CN1178956C - 基于癌抑制基因wt1的产物的癌抗原 - Google Patents
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及Wilms肿瘤癌抑制基因WT1的产物，以该氨基酸序列中包括与I类主要组织适合性抗原(MHC)结合的锚定氨基酸在内的连续7～30个氨基酸构成的肽作为有效成分的癌抗原，以及含有它们的癌疫苗。
Description
技术领域
本发明涉及以Wilms肿瘤的癌抑制基因WT1的产物为基础的癌抗原。该癌抗原作为针对白血病、骨髓异形成综合症、多发性骨髓瘤、恶性淋巴瘤等血癌或实体瘤，例如胃癌、大肠癌、肺癌、乳腺癌、胚细胞瘤、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、子宫颈癌、卵巢癌等以及WT1表达的所有癌的抗癌疫苗上有用的。
背景技术
用于排除异物的免疫机构一般包括与识别抗原作为抗原提示细胞作用的巨噬细胞、识别该巨噬细胞的抗原提示产生各种淋巴因子使其他T-细胞等活化的辅助T细胞、通过该淋巴因子的作用分化成抗体产生细胞的B淋巴细胞等有关的体液免疫以及接受抗原提示分化成的杀伤T细胞攻击破坏靶细胞的细胞免疫。
现在，认为癌的免疫主要是与杀伤T细胞有关的细胞性免疫引起的。在杀伤T细胞引起的癌免疫中，识别以主要组织适合抗原(MajorHistocompatibility Complex，MHC)第I类与癌抗原形成的复合体形式提示的癌抗原的前体T细胞分化增殖生成的杀伤T细胞攻击破坏癌细胞。这时，癌细胞在其细胞表面提示MHC第I类抗原与癌抗原形成的复合体，它成为杀伤T细胞的靶细胞(Cur.Opin，Immunol.，5，709，1993；Cur.Opin，Immunol.，5，719，1993；Cell，82，13，1995；Immunol.Rev，146，167，1995)。
作为靶细胞的癌细胞上通过MHC第I类抗原提示的上述癌抗原可以认为是癌细胞内合成的抗原蛋白质被细胞内蛋白酶处理生成的约8～12个氨基酸构成的肽(Cur.Opin，Immunol.，5，709，1993；Cur.Opin.Immunol.，5，719，1993；Cell，82，13，1995；Immunol.Rev.，146，167，1995)。
现在，对于各种癌进行了抗原蛋白质的检索，证明是癌特异抗原的物质较少。
Wilms肿瘤的癌抑制基因WT1(WT1基因)是根据对Wilms肿瘤、无红彩、泌尿生殖器异常、精神发达迟滞等并发的WAGR综合症的解析，作为Wilms肿瘤的一种原因基因从染色体11p13分离出的物质(Gessler，M.等，Nature，Vol.343，p.774-778(1990))，基因组DNA通过约50kb由10个外显子构成，其cDNA为约3kb。由cDNA推测出的氨基酸序列如序列号1所示(Mol.Cell.Biol.，11，1707，1991)。
WT1基因在人白血病中高度表达，用WT1反义低聚物(antisenseoligomer)处理白血病细胞能够抑制其细胞增殖(特开平9-104627号公报)等提示WT1基因可以促进白血病细胞的增殖。而且，WT1基因在胃癌、大肠癌、肺癌、乳腺癌、胚细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、子宫颈癌、卵巢癌等实体瘤中高度表达(特愿平9-191635)，判断出WT1基因是白血病和实体瘤中新的肿瘤标识物。但是，尚未证明WT1基因表达产物是作为癌疫苗有用的癌特异抗原。
发明公开
因此，本发明确认了WT1基因表达产物作为癌抗原的可能性，提供了一种新型癌抗原。
本发明人为了解决上述问题进行了各种研究，结果合成了WT1基因表达产物的氨基酸序列中含有被预测在小鼠和人的I类MHC和II类MHC的结合中作为锚定氨基酸(anchor amino acid)起作用的至少1个氨基酸的连续7～30个氨基酸构成的多肽，确认这些肽与MHC蛋白质结合，同时确认与I类MHC抗原结合时诱导杀伤T细胞，而且对靶细胞具有杀细胞效果，从而完成了本发明。
因此，本发明提供小鼠WT1表达产物或含有其一部分的癌抗原。在优选的方式中，本发明提供以与WT1的cDNA对应的序列号1所示的氨基酸序列中包括用于与MHC抗原结合的锚定氨基酸在内的6～30个氨基酸构成的肽作为活性成分的癌抗原。
而且本发明提供以与人WT1的cDNA对应的序列号2所示的氨基酸序列中包括用于与MHC抗原结合的锚定氨基酸在内的7～30个氨基酸构成的肽作为活性成分的癌抗原。
本发明还提供含有上述癌抗原的癌疫苗。
附图的简单说明
图1表示实施例1中用Db126肽免疫的细胞与非免疫细胞在流式细胞测量法中CD4+细胞与CD8+细胞的比例。
图2是比较实施例2中用Db126肽免疫的细胞对于用Db126肽脉冲的靶细胞和未脉冲的靶细胞的杀细胞作用。
图3是与图2含义相同的图。
图4中A表示实施例3中使用Db126肽诱导的CTL对于用Db126肽脉冲的T2细胞的杀细胞效果，B表示实施例3中使用WH187肽诱导的CTL对于用WH187肽脉冲的T2细胞的杀细胞效果。
图5表示由Db126肽诱导的CTL的表面标识物通过FACS解析的结果(CD19细胞以及CD3细胞)。
图6表示CD4细胞以及CD8细胞与图5同样的图。
图7表示CD56细胞与图5同样的图。
图8表示WH187肽诱导的CTL的表面标识物通过FACS解析的结果(CD19细胞和CD3细胞)。
图9表示CD4细胞和CD8细胞与图8同样的图。
图10表示CD56细胞与图8同样的图。
图11表示抗HLA-A2.1抗体对Db126肽特异性CTL引起的对于用Db126肽脉冲的T2细胞的特异性细胞溶解的影响。
图12是比较Db126肽特异性CTL对于表达WT1的靶细胞或不表达WT1的靶细胞的细胞溶解活性。a表示E∶T比为7.5∶1的情况下的结果，b表示E∶T比为15∶1的情况下的结果。
图13是比较Db126肽特异性CTL对于先天表达WT1的肿瘤细胞(FBL3)或不表达WT1的肿瘤细胞(RMA)的细胞溶解效果。
图14是比较Db126肽特异性CTL对于用WT1基因胞质转移的细胞以及未进行胞质转移的同一细胞的细胞溶解效果。
图15表示I类抗H-2抗体对Db126肽特异性CTL的细胞毒性的影响。
图16表示使用DbU126肽作为疫苗使用，免疫小鼠时的体内免疫效果。
图17表示将表达WT1的质粒作为DNA疫苗投给小鼠时的免疫效果。
图18是图17的对照，是表示投给不表达WT1的质粒时不产生免疫效果的图。
发明的实施方式
本发明中，作为设计癌抗原肽时的基础，选择小鼠I类MHC的Kb和Db，以及人HLA的A*0201，选择预测与它们具有高亲和性的肽。
根据Immunogenetics Vol.41，p.178-228(1995)的记载，预测与Kb结合的锚定氨基酸是5号的Phe和Tyr以及8号的Leu和Met等，另外预测与Db结合的锚定氨基酸是5号的Asn以及9号的Met和Ile等。
另外，已知癌细胞表面上I类MHC提示的癌抗原肽的大小为约8～12个。因此，本发明的癌抗原肽是序列号1所示WT1基因产物的氨基酸序列中包括锚定氨基酸在内的连续7～30个氨基酸构成的肽。氨基酸的数目优选为8～12个，例如8或9个。
在本发明中，作为其具体例子，I类MHC与Kb结合的肽使用由8个氨基酸构成的下述肽：
Kb 45 Gly Ala Ser Ala
Tyr Gly Ser
Leu(序列号3)
Kb 330 Cys Asn Lys Arg
Tyr Phe Lys
Leu(序列号4)
I类MHC与Db结合的肽使用由9个氨基酸构成的下述肽：
Db 126 Arg Met Phe Pro
Asn Ala Pro Tyr Leu(序列号5)
Db 221 Tyr Ser Ser Asp
Asn Leu Tyr Gln
Met(序列号6)
Db 235 Cys Met Thr Trp
Asn Gln Met Asn Leu(序列号7)
上述序列中带下划线的氨基酸是被预测作为锚发挥作用的氨基酸。
其次，使用未提示抗原肽(empty)但表达Kb以及Db的细胞线测定这些肽中Kb45以及Kb330与I类MHC的Kb的结合性，Db126、Db221和Db235与I类MHC的Db的结合性。
也就是说，在26℃下培养RMA-S，使I类MHC高度表达，在37℃下培养该培养细胞与被测肽溶液1小时。这样，不与肽结合的MHC分子变得不稳定，从细胞表面消失，仅残留与肽结合的I类MHC分子。其次，用识别I类MHC(Kb，Db)的荧光标识单克隆抗体给RMA-S细胞染色。最后，通过FACS解析，由每个细胞的平均荧光量计算结合解离常数(Immunol.Lett.，47，1，1995)。
结果，得到了下述结果。
Kb 45 -4.5784838(log)
Kb 330 -5.7617732
Db 126 -6.2834968
Db 221 -5.7545398
Db 235 -6.1457624
如上所述，与Kb或Db具有强～中度的结合亲和性(kd值)但显示最高结合亲和性的Db126肽在以后的实验中被使用。
另外，对于人，根据Immunogenetics Vol.41，p，178-228(1995)的记载，预测与人HLA-A*0201结合的锚定氨基酸是N-末端至2号Leu和Met以及N-末端至9号Val和Leu。因此合成了人WT1蛋白质的氨基酸序列(Mol.Coll.Biol.Vol.11，p.1707-1712，1991)(序列号2)中符合上述条件的9个氨基酸构成的2种肽。
Db 126；Arg Met Phe Pro Asn Ala Pro Tyr
Leu(序列号5)
(与小鼠中Db126的序列相同)
WH 187；Ser Leu Gly Glu Gln Gln Tyr Ser
Val(序列号8)
(下划线表示锚定氨基酸)
如下所述测定上述肽与HLA-A*0201的结合能。
在37℃下培养上述肽与具有empty的HLA-A*0201的T2细胞(J.Immunol.，150，1763，1993；Blood，88，2450，1996)1小时后，用识别HLA-A2.1的荧光标识单克隆抗体给T2细胞染色，通过FACS解析，由每个细胞的平均荧光量计算结合解离常数。
结合能
肽 Kd(M)
Db126 1.89×10-6
WH187 7.61×10-6
2种肽均具有中度以上的结合亲和性。
使用上述Db126以及WH187作为与人MHC对应的肽，进行以下试验。
本发明还涉及以上述抗原为有效成分的癌疫苗。该疫苗可以用于WT1基因的表达水平上升伴有的癌，例如白血病、骨髓异形成综合症、多发性骨髓瘤、恶性淋巴瘤等血癌，胃癌、大肠癌、肺癌、乳腺癌、胚细胞癌、肝癌、皮肤癌、膀胱癌、前列腺癌、子宫癌、子宫颈癌、卵巢癌等实体瘤的预防或治疗。该疫苗可以通过口服给药或非口服给药，例如腹腔内给药、皮下给药、皮内给药、肌肉内给药、静脉内给药、鼻腔内给药等形式给药。
而且，作为本发明疫苗的给药方法，也可以从患者的末梢血收集单核细胞，从中取出分叶细胞，用本发明的肽脉冲，通过给患者皮下给药等返回到患者中的方法。
疫苗除上述作为有效成分给药的肽之外，还可以含有可药用的载体，例如适当的佐剂，例如氢氧化铝等矿物胶；溶血卵磷脂、普朗尼克多元醇等表面活性剂；聚阴离子；肽；或油乳浊液。或者，也可以混合到脂质体中，或含有多糖和/或疫苗中配合的其它集合体。给药量一般每天0.1μg～1mg/kg。
另外本发明中编码上述多肽疫苗的DNA也可以作为疫苗(DNA疫苗)使用。也就是说，通过将编码WT1或其一部分的核酸，优选将DNA插入适当的载体，优选插入表达载体中后，投给动物，可以产生癌免疫。其具体例子如实施例9所示。
实施例
其次结合实施例说明本发明的肽作为癌抗原和癌疫苗是有用的。
实施例1
在C57BL/6小鼠的腹腔内每周注射2次Db126肽100μg、来源于猪的乳酸脱氢酶(LDH)200μg以及弗罗因德不完全佐剂0.5ml，进行免疫处理。该免疫处理1周后摘出小鼠的脾脏，配制脾脏细胞的悬浮液。另一方面，在37℃下，培养用Db126肽脉冲的同系小鼠的放射线照射脾细胞和含有肽50μg/ml的溶液30分钟，作为抗原提示细胞。
将上述免疫处理后的脾细胞与放射线照射脾细胞混合，一同培养5日，诱导配制杀伤T细胞。另一方面，用Db126肽脉冲(与100μg/ml的肽溶液在37℃下培养30分钟)的Europium标记EL-4细胞(表达Kb和Db)作为靶细胞，采用常规方法，按照下述操作进行Killing分析(表1)。
结果，以Db126脉冲的EL-4细胞作为靶时可见杀细胞效果，但以未用Db126脉冲的EL-4细胞作为靶时，几乎见不到杀细胞效果。
表1
| 小鼠A | 小鼠B | |
| 肽+肽- | 76.6％4.9％ | 37.2％0.9％ |
E/T比40∶1
其次，将Killing分析中具有显著杀细胞效果的脾细胞试样用荧光标识的抗CD4抗体和抗CD8抗体染色，通过流式细胞测量法解析CD4和CD8的表达。
结果，如图1所示，与非免疫对照细胞相比，用Db126肽进行免疫处理的脾细胞中，杀伤T细胞代表的CD8+细胞增加，CD8+细胞对于辅助T细胞等代表的CD4+细胞的比例反向增加。
实施例2
如下所述配制来源于C57BL/6小鼠骨髓的分叶细胞(dendriticcells，DC)。按照常规方法，在GM-CSF存在下培养骨髓细胞，配制来源于骨髓的分叶细胞(J.Exp.Med.182，255，1995)。
将培养7天后的分叶细胞与10μM的OVAII(Ovalbumin II)以及1μM的Db126肽一同培养3小时后，洗净。
其次，将上述DC细胞由皮内注射到C57Bl/6小鼠的foot pads和hands上，第5日取出所属淋巴结，配制细胞悬浮液。另一方面，配制用Db126肽脉冲、放射线照射的B7.1-RMA-S细胞(转染编码Co-stimulatory molecule——B7.1的基因的RMA-S细胞)。
其次，通过混合培养上述来源于淋巴结的细胞悬浮液和B7.1-RMA-S细胞，在体外进行再刺激。
其次，在体外进行再刺激的第5天，以51Cr标记的RMA-S细胞作为靶，进行Killing分析。以再刺激第5天回收的淋巴细胞总体的1/8用作效应细胞时作为最大E/T比(1.0)。
如图2和图3所示，用Db126肽免疫的来源于小鼠淋巴结的效应细胞杀死了用该肽脉冲的靶细胞，相反却没有杀死未用该肽脉冲的靶细胞。
另外，与实施例1同样用流式细胞测量法解析CD4+细胞和CD8+细胞的比为CD4∶CD8＝1∶1.4～1.7，与非免疫小鼠细胞(对照)相比，用Db126肽免疫的小鼠细胞中CD8+细胞增加，CD4+细胞∶CD8+细胞的比(对照细胞中为约2∶1)在免疫的细胞中逆转。
实施例3
共同培养与肽Db126或WH187(40μg/ml)培养1小时后用放射线照射的T2细胞2×104个与具有HLA-A*0201的健康人末梢单核细胞1×106个。一周后，在上述共同培养体系中加入与肽(20μg/ml)培养1小时后用放射线照射的T2细胞，进行再刺激。第二天，在培养液中加入人IL-2(最终浓度100JRU/ml)。
以后，用肽脉冲后经放射线照射的T2细胞反复刺激5次后，以肽被脉冲的T2细胞或肽未被脉冲的T2细胞作为靶，进行Killing分析。另外，对诱导的CTL的表面标识物进行FACS解析。
Killing分析按照常规方法以用Europium标记的T2细胞脉冲肽得到的物质作为靶进行。
Effector：Target比(E/T比)为10∶1
共同培养时间：3小时
培养液中的肽浓度：5μg/ml
结果如图4所示。图4中A表示用Db126肽诱导的CTL对Db126肽脉冲的T2细胞的杀细胞效果，图4中B表示用WH187肽诱导的CTL对WH187脉冲的T2细胞的杀细胞效果。
在任何一种场合下，对于用肽脉冲的T2细胞均可见较强的杀细胞效果。
FACS解析的结果如图5～10所示。图5～7表示用Db126肽诱导的人CTL的结果，几乎所有的细胞都为CD8阳性。图8～图10表示WH187肽诱导的人CTL的结果。CD4阳性细胞和CD8阳性细胞数目几乎相同。
实施例4
为了对Db126肽特异性CTL的细胞溶解活性的MHC限制性进行试验，使用抗HLA-A2.1单克隆抗体以阻滞CTL对于用肽脉冲的T2细胞的细胞毒性活性。在E/T比为5∶1时，在对HLA-A2.1分子的阻滞单克隆抗体(BB7.2)存在下或不存在下，测定用Db126肽脉冲的T2细胞的特异性细胞溶解。
结果如图11所示。该图中符号*表示用抗H-2Kb单克隆抗体代替抗HLA-A2.1单克隆抗体的结果。如该图说明的那样，通过添加60μg/ml的抗HLA-A2.1单克隆抗体，细胞毒性下降至T2细胞的细胞溶解底数。同型的无关单克隆抗体(抗H-2Kb单克隆抗体Y3)对T2细胞的溶解没有效果。
实施例5
对于Db126肽特异性CTL是否能杀死先天表达WT1的HLA-A2.1阳性白血病细胞进行试验。使用TF1细胞(表达WT-1，HLA-A2.1阳性)、JY细胞(不表达WT1，HLA-A2.1阳性)以及Molt-4细胞(表达WT1，HLA-A2.1阴性)作为靶细胞，在E∶T比为7.5∶1(a)或15∶1(b)时，测定细胞毒性。
结果如图12所示。Db126肽特异性CTL对于先天表达WT1的HLA-A2.1阳性的白血病细胞TF1具有显著的细胞毒性，但对于Molt-4(表达WT1，HLA-A2.1阴性)或JY细胞(不表达WT1，HLA-A2.1阳性)显示底数水平的细胞溶解。
实施例6
对于Db126肽特异性CTL是否能识别并溶解先天表达WT1的肿瘤细胞进行试验。对于表达WT1的肿瘤细胞(FBL3)或不表达WT1的肿瘤细胞(RMA)(图13)，或者转染WT1基因的C1498细胞或未转染WT1基因的C1498细胞(图14)，以图13和图14所示E/T比测定特异性细胞溶解。
如图13所示，Db126肽特异性CTL溶解先天表达WT1的FBL3细胞，不溶解不表达WT1的RMA细胞。而且如图14所示，与不表达WT1的母C1498细胞相比，Db126肽特异性CTL可以杀死转染小鼠WT1基因的C1498细胞。这样，由于CTL引起的杀细胞可以确认靶向的分子确实是WT1肽。这些结果表明Db126肽特异性CTL可以通过WT1蛋白质的细胞内加工天然产生，而且可以识别WT1表达细胞的H-2Db分子上存在的Db126肽或有关的肽。
实施例7
为了对CTL的细胞溶解活性是否为MHC限制性进行试验，在I类H-2分子的抗体存在下进行测定。也就是说，在对H-2Kb(28.13.3S)、H-2Db(28.11.5S)或H-2Ld(MA143)的调整了效价的单克隆抗体存在下，测定Db126肽特异性CTL引起的对于用Db126肽脉冲的RMA-S细胞的细胞溶解活性。使用同型的单克隆抗体作为对照单克隆抗体。
结果如图15所示。随着H-2Db的抗体浓度增加，抑制CTL对于用Db126肽脉冲的RMA-S细胞的细胞溶解活性，但是H-2Kb或H-2Ld的抗体不抑制CTL的细胞溶解活性。这些结果表明CTL发挥H-2Db限制性细胞溶解活性。
实施例8
对于Db126肽引起的积极免疫是否会导致生物体内肿瘤免疫进行试验。用Db126肽脉冲的LPS活化脾细胞(图16中的实线)、单纯LPS活化脾细胞(网线)或单纯磷酸缓冲液(PBS)(虚线)使小鼠1周免疫1次。进行3周的免疫后，在腹腔内注射3×107个FBL3白血病细胞。
结果如图16所示。用Db126肽免疫的小鼠克服了肿瘤挑战并生存下来，非免疫小鼠以及仅用LPS活化脾细胞免疫的小鼠不能拒绝肿瘤挑战而死亡。免疫小鼠和非免疫小鼠两者均在上述腹腔内接种肿瘤细胞后3天观察到腹水。非免疫小鼠的腹水继续增加，而且小鼠死亡。另一方面，免疫小鼠的腹水缓慢减少，小鼠完全拒绝肿瘤挑战，并生存下来。非免疫小鼠时刻可以观察到自然的退化(regression)。预测这种退化是特异性CTL对Friend白血病病毒(FBL3白血病细胞是由该病毒进行胞质转移形成的)的自然诱导产生的。这是因为这种CTL诱导在C57BL/6小鼠中时刻可以观察到。
实施例9DNA疫苗
给6～8周龄的C57BL/6小鼠每隔10天肌肉注射100μg表达WT1的质粒DNA(将小鼠WT1cDNA(Molecular and Cellular Biology，Vol.11，No.3，p.1701-1712(1991)，p.1709的左栏)的Sau 3AI片断连接在CMV-IE启动子上，制作持续表达WT1的质粒)(Proc.Natl.Acod.Su，USA.，92，11105-11109(1995))，共计3次。最后肌肉注射的10天后，取出小鼠的脾，调整脾细胞，与表达WT1的mWT1C1498细胞(40Gy放射线照射)在37℃下共同培养6天后，使用表达WT1的C1498(PM5G-mWT1)和不表达WT1的C1498(PM5G)作为靶细胞，进行Killing分析(用Europium标记)。另外，C1498是不表达WT1的小鼠骨髓性白血病细胞株。
诱导产生了细胞毒性T淋巴细胞(CTL)，它可以杀死表达WT1的C1498(PM5G-mWT1)细胞，但不杀死不表达WT1的细胞。
结果如图17所示。
作为对照，进行与上述相同的试验，用不表达WT1(不具有WT1cDNA)的质粒代替表达WT1的质粒给小鼠肌肉注射。与上述试验同样采取脾细胞，用表达WT1的C1498(PM5G-mWT1)体外刺激后，进行killing分析。
如图18所示，不具有WT1cDNA的对照质粒DNA的肌肉注射没有诱导WT1蛋白特异性CTL。
上述结果证明本发明的肽确实发挥癌抗原的作用，诱导增殖针对癌细胞的杀伤T细胞(癌细胞伤害性T细胞)。因此，本发明的癌抗原肽作为针对伴有WT1基因表达上升的白血病和实体瘤的癌疫苗是有用的。
序列表
<110>
<120>基于肿瘤抑制基因WT1的癌抗原
<130>983279
<160>8
<210>1
<211>449
<212>PRT
<213>小鼠
<400>1
Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Ser
5 10 15
Ser Leu Gly Gly Gly Gly Gly Gly Cys Gly Leu Pro Val Ser Gly Ala
20 25 30
Arg Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala
35 40 45
Tyr Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro Pro Pro Pro
50 55 60
Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp Gly Gly
65 70 75 80
Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Leu His Phe
85 90 95
Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe
100 105 110
Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln Ala Arg Met Phe
115 120 125
Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser Gln Pro Thr Ile
130 135 140
Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly Ala Pro Ser Tyr
145 150 155 160
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Gln His Ser Phe
165 170 175
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
180 185 190
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
195 200 205
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp
210 215 220
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
225 230 235 240
Met Asn Leu Gly Ala Thr Leu Lys Gly Met Ala Ala Gly Ser Ser Ser
245 250 255
Ser Val Lys Trp Thr Glu Gly Gln Ser Asn His Gly Ile Gly Tyr Glu
260 265 270
Ser Glu Asn His Thr Ala Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile
275 280 285
His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Ser
290 295 300
Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys
305 310 315 320
Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys
325 330 335
Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro
340 345 350
Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp
355 360 365
Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys Pro Phe Gln
370 375 380
Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr
385 390 395 400
His Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro Phe Ser Cys
405 410 415
Arg Trp His Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val
420 425 430
Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu His Val Ala
435 440 445
Leu
449
<210>2
<211>449
<212>PRT
<213>人
<400>2
Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Pro
5 10 15
Ser Leu Gly Gly Gly Gly Gly Cys Ala Leu Pro Val Ser Gly Ala Ala
20 25 30
Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly Ala Ser Ala Tyr
35 40 45
Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro Pro Pro Pro Pro
50 55 60
Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp Gly Gly
65 70 75 80
Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Val His Phe
85 90 95
Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe
100 105 110
Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln Ala Arg Met Phe
115 120 125
Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser Gln Pro Ala Ile
130 135 140
Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly Thr Pro Ser Tyr
145 150 155 160
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Gln His Ser Phe
165 170 175
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
180 185 190
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
195 200 205
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Ser Ser Asp
210 215 220
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
225 230 235 240
Met Asn Leu Gly Ala Thr Leu Lys Gly Val Ala Ala Gly Ser Ser Ser
245 250 255
Ser Val Lys Trp Thr Glu Gly Gln Ser Asn His Ser Thr Gly Tyr Glu
260 265 270
Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln Tyr Arg Ile
275 280 285
His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val Pro
290 295 300
Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr Ser Glu Lys
305 310 315 320
Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg Tyr Phe Lys
325 330 335
Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly Glu Lys Pro
340 345 350
Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser Arg Ser Asp
355 360 365
Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys Pro Phe Gln
370 375 380
Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys Thr
385 390 395 400
His Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro Phe Ser Cys
405 410 415
Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val
420 425 430
Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala
435 440 445
Leu
449
<210>3
<211>8
<212>PRT
<213>人工序列
<220>
<223>合成肽
<400>3
Gly Ala Ser Ala Tyr Gly Ser Leu
1 5
<210>4
<211>8
<212>PRT
<213>人工序列
<220>
<223>合成肽
<400>4
Cys Asn Lys Arg Tyr Phe Lys Leu
1 5
<210>5
<211>9
<212>PRT
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<220>
<223>合成肽
<400>5
Arg Met Phe Pro Asn Ala Pro Tyr Leu
1 5
<210>6
<211>9
<212>PRT
<213>人工序列
<220>
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Tyr Ser Ser Asp Asn Leu Tyr Gln Met
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<210>7
<211>9
<212>PRT
<213>人工序列
<220>
<223>合成肽
<400>7
Cys Met Thr Trp Asn Gln Met Asn Leu
1 5
<210>8
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<212>PRT
<213>人工序列
<220>
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Ser Leu Gly Glu Gln Gln Tyr Ser Val
1 5
Claims (4)
1.一种肽，其由序列号2所列氨基酸序列的9个连续氨基酸所组成，其中2位上氨基酸残基是亮氨酸或甲硫氨酸，9位上氨基酸残基是缬氨酸或亮氨酸，该肽可结合I类MHC抗原。
2.如权利要求1所述的肽，其选自下组：
位置126-134：Arg Met Phe Pro Asn Ala Pro Tyr Leu(Db 126)，
位置235-243：Cys Met Thr Trp Asn Gln Met Asn Leu(Db 235)，
位置187-195：Ser Leu Gly Glu Gln Gln Tyr Ser Val(WH 187)，
位置7-15： Asp Leu Asn Ala Leu Leu Pro Ala Val，
位置10-18： Ala Leu Leu Pro Ala Val Pro Ser Leu，
位置225-233：Asn Leu Tyr Gln Met Thr Ser Gln Leu，
位置242-250：Asn Leu Gly Ala Thr Leu Lys Gly Val，
位置441-449：Asn Met Thr Lys Leu Gln Leu Ala Leu。
3.如权利要求1或2所述的肽，所说的肽为以下任意一种：
Db 126 Arg Met Phe Pro Asn Ala Pro Tyr Leu(序列号5)
Db 235 Cys Met Thr Trp Asn Gln Met Asn Leu(序列号7)
WH 187 Ser Leu Gly Glu Gln Gln Tyr Ser Val(序列号8)。
4.如权利要求3所述的肽，所说的肽为
Db 126 Arg Met Phe Pro Asn Ala Pro Tyr Leu(序列号5)
或
WH 187 Ser Leu Gly Glu Gln Gln Tyr Ser Val(序列号8)。
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| CNB2005100995114A Expired - Lifetime CN100560130C (zh) | 1998-07-31 | 1999-07-30 | 基于癌抑制基因wt1的产物的癌抗原 |
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