗体或TCR可以彼此是功能相似的，即使存在任何结构差异。在测试免疫原性的功能相似性时，通常用“改变后的”抗原进行免疫并测试由此引起的应答(Ab，CTL，细胞因子生成，等)识别靶抗原的能力。因此，可以设计在某些方面不同但保留相同功能的两种序列。这些设计序列变体就是本发明实施方案之一。
表达盒-编码多肽，可操作连接启动子和其它转录和翻译控制元件包括但不限于增强子，终止密码子，内部核糖体进入位点，和多腺苷酸化位点的多核苷酸序列。盒还可包含有助于将其由一个宿主分子移至另一个的序列。
嵌入的表位-包含于较长多肽中的表位，还可包括嵌入N端或C端使得表位不位于内部位置的表位。
成熟表位-除了当表位结合MHC肽结合缝时所存在的序列不含额外序列的肽。
表位簇-作为包含两个或多个已知或预测表位的天然蛋白质序列的片段的多肽或编码它的核酸序列，所述已知或预测表位对共享的MHC限制元件具有结合亲和力，其中簇内的表位密度超过完整蛋白质序列内所有对共享的MHC限制元件具有结合亲和力的已知或预测表位的密度，正如题为EPITOPE CLUSTERS的美国专利申请号09/561,571中所公开的。
底物或释放序列-包含或编码在较长序列中嵌入的管家表位(依照上文提供的第一项定义)从而提供环境使得直接通过免疫蛋白酶体加工或联合N端修剪或其它加工而释放管家表位的设计或改造后的序列。
胞质蛋白的降解是通过称为蛋白酶体的依赖遍在蛋白质的多重催化，多亚基蛋白酶系统发生的。蛋白酶体降解胞质蛋白，然后生成的片段可以由胞质转移至内质网(ER)并加载到I类MHC上。这些蛋白质片段将称为I类肽。加载了肽的MHC随后转运至细胞表面并可在此受到CTL的检测。
蛋白酶体的多重催化活性是其多亚基结构的结果。亚基是由不同基因表达的，并在翻译后装配成蛋白酶体复合物。蛋白酶体的重要特点是其双峰活性，使其能够以两种不同的切割模式发挥其蛋白酶或切割功能。蛋白酶体的这种双峰作用对于理解CTL如何靶向识别体内的外周细胞和这种靶向如何要求免疫系统与靶细胞之间的同步是极端重要的。
管家蛋白酶体在身体所有外周细胞和组织中是组成型有活性的。管家蛋白酶体的第一种作用模式是降解细胞蛋白质，将它再循环成氨基酸。因此蛋白酶体功能是细胞生命的必需活性。然而，作为其管家蛋白酶活性的必然结果，由管家蛋白酶体生成的I类肽展示在身体所有外周细胞上。
蛋白酶体的第二种功能模式是高度独特的，而且专一发生于pAPC中，或者作为干扰素(IFN)细胞应答的后果。在其第二种活性模式中，蛋白酶体中掺入了独特亚基，取代组成型管家蛋白酶体的催化亚基。“修饰后的”蛋白酶体已经称为免疫蛋白酶体，因为它在pAPC中表达而且是体细胞中IFN诱导的后果。
APC定义全身循环且作为杀伤细胞有潜在活性的CTL集合。CTL是通过与展示于pAPC表面的I类肽的相互作用而激活的。在患病细胞的研究中，激活后的CTL经诱导而增殖并引起全身循环。这就是体内CTL应答被由pAPC生成的I类肽特异确定的原因。重要的是要记住pAPC表达免疫蛋白酶体，而且作为蛋白酶体双峰活性模式的结果，蛋白质的切割模式(及由此生成的I类肽)与表达管家蛋白酶体的外周体细胞中的那些模式不同。因此，在天然感染过程中和治疗性CTL接种策略时考虑pAPC和外周体细胞中的不同蛋白酶体活性是重要的。
体内所有细胞都能够在受到病原体诸如病毒感染的事件中生成IFN。IFN生成继而导致在受感染细胞中免疫蛋白酶体的表达。从而由受感染细胞的免疫蛋白酶体加工病毒抗原，并将由此生成的肽与I类MHC一起展示在细胞表面。同时，pAPC汇集病毒抗原并用它们的免疫蛋白酶体活性加工I类肽，这对于pAPC细胞类型是常规的。由pAPC生成的I类肽特异激发体内CTL应答。幸运的是，受感染细胞同样由免疫蛋白酶体而非常规的管家蛋白酶体生成I类肽。因此，由此生成病毒相关的I类肽，它能够通过确认CTL应答来检测。CTL免疫应答是由pAPC诱发的，与外周体细胞相比，它通常因不同蛋白酶体活性而生成不同I类肽。因此，在感染过程中，在受感染细胞和免疫系统之间发生表位同步化。
在阻断干扰素系统的肿瘤和慢性病毒中情况并非如此。对于肿瘤，肿瘤细胞中没有感染来诱导免疫蛋白酶体表达，而慢性病毒感染或直接或间接阻断免疫蛋白酶体表达。在这两种情况中，患病细胞仍然展示由管家蛋白酶体活性衍生的I类肽，并避免CTL的有效监督。
在通过治疗性接种来根除肿瘤或慢性感染的情况中，蛋白酶体的双峰功能及其在身体APC和外周细胞中的不同活性是显著的。在接种蛋白质抗原之后，CTL应答发生之前，必须获得抗原并将其加工成随后展示于pAPC表面I类MHC上的肽。激活后的CTL进行再循环，搜索表面具有相似I类肽的细胞。具有这种肽的细胞将通过CTL的溶细胞活性进行摧毁。
如果所针对的患病细胞不表达pAPC中存在的免疫蛋白酶体，那么表位未能同步而CTL不能在患病细胞表面找到预期的肽靶目标。
优选的是，治疗性疫苗设计考虑靶组织上实际存在的I类肽。即用于刺激CTL攻击患病组织的有效抗原是天然加工并展示在患病组织表面的那些抗原。对于肿瘤和慢性感染，这通常意味着CTL表位是已经受到管家蛋白酶体加工的那些表位。为了生成有效的治疗性疫苗，根据这些表位事实上是由管家蛋白酶体系统生成的知识来鉴定CTL表位。一旦得到鉴定，表现为肽的这些表位可用于在宿主体内成功免疫或诱发针对表达管家蛋白酶体的靶细胞的治疗性CTL应答。
然而，在DNA疫苗的情况中，存在另一种考虑。用DNA免疫要求APC摄取DNA并表达所编码的蛋白质或肽。有可能在DNA上编码不同的I类肽。通过用这种构建体免疫，能够引发APC表达管家表位，随后展示在细胞表面I类MHC上以激发适当的CTL应答。于2000年4月28日提交的题为EXPRESSION VECTORS ENCODING EPITOPES OFTARGET-ASSOCIATED ANTIGENS的美国专利申请号09/561,572已经描述了用于生成管家表位正确末端的构建体。
本发明的实施方案提供了编码一个或多个嵌入的管家表位的表达盒以及用于设计和测试该表达盒的方法。表达盒和构建体可以编码表位，包括由靶相关抗原衍生的管家表位。可以由盒的翻译产物释放管家表位。例如，在本发明的有些实施方案中，管家表位的侧翼可以是已知有助于免疫蛋白酶体切割位点的任意序列或序列掺入残基。在本发明的其它实施方案中，可以以头尾相连的方式排列多个表位。在有些实施方案中，这些排列可以完全由管家表位组成。同样，这些排列可以包括交替的管家和免疫表位。或者，排列可以包括侧翼为完整或末端截短的免疫表位的管家表位。在有些优选的实施方案中，每个管家表位的侧翼可以一边是免疫表位，使得这种排列在每个管家表位之间有两个免疫表位。另外，排列可以是任何其它类似的排列。对于将管家表位置于排列的末端位置没有限制。载体还可以包含真实蛋白质编码序列或其片段，它们包含表位簇作为免疫表位源。
多份公开书提及了多表位或珠串排列。参阅例如，2001年3月22日的WO0119408A1；1999年11月4日的WO9955730A2；2000年7月13日的WO0040261A2；1996年2月8日的WO9603144A1；2002年2月27日的EP1181314A1；4月5日的WO0123577A3；2000年6月13日的US6074817；1999年10月12日的US5965381；1997年11月6日的WO9741440A1；2000年10月10日的US6130066；1999年12月21日的US6004777；1999年11月23日的US5990091；1998年9月17日的WO9840501A1；1998年9月17日的WO9840500A1；2001年3月15日的WO0118035A2；2002年9月6日的WO02068654A2；2001年11月29日的WO0189281A2；2001年8月16日的WO0158478A；2001年7月25日的EP1118860A1；2001年2月15日的WO0111040A1；2000年12月7日的WO0073438A1；2000年11月30日的WO0071158A1；2000年11月9日的WO0066727A1；2000年9月8日的WO0052451A1；2000年9月8日的WO0052157A1；2000年5月25日的WO0029008A2；2000年2月10日的WO0006723A1。其它公开书包括：Palmowski MJ等，J Immunol，2002，168(9)：4391-8；Fang ZY等，Virology，2001，291(2)：272-84；FiratH等人，J Gene Med，2002，4(1)：38-45；Smith SG等人，Clin Cancer Res，2001，7(12)：4253-61；Vonderheide RH等人，Clin Cancer Res，2001，7(11)：3343-8；Firat H等人，Eur J Immunol，2001，31(10)：3064-74；Le TT等人，Vaccine，2001，19(32)：4669-75；Fayolle C等人，J Virol，2001，75(16)：7330-8；Smith SG，Curr Opin Mol Ther，1999，1(1)：10-5；Firat H等人，Eur JImmunol，1999，29(10)：3112-21；Mateo L等人，J Immunol，1999，163(7)：4058-63；Heemskerk MH等人，Cell Immunol，1999，195(1)：10-7；Woodberry T等人，J Virol，1999，73(7)：5320-5；Hanke T等人，Vaccine，1998，16(4)：426-35；Thomson SA等人，J Immunol，1998，160(4)：1717-23；Toes RE等人，Proc Natl Acad Sci USA，1997，94(26)：14660-5；Thomson SA等人，J Immunol，1996，157(2)：822-6；ThomsonSA等人，Proc Natl Acad Sci USA，1995，92(13)：5845-9；Street MD等人，Immunology，2002，106(4)：526-36；Hirano K等人，Histochem Cell Biol，2002，117(1)：41-53；Ward SM等人，Virus Genes，2001，23(1)：97-104；Liu WJ等人，Virology，2000，273(2)：374-82；Gariglio P等人，Arch MedRes，1998，29(4)：279-84；Suhrbier A，Immunol Cell Biol，1997，75(4)：402-8；Fomsgaard A等人，Vaccine，1999，18(7-8)：681-91；An LL等人，J Virol，1997，71(3)：2292-302；Whitton JL等人，J Virol，1993，67(1)：348-52；RipaltiA等人，J Clin Microbiol，1994，32(2)：358-63；和Gilbert SC等人，NatBiotech，1997，15：1280-1284。
上文所有公开书共有的一个重要特色是它们不看重在pAPC中表达构建体时再生管家表位的愿望。这种理解在本发明之前是不明朗的。本发明的实施方案包括在受到免疫蛋白酶体加工后释放或生成管家表位的序列。本发明的实施方案还可以以免疫原性有效量来释放或生成这些表位。因此，尽管上述参考文献包括涉及多表位排列的公开书，然而都不能获得在pAPC中通过免疫蛋白酶体作用提供或选择能够释放管家表位的多表位所必需的技术。相反，本发明的实施方案基于希望达到此目的的认识。因此，本发明的实施方案包括编码包含至少一个管家表位的多肽的任何核酸构建体，所述管家表位是在促进其通过免疫蛋白酶体活性而生成的环境中提供的，无论管家表位是以珠串排列或其它排列的方式嵌入。本发明的有些实施方案包括上述任何一篇或多篇陈列的参考文献中专门公开的一种或多种核酸构建体或其产物的用途。这些用途包括例如，筛选用于管家表位和/或免疫表位的正确释放环境的多表位，设计能够引发管家表位和/或免疫表位展示在pAPC上的有效免疫原，给患者免疫等等。备选的实施方案包括仅为这些核酸构建体的子集或一个这种构建体的用途，同时出于本文公开的任何目的特别排斥其它这些构建体之一种或多种。有些优选的实施方案采用单独或组合编码多表位排列的这些和/或其它核酸序列。例如，有些实施方案排斥一篇或多篇上述参考文献中的多表位排列的使用。其它实施方案可能共同排斥上述参考文献中的所有多表位排列或其任意组合。有些实施方案包括编码多表位排列的病毒和/或细菌载体，而其它实施方案特别排斥这些载体。这些载体可以编码可能具有一些免疫刺激效应的载体蛋白。有些实施方案包括具有这些免疫刺激/免疫加强效应而非免疫原性效应的这些载体，而其它实施方案可能包括这类载体。另外，在有些情况中，病毒和细菌载体编码预期表位，作为与靶细胞无关的实质完整蛋白质的一部分。有些实施方案包括这些载体和产物，而被其它实施方案排斥。有些实施方案涉及重复施用载体。在那些实施方案中，有些包括非病毒和非细菌载体。同样，有些实施方案包括在表位之间包含额外氨基酸的排列，在有些实施方案中是例如1-6个氨基酸或更多，而其它实施方案特别排斥这些排列。
本发明的实施方案还包括针对各种类型靶目标的方法，用途，疗法和组合物。这些靶目标可以包括例如诸如下表所列肿瘤细胞和受到任何病毒，细菌，原生动物，真菌或其它试剂感染的细胞，它们的实例如下文表1-5所列或上文所列任何参考文献中所公开的。备选实施方案包括仅为下文表1-5或本文公开的任何参考文献中所列的这些肿瘤细胞和受感染细胞子集的或肿瘤细胞和受感染细胞的单个一种，同时出于本文公开的任何目的特别排斥其它这些肿瘤细胞或受感染细胞之一种或多种。下面是可以靶向的肿瘤细胞的实例：人肉瘤和癌，如纤维肉瘤，粘液肉瘤，脂质肉瘤，软骨肉瘤，成骨肉瘤，脊索瘤，血管肉瘤，内皮肉瘤，淋巴管肉瘤，淋巴管内皮肉瘤，滑膜瘤，间皮瘤，尤因瘤，平滑肌肉瘤，横纹肌肉瘤，结肠癌，胰腺癌，乳腺癌，卵巢癌，前列腺癌，鳞状细胞癌，基底细胞癌，腺癌，汗腺癌，皮脂腺癌，乳头状癌，乳头状腺癌，囊腺癌，髓样癌，支气管癌，肾细胞癌，肝癌，胆管癌，绒毛膜癌，精原细胞瘤，胚胎癌，维尔姆斯瘤，子宫颈癌，睾丸肿瘤，肺癌，小细胞肺癌，膀胱癌，上皮癌，神经胶质瘤，星形细胞瘤，成神经管细胞瘤，颅咽管瘤，室管膜瘤，松果体瘤，成血管细胞瘤，听神经瘤，少突神经胶质细胞瘤，脑膜瘤，黑素瘤，成神经细胞瘤，成视网膜细胞瘤；白血病，如急性淋巴细胞白血病和急性髓细胞白血病(成髓细胞，前髓细胞，髓单核细胞，单核细胞和红白血病)；慢性白血病(慢性髓细胞(粒细胞)白血病和慢性淋巴细胞白血病)；和脾大性红细胞增多，淋巴瘤(何杰金病和非何杰金病)，多发性骨髓瘤，瓦尔登斯特伦巨球蛋白血症，重链病，肝细胞癌，脑癌，胃癌，肝癌，等等。感染靶细胞的感染剂的实例可以包括：腺病毒，巨细胞病毒，EB病毒，单纯疱疹病毒1，单纯疱疹病毒2，人疱疹病毒6，水痘带状疱疹病毒，乙肝病毒，丁肝病毒，乳头瘤病毒，细小病毒B19，多瘤病毒BK，多瘤病毒JC，丙肝病毒，麻疹病毒，风疹病毒，人免疫缺陷性病毒(HIV)，人T细胞白血病病毒I，人T细胞白血病病毒II，衣原体(Chlamydia)，利斯特氏菌属(Listeria)，沙门氏菌属(Salmonella)，军团菌属(Legionella)，布鲁氏杆菌属(Brucella)，考克斯氏体属(Coxiella)，立克次氏体属(Rickettsia)，分枝杆菌属(Mycobacterium)，利什曼原虫属(Leishmania)，Trypanasoma，弓形虫(Toxoplasma)，疟原虫属(Plasmodium)等。示例性感染剂和肿瘤细胞也包括在下表1-5中。
另外，靶目标可以包括任何下列参考文献中描述的肿瘤细胞或受到任何下列参考文献中描述的试剂感染的细胞：Jger，E.等人，“Granulocyte-macrophage-colony-stimulating factor enhances immuneresponses to melanoma-associated peptides in vivo”，Int.J Cancer，67：54-62，1996；Kündig，T.M.，Althage，A.，Hengartner，H.&Zinkernagel，R.M.，A skintest to assess CD8+cytotoxic T cell activity，Proc.Natl.Acad.Sci.USA，89：7757-76，1992；Bachmann，M.F.&Kundig，T.M.，“In vitro vs.in vivo assaysfor the assessment of T-and B-cell function”，Curr.Opin.Immunol.，6：320-326，1994；Kundig等人，“On the role of antigen in maintainingcytotoxic T cell memory”，Proceedings.National.Academy.Scicences of theUnited States of America，93：9716-23，(1996)；Steinmann，R.M.，“Thedendritic cells system and its role in immunogenicity”，Annual Review ofImmunology，9：271-96，(1991)；Inaba，K.等人，“Identification of proliferatingdendritic cell precursors in mouse blood”，Journal of Experimental Medicine，175：1157-67，(1992)；Young，J.W.&Inaba，K.，“Dendritic cells as adjuvantsfor class I major histocompatibility complex-restricted anti-tumor immunity”，Journal of Experimental Medicine，183：7-11，(1996)；Kuby，Janis，Immunology，第二版，第15章，W.H.Freeman and公司，(1991)；Austenst，E.，Stahl，T.和de Gruyter，Walter，Insulin Pump Therapy，第3章，柏林，纽约，(1990)；Remington，The Science and Practice of Pharmacy，第19版，第86-88章；Cleland，Jeffery L.和Langer，Robert(编者)，“Formulation anddelivery of proteins and peptides”，American Chemical Society(ACSSymposium Series，第567)(1994)；Dickinson，Becton，使用Tegadenn透明敷料TegadermTM 1624固定，3M，圣保罗，明尼苏达州55144，美国；Santus，Giancarlo和Baker，Richard，“Osmotic drug delivery：A review of thepatent literature”，Journal of Controlled Release，35：1-21，(1995)；Rammensee，美国专利号5,747,269，授权于1998年5月5日；Magruder，美国专利号5,059,423，授权于1991年10月22日；Sandbrook，美国专利号4,552,651，授权于1985年11月25日；Eckenhoff等人，美国专利号3,987,790，授权于1976年10月26日；Theeuwes，美国专利号4,455,145，授权于1984年6月19日；Roth等人，美国专利号4,929,233，授权于1990年5月29日；van der Bruggen等人，美国专利号5,554,506，授权于1996年9月10日；Pfreundschuh，美国专利号5,698,396，授权于1997年12月16日；Magruder，美国专利号5,110,596，授权于1992年5月5日；Eckenhoff，美国专利号4,619,652，授权于1986年10月28日；Higuchi等人，美国专利号3,995,631，授权于1976年12月7日；Maruyama，美国专利号5,017,381，授权于1991年5月21日；Eckenhoff，美国专利号4,963,141，授权于1990年10月16日；van der Bruggen等人，美国专利号5,558,995，授权于1996年9月24日；Stolzenberg等人，美国专利号3,604,417，授权于1971年9月14日；Wong等人，美国专利号5,110,597，授权于1992年5月5日；Eckenhoff，美国专利号4,753,651，授权于1988年6月28日；Theeuwes，美国专利号4,203,440，授权于1980年5月20日；Wong等人，美国专利号5,023,088，授权于1991年6月11日；Wong等人，美国专利号4,976,966，授权于1990年12月11日；van den Eynde等人，美国专利号5,648,226，授权于1997年7月15日；Baker等人，美国专利号4,838,862，授权于1989年6月13日；Magruder，美国专利号5,135,523，授权于1992年8月4日；Higuchi等人，美国专利号3,732,865，授权于1975年5月15日；Theeuwes，美国专利号4,286,067，授权于1981年8月25日；Theeuwes等人，美国专利号5,030,216，授权于1991年7月9日；Boon等人，美国专利号5,405,940，授权于1995年4月11日；Faste，美国专利号4,898,582，授权于1990年2月6日；Eckenhoff，美国专利号5,137,727，授权于1992年8月11日；Higuchi等人，美国专利号3,760,804，授权于1973年9月25日；Eckenhoff等人，美国专利号4,300,558，授权于1981年11月12日；Magruder等人，美国专利号5,034,229，授权于1991年7月23日；Boon等人，美国专利号5,487,974，授权于1996年1月30日；Kam等人，美国专利号5,135,498，授权于1992年8月4日；Magruder等人，美国专利号5,174,999，授权于1992年12月29日；Higuchi，美国专利号3,760,805，1973年9月25日；Michaels，美国专利号4,304,232，授权于1981年12月8日；Magruder等人，美国专利号5,037,420，授权于1991年10月15日；Wolfel等人，美国专利号5,530,096，授权于1996年6月25日；Athadye等人，美国专利号5,169,390，授权于1992年12月8日；Balaban等人，美国专利号5,209,746，授权于1993年5月11日；Higuchi，美国专利号3,929,132，授权于1975年12月30日；Michaels，美国专利号4,340,054，授权于1982年7月20日；Magruder等人，美国专利号5,057,318，授权于1991年10月15日；Wolfel等人，美国专利号5,519,117，授权于1996年5月21日；Athadye等人，美国专利号5,257,987，授权于1993年11月2日；Linkwitz等人，美国专利号5,221,278，授权于1993年6月22日；Nakano等人，美国专利号3,995,632，授权于1976年12月7日；Michaels，美国专利号4,367,741，授权于1983年1月11日；Eckenhoff，美国专利号4,865,598，授权于1989年9月12日；Lethe等人，美国专利号5,774,316，授权于1998年4月28日；Eckenhoff，美国专利号4,340,048，授权于1982年7月20日；Wong，美国专利号5,223,265，授权于1993年6月29日；Higuchi等人，美国专利号4,034,756，授权于1977年7月12日；Michaels，美国专利号4,450,198，授权于1984年5月22日；Eckenhoff等人，美国专利号4,865,845，授权于1989年9月12日；Melief等人，美国专利号5,554,724，授权于1996年9月10日；Eckenhoff等人，美国专利号4,474,575，授权于1984年10月2日；Theeuwes，美国专利号3,760,984，授权于1983年9月25日；Eckenhoff，美国专利号4,350,271，授权于1982年9月21日；Eckenhoff等人，美国专利号4,855,141，授权于1989年8月8日；Zingerman，美国专利号4,872,873，授权于1989年10月10日；Townsend等人，美国专利号5,585,461，授权于1996年12月17日；Carulli，J.P.等人，J.Cellular Biochem Suppl.，30/31：286-96，(1998)；Türeci，.，Sahin，U.和Pfreundschuh，M.，“Serological analysis ofhuman tumor antigens：molecular definition and implications”，MolecularMedicine Today，3：342，(1997)；Rammensee等人，MHC Ligands and PeptideMotifs，Landes Bioscience，奥斯汀市，德克萨斯州，224-27，(1997)；Parker等人，“Scheme for ranking potential HLA-A2 binding peptides based onindependent binding of individual peptide side chains”，J.Immunol.，152：163-175；Kido&Ohshita，Anal.Biochem.，230：41-47，(1995)；Yamada等人，J.Biochem.(东京)，95：1155-60，(1984)；Kawashima等人，KidneyInt.，54：275-8，(1998)；Nakabayshi&Ikezawa，Biochem.Int.，16：1119-25，(1988)；Kanaseki&Ohkuma，J.Biochem.(东京)，110：541-7，1991；Wattiaux等人，J.Cell Biol.，78：349-68，(1978)；Lisman等人，Biochem.J.，178：79-87，(1979)；Dean，B.，Arch.Biochem.Biophys.，227：154-63，(1983)；Overdijk等人，Adv.Exp.Med.Biol.，101：601-10，(1978)；Stromhaug等人，Biochem.J.，335：217-24，(1998)；Escola等人，J.Biol.Chem.，271：27360-05，(1996)；Hammond等人，Am.J.Physiol.，267：F516-27，(1994)；Williams&Smith，Arch.Biochem.Biophys.，305：298-306，(1993)；Marsh，M.，MethodsCell Biol.，31：319-34，(1989)；Schmid&Mellman，Prog.Clin.Biol.Res.，270：35-49，(1988)；Fatk，K.等人，Nature，351：290，(1991)；Ausubel等人，Short Protocols in Molecular Biology，第3版，单元11.2，(1997)；hypertexttransfer protocol address 134.2.96.221/scripts/hlaserver.dll/EpPredict.htm；Levy，Morel，S.等人，Immunity，12：107-117，(2000)；Seipelt等人，VirusResearch，62：159-68，1999；Storkus等人，美国专利号5,989,565，授权于1999年11月23日；Morton，美国专利号5,993,828，授权于1999年11月30日；Virus Research，62：159-168，(1999)；Simard等人，美国专利申请号10/026066，提交于2001年12月7日；Simard等人，美国专利申请号09/561571，提交于2000年4月28日；Simard等人，美国专利申请号09/561572，提交于2000年4月28日；Miura等人，WO99/01283，1999年1月14日；Simard等人，美国专利申请号09/561074，提交于2000年4月28日；Simard等人，美国专利申请号10/225568，提交于2002年8月20日；Simard等人，美国专利申请号10/005905，提交于2001年11月7日；Simard等人，美国专利申请号09/561074，提交于2000年4月28日。
本发明的其它实施方案包括涉及特定抗原的方法，用途，疗法和组合物，无论抗原是衍生自例如诸如上文所述的靶细胞或感染剂。有些优选的实施方案采用本文表1-5或下表中所列抗原之一种，子集或任意组合。例如，有些实施方案排斥使用那些抗原中的一种或多种。其它实施方案可能排斥任意组合或所有那些抗原。这些抗原的几个实例包括MelanA(MART-I)，gp100(Pmel 17)，酪氨酸酶，TRP-1，TRP-2，MAGE-1，MAGE-3，BAGE，GAGE-1，GAGE-2，CEA，RAGE，NY-ESO，SCP-1，Hom/Mel-40，PRAME，p53，H-Ras，HER-2/neu，BCR-ABL，E2A-PRL，H4-RET，IGH-IGK，MYL-RAR，EB病毒抗原，EBNA，人乳头瘤病毒(HPV)抗原E6和E7，TSP-180，MAGE-4，MAGE-5，MAGE-6，p185erbB2，p180erbB-3，c-met，nm-23H1，PSA，TAG-72-4，CAM 17.1，NuMa，K-ras，β-连环蛋白，CDK4，Mum-1，p16，以及上文所述参考文献中提及之任一种。其它抗原包括于下文表1-4。
其它实施方案包括涉及包括例如表1-5所列那些表位在内的表位的方法，用途，组合物和疗法。这些表位可用于例如在筛选载体中侧翼管家表位。有些实施方案包含表1-5的一种和多种表位，而其它实施方案特别排斥这些表位之一种或多种或其组合。
表1
| 病毒 | 蛋白质 | AA位置 | T细胞表位MHC配体(抗原) | MHC分子 |
| 腺病毒3 | E3 9Kd | 30-38 | LIVIGILIL | HLA-A*0201 |
| (SEQ.ID NO.：44) | ||||
| 腺病毒5 | EIA | 234-243 | SGPSNTPPEI | H2-Db |
| (SEQ.ID NO.：45) | ||||
| 腺病毒5 | EIB | 192-200 | VNIRNCCY1 | H2-Db |
| (SEQ.ID NO.：46) | ||||
| 腺病毒5 | EIA | 234-243 | SGPSNIPPEI(T＞I) | H2-Db |
| (SEQ.ID NO.：47) | ||||
| CSFV | NS多蛋白 | 2276-2284 | ENALLVALF | SLA，单倍型d/d |
| (SEQ.ID NO.：48) | ||||
| 登革病毒4 | NS3 | 500-508 | TPEGIIPTL | HLA-B*3501 |
| (SEQ.ID NO.：49) | ||||
| EBV | LMP-2 | 426-434 | CLGGLLTMV | HLA-A*0201 |
| (SEQ.ID NO.：50) | ||||
| EBV | EBNA-1 | 480-484 | NIAEGLRAL | HLA-A*0201 |
| (SEQ.ID NO.：51) | ||||
| EBV | EBNA-1 | 519-527 | NLRRGTALA | HLA-A*0201 |
| (SEQ.ID NO.：52) | ||||
| EBV | EBNA-1 | 525-533 | ALAIPQCRL | HLA-A*0201 |
| (SEQ.ID NO.：53) | ||||
| EBV | EBNA-1 | 575-582 | VLKDAIKDL | HLA-A*0201 |
| (SEQ.ID NO.：54) | ||||
| EBV | EBNA-1 | 562-570 | FMVFLQTHI | HLA-A*0201 |
| (SEQ.ID NO.：55) | ||||
| EBV | EBNA-2 | 15-23 | HLIVDTDSL | HLA-A*0201 |
| (SEQ.ID NO.：56) | ||||
| EBV | EBNA-2 | 22-30 | SLGNPSLSV | HLA-A*0201 |
| (SEQ.ID NO.：57) | ||||
| EBV | EBNA-2 | 126-134 | PLASAMRML | HLA-A*0201 |
| (SEQ.ID NO.：58) | ||||
| EBV | EBNA-2 | 132-140 | RMLWMANY1 | HLA-A*0201 |
| (SEQ.ID NO.：59) | ||||
| EBV | EBNA-2 | 133-141 | MLWMANYTV | HL.A-A*0201 |
| (SEQ.ID NO.：60) | ||||
| EBV | EBNA-2 | 151-159 | ILPQGPQTA | HLA-A*0201 |
| (SEQ.ID NO.：61) | ||||
| EBV | EBNA-2 | 171-179 | PLRPTAPTI | HLA-A*0201 |
| (SEQ.ID NO.：62) | ||||
| EBV | EBNA-2 | 205-213 | PLPPATLTV | HLA-A*0201 |
| (SEQ.ID NO.：63) | ||||
| EBV | EBNA-2 | 246-254 | RMHLPVLHV | HLA-A*0201 |
| (SEQ.ID NO.：64) | ||||
| EBV | EBNA-2 | 287-295 | PMPLPPSQL | HLA-A*0201 |
| (SEQ.ID NO.：65) |
| EBV | EBNA-2 | 294-302 | QLPPPAAPA | HLA-A*0201 | |
| (SEQ.ID NO.：66) | |||||
| EBV | EBNA-2 | 381-389 | SMPELSPVL | HLA-A*0201 | |
| (SEQ.ID NO.：67) | |||||
| EBV | EBNA-2 | 453-461 | DLDESWDYI | HLA-A*0201 | |
| (SEQ.ID NO.：68) | |||||
| EBV | BZLF1 | 43-51 | PLPCVLWPV | HLA-A*0201 | |
| (SEQ.ID NO.：69) | |||||
| EBV | BZLF1 | 167-175 | SLEECDSEL | HLA-A*0201 | |
| (SEQ.ID NO.：70) | |||||
| EBV | BZLF1 | 176-184 | EIKRYKNRV | HLA-A*0201 | |
| (SEQ.ID NO.：71) | |||||
| EBV | BZLF1 | 195-203 | QLLQHYREV | HLA-A*0201 | |
| (SEQ.ID NO.：72) | |||||
| EBV | BZLF1 | 196-204 | LLQHYREVA | HLA-A*0201 | |
| (SEQ.ID NO.：73) | |||||
| EBV | BZLFI | 217-225 | LLKQMCPSL | HLA-A*0201 | |
| (SEQ.ID NO.：74) | |||||
| EBV | BZLF1 | 229-237 | SIIPRTPDV | HLA-A*0201 | |
| (SEQ.ID NO.：75) | |||||
| EBV | EBNA-6 | 284-293 | LLDFVRFMGV | HLA-A*0201 | |
| (SEQ.ID NO.：76) | |||||
| EBV | EBNA-3 | 464-472 | SVRDRLARL | HLA-A*0203 | |
| (SEQ.ID NO.：77) | |||||
| EBV | EBNA-4 | 416-424 | IVTDFSVIK | HLA-A*1101 | |
| (SEQ.ID NO.：78) | |||||
| EBV | EBNA-4 | 399-408 | AVFDRKSDAK | HLA-A*0201 | |
| (SEQ.ID NO.：79) | |||||
| EBV | EBNA-3 | 246-253 | RYSIFFDY | HLA-A24 | |
| (SEQ.ID NO.：80) | |||||
| EBV | EBNA-6 | 881-889 | QPRAPIRPI | HLA-B7 | |
| (SEQ.ID NO.：81) | |||||
| EBV | EBNA-3 | 379-387 | RPPIFIRRL | HLA-B7 | |
| (SEQ.ID NO.：82) | |||||
| EBV | EBNA-1 | 426-434 | EPDVPPGAI | HLA-B7 | |
| (SEQ.ID NO.：83) | |||||
| EBV | EBNA-1 | 228-236 | IPQCRLTPL | HLA-B7 | |
| (SEQ.ID NO.：84) | |||||
| EBV | EBNA-1 | 546-554 | GPGPQPGPL | HLA-B7 | |
| (SEQ.ID NO.：85) | |||||
| EBV | EBNA-1 | 550-558 | QPGPLRESI | HLA-B7 | |
| (SEQ.ID NO.：86) | |||||
| EBV | EBNA-1 | 72-80 | R.PQKRPSCI | HLA-B7 | |
| (SEQ.ID NO.：87) | |||||
| EBV | EBNA-2 | 224-232 | PPTPLLTVL | HLA-B7 | |
| (SEQ.ID NO.：88) | |||||
| EBV | EBNA-2 | 241-249 | TPSPPRMHL | HLA-B7 | |
| (SEQ.DI NO.：89) | |||||
| EBV | EBNA-2 | 244-252 | PPRMHLPVL | HLA-B7 | |
| (SEQ.ID NO.：90) | |||||
| EBV | EBNA-2 | 254-262 | VPDQSMHPL | HLA-B7 | |
| (SEQ.ID NO.：91) | |||||||
| EBV | EBNA-2 | 446-454 | PPSIDPADL | HLA-B7 | |||
| (SEQ.ID NO.：92) | |||||||
| EBV | BZLFI | 44-52 | LPCVLWPVL | HLA-B7 | |||
| (SEQ.ID NO.：93) | |||||||
| EBV | BZLF1 | 222-231 | CPSLDVDSII | HLA-B7 | |||
| (SEQ.ID NO.：94) | |||||||
| EBV | BZLFI | 234-242 | TPDVLHEDL | HLA-B7 | |||
| (SEQ.ID NO.：95) | |||||||
| EBV | EBNA-3 | 339-347 | FLRGRAYGL | HLA-B8 | |||
| (SEQ.ID NO.：96) | |||||||
| EBV | EBNA-3 | 26-34 | QAKWRLQTL | HL-B8 | |||
| (SEQ.ID NO.：97) | |||||||
| EBV | EBNA-3 | 325-333 | AYPLHEQHG | HLA-B8 | |||
| (SEQ.ID NO.：98) | |||||||
| EBV | EBNA-3 | 158-166 | YIKSFVSDA | HLA-B8 | |||
| (SEQ.ID NO.：99) | |||||||
| EBV | LMP-2 | 236-244 | RRRWRRLTV | HLA-B*2704 | |||
| (SEQ.ID NO.：100) | |||||||
| EBV | EBNA-6 | 258-266 | RRIYDLIEL | HLA-B*2705 | |||
| (SEQ.ID NO.：101) | |||||||
| EBV | EBNA-3 | 458-466 | YPLHEQHGM | HLA-B*3501 | |||
| (SEQ.ID NO.：102) | |||||||
| EBV | EBNA-3 | 458-466 | YPLHEQHGM | HLA-B*3503 | |||
| (SEQ.ID NO.：103) | |||||||
| HCV | NS3 | 389-397 | HSKKKCDEL | HLA-B8 | |||
| (SEQ.ID NO.：104) | |||||||
| HCV | env E | 44-51 | ASRCWVAM | HLA-B*3501 | |||
| (SEQ.ID NO.：105) | |||||||
| HCV | 核心蛋白 | 27-35 | GQIVGGVYL | HLA-B*40012 | |||
| (SEQ.ID NO.：106) | |||||||
| HCV | NSI | 77-85 | PPLTDFDQGW | HLA-B*5301 | |||
| (SEQ.ID NO.：107) | |||||||
| HCV | 核心蛋白 | 18-27 | LMGYIPLVGA | H2-Dd | |||
| (SEQ.ID NO.：108) | |||||||
| HCV | 核心蛋白 | 16-25 | ADLMGYIPLV | H2-Dd | |||
| (SEQ.ID NO.：109) | |||||||
| HCV | NS5 | 409-424 | MSYSWTGALVTPCAEE | H2-Dd | |||
| (SEQ.ID NO.：110) | |||||||
| HCV | NS1 | 205-213 | KHPDATYSR | Papa-A06 | |||
| (SEQ.ID NO.：111) | |||||||
| HCV-1 | NS3 | 400-409 | KLVALGINAV | HLA-A*0201 | |||
| (SEQ.ID NO.：112) | |||||||
| HCV-1 | NS3 | 440-448 | GDFDSVIDC | Patr-B16 | |||
| (SEQ.ID NO.：113) | |||||||
| HCV-1 | env E | 118-126 | GNASRCWVA | Patr-BI6 | |||
| (SEQ.ID NO.：114) | |||||||
| HCV-1 | NSI | 159-167 | TRPPLGNWF | Patr-B13 | |||
| (SEQ.ID NO.：115) | |||||||
| HCV-1 | NS3 | 351-359 | VPHPNIEEV | Patr-B13 | |||
| (SEQ.ID NO.：116) | |||||||
| HCV-1 | NS3 | 438-446 | YTGDFDSVI | Patr-B01 | |
| (SEQ.ID NO.：117) | |||||
| HCV-1 | NS4 | 328-335 | SWAIKWEY | Patr-A11 | |
| (SEQ.ID NO.：118) | |||||
| HCV-1 | NSI | 205-213 | KHPDATYSR | Patr-A04 | |
| (SEQ.ID NO.：119) | |||||
| HCV-1 | NS3 | 440-448 | GDFDSVIDC | Patr-A04 | |
| (SEQ.ID NO.：120) | |||||
| HIV | gp41 | 583-591 | RYLKDQQLL | HLA A24 | |
| (SEQ.ID NO.：121) | |||||
| HIV | gagp24 | 267-275 | IVGLNKIVR | HLA-A*3302 | |
| (SEQ.ID NO.：122) | |||||
| HIV | gagp24 | 262-270 | EIYKRWIIL | HLA-B8 | |
| (SEQ.ID NO.：123) | |||||
| HIV | gagp24 | 261-269 | GEIYKRWI1 | HLA-B8 | |
| (SEQ.ID NO.：124) | |||||
| HIV | gagp17 | 93-101 | EIKDTKEAL | HLA-B8 | |
| (SEQ.ID NO.：125) | |||||
| HIV | gp41 | 586-593 | YLKDQQLL | HLA-B8 | |
| (SEQ.ID NO.：126) | |||||
| HIV | gagp24 | 267-277 | ILGLNKIVRMY | HLA-B*1501 | |
| (SEQ.ID NO.：127) | |||||
| HIV | gp41 | 584-592 | ERYLKDQQL | HLA-B14 | |
| (SEQ.ID NO.：128) | |||||
| HIV | nef | 115-125 | YHTQGYFPQWQ | HLA-B17 | |
| (SEQ.ID NO.：129) | |||||
| HIV | nef | 117-128 | TQGYFPQWQNYT | HLA-B17 | |
| (SEQ.ID NO.：130) | |||||
| HIV | gp120 | 314-322 | GRAFVT1GK | HLA-B*2705 | |
| (SEQ.ID NO.：131) | |||||
| HIV | gagp24 | 263-271 | KRWIILGLN | HLA-B*2702 | |
| (SEQ.ID NO.：132) | |||||
| HIV | nef | 72-82 | QVPLRPMTYK | HLA-B*3501 | |
| (SEQ.ID NO.：133) | |||||
| HIV | nef | 117-125 | TQGYFPQWQ | HLA-B*3701 | |
| (SEQ.ID NO.：134) | |||||
| HIV | gagp24 | 143-151 | HQAISPRTI， | HLA-Cw*0301 | |
| (SEQ.ID NO.：135) | |||||
| HIV | gagp24 | 140-151 | QMVHQAISPRTL | HLA-Cw*0301 | |
| (SEQ.ID NO.：136) | |||||
| HIV | gp120 | 431-440 | MYAPPIGGQI | H2-Kd | |
| (SEQ.ID NO.：137) | |||||
| HIV | gp160 | 318-327 | RGPGRAFVTI | H2-Dd | |
| (SEQ.ID NO.：138) | |||||
| HIV | gp120 | 17-29 | MPGRAFVTI | H2-Ld | |
| (SEQ.ID NO.：139) | |||||
| HIV-1 | RT | 476-484 | ILKEPVHGV | HLA-A*0201 | |
| (SEQ.ID NO.：140) | |||||
| HIV-1 | nef | 190-198 | AFHHVAREL | HLA-A*0201 | |
| (SEQ.ID NO.：141) | |||||
| HIV-1 | gpI60 | 120-128 | KLTPLCVTL | HLA-A*0201 | |
| (SEQ.ID NO.：142) | ||||
| HIV-1 | gpl60 | 814-823 | SLLNATDIAV | HLA-A*0201 |
| (SEQ.ID NO.：143) | ||||
| HIV-1 | RT | 179-187 | VIYQYMDDL | HLA-A*0201 |
| (SEQ.ID NO.：144) | ||||
| HIV-1 | gagp 17 | 77-85 | SLYNTVATL | HLA-A*0201 |
| (SEQ.ID NO.：145) | ||||
| HIV-1 | gp160 | 315-329 | RGPGRAFVT1 | HLA-A*0201 |
| (SEQ.ID NO.：146) | ||||
| HIV-1 | gp41 | 768-778 | RLRDLLLIVTR | HLA-A3 |
| (SEQ.ID NO.：147) | ||||
| HIV-1 | nef | 73-82 | QVPLRPMTYK | HLA-A3 |
| (SEQ.ID NO.：148) | ||||
| HIV-1 | gp120 | 36-45 | TVYYGVPVWK | HLA-A3 |
| (SEQ.ID NO.：149) | ||||
| HIV-1 | gagp17 | 20-29 | RLRPGGKKK | HLA-A3 |
| (SEQ.ID NO.：150) | ||||
| HIV-1 | gp120 | 38-46 | VYYGVPVWK | HLA-A3 |
| (SEQ.ID NO.：151) | ||||
| HIV-1 | nef | 74-82 | VPLRPMTYK | HLA-a*1101 |
| (SEQ.ID NO.：152) | ||||
| HIV-1 | gagp24 | 325-333 | AIFQSSMTK | HLA-A*1101 |
| (SEQ.ID NO.：153) | ||||
| HIV-1 | nef | 73-82 | QVPLRPMTYK | HLA-A*1101 |
| (SEQ.ID NO.：154) | ||||
| HIV-1 | nef | 83-94 | AAVDLSHFLKEK | HLA-A*1101 |
| (SEQ.ID NO.：155) | ||||
| HIV-1 | gagp24 | 349-359 | ACQGVGGPGGHK | HLA-A*1101 |
| (SEQ.ID NO.：156) | ||||
| HIV-1 | gagp24 | 203-212 | ETINEEAAEW | HLA-A25 |
| (SEQ.ID NO.：157) | ||||
| HIV-1 | nef | 128-137 | TPGPGVRYPL | HLA-B7 |
| (SEQ.ID NO.：158) | ||||
| HIV-1 | gagp 17 | 24-31 | GGKKKYKL | HLA-B8 |
| (SEQ.ID NO.：159) | ||||
| HIV-1 | gp120 | 2-10 | RVKEKYQHL | HLA-B8 |
| (SEQ.ID NO.：160) | ||||
| HIV-1 | gagp24 | 298-306 | DRFYKTLRA | HLA-B14 |
| (SEQ.ID NO.：161) | ||||
| HIV-1 | NEF | 132-147 | GVRYPLTFGWCYKLVP | HLA-B18 |
| (SEQ.ID NO.：162) | ||||
| HIV-1 | gagp24 | 265-24 | KRWIILGLNK | HLA-B*2705 |
| (SEQ.ID NO.：163) | ||||
| HIV-1 | nef | 190-198 | AFHHVAREL | HLA-B*5201 |
| (SEQ.ID NO.：164) | ||||
| EBV | EBNA-6 | 335-343 | KEHVIQNAF | HLA-B44 |
| (SEQ.ID NO.：165) | ||||
| EBV | EBNA-6 | 130-139 | EENLLDFVRF | HLA-B*4403 |
| (SEQ.ID NO.：166) | ||||
| EBV | EBNA-2 | 42-51 | DTPLIPLTIF | HLA-B51 |
| (SEQ.ID NO.：167) |
| EBV | EBNA-6 | 213-222 | QNGALAINTF | HLA-1362 | |
| (SEQ.ID NO.：168) | |||||
| EBV | EBNA-3 | 603-611 | RLRAEAGVK | HLA-A3 | |
| (SEQ.ID NO.：169) | |||||
| HBV | sAg | 348-357 | GLSPTVWLSV | HLA-A*0201 | |
| (SEQ.ID NO.：170) | |||||
| HBV | SAg | 335-343 | WLSLLVPFV | HLA-A*0201 | |
| (SEQ.ID NO.：171) | |||||
| HBV | cAg | 18-27 | FLPSDFFPSV | HLA-A*0201 | |
| (SEQ.ID NO.：172) | |||||
| HBV | cAg | 18-27 | FLPSDFFPSV | HLA-A*0202 | |
| (SEQ.ID NO.：173) | |||||
| HBV | cAg | 18-27 | FLPSDFFPSV | HLA-A*0205 | |
| (SEQ.ID NO.：174) | |||||
| HBV | cAg | 18-27 | FLPSDFFPSV | HLA-A*0206 | |
| (SEQ.ID NO.：175) | |||||
| HBV | pol | 575-583 | FLLSLGIHL | HLA-A*0201 | |
| (SEQ.ID NO.：176) | |||||
| HBV | pol | 816-824 | SLYADSPSV | HLA-A*0201 | |
| (SEQ.ID NO.：177) | |||||
| HBV | pol | 455-463 | GLSRYVARL | HLA-A*0201 | |
| (SEQ.ID NO.：178) | |||||
| HBV | env | 338-347 | LLVPFVQWFV | HLA-A*0201 | |
| (SEQ.ID NO.：179) | |||||
| HBV | pol | 642-650 | ALMPLYACI | HLA-A*0201 | |
| (SEQ.ID NO.：180) | |||||
| HBV | env | 378-387 | LLPIFFCLWV | HLA-A*0201 | |
| (SEQ.ID NO.：181) | |||||
| HBV | pol | 538-546 | YMDDVVLGA | HLA-A*0201 | |
| (SEQ.ID NO.：182) | |||||
| HBV | env | 250-258 | LLLCLIFLL | HLA-A*0201 | |
| (SEQ.ID NO.：183) | |||||
| HBV | env | 260-269 | LLDYQGMLPV | HLA-A*0201 | |
| (SEQ.ID NO.：184) | |||||
| HBV | env | 370-379 | SIVSPFIPLL | HLA-A*0201 | |
| (SEQ.ID NO.：185) | |||||
| HBV | env | 183-191 | FLLTRILTI | HLA-A*0201 | |
| (SEQ.ID NO.：186) | |||||
| HBV | cAg | 88-96 | YVNVNMGLK | HLA-A*1101 | |
| (SEQ.ID NO.：187) | |||||
| HBV | cAg | 141-151 | STLPETTVVRR | HLA-A*3101 | |
| (SEQ.ID NO.：188) | |||||
| HBV | cAg | 141-151 | STLPETTVVRR | HLA-A*6801 | |
| (SEQ.ID NO.：189) | |||||
| HBV | cAg | 18-27 | FLPSDFFPSV | HLA-A*6801 | |
| (SEQ.ID NO.：190) | |||||
| HBV | sAg | 28-39 | IPQSLDSWWTSL | H2-Ld | |
| (SEQ.ID NO.：191) | |||||
| HBV | cAg | 93-100 | MGLKFRQL | H2-Kb | |
| (SEQ.ID NO.：192) | |||||
| HBV | preS | 141-149 | STBXQSGXQ | HLA-A*0201 | |
| (SEQ.ID NO.：193) | |||||
| HCMV | gpB | 618-628 | FIAGNSAYEYV | HLA-A*0201 | |
| (SEQ.ID NO.：194) | |||||
| HCMV | E1 | 978-989 | SDEEFAIVAYTL | HLA-B18 | |
| (SEQ.ID NO.：195) | |||||
| HCMV | pp65 | 397-411 | DDVWTSGSDSDEELV | HLA-b35 | |
| (SEQ.ID NO.：196) | |||||
| HCMV | pp65 | 123-131 | IPSINVHHY | HLA-B*3501 | |
| (SEQ.ID NO.：197) | |||||
| HCMV | pp65 | 495-504 | NLVPMVATVO | HLA-A*0201 | |
| (SEQ.ID NO.：198) | |||||
| HCMV | pp65 | 415-429 | RKTPRVTOGGAMAGA | HLA-B7 | |
| (SEQ.ID NO.：199) | |||||
| HCV | MP | 17-25 | DLMGYIPLV | HLA-A*0201 | |
| (SEQ.ID NO.：200) | |||||
| HCV | MP | 63-72 | LLALLSCLTV | HLA-A*0201 | |
| (SEQ.ID NO.：201) | |||||
| HCV | MP | 105-112 | ILHTPGCV | HLA-A*0201 | |
| (SEQ.ID NO.：202) | |||||
| HCV | envE | 66-75 | QLRRHIDLLV | HLA-A*0201 | |
| (SEQ.ID NO.：203) | |||||
| HCV | envE | 88-96 | DLCGSVFLV | HLA-A*0201 | |
| (SEQ.ID NO.：204) | |||||
| HCV | envE | 172-180 | SMVGNWAKV | HLA-A*0201 | |
| (SEQ.ID NO.：205) | |||||
| HCV | NSI | 308-316 | HLIIQNIVDV | HLA-A*0201 | |
| (SEQ.ID NO.：206) | |||||
| HCV | NSI | 340-348 | FLLLADARV | HLA-A*0201 | |
| (SEQ.ID NO.：207) | |||||
| HCV | NS2 | 234-246 | GLRDLAVAVEPVV | HLA-A*0201 | |
| (SEQ.ID NO.：208) | |||||
| HCV | NSI | 18-28 | SLLAPGAKQNV | HLA-A*0201 | |
| (SEQ.ID NO.：209) | |||||
| HCV | NSI | 19-28 | LLAPGAKQNV | HLA-A*0201 | |
| (SEQ.ID NO.：210) | |||||
| HCV | NS4 | 192-201 | LLFNILGGWV | HLA-A*0201 | |
| (SEQ.ID NO.：211) | |||||
| HCV | NS3 | 579-587 | YLVAYQATV | HLA-A*0201 | |
| (SEQ.ID NO.：212) | |||||
| HCV | 核心蛋白 | 34-43 | YLLPRRGPRL | HLA-A*0201 | |
| (SEQ.ID NO.：213) | |||||
| HCV | MP | 63-72 | LLALLSCLTI | HLA-A*0201 | |
| (SEQ.ID NO.：214) | |||||
| HCV | NS4 | 174-182 | SLMAFTAAV | HLA-A*0201 | |
| (SEQ.ID NO.：215) | |||||
| HCV | NS3 | 67-75 | CINGVCWTV | HLA-A*0201 | |
| (SEQ.ID NO.：216) | |||||
| HCV | NS3 | 163-171 | LLCPAGHAV | HLA-A*0201 | |
| (SEQ.ID NO.：217) | |||||
| HCV | NS5 | 239-247 | ILDSFDPLV | HLA-A*0201 | |
| (SEQ.ID NO.：218) | |||||
| HCV | NS4A | 236-244 | ILAGYGAGV | HLA-A*0201 |
| (SEQ.ID NO.：219) | ||||
| HCV | NS5 | 714-722 | GLQDCTMLV | HLA-A*0201 |
| (SEQ.ID NO.：220) | ||||
| HCV | NS3 | 281-290 | TGAPVTYSTY | HLA-A*0201 |
| (SEQ.ID NO.：221) | ||||
| HCV | NS4A | 149-157 | HMWNFISGI | HLA-A*0201 |
| (SEQ.ID NO.：222) | ||||
| HCV | NS5 | 575-583 | RVCEKMALY | HLA-A*0201-A3 |
| (SEQ.ID NO.：223) | ||||
| HCV | NS1 | 238-246 | TINYTIFK | HLA-A*1101 |
| (SEQ.ID NO.：224) | ||||
| HCV | NS2 | 109-116 | YISWCLWW | HLA-A23 |
| (SEQ.ID NO.：225) | ||||
| HCV | 核心蛋白 | 40-48 | GPRLGVRAT | HLA-B7 |
| (SEQ.ID NO.：226) | ||||
| HIV-1 | gp120 | 380-388 | SFNCGGEFF | HLA-Cw*0401 |
| (SEQ.ID NO.：227) | ||||
| HIV-1 | RT | 206-214 | TEMEKEGKI | H2-Kk |
| (SEQ.ID NO.：228) | ||||
| HIV-1 | p17 | 18-26 | KIRLRPGGK | HLA-A*0301 |
| (SEQ.ID NO.：229) | ||||
| HIV-1 | P17 | 20-29 | RLRPGGKKKY | HLA-A*0301 |
| (SEQ.ID NO.：230) | ||||
| HIV-I | RT | 325-333 | AIFQSSMTK | HLA-A*0301 |
| (SEQ.ID NO.：231) | ||||
| HIV-1 | p17 | 84-92 | TLYCVHQRI | HLA-A11 |
| (SEQ.ID NO.：232) | ||||
| HIV-1 | RT | 508-517 | TYQEPFKNLK | HLA-A11 |
| (SEQ.ID NO.：233) | ||||
| HIV-1 | p17 | 28-36 | KYKLKHIVW | HLA-A24 |
| (SEQ.ID NO.：234) | ||||
| HIV-1 | gp120 | 53-62 | LFCASDAKAY | HLA-A24 |
| (SEQ.ID NO.：235) | ||||
| HIV-1 | gagp24 | 145-155 | QAISPRTLNAW | HLA-A25 |
| (SEQ.ID NO.：236) | ||||
| HIV-1 | gagp24 | 167-175 | EVIPMFSAL | HLA-A26 |
| (SEQ.ID NO.：237) | ||||
| HIV-1 | RT | 593-603 | ETFYVDGAANR | HLA-A26 |
| (SEQ.ID NO.：238) | ||||
| HIV-1 | gp41 | 775-785 | RLRDLLLIVTR | HLA-A31 |
| (SEQ.ID NO.：239) | ||||
| HIV-1 | RT | 559-568 | PIQKETWETW | HLA-A32 |
| (SEQ.ID NO.：240) | ||||
| HIV-1 | gp120 | 419-427 | RIKQIINMW | HLA-A32 |
| (SEQ.ID NO.：241) | ||||
| HIV-1 | RT | 71-79 | ITLWQRPLV | HLA-A*6802 |
| (SEQ.ID NO.：242) | ||||
| HIV-1 | RT | 85-93 | DTVLEEMNL | HLA-A*6802 |
| (SEQ.ID NO.：243) | ||||
| HIV-1 | RT | 71-79 | TTLWQRPLV | HLA-A*7401 |
| (SEQ.ID NO.：244) | |||||
| HIV-1 | gagp24 | 148-156 | SPRTLNAWV | HLA-B7 | |
| (SEQ.ID NO.：245) | |||||
| HIV-1 | gagp24 | 79-187 | ATPQDLNTM | HLA-B7 | |
| (SEQ.ID NO.：246) | |||||
| HIV-1 | gp120 | 303-312 | RPNNNTRKSI | HLA-B7 | |
| (SEQ.ID NO.：247) | |||||
| HIV-1 | gp41 | 843-851 | IPRRIRQGL | HLA-B7 | |
| (SEQ.ID NO.：248) | |||||
| HIV-1 | p17 | 74-82 | ELRSLYNTV | HLA-B8 | |
| (SEQ.ID NO.：249) | |||||
| HIV-1 | nef | 13-20 | WPTVRERM | HLA-B8 | |
| (SEQ.ID NO.：250) | |||||
| HIV-1 | nef | 90-97 | FLKEKGGL | HLA-B8 | |
| (SEQ.ID NO.：251) | |||||
| HIV-1 | gagp24 | 183-191 | DLNTMLNTV | HLA-B14 | |
| (SEQ.ID NO.：252) | |||||
| HIV-1 | P17 | 18-27 | KIRLRPGGKK | HLA-B27 | |
| (SEQ.ID NO.：253) | |||||
| HIV-1 | p17 | 19-27 | IRLRPGGKK | HLA-B27 | |
| (SEQ.ID NO.：254) | |||||
| HIV-1 | gp41 | 791-799 | GRRGWEALKY | HLA-B27 | |
| (SEQ.ID NO.：255) | |||||
| HIV-1 | nef | 73-82 | QVPLRPMTYK | HLA-B27 | |
| (SEQ.ID NO.：256) | |||||
| HIV-1 | GP41 | 590-597 | RYLKDQQL | HLA-B27 | |
| (SEQ.ID NO.：257) | |||||
| HIV-1 | nef | 105-114 | RRQDILDLWI | HLA-B*2705 | |
| (SEQ.ID NO.：258) | |||||
| HIV-1 | nef | 134-141 | RYPLTFGW | HLA-B*2705 | |
| (SEQ.ID NO.：259) | |||||
| HIV-1 | p17 | 36-44 | WASRELERF | HLA-B35 | |
| (SEQ.ID NO.：260) | |||||
| HIV-1 | GAGP24 | 262-270 | TVLDVGDAY | HLA-B35 | |
| (SEQ.ID NO.：261) | |||||
| HIV-1 | gp120 | 42-52 | VPVWKEATTTL | HLA-B35 | |
| (SEQ.ID NO.：262) | |||||
| HIV-1 | P17 | 36-44 | NSSKVSQNY | HLA-B35 | |
| (SEQ.ID NO.：263) | |||||
| HIV-1 | gagp24 | 254-262 | PPIPVGDIY | HLA-B35 | |
| (SEQ.ID NO.：264) | |||||
| HIV-1 | RT | 342-350 | HPDIVIYQY | HLA-B35 | |
| (SEQ.ID NO.：265) | |||||
| HIV-1 | gp41 | 611-619 | TAVPWNASW | HLA-B35 | |
| (SEQ.ID NO.：266) | |||||
| HIV-1 | gag | 245-253 | NPVPVGNIY | HLA-B35 | |
| (SEQ.ID NO.：267) | |||||
| HIV-1 | nef | 120-128 | YFPDWQNYT | HLA-B37 | |
| (SEQ.ID NO.：268) | |||||
| HIV-1 | gagp24 | 193-201 | GHQAAMQML | HLA-B42 | |
| (SEQ.ID NO.：269) | |||||
| HIV-1 | p17 | 20-29 | RLRPGGKKKY | HLA-B42 |
| (SEQ.ID NO.：270) | ||||
| HIV-1 | RT | 438-446 | YPGIKVRQL | HLA-B42 |
| (SEQ.ID NO.：271) | ||||
| HIV-1 | RT | 591-600 | GAETFYVDGA | HLA-B45 |
| (SEQ.ID NO.：272) | ||||
| HIV-1 | gagp24 | 325-333 | NANPDCKTI | HLA-B51 |
| (SEQ.ID NO.：273) | ||||
| HIV-1 | gagp24 | 275-282 | RMYSPTSI | HLA-B52 |
| (SEQ.ID NO.：274) | ||||
| HIV-1 | gp120 | 42-51 | VPVWKEATTT | HLA-B*5501 |
| (SEQ.ID NO.：275) | ||||
| HIV-1 | gagp24 | 147-155 | ISPRTLNAW | HLA-B57 |
| (SEQ.ID NO.：276) | ||||
| HIV-1 | gagp24 | 240-249 | TSTLQEQIGW | HLA-B57 |
| (SEQ.ID NO.：277) | ||||
| HIV-1 | gagp24 | 162-172 | KAFSPEVIPMF | HLA-B57 |
| (SEQ.ID NO.：278) | ||||
| HIV-1 | gagp24 | 311-319 | QASQEVKNW | HLA-B57 |
| (SEQ.ID NO.：279) | ||||
| HIV-1 | gagp24 | 311-319 | QASQDVKNW | HLA-B57 |
| (SEQ.ID NO.：280) | ||||
| HIV-1 | nef | 116-125 | HTQGYFPDWQ | HLA-B57 |
| (SEQ.ID NO.：281) | ||||
| HIV-1 | nef | 120-128 | YFPDWQNYT | HLA-B57 |
| (SEQ.ID NO.：282) | ||||
| HIV-1 | gagp24 | 240-249 | TSTLQEQIGW | HLA-B58 |
| (SEQ.ID NO.：283) | ||||
| HIV-1 | p17 | 20-29 | RLRPGGKKKY | HLA-B62 |
| (SEQ.ID NO.：284) | ||||
| HIV-1 | p24 | 268-277 | LGLNKJVRMY | HLA-B62 |
| (SEQ.ID NO.：285) | ||||
| HIV-1 | RT | 415-426 | LVGKLNWASQIY | HLA-B62 |
| (SEQ.ID NO.：286) | ||||
| HIV-1 | RT | 476-485 | ILKEPVHGVY | HLA-B62 |
| (SEQ.ID NO.：287) | ||||
| HIV-1 | nef | 117-127 | TQGYFPDWQNY | HLA-B62 |
| (SEQ.ID NO.：288) | ||||
| HIV-1 | nef | 84-91 | AVDLSHFL | HLA-B62 |
| (SEQ.ID NO.：289) | ||||
| HIV-1 | gagp24 | 168-175 | VIPMFSAL | HLA-Cw*0102 |
| (SEQ.ID NO.：290) | ||||
| HIV-1 | gp120 | 376-384 | FNCGGEFFY | HLA-A29 |
| (SEQ.ID NO.：291) | ||||
| HIV-1 | gp120 | 375-383 | SFNCGGEFF | HLA-B15 |
| (SEQ.ID NO.：292) | ||||
| HIV-1 | nef | 136-145 | PLIGWCYKL | HLA-A*0201 |
| (SEQ.ID NO.：293) | ||||
| HIV-1 | nef | 180-189 | VLEWRFDSRL | HLA-A*0201 |
| (SEQ.ID NO.：294) | ||||
| HIV-1 | nef | 68-77 | FPVTPQVPLR | HLA-B7 |
| (SEQ.ID NO.：295) | ||||
| HIV-1 | nef | 128-137 | TPGPGVRYPL | HLA-B7 |
| (SEQ.ID NO.：296) | ||||
| HIV-1 | gagp24 | 308-316 | QASQEVKNW | HLA-Cw*0401 |
| (SEQ.ID NO.：297) | ||||
| HIV-1 IIIB | RT | 273-282 | VPLDEDFRKY | HLA-B35 |
| (SEQ.ID NO.：298) | ||||
| HIV-1 IIIB | RT | 25-33 | NPDIVIYQY | HLA-B35 |
| (SEQ.ID NO.：299) | ||||
| HIV-1 IIIB | gp41 | 557-565 | RAIEAQAHL | HLA-B51 |
| (SEQ.ID NO.：300) | ||||
| HIV-1 IIIB | RT | 231-238 | TAFTIPSI | HLA-B51 |
| (SEQ.ID NO.：301) | ||||
| HIV-1 IIIB | p24 | 215-223 | VHPVHAGPIA | HLA-B*5501 |
| (SEQ.ID NO.：302) | ||||
| HIV-1 IIIB | gp120 | 156-165 | NCSFNISTSI | HLA-Cw8 |
| (SEQ.ID NO.：303) | ||||
| HIV-I IIIB | gp120 | 241-249 | CTNVSTVQC | HLA-Cw8 |
| (SEQ.ID NO.：304) | ||||
| HIV-1 5F2 | gp120 | 312-320 | IGPGRAFHT | H2-Dd |
| (SEQ.ID NO.：305) | ||||
| HIV-1 5F2 | pol | 25-33 | NPDIVIYQY | HLA-B*3501 |
| (SEQ.ID NO.：306) | ||||
| HIV-1 5F2 | pol | 432-441 | EPIVGAETFY | HLA-B*3501 |
| (SEQ.ID NO.：307) | ||||
| HIV-1 5F2 | pol | 432-440 | EPIVGAETF | HLA-B*3501 |
| (SEQ.ID NO.：308) | ||||
| HIV-1 5F2 | pol | 6-14 | SPAIFQSSM | HLA-B*3501 |
| (SEQ.ID NO.：309) | ||||
| HIV-1 5F2 | pol | 59-68 | VPLDKDFRKY | HLA-B*3501 |
| (SEQ.ID NO.：310) | ||||
| HIV-1 5F2 | pol | 6-14 | IPLTEEAEL | HLA-B*3501 |
| (SEQ.ID NO.：311) | ||||
| HIV-1 5F2 | nef | 69-79 | RPQVPLRPMTY | HLA-B*3501 |
| (SEQ.ID NO.：312) | ||||
| HIV-1 5F2 | nef | 66-74 | FPVRPQVPL | HLA-B*3501 |
| (SEQ.ID NO.：313) | ||||
| HIV-1 5F2 | env | 10-18 | DPNPQEVVL | HLA-B*3501 |
| (SEQ.ID NO.：314) | ||||
| HIV-1 5F2 | env | 7-15 | RPIVSTQLL | HLA-B*3501 |
| (SEQ.ID NO.：315) | ||||
| HIV-1 5F2 | pol | 6-14 | IPLTEEAEL | HLA-B51 |
| (SEQ.ID NO.：316) | ||||
| HIV-1 5F2 | env | 10-18 | DPNPQEVVL | HLA-B51 |
| (SEQ.ID NO.：317) | ||||
| HIV-1 5F2 | gagp24 | 199-207 | AMQMLKETI | H2-Kd |
| (SEQ.ID NO.：318) | ||||
| HIV-2 | gagp24 | 182-190 | TPYDrNQML | HLA-B*5301 |
| (SEQ.ID NO.：319) | ||||
| HIV-2 | gag | 260-269 | RRWIQLGLQKV | HLA-B*2703 |
| (SEQ.ID NO.：320) |
| HIV-1 5F2 | gp41 | 593-607 | GIWGCSGKLICTTAV | HLA-B17 | |
| (SEQ.ID NO.：321) | |||||
| HIV-1 5F2 | gp41 | 753-767 | ALIWEDLRSLCLFSY | HLA-B22 | |
| (SEQ.ID NO.：322) | |||||
| HPV 6b | E7 | 21-30 | GLHCYEQLV | HLA-A*0201 | |
| (SEQ.ID NO.：323) | |||||
| HPV 6b | E7 | 47-55 | PLKQHFQIV | HLA-A*0201 | |
| (SEQ.ID NO.：324) | |||||
| HPV11 | E7 | 4-12 | RLVTLKDIV | HLA-A*0201 | |
| (SEQ.ID NO.：325) | |||||
| HPV16 | E7 | 86-94 | TLGVICPIC | HLA-A*0201 | |
| (SEQ.ID NO.：326) | |||||
| HPV16 | E7 | 85-93 | GTLGIVCPI | HLA-A*0201 | |
| (SEQ.ID NO.：327) | |||||
| HPV16 | E7 | 12-20 | MLDLQPETT | HLA-A*0201 | |
| (SEQ.ID NO.：328) | |||||
| HPV16 | E7 | 11-20 | YMLDLQPETT | HLA-A*0201 | |
| (SEQ.ID NO.：329) | |||||
| HPV16 | E6 | 15-22 | RPRKLPQL | HLA-B7 | |
| (SEQ.ID NO.：330) | |||||
| HPV16 | E6 | 49-57 | RAHYNIVTF | HW-Db | |
| (SEQ.ID NO.：331) | |||||
| HSV | gp B | 498-505 | SSIEFARL | H2-Kb | |
| (SEQ.DI NO.：332) | |||||
| HSV-1 | gp C | 480-488 | GIGIGVLAA | HLA-A*0201 | |
| (SEQ.ID NO.：333) | |||||
| HSV-1 | ICP27 | 448-456 | DYATLGVGV | H2-Kd | |
| (SEQ.ID NO.：334) | |||||
| 病毒 | 蛋白质 | T细胞表位MHC配体(抗原) | MHC分子 | ||
| HSV-1 | ICP27 | 322-332 | LYRTFAGNPRA | H2-Kd | |
| (SEQ.ID NO.：335) | |||||
| HSV-1 | UL39 | 822-829 | QTFDFGRL | H2-Kb | |
| (SEQ.ID NO.：336) | |||||
| HSV-2 | gpC | 446-454 | GAGIGVAVL | HLA-A*0201 | |
| (SEQ.ID NO.：337) | |||||
| HLTV-1 | TAX | 11-19 | LLFGYPVYV | HLA-A*0201 | |
| (SEQ.ID NO.：338) | |||||
| 流感 | MP | 58-66 | GILGFVFTL | HLA-A*0201 | |
| (SEQ.ID NO.：339) | |||||
| 流感 | MP | 59-68 | ILGFVFTLTV | HLA-A*0201 | |
| (SEQ.ID NO.：340) | |||||
| 流感 | NP | 265-273 | ILRGSVAHK | HLA-A3 | |
| (SEQ.ID NO.：341) | |||||
| 流感 | NP | 91-99 | KTGGPTYKR | HLA-A*6801 | |
| (SEQ.ID NO.：342) | |||||
| 流感 | NP | 380-388 | ELRSRYWAI | HLA-B8 | |
| (SEQ.ID NO.：343) | |||||
| 流感 | NP | 381-388 | LRSRYWAI | HLA-B*2702 | |
| (SEQ.ID NO.：344) | |||||
| 流感 | NP | 339-347 | EDLVLSFI | HLA-B*3701 | |
| (SEQ.ID NO.：345) | |||||
| 流感 | NSI | 158-166 | GEISPLPSL | HLA-B44 | |
| (SEQ.ID NO.：346) | |||||
| 流感 | NP | 338-346 | FEDLRVLSF | HLA-B44 | |
| (SEQ.ID NO.：347) | |||||
| 流感 | NSI | 158-166 | GEISPLPSL | HLA-B*4402 | |
| (SEQ.ID NO.：348) | |||||
| 流感 | NP | 338-346 | FEDLRVLSF | HLA-B*4402 | |
| (SEQ.ID NO.：349) | |||||
| 流感 | PBI | 591-599 | VSDGGPKLY | HLA-A1 | |
| (SEQ.ID NO.：350) | |||||
| 流感A | NP | 44-52 | CTELKLSDY | HLA-A1 | |
| (SEQ.ID NO.：351) | |||||
| 流感 | NSI | 122-130 | AIMDKNIIL | HLA-A*0201 | |
| (SEQ.ID NO.：352) | |||||
| 流感A | NSI | 123-132 | IMDKNIILKA | HLA-A*0201 | |
| (SEQ.ID NO.：353) | |||||
| 流感A | NP | 383-391 | SRYWAIRTR | HLA-B*2705 | |
| (SEQ.ID NO.：354) | |||||
| 流感A | NP | 147-155 | TYQRTRALV | H2-Kd | |
| (SEQ.ID NO.：355) | |||||
| 流感A | HA | 210-219 | TYVSVSTSTL | H2-Kd | |
| (SEQ.ID NO.：356) | |||||
| 流感A | HA | 518-526 | IYSTVASSL | H2-Kd | |
| (SEQ.ID NO.：357) | |||||
| 流感A | HA | 259-266 | FEANGNLI | H2-Kk | |
| (SEQ.ID NO.：358) | |||||
| 流感A | HA | 10-18 | IEGGWTGM1 | H2-Kk | |
| (SEQ.ID NO.：359) | |||||
| 流感A | NP | 50-57 | SDYEGRLI | H2-Kk | |
| (SEQ.ID NO.：360) | |||||
| 流感a | NSI | 152-160 | EEGAIVGEI | H2-Kk | |
| (SEQ.ID NO.：361) | |||||
| 流感A34 | NP | 336-374 | ASNENMETM | H2Db | |
| (SEQ.ID NO.：362) | |||||
| 流感A68 | NP | 366-374 | ASNENMDAM | H2Db | |
| (SEQ.ID NO.：363) | |||||
| 流感B | NP | 85-94 | KLGEFYNQMM | HLA-A*0201 | |
| (SEQ.ID NO.：364) | |||||
| 流感B | NP | 85-94 | KAGEFYNQMM | HLA-A*0201 | |
| (SEQ.ID NO.：365) | |||||
| 流感JAP | HA | 204-212 | LYQNVGTYV | H2Kd | |
| (SEQ.ID NO.：366) | |||||
| 流感JAP | HA | 210-219 | TYVSVGTSTL | H2-Kd | |
| (SEQ.ID NO.：367) | |||||
| 流感JAP | HA | 523-531 | VYQILATYA | H2-Kd | |
| (SEQ.ID NO.：368) | |||||
| 流感JAP | HA | 529-537 | IYATVAGSL | H2-Kd | |
| (SEQ.ID NO.：369) | |||||
| 流感JAP | HA | 210-219 | TYVSVGTSTI(L＞I) | H2-Kd | |
| (SEQ.ID NO.：370) | |||||
| 流感 JAP | HA | 255-262 | FESTGNLI | H2-Kk |
| (SEQ.ID NO.：371) | ||||
| JHMV | cAg | 318-326 | APTAGAFFF | H2-Ld |
| (SEQ.ID NO.：372) | ||||
| LCMV | NP | 118-126 | RPQASGVYM | H2-Ld |
| (SEQ.ID NO.：373) | ||||
| LCMV | NP | 396-404 | FQPQNGQFI | H2-Db |
| (SEQ.ID NO.：374) | ||||
| LCMV | GP | 276-286 | SGVENPGGYCL | H2-Db |
| (SEQ.ID NO.：375) | ||||
| LCMV | GP | 33-42 | KAVYNFATCG | H2-Db |
| (SEQ.ID NO.：376) | ||||
| MCMV | pp89 | 168-176 | YPHFMPTNL | H2-Ld |
| (SEQ.ID NO.：377) | ||||
| MHV | 刺突蛋白 | 510-518 | CLSWNGPHL | H2-Db |
| (SEQ.ID NO.：378) | ||||
| MMTV | env gp36 | 474-482 | SFAVATTAL | H2-Kd |
| (SEQ.ID NO.：379) | ||||
| MMTV | gag p27 | 425-433 | SYETFISRL | H2-Kd |
| (SEQ.ID NO.：380) | ||||
| MMTV | env gp73 | 544-551 | ANYDFICV | H2-Kb |
| (SEQ.ID NO.：381) | ||||
| MuLV | env p15E | 574-581 | KSPWFTTL | H2-Kb |
| (SEQ.ID NO.：382) | ||||
| MuLV | env gp70 | 189-196 | SSWDFITV | H2-Kb |
| (SEQ.ID NO.：383) | ||||
| MuLV | gag 75K | 75-83 | CCLCLTVFL | H2-Db |
| (SEQ.ID NO.：384) | ||||
| MuLV | env gp70 | 423-431 | SPSYVYHQF | H2Ld |
| (SEQ.ID NO.：385) | ||||
| MV | F蛋白 | 437-447 | SRRYPDAVYLH | HLA-B*2705 |
| (SEQ.ID NO.：386) | ||||
| Mv | F蛋白 | 438-446 | RRYPDAVYL | HLA-B*2705 |
| 病毒 | 蛋白质 | AA位置 | T细胞表位MHC配体(抗原) | MHC分子 |
| (SEQ.ID NO.：387) | ||||
| Mv | NP | 281-289 | YPALGLHEF | H2-Ld |
| (SEQ.ID NO.：388) | ||||
| Mv | HA | 343-351 | DPVIDRLYL | H2-Ld |
| (SEQ.ID NO.：389) | ||||
| MV | HA | 544-552 | SPGRSFSYF | H2-Ld |
| (SEQ.ID NO.：390) | ||||
| 脊髓灰质炎病毒 | VP1 | 111-118 | TYKDTVQL | H2-kd |
| (SEQ.ID NO.：391) | ||||
| 脊髓灰质炎病毒 | VP1 | 208-217 | FYDGFSKVPL | H2-Kd |
| (SEQ.ID NO.：392) | ||||
| 假狂犬病毒gp | G111 | 455-463 | IAGIGILAI | HLA-A*0201 |
| (SEQ.ID NO.：393) | ||||
| 狂犬病毒 | NS | 197-205 | VEAEIAHQI | H2-Kk |
| (SEQ.ID NO.：394) | ||||
| 轮状病毒 | VP7 | 33-40 | 11YRFLL1 | H2-Kb |
| (SEQ.ID NO.：395) | ||||
| 轮状病毒 | VP6 | 376-384 | VGPVFPPGM | H2-Kb |
| (SEQ.ID NO.：396) | ||||
| 轮状病毒 | VP3 | 585-593 | YSGYIFRDL | H2-Kb |
| (SEQ.ID NO.：397) | ||||
| RSV | M2 | 82-90 | SYIGSINNI | H2-Kd |
| (SEQ.ID NO.：398) | ||||
| SIV | gagp11C | 179-190 | EGCTPYDTNQML | Mamu-A*01 |
| (SEQ.ID NO.：399) | ||||
| SV | NP | 324-332 | FAPGNYPAL | H2-Db |
| (SEQ.ID NO.：400) | ||||
| SV | NP | 324-332 | FAPCTNYPAL | H2-Kb |
| (SEQ.ID NO.：401) | ||||
| SV40 | T | 404-411 | VVYDFLKC | H2-Kb |
| (SEQ.ID NO.：402) | ||||
| SV40 | T | 206-215 | SAINNYAQKL | H2-Db |
| (SEQ.ID NO.：403) | ||||
| SV40 | T | 223-231 | CKGVNKEYL | H2-Db |
| (SEQ.ID NO.：404) | ||||
| SV40 | T | 489-497 | QGINNLDNL | H2-Db |
| (SEQ.ID NO.：405) | ||||
| SV40 | T | 492-500(501) | NNLDNLRDY(L) | H2-Db |
| (SEQ.ID NO.：406) | ||||
| SV40 | T | 560-568 | SEFLLEKRI | H2-Kk |
| (SEQ.ID NO.：407) | ||||
| VSV | NP | 52-59 | RGYVYQGL | H2-Kb |
| (SEQ.ID NO.：408) |
表2
| HLA-A1 | 位置(抗原) | 来源 |
| T细胞表位 | EADPTGHSY | MAGE-1 161-169 |
| (SEQ.ID NO.：409) | ||
| VSDGGPNLY | 流感APB 1591-599 | |
| (SEQ.ID NO.：410) | ||
| CTELKLSDY | 流感A NP 44-52 | |
| (SEQ.ID NO.：411) | ||
| EVDPIGHLY | MAGE-3 168-176 | |
| (SEQ.ID NO.：412) | ||
| HLA-A201 | MLLSVPLLLG | 钙网蛋白信号序列1-10 |
| (SEQ,ID NO.：413) | ||
| STBXQSGXQ | HBV PRE-S 蛋白 141-149 | |
| (SEQ.ID NO.：414) | ||
| YMDGTMSQV | 酪氨酸酶369-377 | |
| (SEQ.ID NO.：415) | ||
| ILKEPVHGV | HIV-IRT 476-484 | |
| (SEQ.ID NO.：416) | ||
| LLGFVFTLTV | 流感MP 59-68 | |
| (SEQ.ID NO.：417) | ||
| LLFGYPVYVV | HTLV-1 tax 11-19 | |
| (SEQ.ID NO.：418) | ||
| GLSPTVWLSV | HBV sAg 348-357 | |
| (SEQ.ID NO.：419) | ||
| WLSLLVPFV | HBV sAg 335-343 | |
| (SEQ.ID NO.：420) | ||
| FLPSDFFPSV | HBV cAg 18-27 | |
| (SEQ.ID NO.：421) | ||
| CLG0LLTMV | EBV LMP-2 426-434 | |
| (SEQ.ID NO.：422) | ||
| FLAGNSAYEYV | HCMV gp 618-628B | |
| (SEQ.ID NO.：423) | ||
| KLGEFYNQMM | 流感BNP 85-94 | |
| (SEQ.ID NO.：424) | ||
| KLVALGINAV | HCV-1 NS3 400-409 | |
| (SEQ.ID NO.：425) | ||
| DLMGYIPLV | HCV MP 17-25 | |
| (SEQ.ID NO.：426) | ||
| RLVTLKDIV | HPV 11 EZ 4-12 | |
| (SEQ.ID NO.：427) | ||
| MLLAVLYCL | 酪氨酸酶1-9 | |
| (SEQ.ID NO.：428) | ||
| AAGIGILTV | Melan AMart-127-35 | |
| (SEQ.ID NO.：429) | ||
| YLEPGPVTA | Pmel 17/gp 100 480-488 | |
| (SEQ.ID NO.：430) | ||
| ILDGTATLRL | Pmel 17/gp 100 457-466 |
| (SEQ.ID NO.：431) | ||
| LLDGTATLRL | Pmel gp 100 457-466 | |
| (SEQ.ID NO.：432) | ||
| ITDQVPFSV | Pmel gp 100 209-217 | |
| (SEQ.ID NO.：433) | ||
| KTWGQYWQV | Pmel gp 100 154-162 | |
| (SEQ.ID NO.：434) | ||
| TITDQVPFSV | Pmel gp 100 208-217 | |
| (SEQ.ID NO.：435) | ||
| AFHIIVAREL | HIV-I nef 190-198 | |
| (SEQ.ID NO.：436) | ||
| YLNKIQNSL | P.falciparum CSP 334-342 | |
| (SEQ.ID NO.：437) | ||
| MMRKLAILSV | P.falciparum CSP 1-10 | |
| (SEQ.ID NO.：438) | ||
| KAGEFYNQMM | 流感BNP 85-94 | |
| (SEQ.ID NO.：439) | ||
| NIAEGLRAL | EBNA-1 480-488 | |
| (SEQ.ID NO.：440) | ||
| NLRRGTALA | EBNA-1 519-527 | |
| (SEQ.ID NO.：441) | ||
| ALAIPQCRL | EBNA-1 525-533 | |
| (SEQ.ID NO.：442) | ||
| VLKDAIKDL | EBNA-1 575-582 | |
| (SEQ.ID NO.：443) | ||
| FMVFLQTHI | EBNA-1 562-570 | |
| (SEQ.ID NO.：444) | ||
| HLIVDTDSL | EBNA-2 15-23 | |
| (SEQ.ID NO.：445) | ||
| SLGNPSLSV | EBNA-2 22-30 | |
| (SEQ.ID NO.：446) | ||
| PLASAMRML | EBNA-2 126-134 | |
| (SEQ.ID NO.：447) | ||
| RMLWMANYI | EBNA-2 132-140 | |
| (SEQ.ID NO.：448) | ||
| MLWMANYIV | EBNA-2 133-141 | |
| (SEQ.ID NO.：449) | ||
| ILPQGPQTA | EBNA-2 151-159 | |
| (SEQ.ID NO.：450) | ||
| PLRPTAPTTI | EBNA-2 171-179 | |
| (SEQ.ID NO.：451) | ||
| PLPPATLTV | EBNA-2 205-213 | |
| (SEQ.ID NO.：452) | ||
| RMHLPVLHV | EBNA-2 246-254 | |
| (SEQ.ID NO.：453) | ||
| PMPLPPSQL | EBNA-2 287-295 | |
| (SEQ.ID NO.：454) | ||
| QLPPPAAPA | EBNA-2 294-302 |
| (SEQ.ID NO.：455) | ||
| SMPELSPVL | EBNA-2 381-389 | |
| (SEQ.ID NO.：456) | ||
| DLDESWDYI | EBNA-2 453-461 | |
| (SEQ.ID NO.：457) | ||
| PLPCVLWPVV | BZLF1 43-51 | |
| (SEQ.ID NO.：458) | ||
| SLEECDSEL | BZLF1 167-175 | |
| (SEQ,ID NO.：459) | ||
| EIKRYKNRV | BZLFI 176-184 | |
| (SEQ.ID NO.：460) | ||
| QLLQFIYREV | BZLF1 195-203 | |
| (SEQ.ID NO.：461) | ||
| LLQHYREVA | BZLFI 196-204 | |
| (SEQ.ID NO.：462) | ||
| LLKQMCPSL | BZLFI 217-225 | |
| (SEQ.ID NO.：463) | ||
| SIIPRTPDV | BZLFI 229-237 | |
| (SEQ.ID NO.：464) | ||
| AIMDKNIIL | 流感A NS1 122-130 | |
| (SEQ.ID NO.：465) | ||
| IMDKNIILKA | 流感A NS1 123-132 | |
| (SEQ.ID NO.：466) | ||
| LLALLSCLTV | HCV MP 63-72 | |
| (SEQ.ID NO.：467) | ||
| ILHTPGCV | HCV MP 105-112 | |
| (SEQ.ID NO.：468) | ||
| QLRRHIDLLV | HCV env E 66-75 | |
| (SEQ,ID NO.：469) | ||
| DLCGSVFLV | HCV env E 88-96 | |
| (SEQ.ID NO.：470) | ||
| SMVGNWAKV | HCV env E 172-180 | |
| (SEQ.ID NO.：471) | ||
| HLHQNIVDV | HCV NSI 308-316 | |
| (SEQ.ID NO.：472) | ||
| FLLLADARV | HCV NSI 340-348 | |
| (SEQ.ID NO.：473) | ||
| GLRDLAVAVEPVV | HCV NS2 234-246 | |
| (SEQ.ID NO.：474) | ||
| SLLAPGAKQNV | HCV NS1 18-28 | |
| (SEQ.ID NO.：475) | ||
| LLAPGAKQNV | HCV NS1 19-28 | |
| (SEQ.ID NO.：476) | ||
| FLLSLGIHL | HBV pol 575-583 | |
| (SEQ.ID NO.：477) | ||
| SLYADSPSV | HBV pol 816-824 | |
| (SEQ.ID NO.：478) | ||
| GLSRYVARL | HBV POL 455-463 |
| (SEQ.ID NO.：479) | ||
| KIFGSLAFL | HER-2 369-377 | |
| (SEQ.ID NO.：480) | ||
| ELVSEFSRM | HER-2 971-979 | |
| (SEQ.ID NO.：481) | ||
| KLTPLCVTL | HIV-I gp 160 120-128 | |
| (SEQ.ID NO.：482) | ||
| SLLNATDIAV | HIV-I GP 160 814-823 | |
| (SEQ.ID NO.：483) | ||
| VLYRYGSFSV | Pmel gp100 476-485 | |
| (SEQ.ID NO.：484) | ||
| YIGEVLVSV | 无细丝形成I型肌球蛋白家族(HA-2)** | |
| (SEQ.ID NO.：485) | ||
| LLFNILGGWV | HCV NS4 192-201 | |
| (SEQ.ID NO.：486) | ||
| LLVPFVQWFW | HBV env 338-347 | |
| (SEQ.DI NO.：487) | ||
| ALMPLYACI | HBV pol 642-650 | |
| (SEQ.ID NO.：488) | ||
| YLVAYQATV | HCV NS3 579-587 | |
| (SEQ.ID NO.：489) | ||
| TLGIVCPIC | HIPV 16 E7 86-94 | |
| (SEQ.ID NO.：490) | ||
| YLLPRRGPRL | HCV 核心蛋白 34-43 | |
| (SEQ.ID NO.：491) | ||
| LLPIFFCLWV | HBV env 378-387 | |
| (SEQ.ID NO.：492) | ||
| YMDDVVLGA | HBV Pol 538-546 | |
| (SEQ.ID NO.：493) | ||
| GTLGIVCPI | HPV16 E7 85-93 | |
| (SEQ.ID NO.：494) | ||
| LLALLSCLTI | HCV MP 63-72 | |
| (SEQ.ID NO.：495) | ||
| MLDLQPETT | HPV 16 E7 12-20 | |
| (SEQ.ID NO.：496) | ||
| SLMAFTAAV | HCV NS4 174-182 | |
| (SEQ.ID NO.：497) | ||
| CINGVCWTV | HCV NS3 67-75 | |
| (SEQ.ID NO.：498) | ||
| VMNILLQYVV | 谷氨酸脱羧酶114-123 | |
| (SEQ.ID NO.：499) | ||
| ILTVILGVL | Melan A/Mart-32-40 | |
| (SEQ.ID NO.：500) | ||
| FLWGPRALV | MAGE-3 271-279 | |
| (SEQ.ID NO.：501) | ||
| LLCPAGHAV | HCV NS3 163-171 | |
| (SEQ.ID NO.：502) |
| ILDSFDPLV | HCV NSS 239-247 | |
| (SEQ.ID NO.：503) | ||
| LLLCLIFLL | HBV env 250-258 | |
| (SEQ.ID NO.：504) | ||
| LIDYQGMLPV | HBV env 260-269 | |
| (SEQ.ID NO.：505) | ||
| SIVSPFIPLL | HBV env 370-379 | |
| (SEQ.ID NO.：506) | ||
| FLLTRILTI | HBV env 183-191 | |
| (SEQ.ID NO.：507) | ||
| HLGNVKYLV | P.faciparum TRAP 3-11 | |
| (SEQ.ID NO.：508) | ||
| GIAGGLALL | P.faciparum TRAP 500-508 | |
| (SEQ.ID NO.：509) | ||
| ILAGYGAGV | HCV NS S4A 236-244 | |
| (SEQ.ID NO.：510) | ||
| GLQDCTMLV | HCV NS5 714-722 | |
| (SEQ.ID NO.：511) | ||
| TGAPVTYSTY | HCV NS3 281-290 | |
| (SEQ.ID NO.：512) | ||
| VIYQYMDDLV | HIV-1RT 179-187 | |
| (SEQ.ID NO.：513) | ||
| VLPDVFIRCV | N-乙酰葡糖胺基转移酶V Gnt-V 内含子 | |
| (SEQ.ID NO.：514) | ||
| VLPDVFIRC | N-乙酰葡糖胺基转移酶V Gnt-V 内含子 | |
| (SEQ.ID NO.：515) | ||
| AVGIGIAVV | 人CD9 | |
| (SEQ.ID NO.：516) | ||
| LVVLGLLAV | 人谷氨酰转移酶 | |
| (SEQ.ID NO.：517) | ||
| ALGLGLLPV | 人G蛋白偶联受体 | |
| (SEQ.ID NO.：518)164-172 | ||
| GIGIGVLAA | HSV-I gp C480-488 | |
| (SEQ.ID NO.：519) | ||
| GAGIGVAVL | HSV-2 gp C446-454 | |
| (SEQ.ID NO.：520) | ||
| IAGIGILAI | 假狂犬病gpGIN 455-463 | |
| (SEQ.ID NO.：521) | ||
| LIVIGILIL | 腺病毒3 E3 9kD 30-38 | |
| (SEQ.ID NO.：522) | ||
| LAGIGLIAA | S.Lincolnensis ImrA | |
| (SEQ.ID NO.：523) | ||
| VDGIGILTI | 酵母ysa-1 77-85 | |
| (SEQ.ID NO.：524) | ||
| GAGIGVLTA | B.polymyxa，βcndoxylanase 149-157 |
| (SEQ.ID NO.：525)157 | ||
| AAGIGIIQI | 大肠杆菌甲硫氨酸合酶590-598 | |
| (SEQ.ID NO.：526) | ||
| QAGIGILLA | 大肠杆菌假拟蛋白4-12 | |
| (SEQ.ID NO.：527) | ||
| KARDPHSGHFV | CDK4wl 22.32 | |
| (SEQ.ID NO.：528) | ||
| KACDPI-ISGIIFV | CDK4-R24C 22-32 | |
| (SEQ.ID NO.：529) | ||
| ACDPFISGHFV | CDK4-R24C 23-32 | |
| (SEQ.ID NO.：530) | ||
| SLYNTVATL | HIV-I gag p 17 77-85 | |
| (SEQ.ID NO.：531) | ||
| ELVSEFSRV | HER-2，m＞V 取代的 971-979 | |
| (SEQ.ID NO.：532) | ||
| RGPGRAFVTI | HIV-I gp 160 315-329 | |
| (SEQ.ID NO.：533) | ||
| HMWNFISGI | HCV NS4A 149-157 | |
| (SEQ.ID NO.：534) | ||
| NLVPMVATVQ | HCMV pp65 495-504 | |
| (SEQ.ID NO.：535) | ||
| GLHCYEQLV | HPV 6b E7 21-30 | |
| (SEQ.ID NO.：536) | ||
| PLKQHFQIV | HPV 6b E7 47-55 | |
| (SEQ.ID NO.：537) | ||
| LLDFVRFMGV | EBNA-6 284-293 | |
| (SEQ.ID NO.：538) | ||
| AIMEKNIML | 阿拉斯加流感NS 1 122-130 | |
| (SEQ.ID NO.：539) | ||
| YLKTIQNSL | P.falciparum cp36 CSP | |
| (SEQ.ID NO.：540) | ||
| YLNKIQNSL | P.falciparurn cp39 CSP | |
| (SEQ.ID NO.：541) | ||
| YMLDLQPETT | HPV 16 E7 11-20* | |
| (SEQ.ID NO.：542) | ||
| LLMGTLGIV | HPV16 E7 82-90** | |
| (SEQ.ID NO.：543) | ||
| TLGIVCPI | HPV 16 E7 86-93 | |
| (SEQ.ID NO.：544) | ||
| TLTSCNTSV | HIV-1 gp120 197-205 | |
| (SEQ.ID NO.：545) | ||
| KLPQLCTEL | HPV 16 E6 18-26 | |
| (SEQ.ID NO.：546) | ||
| TIHDIILEC | HPV16 E6 29-37 | |
| (SEQ.ID NO.：547) | ||
| LGIVCPICS | HPV16 E7 87-95 | |
| (SEQ.ID NO.：548) |
| VILGVLLLI | Melan a/Mart-1 35-43 | |
| (SEQ.ID NO.：549) | ||
| ALMDKSLHV | Melan A/Mart-1 56-64 | |
| (SEQ.ID NO.：550) | ||
| GILTVILGV | Melan A/Mart-1 31-39 | |
| (SEQ.ID NO.：551) | ||
| T细胞表位 | MINAYLDKL | P.Falciparum STARP 523-531 |
| (SEQ.ID NO.：552) | ||
| AAGIGILTV | Melan A/Mart-127-35 | |
| (SEQ.ID NO.：553) | ||
| FLPSDFFPSV | HBV cAg 18-27 | |
| (SEQ.ID NO.：554) | ||
| 未知基序 | SVRDRLARL | EBNA-3 464-472 |
| T细胞表位 | (SEQ.ID NO.：555) | |
| T细胞表位 | AAGIGILTV | Melan A/Mart-1 27-35 |
| (SEQ.ID NO.：556) | ||
| FAYDGKDYI | 人MHC I-ot 140-148 | |
| (SEQ.ID NO.：557) | ||
| T细胞表位 | AAGIGILTV | Melan A/Mart-1 27-35 |
| (SEQ.ID NO.：558) | ||
| FLPSDFFPSV | HBV cAg 18-27 | |
| (SEQ.ID NO.：559) | ||
| 未知基序 | AAGIGILTV | Meland A/Mart-1 27-35 |
| T细胞表位 | (SEQ.ID NO.：560) | |
| FLPSDFFPSV | HBV cAg 18-27 | |
| (SEQ.ID NO.：561) | ||
| AAGIGILTV | Melan A/Mart-1 27-35 | |
| (SEQ.ID NO.：562) | ||
| ALLAVGATK | Pmel17 gp 100 17-25 | |
| (SEQ.ID NO.：563) | ||
| RLRDLLLIVTR | HIV-1 gp41 768-778 | |
| T细胞表位 | (SEQ.ID NO.：564) | |
| QVPLRPMTYK | HIV-1 nef 73-82 | |
| (SEQ.ID NO.：565) | ||
| TVYYGVPVWK | HIV-1 gp120-36-45 | |
| (SEQ.ID NO.：566) | ||
| RLRPGGKKK | HIV-1 gag p17 20-29 | |
| (SEQ.ID NO.：567) | ||
| ILRGSVAHK | 流感NP 265-273 | |
| (SEQ.ID NO.：568) | ||
| RLRAEAGVK | EBNA-3 603-611 | |
| (SEQ.ID NO.：569) | ||
| RLRDLLLIVTR | HIV-1 gp41 770-780 | |
| (SEQ.ID NO.：570) | ||
| VYYGVPVWK | HIV-I GP 120 38-46 | |
| (SEQ.ID NO.：571) | ||
| RVCEKMALY | HCV NS5 575-583 | |
| (SEQ.ID NO.：572) |
| 未知基序 | KIFSEVTLK | 未知；突变黑素瘤肽ted(p I 83L)175-183 |
| T细胞表位 | (SEQ.DI NO.：573) | |
| YVNVNMGLK* | HBV cAg 88-96 | |
| (SEQ.ID NO.：574) | ||
| T细胞表位 | IVTDFSVIK | EBNA-4 416-424 |
| (SEQ.ID NO.：575) | ||
| ELNEALELK | P53 343-351 | |
| (SEQ.ID NO.：576) | ||
| VPLRPMTYK | HIV-1 NEF 74-82 | |
| (SEQ.ID NO.：577) | ||
| AIFQSSMTK | HIV-I gag p24 325-333 | |
| (SEQ.ID NO.：578) | ||
| QVPLRPMTYK | HIV-1 nef 73-82 | |
| (SEQ.ID NO.：579) | ||
| TINYTIFKHCV | NSI 238-246 | |
| (SEQ.ID NO.：580) | ||
| AAVDLSHFLKEK | HIV-1 nef 83-94 | |
| (SEQ.ID NO.：581) | ||
| ACQGVGGPGGHK | HIV-1 II 1B p24 349-359 | |
| (SEQ.ID NO.：581) | ||
| HLA-A24 | SYLDSGIHF* | β-连环蛋白，突变的(原-癌基因)29-37 |
| (SEQ.ID NO.：582) | ||
| T细胞表位 | RYLKDQQLL | HIV GP 41 583-591 |
| (SEQ.ID NO.：583) | ||
| AYGLDFYIL | P15 黑素瘤 Ag 10-18 | |
| (SEQ.ID NO.：584) | ||
| AFLPWHRLFL | 酪氨酸酶206-215 | |
| (SEQ.ID NO.：585) | ||
| AFLPWHRLF | 酪氨酸酶206-214 | |
| (SEQ.ID NO.：586) | ||
| RYSIFFDY | Ebna-3 246-253 | |
| (SEQ.ID NO.：587) | ||
| T细胞表位 | ETINEEAAEW | HIV-1 gag p24 203-212 |
| (SEQ.ID NO.：588) | ||
| T细胞表位 | STLPETTVVRR | HBV cAg 141-151 |
| (SEQ.ID NO.：589) | ||
| MSLQRQFLR | ORF 3P-gp75 294-321(bp) | |
| (SEQ.ID NO.：590) | ||
| LLPGGRPYR | TRP(酪氨酸酶rel.)197-205 | |
| (SEQ.ID NO.：591) | ||
| T细胞表位 | IVGLNKIVR | HIV gag p24 267-267-275 |
| (SEQ.ID NO.：592) | ||
| AAGIGILTV | Melan A/mart-127 35 | |
| (SEQ.ID NO.：593) |
表3列出了可用于本发明且可由路德维格癌症学会(Ludwig CancerInstitute)获得的其它抗原。该表提到了可以找到经鉴定抗原的专利。TRA指肿瘤相关抗原，LUD编号指路德维格学会编号。
表3
| TRA | LUDNo. | 专利号 | 专利授权日期 | 肽(抗原) | HLA |
| MAGE-4 | 5293 | 5,405,940 | 1995年4月11日 | EVDPASNTY | HLA-A1 |
| (SEQ.ID NO.：532) | |||||
| MAGE-41 | 5293 | 5,405,940 | 1995年4月11日 | EVDPTSNTY | HLA-A1 |
| (SEQ ID NO：533) | |||||
| MAGE-5 | 5293 | 5,405,940 | 1995年4月11日 | EADPTSNTY | HLA-A1 |
| (SEQ ID NO：534) | |||||
| MAGE-51 | 5293 | 5,405,940 | 1995年4月11日 | EADPTSNTY | HLA-A1 |
| (SEQ ID NO：534) | |||||
| MAGE-6 | 5294 | 5,405,940 | 1995年4月11日 | EVDPIGHVY | HLA-A1 |
| (SEQ ID NO：535) | |||||
| 5299.2 | 5,487,974 | 1996年1月30日 | MLLAVLYCLL | HLA-A2 | |
| (SEQ ID NO：536) | |||||
| 5360 | 5,530,096 | 1996年6月25日 | MLLAVLYCL | HLA-B44 | |
| (SEQ ID NO：537) | |||||
| 酪氨酸酶 | 5360.1 | 5,519,117 | 1996年5月21日 | SEIWRDIDFA | HLA-B44 |
| (SEQ ID NO：538) | |||||
| SEIWRDIDF | |||||
| (SEQ ID NO：539) | |||||
| 酪氨酸酶 | 5431 | 5,774,316 | 1998年4月28日 | XEIWRDIDF | HLA-B44 |
| (SEQ ID NO：540) | |||||
| MAGE-2 | 5340 | 5,554,724 | 1996年9月10日 | STLVEVTLGEV | HLA-A2 |
| (SEQ ID NO：541) | |||||
| LVEVTLGEV | |||||
| (SEQ ID NO：542) | |||||
| VIFSKASEYL | |||||
| (SEQ ID NO：543) | |||||
| IIVLAIIAI | |||||
| (SEQ ID NO：544) | |||||
| (续) | KIWEELSMLEV | ||||
| (SEQ ID NO：545) | |||||
| TRA | LUDNo. | 专利号 | 专利授权日期 | 肽(抗原) | HLA |
| LIETSYVKV | |||||
| (SEQ ID NO：546) | |||||
| 5327 | 5,585,461 | 1996年12月17日 | FLWGPRALV | HLA-A2 | |
| (SEQ ID NO：547) | |||||
| TLVEVTLGEV | |||||
| (SEQ ID NO：548) | |||||
| ALVETSYVKV | |||||
| (SEQ ID NO：549) | |||||
| MAGE-3 | 5344 | 5,554,506 | 1996年9月10日 | KIWEELSVL | HLA-A2 |
| (SEQ ID NO：550) | |||||
| MAGE-3 | 5393 | 5,405,940 | 1995年4月11日 | EVDPIGHLY | HLA-A1 |
| (SEQ ID NO：551) | |||||
| MAGE | 5293 | 5,405,940 | 1995年4月11日 | EXDX5Y | HLA-A1 |
| (SEQ.ID NO.：552) | |||||
| (但非EADPTGHSY) | |||||
| (SEQ.ID NO.：553) | |||||
| E(A/V)D X5 Y | |||||
| (SEQ.ID NO.：554) | |||||
| E(A/V)DP X4 Y | |||||
| (SEQ.ID NO.：555) | |||||
| E(A/V)DP(I/A/T)X3 Y | |||||
| (SEQ.ID NO.：556) | |||||
| E(A/V)DP(I/A/T)(G/S)X2 Y | |||||
| (SEQ.ID NO.：557) | |||||
| E(A/V)DP(I/A/T)(G/S)(H/N)XY | |||||
| E(A/V)DP(I/A/T)(G/S)(H/N)(L/T/V)Y | |||||
| (SEQ.11)NO.：559) | |||||
| MAGE-1 | 5361 | 5,558.995 | 1996年9月24日 | ELHSAYGEPRKLLTQD | HLA-C |
| (SEQ ID NO：560) | 克隆10 | ||||
| EHSAYGEPRKLL | |||||
| (SEQ ID NO：561) | |||||
| SAYGEPRKL | |||||
| (SEQ ID NO：562) | |||||
| MAGE-1 | 5253.4 | TBA | TBA | EADPTGHSY | HLA-A1 |
| (SEQ ID NO：563) |
| TRA | LUDNo. | 专利号 | 专利授权日期 | 肽(抗原) | HLA |
| BAGE | 5310.1 | TBA | TBA | MAARAVFLALSAQLLQARLMKE | HLA-C |
| (SEQ ID NO：564) | 克隆10 | ||||
| MAARAVFLALSAQLLQ | HLA-C | ||||
| (SEQ ID NO：565) | 克隆10 | ||||
| AARAVFLAL | HLA-C | ||||
| (SEQ ID NO：566) | 克隆10 | ||||
| GAGE | 5323.2 | 5,648,226 | 1997年7月15日 | YRPRPRRY | HLA-CW6 |
| (SEQ.ID NO.：567) |
表4
| 来源 | 蛋白质 | AA位置 | MHC分子 | T细胞表位MHC配体(抗原) | 参考文献 |
| 合成的肽 | 合成的肽 | 合成的肽 | HLA-A2 | ALFAAAAAV | Parker，等.，“Scheme forrankingpotential HLA-A2 bindingpeptides basedon independentbinding ofindividualpeptide side-chains，”J.Immunol.152：163-175 |
| “ | GIFGGVGGV | “ | |||
| “ | GLDKGGGV | “ | |||
| “ | GLFGGFGGV | “ | |||
| “ | GLFGGGAGV | “ | |||
| “ | GLFGGGEGV | “ | |||
| “ | GLFGGGFGV | “ | |||
| “ | GLFGGGGGL | “ | |||
| “ | GLFGGGGGV | “ | |||
| “ | GLFGGGVGV | “ | |||
| “ | GLFGGVGGV | “ | |||
| “ | GLFGGVGKV | “ | |||
| “ | GLFKGVGGV | “ | |||
| “ | GLGGGGFGV | “ | |||
| “ | GLLGGGVGV | “ | |||
| “ | GLYGGGGGV | “ | |||
| “ | GMFGGGGGV | “ | |||
| “ | GMFGGVGGV | “ | |||
| “ | GQFGGVGGV | “ | |||
| “ | GVFGGVGGV | “ | |||
| “ | KLFGGGGGV | “ | |||
| “ | KLFGGVGGV | “ | |||
| “ | AILGFVFTL | “ | |||
| “ | GAIGFVFTL | “ | |||
| “ | GALGFVFTL | “ | |||
| “ | GELGFVFTL | “ | |||
| “ | GIAGFVFTL | “ | |||
| “ | GIEGFVFTL | “ | |||
| “ | GILAFVFTL | “ | |||
| “ | GILGAVFTL | “ | |||
| “ | GILGEVFTL | “ |
| “ | GILFGAFTL | “ | |||
| “ | GILGFEFTL | “ | |||
| “ | GILGFKFTL | “ | |||
| “ | GILGFVATL | “ | |||
| “ | GILGFVETL | “ | |||
| “ | GILGFVFAL | “ | |||
| “ | GILGFVFEL | “ | |||
| “ | GILGFVFKL | “ | |||
| “ | GILGFVFTA | “ | |||
| “ | GILGFVFTL | “ | |||
| “ | GILGFVFVL | “ | |||
| “ | GILGFVKTL | “ | |||
| “ | GILGKVFTL | “ | |||
| “ | GILKFVFTL | “ | |||
| “ | GILPFVFTL | “ | |||
| “ | GIVGFVFTL | “ | |||
| “ | GKLGFVFTL | “ | |||
| “ | GLLGFVFTL | “ | |||
| “ | GQLGFVFTL | “ | |||
| “ | KALGFVFTL | “ | |||
| “ | KILGFVFTL | “ | |||
| “ | KILGKVFTL | “ | |||
| “ | AILLGVFML | “ | |||
| “ | AIYKRWIIL | “ | |||
| “ | ALFFFDIDL | “ | |||
| “ | ATVELLSEL | “ | |||
| “ | CLFGYPVYV | “ | |||
| “ | FIFPNYTIV | “ | |||
| “ | IISLWDSQL | “ | |||
| “ | ILASLFAAV | “ | |||
| “ | ILESLFAAV | “ | |||
| “ | KLGEFFNQM | “ | |||
| “ | KLGEFYNQM | “ | |||
| “ | LLFGYPVYV | “ | |||
| “ | LLWKGEGAV | “ | |||
| “ | LMFGYPVYV | “ | |||
| “ | LNFGYPVYV | “ | |||
| “ | LQFGYPVYV | “ | |||
| “ | NIVAHTFKV | “ | |||
| “ | NLPMVATV | “ | |||
| “ | QMLLAIARL | “ | |||
| “ | QMWQARLTV | “ | |||
| “ | RLLQTGIHV | “ | |||
| “ | RLVNGSLAL | “ | |||
| “ | SLYNTVATL | “ | |||
| “ | TLNAWVKVV | “ | |||
| “ | WLYRETCNL | “ |
| “ | YLFKRMIDL | “ | |||||
| “ | GAFGGVGGV | “ | |||||
| “ | GAFGGVGGY | “ | |||||
| “ | GEFGGVGGV | “ | |||||
| “ | GGFGGVGGV | “ | |||||
| “ | GIFGGGGGV | “ | |||||
| “ | GIGGFGGGL | “ | |||||
| “ | GIGGGGGGL | “ | |||||
| “ | GLDGGGGGV | “ | |||||
| “ | GLDGKGGGV | “ | |||||
| “ | GLDKKGGGV | “ | |||||
| “ | GLFGGGFGF | “ | |||||
| “ | GLFGGGFGG | “ | |||||
| “ | GLFGGGFGN | “ | |||||
| “ | GLFGGGFGS | “ | |||||
| “ | GLFGGGGGI | “ | |||||
| “ | GLFGGGGGM | “ | |||||
| “ | GLFGGGGGT | “ | |||||
| “ | GLFGGGGGY | “ | |||||
| “ | GLGFGGGGV | “ | |||||
| “ | GLGGFGGGV | “ | |||||
| “ | GLGGGFGGV | “ | |||||
| “ | GLGGGGGFV | “ | |||||
| “ | GLGGGGGGY | “ | |||||
| “ | GLGGGVGGV | “ | |||||
| “ | GLLGGGGGV | “ | |||||
| “ | GLPGGGGGV | “ | |||||
| “ | GNFGGVGGV | “ | |||||
| “ | GSFGGVGGV | “ | |||||
| “ | GTFGGVGGV | “ | |||||
| “ | AGNSAYEYV | “ | |||||
| “ | GLFPGQFAY | “ | |||||
| “ | HILLGVFML | “ | |||||
| “ | ILESLFRAV | “ | |||||
| “ | KKKYKLKHI | “ | |||||
| “ | MLASIDLKY | “ | |||||
| “ | MLERELVRK | “ | |||||
| “ | KLFGFVFTV | “ | |||||
| “ | ILDKKVEKV | “ | |||||
| “ | ILKEPVHGV | “ | |||||
| “ | ALFAAAAAY | “ | |||||
| “ | GIGFGGGGL | “ | |||||
| “ | GKFGGVGGV | “ | |||||
| “ | GLFGGGGGK | “ | |||||
| “ | EILGFVFTL | “ | |||||
| “ | GILGFVFTL | “ | |||||
| “ | GQLGFVFTK | “ | |||||
| “ | ILGFVFTLT | “ | |||
| “ | KILGFVFTK | “ | |||
| “ | KKLGFVFTL | “ | |||
| “ | KLFEKVYNY | “ | |||
| “ | LRFGYPVYV | “ | |||
| 人 | HSP60 | 140-148 | HLA-B27 | IRRGVMLAV | Rammensee等1997160 |
| “ | “ | 369-377 | “ | KRIQEIIEQ | “ |
| “ | “ | 469-477 | “ | KRTLKIPAM | “ |
| HSP60 | 35-43 | “ | GRNVVLDKS | “ | |
| “ | 117-125 | “ | KRGIDKAVI | “ | |
| “ | “ | 420-428 | “ | IRAASAITA | “ |
| “ | HSP 60 | 284-292 | HLA-B*2705 | RRKAMFEDI | 169 |
| 恶性疟原虫 | LSA-1 | 1850-1857 | HLA-B3501 | KPKDELDY | 170 |
| 流感NP | 379-387 | HLA-B*4402 | LELRSRYWA | 183 | |
| Tum-P35B | 4-13 | HLA-Dd | GPPHSNNFGY | 230 | |
| 轮状病毒 | VP7 | 33-40 | IIYRFLLI | 262 | |
| OGDH(F108Y) | 104-112 | H2-Ld | QLSPYPFDL | 253 | |
| TRP-2 | 181-188 | p287 | VYDFFVWL | 284 | |
| DEAD盒p 68 | 547-554 | p287 | SNFVFAGI | 283 | |
| 人造载体 | p287 | SVVEFSSL | 260 |
| 肿瘤抗原的表位模拟物 | p287 | AHYLFRNL | 278 | ||
| “ | THYLFRNL | “ | |||
| H-3 miH抗原的表位模拟物 | “ | LIVIYNTL | 279 | ||
| LIYEFNTL | “ | ||||
| “ | IPYIYNTL | “ | |||
| “ | IIYIYHRL | “ | |||
| “ | LIYIFNTL | “ | |||
| HBV cAg | 93-100 | “ | MGLKFRQL | 280 | |
| 人 | 自身抗原LA | 51-58 | “ | IMIKFRNRL | 281 |
| 小鼠 | UTY蛋白质 | H2Db | WMHHNMDLI | 303 | |
| 小鼠 | p53 | 232-240 | “ | KYMCNSSCM | 302 |
| 鼠 | MDM2 | 441-449 | “ | GRPKNGCIV | 277 |
| 天然表位模拟物 | “ | AQHPNAELL | 278 | ||
| MuLVgag75K | 75-83 | “ | CCLCLTVFL | 301 | |
| 恶性疟原虫 | CSP | 375-383 | p290 | YENDIEKK | 315 |
| “ | “ | 371-379 | “ | DELDYENDI | 315 |
| HIV | -1RT | 206-214 | “ | TEMEKEGKI | 316 |
| 狂犬病 | NS | 197-205 | “ | VEAEIAHQI | 309，310 |
| 流感A | NS1 | 152-160 | “ | EEGAIVGEI | 304 |
| 鼠 | SMCY | p291 | TENSGKDI | 317 | |
| I类MHC前导序列 | 3-11 | p293 | AMAPRTLLL | 318 | |
| ND1 alpha | 1-12 | p293 | FFINILTLLVP | 323 | |
| ND Beta | 1-12 | p293 | FFINILTLLVP | 323 | |
| ND alpha | 1-17 | “ | FFINILTLLVPILIAM | 324 | |
| ND Beta | 1-17 | “ | FFINALTLLVPILIAM | “ | |
| COI 线粒体 | 1-6 | “ | FINRW | 325 |
| L.单核细胞基因 | LemA | 1-6 | “ | IGWII | 326 |
| SIV gagp11C | 179-190 | Mamu-A*01 | EGCTPYDINQML | 334 | |
| MAGE-3 | HLA-A2 | ALSRKVAEL | 5,554,506 | ||
| “ | IMPKAGLLI | “ | |||
| “ | KIWEELSVL | “ | |||
| “ | ALVETSYVKV | “ | |||
| “ | ThrLeuValGluValThrLeuGlyGluVal | “ | |||
| “ | AlaLeuSerArgLysValAlaGluLeu | “ | |||
| “ | IleMetProLysAlaGlyLeuLeuIle | “ | |||
| “ | LysIleTrpGluGluLeuSerValLeu | “ | |||
| “ | AlaLeuValGluThrSerTyrValLysVal | “ | |||
| “ | |||||
| 结合MHC的肽 | HLA-A2 | Lys Gly Ile Leu GlyPhe Val Phe Thr LeuThr Val | 5,989,565 | ||
| “ | Gly Ile Ile Gly Phe ValPhe Thr Ile | “ | |||
| “ | Gly Ile Ile Gly Phe ValPhe Thr Leu | “ | |||
| “ | Gly Ile Leu Gly PheVal Phe Thr Leu | “ | |||
| “ | Gly Leu Leu Gly PheVal Phe Thr Leu | “ | |||
| “ | XXTVXXGVX，X＝Leu or Ile(6-37) | “ | |||
| “ | Ile Leu Thr Val Ile LeuGly Val Leu | “ | |||
| “ | Tyr Leu Glu Pro GlyPro Val Thr Ala | “ | |||
| “ | Gln Val Pro Leu ArgPro Met Thr Tyr Lys | “ |
| “ | Asp Gly Leu Ala ProPro Gln His Leu IleArg | “ | |||
| “ | Leu Leu Gly Arg AsnSer Phe Glu Val | “ | |||
| 来自MAGE-1的肽 | HLA-C克隆10 | GluHisSerAlaTyrGlyGluProArgLysLeuLeuThrGlnAspLeu | 5,558,995 | ||
| “ | GluHisSerAlaTyrGlyGluProArgLysLeuLeu | “ | |||
| “ | SerAlaTyrGlyGluProArgLysLeu | “ | |||
| GAGE | HLA-Cw6 | TyrArgProArgProArgArgTyr | 5,648,226 | ||
| “ | ThrTyrArgProArgProArgArgTyr | “ | |||
| “ | TyrArgProArgProArgArgTyrVal | “ | |||
| “ | ThrTyrArgProArgProArgArgTyrVal | “ | |||
| “ | ArgProArgProArgArgTyrValGlu | “ | |||
| “ | MetSerTrpArgGlyArgSerThrTyrArgProArgProArgArg | “ | |||
| “ | ThrTyrArgProArgProArgArgTyrValGluProProGluMetIle | “ | |||
| MAGE | HLA-A1，主要地 | 分离的九肽，其在N-末端具有Glu，在C-末端具有Tyr，在从N-末端开始的第三个残基具有Asp，条件是所述分离的九肽不是GluAla Asp Pro ThrGly His Ser Tyr(SEQ ID NO：1)，和其中所述分离的九肽在细胞上结合人白细胞抗原分子以形成复合物，所述复合物通过特异于所述复合物的细胞毒性T细胞激发所述细胞的裂解 | 5,405,940 |
| “ | GluValValProIleSerHisLeuTyr | “ | |||
| “ | GluValValArgIleGlyHisLeuTyr | “ | |||
| “ | GluValAspProIleGlyHisLeuTyr | “ | |||
| “ | GluVaLAspProAlaSerAsnThrTyr | “ | |||
| “ | GluValAspProThrSerAsnThrTyr | “ | |||
| “ | GluAlaAspProtHrSerAsnThrTyr | “ | |||
| “ | GluValAspProIleGlyHisValTyr | “ | |||
| “ | GAAGTGGTCCCCATCAGCCACTTGTAC | “ | |||
| “ | GAAGTGGTCCGCATCGGCCACTTGTAC | “ | |||
| “ | GAAGTGGACCCCATCGGCCACTTGTAC | “ | |||
| “ | GAAGTGGACCCCGCCAGCAACACCTAC | “ | |||
| “ | GAAGTGGACCCCACCAGCAACACCTAC | “ | |||
| “ | GAAGCGGACCCCACCAGCAACACCTAC | “ | |||
| “ | GAAGCGGACCCCACCAGCAACACCTAC | “ | |||
| “ | GAAGTGGACCCCATCGGCCACGTGTAC | “ | |||
| “ | GluAlaAspProThrGlyHisSer | “ | |||
| “ | AlaAspProTrpGlyHisSerTyr | “ | |||
| MAGE肽 | HLA-A2 | SerThrLeuValGluValThrLeuGlyGluVal | 5,554,724 | ||
| “ | “ | LeuValGluValThrLeuGlyGluVal | “ | ||
| “ | “ | LysMetValGluLeuValHisPheLeu | “ | ||
| “ | “ | ValIlePheSerLysAlaSerGluTyrLeu | “ | ||
| “ | “ | TyrLeuGlnLeuValPheGlyIleGluVal | “ |
| “ | “ | GlnLeuValPheGlyIleGluValVal | “ | ||
| “ | “ | GlnLeuValPheGlyIleGluValValGluVal | “ | ||
| “ | “ | IleIleValLeuAlaIleIleAlaIle | “ | ||
| “ | “ | LysIleTrpGluGluLeuSerMetLeuGluVal | “ | ||
| “ | “ | AlaLeuIleGluThrSerTyrValLysVal | “ | ||
| “ | “ | LeuIleGluThrSerTyrValLysVal | “ | ||
| “ | “ | GlyLeuGluAlaArgGlyGluAlaLeuGlyLeu | “ | ||
| “ | “ | GlyLeuGluAlaArgGlyGluAlaLeu | “ | ||
| “ | “ | AlaLeuGlyLeuValGlyAlaGlnAla | “ | ||
| “ | “ | GlyLeuValGlyAlaGlnAlaProAla | “ | ||
| “ | “ | AspLeuGluSerGluPheGlnAlaAla | “ | ||
| “ | “ | AspLeuGluSerGluPheGlnAlaAlaIle | “ | ||
| “ | “ | AlaIleSerArgLysMetValGluLeuVal | “ | ||
| “ | “ | AlaIleSerArgLysMetValGluLeu | “ | ||
| “ | “ | LysMetValGluLeuValHisPheLeuLeu | “ | ||
| “ | “ | LysMetValGluLeuValHisPheLeuLeuLeu | “ | ||
| “ | “ | LeuLeuLenLysTyrArgAlaArgGluProVal | “ | ||
| “ | “ | LeuLeuLysTyrArgAlaArgGluProVal | “ | ||
| “ | “ | ValLeuArgAsnCysGlnAspPhePheProVal | “ | ||
| “ | “ | TyrLeuGlnLeuValPheGlyIleGluValVal | “ | ||
| “ | “ | GlyIleGluValValGluValValProIle | “ | ||
| “ | “ | ProIleSerHisLeuTyrIleLeuVal | “ | ||
| “ | “ | HisLeuTyrIleLeuValThrCysLeu | “ | ||
| “ | “ | HisLeuTyrIleLeuValThrCysLeuGlyLeu | “ |
| “ | “ | TyrIleLeuValThrCysLeuGlyLeu | “ | ||
| “ | “ | CysLeuGlyLeuSerTyrAspGlyLeu | “ | ||
| “ | “ | CysLeuGlyLeuSerTyrAspGlyLeuLeu | “ | ||
| “ | “ | ValMetProLysThrGlyLeuLeuIle | “ | ||
| “ | “ | ValMetProLysThrGlyLeuLeuIleIle | “ | ||
| “ | “ | ValMetProLysThrGlyLeuLeuIleIleVal | “ | ||
| “ | “ | GlyLeuLeuIleIleValLeuAlaIle | “ | ||
| “ | “ | GlyLeuLeuIleIleValLeuAlaIleIle | “ | ||
| “ | “ | GlyLeuLeuIleIleValLeuAlaIleIleAla | “ | ||
| “ | “ | LeuLeuIleIleValLeuAlaIleIle | “ | ||
| “ | “ | LeuLeuIleIleValLeuAlaIleIleAla | “ | ||
| “ | “ | LeuLeuIleIleValLeuAlaIleIleAlaIle | “ | ||
| “ | “ | LeuIleIleValLeuAlaIleIleAla | “ | ||
| “ | “ | LeuIleIleValLeuAlaIleIleALaIle | “ | ||
| “ | “ | IleIleAlaIleGluGlyAspCysAla | “ | ||
| “ | “ | LysIleTrpGluGluLeuSerMetLeu | “ | ||
| “ | “ | LeuMetGlnAspLeuValGlnGluAsnTyrLeu | “ | ||
| “ | “ | PheLeuTrpGlyProArgAlaLeuIle | “ | ||
| “ | “ | LeuIleGluThrSerTyrValLysVal | “ | ||
| “ | “ | AlaLeuIleGluThrSerTyrValLysValLeu | “ | ||
| “ | “ | ThrLeuLysIleGlyGlyGluProHisIle | “ | ||
| “ | “ | HisIleSerTyrProProLeuHisGluArgAla | “ | ||
| “ | “ | GlnThrAlaSerSerSerSerThrLeu | “ | ||
| “ | “ | GlnThrAlaSerSerSerSerThrLeuVal | “ |
| “ | “ | ValThrLeuGlyGluValProAlaAla | “ | ||
| “ | “ | ValThrLysAlaGluMetLeuGluSerVal | “ | ||
| “ | “ | ValThrLysAlaGluMetLeuGluSerValLeu | “ | ||
| “ | “ | ValThrCysLeuGlyLeuSerTyrAspGlyLeu | “ | ||
| “ | “ | LysThrGlyLeuLeuIleIleValLeu | “ | ||
| “ | “ | LysThrGlyLeuLeuIleIleValLeuAla | “ | ||
| “ | “ | LysThrGlyLeuLeuIleIleValLeuAlaIle | “ | ||
| “ | “ | HisThrLeuLysIleGlyGlyGluProHisIle | “ | ||
| “ | “ | MetLeuAspLeuGlnProGluThrThr | “ | ||
| Mage-3肽 | HLA-A2 | GlyLeuGluAlaArgGlyGluAlaLeu | 5,585,461 | ||
| “ | “ | AlaLeuSerArgLysValAlaGluLeu | “ | ||
| “ | “ | PheLeuTrpGlyProArgAlaLeuVal | “ | ||
| “ | “ | ThrLeuValGluValThrLeuGlyGluVal | “ | ||
| “ | “ | AlaLeuSerArgLysValAlaGluLeuVal | “ | ||
| “ | “ | AlaLeuValGluThrSerTyrValLysVal | “ | ||
| 酪氨酸酶 | HLA-A2 | TyrMetAsnGlyThrMetSerGlnVal | 5,487,974 | ||
| “ | “ | MetLeuLeuAlaValLeuTyrCysLeuLeu | “ | ||
| “ | “ | “ | |||
| 酪氨酸酶 | HLA-A2 | MetLeuLeuAlaValLeuTyrCysLeu | 5,530,096 | ||
| “ | “ | LeuLeuAlaValLeuTyrCysLeuLeu | “ | ||
| 酪氨酸酶 | HLA-A2和HLA-B44 | SerGluIleTrpArgAspIleAspPheAlaHisGluAla | 5,519,117 | ||
| “ | “ | SerGluIleTrpArgAspIleAspPhe | “ | ||
| “ | “ | GluGluAsnLeuLeuAspPheValArggPhe | “ | ||
| Melan | “ | EAAGIGILTV | Jger，E.等 |
| A/MART-1 | Granulocyte-macrophage-colony-stimulatingFactor EnhancesImmuneResponses ToMelanoma-′associatedPepttdes in vivoInt.J Cancer 67，54-62(1996) | ||||
| 酪氨酸酶 | MLLAVLYCL | “ | |||
| “ | YMDGTMSQV | “ | |||
| gp100/Pmel17 | YLEPGPVTA | “ | |||
| “ | LLDGTATLRL | “ | |||
| 流感基质 | GILGFVFTL | “ | |||
| MAGE-1 | EADPTGHSY | “ | |||
| MAGE-1 | HLA-A1 | EADPTGHSY | 直接来自DAVID’S的列表 | ||
| BAGE | HLA-C | MAARAVFLALSAQLLQARLMKE | “ | ||
| “ | “ | MAARAVFLALSAQLLQ | “ | ||
| “ | “ | AARAVFLAL | “ | ||
| 流感 | PR8 NP | 147-154 | Kd | IYQRIRALV | Falk等.，Allele-specificmotifs revealedby sequencingof self-peptideseluted fromMHC molecules |
| 自身肽 | P815 | “ | SYFPEITHI | “ | |
| 流感 | Jap HA523-549 | “ | IYATVAGSL | “ | |
| “ | “ | “ | VYQILAIYA | “ | |
| “ | “ | “ | IYSTVASSL | “ | |
| “ | JAP HA202-221 | “ | LYQNVGTYV | “ | |
| HLA-A24 | “ | RYLENQKRT | “ | ||
| HLA-Cw3 | “ | RYLKNGKET | “ | ||
| P815 | “ | KYQAVTTTL | “ |
| 伯氏疟原虫 | CSP | “ | SYIPSAEKI | “ | |
| 尤氏疟原虫 | CSP | “ | SYVPSAFQI | “ | |
| 水泡性口炎病毒 | NP 52-59 | Kb | RGYVYQGL | “ | |
| 卵清蛋白 | “ | SIINFEKL | “ | ||
| Sandal病毒 | NP 321-332 | “ | APGNYPAL | “ | |
| VPYGSFKHV | Morel等.，Processing ofsome antigensby the standardproteasome butnot by theimmunoproteasome results inpoorpresentation bydendritic cells，Immunity，卷.12：107-117，2000. |
| 基序 | |||||
| 流感 | PR8 NP | Kd限制的肽基序 | TYQRTRALV | 5,747,269 | |
| 自身肽 | P815 | “ | SYFPEITHI | “ | |
| 流感 | JAP HA | “ | IYATVAGSL | “ | |
| 流感 | JAP HA | “ | VYQILAIYA | “ | |
| 流感 | PR8 HA | “ | IYSTVASSL | “ | |
| 流感 | JAP HA | “ | LYQNVGTYV | “ | |
| HLA-A24 | RYLENGKETL | “ | |||
| HLA-Cw3 | RYLKNGKETL | “ | |||
| P815肿瘤抗原 | “ | KYQAVTTTL | “ | ||
| 伯氏疟原虫 | CSP | “ | SYIPSAEKI | “ | |
| 尤氏疟原虫 | CSP | “ | SYVPSAEQI | “ | |
| 流感 | NP | Db-限制的肽基序 | ASNENMETM | “ | |
| 腺病毒 | E1A | “ | SGPSNTPPEI | “ | |
| 淋巴细胞性脉络丛脑膜炎 | “ | SGVENPGGYCL | “ | ||
| 猿猴病毒 | 40T | “ | SAINNY... | “ | |
| HIV | 逆转录酶 | HLA-A2.1-限制的肽基序 | ILKEPVHGV | “ | |
| 流感基质蛋白 | “ | GILGFVFTL | “ | ||
| 流感 | 流感基质蛋白 | “ | ILGFVFTLTV | “ | |
| HIV | Gag蛋白 | FLQSRPEPT | “ | ||
| HIV | Gag蛋白 | AMQMLKE.. | “ | ||
| HIV | Gag蛋白 | PIAPGQMRE | “ | ||
| HIV | Gag蛋白 | QMKDCTERQ | “ | ||
| HLA-A*0205限制的肽基序 | VYGVIQK | “ |
表5
| VSV-NP 肽 (49-62) |
| LCMV-NP 肽 (118-132) |
| LCMV 糖蛋白肽 33-41 |
| ISNQLTLDSNTKYFHKLN |
| ISNQLTLDSNTKYFHKL |
| ISNQLTLDSNTKYFHK |
| VDTFLEDVKNLYHSEA |
| KPRAIVVDPVHGFMY |
| KQTISPDYRNMI |
| Y[KFIMDPKEKDKV |
| NIQLINDQEVARFD |
| LLSFVRDLNQYRADI |
| LPKPPKPVSKMRMATPL |
| LPKPPKPVSKMRMATPLLMOALP |
| LPKPPKPVSKMRMATPLLMQALPM |
| PKPPKPVSKMRMATPL |
| PKPPKPVSKMRMATPLLMOA |
| KPPKPVSKMRMATPLLMQ |
| KPPKPVSKMRMATPLLMOALPM |
| VDDTQFVRFDSDAASQ |
| ATKYGNMTEDHVMHLLQNA |
| VFLLLLADKVPETSLS |
| LNKILLDEQAQWK |
| GPPKLDIRKEEKQIMIDIFH |
| GPPKLDIRKEEKQIMIDIFHP |
| GFKAIRPDKKSNPIIRTV |
| YANILLDRRVPQTDMTF |
| NLFLKSDGRIKYTLNKNSLK |
| IPDNLFLKSDGRIKYTLNKN |
| IPDNLFLKSDGRIKYTLNK |
| IPDNLFLKSDGRIKYTLN |
| IPDNLFLKSDGRIKYTL |
| NLFLKSDGRIKYTLNK |
| NLFLKSDGRIKYTLN |
| VTTLNSDLKYNALDLTN |
| VGSDWRFLRGYHQYA |
其它实施方案致力于涉及对MHC具有特异性的表位的方法，用途，疗法和组合物，包括例如表6-10中所列。其它实施方案包括表6-10中所列一种或多种MHC，包括它们的组合，而其它实施方案特别排斥任何一种或多种MHC或其组合。表8-10包括所列HLA抗原的频率。
I类 I类MHC分子
人
HLA-A1
HLAA*0101
HLA-A*0201
HLA-A*0202
HLA-A*0203
HLA-A*0204
HLA-A*0205
HLA-A*0206
HLA-A*0207
HLA-A*0209
HLA-A*0214
HLA-A3
HLA-A*0301
HLA-A*1101
HLA-A23
HLA-A24
HLA-A25
HLA-A*2902
HLA-A*3101
HLA-A*3302
HLA-A*6801
HLA-A*6901
HLA-B7
HLA-B*0702
HLA-B*0703
HLA-B*0704
HLA-B*0705
HLA-B8
HLA-B13
HLA-B14
HLA-B*1501(B62)
HLA-B17
HLA-B18
HLA-B22
HLA-B27
HLA-B*2702
HLA-B*2704
HLA-B*2705
HLA-B*2709
HLA-B35
HLA-B*3501
HLA-B*3502
HLA-B*3701
HLA-B*3801
HLA-B*39011
HLA-B*3902
HLA-B40
HLA-B*40012(B60)
HLA-B*4006(B61)
HLA-B44
HLA-B*4402
HLA-B*4403
HLA-B*4501
HLA-B*4601
HLA-B51
HLA-B*5101
HLA-B*5102
HLA-B*5103
HLA-B*5201
HLA-B*5301
HLA-B*5401
HLA-B*5501
HLA-B*5502
HLA-B*5601
HLA-B*5801
HLA-B*6701
HLA-B*7301
HLA-B*7801
HLA-Cw*0102
HLA-Cw*0301
HLA-Cw*0304
HLA-Cw*0401
HLA-Cw*0601
HLA-Cw*0602
HLA-Cw*0702
HLA-Cw8
HLA-Cw*1601 M
HLA-G
鼠
H2-Kd
H2-Dd
H2-Ld
H2-Kb
H2-Db
H2-Kk
H2-Kkm1
Qa-1a
Qa-2
H2-M3
大鼠
RT1.Aa
RT1.A1
牛
Bota-A11
Bota-A20
鸡
B-F4
B-F12
B-F15
B-F19
黑猩猩
Patr-A*04
Patr-A*11
Patr-B*01
Patr-B*13
Patr-B*16
狒狒
Papa-A*06
短尾猿
Mamu-A*01
猪
SLA(haplotype d/d)
病毒同系物
hCMV class I homolog UL18
表7
I类MHC分子
I类
人
HLA-A1
HLA-A*0101
HLA-A*0201
HLA-A*0202
HLA-A*0204
HLA-A*0205
HLA-A*0206
HLA-A*0207
HLA-A*0214
HLA-A3
HLA-A*1101
HLA-A24
HLA-A*2902
HLA-A*3101
HLA-A*3302
HLA-A*6801
HLA-A*6901
HLA-B7
HLA-B*0702
HLA-B*0703
HLA-B*0704
HLA-B*0705
HLA-B8
HLA-B14
HLA-B*1501(B62)
HLA-B27
HLA-B*2702
HLA-B*2705
HLA-B35
HLA-B*3501
HLA-B*3502
HLA-B*3701
HLA-B*3801
HLA-B*39011
HLA-B*3902
HLA-B40
HLA-B*40012(B60)
HLA-B*4006(B61)
HLA-B44
HLA-B*4402
HLA-B*4403
HLA-B*4601
HLA-B51
HLA-B*5101
HLA-B*5102
HLA-B*5103
HLA-B*5201
HLA-B*5301
HLA-B*5401
HLA-B*5501
HLA-B*5502
HLA-B*5601
HLA-B*5801
HLA-B*6701
HLA-B*7301
HLA-B*7801
HLA-Cw*0102
HLA-Cw*0301
HLA-Cw*0304
HLA-Cw*0401
HLA-Cw*0601
HLA-Cw*0602
HLA-Cw*0702
HLA-G
鼠
H2-Kd
H2-Dd
H2-Ld
H2-Kb
H2-Db
H2-Kk
H2-Kkm1
Qa-2
大鼠
RT1.Aa
RT1.A1
牛
Bota-A11
Bota-A20
鸡
B-F4
B-F12
B-F15
B-F19
病毒同系物
hCMV I类同系物UL18
表8
[0079] 评估的HLA-A抗原的基因频率
| 抗原 | CAU | AFR | ASI | LAT | NAT | |||||
| Gfa | SEb | Gf | SE | Gf | SE | Gf | SE | Gf | SE | |
| A1A2A3A28A36 | 15.184328.653513.38904.46520.0221 | 0.04890.06190.04630.02800.0020 | 5.725618.88498.44069.92691.8836 | 0.07710.13170.09250.09970.0448 | 4.481824.63522.64541.76570.0148 | 0.08460.17940.06550.05370.0049 | 7.400728.11988.07898.94460.1584 | 0.09780.17000.10190.10670.0148 | 12.031629.340811.02935.38560.1545 | 0.25330.35850.24370.17500.0303 |
| A23A24A9整体的A9整个的 | 1.82879.32510.080911.2347 | 0.01810.03950.00380.0429 | 10.20862.96680.036713.2121 | 0.10100.05600.00630.1128 | 0.325622.03910.085822.4505 | 0.02310.17220.01190.1733 | 2.926913.26100.053716.2416 | 0.06280.12710.00860.1382 | 1.990312.66130.035614.6872 | 0.10800.25900.01450.2756 |
| A25 | 2.1157 | 0.0195 | 0.4329 | 0.0216 | 0.0990 | 0.0128 | 1.1937 | 0.0404 | 1.4520 | 0.0924 |
| A26A34A43A66A10整体的A10整个的 | 3.87950.15080.00180.01730.07906.2441 | 0.02620.00520.00060.00180.00380.0328 | 2.82843.52280.03340.22330.09397.1348 | 0.05470.06100.00600.01550.01010.0850 | 4.66281.35290.02310.04780.12556.3111 | 0.08620.04700.00620.00890.01440.0993 | 3.26120.49280.00550.03990.06475.0578 | 0.06620.02600.00280.00740.00940.0816 | 2.42920.31500.00590.05340.02984.2853 | 0.11910.04320.00590.01780.01330.1565 |
| A29A30A31A32A33A74A19整个的A19整个的 | 3.57962.50672.73863.69561.20800.02770.056713.8129 | 0.02520.02120.02210.02560.01480.00220.00320.0468 | 3.207113.09691.65561.53846.56071.99490.205728.2593 | 0.05820.11290.04200.04050.08220.04610.01490.1504 | 1.12332.20253.60051.03319.27010.05610.099017.3846 | 0.04290.05980.07610.04110.11910.00960.01280.1555 | 4.51564.48734.83282.70642.65930.20270.121119.5252 | 0.07740.07720.08000.06040.05990.01670.01290.1481 | 3.43452.53146.08812.55211.07540.10680.047515.8358 | 0.14100.12150.18550.12200.07960.02520.01680.2832 |
| AX | 0.8204 | 0.0297 | 4.9506 | 0.0963 | 2.9916 | 0.1177 | 1.6332 | 0.0878 | 1.8454 | 0.1925 |
a基因频率
b标准误差
表9
评估的HLA-B抗原的基因频率
| 抗原 | CAU | AFR. | ASI | LAT | NAT | |||||
| Gfa | SEb | Gf | SE | Gf | SE | Gf | SE | Gf | SE | |
| B7B8B13B14B18B27B35B37B41B42B46B47B48B53 | 12.17829.40772.30614.34814.79804.38319.66141.40320.92110.06080.00990.20690.08650.4620 | 0.04450.03970.02030.02770.02900.02780.04020.01590.01290.00330.00130.00610.00400.0092 | 10.59603.83150.81033.03313.20571.29188.51720.59160.81835.69910.01510.13050.131610.9529 | 0.10240.06340.02950.05660.05820.03720.09270.02520.02960.07680.00400.01190.01190.1039 | 4.26911.33224.92220.50041.12462.23558.12031.23270.13030.08414.92920.09562.02760.4315 | 0.08270.04670.08860.02870.04290.06030.11220.04490.01470.01180.08860.01260.05750.0266 | 6.44773.82251.26995.41664.23492.372414.65160.78071.28180.58660.02340.18321.59151.6982 | 0.09180.07150.04160.08460.07520.05670.13290.03270.04180.02840.00570.01590.04660.0481 | 10.98458.57891.74952.98233.34225.197010.11980.97550.47660.28560.02380.21391.02671.0804 | 0.24320.21760.10130.13160.13910.17210.23450.07590.05310.04110.01190.03560.07780.0798 |
| 抗原 | CAU | AFR | ASI | LAT | NAT | |||||||||
| Gfa | SEb | Gf | SE | Gf | SE | Gf | SE | Gf | SE | |||||
| B59B67B70B73 | 0.00200.00400.32700.0108 | 0.00060.00090.00770.0014 | 0.00320.00867.35710.0032 | 0.00190.00300.08660.0019 | 0.42770.22760.89010.0132 | 0.02650.01940.03820.0047 | 0.00550.00551.92660.0261 | 0.00280.00280.05120.0060 | 0c0.00590.69010c | -0.00590.0639 | ||||
| B51B52B5整体的B5整个的 | 5.42150.96580.15656.5438 | 0.03070.01320.00530.0435 | 2.59801.37120.15224.1214 | 0.05250.03830.01280.0747 | 7.47513.51210.128811.1160 | 0.10800.07520.01460.1504 | 6.81472.24470.15469.2141 | 0.09430.05520.01460.1324 | 6.90770.69600.13077.7344 | 0.19680.06410.02780.2784 | ||||
| B44B45B12整体的B12整个的 | 13.48380.57710.078814.1440 | 0.04650.01020.00380.0474 | 7.01374.80690.028011.8486 | 0.08470.07080.00550.1072 | 5.68070.18160.00495.8673 | 0.09480.01730.00290.0963 | 9.92531.88120.019311.8258 | 0.11210.05060.00510.1210 | 11.80240.76030.065412.6281 | 0.25110.06700.01970.2584 | ||||
| B62B63B75B76B77B15整体的B15整个的 | 5.91170.43020.01040.00260.00570.13056.4910 | 0.03200.00880.00140.00070.00100.00490.0334 | 1.52671.88650.02260.00650.01190.06913.5232 | 0.04040.04480.00490.00260.00360.00860.0608 | 9.22490.44381.96730.08740.05770.430112.2112 | 0.11900.02700.05660.01200.00980.02660.1344 | 4.18250.80830.11010.00550.00830.18205.2967 | 0.07470.03330.01230.00280.00340.01580.0835 | 6.94210.37380.035600c0.00590.07157.4290 | 0.19730.04710.0145-0.00590.02060.2035 | ||||
| B38B39B16整体的B16整个的 | 2.44131.96140.06384.4667 | 0.02090.01880.00340.0280 | 0.33231.28930.02371.6453 | 0.01890.03710.00510.0419 | 3.28182.03520.06445.3814 | 0.07280.05760.01030.0921 | 1.96526.30400.12268.3917 | 0.05170.09090.01300.1036 | 1.10174.55270.05935.7137 | 0.08060.16150.01880.1797 | ||||
| B57B58B17整体的B17整个的 | 3.59550.71520.28454.5952 | 0.02520.01140.00720.0284 | 5.67465.95460.324811.9540 | 0.07660.07840.01870.1076 | 2.57824.01890.37516.9722 | 0.06470.08030.02480.1041 | 2.18001.24810.14463.5727 | 0.05440.04130.01410.0691 | 2.72650.93980.26743.9338 | 0.12600.07450.03980.1503 | ||||
| B49B50B21整体的B21整个的 | 1.64521.05800.07022.7733 | 0.01720.01380.00360.0222 | 2.62860.86360.02703.5192 | 0.05280.03040.00540.0608 | 0.24400.44210.01320.6993 | 0.02000.02700.00470.0339 | 2.33531.88830.07714.3007 | 0.05620.05070.01030.0755 | 1.54620.78620.03562.3680 | 0.09530.06810.01450.1174 | ||||
| B54B55B56B22整体的B22整个的 | 0.01241.90460.55270.16822.0852 | 0.00150.01850.01000.00550.0217 | 0.01830.48950.26860.04960.8261 | 0.00440.02290.01700.00730.0297 | 2.68732.24440.82600.27306.0307 | 0.06600.06040.03680.02120.0971 | 0.02890.95150.35960.03721.3771 | 0.00630.03610.02220.00710.0433 | 0.05341.40540.33870.12461.9221 | 0.01780.09090.04480.02720.1060 | ||||
| B60B61B40整体的B40整个的 | 5.22221.19160.26966.6834 | 0.03020.01470.00700.0338 | 1.52990.47090.03882.0396 | 0.04040.02250.00650.0465 | 8.32546.20720.320514.8531 | 0.11350.09890.02300.1462 | 2 25384.66910.24737.1702 | 0.05530.07880.01840.0963 | 5.72182.60230.22718.5512 | 0.18010.12310.03670.2168 | ||||
| BX | 1.0922 | 0.0252 | 3.5258 | 0.0802 | 3.8749 | 0.0988 | 2.5266 | 0.0807 | 1.9867 | 0.1634 | ||||
a基因频率 b标准误差 c观察到的基因计数是零
表10
评估的HLA-DR抗原的基因频率
| 抗原 | CAU | AFR | ASI | LAT | NAT | |||||
| Gfa | SEb | Gf | SE | Gf | SE | Gf | SE | Gf | SE | |
| DR1DR2DR3DR4DR6DR7DR8DR9DR10 | 10.227915.240810.870816.758914.393713.28072.88201.06161.4790 | 0.04130.04910.04240.05110.04790.04630.02270.01390.0163 | 6.820016.237313.30805.708418.611710.13176.26732.96462.0397 | 0.08320.12220.11240.07650.12910.09970.08000.05590.0465 | 3.462818.61624.722315.462313.44716.92706.54139.75272.2304 | 0.07470.16080.08670.14900.14040.10400.10130.12180.0602 | 7.985911.23897.899820.537317.026510.67269.77311.07121.8044 | 0.10130.11820.10080.15200.14110.11550.11100.03830.0495 | 8.251215.393210.254919.826414.802110.42196.00592.86621.0896 | 0.21390.28180.23610.31230.27720.23780.18440.12910.0801 |
| DR11DR12DR5整体的DR5整个的 | 9.31801.90701.219912.4449 | 0.03960.01850.01490.0045 | 10.61514.11522.295717.0260 | 0.10180.06550.04930.1243 | 4.737510.13651.411816.2858 | 0.08690.12390.04800.1516 | 7.04111.72441.822510.5880 | 0.09550.04840.04980.1148 | 5.31522.01321.67699.0052 | 0.17400.10860.09920.2218 |
| DRX | 1.3598 | 0.0342 | 0.8853 | 0.0760 | 2.5521 | 0.1089 | 1.4023 | 0.0930 | 2.0834 | 0.2037 |
a基因频率
b标准误差
可能期望在较大蛋白质的环境中表达管家肽。甚至在表位末端之外存在少量氨基酸时仍能检测到加工。小肽激素常常是由长度范围常为大约60-120个氨基酸的较长翻译产物经蛋白酶解加工而成的。根据这一事实在一定程度上可以假设这就是能够有效翻译的最小长度。例如，在有些实施方案中，可能将管家肽嵌入至少大约60个氨基酸的翻译产物；在其它实施方案中是70，80，或90个氨基酸，在还有一些实施方案中是100，110，或120个氨基酸。在其它实施方案中，可能将管家肽嵌入至少大约50，30，或15个氨基酸的翻译产物。
由于不同的蛋白酶体加工，由pAPC的免疫蛋白酶体生成的肽与由外周体细胞中的管家蛋白酶体生成的肽不同。因此，在较大蛋白质的环境中表达管家表位时，优选在pAPC中在其全长天然序列以外的环境中进行表达，因为管家表位通常只能通过管家蛋白酶体由天然蛋白质有效加工而成，而管家蛋白酶体在pAPC中没有活性。为了在编码较大多肽的DNA序列中编码管家表位，有用的是在编码表位的序列两端的发现侧翼区域，其容许免疫蛋白酶体的适当切割从而释放该管家表位。促进适当切割的这种序列在下文中称为具有底物或释放序列功能。改变预期管家表位N端和C端的侧翼氨基酸残基可能有助于在pAPC中适当切割和生成管家表位。可以重新设计嵌入管家表位的序列，并通过筛选来确定哪种能够得到免疫蛋白酶体的成功加工而释放管家表位。
或者，另一种策略对于鉴定能够在APC中生成管家表位的序列很有效。可以将一种或多种管家表位头尾排列而生成连续氨基酸序列。将表达这种序列的构建体用于免疫动物，并评估由此产生的T细胞应答以测定其对排列中一种或多种表位的特异性。这些免疫应答指示在pAPC中得到有效加工的管家表位。由此定义该表位周围的必需侧翼区域。预期肽一侧大约4-6个氨基酸的侧翼区域的使用能够提供有助于免疫蛋白酶体对管家表位的蛋白酶体加工的必需信息。因此，可以将大约16-22个氨基酸的底物或释放序列有效插入或融合任何蛋白质序列，从而能够在APC中生成该管家表位。在有些实施方案中，更广环境的底物序列也能够影响加工。在这些实施方案中，多种环境中释放序列的比较对于进一步优化特定底物序列可能是有用的。在备选实施方案中，可以类似的将表位的整个头尾排列或仅仅与正确加工的管家表位直接相邻的表位由测试构建体转移至疫苗载体。
在优选的实施方案中，可以将管家表位嵌入已知免疫表位或其片段之间，从而为加工提供适当环境。管家和免疫表位的邻接能够生成必需环境，使得免疫蛋白酶体释放管家表位或较大片段，优选包含正确C末端。筛选构建体以确认生成了预期表位可能是有用的。管家表位的邻接能够生成免疫蛋白酶体可切割的位点。本发明的有些实施方案在测试底物中管家表位的侧翼采用已知表位；在其它实施方案中，无论侧翼区是任意序列或是天然侧翼序列的突变体，无论在设计底物时是否使用了蛋白酶体切割偏爱性的知识，进行下文描述的筛选。
表位成熟N端的切割尽管有利但并不需要，因为细胞中存在多种N端修剪活性，能够在蛋白酶体加工后生成表位成熟N端。优选的是这种N端延伸的长度小于大约25个氨基酸，更优选的是延伸具有少数或没有脯氨酸残基。优选的是，在筛选时，不仅要考虑表位末端(至少是其C端)的切割，还可考虑确保表位内部的有限切割。
鸟枪法可用于设计测试底物，而且能够提高筛选效率。在一个实施方案中，可以相继装配多个表位，个别表位可能出现超过一次。可以筛选底物以确定可以生成哪种表位。在关注一种特定表位时，可以设计它出现在多个不同环境中的底物。若底物释放超过一个环境中出现的单一表位，可以使用额外的第二测试底物，其中表位的个别实例被移除，失效，或是唯一的，以确定释放了哪一个并真正赋予底物或释放序列功能。
存在几种易于实践的筛选。一种优选的体外筛选利用蛋白酶体消化分析，使用纯化后的免疫蛋白酶体，以测定是否能够由包含待测序列的合成肽释放预期管家表位。可以通过诸如质谱，HPLC，和N端混合测序技术来确定所得到的切割位点；如美国专利申请号09/561,074，09/560,465和10/117,937以及临时美国专利申请号60/282,211，60/337,017和60/363,210中有更为详细的描述。
或者，可以采用体内和基于细胞的筛选诸如免疫或靶敏化。对于免疫，使用能够表达待测序列的核酸构建体。可以对收获的CTL测试它们识别展示待测管家表位的靶细胞的能力。这些靶细胞最容易通过用嵌入成熟管家表位的合成肽脉冲表达适当MHC分子的细胞来获得。或者，可以使用已知或是内源或是通过遗传工程而表达管家蛋白酶体和衍生管家表位的抗原的细胞进行免疫。为了进行靶敏化作为筛选，可以使用识别管家表位的CTL或优选的是CTL克隆。在这种情况中，是靶细胞表达嵌入的管家表位(而非免疫过程中的pAPC)，而且它必须表达免疫蛋白酶体。通常，可以用适当的核酸构建体转化细胞或靶细胞以赋予嵌入的管家表位的表达。使用加载了肽的脂质体装载包含嵌入表位的合成肽，或者与阳离子脂蛋白转移剂诸如BIOPORTERTM混合(基因疗法系统，圣迭戈，加利福尼亚州)提供了候选方法。
一旦鉴定了具有底物或释放序列功能的序列，可以在化学合成或重组生成的核酸载体中编码它们。在任何一种的这些形式中，可以将它们掺入免疫原性组合物。在体外，这些组合物可用于疫苗开发，或者生成或扩增将用于过继性免疫疗法的CTL。在体内，它们可用于诱导，扩大或维持和激活免疫应答。在其它方法中，通过阳离子脂质包装，添加痕量的阳离子氨基酸诸如聚L-赖氨酸(Ryser，H.J.等人，J.Cell Physiol.，113：167-178，1982；Shen，W.C.&Ryser，H.J.，Proc.Natl.Acad.Sci.USA)，75：1872-1876，1978)，掺入具有输入信号的分支结构(Sheldon，K.等人，Proc.Natl.Acad.Sci.USA，92：2056-2060，1995)，或者混合或融合具有蛋白质转移功能的多肽包括肽载体诸如pep-1(Morris，M.C.等人，Nat.Biotech.，19：1173-1176，2001)，乙肝病毒表面抗原的PreS2转位基序，疱疹病毒的VP22，和HIV-TAT蛋白质(Oess，S.&Hildt，E.，Gene Ther.，7：750-758，2000；Ford，K.G.等人，Gene Ther.，8：1-4，2001；Hung，C.F.等人，J.Virol.，76：2676-2682，2002；Oliveira，S.C.等人，Hum.Gene Ther.，12：1353-1359，2001；Normand，N.等人，J.Biol.Chem.，276：15042-15050，2001；Schwartz，J.J.&Zhang，S.，Curr.Opin.Mol.Ther.，2：162-167，2000；Elliot，G.，7 Hare，P.，Cell，88：223-233，1997)等方法，可以大大增强多肽的摄取以进行加工和呈递。特别是对融合蛋白，可以通过培养生成免疫原并施用纯化后的蛋白质，或者可以施用核酸载体从而由经体内转化的细胞生成并分泌免疫原。在这两种情况中，融合蛋白的转运功能有助于pAPC的摄取。
实施例
实施例1
构建了重组DNA质粒疫苗pMA2M，它所编码的一个多肽具有来自melan-A(26-35A27L)的HLA A2特异性CTL表位ELAGIGILTV(SEQ ID NO.1)以及melan-A(SEQ ID NO.2)的一部分(第31-96位氨基酸)，包括第31-48位和第56-69位氨基酸处的表位簇。这些簇以前曾公开于题为“EPITOPE CLUSTERS”的美国专利申请号09/561,571。在限定的melan-ACTL表位的侧翼是衍生自人酪氨酸酶的短氨基酸序列(SEQ IN NO.3)，从而有助于通过免疫蛋白酶体加工来释放melan-A管家表位。另外，这些氨基酸序列自身展示潜在的CTL表位。质粒中多肽的cDNA序列处于来自巨细胞病毒的启动子/增强子序列(CMVp)的控制之下(见图1)，从而能够在被APC摄取后有效转录多肽的信使。位于编码序列3’端的牛生长激素聚腺苷酸信号(BGH polyA)为信使的聚腺苷酸化以增加其稳定性以及由细胞核转移至细胞质以进行翻译提供了信号。为了便于在摄取后将质粒转移到细胞核内，已经将来自猿猴病毒40(SV40)的核输入信号(NIS)插入质粒骨架。质粒携带两个拷贝的CpG免疫刺激基序，一个位于NIS序列中，一个位于质粒骨架中。最后，质粒中的两个原核遗传元件负责大肠杆菌中的扩增，卡那霉素抗性基因(Kan R)和pMB1细菌复制起点。
底物或释放序列
下文给出了所编码的多肽(长度为94个氨基酸残基)(SEQ ID NO.4)的氨基酸序列，所述多肽在其N端包含28个氨基酸的底物或释放序列(SEQID NO.5)：MLLAVLYCL-ELAGIGILTV-YMDGTMSQV-GILTVILGVLLLIGCWYCRRRNGYRALMDKSLHVGTQCALTRRCPQEGFDHRDSKVSLQEKNCEPV
前9个氨基酸残基衍生自酪氨酸酶1-9(SEQ ID NO.6)，随后的10个氨基酸残基构成melan-A(26-35A27L)(SEQ ID NO.1)，而第20-29位氨基酸残基衍生自酪氨酸酶369-377(SEQ ID NO.7)。这两个酪氨酸酶九聚物序列都展示潜在的HLA A2特异性CTL表位。第10-19位氨基酸残基构成melan-A(26-35A27L)，来自melan-A的HLA A2特异性CTL表位的类似物，EAAGIGILTV(SEQ ID NO.8)，在人PBMC的体外免疫和小鼠的体内免疫过程中诱发CTL应答的能力提高。组成多肽剩余部分(第30-94位氨基酸残基)的melan-A片段包含一些预测的HLA A2特异性表位，包括上文引用的表位簇，因而可用于产生针对免疫表位的应答，正如专利申请“EpitopeSynchronization in Antigen Presenting Cells”和“Epitope Clusters”中所详细描述的。包含该区域也是为了克服可能与表达较短序列有关的任何困难。图1显示了pMA2M示意图。
质粒构建
合成一对长的互补寡核苷酸，它们编码前30个氨基酸残基。另外，这些寡核苷酸在退火后在5’端产生Afl II的粘端，在3’端产生EcoR I的粘端。使用携带限制性位点-5’端是EcoR I和3’端是Not I的寡核苷酸通过PCR扩增melan-A31-96区域。用EcoR I和Not I消化PCR产物，并在三片段连接反应中与编码氨基端区域的退火寡核苷酸一起连接到已经Afl II和Not I消化的实施例1中所述的载体骨架中。通过DNA测序确认整个编码序列。SEQ ID NO.9公开了整个插入片段的序列，由5’端的AflII位点至3’端的Not I位点。第12-293位核苷酸编码多肽。
实施例2
对包含melan-A(26-35A27L)(SEQ ID NO.1)作为嵌入的管家表位的三种载体测试它们在HLA-A2转基因HHD小鼠中诱发针对该表位的CTL应答的能力(Pascolo等人，J.Exp.Med.，185：2043-2051，1997)。一种载体是上文所述的pMA2M(在图3中称为pVAXM3)。在pVAXM2中，三个表位的相同基群重复数次，而且排列的各个重复片段中侧翼表位有不同程度的截短。盒的具体组成如下：M-Tyr(5-9)-ELA-Tyr(369-373)-Tyr(4-9)-ELA-Tyr(369-374)-Tyr(3-9)-ELA-Tyr(369-375)-Tyr(2-9)-ELA(SEQ ID NO.10)
其中ELA代表melan-A(26-35A27L)(SEQ ID NO.1)。将该盒插入与pVAXM3所用相同的质粒骨架中。第三种载体pVAXM1除了表位排列之后是与编码melan-A 31-70的读码框架相连的IRES(脑心肌炎病毒的内部核糖体进入位点)之外与pVAXM2是相同的。
第0，3，和6天对四组(每组三只)HHD A2.1小鼠以节内注射方式将25μl溶于PBS的1mg/ml质粒DNA注入通过外科手术暴露的腹股沟淋巴结，每组接受三种载体之一或只是PBS。第14天收获脾并用经肽(melan-A(26-35A27L)(SEQ ID NO.1))脉冲的3天LPS胚细胞再次体外刺激一次。第3天用大鼠T-Stim(Collaborative Biomedical Products)补充体外培养物，并在第7天用标准51Cr释放试验测试溶细胞活性。图2-5显示了T2靶细胞及经melan-A(26-35A27L)(ELA)(SEQ ID NO.1)脉冲的T2靶细胞分别经PBS，pVAXM1，pVAXM2，和pVAXM3免疫后获得的特异溶解百分比。所有这三种载体都产生了强烈的CTL应答。这些数据显示质粒已被APC摄取，所编码的多肽已经合成并经蛋白酶解加工而产生讨论中的十聚物(decamer)表位(即它具有底物或释放序列功能)，而且表位变成了为呈递而结合的HLA-A2。此外，终止于第55位氨基酸之后的pVAXM2分离变体的效果与全长版本相似(数据未显示)。可以通过测试针对经相应合成肽脉冲的靶细胞的CTL活性来确定是否也能生成表达盒内的其它潜在表位且对诱发CTL应答有活性。
实施例3
NY-ESO-1(SEQ ID NO.11)底物/释放序列
通过其它6种表位排列的测试鉴定了管家表位NY-ESO-1157-165(SEQ IDNO.11)的底物/释放序列。排列的组成表位如下：
SSX-241-49： KASEKIFYV (SEQ ID NO.13)排列元件A
NY-ESO-1157-165： SLLMWITQC (SEQ ID NO.12)排列元件B
NY-ESO-1163-171： TQCFLPVFL (SEQ ID NO.14)排列元件C
PSMA288-297： GLPSIPVHPI (SEQ ID NO.15)排列元件D
TYR4-9： AVLYCL (SEQ ID NO.16)排列元件E
这6种排列在由起始子甲硫氨酸起始后具有如下元件排列：
pVAX-PC-A： B-A-D-D-A-B-A-A
pVAX-PC-B： D-A-B-A-A-D-B-A
pVAX-PC-C： E-A-D-B-A-B-E-A-A
pVAX-BC-A： B-A-C-B-A-A-C-A
pVAX-BC-B： C-A-B-C-A-A-B-A
pVAX-BC-C： E-A-A-B-C-B-A-A
将这些排列插入上文实施例中所述的相同载体骨架。基本上如实施例2所述，将质粒载体用于免疫小鼠，并对由此产生的CTL测试它们特异溶解经肽NY-ESO-1157-165(对应于上文元件B)脉冲的靶细胞的能力。发现pVAX-PC-A和pVAX-BC-A都诱发了特异性溶解活性。比较多种排列中表位(元件B)的环境，尤其是pVAX-PC-A与pVAX-BC-A之间，pVAX-PC-A与pVAX-PC-B之间，以及pVAX-BC-A与pVAX-BC-C之间，得出如下结论，是pVAX-PC-A和pVAX-BC-A中表位的首次出现得到了正确加工和展示。换言之，起始子甲硫氨酸之后跟随元件B-A构成了元件B呈递的底物/释放序列。在此基础上构建了编码以下元件的新表达盒用作疫苗：起始子甲硫氨酸，NY-ESO-1157-165(粗体)-管家表位，SSX241-49(斜体)-为加工提供适当环境，和NY-ESO-177-180-避免“短序列”问题并提供免疫表位。
因此构建体编码以下氨基酸序列：M-SLLMWITQC-KASEKIFYV-RCGARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPLPVPGVLLKEFTVSGNILTIRLTAADHRQLQLSISSCLQQLSLLMWITQCFLPVFLAQPPSGQRR(SEQ ID NO.17)，而MSLLMWITQCKASEKIFYV(SEQ ID NO.18)构成了释放或底物序列。将编码SEQ ID NO.17的多核苷酸(SEQ ID NO.19：核苷酸12-380)插入pMA2M所用相同质粒骨架，产生质粒pN157。
实施例4
还制备了与pN157类似包含来自pVAX-PC-A的完整表位排列的构建体，并命名为pBPL。因此pBPL中所编码的氨基酸序列是：M-SLLMWITQC-KASEKIFYV-GLPSIPVHPI-GLPSIPVHPI-KASEKIFYV-SLLMWITQC-KASEKIFYV-KASEKIFYV-RCGARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPLPVPGVLLKEFTVSGNILTIRLTAADHRQLQLSISSCLQQLSLLMWITQCFLPVFLAQPPSGQRR(SEQ ID NO.20)。
SEQ ID NO.21是编码pBPL中所使用的SEQ ID NO.20的多核苷酸。
作为合成肽制备SEQ ID NO.20的一部分-IKASEKIFYVSLLMWITQCKASEKIFYVK(SEQ ID NO.22)，并通过质谱和N端混合测序用人免疫蛋白酶体进行体外蛋白酶体消化分析。位于C残基之后的切割的鉴别指示该构建体片段可作为NY-ESO-1157-165(SEQ ID NO.12)表位的底物或释放序列发挥功能(见图6)。图7显示了SLLMWITQC表位(SEQID NO.12)在其天然环境中的不同加工，其中管家蛋白酶体比免疫蛋白酶体更有效的在C之后产生切割。免疫蛋白酶体还在表位内部产生主要切割，当表位处于其天然环境中时位于T与Q之间，但在SEQ ID NO.22的环境中并非如此(比较图6和7)。
实施例5
通过其它表位排列的筛选鉴定了促进表位SSX-241-49(SEQ ID NO.13)表达的构建体。除了实施例3中定义的一些排列元件，还使用了以下额外元件：
SSX-457-65： VMTKLGFKV (SEQ ID NO.23)排列元件F
PSMA730-739：RQIYVAAFTV (SEQ ID NO.24)排列元件G
发现命名为CTLA02，编码起始子甲硫氨酸和排列F-A-G-D-C-F-G-A的构建体成功免疫HLA-A2转基因小鼠产生识别肽SSX-241-49(SEQ ID NO.13)的CTL应答。
如上所述，期望将具有底物或释放序列功能的序列与可加工成免疫表位的序列相联合。因此将SSX-215-183(SEQ ID NO.25)与全部或部分排列如下联合：
CTLS1：F-A-G-D-C-F-G-A-SSX-215-183 (SEQ ID NO.26)
CTLS2：SSX-215-183-F-A-G-D-C-F-G-A (SEQ ID NO.27)
CTLS3：F-A-G-D-SSX-215-183 (SEQ ID NO.28)
CTLS4：SSX-215-183-C-F-G-A (SEQ ID NO.29)
除了CTLS3之外的所有构建体都能诱发识别肽SSX-241-49(SEQ ID NO.13)的CTL。CTLS3是这四种构建体中唯一不含来自CTLA02的第二元件A的一种，说明正是这一基元的第二次出现提供了底物或释放序列功能。如同在CTLA02中，在CTLS2和CTLS4中A元件位于排列的C末端。在CTLS1中，A元件之后直接连接以丙氨酸开始的SSX-215-183片段，常常发现该残基位于蛋白酶体切割位点之后(Toes，R.E.M.等人，J.Exp.Med.，194：1-12，2001)。SEQ ID NO.30是编码CTLS1中所使用的SEQ ID NO.26的多核苷酸序列，也称为pCBP。
作为合成肽制备包含排列元件F-A-SSX-215-23的CTLS1一部分(SEQ IDNO.26)及序列RQIYVAAFTV-KASEKIFYV-AQIPEKIQK(SEQ ID NO.31)，并通过质谱和N端混合测序用人免疫蛋白酶体进行体外蛋白酶体消化分析。观察到产生了SSX-241-49表位(SEQ ID NO.13)的C末端(见图8)，这为支持底物或释放序列功能提供了进一步的证据。图9的数据显示了SSX-241-49表位KASEKIFYV(SEQ ID NO.13)在其天然环境中的不同加工，其中V之后的切割是由管家蛋白酶体产生的主要切割，而免疫蛋白酶体则在序列的其它位置具有数个主要切割位点。通过将该表位移入由SEQ ID NO.31提供的环境中，预期切割成为主要切割，而且它与其它免疫蛋白酶体切割相比的相对频率得到提高(比较图8和9)。图8B的数据还显示了小鼠和人蛋白酶体特异性的相似性，从而支持转基因小鼠模型预测人抗原加工的有效性。
实施例6
筛选还揭示了酪氨酸酶表位Tyr207-215(SEQ ID NO.32)的底物或释放序列功能，该表位是由序列[Tyr1-17-Tyr207-215]4，[MLLAVLYCLLWSFQTSA-FLPWHRLFL]4(SEQ ID NO.33)组成的排列的一部分。将上文所述相同载体骨架用于表达该排列。该排列与其它实施例的排列不同，因为作为免疫表位源而包含的Tyr1-17片段用作排列的重复元件。这与其它实施例中所显示的模式相反，在其它实施例中，作为免疫表位源和/或长度而包含的序列在排列的起点或终点只出现一次，排列的其余部分是由个别表位或较短序列组成的。
质粒构建
通过退火合成寡核苷酸的装配产生编码SEQ ID NO.33的多核苷酸。合成了4对互补的寡核苷酸，其跨越整个编码序列，两端是Afl II和EcoRI限制性位点的粘端。首先将各对互补寡核苷酸退火，逐步连接由此产生的DNA片段，并将装配好的DNA片段插入经Afl II/EcoR I预先消化的上文所述相同载体骨架中。此构建体称为CTLT2/pMEL，而SEQ ID NO.34是用于编码SEQ ID NO.33的多核苷酸序列。
实施例7
对人施用针对黑素瘤的免疫治疗性DNA质粒制剂
在1％苯甲醇，1％乙醇，0.5mM EDTA，柠檬酸盐-磷酸盐缓冲液pH7.6中配制具有上文实施例1中所述序列的MA2M黑素瘤疫苗。制备200，400和600μg DNA/ml的等分试样，装载到MINIMED 407C灌输泵中。将SILHOUETTE灌输装置的导管插入超声成像显现的腹股沟淋巴节中。泵和灌输装置的装配最初是为了给糖尿病患者投递胰岛素而设计的。在此应用中用31mm的导管取代了常用的17mm导管。灌输装置保持打开状态4天(约96小时)，灌输速率为约25μl/小时，总灌输体积为约2.4ml。因此对于上文所述三个浓度而言，每次灌输的总给予剂量分别为约500和1000μg；并且可以是1500μg。灌输后，在开始下次灌输前给予受试者10天的休息期。考虑到施用后淋巴结中质粒DNA的继续滞留和抗原消失后CTL应答的常规动力学，该方案将足以维持免疫学CTL应答。
实施例8
作为合成肽制备SEQ ID NO.22并用阳离子脂蛋白转移剂进行包装。将组合物直接注入腹股沟淋巴结(见实施例7)，灌输速率为200-600μg肽/天，灌输7天，然后休息7天。进行3-8个循环的起始治疗。
实施例9
通过将SEQ ID NO.34添加到编码单纯疱疹病毒1 VP22(SEQ ID NO.42)的核苷酸序列的3’端，在适当的哺乳动物表达载体中制备融合蛋白，上文所用载体是合适的。将载体用于转化HEK 293细胞，并于48-72小时后沉淀细胞，溶解细胞并制备可溶性提取物。使用抗VP22单克隆抗体通过亲和层析纯化融合蛋白。结内施用纯化后的融合蛋白，速率10-100μg/天，施用7天，然后休息7天。进行3-8个循环的起始治疗。
此外，本发明可利用如下多个方面：于1999年9月1日提交的题为“A METHOD OF INDUCING A CTL RESPONSE”的美国专利申请号09/380,534；于2001年2月2日提交的题为“METHOD OF INDUCING A CTL RESPONSE”的09/776,232；于2000年11月16日提交的题为“AVOIDANCE OFUNDESIRABLE REPLICATION INTERMEDIATES IN PLASMID PROPAGATION”的09/715,835；于2000年11月7日提交的题为“METHODS OF COMMERCIALIZINGAN ANTIGEN”的09/999,186；和于2001年3月7日提交的题为“ANTI-NEOVASCULAR VACCINES FOR CANCER”的临时美国专利申请号60/274,063。
表11
SEQ ID NOS的部分列表
| 1 | ELAGIGILTV | melan-A 26-35(A27L) |
| 2 | Melan-A蛋白 | 登记号：NP 005502 |
| 3 | 酪氨酸酶蛋白 | P14679 |
| 4 | MLLAVLYCLELAGIGILTVYMDGTMSQVGILTVILGVLLLIGCWYCRRRNGYRALMDKSLHVGTQCALTRRCPQEGFDHRDSKVSLQEKNCEPV | pMA2M表达产物 |
| 5 | MLLAVLYCLELAGIGILTVYMDGTMSQV | 来自pMA2M的SEQ IDNO.1的释放或底物序列 |
| 6 | MLLAVLYCL | 酪氨酸酶1-9 |
| 7 | YMDGTMSQV | 酪氨酸酶369-377 |
| 8 | EAAGIGILTV | melan-A 26-35 |
| 9 | cttaagccaccatgttactagctgttttgtactgcctggaactagcagggatcggcatattgacagtgtatatggatggaacaatgtcccaggtaggaattctgacagtgatcctgggagtcttactgctcatcggctgttggtattgtagaagacgaaatggatacagagccttgatggataaaagtcttcatgttggcactcaatgtgccttaacaagaagatgcccacaagaagggtttgatcatcgggacagcaaagtgtctcttcaagagaaaaactgtgaacctgtgtagtgagcggccgc | pMA2M插入片段 |
| 10 | MVLYCLELAGIGILTVYMDGTAVLYCLELAGI | 来自pVAXM2和pVAXM1的表位排列 |
| GILTVYMDGTMLAVLYCLELAGIGILTVYMDGTMSLLAVLYCLELAGIGILTV | ||
| 11 | NY-ESO-1蛋白 | 登记号：P78358 |
| 12 | SLLMWITQC | NY-ESO-1 157-165 |
| 13 | KASEKIFYV | SSX-2 41-49 |
| 14 | TQCFLPVFL | NY-ESO-1 163-171 |
| 15 | GLPSIPVHPI | PSMA 288-297 |
| 16 | AVLYCL | 酪氨酸酶4-9 |
| 17 | MSLLMWITQCKASEKIFYVRCGARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPLPVPGVLLKEFTVSGNILTIRLTAADHRQLQLSISSCLQQLSLLMWITQCFLPVFLAQPPSGQRR | pN157表达产物 |
| 18 | MSLLMWTTQCKASEKIFYV | 来自pN157的SEQ IDNO.12的释放或底物序列 |
| 19 | cttaagccaccatgtccctgttgatgtggatcacgcagtgcaaagcttcggagaaaatcttctacgtacggtgcggtgccagggggccggagagccgcctgcttgagttctacctcgccatgcctttcgcgacacccatggaagcagagctggcccgcaggagcctggcccaggatgccccaccgcttcccgtgccaggggtgcttctgaaggagttcactgtgtccggcaacatactgactatccgactgactgctgcagaccaccgccaactgcagctctccatcagctcctgtctccagcagctttccctgttgatgtggatcacgcagtgctttctgcccgtgtttttggctcagcctccctcagggcagaggcgctagtgagaattc | pN157的插入片段 |
| 20 | MSLLMWITQCKASEKIFYVGLPSIPVHPIGLPSIPVHPIKASEKIFYVSLLMWITOCKASEKIFYVKASEKIFYVRCGARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPLPVPGVLLKEFTVSGNILTIRLTAADHRQLQLSISSCLQQLSLLMWTTQCFLPVFLAQPPSGQRR | pBPL表达产物 |
| 21 | atgtccctgttgatgtggatcacgcagtgcaaagcttcggagaaaatcttctatgtgggtcttccaagtattcctgttcatccaattggtcttccaagtattcctgttcatccaattaaagcttcggagaaaatcttctatgtgtccctgttgatgtggatcacgcagtgcaaagcttcggagaaaatcttctatgtgaaagcttcggagaaaatcttctacgtacggtgcggtgccagggggccggagagccgcctgcttgagttctacctcgccatgcctttcgcgacacccatggaagcagagctggcccgcaggagcctggcccaggatgccccaccgcttcccgtgccaggggtgcttctgaaggagttcactgtgtccggcaacatactgactatccgactgactgctgcagaccaccgccaactgcagctctccatcagctcctctctccagcagctttccctgttgatgtggatcacgcagtgctttctgcccgtgtttttggctcagcctccctcagggcagaggcgctagtga | pBPL插入片段编码区 |
| 22 | ILASEKIFYVSLLMWITQCKASEKIFYVK | 图6中的底物 |
| 23 | VMTKLGFKV | SSX-457-65 |
| 24 | RQIYVAAFTV | PSMA730-739 |
| 25 | AQIPEKIQKAFDDIAKYFSKEEWEKMKASEKIFYVYMKRKYEAMTKLGFKATLPPFMCNKRAEDFQGNDLDNDPNRGNQVERPQMTFGRLQGISPKIMPKKPAEEGNDSEEVPEASGPQNDGKELCPPGKPTTSEKIHERSGPKRGEHAWTHRLRERKQLVIYEEISDP | SSX-215-183 |
| 26 | MVMTKLGFKVKASEKIFYVRQIYVAAFTVGLPSIPVHPITQCFLPVFLVMTKLGFKVRQIYVAAFTVKASEKIFYVAQIPEKIQKAFDDIAKYFSKEEWEKMKASEKIFYVYMKRKYEAMTKLGFKATLPPFMCNKRAEDFQGNDLDNDPNRGNQVERPQMTFGRLQGISPKIMPKKPAEEGNDSEEVPEASGPQNDGKELCPPGKPTTSEKIHERSGPKRGEHAWTHRLRERKQLVIYEEISDP | CTLS1/pCBP表达产物 | |
| 27 | MAQIPEKIQKAFDDIAKYFSKEEWEKMKASEKIFYVYMKRKYEAMTKLGFKATLPPFMCNKRAEDFQGNDLDNDPNRGNQVERPQMTFGRLQGISPKIMPKKPAEEGNDSEEVPEASGPQNDGKELCPPGKPTTSEKIHERSGPKRGEHAWTHRLRERKQLVIYEEISDPVMTKLGFKVKASEKTFYVRQIYVAAFTVGLPSIPVHPITQCFLPVFLVMTKLGFKVRQIYVAAFTVKASEKIFYV | CTLS2表达产物 | |
| 28 | MVMTKLGFKVKASELIFYVRPIYVAAFTVGLPSIPVHPIAQIPEKIQKAFDDIAKYFSKEEWEKMKASEKIFYVYMKRKYEAMTKLGFKATLPPFMCNKRAEDFQGNDLDNDPNRGNQVERPOMTFGRLQGISPKIMPKKPAEEGNDSEEVPEASGPQNDGKELCPPGKPTTSEKIHERSGPKRGEHAWTHRLRERKQLVIYEEISDP | CTLS3表达产物 | |
| 29 | MAQIPEKIQKAFDDIAKYFSKEEWEKMKASEKIFYVYMKRKYEAMTKLGFKATLPPFMCNKRAEDFQGNDLDNDPNRGNQVERPQMTFGRLQGISPKIMPKKPAEEGNDSEEVPEASGPQNDGKELCPPGKPTTSEKIHERSGPKRGEHAWTHRLRERKQLVIYEEISDPTQCFLPVFLVMTKLGFKVRQIYVAAFTVKASEKIFYV | CTLS4表达产物 | |
| 30 | atggtcatgactaaactaggtttcaaggtcaaagcttcggagaaaatcttctatgtgagacagatttatgttgcagccttcacagtgggtcttccaagtattcctgttcatccaattacgcagtgctttctgcccgtgtttttggtcatgactaaactaggtttcaaggtcagacagatttatgttgcagccttcacagtgaaagcttcggagaaaatcttctacgtagctcaaataccagagaagatccaaaaggccttcgatgatattgccaaatacttctctaaggaagagtgggaaaagatgaaagcctcggagaaaatcttctatgtgtatatgaagagaaagtatgaggctatgactaaactaggtttcaaggccaccctcccacctttcatgtgtaataaacgggccgaagacttccaggggaatgatttggataatgaccctaaccgtgggaatcaggttgaacgtcctcagatgactttcggcaggctccagggaatctccccgaagatcatgcccaagaagccagcagaggaaggaaatgattcggaggaagtgccagaagcatctggcccacaaaatgatgggaaagagctgtgccccccgggaaaaccaactacctctgagaagattcacgagagatctggacccaaaaggggggaacatgcctggacccacagactgcgtgagagaaaacagctggtgatttatgaagagatcagcgacccttagtga | pCBP插入片段编码区 | |
| 31 | RQIYVAAFTVKASEKIFYVAQIPEKIQK | 图8底物/CTLS1-2 | |
| 32 | FLPWHRLFL | TYR207-215 | |
| 33 | MLLAVLYCLLWSFQTSAFLPWHRLFLMLLAVLYCLLWSFQTSAFLPWHRLFLMLLAVLYCLL | CTL T2/pMEL表达产物 | |
| WSFQTSAFLPWHRLFLMLLAVLYCLLWSFQTSAFLPWHRLFL | ||
| 34 | atgctcctggctgttttgtactgcctgctgtggagtttccagacctccgcttttctgccttggcatagactcttcttgatgctcctggctgttttgtactgcctgctgtggagtttccagacctccgcttttctgccttggcatagactcttcttgatgctcctggctgttttgtactgcctgctgtggagtttccagacctccgcttttctgccttggcatagactcttcttgatgctcctggctgttttgtactgcctgctgtggagtttccagacctccgcttttctgccttggcatagactcttcttgtagtga | CTL T2/pMEL插入片段编码区 |
| 35 | MELAN-A cDNA | 登记号：NM 005511 |
| 36 | 酪氨酸酶cDNA | 登记号：NM 000372 |
| 37 | NY-ESO-1 cDNA | 登记号：U87459 |
| 38 | PSMA蛋白 | 登记号：NP 004467 |
| 39 | PSMA cDNA | 登记号：NM 004476 |
| 40 | SSX-2蛋白 | 登记号：NP 003138 |
| 41 | SSX-2 cDNA | 登记号：NM 003147 |
| 42 | atgacctctcgccgctccgtgaagtcgggttccgcgggaggttccgcgcgatgagtacgaggatctgtactacaccccgtcttcaggtatggcgagtcccgatagtccgcctgacacctcccgccgtggcgccctacagacacgctcgcgccagaggggcgaggtccgtttcgtccagtacgacgagtcggattatgccctctacgggggctcgtcatccgaagacgacgaacacccggaggtcccccggacgcggcgtcccgtttccggggcggttttgtccggcccggggcctgcgcgggcgcctccgccacccgctgggtccggaggggccggacgcacacccaccaccgccccccgggccccccgaacccagcgggtggcgactaaggcccccgcggccccggcggcggagaccacccgcggcaggaaatcggcccagccagaatccgccgcactcccagacgcccccgcgtcgacggcgccaacccgatccaagacacccgcgcaggggctggccagaaagctgcactttagcaccgcccccccaaaccccgacgcgccatggaccccccgggtggccggctttaacaagcgcgtcttctgcgccgcggtcgggcgcctggcggccatgcatgcccggatggcggcggtccagctctgggacatgtcgcgtccgcgcacagacgaagacctcaacgaactccttggcatcaccaccatccgcgtgacggtctgcgagggcaaaaacctgcttcagcgcgccaacgagttggtgaatccagacgtggtgcaggacgtcgacgcggccacggcgactcgagggcgttctgcggcgtcgcgccccaccgagcgacctcgagccccagcccgctccgcttctcgccccagacggcccgtcgag | 来自编号：D10879单纯疱疹病毒1 UL49编码序列(VP22) |
| 43 | MTSRRSVKSGPREVPRDEYEDLYYTPSSGMASPDSPPDTSRRGALFTQTRSRQRGEVRFVQYDESDYALYGGSSSEDDEHPEVPRTRRPVSGAVLSGPGPARAPPPFTPAGSGGAGRTPTTAPRAPRTQRVATKAPAAPAAETTRGRKSAQPESAALPDAPASTAPTFTRSKTPAQGLARKLHFSTAPPNPDAPWTPRVAGFNKRVFCAAVGRLAAMHARMAAVQLWDFTMSRPRTDEDLNELLGITTIRVTVCEGKNLLQRANELVNPDVVQDVDAATATRGRSAASRFTPTERPRAPARSASRPRRPVE | 登记号：P10233单纯疱疹病毒1 UL49/VP22蛋白质序列 |
Melan-A mRNA序列
基因座 NM_005511 1524bp mRNA PRI 14-OCT-2001
定义 人melan-A(MLANA)，mRNA.
编号 NM_005511
版本 NM_005511.1 GI：5031912
(SEQ ID NO.2)
/翻译＝”MPREDAHFIYGYPKKGHGHSYTTAEEAAGIGILTVILGVLLLIGCWYCRRRNGY
RALMDKSLHVGTQCALTRRCPQEGFDHRDSKVSLQEKNCEPVVPNAPPAYEKLSAEQSPPP
YSP″
(SEQ ID NO.35)
起始
1 agcagacaga ggactctcat taaggaaggt gtcctgtgcc ctgaccctac aagatgccaa
61 gagaagatgc tcacttcatc tatggttacc ccaagaaggg gcacggccac tcttacacca
121 cggctgaaga ggccgctggg atcggcatcc tgacagtgat cctgggagtc ttactgctca
181 tcggctgttg gtattgtaga agacgaaatg gatacagagc cttgatggat aaaagtcttc
241 atgttggcac tcaatgtgcc ttaacaagaa gatgcccaca agaagggttt gatcatcggg
301 acagcaaagt gtctcttcaa gagaaaaact gtgaacctgt ggttcccaat gctccacctg
361 cttatgagaa actctctgca gaacagtcac caccacctta ttcaccttaa gagccagcga
421 gacacctgag acatgctgaa attatttctc tcacactttt gcttgaattt aatacagaca
481 tctaatgttc tcctttggaa tggtgtagga aaaatgcaag ccatctctaa taataagtca
541 gtgttaaaat tttagtaggt ccgctagcag tactaatcat gtgaggaaat gatgagaaat
601 attaaattgg gaaaactcca tcaataaatg ttgcaatgca tgatactatc tgtgccagag
661 gtaatgttag taaatccatg gtgttatttt ctgagagaca gaattcaagt gggtattctg
721 gggccatcca atttctcttt acttgaaatt tggctaataa caaactagtc aggttttcga
781 accttgaccg acatgaactg tacacagaat tgttccagta ctatggagtg ctcacaaagg
841 atacttttac aggttaagac aaagggttga ctggcctatt tatctgatca agaacatgtc
901 agcaatgtct ctttgtgctc taaaattcta ttatactaca ataatatatt gtaaagatcc
961 tatagctctt tttttttgag atggagtttc gcttttgttg cccaggctgg agtgcaatgg
1021 cgcgatcttg gctcaccata acctccgcct cccaggttca agcaattctc ctgccttagc
1081 ctcctgagta gctgggatta caggcgtgcg ccactatgcc tgactaattt tgtagtttta
1141 gtagagacgg ggtttctcca tgttggtcag gctggtctca aactcctgac ctcaggtgat
1201 ctgcccgcct cagcctccca aagtgctgga attacaggcg tgagccacca cgcctggctg
1261 gatcctatat cttaggtaag acatataacg cagtctaatt acatttcact tcaaggctca
1321 atgctattct aactaatgac aagtattttc tactaaacca gaaattggta gaaggattta
1381 aataagtaaa agctactatg tactgcctta gtgctgatgc ctgtgtactg ccttaaatgt
1441 acctatggca atttagctct cttgggttcc caaatccctc tcacaagaat gtgcagaaga
1501 aatcataaag gatcagagat tctg
酪氨酸酶mRNA序列
基因座 NM_000372 1964bp mRNA PRI 31-OCT-2000
定义 人酪氨酸酶(眼皮白化病IA)(TYR)，mRNA
编号 NM 000372
版本 NM_000372.1 GI：4507752
(SEQ ID NO.3)
/翻译＝”MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRS
PCGQLSGRGSCQNILLSNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFG
FWGPNCTERRLLVRRNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFND
INIYDLFVWMHYYVSMDALLGGSEIWRDIDFAHEAPAFLPWHRLFLLRWEQEIQKLTGDENF
TIPYWDWRDAEKCDICTDEYMGGQHPTNPNLLSPASFFSSWQIVCSRLEEYNSHQSLCNGTP
EGPLRRNPGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRNTLEGFASPLTGIAD
ASQSSMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQWLRRHRPLQEVYPEANAPI
GHNRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLGA
AMVGAVLTALLAGLVSLLCRHKRKQLP EEKQPLLMEKEDYHSLYQSHL″
(SEQ ID NO.36)
起始
1 atcactgtag tagtagctgg aaagagaaat ctgtgactcc aattagccag ttcctgcaga
61 ccttgtgagg actagaggaa gaatgctcct ggctgttttg tactgcctgc tgtggagttt
121 ccagacctcc gctggccatt tccctagagc ctgtgtctcc tctaagaacc tgatggagaa
181 ggaatgctgt ccaccgtgga gcggggacag gagtccctgt ggccagcttt caggcagagg
241 ttcctgtcag aatatccttc tgtccaatgc accacttggg cctcaatttc ccttcacagg
301 ggtggatgac cgggagtcgt ggccttccgt cttttataat aggacctgcc agtgctctgg
361 caacttcatg ggattcaact gtggaaactg caagtttggc ttttggggac caaactgcac
421 agagagacga ctcttggtga gaagaaacat cttcgatttg agtgccccag agaaggacaa
481 attttttgcc tacctcactt tagcaaagca taccatcagc tcagactatg tcatccccat
541 agggacctat ggccaaatga aaaatggatc aacacccatg tttaacgaca tcaatattta
601 tgacctcttt gtctggatgc attattatgt gtcaatggat gcactgcttg ggggatctga
661 aatctggaga gacattgatt ttgcccatga agcaccagct tttctgcctt ggcatagact
721 cttcttgttg cggtgggaac aagaaatcca gaagctgaca ggagatgaaa acttcactat
781 tccatattgg gactggcggg atgcagaaaa gtgtgacatt tgcacagatg agtacatggg
841 aggtcagcac cccacaaatc ctaacttact cagcccagca tcattcttct cctcttggca
901 gattgtctgt agccgattgg aggagtacaa cagccatcag tctttatgca atggaacgcc
961 cgagggacct ttacggcgta atcctggaaa ccatgacaaa tccagaaccc caaggctccc
1021 ctcttcagct gatgtagaat tttgcctgag tttgacccaa tatgaatctg gttccatgga
1081 taaagctgcc aatttcagct ttagaaatac actggaagga tttgctagtc cacttactgg
1141 gatagcggat gcctctcaaa gcagcatgca caatgccttg cacatctata tgaatggaac
1201 aatgtcccag gtacagggat ctgccaacga tcctatcttc cttcttcacc atgcatttgt
1261 tgacagtatt tttgagcagt ggctccgaag gcaccgtcct cttcaagaag tttatccaga
1321 agccaatgca cccattggac ataaccgggt atcctacatg gttcctttta taccactgta
1381 cagaaatggt gatttcttta tttcatccaa agatctgggc tatgactata gctatctaca
1441 agattcagac ccagactctt ttcaagacta cattaagtcc tatttggaac aagcgagtcg
1501 gatctggtca tggctccttg gggcggcgat ggtaggggcc gtcctcactg ccctgctggc
1561 agggcttgtg agcttgctgt gtcgtcacaa gagaaagcag cttcctgaag aaaagcagcc
1621 actcctcatg gagaaagagg attaccacag cttgtatcag agccatttat aaaaggctta
1681 ggcaatagag tagggccaaa aagcctgacc tcactctaac tcaaagtaat gtccaggttc
1741 ccagagaata tctgctggta tttttctgta aagaccattt gcaaaattgt aacctaatac
1801 aaagtgtagc cttcttccaa ctcaggtaga acacacctgt ctttgtcttg ctgttttcac
1861 tcagcccttt taacattttc ccctaagccc atatgtctaa ggaaaggatg ctatttggta
1921 atgaggaact gttatttgta tgtgaattaa agtgctctta tttt
NY-ESO-1 mRNA序列
基因座 HSU87459 752bp mRNA PRI 22-DEC-1999
定义 人自身免疫原性癌症/睾丸抗原NY-ESO-1 mRNA，完整cds
编号 U87459
版本 U87459.1 GI：1890098
(SEQ ID NO.11)
/翻译＝”MQAEGRGTGGSTGDADGPGGPGIPDGPGGNAGGPGEAGATGGRGPRGAGAAR
ASGPGGGAPRGPHGGAASGLNGCCRCGARGPESRLLEFYLAMPFATPMEAELARRSLAQDA
PPLPVPGVLLKEFTVSGNILTIRLTAADHRQLQLSISSCLQQLSLLM
WITQCFLPVFLAQPPSGQRR″
(SEQ ID NO.37)
起始
1 atcctcgtgg gccctgacct tctctctgag agccgggcag aggctccgga gccatgcagg
61 ccgaaggccg gggcacaggg ggttcgacgg gcgatgctga tggcccagga ggccctggca
121 ttcctgatgg cccagggggc aatgctggcg gcccaggaga ggcgggtgcc acgggcggca
181 gaggtccccg gggcgcaggg gcagcaaggg cctcggggcc gggaggaggc gccccgcggg
241 gtccgcatgg cggcgcggct tcagggctga atggatgctg cagatgcggg gccagggggc
301 cggagagccg cctgcttgag ttctacctcg ccatgccttt cgcgacaccc atggaagcag
361 agctggcccg caggagcctg gcccaggatg ccccaccgct tcccgtgcca ggggtgcttc
421 tgaaggagtt cactgtgtcc ggcaacatac tgactatccg actgactgct gcagaccacc
481 gccaactgca gctctccatc agctcctgtc tccagcagct ttccctgttg atgtggatca
541 cgcagtgctt tctgcccgtg tttttggctc agcctccctc agggcagagg cgctaagccc
601 agcctggcgc cccttcctag gtcatgcctc ctcccctagg gaatggtccc agcacgagtg
661 gccagttcat tgtgggggcc tgattgtttg tcgctggagg aggacggctt acatgtttgt
721 ttctgtagaa aataaaactg agctacgaaa aa
PSMA cDNA序列
基因座 NM_004476 2653bp mRNA PRI 01-NOV-2000
定义 人叶酸水解酶(前列腺特异性膜抗原)1(FOLH1)，mRNA
编号 NM_004476
版本 NM_004476.1 GI：4758397
(SEQ ID NO.38)
/翻译＝”MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNIT
PKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD
VLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNY
ARTEDFFKLERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVK
SYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDA
QKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRG
AVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEF
GLLGSTEWAEENSRLLQERGVAYINADS SIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGF
EGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPL
YHSVYETYELVEKFYDPMFKYHLTVAOVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIY
SISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAF
IDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFT
VQAAAETLSEVA″
(SEQ ID NO.39)
起始
1 ctcaaaaggg gccggatttc cttctcctgg aggcagatgt tgcctctctc tctcgctcgg
61 attggttcag tgcactctag aaacactgct gtggtggaga aactggaccc caggtctgga
121 gcgaattcca gcctgcaggg ctgataagcg aggcattagt gagattgaga gagactttac
181 cccgccgtgg tggttggagg gcgcgcagta gagcagcagc acaggcgcgg gtcccgggag
241 gccggctctg ctcgcgccga gatgtggaat ctccttcacg aaaccgactc ggctgtggcc
301 accgcgcgcc gcccgcgctg gctgtgcgct ggggcgctgg tgctggcggg tggcttcttt
361 ctcctcggct tcctcttcgg gtggtttata aaatcctcca atgaagctac taacattact
421 ccaaagcata atatgaaagc atttttggat gaattgaaag ctgagaacat caagaagttc
481 ttatataatt ttacacagat accacattta gcaggaacag aacaaaactt tcagcttgca
541 aagcaaattc aatcccagtg gaaagaattt ggcctggatt ctgttgagct agcacattat
601 gatgtcctgt tgtcctaccc aaataagact catcccaact acatctcaat aattaatgaa
661 gatggaaatg agattttcaa cacatcatta tttgaaccac ctcctccagg atatgaaaat
721 gtttcggata ttgtaccacc tttcagtgct ttctctcctc aaggaatgcc agagggcgat
781 ctagtgtatg ttaactatgc acgaactgaa gacttcttta aattggaacg ggacatgaaa
841 atcaattgct ctgggaaaat tgtaattgcc agatatggga aagttttcag aggaaataag
901 gttaaaaatg cccagctggc aggggccaaa ggagtcattc tctactccga ccctgctgac
961 tactttgctc ctggggtgaa gtcctatcca gatggttgga atcttcctgg aggtggtgtc
1021 cagcgtggaa atatcctaaa tctgaatggt gcaggagacc ctctcacacc aggttaccca
1081 gcaaatgaat atgcttatag gcgtggaatt gcagaggctg ttggtcttcc aagtattcct
1141 gttcatccaa ttggatacta tgatgcacag aagctcctag aaaaaatggg tggctcagca
1201 ccaccagata gcagctggag aggaagtctc aaagtgccct acaatgttgg acctggcttt
1261 actggaaact tttctacaca aaaagtcaag atgcacatcc actctaccaa tgaagtgaca
1321 agaatttaca atgtgatagg tactctcaga ggagcagtgg aaccagacag atatgtcatt
1381 ctgggaggtc accgggactc atgggtgttt ggtggtattg accctcagag tggagcagct
1441 gttgttcatg aaattgtgag gagctttgga acactgaaaa aggaagggtg gagacctaga
1501 agaacaattt tgtttgcaag ctgggatgca gaagaatttg gtcttcttgg ttctactgag
1561 tgggcagagg agaattcaag actccttcaa gagcgtggcg tggcttatat taatgctgac
1621 tcatctatag aaggaaacta cactctgaga gttgattgta caccgctgat gtacagcttg
1681 gtacacaacc taacaaaaga gctgaaaagc cctgatgaag gctttgaagg caaatctctt
1741 tatgaaagtt ggactaaaaa aagtccttcc ccagagttca gtggcatgcc caggataagc
1801 aaattgggat ctggaaatga ttttgaggtg ttcttccaac gacttggaat tgcttcaggc
1861 agagcacggt atactaaaaa ttgggaaaca aacaaattca gcggctatcc actgtatcac
1921 agtgtctatg aaacatatga gttggtggaa aagttttatg atccaatgtt taaatatcac
1981 ctcactgtgg cccaggttcg aggagggatg gtgtttgagc tagccaattc catagtgctc
2041 ccttttgatt gtcgagatta tgctgtagtt ttaagaaagt atgctgacaa aatctacagt
2101 atttctatga aacatccaca ggaaatgaag acatacagtg tatcatttga ttcacttttt
2161 tctgcagtaa agaattttac agaaattgct tccaagttca gtgagagact ccaggacttt
2221 gacaaaagca acccaatagt attaagaatg atgaatgatc aactcatgtt tctggaaaga
2281 gcatttattg atccattagg gttaccagac aggccttttt ataggcatgt catctatgct
2341 ccaagcagcc acaacaagta tgcaggggag tcattcccag gaatttatga tgctctgttt
2401 gatattgaaa gcaaagtgga cccttccaag gcctggggag aagtgaagag acagatttat
2461 gttgcagcct tcacagtgca ggcagctgca gagactttga gtgaagtagc ctaagaggat
2521 tctttagaga atccgtattg aatttgtgtg gtatgtcact cagaaagaat cgtaatgggt
2581 atattgataa attttaaaat tggtatattt gaaataaagt tgaatattat atataaaaaa
2641 aaaaaaaaaa aaa
NM 003147 人滑膜肉瘤，X断点2(SSX2)，mRNA
基因座 NM_003147 766bp mRNA PRI 14-MAR-2001
定义 人滑膜肉瘤，X断点2(SSX2)，mRNA
编号 NM_003147
版本 NM_003147.1 GI：10337582
SEQ ID NO.40
/翻译＝”MNGDDAFARRPTVGAQIPEKIQKAFDDIAKYFSKEEWEKMKASE
KIFYVYMKRKYEAMTKLGFKATLPPFMCNKRAEDFQGNDLDNDPNRGNQVERPQMTFG
RLQGISPKIMPKKPAEEGNDSEEVPEASGPQNDGKELCPPGKPTTSEKIHERSGPKRG
EHAWTHRLRERKQLVIYEEISDPEEDDE″
SEQ ID NO 41
1 ctctctttcg attcttccat actcagagta cgcacggtct gattttctct ttggattctt
61 ccaaaatcag agtcagactg ctcccggtgc catgaacgga gacgacgcct ttgcaaggag
121 acccacggtt ggtgctcaaa taccagagaa gatccaaaag gccttcgatg atattgccaa
181 atacttctct aaggaagagt gggaaaagat gaaagcctcg gagaaaatct tctatgtgta
241 tatgaagaga aagtatgagg ctatgactaa actaggtttc aaggccaccc tcccaccttt
301 catgtgtaat aaacgggccg aagacttcca ggggaatgat ttggataatg accctaaccg
361 tgggaatcag gttgaacgtc ctcagatgac tttcggcagg ctccagggaa tctccccgaa
421 gatcatgccc aagaagccag cagaggaagg aaatgattcg gaggaagtgc cagaagcatc
481 tggcccacaa aatgatggga aagagctgtg ccccccggga aaaccaacta cctctgagaa
541 gattcacgag agatctggac ccaaaagggg ggaacatgcc tggacccaca gactgcgtga
601 gagaaaacag ctggtgattt atgaagagat cagcgaccct gaggaagatg acgagtaact
661 cccctcaggg atacgacaca tgcccatgat gagaagcaga acgtggtgac ctttcacgaa
721 catgggcatg gctgcggacc cctcgtcatc aggtgcatag caagtg
Claims (21)
1.一种鉴定适用于表位释放的多肽的方法，所述方法包括下列步骤：
鉴定目的表位；
提供包含所述表位的底物多肽序列，其中所述底物多肽容许蛋白酶体的加工；
在支持所述蛋白酶体加工所述底物多肽的条件下使所述底物多肽接触包含所述蛋白酶体的组合物；和测定所述表位释放。
2.权利要求1的方法，其中所述表位被嵌入所述底物多肽。
3.权利要求1的方法，其中所述表位是管家表位。
4.权利要求1的方法，其中所述底物多肽是合成肽。
5.权利要求1的方法，其中所述底物多肽是融合蛋白。
6.权利要求1的方法，其中所述接触步骤包含使用所述底物多肽进行免疫。
7.权利要求1的方法，其中所述底物多肽是由多核苷酸编码的。
8.权利要求7的方法，其中所述接触步骤包含使用含所述多核苷酸的载体进行免疫。
9.权利要求7的方法，其中所述接触步骤包含使用含所述多核苷酸的载体转化细胞。
10.权利要求1的方法，其中所述蛋白酶体加工发生于体外。
11.权利要求1的方法，其中所述测定步骤由一种技术组成，所述技术选自由质谱，N端混合测序，和HPLC组成的组。
12.权利要求1的方法，其中所述测定步骤包含T细胞靶识别测定。
13.权利要求1的方法，其中所述底物多肽还包含额外表位的排列。
14.权利要求13的方法，其中所述排列包含管家和免疫表位。
15.权利要求1的方法，其中所述底物多肽还包含表位排列和表位簇。
16.权利要求1的方法，其中所述蛋白酶体是免疫蛋白酶体。
17.一种包含管家表位表达盒的载体，其中所述管家表位是由靶相关抗原衍生的，其中所述管家表位是通过免疫蛋白酶体加工由盒的翻译产物释放的。
18.权利要求17的载体，其中所述表达盒编码两个或多个表位的排列或者至少一个表位和至少一个表位簇。
19.权利要求17的载体，其中所述靶相关抗原是由肿瘤或胞内寄生物衍生或与肿瘤或胞内寄生物相关的抗原。
20.一种激活T细胞的方法，其包含将权利要求17的载体接触APC和将所述APC接触T细胞。
21.一种包含管家表位的底物多肽，其中所述管家表位可以在pAPC中通过免疫蛋白酶体加工而释放。
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| DE19936563A1 (de) | 1999-08-04 | 2001-02-08 | Boehringer Ingelheim Int | Tumorassoziiertes Antigen |
| EP1210430B1 (en) | 1999-09-08 | 2006-08-30 | Transgene S.A. | Muc-1 derived peptides |
| WO2001019408A1 (en) | 1999-09-16 | 2001-03-22 | Zycos Inc. | Nucleic acids encoding polyepitope polypeptides |
| WO2001023577A2 (en) | 1999-09-30 | 2001-04-05 | Institut Pasteur | Hybrid or chimeric polynucleotides, proteins, and compositions comprising hepatitis b virus sequences |
| EP1118860A1 (en) * | 2000-01-21 | 2001-07-25 | Rijksuniversiteit te Leiden | Methods for selecting and producing T cell peptide epitopes and vaccines incorporating said selected epitopes |
| CA2398743C (en) * | 2000-01-28 | 2015-06-23 | The Government Of The United States Of America | Novel mhc class ii restricted t cell epitopes from the cancer antigen, ny eso-1 |
| US6756044B1 (en) | 2000-02-09 | 2004-06-29 | Genvec, Inc. | Antigenic complexes and methods |
| WO2001062917A1 (en) * | 2000-02-22 | 2001-08-30 | Ludwig Institute For Cancer Research | Isolated genomic sequences which encode the ny-eso-1 cancer testis tumor antigen and uses thereof |
| DK1276896T3 (da) | 2000-04-28 | 2010-10-18 | Mannkind Corp | Epitop-synkronisering i antigen-præsenterende celler |
| US20030215425A1 (en) * | 2001-12-07 | 2003-11-20 | Simard John J. L. | Epitope synchronization in antigen presenting cells |
| DE10025521A1 (de) | 2000-05-23 | 2001-12-06 | Boehringer Ingelheim Int | Tumor-assoziiertes Antigen B132 |
| AUPQ776100A0 (en) | 2000-05-26 | 2000-06-15 | Australian National University, The | Synthetic molecules and uses therefor |
| CU23235A1 (es) | 2001-02-28 | 2007-09-26 | Ct Ingenieria Genetica Biotech | POXVIRUS RECOMBINANTES PARA PROTEINAS QUIMéRICAS DEL VIRUS DE LA INMUNODEFICIENCIA HUMANA Y SU APLICACION EN LA TERAPéUTICA Y LA PREVENCION DEL SIDA |
| WO2003008537A2 (en) * | 2001-04-06 | 2003-01-30 | Mannkind Corporation | Epitope sequences |
| GB0118532D0 (en) * | 2001-07-30 | 2001-09-19 | Isis Innovation | Materials and methods relating to improved vaccination strategies |
| DK1453471T3 (da) * | 2001-11-07 | 2011-03-28 | Mannkind Corp | Ekspressionsvektorer, der koder for epitoper af antigener, og fremgangsmåde til deres konstruktion |
| JP4179585B2 (ja) | 2002-03-29 | 2008-11-12 | ユニ・チャーム株式会社 | 印刷が施された生分解性プラスチックフィルム |
| MXPA05002455A (es) | 2002-09-06 | 2005-06-03 | Mannkind Corp | Secuencias de epitopes. |
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2002
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- 2002-11-07 MX MXPA04005382A patent/MXPA04005382A/es active IP Right Grant
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- 2002-11-07 DE DE60238864T patent/DE60238864D1/de not_active Expired - Lifetime
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- 2002-11-07 EP EP20020806695 patent/EP1453471B1/en not_active Expired - Lifetime
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105025932A (zh) * | 2013-03-15 | 2015-11-04 | 宾夕法尼亚大学理事会 | 癌疫苗及使用其的治疗方法 |
| US11419925B2 (en) | 2013-03-15 | 2022-08-23 | The Trustees Of The University Of Pennsylvania | Cancer vaccines and methods of treatment using the same |
Also Published As
| Publication number | Publication date |
|---|---|
| US8252916B2 (en) | 2012-08-28 |
| ES2358642T3 (es) | 2011-05-12 |
| EP1453471B1 (en) | 2011-01-05 |
| CN1313617C (zh) | 2007-05-02 |
| EP1453471A2 (en) | 2004-09-08 |
| DK1453471T3 (da) | 2011-03-28 |
| ATE494387T1 (de) | 2011-01-15 |
| EP2314712B1 (en) | 2014-01-08 |
| CN101024842A (zh) | 2007-08-29 |
| MXPA04005382A (es) | 2005-02-24 |
| US8637305B2 (en) | 2014-01-28 |
| WO2003063770A3 (en) | 2004-04-01 |
| US20040132088A1 (en) | 2004-07-08 |
| US7232682B2 (en) | 2007-06-19 |
| WO2003063770A9 (en) | 2004-06-17 |
| WO2003063770A2 (en) | 2003-08-07 |
| AU2008229722A1 (en) | 2008-10-30 |
| CA2469738A1 (en) | 2003-08-07 |
| US20040203051A1 (en) | 2004-10-14 |
| EP1453471A4 (en) | 2006-11-29 |
| AU2008229722B2 (en) | 2012-09-06 |
| DE60238864D1 (de) | 2011-02-17 |
| US20030228634A1 (en) | 2003-12-11 |
| EP2314712A1 (en) | 2011-04-27 |
| HK1068807A1 (en) | 2005-05-06 |
| HK1075473A1 (en) | 2005-12-16 |
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