CN1216551A - 适宜用于抗原特异性免疫抑制治疗的新型肽 - Google Patents
适宜用于抗原特异性免疫抑制治疗的新型肽 Download PDFInfo
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- CN1216551A CN1216551A CN97194031A CN97194031A CN1216551A CN 1216551 A CN1216551 A CN 1216551A CN 97194031 A CN97194031 A CN 97194031A CN 97194031 A CN97194031 A CN 97194031A CN 1216551 A CN1216551 A CN 1216551A
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Abstract
本发明涉及含有16到55个氨基酸残基的肽,该肽含有至少一种下列氨基酸序列:LVCYYTSWS(SEQ IDNO:60),FLCTHIIYS(SEQ ID NO:61),IIYSFANIS(SEQ IDNO:62),LKTLLSVGG(SEQ ID NO:63),FIKSVPPFL(SEQ IDNO:64),FDGLDLAWL(SEQ ID NO:65),LYPGRRDKQ(SEQ IDNO:66),YDIAKISQH(SEQ ID NO:67),LDFISIMTY(SEQ IDNO:68),FISIMTYDF(SEQ ID NO:69),FRGQEDASP(SEQ IDNO:70),YAVGYMLRL(SEQ ID NO:71),MLRLGAPAS(SEQ IDNO:72),LAYYEICDF(SEQ ID NO:73),LRGATVHRT(SEQ IDNO:74),YLKDRQLAG(SEQ ID NO:75),LAGAMVWAL(SEQ IDNO:76),VWALDLDDF(SEQ ID NO:77)或LDLDDFQGS(SEQID NO:78)。该肽可以用于T-细胞介导的关节软骨的破坏的治疗。基于这些肽的药物组合物可用于诱导对在自身反应性T-细胞进攻下的自身抗原的系统性免疫耐受。
Description
本发明涉及一些肽以及它们在自身免疫疾病中关节软骨的慢性破坏的治疗中的用途、含有这些肽的药物组合物、检测样品中自身反应性T细胞的诊断方法以及用于该方法的检测试剂盒。
免疫系统是建立在通过构建针对自身抗原的耐受性而获得的对异源抗原(非自体抗原)和自身抗原(自体抗原,衍生自个体自身)区别对待的原则上的。
免疫系统对抗异源蛋白对个体加以保护且通过激活如T-和B-淋巴细胞的特异性细胞和产生象白细胞介素、抗体和补体因子的可溶性因子对异源抗原的出现加以应答。免疫系统应答的抗原由抗原提呈细胞(APC)降解且该抗原的一个片段与一种主要组织相容性复合物(MHC)Ⅱ类糖蛋白一起表达在细胞表面上。此MHC糖蛋白-抗原片段复合物被提呈到T细胞上,后者凭借其T细胞受体共同识别抗原片段和与其结合的MHCⅡ类蛋白质。这样,该T细胞被活化(即增殖和/或产生白细胞介素)导致引起该抗原遭受攻击的活化的淋巴细胞的扩展(Grey等人,科学美国人(Sci.Am.)261:38-46,1989)。
自体抗原作为抗原片段通过MHC糖蛋白也不断被加工和提呈到T细胞(Jardetsky等人,自然(Nature)353:326-329,1991)。自体识别因此对免疫系统而言是固有的。在普通环境下免疫系统对自体抗原耐受且避免激活对这些自体抗原的免疫应答。
当失去对自体抗原的耐受,免疫系统针对一种或多种自体抗原被激活,从而导致自身反应性T细胞的活化以及自身抗体的产生。这些现象称为自身免疫。由于免疫反应一般是破坏性的(即指破坏入侵的异源抗原),自身免疫反应可引起身体自己组织的破坏。
已通过一些研究确立了T细胞对自身免疫疾病的作用。在鼠中,实验性自身免疫脑脊髓炎(EAE)通过一高度限制性T细胞群介导,它们通过对复合到MHCⅡ类分子上的髓鞘质碱性蛋白质(MBP)的单一表位的特异性相关联。在Lewis大鼠(一个对不同自身免疫疾病有高度易感性的种)中,已证实由T细胞介导该疾病。
在人自身免疫疾病中也认为与自身攻击性T细胞的发育有关。一种破坏性自身免疫反应已参与不同疾病如类风湿性关节炎(RA),其中关节软骨的完整性通过慢性炎症过程被破坏。软骨的存在似乎对维持局部炎症反应是必需的:已证实在RA中软骨的降解与软骨反应性自身反应性T细胞的活性相关(Sigall等人,临床实验类风湿学(Clin.Exp.Rheumat.)6:59,1988;Glant等人,Biochem.Soc.Trans.18:796,1990;Burmester等人,类风湿性关节炎(Rheumatoicl arthritis)Smolen,Kalden,Maini(编)Springer-Verlag Berlin Heidel berg,1992)。此外,通过外科手术从RA病人中移去软骨显示降低了炎症过程。因此软骨蛋白被认为是有能力刺激T细胞的靶自身抗原。这些自身反应性T细胞的激活导致自身免疫疾病的发展。因此可以预期这些T细胞功能性的消除可对破坏性自身免疫过程的下调是有益的。然而,对类风湿性关节炎起始起作用的自身抗原性成分的确认目前仍旧难以捉摸。
导致软骨破坏的炎性反应可以用不同的药物治疗。然而,这些药物是非特异性的且有毒性副作用的免疫抑制剂。非特异性免疫抑制法因之成为极不适宜的治疗。
抗原特异性无毒性免疫抑制法如WO-A-95 10 301中所述提供了一种非常吸引人的非特异性免疫抑制法的替代疗法。该抗原特异性治疗包括:用类似或模拟存在于自身抗原之表位的合成T细胞反应性肽对病人治疗。这些肽因而可用于诱导既针对它们自身也针对自身抗原的系统性免疫耐受(即特异性T细胞耐受)。诱导的系统性免疫耐受是基于长期观察的现象,即已用一种抗原或表位喂食或吸入它后的动物当通过系统性途径用该抗原或表位诱导该动物时不易产生针对该抗原或表位的系统性免疫应答。为了有效地使用肽诱导的系统性免疫耐受疗法以治疗T细胞介导的软骨破坏,十分需要这样的T细胞反应性肽,它们可使病人对活化负责炎性过程的T细胞的自身抗原脱敏。
本发明的目的在于提供在患T细胞介导的软骨破坏的病人中可诱导对相应的软骨抗原的系统性免疫耐受的肽,更具体地为特异性T细胞耐受。本发明的另一目的在于提供一种检测参与关节软骨破坏的自身反应性T细胞的方法以及用于此方法的检测试剂盒。
本发明提供这样的肽。
在本发明的第一方面提供了含有16到55个氨基酸的肽,该肽含有至少一种下列的氨基酸序列:LVCYYTSWS (SEQ ID NO:60), FLCTHIIYS (SEQ ID NO:61), IIYSFANIS(SEQ ID NO:62), LKTLLSVGG (SEQ ID NO:63) , FIKSVPPFL (SEQ IDNO:64), FDGLDLAWL (SEQ ID NO: 65), LYPGRRDKQ (SEQ ID NO:66),YDIAKISQH (SEQ ID NO:67), LDFISIMTY (SEQ ID NO:68), FISIMTYDF(SEQ ID NO:69), FRGQEDASP (SEQ ID NO:70), YAVGYMLRL (SEQ IDNO:71), MLRLGAPAS (SEQ ID NO:72), LAYYEICDF (SEQ ID NO:73),LRGATVHRT (SEQ ID NO:74), YLKDRQLAG (SEQ ID NO:75), LAGAMVWAL(SEQ ID NO:76), VWALDLDDF(SEQ ID NO:77) 或LDLDDFQGS(SEQ IDNO:78)。
具体的,根据本发明的肽含有至少一种下列氨基酸序列:YKLVCYYTSWSQYREG (SEQ ID NO:1), YTSWSQYREGDGSCFP (SEQ ID NO:2),LDRFLCTHIIYSFANI (SEQ ID NO:5), THIIYSFANISNDHID (SEQ ID NO:6),PNLKTLLSVGGWNFGS (SEQ ID NO:12), NTQSRRTFIKSVPPFL (SEQ IDNO:16), TFIKSVPPFLRTHGFD (SEQ ID NO:17), PPFLRTHGFDGLDLAW (SEQID NO:18), HGFDGLDLAWLYPGRR (SEQ ID NO:19), DLAWLYPGRRDKQHFT(SEQ ID NO:20), TIDSSYDIAKISQHLD (SEQ ID NO:28),DIAKISQHLDFISIMT (SEQ ID NO:29), QHLDFISIMTYDFHGA (SEQ IDNO:30), SPLFRGQEDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQID NO:37), MLRLGAPASKLVMGIP (SEQ ID NO:38), PASKLVMGIPTFGRSF(SEQ ID NO:39), GTLAYYEICDFLRGAT (SEQ ID NO:46),EICDFLRGATVHRTLG (SEQ ID NO:47), RGATVHRTLGQQVPYA (SEQ IDNO:48), VKSKVQYLKDRQLAGA (SEQ ID NO:53), YLKDRQLAGAMVWALD (SEQID NO:54), LAGAMVWALDLDDFQG (SEQ ID NO:55), WALDLDDFQGSFCGQD(SEQ ID NO:56)或DFQGSFCGQDLRFPLT(SEQ ID NO:57)。
优选的,根据本发明的肽含有一种下列的氨基酸序列:YKLVCYYTSWSQYREG (SEQID NO:1), YTSWSQYREGDGSCFP (SEQ ID NO:2), LDRFLCTHIIYSFANI (SEQID NO:5), THIIYSFANISNDHID (SEQ ID NO:6), PNLKTLLSVGGWNFGS (SEQID NO:12), QHLDFISIMTYDFHGA (SEQ ID NO:30), SPLFRGQEDASPDRFS(SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37),MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD (SEQ ID NO:54)或 LAGAMVWALDLDDFQG (SEQ ID NO:55) 。
更优选的,根据本发明的肽含有一种或多种下列氨基酸序列:YTSWSQYREGDGSCFP (SEQ ID NO:2), SPLFRGQEDASPDRFS (SEQ ID NO:34),MLRLGAPASKLVMGIP (SEQ ID NO:38),YLKLDRQLAGAMVWALD (SEQ ID NO:54)或LAGAMVWALDLDDFQG (SEQ ID NO:55)。
根据本发明的肽含有16到55,优选地16到35,更优选地16到25,最优选地为16个氨基酸残基。
根据本发明高度优选的肽是含有下列氨基酸序列的十六肽:YKLVCYYTSWSQYREG (SEQ ID NO:1) YTSWSQYREGDGSCFP (SEQ ID NO:2),LDRFLCTHIIYSFANI (SEQ ID NO:5), THIIYSFANISNDHID (SEQ ID NO:6),PNLKTLLSVGGWNFGS (SEQ ID NO:12), QHLDFISIMTYDFHGA (SEQ IDNO:30), SPLFRGQEDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQID NO:37), MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD(SEQ ID NO:54) 或 LAGAMVWALDLDDFQG (SEQ ID NO:55),
更具体的氨基酸序列是:YTSWSOYREGDGSCFP (SEQ IDNO:2), SPLFRGQEDASPDRFS (SEQ ID NO:34), MLRLGAPASKLVMGIP (SEQ IDNO:38), YLKDRQLAGAMVWALD (SEQ ID NO:54) 或 LAGAMVWALDLDDFQG (SEQID NO:55)。
也在发明的范围内的是根据本发明的肽的多聚体,如根据本发明的肽的二聚体或三聚体。一个根据本发明的多聚体也可以是含有同一肽的多聚体的均聚体(homomer)或是含有不同肽的异聚体(heteromer)。
根据发明的肽的特征性氨基酸序列可由随机氨基酸序列做为两侧翼序列。优选的是对该肽有稳定化效果从而增加它们的生物学效力的两侧翼序列。
本发明基于这样的出乎意料的发现,即人软骨糖蛋白39(此后称为HC gp-39)是激活特异性T细胞从而引起或介导炎性过程的RA病人中的靶自身抗原。HC gp-39产生的肽主要由来自RA病人的自身反应性T细胞识别而极少由来自健康供体的T细胞识别,这表明HC gp-39是RA中一种自身抗原。HC gp-39的关节炎致病特性在Balb/c鼠中被进一步证实。在Balb/c鼠中该蛋白的单次皮下注射可以引发动物中关节炎的征兆。HC gp-39所诱导疾病的过程特征为在前爪和/或后爪中周期性间歇发作且逐渐从轻微关节炎发展成为更严重的形式。也观察到受损关节的对称分布,其与间歇性发作的复发和结节的形成的观察资料一起提示关节炎中尤其是RA的疾病过程。
更令人吃惊的是发现HC gp-39的使用导致免疫耐受且更重要的是延迟和/或抑制关节炎的发展。
由SEQ ID No.60-78列出的氨基酸序列,更具体的由SEQ ID No.1,2,5,6,12,16-20,28-30,34,37-39,46-48,53-57列出的序列与存在于HC gp-39的MHCⅡ类限制性T细胞表位相似。因此,根据发明的肽也可以理解为包括含有一种或多种上述确认的MHCⅡ类限制性T细胞表位的自身抗原HC gp-39的片段,它们也在本发明范围之内。
虽然HC gp-39已在Hakala等人生物化学杂志(J.Biol.Chem.)268卷,No.34,25803(1993)中描述,其中它被描述为几丁质酶蛋白质并建议作为类风湿性关节炎的一种合适的标记,但没有针对HC gp-39的关节炎致病特性的暗示和建议。
根据发明的这些肽可以通过周知的用于肽合成的有机化学方法来制备,例如在美国化学协会杂志(J.Amer.Chem.Soc.)85:2149(1963)和国际肽蛋白质研究(Int.J.Peptide Protein Res.)35:161-214(1990)中所述的固相肽合成。
根据发明的这些肽也可由重组DNA技术制备。编码根据发明的肽或其多聚体的核苷酸序列被插入到一个表达载体中。合适的表达载体是包含有复制和表达必需的控制区域的质粒、粘粒、病毒和YAC(酵母人工染色体)等等。表达载体可以被引入一宿主细胞中表达。合适的宿主细胞是例如:细菌、酵母细胞和哺乳动物细胞。这些技术为本领域周知,如见Sambrook等人,分子克隆:实验室手册,冷泉港实验室出版社,冷泉港,1989。
根据发明的这些肽是T细胞反应性肽,其能被活化的自身反应性T细胞所识别也能刺激它们。这些自身反应性T细胞可在RA病人的血液中发现,但极少在健康供体中发现。
因此,根据本发明的这些合成肽(这些肽与在靶自身抗原HC gp-39上的MHCⅡ类限制性T细胞表位相似)非常适于治疗,以在患T细胞介导的软骨破坏(如关节炎,更具体的为类风湿性关节炎)的哺乳动物(更具体的为人)中诱导对HC gp-39的特异性T细胞耐受。
虽然WO95/01995和WO95/02188描述了作为RA标记的HCgp-39的诊断用途,但既未公开也未涉及HC gp-39的致关节炎特性。他们也未暗示或涉及根据本发明的HC gp-39或T细胞反应性肽的片段在抗原或肽特异性治疗中用以在遭到攻击的软骨中诱导对HC gp-39的T细胞特异性耐受的用途。
根据本发明,关节软骨受到T细胞介导的破坏的病人可以用包含一种或多种根据本发明的肽以及一种药学可接受的载体的药物组合物治疗。根据本发明的药物组合物的使用将诱导对遭受攻击的关节软骨中的自身抗原性蛋白质和其它显示由一种或多种根据发明的肽的氨基酸序列表征的或模拟的确定的MHCⅡ类结合性T细胞表位的自身抗原的系统性免疫耐受,特别是对这些病人的特异性自身反应性T细胞的耐受。所诱导的耐受从而将导致在遭受攻击的关节软骨中局部炎性反应的降低。
非常适用于本发明的药物组合物中的肽是有16-55,优选地16-35,更优选地16-25,最优选地16个氨基酸残基的肽,这些肽包含至少一种下列的氨基酸序列:LVCYYTSWS (SEQ ID NO:60), FLCTHIIYS(SEQ ID NO:61), IIYSFANIS (SEQ ID NO:62), LKTLLSVGG (SEQ IDNO:63), FIKSVPPFL (SEQ ID NO:64), FDGLDLAWL (SEQ ID NO: 65),LYPGRRDKQ (SEQ ID NO:66), YDIAKISQH (SEQ ID NO:67), LDFISIMTY(SEQ ID NO:68), FISIMTYDF (SEQ ID NO:69), FRGQEDASP (SEQ IDNO:70), YAVGYMLRL (SEQ ID NO:71), MLRLGAPAS (SEQ ID NO:72),LAYYEICDF (SEQ ID NO:73), LRGATVHRT (SEQ ID NO:74), YLKDRQLAG(SEQ ID NO:75), LAGAMVWAL (SEQ ID NO:76), VWALDLDDF (SEQ IDNO:77) 或 LDLDDFQGS (SEQ ID NO:78),更具体的是一种下列的氨基酸序列:YKLVCYYTSWSQYREG (SEQ ID NO:1),YTSWSQYREGDGSCFP (SEQ ID NO:2), LDRFLCTHIIYSFANI (SEQ ID NO:5),THIIYSFANISNDHID (SEQ ID NO:6), PNLKTLLSVGGWNFGS (SEQ ID NO:12),NTQSRRTFIKSVPPFL (SEQ ID NO:16), TFIKSVPPFLRTHGFD (SEQ IDNO:17), PPFLRTHGFDGLDLAW (SEQ ID NO:18), HGFDGLDLAWLYPGRR (SEQID NO:19), DLAWLYPGRRDKQHFT (SEQ ID NO:20), TIDSSYDIAKISQHLD(SEQ ID NO:28), DIAKISQHLDFISIMT (SEQ ID NO:29),QHLDFISIMTYDFHGA (SEQ ID NO:30), SPLFRGQEDASPDRFS (SEQ IDNO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37), MLRLGAPASKLVMGIP (SEQID NO:38), PASKLVMGIPTFGRSF (SEQ ID NO:39), GTLAYYEICDFLRGAT(SEQ ID NO:46), EICDFLRGATVHRTLG (SEQ ID NO:47),RGATVHRTLGQQVPYA (SEQ ID NO:48), VKSKVQYLKDRQLAGA (SEQ IDNO:53), YLKDRQLAGAMVWALD (SEQ ID NO:54), LAGAMFVWALDLDDFQG (SEQID NO:55), WALDLDDFQGSFCGQD (SEQ ID NO:56) 或 DFQGSFCGQDLRFPLT(SEQ ID NO:57)。
在根据发明的药物组合物中特别优选的是有16-55,优选地16-35,更优选地16-25,最优选地为16个氨基酸残基的肽,这些肽包含至少一种下列氨基酸序列: YKLVCYYTSWSQYREG (SEQ ID NO:1),YTSWSQYREGDGSCFP (SEQ ID NO:2), LDRFLCTHIIYSFANI (SEQ ID NO:5),THIIYSFANISNDHID (SEQ ID NO:6), PNLKTLLSVGGWNFGS (SEQ ID NO:12),QHLDFISIMTYDFHGA (SEQ ID NO:30), SPLFRGQEDASPDRFS (SEQ IDNO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37), MLRLGAPASKLVMGIP (SEQID NO:38), YLKDRQLAGAMVWALD (SEQ ID NO:54) 或 LAGAMVWALDLDDFQG(SEQ ID NO:55)。
在根据发明的药物组合物中高度优选地是有16-55,优选地16-35,更优选地16-25,最优选地为16个氨基酸残基的肽,这些肽包含至少一种下列氨基酸序列:
YTSWSQYREGDGSCFP (SEQ ID NO:2), SPLFRGQEDASPDRFS (SEQID NO:34), MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD(SEQ ID NO:54) 或 LAGAMVWALDLDDFQG (SEQ ID NO:55)。
在根据发明的药物组合物中最优选的是含有下列氨基酸序列的十六肽: YKLVCYYTSWSQYREG (SEQ ID NO:1) YTSWSQYREGDGSCFP (SEQIDNO:2), LDRFLCTHIIYSFANI (SEQ ID NO:5), THIIYSFANISNDHID (SEQ IDNO:6), PNLKTLLSVGGWNFGS (SEQ ID NO:12), QHLDFISIMTYDFHGA (SEQ IDNO:30), SPLFRGQEDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQID NO:37), MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD(SEQ ID NO:54) 或 LAGAMVWALDLDDFQG (SEQ ID NO:55),更具体的是氨基酸序列 YTSWSQYREGDGSCFP (SEQ IDNO:2), SPLFRGQEDASPDRFS (SEQ ID NO:34), MLRLGAPASKLVMGIP (SEQ IDNO:38), YLKDRQLAGAMVWALD (SEQ ID NO:54) 或 LAGAMVWALDLDDFQG (SEQID NO:55).
根据发明的这些肽有这样的优点:与免疫抑制药物的非特异性抑制效果相比它们对自身反应性T细胞有特异性效果从而使免疫系统的其它组份未受触动。使用根据发明的这些肽的治疗将是安全的且不会有毒性副作用。
通过使用高或低剂量的根据发明的这些肽可以获得系统性免疫耐受。肽的量将依赖于给药的路线、给药时间、病人的年龄以及一般健康状况和饮食。
一般地,可以使用0.01到1000μg肽每千克体重,优选地0.5到500μg,更优选地0.1到100μg的肽。
药学可接受的载体为本领域技术人员周知,且包括:如无菌盐水、乳糖、蔗糖、磷酸钙、明胶、糊精、琼脂、果胶、花生油、橄榄油、芝麻油和水。其它载体可以是如MHCⅡ类分子,如需要后者可植入脂质体中。
此外,依据发明的药物组合物可以包含一种或多种佐剂。合适的佐剂包括:氢氧化铝、磷酸铝、amphigen、tocophenols、单苯膦基脂质A、胞壁酰二肽和皂角苷如Quill A。优选地,根据发明用于耐受治疗的佐剂是粘膜性佐剂如霍乱毒素B亚单位或carbomers,其结合到粘膜性上皮上。佐剂的量取决于该佐剂自身的本质。
此外,根据发明的药物组合物可以包含一种或多种稳定剂如:碳水化合物包括:山梨糖醇、甘露糖醇、淀粉、蔗糖、糊精和葡萄糖,蛋白质如白蛋白或酪蛋白以及象碱性磷酸盐的缓冲液。
合适的给药路线是肌内注射、皮下注射、静脉注射或腹膜内注射、口腔给药和鼻喷雾。
根据发明的这些肽也非常适用于检测参与慢性炎症及关节软骨破坏的活化的自身反应性T细胞的存在的诊断方法。
根据发明的诊断方法包括下列步骤:
a)从个体的血样中分离外周血单核细胞(PBMC),
b)在合适条件下培养该PBMC,
c)在根据发明的一种或多种肽存在下培养该PBMC培养物,且
d)检测T细胞反应,如一种增殖反应,指示在个体中活化的自身反应性T细胞的存在。
T细胞增殖反应的检测可以通过3H-胸腺嘧啶脱氧核苷的掺入来检测。
也包括在发明的范围内的是含有一种或多种根据发明的肽的检测试剂盒。这些检测试剂盒也适于在根据发明的诊断方法中使用。
下面的实施例是发明的阐明且不应解释为限制发明的范围。
实施例
方法
病人
本研究包括7名依照ARA标准(Arnett等人,(1988),类风湿关节炎(Arthritis Rheum.)31,315)诊断为患RA的DR4(DRB1*0401)阳性病人。经同意取得外周血样品。他们是年龄在46-79岁的5名女性和2名男性。他们疾病的持续时间从10年以上到30年以上。七位病人中的三位至少有3个肿胀的关节。四位病人未显示任何活动性疾病的迹象。所有病人均服药:四位病人用泼尼松(Prednisone)治疗,三位病人接受抗类风湿剂且有四位病人同时用NSAID治疗。
带有DR4(DRB1*0401)特异性的来自5位健康供体的外周血样品经同意后取得且包括在本次研究中作为对照。HLA-DR多态性的定义
通过Ficoll-Paque梯度的标准离心方法分离自肝素化的外周血的病人和健康供体的外周血单核细胞用PHA(Welcome,Dartford,英国)刺激以获得5×106-107个淋巴细胞。QIA amp血试剂盒(QIAGEN Inc.)用于根据制造商指示从培养的细胞中纯化染色体DNA。利用一种DR“低分辨率”SSP试剂盒分析染色体DNA提取物。用Dynal DRB1*04-SSP试剂盒进行DR4亚型分型。MHC DR型分型在荷兰(Nijmegen)University Hospital移植血清学实验室(TramsplantSerology Laboratory)中进行。
表Ⅰ
肽的合成
RA病人 | 期 | 滑膜炎 | 持续时间 | HLA-DR |
191 | Ⅳ | 否 | >30年 | 0401/01 |
259 | Ⅲ-Ⅳ | 是 | >30年 | 0401/16 |
262 | Ⅲ-Ⅳ | 是 | >10年 | 0401/0408 |
272 | Ⅲ-Ⅳ | 否 | >30年 | 0401/0701 |
276 | Ⅳ | 否 | >30年 | 0401/14 |
286 | Ⅳ | 否 | 20年 | 0401/0408 |
287 | Ⅲ-Ⅳ | 是 | 20年 | 0401/13 |
HD | HLA-DR | |||
155 | 0401/14 | |||
157 | 0401/13 | |||
168 | 0401/07 | |||
230 | 0401/07 | |||
235 | 0401/13 |
在Eurosequence(Groningen,荷兰)合成这些肽。利用固相FMOC化学法以10μmol的规模从C-端到N-端合成这些肽。通过一些其它制备方法部分纯化粗品肽。如制造商所示,至少35%的冻干产品中含有所需的全长产品。剩余部分含盐和残留的溶剂。利用序列分析、氨基酸序列分析和/或RF-HPLC检查终产品的质量。合成的肽的序列列于表Ⅱ。
表Ⅱ:用于本研究的肽的氨基酸序列
肽的HLA-DR结合鉴定
SEQ ID NO: | 残基 | 肽 |
1 | 22-37 | YKLVCYYTSWSQYREG |
2 | 28-43 | YTSWSQYREGDGSCFP |
3 | 34-49 | YREGDGSCFPDALDRF |
4 | 40-55 | SCFPDALDRFLCTHII |
5 | 46-61 | LDRFLCTHIIYSFANI |
6 | 52-67 | THIIYSFANISNDHID |
7 | 58-73 | FANISNDHIDTWEWND |
8 | 64-79 | DHIDTWEWNDVTLYGM |
9 | 70-85 | EWNDVTLYGMLNTLKN |
10 | 76-91 | LYGMLNTLKNRNPNLK |
11 | 82-97 | TLKNRNPNLKTLLSVG |
12 | 88-103 | PNLKTLLSVGGWNFGS |
13 | 94-109 | LSVGGWNFGSQRFSKI |
14 | 100-115 | NFGSQRFSKIASNTQS |
15 | 106-121 | FSKIASNTQSRRTFIK |
16 | 112-127 | NTQSRRTFIKSVPPFL |
17 | 118-133 | TFIKSVPPFLRTHGFD |
18 | 124-139 | PPFLRTHGFDGLDLAW |
19 | 130-145 | HGFDGLDLAWLYPGRR |
20 | 136-151 | DLAWLYPGRRDKQHFT |
21 | 142-157 | PGRRDKQHFTTLIKEM |
22 | 148-163 | QHFTTLIKEMKAEFIK |
23 | 154-169 | IKEMKAEFIKEAQPGK |
24 | 160-175 | E FIKEAQPGKKQLLLS |
25 | 166-181 | QPGKKQLLLSAALSAG |
26 | 172-187 | LLLSAALSAGKVTIDS |
27 | 178-193 | LSAGKVTIDSSYDIAK |
28 | 184-199 | TIDSSYDIAKISQHLD |
29 | 190-205 | DIAKISQHLDFISIMT |
30 | 196-211 | QHLDFISIMTYDFHGA |
31 | 202-217 | SIMTYDFHGAWRGTTG |
32 | 208-223 | FHGAWRGTTGHHSPLF |
33 | 214-229 | GTTGHHSPLFRGQEDA |
34 | 220-235 | SPLFRGQEDASPDRFS |
35 | 226-241 | QEDASPDRFSNTDYAV |
36 | 232-247 | DRFSNTDYAVGYMLRL |
37 | 238-253 | DYAVGYMLRLGAPASK |
38 | 244-259 | MLRLGAPASKLVMGIP |
39 | 250-265 | PASKLVMGIPTFGRSF |
40 | 256-271 | MGIPTFGRSFTLASSE |
41 | 262-277 | GRSFTLASSETGVGAP |
42 | 268-283 | ASSETGVGAPISGPGI |
43 | 274-289 | VGAPISGPGIPGRFTK |
44 | 280-295 | GPGIPGRFTKEAGTLA |
45 | 286-301 | RFTKEAGTLAYYEICD |
46 | 292-307 | GTLAYYEICDFLRGAT |
47 | 298-313 | EICDFLRGATVHRTLG |
48 | 304-319 | RGATVHRTLGQQVPYA |
49 | 310-325 | RTLGQQVPYATKGNQW |
50 | 316-331 | VPYATKGNQWVGYDDQ |
51 | 322-337 | GNQWVGYDDQESVKSK |
52 | 328-343 | YDDQESVKSKVQYLKD |
53 | 334-349 | VKSKVQYLKDRQLAGA |
54 | 340-355 | YLKDRQLAGAMVWALD |
55 | 346-361 | LAGAMVWALDLDDFQG |
56 | 352-377 | WALDLDDFQGSFCGQD |
57 | 358-373 | DFQGSFCGQDLRFPLT |
58 | 364-379 | CGQDLRFPLTNAIKDA |
59 | 368-383 | LRFPLTNAIKDALAAT |
利用针对DR-复合物上一种单形态决定簇的单克隆抗体L243(Lampson,L.A和R.Levy,(1980),免疫学杂志(J.Immunol)125:293-299)从纯合的EBV转化的人B成淋巴细胞细胞系Huly138IC2和BM92中纯化DR4(DRB1*0401)和DR4(DRB1*0404)分子。
通过半定量竞争结合鉴定完成肽结合研究(Joosten等人,1994,国际免疫学(Int.Immunol.)6:751)。简言之,纯化的HLA-DR分子(30nM DR4(DRB1*0401)或15nM DR4(DRB1*0404))在pH5.0下与50nM生物素化的标记肽(HA309Y→F)及一定浓度范围的竞争性肽在终体积25μl的结合缓冲液中(含有0.01%NaN3,0.05%NP-40,5%DMSO,1mM AEBSF,1mM N-乙酰马来酰亚胺,8mM EDTA和10μM胃酶抑素A)一起培养。在室温(RT)下培养44小时后,利用96孔真空点杂交仪(Hybri.dot,BRL)和硝酸纤维素膜(Hybond ECL,Amersham,英国)从游离的标记肽中分离HLA-DR-结合标记肽。该硝酸纤维素滤膜用在0.1M马来酸,150mM NaClpH7.5中的0.5%DNA封闭液(Boehringer)封闭0.5-1小时后,用含0.05%Tween20(Sigma)的PBS洗涤滤膜且与1∶10,000稀释的链亲和素-HRPO一起孵育(Southern生物技术)。通过Western杂交ECL试剂盒(Amersham)采用增强的化学发光术检测生物素化的肽。对预闪的胶片曝光10分钟(Hyperfilm-ECL,Amersham)。通过扫描胶片且用Image Quant/Excel分析软件分析图像。
结合DRB1*0401-编码的分子的特定肽的亲和力与标记肽的竞争相关。这种相对结合的亲和力用信号降低到50%(IC50)时肽的浓度来表示。血单核细胞的增殖反应
为了确认在HC gp-39内的T细胞表位,测定长度为16个氨基酸、重叠10个氨基酸的59个肽诱导来自带有DR4(DRB1*0401)特异性的(表1)RA病人和健康对照的PBMC的增殖反应的能力。表2列出了所测试的肽的序列。
通过Ficoll-Paque梯度的标准离心法分离获自肝素化的静脉外周血中的PBMC。四份浓度为1.5×105细胞/孔的细胞在补加10%热灭活的自身血浆、L-谷氨酸、2-ME和抗生素的培养基中于平底微孔板中培养。细胞分别在仅有培养基、或者有植物血细胞凝集素(PHA)存在时(2.5μg/ml)以鉴定细胞的存活、或者在有10或100μg/ml的HC gp-39衍生的肽存在下培养。在一些情况下,由于单个供者的有限的PMBC数量则测试了2或3套系列肽。培养物在总体积210μl下37℃且有5%CO2的湿润空气中培养7天。在最后18小时时用0.25μCi 3H-胸腺嘧啶脱氧核苷([3H]TdR)脉冲标记培养物。在烧结玻璃漏斗上收集细胞且用气体闪烁法(Packard Matrix 96β计数仪)测量[3H]TdR的掺入。只有在10和100μg/ml均引起增殖反应的肽才认为含有一种T细胞表位。如果刺激系数值(SI,抗原特异性计数每5分钟(cp5m)/背景cp5m)超过或等于2就定义为反应阳性。结果通过血单核细胞的增殖反应对T细胞表位的检定
通过测量在DR4(DRB1*0401)-阳性的RA病人和健康供体中的PBMC增殖反应来分析针对HC gp-39-衍生的肽的T细胞反应性。在自身血浆中测试增殖反应。在表ⅢA和ⅢB中列出的7次实验的结果显示针对59个衍生于HC gp-39的重叠序列的RA病人的反应(表ⅢA)和健康供体的反应(表ⅢB)。发现对两种浓度(100和10μg/ml)的肽均反应的供体称为反应者,而对所测的两种浓度均不反应的供体称为无反应者(NR)。
在一个或多个供体中观察到对单独的肽1、2、5、6、12、15、30、34、37、38、40、41、54和55(号码对应于相应每种肽的SEQ ID NO,例如,肽30指有SEQ ID NO:30的氨基酸序列的肽)有反应,因此将这些序列确定为T细胞表位。
有趣的是,仅在RA病人中观察到对肽2、34、38、40、54和55有反应。
另一方面,目前肽12和41仅诱导健康供体(230,235)中的反应。
此外,如表3中所见,也发现对下列套肽:肽1/2、1/2/3、4/5/6、5/6、15/16、17/18、19/20、28/29/30、29/30、37/38、37/38/39/、39/40、46/47/48、53/54、55/56和55/56/57的反应。这些结果与上面提到的大多数单独的肽的结果相一致。此外,针对套肽的反应限定了含有附加T细胞表位的区域,即:由肽16-20(112-151残基)、28-29(184-205残基)、38-40(244-271残基)、46-48(292-319残基)和53-57(334-373残基)所覆盖的区域。
7个DR4(DRB1*0401)阳性RA病人中的6个有针对HC gp-39衍生的肽或肽套的反应,因此将其称为反应者。在健康供体组(HD),5个供体中的3个被称为反应者。一般地,RA病人似乎比健康供体(健康供体230是一个例外)对更多的HC gp-39区域有反应。例如:针对单独肽测试的来自RA病人272的PBMC似乎与总数达11个肽(1、2、5、6、30、34、37、38、40、54和55)反应。其它病人(病人287是一个例外)的PBMC显示针对与这11个肽重叠的肽套的反应且确认了含有T细胞表位(肽14-20和46-48)的一些附加区域。
来自健康供体(230)的PBMC进一步证实了在肽1、5、6、15、30和37中T细胞表位的存在。
总之,最经常识别的肽或肽套中含有肽1/2、5/6、30、37/38、54/55。T细胞表位和DRB4(DRB1*0401)结合的关联
肽1、2、5、6、12、15、30、34、37、38、40、41、54和55均被发现刺激外周血衍生的T细胞。与此发现相应的是,已发现所有这些肽以相对高的亲和力结合到DR4(DRB1*0401)上(除了以中等相对亲和力结合的肽2和38)。用肽套而不是用单独的肽测试肽3、4、16、17、18、19、20、28、29、30、46、47、48、53、56和57。非常可能的是这些肽中的一些也含有相关T细胞表位。在任何情况下,这些肽全能以从高到中等的相对亲和力(除了以弱相对亲和力结合的肽20)与DRB4(DRB1*0401)结合。
表ⅢA:来自RA病人的PBMC的肽诱导的增殖反应
pos=对100和10μg/ml的肽或肽套的反应呈阳性(SI≥2均认为阳性)。这些肽一起(长度为16个氨基酸且重叠10个氨基酸)覆盖了成熟HC gp-39的完整的成熟序列(残基22-383)。在Eurosequence合成这些肽(Groningen,荷兰)。RA=类风湿性关节炎病人。0401=带有RA相关的HLA-DRB1*0401特异性的供体。NR=无反应者。R=反应者。BG=无抗原的孔中每5分钟×10-3所测量的背景计数的平均值。+++=高亲和力结合物(IC50<1μM);++=良好亲和力结合物(1<IC50<10μM);+=中等结合物(10<IC50<100μM);+/-=弱结合物(100<IC50<1000μM);-=不结合物(IC50>1000μM)。表ⅢB:来自健康供体的PBMC的肽诱导的增殖反应
pos=对100和10μg/ml的肽或肽套的反应呈阳性(SI≥2均认为阳性)。这些肽一起(长度为16个氨基酸且重叠10个氨基酸)覆盖了成熟HC gp-39的完整的成熟序列(残基22-383)。在Eurosequence合成这些肽(Groningen,荷兰)。RA=类风湿性关节炎病人。0401=带有RA相关的HLA-DRB1*0401特异性的供体。NR=无反应者。R=反应者。BG=无抗原的孔中每5分钟×10-3所测量的背景计数的平均值。+++=高亲和力结合物(IC50<1μM);++=良好亲和力结合物(1<IC50<10μM);+=中等结合物(10<IC50<100μM);+/-=弱结合物(100<IC50<1000μM);-=不结合物(IC50>1000μM)。缩略语AEBSF:4-(2-氨乙酰基)-苯磺酰氟BB:结合缓冲液BCA:二辛可宁酸BSA:牛血清白蛋白DMSO:二甲基亚砜ECL:增强化学发光法EDTA:乙二胺四乙酸FACS:荧光活化的细胞分选仪HLA:人白细胞抗原HPLC:高压液相色谱HRP:辣根过氧化物酶MHC ClassⅡ:主要组织相容性复合物Ⅱ类NMR:核磁共振NP-40:Nonider P-40PBS:磷酸缓冲盐溶液PVDF:聚偏二氟乙烯RA:类风湿性关节炎SDS-PAGE:十二烷基硫酸钠聚丙烯酰胺凝胶电泳
RA: | 272 | 262 | 276 | 286 | 191 | 287 | 259 | 0401 |
肽 | 0401 | 0401 | 0401 | 0401 | 0401 | 0401 | 0401 | 结合 |
R | R | R | R | R | NR | R | ||
1 | pos | pos | pos | pos | pos | |||
2 | pos | + | ||||||
3 | + | |||||||
4 | pos | + | ||||||
5 | pos | pos | pos | +++ | ||||
6 | pos | +++ | ||||||
7 | ||||||||
8 | ||||||||
9 | ||||||||
10 | ||||||||
11 | ||||||||
12 |
13 | ||||||||
14& | ||||||||
15& | pos | +++ | ||||||
16 | +++ | |||||||
17 | pos | ++ | ||||||
18 | + | |||||||
19 | pos | + | ||||||
20 | +/- | |||||||
21 | ||||||||
22 | ||||||||
23 | ||||||||
24 | ||||||||
25 | ||||||||
26 | ||||||||
27 | ||||||||
28 | pos | |||||||
29 | pos | pos | pos | |||||
30 | pos | |||||||
31 | ||||||||
32 | ||||||||
33 | ||||||||
34 | pos | |||||||
35 | ||||||||
36 | ||||||||
37 | pos | pos | pos | pos | pos | +++ | ||
38 | pos | |||||||
39 | pos | |||||||
40& | pos | |||||||
41& |
42 | ||||||||
43 | ||||||||
44 | ||||||||
45 | ||||||||
46 | pos | |||||||
47 | +++ | |||||||
48 | + | |||||||
49 | ||||||||
50 | ||||||||
51& | ||||||||
52& | ||||||||
53 | pos | pos | +++ | |||||
54 | pos | +++ | ||||||
55 | pos | pos | pos | +++ | ||||
56 | +++ | |||||||
57 | ++ | |||||||
58 | ||||||||
59 | ||||||||
BG | 0.2 | 0.7 | 0.5 | 0.8 | 2.4 | 0.9 | 0.2 |
HD | 155 | 157 | 168 | 230 | 235 | 0401 |
肽 | 0401 | 0401 | 0401 | 0401 | 0401 | 结合 |
R | NR | NR | R | R | ||
1 | pos | +++ | ||||
2 | ||||||
3 | ||||||
4 | ||||||
5 | pos | +++ | ||||
6 | pos | +++ | ||||
7 | ||||||
8 | ||||||
9 | ||||||
10 | ||||||
11 | ||||||
12 | pos | +++ | ||||
13 |
14& | ||||||
15& | pos | +++ | ||||
16 | ||||||
17 | ||||||
18 | ||||||
19 | ||||||
20 | ||||||
21 | ||||||
22 | ||||||
23 | ||||||
24 | ||||||
25 | ||||||
26 | ||||||
27 | ||||||
28 | ||||||
29 | ||||||
30 | pos | +++ | ||||
31 | ||||||
32 | ||||||
33 | ||||||
34 | ||||||
35 | ||||||
36 | ||||||
37 | pos | pos | pos | +++ | ||
38 | ||||||
39 | ||||||
40 | ||||||
41 | pos | +++ | ||||
42 | ||||||
43 |
44 | ||||||
45 | ||||||
46 | ||||||
47 | ||||||
48 | ||||||
49 | ||||||
50 | ||||||
51 | ||||||
52 | ||||||
53 | ||||||
54 | ||||||
55 | ||||||
56 | ||||||
57 | ||||||
58 | ||||||
59 | ||||||
BG | 4,2 | 10,4 | 2,2 | 3,6 | 3,5 |
序列表
(1)一般信息:
(ⅰ)申请人:
(A)姓名:Akzo Nobel N.V.
(B)街道:Velperweg76
(C)城市:Arnhem
(D)国家:荷兰
(F)邮编代码:6824BM
(G)电话:6421-666376
(H)传真:0421-650592
(I)电传:37503akpha nl
(ⅱ)发明名称:适宜用于抗原特异性免疫抑制治疗的新型肽
(ⅲ)序列数:78
(ⅳ)计算机可读形式:
(A)介质类型:软盘
(B)计算机:IBM PC兼容机
(C)操作系统;PC-DOS/MS-DOS
(D)软件:Patent In Release#1.0,version#1.30(EPO)
(2)SEQ ID NO:1的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:1:的序列描述Tyr Lys Leu Val Cys Tyr Tyr Thr Ser Trp Ser Gln Tyr Arg Glu Gly1 5 10 15
(2)SEQ ID NO:2的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:2:的序列描述Tyr Thr Ser Trp Ser Gln Tyr Arg Glu Gly Asp Gly Ser Cys Phe Pro1 5 10 15
(2)SEQ ID NO:3的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:3:的序列描述Tyr Arg Glu Gly Asp Gly Ser Cys Phe Pro Asp Ala Leu Asp Arg Phe1 5 10 15
(2)SEQ ID NO:4的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:4:的序列描述Ser Cys Phe Pro Asp Ala Leu Asp Arg Phe Leu Cys Thr His Ile Ile1 5 10 15
(2)SEQ ID NO:5的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:5:的序列描述Leu Asp Arg Phe Leu Cys Thr His Ile Ile Tyr Ser Phe Ala Asn Ile1 5 10 15
(2)SEQ ID NO:6的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:6:的序列描述Thr His Ile Ile Tyr Ser Phe Ala Asn Ile Ser Asn Asp His Ile Asp1 5 10 15
(2)SEQ ID NO:7的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:7:的序列描述Phe Ala Asn Ile Ser Asn Asp His Ile Asp Thr Trp Glu Trp Asn Asp1 5 10 15
(2)SEQ ID NO:8的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:8:的序列描述Asp His Ile Asp Thr Trp Glu Trp Asn Asp Val Thr Leu Tyr Gly Met1 5 10 15
(2)SEQ ID NO:9的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:9:的序列描述Glu Trp Asn Asp Val Thr Leu Tyr Gly Met Leu Asn Thr Leu Lys Asn1 5 10 15
(2)SEQ ID NO:10的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:10:的序列描述Leu Tyr Gly Met Leu Asn Thr Leu Lys Asn Arg Asn Pro Asn Leu Lys1 5 10 15
(2)SEQ ID NO:11的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:11:的序列描述Thr Leu Lys Asn Arg Asn Pro Asn Leu Lys Thr Leu Leu Ser Val Gly1 5 10 15
(2)SEQ ID NO:12的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:12:的序列描述Pro Asn Leu Lys Thr Leu Leu Ser Val Gly Gly Trp Asn Phe Gly Ser1 5 10 15
(2)SEQ ID NO:13的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:13:的序列描述Leu Ser Val Gly Gly Trp Asn Phe Gly Ser Gln Arg Phe Ser Lys Ile1 5 10 15
(2)SEQ ID NO:14的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:14:的序列描述Asn Phe Gly Ser Gln Arg Phe Ser Lys Ile Ala Ser Asn Thr Gln Ser1 5 10 15
(2)SEQ ID NO:15的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅹⅰ)SEQ ID NO:15:的序列描述Phe Ser Lys Ile Ala Ser Asn Thr Gln Ser Arg Arg Thr Phe Ile Lys1 5 10 15
(2)SEQ ID NO:16的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:16:的序列描述Asn Thr Gln Ser Arg Arg Thr Phe Ile Lys Ser Val Pro Pro Phe Leu1 5 10 15
(2)SEQ ID NO:17的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:17:的序列描述Thr Phe Ile Lys Ser Val Pro Pro Phe Leu Arg Thr His Gly Phe Asp1 5 10 15
(2)SEQ ID NO:18的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:18:的序列描述Pro Pro Phe Leu Arg Thr His Gly Phe Asp Gly Leu Asp Leu Ala Trp1 5 10 15
(2)SEQ ID NO:19的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:19:的序列描述His Gly Phe Asp Gly Leu Asp Leu Ala Trp Leu Tyr Pro Gly Arg Arg1 5 10 15
(2)SEQ ID NO:20的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:20:的序列描述Asp Leu Ala Trp Leu Tyr Pro Gly Arg Arg Asp Lys Gln His Phe Thr1 5 10 15
(2)SEQ ID NO:21的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:21:的序列描述Pro Gly Arg Arg Asp Lys Gln His Phe Thr Thr Leu Ile Lys Glu Met1 5 10 15
(2)SEQ ID NO:22的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:22:的序列描述Gln His Phe Thr Thr Leu Ile Lys Glu Met Lys Ala Glu Phe Ile Lys1 5 10 15
(2)SEQ ID NO:23的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:23:的序列描述Ile Lys Glu Met Lys Ala Glu Phe Ile Lys Glu Ala Gln Pro Gly Lys1 5 10 15
(2)SEQ ID NO:24的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:24:的序列描述Glu Phe Ile Lys Glu Ala Gln Pro Gly Lys Lys Gln Leu Leu Leu Ser1 5 10 15
(2)SEQ ID NO:25的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:25:的序列描述Gln Pro Gly Lys Lys Gln Leu Leu Leu Ser Ala Ala Leu Ser Ala Gly1 5 10 15
(2)SEQ ID NO:26的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:26:的序列描述Leu Leu Leu Ser Ala Ala Leu Ser Ala Gly Lys Val Thr Ile Asp Ser1 5 10 15
(2)SEQ ID NO:27的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:27:的序列描述Leu Ser Ala Gly Lys Val Thr Ile Asp Ser Ser Tyr Asp Ile Ala Lys1 5 10 15
(2)SEQ ID NO:28的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:28:的序列描述Thr Ile Asp Ser Ser Tyr Asp Ile Ala Lys Ile Ser Gln His Leu Asp1 5 10 15
(2)SEQ ID NO:29的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:29:的序列描述Asp Ile Ala Lys Ile Ser Gln His Leu Asp Phe Ile Ser Ile Met Thr1 5 10 15
(2)SEQ ID NO:30的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:30:的序列描述Gln His Leu Asp Phe Ile Ser Ile Met Thr Tyr Asp Phe His Gly Ala1 5 10 15
(2)SEQ ID NO:31的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:31:的序列描述Ser Ile Met Thr Tyr Asp Phe His Gly Ala Trp Arg Gly Thr Thr Gly1 5 10 15
(2)SEQ ID NO:32的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:32:的序列描述Phe His Gly Ala Trp Arg Gly Thr Thr Gly His His Ser Pro Leu Phe1 5 10 15
(2)SEQ ID NO:33的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:33:的序列描述Gly Thr Thr Gly His His Ser Pro Leu Phe Arg Gly Gln Glu Asp Ala1 5 10 15
(2)SEQ ID NO:34的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:34:的序列描述Ser Pro Leu Phe Arg Gly Gln Glu Asp Ala Ser Pro Asp Arg Phe Ser1 5 10 15
(2)SEQ ID NO:35的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:35:的序列描述Gln Glu Asp Ala Ser Pro Asp Arg Phe Ser Asn Thr Asp Tyr Ala Val1 5 10 15
(2)SEQ ID NO:36的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:36:的序列描述Asp Arg Phe Ser Asn Thr Asp Tyr Ala Val Gly Tyr Met Leu Arg Leu1 5 10 15
(2)SEQ ID NO:37的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:37:的序列描述Asp Tyr Ala Val Gly Tyr Met Leu Arg Leu Gly Ala Pro Ala Ser Lys1 5 10 15
(2)SEQ ID NO:38的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:38:的序列描述Met Leu Arg Leu Gly Ala Pro Ala Ser Lys Leu Val Met Gly Ile Pro1 5 10 15
(2)SEQ ID NO:39的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:39:的序列描述Pro Ala Ser Lys Leu Val Met Gly Ile Pro Thr Phe Gly Arg Ser Phe1 5 10 15
(2)SEQ ID NO:40的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:40:的序列描述Met Gly Ile Pro Thr Phe Gly Arg Ser Phe Thr Leu Ala Ser Ser Glu1 5 10 15
(2)SEQ ID NO:41的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:41:的序列描述Gly Arg Ser Phe Thr Leu Ala Ser Ser Glu Thr Gly Val Gly Ala Pro1 5 10 15
(2)SEQ ID NO:42的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:42:的序列描述Ala Ser Ser Glu Thr Gly Val Gly Ala Pro Ile Ser Gly Pro Gly Ile1 5 10 15
(2)SEQ ID NO:43的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:43:的序列描述Val Gly Ala Pro Ile Ser Gly Pro Gly Ile Pro Gly Arg Phe Thr Lys1 5 10 15
(2)SEQ ID NO:44的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:44:的序列描述Gly Pro Gly Ile Pro Gly Arg Phe Thr Lys Glu Ala Gly Thr Leu Ala1 5 10 15
(2)SEQ ID NO:45的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:45:的序列描述Arg Phe Thr Lys Glu Ala Gly Thr Leu Ala Tyr Tyr Glu Ile Cys Asp1 5 10 15
(2)SEQ ID NO:46的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:46:的序列描述Gly Thr Leu Ala Tyr Tyr Glu Ile Cys Asp Phe Leu Arg Gly Ala Thr1 5 10 15
(2)SEQ ID NO:47的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:47:的序列描述Glu Ile Cys Asp Phe Leu Arg Gly Ala Thr Val His Arg Thr Leu Gly1 5 10 15
(2)SEQ ID NO:48的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:48:的序列描述Arg Gly Ala Thr Val His Arg Thr Leu Gly Gln Gln Val Pro Tyr Ala1 5 10 15
(2)SEQ ID NO:49的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:49:的序列描述Arg Thr Leu Gly Gln Gln Val Pro Tyr Ala Thr Lys Gly Asn Gln Trp1 5 10 15
(2)SEQ ID NO:50的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:50:的序列描述Val Pro Tyr Ala Thr Lys Gly Asn Gln Trp Val Gly Tyr Asp Asp Gln1 5 10 15
(2)SEQ ID NO:51的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:51:的序列描述Gly Asn Gln Trp Val Gly Tyr Asp Asp Gln Glu Ser Val Lys Ser Lys1 5 10 15
(2)SEQ ID NO:52的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:52:的序列描述Tyr Asp Asp Gln Glu Ser Val Lys Ser Lys Val Gln Tyr Leu Lys Asp1 5 10 15
(2)SEQ ID NO:53的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:53:的序列描述Val Lys Ser Lys Val Gln Tyr Leu Lys Asp Arg Gln Leu Ala Gly Ala1 5 10 15
(2)SEQ ID NO:54的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:54:的序列描述Tyr Leu Lys Asp Arg Gln Leu Ala Gly Ala Met Val Trp Ala Leu Asp1 5 10 15
(2)SEQ ID NO:55的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:55:的序列描述Leu Ala Gly Ala Met Val Trp Ala Leu Asp Leu AspAsp Phe Gln Gly1 5 10 15
(2)SEQ ID NO:56的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:56:的序列描述Trp Ala Leu Asp Leu Asp Asp Phe Gln Gly Ser Phe Cys Gly Gln Asp1 5 10 15
(2)SEQ ID NO:57的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:57:的序列描述Asp Phe Gln Gly Ser Phe Cys Gly Gln Asp Leu Arg Phe Pro Leu Thr1 5 10 15
(2)SEQ ID NO:58的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:58:的序列描述Cys Gly Gln Asp Leu Arg Phe Pro Leu Thr Asn Ala Ile Lys Asp Ala1 5 10 15
(2)SEQ ID NO:59的信息:
(ⅰ)序列特征:
(A)长度:16个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:59:的序列描述Leu Arg Phe Pro Leu Thr Asn Ala Ile Lys Asp Ala Leu Ala Ala Thr1 5 10 15
(2)SEQ ID NO:60的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:60:的序列描述Leu Val Cys Tyr Tyr Thr Ser Trp Ser1 5
(2)SEQ ID NO:61的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:61:的序列描述Phe Leu Cys Thr His Ile Ile Tyr Ser1 5
(2)SEQ ID NO:62的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:62:的序列描述Ile Ile Tyr Ser Phe Ala Asn Ile Ser1 5
(2)SEQ ID NO:63的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:63:的序列描述Leu Lys Thr Leu Leu Ser Val Gly Gly1 5
(2)SEQ ID NO:64的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:64:的序列描述Phe Ile Lys Ser Val Pro Pro Phe Leu1 5
(2)SEQ ID NO:65的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:65:的序列描述Phe Asp Gly Leu Asp Leu Ala Trp Leu1 5
(2)SEQ ID NO:66的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:66:的序列描述Leu Tyr Pro Gly Arg Arg Asp Lys Gln1 5
(2)SEQ ID NO:67的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:67:的序列描述Tyr Asp Ile Ala Lys Ile Ser Gln His1 5
(2)SEQ ID NO:68的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:68:的序列描述Leu Asp Phe Ile Ser Ile Met Thr Tyr1 5
(2)SEQ ID NO:69的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:69:的序列描述Phe Ile Ser Ile Met Thr Tyr Asp Phe1 5
(2)SEQ ID NO:70的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:70:的序列描述Phe Arg Gly Gln Glu Asp Ala Ser Pro1 5
(2)SEQ ID NO:71的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:71:的序列描述Tyr Ala Val Gly Tyr Met Leu Arg Leu1 5
(2)SEQ ID NO:72的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:72:的序列描述Met Leu Arg Leu Gly Ala Pro Ala Ser1 5
(2)SEQ ID NO:73的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:73:的序列描述Leu Ala Tyr Tyr Glu Ile Cys Asp Phe1 5
(2)SEQ ID NO:74的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:74:的序列描述Leu Arg Gly Ala Thr Val His Arg Thr1 5
(2)SEQ ID NO:75的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:75:的序列描述Tyr Leu Lys Asp Arg Gln Leu Ala Gly1 5
(2)SEQ ID NO:76的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:76:的序列描述Leu Ala Gly Ala Met Val Trp Ala Leu1 5
(2)SEQ ID NO:77的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:77:的序列描述Val Trp Ala Leu Asp Leu Asp Asp Phe1 5
(2)SEQ ID NO:78的信息:
(ⅰ)序列特征:
(A)长度:9个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构:线性
(ⅱ)分子类型:肽
(ⅴ)片段类型:内部的
(ⅹⅰ)SEQ ID NO:78:的序列描述Leu Asp Leu Asp Asp Phe Gln Gly Ser1 5
Claims (9)
1.含有16到55个氨基酸残基的肽,该肽含有至少一种下列氨基酸序列: LVCYYTSWS (SEQ ID NO:60), FLCTHIIYS (SEQ IDNO:61), IIYSFANIS (SEQ ID NO:62), LKTLLSVGG (SEQ IDNO:63), FIKSVPPFL (SEQ ID NO:64), FDGLDLAWL (SEQ ID NO:65), LYPGRRDKQ (SEQ ID NO:66), YDIAKISQH (SEQ ID NO:67),LDFISIMTY (SEQ ID NO:68), FISIMTYDF (SEQ ID NO:69),FRGQEDASP (SEQ ID NO:70), YAVGYMLRL (SEQ ID NO:71),MLRLGAPAS (SEQ ID NO:72), LAYYEICDF (SEQ ID NO:73),LRGATVHRT (SEQ ID NO:74), YLKDRQLAG (SEQ ID NO:75),LAGAMVWAL (SEQ ID NO:76), VWALDLDDF (SEQ ID NO:77)或LDLDDFQGS (SEQ ID NO:78)。
2.含有16到55个氨基酸残基的肽,该肽含有至少一种下列氨基酸序列:YKLVCYYTSWSQYREG (SEQ ID NO:1), YTSWSQYREGDGSCFP(SEQ ID NO:2), LDRFLCTHIIYSFANI (SEQ ID NO:5),THIIYSFANISNDHID (SEQ ID NO:6), PNLKTLLSVGGWNFGS (SEQ IDNO:12), NTQSRRTFIKSVPPFL (SEQ ID NO:16), TFIKSVPPFLRTHGFD(SEQ ID NO:17), PPFLRTHGFDGLDLAW (SEQ ID NO:18),HGFDGLDLAWLYPGRR (SEQ ID NO:19), DLAWLYPGRRDKQHFT (SEQ IDNO:20), TIDSSYDIAKISQHLD (SEQ ID NO:28), DIAKISQHLDFISIMT(SEQ ID NO:29), QHLDFISIMTYDFHGA (SEQ ID NO:30),SPLFRGQEDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQ IDNO:37), MLRLGAPASKLVMGIP (SEQ ID NO:38), PASKLVMGIPTFGRSF(SEQ ID NO:39), GTLAYYEICDFLRGAT (SEQ ID NO:46),EICDFLRGATVHRTLG (SEQ ID NO:47), RGATVHRTLGQQVPYA (SEQ IDNO:48), VKSKVQYLKDRQLAGA (SEQ ID NO:53), YLKDRQLAGAMVWALD(SEQ ID NO:54), LAGAMVWALDLDDFQG (SEQ ID NO:55),WALDLDDFQGSFCGQD (SEQ ID NO:56) 或 DFQGSFCGQDLRFPLT (SEQID NO:57)。
3.根据权利要求1或2的肽,该肽含有至少一种下列氨基酸序列:YKLVCYYTSWSQYREG(SEQ ID NO:1), YTSWSQYREGDGSCFP (SEQ ID NO:2),LDRFLCTHIIYSFANI (SEQ ID NO:5), THIIYSFANISNDHID (SEQ IDNO:6), PNLKTLLSVGGWNFGS (SEQ ID NO:12), QHLDFISIMTYDFHGA(SEQ ID NO:30), SPLFRGQEDASPDRFS (SEQ ID NO:34),DYAVGYMLRLGAPASK (SEQ ID NO:37), MLRLGAPASKLVMGIP (SEQ IDNO:38), YLKDRQLAGAMVWALD (SEQ ID NO:54) 或LAGAMVWALDLDDFQG (SEQ ID NO:55)。
4.根据权利要求1到3的任一项的肽,该肽含有至少一种下列氨基酸序列:YTSWSQYREGDGSCFP (SEQ ID NO:2), SPLFRGQEDASPDRFS (SEQ IDNO:34), MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDROLAGAMVWALD(SEQ ID NO:54) 或 LAGAMVWALDLDDFQG (SEQ ID NO:55)。
5.根据权利要求1到4的十六肽,该肽含一种下列氨基酸序列:
YKLVCYYTSWSQYREG (SEQ ID NO:1) YTSWSQYREGDGSCFP(SEQ ID NO:2) , LDRFLCTHIIYSFANI (SEQ ID NO:5),THIIYSFANISNDHID (SEQ ID NO:6), PNLKTLLSVGGWNFGS (SEQ IDNO:12), QHLDFISIMTYDFHGA (SEQ ID NO:30), SPLFRGQEDASPDRFS(SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37),MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD (SEQ IDNO:54) 或 LAGAMVWALDLDDFQG (SEQ ID NO:55)。
6.根据权利要求1到5的任一项的肽,其用作一种药物。
7.含有根据权利要求1到5的任一项的一种或多种肽以及药学可接受的载体的药物组合物。
8.一种用于检测活化的自身反应性T-细胞的诊断方法,其包括下列步骤:a)从个体血样分离外周血单核细胞(PBMC),b)在合适条件下培养PBMC,c)在根据权利要求1到5的任一项的一种或多种肽存在下培养该PBMC培养物,和d)检测T-细胞反应,如增殖反应,显示个体中活化的自身反应性T细胞的存在。
9.用于检测活化的自身免疫反应性T细胞的检测试剂盒,该检测试剂盒包含一种或多种根据权利要求1到5的任一项的肽。
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EP (1) | EP0920451A1 (zh) |
JP (1) | JP2000510106A (zh) |
KR (1) | KR20000010561A (zh) |
CN (1) | CN1216551A (zh) |
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CZ2001286A3 (en) * | 1998-07-23 | 2001-08-15 | Akzo Nobel Nv | Use of isolated DNA or RNA molecule, viral vector and process for preparing thereof |
WO2001029081A1 (en) * | 1999-10-18 | 2001-04-26 | Akzo Nobel N.V. | Modified peptides and peptidomimetics for use in immunotherapy |
IL132611A0 (en) | 1999-10-27 | 2001-03-19 | Yeda Res & Dev | Synthetic genes and polypeptides and pharmaceutical compositions comprising them |
ES2281434T3 (es) | 2000-08-14 | 2007-10-01 | Ortho-Mcneil Pharmaceutical, Inc. | Pirazoles sustituidos. |
US7002985B2 (en) * | 2001-01-16 | 2006-02-21 | Motorola, Inc. | Method and apparatus for organizing and scheduling multimedia data transfers over a wireless channel |
ES2534752T3 (es) * | 2004-12-07 | 2015-04-27 | Toray Industries, Inc. | Nuevo péptido antigénico contra el cáncer y utilización del mismo |
DE602006019205D1 (de) * | 2005-02-28 | 2011-02-10 | Bio Y As | Monoklonale ykl-40-antikörper |
FR2908654B1 (fr) | 2006-11-20 | 2014-04-04 | Oreal | Utilisation cosmetique de proteines de type chitinase |
RS53782B1 (en) * | 2008-10-01 | 2015-06-30 | Immatics Biotechnologies Gmbh | TUMOR-ASSOCIATED PEPTIDES PREPARED AND ANTI-CHANGE RESPONSE FOR GLIOBLASTOMA (GBM) AND OTHER CANCER TREATMENTS |
RU2008140688A (ru) * | 2008-10-15 | 2010-04-20 | Михаил Аркадьевич Шурдов (RU) | Иммуносупрессивный пептид |
CA2768246A1 (en) | 2009-06-11 | 2010-12-16 | The University Of Guelph | Serine rich peptides having antioxidative stress properties |
CA2779161A1 (en) | 2009-10-28 | 2011-05-05 | University Of Manitoba | Yellow pea seed protein-derived peptides |
CA2801237A1 (en) | 2010-05-31 | 2011-12-08 | London Health Sciences Centre Research Inc. | Rhamm binding peptides |
WO2018129261A1 (en) | 2017-01-05 | 2018-07-12 | Brown University | Methods and compositions relating to anti-chi3l1 antibody reagents |
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WO1997040068A1 (en) | 1997-10-30 |
NO984937D0 (no) | 1998-10-23 |
JP2000510106A (ja) | 2000-08-08 |
HUP9901375A2 (hu) | 1999-08-30 |
US6184204B1 (en) | 2001-02-06 |
RU2199548C2 (ru) | 2003-02-27 |
IL120561A0 (en) | 1997-07-13 |
AU2768597A (en) | 1997-11-12 |
HUP9901375A3 (en) | 2000-10-30 |
TW575583B (en) | 2004-02-11 |
NZ332427A (en) | 2000-03-27 |
EP0920451A1 (en) | 1999-06-09 |
BR9708744A (pt) | 1999-08-03 |
TR199802135T2 (xx) | 1999-01-18 |
AR006813A1 (es) | 1999-09-29 |
AU719481B2 (en) | 2000-05-11 |
CA2251680A1 (en) | 1997-10-30 |
NO984937L (no) | 1998-12-01 |
KR20000010561A (ko) | 2000-02-15 |
PL329618A1 (en) | 1999-03-29 |
ZA973071B (en) | 1998-08-05 |
CZ340698A3 (cs) | 1999-02-17 |
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