CN116472050A - 识别p53中r273c或y220c突变的t细胞受体 - Google Patents
识别p53中r273c或y220c突变的t细胞受体 Download PDFInfo
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Abstract
本申请公开了具有针对人类p53R273C或人类p53Y220C的抗原特异性的分离或纯化的T细胞受体(TCR)。还提供了相关的多肽和蛋白质,以及相关的核酸、重组表达载体、宿主细胞、细胞群和药物组合物。还公开了检测哺乳动物中癌症的存在的方法以及治疗或预防哺乳动物中癌症的方法。
Description
相关申请的交叉引用
本专利申请要求2020年9月4日提交的第63/074,747号美国临时专利申请的权益,将所述美国临时专利申请通过引用以其整体并入本文。
关于联邦资助的研究或开发的声明
本发明是在政府支持下由美国国立卫生研究院的国家癌症研究所在项目编号BC010985下完成的。政府对本发明享有一定的权利。
以电子方式提交的材料的引用并入
与本文同时提交并如下鉴定的计算机可读核苷酸/氨基酸序列表通过引用以其整体并入本文:一个名称为“757042_ST25.txt”的222,016字节ASCII(文本)文件,日期为2021年8月18日。
发明背景
一些癌症的治疗选项可能非常有限,在癌症变成转移的且不可切除时尤为如此。尽管在诸如手术、化学疗法以及放射疗法之治疗中取得进展,但诸如胰脏癌、大肠直肠癌、肺癌、子宫内膜癌、卵巢癌以及前列腺癌的许多癌症的预后可能不良。因此,对癌症的额外治疗存在未满足的需求。
发明概述
本发明的一个实施方案提供一种分离或纯化的T细胞受体(TCR),其对人类p53R273C或人类p53Y220C氨基酸序列具有抗原特异性,其中该TCR包含如下氨基酸序列:(1)SEQ IDNO:2-7全部;(2)SEQ ID NO:21-26全部;(3)SEQ ID NO:40-45全部;(4)SEQ ID NO:59-64全部;或(5)SEQ ID NO:78-83全部。
本发明的其他实施方案提供与本发明的TCR相关的多肽、蛋白质、核酸、重组表达载体、宿主细胞、细胞群以及药物组合物。
本发明的其他实施方案提供检测哺乳动物中癌症的存在的方法、诱导针对哺乳动物的癌症的免疫反应的方法以及治疗或预防哺乳动物的癌症的方法。
本发明的额外实施方案提供产生表达TCR的宿主细胞的方法以及产生TCR、多肽或蛋白质的方法。
附图若干视图的简述
图1A为显示在将患者4343肿瘤碎片编号F1-F7以及F9-F24与用DMSO(溶媒)或突变体p53-Y220C(图1A)脉冲的自体性DC共培养之后测量的IFN-γ斑点(每2e4个细胞)的数目的图。具有突变体p53反应性的碎片在方框内。
图1B为显示在将患者4386肿瘤碎片编号F1至F24与用DMSO(溶媒)或突变体p53-R273C(图1B)脉冲的自体性DC共培养之后测量的IFN-γ斑点(每2e4个细胞)的数目的图。具有突变体p53反应性的碎片在方框内。
图1C为显示在将自患者4386的新鲜肿瘤(肿瘤1A或肿瘤1B的)消化物的经分选的T细胞与用DMSO(溶媒)或突变体p53-R273C脉冲的自体性DC共培养之后测量的IFN-γ斑点(每2e4个细胞)的数目的图。基于指定细胞表面标记物的表达而对T细胞进行分选。具有突变体p53反应性的经分选的T细胞群在方框内。
图1D显示在将来自患者4386的TIL与用DMSO(溶媒)或突变体p53-R273C肽脉冲的自体性DC共培养之后,表达OX40以及4-1BB的T细胞的百分比,如通过流式细胞术所测量的。
图2A为显示在将目标细胞与效应细胞共培养之后,表达4-1BB的鼠类TCR恒定区阳性细胞的百分比的图。效应细胞用4343-D TCR转导。目标细胞为用所示的II类HLA异二聚体中之一者转染的COS7细胞,且用p53-Y220C 25-mer肽脉冲。
图2B为展示在将目标细胞与效应细胞共培养之后,表达4-1BB的CD3阳性细胞的百分比的图。效应细胞为含有识别p53-R273C的T细胞的TIL。目标细胞为用所示的II类HLA异二聚体中之一者转染的COS7细胞,且用p53-Y220C 25-mer肽脉冲。
图3A为展示在将目标细胞与效应细胞共培养之后测量的IFN-γ分泌(斑点数目/2e4个细胞)的图。效应细胞为经4343-D TCR转导的T细胞。目标细胞为用所示浓度(μg/mL)的p53-Y220C 25-mer肽(正方形)或对应WT 25-mer肽(圆形)脉冲的自体DC。
图3B至图3C为显示在将目标细胞与效应细胞共培养之后,表达4-1BB的鼠类TCR恒定区阳性细胞的百分比的图。效应细胞为经4343-D TCR转导的来自供体C(3B)或供体H(3C)的T细胞。目标细胞为用所示浓度(μg/mL)的与含有AABA取代的对应WT 25-mer肽(圆形)相对比的含有α-胺基丁酸(AABA)取代的突变p53-Y220C 25-mer肽(正方形)脉冲的自体B细胞。
图3D至图3G为展示在将目标细胞与效应细胞共培养之后测量的IFN-γ分泌(pg/mL)的图表。效应细胞为分别经4386-F TCR(图3D)、4386-G TCR(图3E)、4386-H TCR(图3F)或4386-O TCR(图3G)转导的T细胞。目标细胞为用所示浓度(ng/mL)的p53-R273C 25-mer肽(正方形)或对应WT 25-mer肽(圆形)脉冲的自体DC。
图4展示九个p53剪接变体的氨基酸序列的比对。SP|P04637|P53_HUMAN(SEQ IDNO:1);SP|P04637-2|P53_HUMAN(SEQ ID NO:101);SP|P04637-3|P53_HUMAN(SEQ ID NO:102);SP|P04637-4|P53_HUMAN(SEQ ID NO:103);SP|P04637-5|P53_HUMAN(SEQ ID NO:104);SP|P04637-6|P53_HUMAN(SEQ ID NO:105);SP|P04637-7|P53_HUMAN(SEQ ID NO:106);SP|P04637-8|P53_HUMAN(SEQ ID NO:107);以及SP|P04637-9|P53_HUMAN(SEQ IDNO:108)。
发明详述
肿瘤蛋白P53(亦称为“TP53”或“p53”)通过例如调节细胞分裂而充当肿瘤抑制剂。p53蛋白位于细胞的细胞核中,p53蛋白在细胞核中直接结合DNA。当DNA受损时,p53蛋白参与确定是否将修复DNA或受损细胞是否将经历细胞凋亡。若可修复DNA,则p53活化其他基因以修复损伤。若不能修复DNA,则p53蛋白防止细胞分裂,且对经历细胞凋亡的细胞进行信号传导。通过阻止含有突变或受损DNA的细胞分裂,p53有助于防止肿瘤发展。WT(正常)全长p53包含氨基酸序列SEQ ID NO:1。
p53蛋白中的突变可能降低或消除p53蛋白的肿瘤抑制功能。或者或另外地地,p53突变可通过以显性阴性方式干扰WT p53而成为功能获得型突变。突变的p53蛋白可表达于多种人类癌症中的任一种中,诸如胆管癌、黑色素瘤、结肠癌、直肠癌、卵巢癌、子宫内膜癌、非小细胞肺癌(NSCLC)、胶质母细胞瘤、子宫颈癌、头颈癌、乳腺癌、胰脏癌或膀胱癌。
本发明的一个实施方案提供一种分离或纯化的T细胞受体(TCR),其对突变的人类p53R273C或人类p53Y220C氨基酸序列(在下文中,“突变的p53”)具有抗原特异性。在下文中,除非另有规定,否则提以及“TCR”亦指代TCR的功能部分以及功能变体。本文中参考全长的WTp53的氨基酸序列(SEQ ID NO:1)来定义p53的突变。本文参考存在于特定位置处的氨基酸残基,继之以位置编号,继之以在所论述特定突变中置换残基的氨基酸来描述p53的突变。p53氨基酸序列(例如p53肽)可包含少于全长WT p53蛋白的全部氨基酸残基。因此,在理解p53氨基酸序列的一特定实例中的对应残基的实际位置可不同的情况下,本文参考WT全长p53蛋白(亦即SEQ ID NO:1)来定义位置编号。由于位置如由SEQ ID NO:1所定义,故术语“R273C”指示存在于SEQ ID NO:1的位置273处的精氨酸被半胱氨酸取代,而“Y220C”指示存在于SEQ ID NO:1的位置220处的酪氨酸被半胱氨酸取代。举例而言,当p53氨基酸序列的特定实例为例如SGNLLGRNSFEVRVCACPGRDRRTE(SEQ ID NO:116)(对应于SEQ ID NO:1的连续氨基酸残基261至285的例示性WT p53肽)时,“R273C”系指SEQ ID NO:116中加下划线的精氨酸被半胱氨酸取代,即使SEQ ID NO:116中加下划线的精氨酸的实际位置为13。含有R273C突变的人类p53氨基酸序列在下文中称为“R273C”或“p53R273C”。含有Y220C突变的人类p53氨基酸序列在下文中称为“Y220C”或“p53Y220C”。如本文所用,“突变p53”系指人类p53R273C或人类p53Y220C。
P53具有九个已知剪接变体。本文所描述的p53突变保留于全部九个p53剪接变体上。九个p53剪接变体的比对展示于图4中。因此,本发明的TCR可对本文所描述的由九个p53剪接变体中的任一者编码的任何突变的p53氨基酸序列具有抗原特异性。由于位置如由SEQID NO:1所定义,故p53的特定剪接变体的氨基酸序列的实际位置相对于SEQ ID NO:1的对应位置而定义,且如由SEQ ID NO:1所定义的位置可不同于特定剪接变体中的实际位置。因此,举例而言,在理解剪接变体中的实际位置可不同的情况下,突变是指对应于SEQ ID NO:1的393-氨基酸序列的所指示位置的p53特定剪接变体的氨基酸序列中的氨基酸残基的取代。
在本发明的一个实施方案中,TCR对在如通过SEQ ID NO:1所定义的位置273处含有突变的人类p53具有抗原特异性。位置273处的p53突变可为任何错义突变。因此,在位置273处的突变可为存在于位置273处的天然(WT)精氨酸残基被除精氨酸外的任何氨基酸残基取代。在本发明的一个实施方案中,TCR对人类p53R273C氨基酸序列具有抗原特异性。举例而言,TCR可对人类p53R273C氨基酸序列SGNLLGRNSFEVCVCACPGRDRRTE(SEQ ID NO:117)具有抗原特异性。在本发明的一个实施方案中,TCR对野生型人类p53氨基酸序列SGNLLGRNSFEVRVCACPGRDRRTE(SEQ ID NO:116)不具有抗原特异性。
在本发明的一个实施方案中,TCR对在如由SEQ ID NO:1所定义的位置220处含有突变的人类p53具有抗原特异性。位置220处的p53突变可为任何错义突变。因此,在位置220处的突变可为存在于位置220处的天然(WT)酪氨酸残基被除酪氨酸外的任何氨基酸残基取代。在本发明的一个实施方案中,TCR对人类p53Y220C氨基酸序列具有抗原特异性。举例而言,TCR可对人类p53Y220C氨基酸序列DRNTFRHSVVVPCEPPEVGSDCTTI(SEQ ID NO:115)具有抗原特异性。在本发明的一个实施方案中,TCR对野生型人类p53氨基酸序列DRNTFRHSVVVPYEPPEVGSDCTTI(SEQ ID NO:114)不具有抗原特异性。
在本发明的一个实施方案中,本发明的TCR可能够以HLA(人类白血球抗原)分子依赖性方式识别突变的p53。如本文所用的“HLA分子依赖性方式”意谓TCR在存在HLA分子的环境中与突变的p53结合后引发免疫反应,该HLA分子由从其分离TCR的患者表达。本发明的TCR可能够识别由适用的HLA分子呈递的突变p53,且除突变的p53外,还可与HLA分子结合。
在本发明的一个实施方案中,本发明的TCR能够识别由II类HLA分子呈递的R273C。就此而言,TCR可在存在II类HLA分子的环境内与R273C结合后引发免疫反应。本发明的TCR可能够识别由II类HLA分子呈递的之R273C,且除R273C外,还可与II类HLA分子结合。
在本发明的一个实施方案中,II类HLA分子为HLA-DP分子。HLA-DP分子为α链(DPA)以及β链(DPB)的异二聚体。HLA-DPA链可为任何HLA-DPA链。HLA-DPB链可为任何HLA-DPB链。在本发明的一个实施方案中,II类HLA分子为HLA-DPA1链以及HLA-DPB1链的异二聚体。HLA-DPA1分子的实例可包括但不限于由以下编码的那些分子:HLA-DPA1*01:03、HLA-DPA1*01:04、HLA-DPA1*01:05、HLA-DPA1*01:06、HLA-DPA1*01:07、HLA-DPA1*01:08、HLA-DPA1*01:09、HLA-DPA1*01:10、HLA-DPA1*02:01、HLA-DPA1*02:02、HLA-DPA1*02:03、HLA-DPA1*02:04、HLA-DPA1*03:01、HLA-DPA1*03:02、HLA-DPA1*03:03以及HLA-DPA1*04:01等位基因。HLA-DPB1分子的实例可包括但不限于由以下编码的那些分子:HLA-DPB1*01:01、HLA-DPB1*02:01、HLA-DPB1*02:02、HLA-DPB1*03:01、HLA-DPB1*04:01、HLA-DPB1*04:02、HLA-DPB1*05:01、HLA-DPB1*06:01、HLA-DPB1*07:01、HLA-DPB1*08:01、HLA-DPB1*09:01以及HLA-DPB1*10:01等位基因。优选地,II类HLA分子为HLA-DPA1*01:03链以及HLA-DPB1*04:02链的异二聚体。
在本发明的一个实施方案中,本发明的TCR中之一者能够识别由II类HLA分子呈递的Y220C。就此而言,TCR可在存在于II类HLA分子的环境内与Y220C结合后引发免疫反应。本发明的TCR能够识别由II类HLA分子呈递的Y220C,且除Y220C外,还可与II类HLA分子结合。
在本发明的一个实施方案中,II类HLA分子为HLA-DR异二聚体。HLA-DR异二聚体为包括α链以及β链的细胞表面受体。HLA-DRα链由HLA-DRA基因编码。在一实施例中,II类HLA分子的α链由HLA-DRA1*01:01:01等位基因表达。HLA-DRβ链由HLA-DRB1基因、HLA-DRB3基因、HLA-DRB4基因或HLA-DRB5基因编码。由HLA-DRB1基因编码的分子的实例可包括但不限于HLA-DR1、HLA-DR2、HLA-DR3、HLA-DR4、HLA-DR5、HLA-DR6、HLA-DR7、HLA-DR8、HLA-DR9、HLA-DR10、HLA-DR11、HLA-DR12、HLA-DR13、HLA-DR14、HLA-DR15、HLA-DR16以及HLA-DR17。HLA-DRB3基因编码HLA-DR52。HLA-DRB4基因编码HLA-DR53。HLA-DRB5基因编码HLA-DR51。在本发明的一个实施方案中,II类HLA分子为HLA-DRB3:HLA-DRA异二聚体。II类HLA分子的β链可由HLA-DRB3*01:01、HLA-DRB3*02:02或HLA-DRB3*03:01等位基因表达。优选地,II类HLA分子的β链由HLA-DRB3*02:02:01等位基因表达。在一优选的实施例中,II类HLA分子为HLA-DRA1*01:01:01链以及HLA-DRB3*02:02:01链的异二聚体。
本发明的TCR可提供多种优势中的任一种或多种,包括在由细胞表达时用于过继细胞转移。突变的p53由癌细胞表达且不由正常的非癌细胞表达。不受特定理论或机制的束缚,认为本发明的TCR有利地靶向癌细胞的破坏,同时最小化或消除正常非癌细胞的破坏,从而例如通过最小化或消除来降低毒性。此外,本发明的TCR可有利地成功治疗或预防对诸如化学疗法、手术或放射的其他类型治疗无反应的突变的p53阳性癌症。另外,本发明的TCR可提供对突变p53的高度亲合识别,其可提供识别未经操纵的肿瘤细胞(例如,尚未用干扰素(IFN)-γ、用编码突变p53以及适用HLA分子中之一或两者的载体转染、用含有p53突变的p53肽脉冲或其组合处理的肿瘤细胞)的能力。全部肿瘤中的大约一半携带p53中的突变,其中约一半将为错义突变。R273C突变由所有癌症的约2.8%表达,且HLA-DPB1*04:02等位基因由约24%的美国高加索人群体以及约60%至约80%的美国西班牙裔群体表达。Y220C突变出现于所有癌症的约1.5%中,且HLA-DRB3*02:02等位基因由约33%的美国高加索人群体表达。R273C以及Y220C突变产生于许多癌症组织结构中,表明多种患者群体可受益于本发明的TCR。因此,本发明的TCR可以增加可符合免疫疗法治疗条件的患者的数目。
如本文所用的短语“抗原特异性”意谓TCR可以高亲合力特异性结合于突变的p53且免疫识别突变的p53。举例而言,若在与以下共培养之后,约1×104至约1×105个表达TCR的T细胞分泌至少约200pg/mL或更多(例如200pg/mL或更多、300pg/mL或更多、400pg/mL或更多、500pg/mL或更多、600pg/mL或更多、700pg/mL或更多、1,000pg/mL或更多、5,000pg/mL或更多、7,000pg/mL或更多、10,000pg/mL或更多、20,000pg/mL或更多、或任何两个前述值限定的范围)的IFN-γ,则可将TCR视为对突变的p53具有“抗原特异性”:(a)用低浓度的突变p53肽(例如约0.05ng/mL至约5ng/mL、0.05ng/mL、0.1ng/mL、0.5ng/mL、1ng/mL、5ng/mL或任何两个前述值限定的范围)脉冲的抗原阴性的适用HLA分子阳性目标细胞;或(b)已引入编码突变p53的核苷酸序列以使得目标细胞表达突变p53的抗原阴性的适用HLA分子阳性目标细胞。表达本发明的TCRTCR的细胞亦可在与用较高浓度的突变p53肽脉冲的抗原阴性的适用HLA分子阳性目标细胞共培养之后分泌IFN-γ。
或者或另外地,若在与(a)用低浓度的突变p53肽脉冲的抗原阴性的适用HLA分子阳性目标细胞或(b)已引入编码突变p53的核苷酸序列以使得目标细胞表达突变p53的抗原阴性的适用HLA分子阳性目标细胞共培养之后,与由阴性对照表达的IFN-γ的量相比,表达TCR的T细胞分泌至少两倍的IFN-γ,则可将TCR视为对突变p53具有“抗原特异性”。阴性对照可为例如(i)与以下共培养的表达TCR的T细胞:(a)用相同浓度的不相关肽(例如具有不同于突变p53肽的序列的某种其他的肽)脉冲的抗原阴性的适用HLA分子阳性目标细胞,或(b)已引入编码不相关肽的核苷酸序列以使得目标细胞表达不相关肽的抗原阴性的适用HLA分子阳性目标细胞;或(ii)与以下共培养的未经转导的T细胞(例如来源于PBMC,不表达TCR):(a)用相同浓度的突变p53肽脉冲的抗原阴性的适用HLA分子阳性目标细胞,或(b)已引入编码突变p53的核苷酸序列以使得目标细胞表达突变p53的抗原阴性的适用HLA分子阳性目标细胞。IFN-γ分泌可通过现有技术中已知的诸如酶联免疫吸附分析(ELISA)的方法测量。
或者或另外地,若在与(a)用低浓度的突变p53肽脉冲的抗原阴性的适用HLA分子阳性目标细胞或(b)已引入编码突变p53的核苷酸序列以使得目标细胞表达突变p53的抗原阴性的适用HLA分子阳性目标细胞共培养之后,与分泌IFN-γ的阴性对照T细胞的数目相比,表达TCR的T细胞分泌至少两倍数目的IFN-γ,则可将TCR视为对突变p53具有“抗原特异性”。肽以及阴性对照的浓度可如本文关于本发明的其他方面所描述。分泌IFN-γ的细胞的数目可通过现有技术中已知的诸如酶联免疫斑点(ELISpot)分析的方法来测量。
可替代地或另外地,若在与(a)用低浓度的突变p53肽脉冲的抗原阴性的适用HLA分子阳性目标细胞或(b)已引入编码突变p53的核苷酸序列以使得目标细胞表达突变p53的抗原阴性的适用HLA分子阳性目标细胞共培养之后,与通过ELISpot针对与相同目标细胞共培养的阴性对照T细胞检测的斑点数目相比,通过ELISpot针对表达TCR的T细胞检测到至少两倍的斑点,则可将TCR视为对突变p53具有“抗原特异性”。肽以及阴性对照的浓度可如本文关于本发明的其他方面所描述。
或者或另外地,若在与(a)用低浓度的突变p53肽脉冲的抗原阴性的适用HLA分子阳性目标细胞或(b)已引入编码突变p53的核苷酸序列以使得目标细胞表达突变p53的抗原阴性的适用HLA分子阳性目标细胞共培养之后,通过ELISpot针对表达TCR的T细胞检测到大于约50个斑点,则可将TCR视为对突变p53具有“抗原特异性”。肽的浓度可如本文关于本发明的其他方面所描述。
或者或另外地,若在用表达突变p53的目标细胞刺激之后,如通过例如流式细胞测量术所测量,表达TCR的T细胞上调4-1BB以及OX40中之一或两者的表达,则可将TCR视为对突变p53具有“抗原特异性”。
本发明的一个实施方案提供一种TCR,其包含两种多肽(亦即多肽链),诸如TCR的α链、TCR的β链、TCR的γ链、TCR的δ链或其组合。本发明的TCR的多肽可包含任何氨基酸序列,前提条件为TCR对突变p53具有抗原特异性。
在本发明的一个实施方案中,TCR包含两个多肽链,其中每一者包含可变区,该可变区包含TCR的互补决定区(CDR)1、CDR2以及CDR3。在本发明的一个实施方案中,TCR包含:第一多肽链,其包含α链CDR1(CDR1α)、α链CDR2(CDR2α)以及α链CDR3(CDR3α);以及第二多肽链,其包含β链CDR1(CDR1β)、β链CDR2(CDR2β)以及β链CDR3(CDR3β)。在本发明的一个实施方案中,TCR包含以下氨基酸序列:(1)SEQ ID NO:2-7全部;(2)SEQ ID NO:21-26全部;(3)SEQID NO:40-45全部;(4)SEQ ID NO:59-64全部;或(5)SEQ ID NO:78-83全部。在此段落中的氨基酸序列的前述五个集合中的每一者阐述对突变人类p53具有抗原特异性的五种不同TCR中每一者的六个CDR区。各集合中六个氨基酸序列分别对应于TCR的CDR1α、CDR2α、CDR3α、CDR1β、CDR2β以及CDR3β。
在本发明的一个实施方案中,TCR包含一同包含上文所阐述的CDR集合中之一的α链可变区氨基酸序列以及β链可变区氨基酸序列。就此而言,TCR可例如包含以下任一氨基酸序列:SEQ ID NO:8、9、10、11、12、13、27、28、29、30、31、32、46、47、48、49、50、51、65、66、67、68、69、70、84、85、86、87、88、89、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137以及138。举例而言,TCR可包含以下的氨基酸序列:(1)SEQ ID NO:8以及9两者;(2)SEQ ID NO:10以及11两者;(3)SEQ ID NO:12以及13两者;(4)SEQ ID NO:12以及11两者;(5)SEQ ID NO:121以及13两者;(6)SEQ ID NO:121以及122两者;(7)SEQ ID NO:8以及120两者;(8)SEQ ID NO:119以及9两者;(9)SEQ ID NO:119以及120两者;(10)SEQ ID NO:27以及28两者;(11)SEQ ID NO:29以及30两者;(12)SEQ ID NO:31以及32两者;(13)SEQ ID NO:31以及30两者;(14)SEQ ID NO:125以及32两者;(15)SEQID NO:125以及126两者;(16)SEQ ID NO:27以及124两者;(17)SEQ ID NO:123以及28两者;(18)SEQ ID NO:123以及124两者;(19)SEQ ID NO:46以及47两者;(20)SEQ ID NO:48以及49两者;(21)SEQ ID NO:50以及51两者;(22)SEQ ID NO:50以及49两者;(23)SEQ ID NO:129以及51两者;(24)SEQ ID NO:129以及130两者;(25)SEQ ID NO:46以及128两者;(26)SEQ ID NO:127以及47两者;(27)SEQ ID NO:127以及128两者;(28)SEQ ID NO:65以及66两者;(29)SEQ ID NO:67以及68两者;(30)SEQ ID NO:69以及70两者;(31)SEQ ID NO:69以及68两者;(32)SEQ ID NO:133以及70两者;(33)SEQ ID NO:133以及134两者;(34)SEQ IDNO:65以及132两者;(35)SEQ ID NO:131以及66两者;(36)SEQ ID NO:131以及132两者;(37)SEQ ID NO:84以及85两者;(38)SEQ ID NO:86以及87两者;(39)SEQ ID NO:88以及89两者;(40)SEQ ID NO:88以及87两者;(41)SEQ ID NO:137以及89两者;(42)SEQ ID NO:137以及138两者;(43)SEQ ID NO:84以及136两者;(44)SEQ ID NO:135以及85两者;或(45)SEQID NO:135以及136两者。在此段落中的氨基酸序列的前述集合中每一者示出对突变人类p53具有抗原特异性的不同TCR中每一者的两个可变区。各集合中两个氨基酸序列分别对应于TCR的α链可变区以及β链可变区。
本发明的TCR可进一步包含恒定区。恒定区可来源于诸如人类或小鼠的任何适合物种。在本发明的一个实施方案中,TCR进一步包含鼠类恒定区。如本文所用,当提以及本文所描述的TCR或TCR的任何组分(例如互补决定区(CDR)、可变区、恒定区、α链以及和/或β链)时,术语“鼠类”或“人类”分别意指来源于小鼠或人类的TCR(或其组分),亦即分别来源于小鼠T细胞或人类T细胞或曾经由小鼠T细胞或人类T细胞表达的TCR(或其组分)。在本发明的一个实施方案中,TCR可包含鼠类α链恒定区以及鼠类β链恒定区。鼠类α链恒定区可经修饰或未经修饰。经修饰的鼠类α链恒定区可为例如被半胱氨酸取代、被LVL修饰或被半胱氨酸取代且被LVL修饰两者,如例如在美国专利第10,174,098号中所描述。鼠类β链恒定区可经修饰或未经修饰。经修饰鼠类β链恒定区可例如经半胱氨酸取代,如例如在美国专利第10,174,098号中所描述。在本发明的一些实施例中,TCR包含经半胱氨酸取代、经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:97。在本发明的一些实施例中TCR包含经半胱氨酸取代、经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:98。在本发明的一些实施例中,TCR包含经半胱氨酸取代、经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQID NO:143。在本发明的一些实施例中,TCR包含经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:144。在本发明的一些实施例中,TCR包含经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:145。在本发明的一些实施例中,TCR包含经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:146。在本发明的一些实施例中,TCR包含经LVL修饰的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:147。在本发明的一些实施例中,TCR包含经半胱氨酸取代的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:148。在本发明的一些实施例中,TCR包含经半胱氨酸取代的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:149。在本发明的一个实施方案中,TCR包含D1鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:139。在本发明的一些实施例中,TCR包含简并氨基酸序列中所描述的鼠类α链恒定区,其包含氨基酸序列SEQ ID NO:141。在本发明的一个实施方案中,TCR包含经半胱氨酸取代的鼠类β链恒定区,其包含氨基酸序列SEQ ID NO:99。在本发明的一个实施方案中,TCR包含野生型鼠类β链恒定区,其包含氨基酸序列SEQ ID NO:140。在本发明的一些实施例中,TCR包含简并氨基酸序列中所描述的鼠类β链恒定区,其包含氨基酸序列SEQ ID NO:142。
示例性Cα区序列以及Cβ区序列显示于表1以及表2中。
表1TCR Cα区的氨基酸序列
表2TCR Cβ区的氨基酸序列
在本发明的一个实施方案中,本发明的TCR可包含TCR的α链以及TCR的β链。TCR的α链可包含α链的可变区以及α链的恒定区。此类型的α链可与TCR的任何β链配对。该β链可包含β链的可变区以及β链的恒定区。
在一些实施例中,本文所揭示的α链以及和/或β链中的任一者的氨基酸序列在C端末端处进一步包含氨基酸序列RAKR(SEQID NO:118)。
在本发明的一个实施方案中,TCR包含以下任一氨基酸序列:SEQ ID NO:14、15、16、17、18、19、33、34、35、36、37、38、52、53、54、55、56、57、71、72、73、74、75、76、90、91、92、93、94以及95。举例而言,TCR可包含以下氨基酸序列:(1)SEQ ID NO:14以及15两者;(2)SEQID NO:16以及17两者;(3)SEQ ID NO:18以及19两者;(4)SEQ ID NO:33以及34两者;(5)SEQID NO:35以及36两者;(6)SEQ ID NO:37以及38两者;(7)SEQ ID NO:52以及53两者;(8)SEQID NO:54以及55两者;(9)SEQ ID NO:56以及57两者;(10)SEQ ID NO:71以及72两者;(11)SEQ ID NO:73以及74两者;(12)SEQ ID NO:75以及76两者;(13)SEQ ID NO:90以及91两者;(14)SEQ ID NO:92以及93两者;或(15)SEQ ID NO:94以及95两者。在此段落中的氨基酸序列的前述集合中的每一个阐述对突变的人类p53具有抗原特异性的不同TCR中的每一个的α链以及β链。各集合中的两个氨基酸序列分别对应于TCR的α链以及β链。
本文所描述的本发明的TCR的功能变体包括于本发明的范畴中。如本文所用,术语“功能变体”是指与亲本TCR、多肽或蛋白质具有实质或显著序列一致性或类似性的TCR、多肽或蛋白质,该功能变体保留衍生其作为变体的TCR、多肽或蛋白质的生物活性。功能变体涵盖例如本文所描述的TCR、多肽或蛋白质(亲本TCR、多肽或蛋白质)的那些变体,其保留以与亲本TCR、多肽或蛋白质类似的程度、相同的程度或更高的程度特异性结合于突变的p53的能力,亲本TCR对该突变p53具有抗原特异性或者亲本多肽或蛋白质特异性结合于该突变p53。参考亲本TCR、多肽或蛋白质,功能变体可在氨基酸序列方面分别与亲本TCR、多肽或蛋白质例如至少约30%、至少约50%、至少约75%、至少约80%、至少约90%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%一致或具更高一致性。
功能变体可例如包含含有至少一个保守氨基酸取代的亲本TCR、多肽或蛋白质的氨基酸序列。保守氨基酸取代为现有技术中已知的且包括其中一个具有某些物理以及和/或化学特性的氨基酸被另一个具有相同化学或物理特性的氨基酸交换的氨基酸取代。举例而言,保守氨基酸取代可为酸性氨基酸被取代为另一酸性氨基酸(例如Asp或Glu)、具有非极性侧链的氨基酸被取代为另一具有非极性侧链的氨基酸(例如Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Val等)、碱性氨基酸被取代为另一碱性氨基酸(Lys、Arg等)、具有极性侧链的氨基酸被取代为另一具有极性侧链的氨基酸(Asn、Cys、Gln、Ser、Thr、Tyr等),等等。
或者或另外地,功能变体可包含含有至少一个非保守氨基酸取代的亲本TCR、多肽或蛋白质的氨基酸序列。在此情况下,非保守氨基酸取代不干扰或抑制功能变体的生物活性是优选的。优选地,非保守性氨基酸取代增强功能变体的生物活性,使得与亲本TCR、多肽或蛋白质相比,功能变体的生物活性增加。
TCR、多肽或蛋白质可基本上由指定氨基酸序列或本文所描述的序列组成,使得TCR、多肽或蛋白质的其他组分(例如其他氨基酸)不实质上改变TCR、多肽或蛋白质的生物活性。
本发明亦提供一种多肽,其包含本文所描述的TCR中的任一者的功能部分。如本文所用的术语“多肽”包括寡肽,且系指由一或多个肽键连接的单个氨基酸链。
关于本发明的多肽,功能部分可为包含其作为组成部分的TCR的连续氨基酸的任何部分,其前提条件为功能部分特异性结合于突变的p53。术语“功能部分”当在提以及TCR使用时,系指本发明的TCR的任何部分或片段,该部分或片段保留其作为组成部分的TCR(亲本TCR)的生物活性。功能部分涵盖例如保留以与亲本TCR类似的程度、相同的程度或更高的程度特异性结合于突变的p53(例如以适用HLA分子依赖性方式)或检测、治疗或防止癌症之能力的TCR的彼等部分。关于亲本TCR,功能部分可包含亲本TCR的例如约10%、约25%、约30%、约50%、约70%、约80%、约90%、约95%或更多。
功能部分可在该部分的氨基或羧基端或在两个端处包含额外氨基酸,该额外氨基酸在亲本TCR的氨基酸序列中未发现。理想地,该额外氨基酸不干扰功能部分分人生物功能,例如特异性结合于突变p53;以及和/或能够检测癌症、治疗或预防癌症等。更理想地,与亲本TCR的生物活性相比,该额外氨基酸增强生物活性。
多肽可包含本发明的TCR的α链以及β链中的任一者或两者的功能部分,诸如包含本发明的TCR的α链以及和/或β链的可变区的CDR1、CDR2以及CDR3中一个或多个的功能部分。在本发明的一个实施方案中,多肽可包含以下氨基酸序列:(1)SEQ ID NO:2-7全部;(2)SEQ ID NO:21-26全部;(3)SEQ ID NO:40-45全部;(4)SEQ ID NO:59-64全部;或(5)SEQ IDNO:78-83全部。
在本发明的一个实施方案中,本发明多肽可包含例如本发明的TCR的可变区,其包含上文阐述的CDR区的组合。就此而言,多肽可包含例如以下氨基酸序列:(1)SEQ ID NO:8以及9两者;(2)SEQ ID NO:10以及11两者;(3)SEQ ID NO:12以及13两者;(4)SEQ ID NO:12以及11两者;(5)SEQ ID NO:121以及13两者;(6)SEQ ID NO:121以及122两者;(7)SEQ IDNO:8以及120两者;(8)SEQ ID NO:119以及9两者;(9)SEQ ID NO:119以及120两者;(10)SEQID NO:27以及28两者;(11)SEQ ID NO:29以及30两者;(12)SEQ ID NO:31以及32两者;(13)SEQ ID NO:31以及30两者;(14)SEQ ID NO:125以及32两者;(15)SEQ ID NO:125以及126两者;(16)SEQ ID NO:27以及124两者;(17)SEQ ID NO:123以及28两者;(18)SEQ ID NO:123以及124两者;(19)SEQ ID NO:46以及47两者;(20)SEQ ID NO:48以及49两者;(21)SEQ IDNO:50以及51两者;(22)SEQ ID NO:50以及49两者;(23)SEQ ID NO:129以及51两者;(24)SEQ ID NO:129以及130两者;(25)SEQ IDNO:46以及128两者;(26)SEQ ID NO:127以及47两者;(27)SEQ ID NO:127以及128两者;(28)SEQ ID NO:65以及66两者;(29)SEQ ID NO:67以及68两者;(30)SEQ ID NO:69以及70两者;(31)SEQ ID NO:69以及68两者;(32)SEQ ID NO:133以及70两者;(33)SEQ ID NO:133以及134两者;(34)SEQ ID NO:65以及132两者;(35)SEQ ID NO:131以及66两者;(36)SEQ ID NO:131以及132两者;(37)SEQ ID NO:84以及85两者;(38)SEQ ID NO:86以及87两者;(39)SEQ ID NO:88以及89两者;(40)SEQ ID NO:88以及87两者;(41)SEQ ID NO:137以及89两者;(42)SEQ ID NO:137以及138两者;(43)SEQ IDNO:84以及136两者;(44)SEQ ID NO:135以及85两者;或(45)SEQ ID NO:135以及136两者。
在本发明的一个实施方案中,本发明的多肽可进一步包含上文阐述的本发明的TCR的恒定区。就此而言,多肽可包含例如以下氨基酸序列:(i)SEQ ID NO 97-99以及139-149中之一;或(ii)SEQ ID NO:99、140以及142中之一以及SEQ ID NO:97、98、139、141以及143-149中之一。
在本发明的一个实施方案中,本发明多肽可包含本发明的TCR的α链以及β链。就此而言,多肽可包含例如以下氨基酸序列:(1)SEQ ID NO:14以及15两者;(2)SEQ ID NO:16以及17两者;(3)SEQ ID NO:18以及19两者;(4)SEQ ID NO:33以及34两者;(5)SEQ ID NO:35以及36两者;(6)SEQ ID NO:37以及38两者;(7)SEQ ID NO:52以及53两者;(8)SEQ ID NO:54以及55两者;(9)SEQ ID NO:56以及57两者;(10)SEQ ID NO:71以及72两者;(11)SEQ IDNO:73以及74两者;(12)SEQ ID NO:75以及76两者;(13)SEQ ID NO:90以及91两者;(14)SEQID NO:92以及93两者;或(15)SEQ ID NO:94以及95两者。
本发明的一个实施方案进一步提供蛋白质,其包含本文所描述的多肽中的至少一种。“蛋白质”意指包含一或多个多肽链的分子。在一实施例中,本发明的蛋白质可包含:(1)包含SEQ ID NO:2-4中全部的氨基酸序列的第一多肽链以及包含SEQ ID NO:5-7中全部的氨基酸序列的第二多肽链;(2)包含SEQ ID NO:21-23中全部的氨基酸序列的第一多肽链以及包含SEQ ID NO:24-26中全部的氨基酸序列的第二多肽链;(3)包含SEQ ID NO:40-42中全部的氨基酸序列的第一多肽链以及包含SEQ ID NO:43-45中全部的氨基酸序列的第二多肽链;(4)包含SEQ ID NO:59-61中全部的氨基酸序列的第一多肽链以及包含SEQ ID NO:62-64中全部的氨基酸序列的第二多肽链;或(5)包含SEQ ID NO:78-80中全部的氨基酸序列的第一多肽链以及包含SEQ ID NO:81-83中全部的氨基酸序列的第二多肽链。
在本发明的一个实施方案中,蛋白质包含:(1)包含SEQ ID NO:8的氨基酸序列的第一多肽链以及包含SEQ ID NO:9的氨基酸序列的第二多肽链;(2)包含SEQ ID NO:10的氨基酸序列的第一多肽链以及包含SEQ ID NO:11的氨基酸序列的第二多肽链;(3)包含SEQID NO:12的氨基酸序列的第一多肽链以及包含SEQ ID NO:13的氨基酸序列的第二多肽链;(4)包含SEQ ID NO:12的氨基酸序列的第一多肽链以及包含SEQ ID NO:11的氨基酸序列额第二多肽链;(5)包含SEQ ID NO:121的氨基酸序列的第一多肽链以及包含SEQ ID NO:13的氨基酸序列的第二多肽链;(6)包含SEQ ID NO:121的氨基酸序列的第一多肽链以及包含SEQ ID NO:122的氨基酸序列的第二多肽链;(7)包含SEQ ID NO:8的氨基酸序列的第一多肽链以及包含SEQ ID NO:120的氨基酸序列的第二多肽链;(8)包含SEQ ID NO:119的氨基酸序列的第一多肽链以及包含SEQ ID NO:9的氨基酸序列的第二多肽链;(9)包含SEQ IDNO:119的氨基酸序列的第一多肽链以及包含SEQ ID NO:120的氨基酸序列的第二多肽链;(10)包含SEQ ID NO:27的氨基酸序列的第一多肽链以及包含SEQ ID NO:28的氨基酸序列的第二多肽链;(11)包含SEQ ID NO:29的氨基酸序列的第一多肽链以及包含SEQ ID NO:30的氨基酸序列的第二多肽链;(12)包含SEQ ID NO:31的氨基酸序列的第一多肽链以及包含SEQ ID NO:32的氨基酸序列的第二多肽链;(13)包含SEQ ID NO:31的氨基酸序列的第一多肽链以及包含SEQ ID NO:30的氨基酸序列的第二多肽链;(14)包含SEQ ID NO:125氨基酸序列的第一多肽链以及包含SEQ ID NO:32的氨基酸序列的第二多肽链;(15)包含SEQ IDNO:125的氨基酸序列的第一多肽链以及包含SEQ ID NO:126的氨基酸序列的第二多肽链;(16)包含SEQ ID NO:27的氨基酸序列的第一多肽链以及包含SEQ ID NO:124的氨基酸序列的第二多肽链;(17)包含SEQ ID NO:123的氨基酸序列的第一多肽链以及包含SEQ ID NO:28的氨基酸序列的第二多肽链;(18)包含SEQ ID NO:123的氨基酸序列的第一多肽链以及包含SEQ ID NO:124的氨基酸序列的第二多肽链;(19)包含SEQ ID NO:46的氨基酸序列的第一多肽链以及包含SEQ ID NO:47的氨基酸序列的第二多肽链;(20)包含SEQ ID NO:48的氨基酸序列的第一多肽链以及包含SEQ ID NO:49的氨基酸序列的第二多肽链;(21)包含SEQ ID NO:50的氨基酸序列的第一多肽链以及包含SEQ ID NO:51的氨基酸序列的第二多肽链;(22)包含SEQ ID NO:50的氨基酸序列的第一多肽链以及包含SEQ ID NO:49的氨基酸序列的第二多肽链;(23)包含SEQ ID NO:129的氨基酸序列的第一多肽链以及包含SEQ IDNO:51的氨基酸序列的第二多肽链;(24)包含SEQ ID NO:129的氨基酸序列的第一多肽链以及包含SEQ ID NO:130的氨基酸序列的第二多肽链;(25)包含SEQ ID NO:46的氨基酸序列的第一多肽链以及包含SEQ ID NO:128的氨基酸序列的第二多肽链;(26)包含SEQ ID NO:127的氨基酸序列的第一多肽链以及包含SEQ ID NO:47的氨基酸序列的第二多肽链;(27)包含SEQ ID NO:127的氨基酸序列的第一多肽链以及包含SEQ ID NO:128的氨基酸序列的第二多肽链;(28)包含SEQ ID NO:65的氨基酸序列的第一多肽链以及包含SEQ ID NO:66的氨基酸序列的第二多肽链;(29)包含SEQ ID NO:67的氨基酸序列的第一多肽链以及包含SEQ ID NO:68的氨基酸序列的第二多肽链;(30)包含SEQ ID NO:69的氨基酸序列的第一多肽链以及包含SEQ ID NO:70的氨基酸序列的第二多肽链;(31)包含SEQ ID NO:69的氨基酸序列的第一多肽链以及包含SEQ ID NO:68的氨基酸序列的第二多肽链;(32)包含SEQ IDNO:133的氨基酸序列的第一多肽链以及包含SEQ ID NO:70的氨基酸序列的第二多肽链;(33)包含SEQ ID NO:133的氨基酸序列的第一多肽链以及包含SEQ ID NO:134的氨基酸序列的第二多肽链;(34)包含SEQ ID NO:65的氨基酸序列的第一多肽链以及包含SEQ ID NO:132的氨基酸序列的第二多肽链;(35)包含SEQ ID NO:131的氨基酸序列的第一多肽链以及包含SEQ ID NO:66的氨基酸序列的第二多肽链;(36)包含SEQ ID NO:131的氨基酸序列的第一多肽链以及包含SEQ ID NO:132的氨基酸序列的第二多肽链;(37)包含SEQ ID NO:84的氨基酸序列的第一多肽链以及包含SEQ ID NO:85的氨基酸序列的第二多肽链;(38)包含SEQ ID NO:86的氨基酸序列的第一多肽链以及包含SEQ ID NO:87的氨基酸序列的第二多肽链;(39)包含SEQ ID NO:88的氨基酸序列的第一多肽链以及包含SEQ ID NO:89的氨基酸序列的第二多肽链;(40)包含SEQ ID NO:88的氨基酸序列的第一多肽链以及包含SEQ IDNO:87的氨基酸序列的第二多肽链;(41)包含SEQ ID NO:137的氨基酸序列的第一多肽链以及包含SEQ ID NO:89的氨基酸序列的第二多肽链;(42)包含SEQ ID NO:137的氨基酸序列的第一多肽链以及包含SEQ ID NO:138的氨基酸序列的第二多肽链;(43)包含SEQ ID NO:84的氨基酸序列的第一多肽链以及包含SEQ ID NO:136的氨基酸序列的第二多肽链;(44)包含SEQ ID NO:135的氨基酸序列的第一多肽链以及包含SEQ ID NO:85的氨基酸序列的第二多肽链;或(45)包含SEQ ID NO:135的氨基酸序列的第一多肽链以及包含SEQ ID NO:136的氨基酸序列的第二多肽链。
在本发明的一个实施方案中,蛋白质可进一步包含上文阐述的本发明的TCR的恒定区。就此而言,第一多肽链可包含SEQ ID NO:99、140以及142中之一者,且第二多肽链可包含SEQ ID NO:97、98、139、141以及143-149中之一者。
在本发明的一个实施方案中,蛋白质包含:(1)包含氨基酸序列SEQ ID NO:14的第一多肽链以及包含氨基酸序列SEQ ID NO:15的第二多肽链;(2)包含氨基酸序列SEQ IDNO:16的第一多肽链以及包含氨基酸序列SEQ ID NO:17的第二多肽链;(3)包含氨基酸序列SEQ ID NO:18的第一多肽链以及包含氨基酸序列SEQ ID NO:19的第二多肽链;(4)包含氨基酸序列SEQ ID NO:33的第一多肽链以及包含氨基酸序列SEQ ID NO:34的第二多肽链;(5)包含氨基酸序列SEQ ID NO:35之第一多肽链以及包含氨基酸序列SEQ ID NO:36之第二多肽链;(6)包含氨基酸序列SEQ ID NO:37的第一多肽链以及包含氨基酸序列SEQ ID NO:38的第二多肽链;(7)包含氨基酸序列SEQ ID NO:52的第一多肽链以及包含氨基酸序列SEQID NO:53的第二多肽链;(8)包含氨基酸序列SEQ ID NO:54的第一多肽链以及包含氨基酸序列SEQ ID NO:55的第二多肽链;(9)包含氨基酸序列SEQ ID NO:56的第一多肽链以及包含氨基酸序列SEQ ID NO:57的第二多肽链;(10)包含氨基酸序列SEQ ID NO:71的第一多肽链以及包含氨基酸序列SEQ ID NO:72的第二多肽链;(11)包含氨基酸序列SEQ ID NO:73的第一多肽链以及包含氨基酸序列SEQ ID NO:74的第二多肽链;(12)包含氨基酸序列SEQ IDNO:75的第一多肽链以及包含氨基酸序列SEQ ID NO:76的第二多肽链;(13)包含氨基酸序列SEQ ID NO:90的第一多肽链以及包含氨基酸序列SEQ ID NO:91的第二多肽链;(14)包含氨基酸序列SEQ ID NO:92的第一多肽链以及包含氨基酸序列SEQ ID NO:93的第二多肽链;或(15)包含氨基酸序列SEQ ID NO:94的第一多肽链以及包含氨基酸序列SEQ ID NO:95的第二多肽链。
本发明的蛋白质可为TCR。或者,若蛋白质的第一以及和/或第二多肽链进一步包含其他氨基酸序列,例如编码免疫球蛋白或其部分的氨基酸序列,则本发明蛋白质可为融合蛋白。就此而言,本发明的一个实施方案亦提供融合蛋白,其包含本文所描述的本发明多肽中的至少一者以及至少一种其他多肽。另一种多肽能够作为融合蛋白的单独多肽存在,或可以作为与本文所描述的本发明的多肽中的一个同框(以串联方式)表达的多肽存在。另一种多肽可编码任何肽或蛋白质分子或其部分,包括但不限于免疫球蛋白、CD3、CD4、CD8、MHC分子、CD1分子,例如CD1a、CD1b、CD1c、CD1d等。
融合蛋白可包含本发明的多肽的一或多个拷贝以及和/或另一种多肽的一或多个复本。举例而言,融合蛋白可包含本发明多肽以及和/或另一种多肽的1、2、3、4、5或更多个复本。制备融合蛋白的适合方法为现有技术中已知的,且包括例如重组方法。
在本发明的一些实施例中,本发明的TCR、多肽以及蛋白质可表达为包含连接α链以及β链的接头肽的单一蛋白质。就此而言,本发明的TCR、多肽以及蛋白质可进一步包含接头肽。接头肽可有利地促进重组TCR、多肽以及和/或蛋白质在宿主细胞中的表达。接头肽可包含任何适合的氨基酸序列。举例而言,接头肽可包含氨基酸序列RAKRSGSGATNFSLLKQAGDVEENPGP(SEQ ID NO:100)。当通过宿主细胞表达包括接头肽的构建体时,接头肽可被裂解,从而产生分离的α链以及β链。在本发明的一个实施方案中,TCR、多肽或蛋白质可包含含有全长α链、全长β链以及位于α链与β链的间的接头肽的氨基酸序列。
在一些实施例中,本文所公开的TCR、多肽或蛋白质包含如本文所公开的包含信号肽的α链以及和/或β链。在一些实施例中,本文所公开的α链以及和/或β链中的任一者的信号肽的序列包含在位置2处取代野生型残基的丙氨酸或组氨酸残基。
在一些实施例中,本文所公开的TCR、多肽或蛋白质包含如本文所公开的α链以及和/或β链的缺乏信号肽的成熟型式。
本发明的蛋白质可为重组抗体或其抗原结合部分,其包含本文所描述的本发明多肽中的至少一者。如本文所用,“重组抗体”系指包含本发明的多肽中的至少一者以及抗体或其抗原结合部分的多肽链的重组(例如经基因工程改造)蛋白。抗体或其抗原结合部分的多肽可为抗体的重链、轻链、重链或轻链的可变区或恒定区、单链可变片段(scFv)或Fc、Fab或F(ab)2'片段等。抗体或其抗原结合部分的多肽链可以重组抗体的独立多肽形式存在。或者,抗体或其抗原结合部分的多肽链可以多肽的形式存在,其与本发明的多肽同框(以串联方式)表达。抗体或其抗原结合部分的多肽可为任何抗体或任何抗体片段(包括本文所描述的任何抗体以及抗体片段)的多肽。
本发明的TCR、多肽以及蛋白质可具有任何长度,亦即可包含任何数目的氨基酸,条件是TCR、多肽或蛋白质保留其生物活性,例如能够特异性结合于突变p53、检测哺乳动物的癌症、或治疗或预防哺乳动物的癌症等的能力。举例而言,多肽的长度可在约50至约5,000个氨基酸的范围内,诸如长度为50、70、75、100、125、150、175、200、300、400、500、600、700、800、900、1000或更多个氨基酸。就此而言,本发明的多肽亦包括寡肽。
本发明的TCR、多肽以及蛋白质可包含代替一或多种天然存在的氨基酸的合成氨基酸。此类合成氨基酸为现有技术中已知的,且包括例如氨基环己烷甲酸、正亮氨酸、α-氨基正癸酸、高丝氨酸、S-乙酰氨基甲基-半胱氨酸、反式-3-羟脯氨酸以及反式-4-羟脯氨酸、4-氨基苯丙氨酸、4-硝基苯丙氨酸、4-氯苯丙氨酸、4-羧基苯丙氨酸、β-苯基丝氨酸β-羟基苯基丙氨酸、苯基甘氨酸、α-萘基丙氨酸、丙氨酸环己酯、环己基甘氨酸、吲哚啉-2-甲酸、1,2,3,4-四氢异喹啉-3-甲酸、氨基丙二酸、氨基丙二酸单酰胺、N'-苯甲基-N'-甲基-赖氨酸、N',N'-二苯甲基-赖氨酸、6-赖氨酸羟基赖氨酸、鸟氨酸、α-氨基环戊烷甲酸、α-氨基环己烷甲酸、α-氨基环庚烷甲酸、α-(2-氨基-2-降莰烷)-甲酸、α,γ-二氨基丁酸、α,β-二氨基丙酸、高苯丙氨酸以及α-三级丁基甘氨酸。
本发明的TCR、多肽以及蛋白质可例如经糖基化、酰胺化、羧化、磷酸化、酯化、正酰基化、经由例如二硫桥键环化或转化成酸加成盐以及和/或任选地二聚合或聚合,或缀合。
本发明的TCR、多肽以及和/或蛋白质可通过现有技术中已知的诸如重新合成的方法获得。此外,多肽以及蛋白质可使用本文所描述的核酸、使用标准重组方法以重组方式产生。参见例如Green以及Sambrook,Molecular Cloning:A Laboratory Manual,第4版,ColdSpring Harbor Press,Cold Spring Harbor,NY(2012)。或者,本文所描述的TCR、多肽以及和/或蛋白质可由各种商业实体中的任一者合成。就此而言,本发明的TCR、多肽以及蛋白质可为合成的、重组的、分离的以及和/或纯化的。
本发明的一个实施方案提供核酸,其包含编码本文所描述的TCR、多肽或蛋白质中的任一者的核苷酸序列。如本文所用的“核酸”包括“聚核苷酸”、“寡核苷酸”以及“核酸分子”,且通常意谓可为单股或双股的DNA或RNA的聚合物,其可含有天然、非天然或改变的核苷酸,且其可含有天然、非天然或改变的核苷酸间键,诸如磷酰胺酸键或硫代磷酸酯键而非未经修饰的寡核苷酸的核苷酸之间存在的磷酸二酯。在一实施例中,核酸包含互补DNA(cDNA)。通常,核酸不包含任何插入、缺失、倒位以及和/或取代是优选的。然而,在一些情况下,如本文所论述,核酸包含一或多个插入、缺失、倒位以及和/或取代是适合的。
本发明的实施方案提供分离或纯化的核酸,其自5'至3'包含第一核苷酸序列以及第二核苷酸序列,其中该第一以及第二核苷酸序列分别编码以下氨基酸序列:SEQ ID NO:8以及9;9以及8;10以及11;11以及10;12以及13;13以及12;12以及11;11以及12;121以及13;13以及121;121以及122;122以及121;8以及120;120以及8;119以及9;9以及119;119以及120;120以及119;14以及15;15以及14;16以及17;17以及16;18以及19;19以及18;27以及28;28以及27;29以及30;30以及29;31以及32;32以及31;31以及30;30以及31;125以及32;32以及125;125以及126;126以及125;27以及124;124以及27;123以及28;28以及123;123以及124;124以及123;33以及34;34以及33;35以及36;36以及35;37以及38;38以及37;46以及47;47以及46;48以及49;49以及48;50以及51;51以及50;50以及49;49以及50;129以及51;51以及129;129以及130;130以及129;46以及128;128以及46;127以及47;47以及127;127以及128;128以及127;52以及53;53以及52;54以及55;55以及54;56以及57;57以及56;65以及66;66以及65;67以及68;68以及67;69以及70;70以及69;69以及68;68以及69;133以及70;70以及133;133以及134;134以及133;65以及132;132以及65;131以及66;66以及131;131以及132;132以及131;71以及72;72以及71;73以及74;74以及73;75以及76;76以及75;84以及85;85以及84;86以及87;87以及86;88以及89;89以及88;88以及87;87以及88;137以及89;89以及137;137以及138;138以及137;84以及136;136以及84;135以及85;85以及135;135以及136;136以及135;90以及91;91以及90;92以及93;93以及92;94以及95;或95以及94。
在本发明的一个实施方案中,核酸进一步包含插入于第一与第二核苷酸序列之间的第三核苷酸序列,其中该第三核苷酸序列编码可裂解的接头肽。举例而言,可裂解的接头肽可包含氨基酸序列RAKRSGSGATNFSLLKQAGDVEENPGP(SEQ ID NO:100)。在本发明的一个实施方案中,核酸编码选自以下的氨基酸序列:SEQ ID NO:20、39、58、77以及96。举例而言,核酸可包含选自SEQ ID NO:109-113的核苷酸序列。
优选地,本发明的核酸为重组的。如本文所用,术语“重组”系指(i)通过将天然或合成的核酸片段接合至可在活细胞中复制的核酸分子而在活细胞外部构建的分子,或(ii)由上文(i)中描述的那些分子的复制产生的分子。出于本文的目的,复制可为活体外复制或活体内复制。
核酸可使用现有技术中已知的程序基于化学合成以及和/或酶连接反应进行构建。参见例如Green以及Sambrook等人,同上。举例而言,核酸可使用天然存在的核苷酸或不同地经修饰的核苷酸化学合成,所述经修饰的核苷酸经设计以增加分子的生物稳定性或增加杂交时形成的双螺旋的物理稳定性(例如,经硫代磷酸酯衍生物以及吖啶取代的核苷酸)。可用以产生核酸的经修饰核苷酸的实例包括但不限于5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、次黄嘌呤、黄嘌呤、4-乙酰胞嘧啶、5-(羧基羟甲基)尿嘧啶、5-羧甲基氨基甲基-2-硫代尿苷、5-羧甲基氨基甲基尿嘧啶、二氢尿嘧啶、β-D-半乳糖苷基Q核苷、肌苷、N6-异戊烯基腺嘌呤、1-甲基鸟嘌呤、1-甲基肌苷、2,2-二甲基鸟嘌呤、2-甲基腺嘌呤、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、经N6取代的腺嘌呤、7-甲基鸟嘌呤、5-甲氨基甲基尿嘧啶、5-甲氧基胺甲基-2-硫尿嘧啶、β-D-甘露糖苷基Q核苷、5-甲氧基羧基甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-异戊烯基腺嘌呤、尿嘧啶-5-氧基乙酸(v)、怀丁氧苷(wybutoxosine)、假尿嘧啶、Q核苷、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、尿嘧啶-5-氧基乙酸甲酯、3-(3-氨基-3-N-2-羧丙基)尿嘧啶以及2,6-二氨基嘌呤。或者,本发明的一或多种核酸可购自各种商业实体中的任一者。
在本发明的一个实施方案中,核酸包含编码本文所描述的TCR、多肽或蛋白质中的任一者的密码子最佳化核苷酸序列。不受任何特定理论或机制束缚,认为核苷酸序列的密码子最佳化增加mRNA转录物的转译效率。核苷酸序列的密码子最佳化可涉以及用另一密码子取代原生密码子,该另一密码子编码相同氨基酸但可由细胞内更容易获得的tRNA转译,因此增加转译效率。核苷酸序列的最佳化亦可减少会干扰转译的二级mRNA结构,因此增加转译效率。
本发明的一个实施方案也提供一种核酸,其包含与本文所描述的核酸中的任一者的核苷酸序列互补的核苷酸序列或在严格条件下与本文所描述的核酸中的任一者的核苷酸序列杂交的核苷酸序列。
核苷酸序列在严格条件下杂交,优选地在高严格度条件下杂交。“高严格度条件”意指以比非特异性杂交的可检测性更强的量将核苷酸序列特异性杂交至目标序列(本文所描述的核酸中的任一者的核苷酸序列)。高严格度条件包括会将具有确切互补序列的聚核苷酸,或仅含有少量分散错配的聚核苷酸与碰巧具有匹配核苷酸序列的少量小区域(例如3至10个碱基)的随机序列进行区分的条件。此类具有互补性的小区域比具有14至17个或更多个碱基的全长互补序列更易于解链,且高严格度杂交使其可易于区分。相对高严格度条件将包括例如低盐以及和/或高温条件,诸如在约50至70℃的温度下通过约0.02至0.1MNaCl或等效物提供。此类高严格度条件容许核苷酸序列与模板或目标股的间的少量(若存在)错配,且尤其适合于检测本发明的TCR中的任一者的表达。通常应了解,通过添加渐增量的甲酰胺,可使条件更严格。
本发明的一个实施方案亦提供一种核酸,其包含与本文所描述的核酸中的任一者至少约70%或更高,例如约80%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%或约99%一致的核苷酸序列。就此而言,核酸可基本上由任何本文所描述的核苷酸序列组成。
本发明的核酸可并入至重组表达载体中。就此而言,本发明的一个实施方案提供一种重组表达载体,其包含本发明的核酸中的任一者。在本发明的一个实施方案中,重组表达载体包含编码α链、β链以及接头肽的核苷酸序列。
出于本文的目的,术语“重组表达载体”意指经基因修饰的寡核苷酸或聚核苷酸构建体,当构建体包含编码mRNA、蛋白质、多肽或肽的核苷酸序列,且载体在足以使mRNA、蛋白质、多肽或肽在细胞内表达的条件下与细胞接触时,允许通过宿主细胞表达mRNA、蛋白质、多肽或肽。本发明的载体整体上不为天然存在的。然而,部分载体可为天然存在的。本发明的重组表达载体可包含任何类型的核苷酸,其包括但不限于可为单股或双股、合成的或部分自天然来源中获得且可含有天然、非天然或改变的核苷酸的DNA以及RNA。重组表达载体可包含天然存在的、非天然存在的核苷酸间键或两种类型的键。优选地,非天然存在或改变的核苷酸或核苷酸间键不阻碍载体的转录或复制。
本发明的重组表达载体可为任何适合的重组表达载体,且可用以转化或转染任何适合的宿主细胞。适合载体包括设计成用于增殖以及扩增或用于表达或用于此两者的那些载体,诸如质体以及病毒。载体可选自由以下组成的群:转座子/转位酶系列pUC系列(Fermentas Life Sciences)、pBluescript系列(Stratagene,La Jolla,CA)、pET系列(Novagen,Madison,WI)、pGEX系列(Pharmacia Biotech,Uppsala,Sweden)以及pEX系列(Clontech,Palo Alto,CA)。亦可使用噬菌体载体,诸如λGT10、λGT11、λZapII(Stratagene)、λEMBL4以及λNM1149。植物表达载体的实例包括pBI01、pBI101.2、pBI101.3、pBI121以及pBIN19(Clontech)。动物表达载体的实例包括pEUK-Cl、pMAM以及pMAMneo(Clontech)。优选地,重组表达载体为转座子或病毒载体,例如慢病毒载体或反转录病毒载体。
本发明的重组表达载体可使用描述于例如Green以及Sambrook等人,同上中的标准重组DNA技术制备。环形或线形的表达载体构建体可经制备以含有在原核或真核宿主细胞中起作用的复制系统。复制系统可来源于例如ColEl、2μ质体、λ、SV40、牛乳突状瘤病毒以及类似者。
理想地,重组表达载体包含诸如转录以及转译起始以及终止密码子的调节序列,该调节序列按需要且考虑载体是基于DNA抑或基于RNA而对将引入载体的宿主细胞类型(例如细菌、真菌、植物或动物)具有特异性。
重组表达载体可包括一或多个标记基因,其允许选择经转化或经转染宿主细胞。标记基因包括杀生物剂耐性(例如,对抗生素、重金属等具有耐性)、营养缺陷型宿主细胞中用以提供原营养的补充物以及类似者。用于本发明表达载体的适合的标记基因包括例如耐新霉素/G418基因、耐潮霉素基因、耐组胺醇基因、耐四环素基因以及耐氨苄青霉素(ampicillin)基因。
重组表达载体能够包含可操作地连接于编码TCR、多肽或蛋白质的核苷酸序列或连接于与编码TCR、多肽或蛋白质的核苷酸序列互补或杂交的核苷酸序列的天然或非天然启动子。启动子(例如强、弱、诱导性、组织特异性以及发育特异性启动子)的选择在本领域技术人员的普通技能内。类似地,核苷酸序列与启动子的组合亦在本领域技术人员的技能内。启动子可为例如人类延长因子-1α启动子的非病毒启动子,或例如巨细胞病毒(CMV)启动子的病毒启动子、SV40启动子、RSV启动子以及发现于鼠类干细胞病毒的长端重复序列中的启动子。
本发明重组表达载体可经设计用于瞬时表达、用于稳定表达或用于两者。此外,重组表达载体可经制备用于组成性表达或用于诱导性表达。
此外,重组表达载体可经制备为包括自杀基因。如本文所用,术语“自杀基因”是指使表达自杀基因的细胞死亡的基因。自杀基因可为对表达基因的细胞赋予针对药剂(例如药物)的敏感性的基因,且当细胞与药剂接触或暴露于药剂时,该基因使细胞死亡。自杀基因为现有技术中已知的,且包括例如单纯疱疹病毒(HSV)胸苷激酶(TK)基因、胞嘧啶脱胺酶、嘌呤核苷磷酸化酶以及硝基还原酶。
本发明的另一实施例提供分离或纯化的TCR、多肽或蛋白质,其由本文关于本发明的其他方面所描述的核酸或载体中的任一者编码。
本发明的另一实施例提供分离或纯化的TCR、多肽或蛋白质,其由本文关于本发明的其他方面所描述的核酸或载体中的任一者的表达产生。
本发明的另一实施例进一步提供宿主细胞,其包含本文所描述的核酸中的任一者或重组表达载体中的任一者。如本文所用,术语“宿主细胞”是指可含有本发明的重组表达载体的任何类型的细胞。宿主细胞可为真核细胞(例如植物、动物、真菌或藻类)或可为原核细胞(例如细菌或原虫)。宿主细胞可为经培养的细胞或原代细胞,亦即直接自生物体(例如人类)分离。宿主细胞可为贴壁细胞或悬浮细胞,亦即在悬浮液中生长的细胞。适合的宿主细胞为现有技术中已知的且包括例如DH5α大肠杆菌细胞、中国仓鼠卵巢细胞、猴VERO细胞、COS细胞、HEK293细胞以及其类似者。出于扩增或复制重组表达载体的目的,宿主细胞较佳为原核细胞,例如DH5α细胞。出于产生重组TCR、多肽或蛋白质的目的,宿主细胞较佳为哺乳动物细胞。最佳地,宿主细胞为人类细胞。举例而言,宿主细胞可为人类淋巴细胞。在本发明的一个实施方案中,宿主细胞系选自以下组成的群:T细胞、自然杀伤T(NKT)细胞、恒定自然杀伤T(iNKT)细胞以及自然杀伤(NK)细胞。虽然宿主细胞可为任何细胞类型,可来源于任何类型的组织,且可为任何发育阶段,但宿主细胞较佳为周边血液淋巴细胞(PBL)或周边血液单核细胞(PBMC)。更优选地,宿主细胞为T细胞。
出于本文的目的,T细胞可为任何T细胞,诸如经培养T细胞(例如原代T细胞),或来自经培养T细胞株的T细胞(例如Jurkat,SupT1等),或获自哺乳动物的T细胞。若自哺乳动物获得,则T细胞可自众多来源获得,包括但不限于血液、骨髓、淋巴结、胸腺或其他组织或体液。T细胞亦可经富集或纯化。优选地,T细胞为人类T细胞。T细胞可为任何类型的T细胞且可为任何发育阶段,其包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞(例如Th1以及Th2细胞)、CD4+T细胞、CD8+T细胞(例如细胞毒性T细胞)、肿瘤浸润性淋巴细胞(TIL)、记忆T细胞(例如中枢记忆T细胞以及效应记忆T细胞)、初始T细胞以及类似者。
本发明的一个实施方案还提供细胞群,其包含至少一种本文所描述的宿主细胞。所述细胞群可以是异质的群体,包括包含所述任何重组表达载体的宿主细胞,以及至少一个其他细胞,例如,不包含任何重组表达载体的宿主细胞(例如,T细胞),或T细胞以外的细胞,例如,B细胞、巨噬细胞、中性粒细胞、红细胞、肝细胞、内皮细胞、上皮细胞、肌肉细胞、脑细胞等。或者,细胞群可为实质上均质群,其中该群体包含主要包含重组表达载体(例如基本上由重组表达载体组成)的宿主细胞。该群体亦可为细胞的克隆群体,其中群体中的所有细胞为包含重组表达载体的单一宿主细胞的克隆,使得群体中的所有细胞包含重组表达载体。在本发明的一个实施例中,细胞群为包含宿主细胞的克隆群体,该等宿主细胞包含如本文所描述的重组表达载体。
在本发明的一个实施方案中,群体中细胞的数目可快速扩增。如例如美国专利8,034,334、美国专利8,383,099、美国专利申请公开案第2012/0244133号、Dudley等人,J.Immunother.,26:332-42(2003)以及Riddell等人,J.Immunol.Methods,128:189-201(1990)中所描述,可通过如现有技术中已知的许多方法中的任一者实现T细胞的数目的扩增。在一实施例中,通过用OKT3抗体、IL-2以及供给PBMC(例如经辐射同种异体PBMC)培养T细胞来进行T细胞的数目的扩增。
本发明的一个实施方案提供一种产生表达TCR的宿主细胞的方法,该TCR对肽DRNTFRHSVVVPCEPPEVGSDCTTI(SEQ ID NO:115)或SGNLLGRNSFEVCVCACPGRDRRTE(SEQ IDNO:117)具有抗原特异性,该方法包含使细胞与本文所描述的载体中的任一者在允许将载体引入至细胞中的条件下接触。
本发明的TCR、多肽、蛋白质、核酸、重组表达载体以及宿主细胞(包括其群体)可经分离以及和/或经纯化。如本文所用的术语“分离的”」意指已自其天然环境移除。如本文所用的术语“纯化的”经意谓纯度已增加,其中“纯度”为相对术语,且不必解释为绝对纯度。举例而言,纯度可为至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约95%或可为约100%。
本发明的TCR、多肽、蛋白质、核酸、重组表达载体以及宿主细胞(包括其群体)在下文中皆统称为“本发明的TCR物质”,其可配制为组合物,诸如药物组合物。就此而言,本发明的一个实施方案提供一种药物组合物,其包含本文所描述的TCR、多肽、蛋白质、核酸、表达载体以及宿主细胞(包括其群体)中的任一者以及药学上可接受的载体。含有本发明的TCR物质中的任一者的本发明药物组合物可包含超过一种本发明的TCR物质,例如多肽以及核酸或两种或更多种不同TCR。或者,药物组合物可包含本发明的TCR物质与另外医药活性剂或药物的组合,医药活性剂或药物诸如化学治疗剂,例如天冬酰胺酶、硫酸布他卡因(busulfan)、卡铂(carboplatin)、顺铂(cisplatin)、道诺霉素(daunorubicin)、阿霉素(doxorubicin)、氟尿嘧啶、吉西他滨(gemcitabine)、羟基脲、甲胺喋呤、太平洋紫杉醇、利妥昔单抗(rituximab)、长春碱(vinblastine)、长春新碱(vincristine)等。
优选地,载体为药学上可接受的载体。关于药物组合物,载体可为常规用于考虑中的特定本发明的TCR物质的那些载体中的任一者。用于制备可投与组合物的方法对熟习现有技术者为已知的或显而易见的且更详细地描述于例如Remington:The Science andPractice of Pharmacy,第22版,Pharmaceutical Press(2012)中。优选地,药学上可接受的载体为在使用条件下不具有有害副作用或毒性的载体。
载体的选择将部分由特定本发明的TCR物质以及用于投与本发明的TCR物质的特定方法决定。因此,存在本发明的药物组合物的多种适合调配物。适合的调配物可包括用于非经肠、皮下、静脉内、肌肉内、动脉内、鞘内、瘤内或腹膜内投与的那些调配物中的任一者。可使用超过一种途径来投与本发明的TCR物质,且在某些情况下,特定途径可提供比另一种途径更直接且更有效的反应。
优选地,本发明的TCR物质系通过注射(例如经静脉内注射)投与。当本发明的TCR物质为表达本发明的TCR的宿主细胞时,用于注射的细胞的药学上可接受的载体可包括任何等张载体,诸如标准生理盐水(约0.90%w/v的NaCl于水中、约300mOsm/L NaCl于水中或每公升水约9.0g NaCl)、NORMOSOL R电解质溶液(Abbott,Chicago,IL)、PLASMA-LYTE A(Baxter,Deerfield,IL)、约5%右旋糖于水中或林格氏乳酸盐(Ringer's lactate)。在一实施例中,药学上可接受的载体补充有人类血清蛋白。
施用的本发明的TCR物质的量或剂量(例如当本发明的TCR物质为一或多种细胞时,为细胞的数目)应足以在合理时段内在个体或动物中实现例如治疗性或预防性反应。举例而言,本发明的TCR物质的剂量应足以在自施用的时间起约2小时或更长(例如12至24或更多个小时)的时段中结合于癌症抗原(例如突变p53),或检测、治疗或预防癌症。在某些实施例中,该时段可更长。剂量将由特定的本发明的TCR物质的功效以及待治疗的动物(例如人类)的病况以及动物(例如人类)的体重决定。
用于确定施用剂量的许多分析为现有技术中已知的。举例而言,可使用分析来测定待向哺乳动物施用的起始剂量,该分析包括在向哺乳动物施用给定剂量的所述T细胞后(一组哺乳动物中各自被施用不同剂量的T细胞)比较靶细胞被裂解的程度或表达本发明的TCR、多肽或蛋白质的T细胞分泌IFN-γ的程度。在施用一定剂量后靶细胞裂解或IFN-γ分泌的程度可通过本领域已知的方法进行测定。
本发明的TCR物质的剂量也由可能伴随特定的本发明的TCR物质的施用的任何不良副作用的存在、性质以及程度决定。通常,主治医师将考虑多种诸如年龄、体重、一般健康状况、膳食、性别、待施用的本发明的TCR物质、施用途径以及所治疗癌症的严重程度的因素来决定用以治疗各个别患者的本发明的TCR物质的剂量。在本发明的TCR物质为细胞群的一实施例中,每次输注施用的细胞的数目可例如自约1×106至约1×1012个细胞或更多变化。在某些实施例中,可施用少于1×106个细胞。
本领域普通技术人员将容易了解本发明的TCR物质可以多种方式进行修饰,使得通过修饰来提高本发明的TCR物质的治疗或预防功效。举例而言,本发明的TCR物质可直接地或间接地经由桥键与化学治疗剂结合。将化合物与化学治疗剂结合的实践为现有技术中已知。本领域普通技术人员认识到,本发明的TCR物质上对于本发明的TCR物质的功能并非必需的位点为理想地用于连接桥键以及和/或化学治疗剂的位点,其条件为桥键以及和/或化学治疗剂在连接至本发明的TCR物质后不干扰本发明的TCR物质的功能,亦即结合于突变p53或检测、治疗或预防癌症的能力。
考虑本发明的药物组合物、TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞以及细胞群可用于治疗或预防癌症的方法中。不受特定理论的束缚,认为本发明的TCR特异性结合于突变p53,使得TCR(或相关的本发明多肽或蛋白质)在由细胞表达时,能够介导针对表达突变的p53的靶细胞的免疫反应。就此而言,本发明的一个实施方案提供一种治疗或预防哺乳动物的癌症的方法,其包含以可有效治疗或预防哺乳动物的癌症的量向哺乳动物施用本文所描述的药物组合物、TCR、多肽或蛋白质中的任一者,包含编码本文所描述的TCR、多肽、蛋白质中的任一者的核苷酸序列的任何核酸或重组表达载体,或包含编码本文所描述的TCR、多肽或蛋白质中的任一者的重组载体的任何宿主细胞或细胞群。
本发明的一个实施方案提供用于治疗或预防哺乳动物的癌症的本文所描述的药物组合物、TCR、多肽或蛋白质中的任一者,包含编码本文所描述的TCR、多肽、蛋白质中的任一者的核苷酸序列的任何核酸或重组表达载体,或包含编码本文所描述的TCR、多肽或蛋白质中的任一者的重组载体的任何宿主细胞或细胞群。
如本文所用,术语“治疗”以及“预防”以及自其衍生的字语不一定暗示100%或完全治疗或预防。实际上,本领域普通技术人员识别为具有潜在益处或治疗作用的治疗或预防存在变化的程度。就此而言,本发明方法可提供任何量的对哺乳动物的癌症的任何程度的治疗或预防。此外,通过本发明方法提供的治疗或预防可包括治疗或预防所治疗或预防的癌症的一或多种病况或症状。举例而言,治疗或预防可包括促进肿瘤的消退。另外,出于本文的目的,“预防”可涵盖延缓癌症或其症状或病况的发作。或者或另外地,“预防”可涵盖预防或延缓癌症或其症状或病况的复发。
亦考虑本发明药物组合物、TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞以及细胞群可用于诱导针对哺乳动物的癌症的免疫反应的方法中。就此而言,本发明的一个实施方案提供诱导针对哺乳动物的癌症的免疫反应的方法,其包含以可有效诱导针对哺乳动物的癌症的免疫反应的量向哺乳动物施用本文所描述的药物组合物、TCR、多肽或蛋白质中的任一者,包含编码本文所描述的TCR、多肽、蛋白质中的任一者的核苷酸序列的任何核酸或重组表达载体,或包含编码本文所描述的TCR、多肽或蛋白质中的任一者的重组载体的任何宿主细胞或细胞群。
本发明的一个实施方案提供本文所描述的药物组合物、TCR、多肽或蛋白质中的任一者,包含编码本文所描述的TCR、多肽、蛋白质中的任一者的核苷酸序列的任何核酸或重组表达载体,或包含编码本文所描述的TCR、多肽或蛋白质中的任一者的重组载体的任何宿主细胞或细胞群,其用于诱导针对哺乳动物的癌症的免疫反应。
本发明的一个实施方案亦提供一种检测哺乳动物中癌症的存在的方法。该方法包含:(i)将包含来自哺乳动物的一或多个细胞的样本与本文所描述的本发明的TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞、细胞群或药物组合物中的任一者进行接触,由此形成复合物;以及(ii)检测所述复合物,其中复合物的检出指示哺乳动物中癌症的存在。
关于检测哺乳动物的癌症的本发明方法,细胞的样本可为包含全细胞、其裂解产物,或全细胞裂解产物的一部分(例如核或细胞质部分、全蛋白部分或核酸部分)的样本。
出于本发明检测方法的目的,关于哺乳动物,接触可活体外或活体内进行。优选地,接触系在活体外。
此外,复合物的检测可经由现有技术中已知的许多方式进行。举例而言,可用可检测标记来标记本文所描述的本发明的TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞或细胞群,该可检测标记诸如放射性同位素、萤光团(例如异硫氰酸萤光素(FITC)、藻红素(PE))、酶(例如碱性磷酸酶、辣根过氧化酶)以及元素粒子(例如金粒子)。
出于本发明方法的目的,其中施用宿主细胞或细胞群,细胞可为对于哺乳动物而言同种异体或自体的细胞。优选地,细胞为对于哺乳动物而言自体的。
关于本发明方法,癌症可为任何癌症,包括例如急性淋巴细胞性癌症、急性骨髓性白血病、齿槽横纹肌肉瘤、骨癌、脑癌、乳腺癌、肛门癌、肛管癌或肛肠癌、眼癌、肝内胆管癌、关节癌、颈癌、胆囊癌或胸膜癌、鼻癌、鼻腔癌或中耳癌、口腔癌、阴道癌、外阴癌、慢性淋巴细胞性白血病、慢性骨髓癌、结肠癌、大肠直肠癌、子宫内膜癌、食道癌、子宫颈癌、胃肠类癌瘤、神经胶质瘤、霍奇金氏淋巴瘤(Hodgkin lymphoma)、下咽癌、肾脏癌、喉癌、肝癌、肺癌、恶性间皮瘤、黑色素瘤、多发性骨髓瘤、鼻咽癌、非霍奇金氏淋巴瘤、口咽癌、卵巢癌、阴茎癌、胰脏癌、腹膜癌、网膜癌以及肠系膜癌、咽癌、前列腺癌、直肠癌、肾癌、皮肤癌、小肠癌、软组织癌、胃癌、睾丸癌、甲状腺癌、子宫癌、尿管癌以及膀胱癌中的任一者。在一优选的实施例中,癌症为表达突变p53的癌症。癌症可表达在如由SEQ ID NO:1所定义的位置273以及220中的一者或两者处含有突变的p53。癌症可表达具有以下人类p53突变中的一者或两者的p53:R273C以及Y220C。在本发明的一个实施方案中,癌症为上皮癌。在本发明的一个实施方案中,癌症为胆管癌、黑色素瘤、结肠癌、直肠癌、卵巢癌、子宫内膜癌、非小细胞肺癌(NSCLC)、胶质母细胞瘤、子宫颈癌、头颈癌、乳腺癌、胰脏癌或膀胱癌。可已知癌症包含人类p53中的R273C或Y220C突变。
本发明方法中提以及的哺乳动物可为任何哺乳动物。如本文所用,术语「哺乳动物」系指任何哺乳动物,包括但不限于啮齿目的哺乳动物(诸如小鼠以及仓鼠)以及兔形目的哺乳动物(诸如兔)。优选地,哺乳动物来自食肉目,包括猫科动物(猫)以及犬科动物(狗)。更优选地,哺乳动物来自偶蹄目,包括牛科动物(奶牛)以及猪科动物(猪);或奇蹄目,包括马科动物(马)。最佳地,哺乳动物为灵长目、猿目或猴目(猴)或类人猿目(人类以及猿)。尤佳的哺乳动物为人类。
以下实施例进一步说明本发明,但当然不应解释为以任何方式限制本发明的范围。
实施例1
此实施例展现患者4343的TIL中抗p53-Y220C T细胞反应性的鉴别。
将从患有激素阳性、HER2阳性转移性乳腺癌的患者4343切除的肿瘤切成23个碎片且在细胞介素IL-2存在下培养以使TIL离体生长。通过与用DMSO(溶媒)或突变p53-Y220C肽DRNTFRHSVVVPCEPPEVGSDCTTI(SEQ ID NO:115)脉冲的自体树突状细胞共培养来检测碎片(编号为F1至F7以及F9至F24)的肿瘤特异性新生抗原反应性,包括突变的p53。通过ELISpot分析测量IFN-γ产生。结果展示于图1A中。鉴别出编号为F2、F3、F11、F21以及F23的碎片含有识别p53-Y220C的TIL。
实施例2
此实施例展现患者4386的TIL中抗p53-R273C T细胞反应性的鉴别。
将从患者4386的左乳房腋下淋巴结切除的肿瘤切成24个碎片且在细胞介素IL-2存在下培养以使TIL离体生长。通过与用DMSO(溶媒)或突变p53-R273C肽SGNLLGRNSFEVCVCACPGRDRRTE(SEQ ID NO:117)脉冲的自体树突状细胞共培养来测试碎片(编号为F1至F24)的肿瘤特异性新生抗原反应性,包括突变p53。通过ELISpot分析测量IFN-γ产生。结果展示于图1B中。鉴别出编号为F7碎片含有识别p53-R273C的TIL。
基于CD3以及一或多种细胞表面标记物CD4、CD8、CD39、PD-1以及TIGIT的表达来分选来自患者4386的新鲜肿瘤消化物(肿瘤1A或肿瘤1B)的T细胞。使经分选细胞群扩增且针对突变p53-R273C肽或DMSO测试反应性。通过ELISpot分析测量IFN-γ产生。结果展示于图1C中。鉴别出来自肿瘤1A的两个细胞群含有识别p53-R273C:CD3+CD4+CD39+PD-1+TIGIT+以及CD3+CD4+CD39+PD-1+TIGIT-的T细胞。
对来自患者4386的TIL进行活体外敏化以富集新生抗原反应性T细胞,接着针对DMSO或突变p53-R273C肽进行测试。通过流式细胞测量术测量T细胞活化标记物4-1BB以及OX40。结果展示于图1D中。
实施例3
此实施例展现抗p53-Y220C TCR与实施例1的反应性TIL的分离。
反应性TIL被再刺激且通过4-1BB上调而分选至96孔培养盘中以供单细胞T细胞受体(TCR)测序。发现TCR,亦即4343-DTCR(TRAV12-3/TRBV27)。
通过单细胞TCR测序鉴别TCRα以及β链可变区的序列。α以及β链可变区的氨基酸序列展示于表3中。CDR加下划线。N端信号肽呈粗体字。
表3
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实施例4
此实施例展现抗p53-R273C TCR与实施例2的反应性TIL的分离。
反应性TIL被再刺激且通过4-1BB上调而分选至96孔培养盘中以供单细胞T细胞受体(TCR)测序。发现四种TCR,即4386-F TCR(TRAV13-2/TRBV4-3)、4386-G TCR(TRAV3/TRBV20-1)、4386-H TCR(TRAV23/TRBV7-2)以及4386-O TCR(TRAV13-2/TRBV7-3)。
通过单细胞TCR测序鉴别TCRα以及β链可变区的序列。α以及β链可变区的氨基酸序列展示于表4中。CDR加下划线。N端信号肽呈粗体字。
表4
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实施例5
此实施例展现实施例3至4的编码各自TCR的反转录病毒载体的构建。
获得编码表3至4的的TCR的α以及β链的可变区的核苷酸序列,且进行密码子最优化。使TCRβVDJ区与小鼠TCRβ恒定链融合。使TCRαVJ区与小鼠TCRα恒定链融合。不受特定理论或机制束缚,认为用对应鼠类恒定区置换人类TCRα以及TCRβ链的恒定区可改良TCR表达以及功能性(Cohen等人,Cancer Res.,66(17):8878-86(2006))。
另外,鼠类TCRα以及TCRβ恒定链经半胱氨酸修饰。将跨膜疏水性突变引入至鼠类TCRα恒定链中。不受特定理论或机制束缚,认为这些修饰使得所引入的TCR链优先配对且TCR表面表达以及功能增强(Cohen等人,Cancer Res.,67(8):3898-903(2007);Haga-Friedman等人,J.Immu.,188:5538-5546(2012))。
为了促进将TCR表达盒克隆至MSGV1载体5'NcoI位点中,且为了引入Kozak序列,将TCRVα链的N端信号肽中的第二氨基酸变成组氨酸(H),且将TCRVβ链的N端信号肽中的第二氨基酸变成丙氨酸(A)。
五个TCR中的每一者的全长α以及β链,包括对恒定区的这些修饰,展示于表5中。在表5中,CDR加下划线,恒定区呈斜体字,且恒定区的经修饰氨基酸残基加下划线且呈粗体。
表5
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将编码表5的的TCR的α以及β链的可变区的核苷酸序列克隆至具有以下表达盒构型的基于MSGV1的反转录病毒载体中:5'NcoI-VDJβ-mCβ-弗林蛋白酶(Furin)/SerGly/P2A-VJα-mCα-EcoRI3'。
TCRβ链以及TCRα链通过弗林蛋白酶Ser/Gly P2A接头RAKRSGSGATNFSLLKQAGDVEENPGP(SEQ ID NO:100)分开。不受特定理论或机制束缚,认为该接头为两条链提供相当的表达效率(Szymczak等人,Nat.Biotechnol.,22(5):589-94(2004))。
反转录病毒载体的TCR表达盒自5'至3'编码通过接头分开的TCRβ以及TCRα链。TCR表达盒的核苷酸序列展示于表6中。
表6
由各各别TCR表达卡匣编码的氨基酸序列展示于表7中。在表7中,CDR加底线,恒定区呈斜体,且连接子以粗体展示。
表7
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实施例6
此实施例展现由实施例5的反转录病毒载体表达的抗p53-Y220C TCR的亲合力。
同种异体PBL独立地被实施例5的编码4343-D TCR的反转录病毒载体转导。以图3A中所示的多种浓度中的一种用突变p53-Y220C 25-mer肽DRNTFRHSVVVPCEPPEVGSDCTTI(SEQID NO:115)或对应WT 25-mer肽DRNTFRHSVVVPYEPPEVGSDCTTI(SEQ ID NO:114)对自体DC脉冲两小时。将细胞洗涤两次且以1:1的比率与经转导T细胞共培养16小时。通过ELISpot分析测量IFN-γ分泌。如图3A中所示,经TCR转导的细胞展现用p53-Y220C 25-mer肽脉冲的DC的特异性以及亲合识别。
不受特定理论或机制束缚,认为存在于WT 25-mer肽(SEQ ID NO:114)以及突变的p53 Y220C 25-mer肽(SEQ ID NO:115)中的半胱氨酸残基可能易于氧化以及均二聚化,可最终导致T细胞效力降低(Sachs等人,J.Immunol.,205(2):539-549(2020))。Y220C突变自身引入另一半胱氨酸残基。假设另一半胱氨酸残基可影响TCR对突变肽的识别。
通过将野生型肽以及突变肽两者的原始序列中的半胱氨酸残基全部修饰成不再易于氧化或二聚化的AABA来测试此假设。经修饰的肽展示于表8中。
表8
同种异体PBL独立地用实施例5的编码4343-D TCR的反转录病毒载体转导。以图3B至图3C中所示的各种浓度中的一种用含有AABA取代的突变p53-Y220C 25-mer肽(SEQ IDNO:151)或含有AABA取代的对应WT 25-mer肽(SEQ ID NO:150)对自体B细胞脉冲两小时。将细胞洗涤两次且以1:1的比率与经转导的T细胞共培养16小时。通过流式细胞测量术,通过测量鼠类TCR恒定区阳性细胞中T细胞活化标记物4-1BB的上调来测试反应性。
如图3B至图3C中所示,结果验证上文所描述的此实施例中的假设。观测到相对于含有AABA取代的对应WT 25-mer肽,含有AABA取代的突变p53-Y220C 25-mer肽具有对数或更大TCR效力。
实施例7
此实施例展现由实施例5的反转录病毒载体表达的抗p53-R273C TCR的亲合力。
同种异体PBL独立地用实施例5的编码4386-F TCR、4386-G TCR、4386-H TCR或4386-O TCR的反转录病毒载体转导。以图3D至图3G中所示的多种浓度中的一种用p53-R273C 25-mer肽SGNLLGRNSFEVCVCACPGRDRRTE(SEQ ID NO:117)或对应WT 25-mer肽SGNLLGRNSFEVRVCACPGRDRRTE(SEQ ID NO:116)对自体DC脉冲两小时。将细胞洗涤两次且以1:1的比率与经转导的T细胞共培养16小时。通过ELISA测量IFN-γ分泌(图3D至图3G)。如图3D至图3G中所示,经TCR转导的细胞对用突变p53-R273C 25-mer肽脉冲的DC显示出特异性以及亲合识别。
实施例8
此实施例展现由实施例5的反转录病毒载体表达的抗p53-Y220C TCR识别由HLA-DRB3*02/HLA-DRA1*01异二聚体的呈递的突变p53。
使用外显子体以及mRNA测序来测定由患者4343表达的II类MHC分子。所表达的II类MHC分子展示于图2A中。
效应细胞为经实施例5的编码4343-D TCR的反转录病毒载体转导的同种异体PBL。靶细胞为COS7细胞,其独立地用图2A中所示的II类HLA异二聚体中的一种转染且用p53-Y220C 25-mer肽DRNTFRHSVVVPCEPPEVGSDCTTI(SEQ ID NO:115)脉冲。
通过流式细胞测量术,通过测量鼠类TCR恒定区阳性细胞中T细胞活化标记物4-1BB的上调来测试反应性。结果展示于图2A中。如图2A中所示,仅在将经4343-D TCR转导的细胞与已经用编码HLA-DRA1*01:01:01/HLA-DRB3*02:02:01异二聚体的核苷酸序列转导的负载p53-Y220C 25-mer的靶细胞共培养后,观测到反应性。
实施例9
此实施例展现实施例2的TIL识别由HLA-DPB1*04:02/HLA-DPA1*01异二聚体呈递的突变p53。
使用外显子体以及mRNA测序来测定由患者4386表达的II类MHC分子。所表达的II类MHC分子展示于图2B中。
效应细胞为含有实施例2中所鉴别的识别p53-R273C的T细胞的TIL。靶细胞为COS7细胞,其独立地用图2B中展示的II类HLA异二聚体中的一种转染且用p53-R273C 25-mer肽SGNLLGRNSFEVCVCACPGRDRRTE(SEQ ID NO:117)脉冲。
通过流式细胞测量术,通过测量CD3阳性细胞中T细胞活化标记物4-1BB的上调来测试反应性。结果展示于图2B中。如图2B中所示,仅在将TIL与已经用编码HLA-DPA1*01:03/HLA-DPB1*04:02异二聚体的核苷酸序列转导的负载p53-R273C 25-mer的靶细胞共培养后,观测到反应性。
本文所引用的所有参考文献(包括出版物、专利申请以及专利)以引用的方式并入本文中,其引用程度就如同各参考文献被单独地以及特定地指出以引用的方式整体并入并阐述。
除非本文另有指示或明显与上下文矛盾,否则在描述本发明的上下文中(尤其在随后权利要求书的上下文中),使用术语“一个”、“一种”、“该”以及“至少一个”以及类似提及物应解释为涵盖单数以及复数两者。除非本文另有指示或明显与上下文矛盾,否则使用接一或多个项目的清单的术语“至少一个”(例如“A以及B中的至少一者”)应解释为意谓选自所列项目的一个项目(A或B)或所列项目中的两者或更多者的任何组合(A以及B)。除非另外指出,否则术语“包含”、“具有”、“包括”以及“含有”应理解为开放式术语(亦即,意味着“包括但不限于”)。除非本文另有指示,否则本文的值范围的列举仅意欲充当个别地提以及属于该范围内的各独立值的简写方法,且各独立值并入至本说明书中,如同在本文中单独列举一般。除非本文另有指示或以其他方式明显与上下文相矛盾,否则本文所描述的所有方法可以任何适合的次序执行。除非另有主张,否则使用本文所提供的任何以及所有实施例或例示性语言(例如,“诸如”)仅意欲优选地阐明本发明而不对本发明的范畴造成限制。本说明书中的语言不应理解为指示实践本发明所必需的任何未主张要素。
本文描述本发明的优选的实施例,其包括本发明者已知用于进行本发明的最佳模式。在阅读前述描述之后,那些优选的实施例的变化形式对于本领域技术人员可变得显而易见。本发明人期望本领域技术人员适当时采用这些变化形式,且本发明人意欲以不同于本文中特定描述的其他方式来实施本发明。因此,若适用法律准许,则本发明包括在随附于本文的申请专利范围中所叙述的主题的所有修改以及等效物。此外,除非本文另有指示或以其他方式明显与上下文矛盾,否则本发明涵盖上文所描述的要素以其所有可能变化形式的任何组合。
序列表
<110> 美国卫生和人力服务部
<120> 识别P53中R273C或Y220C突变的T细胞受体
<130> 757042
<150> US 63/074,747
<151> 2020-09-04
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Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr
115 120 125
Val His Pro
130
<210> 13
<211> 131
<212> PRT
<213> 智人 (Homo sapiens)
<400> 13
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu
115 120 125
Ser Ile Leu
130
<210> 14
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 14
Met His Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr
115 120 125
Val His Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
130 135 140
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
165 170 175
Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
180 185 190
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
195 200 205
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
210 215 220
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 15
<211> 304
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 15
Met Ala Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu
115 120 125
Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
195 200 205
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
210 215 220
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
225 230 235 240
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
245 250 255
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
260 265 270
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
275 280 285
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 16
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 16
Met Met Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr
115 120 125
Val His Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
130 135 140
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
165 170 175
Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
180 185 190
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
195 200 205
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
210 215 220
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 17
<211> 304
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 17
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu
115 120 125
Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
195 200 205
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
210 215 220
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
225 230 235 240
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
245 250 255
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
260 265 270
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
275 280 285
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 18
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 18
Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu
1 5 10 15
Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln
20 25 30
Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu
35 40 45
Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala
50 55 60
Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser
65 70 75 80
Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly
85 90 95
Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro Asn Ile
100 105 110
Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln
115 120 125
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val
130 135 140
Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu
145 150 155 160
Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser
165 170 175
Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala
180 185 190
Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys
195 200 205
Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile
210 215 220
Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
225 230 235 240
Thr Leu Arg Leu Trp Ser Ser
245
<210> 19
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 19
Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly Lys Lys
1 5 10 15
Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met Ser Trp
20 25 30
Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr Ser Met
35 40 45
Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr Lys Val
50 55 60
Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser Pro Ser
65 70 75 80
Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Phe Ile Ser Asn
85 90 95
Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu Glu Asp
100 105 110
Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys
115 120 125
Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg
130 135 140
Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys
145 150 155 160
Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser
165 170 175
Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe
180 185 190
Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly
195 200 205
Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr
210 215 220
Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr
225 230 235 240
Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu
245 250 255
Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu
260 265 270
Val Val Met Ala Met Val Lys Arg Lys Asn Ser
275 280
<210> 20
<211> 599
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 20
Met Ala Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu
115 120 125
Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
195 200 205
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
210 215 220
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
225 230 235 240
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
245 250 255
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
260 265 270
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
275 280 285
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
305 310 315 320
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Lys Ser Leu
325 330 335
Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser Trp Val Trp Ser
340 345 350
Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu
355 360 365
Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln
370 375 380
Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu
385 390 395 400
Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala
405 410 415
Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser
420 425 430
Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly
435 440 445
Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro Asn Ile
450 455 460
Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln
465 470 475 480
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val
485 490 495
Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu
500 505 510
Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser
515 520 525
Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala
530 535 540
Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys
545 550 555 560
Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile
565 570 575
Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
580 585 590
Thr Leu Arg Leu Trp Ser Ser
595
<210> 21
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 21
Asn Ser Ala Ser Asp Tyr
1 5
<210> 22
<211> 7
<212> PRT
<213> 智人 (Homo sapiens)
<400> 22
Ile Arg Ser Asn Met Asp Lys
1 5
<210> 23
<211> 12
<212> PRT
<213> 智人 (Homo sapiens)
<400> 23
Cys Ala Glu Lys Ser Thr Gly Asn Gln Phe Tyr Phe
1 5 10
<210> 24
<211> 5
<212> PRT
<213> 智人 (Homo sapiens)
<400> 24
Leu Gly His Asn Ala
1 5
<210> 25
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 25
Tyr Ser Leu Glu Glu Arg
1 5
<210> 26
<211> 14
<212> PRT
<213> 智人 (Homo sapiens)
<400> 26
Cys Ala Ser Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe
1 5 10
<210> 27
<211> 110
<212> PRT
<213> 智人 (Homo sapiens)
<400> 27
Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp
1 5 10 15
Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe
20 25 30
Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp
35 40 45
Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu
50 55 60
Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln
65 70 75 80
Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly Asn
85 90 95
Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro
100 105 110
<210> 28
<211> 114
<212> PRT
<213> 智人 (Homo sapiens)
<400> 28
Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met Gly Met
1 5 10 15
Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His Asn Ala
20 25 30
Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu Met Phe
35 40 45
Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro Ser Arg
50 55 60
Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His Leu His
65 70 75 80
Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg
85 90 95
Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
100 105 110
Val Leu
<210> 29
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 29
Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr
115 120 125
Val Ile Pro
130
<210> 30
<211> 132
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 30
Met Ala Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His
35 40 45
Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu
50 55 60
Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His
85 90 95
Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu
130
<210> 31
<211> 131
<212> PRT
<213> 智人 (Homo sapiens)
<400> 31
Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr
115 120 125
Val Ile Pro
130
<210> 32
<211> 132
<212> PRT
<213> 智人 (Homo sapiens)
<400> 32
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His
35 40 45
Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu
50 55 60
Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His
85 90 95
Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu
130
<210> 33
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 33
Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr
115 120 125
Val Ile Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
130 135 140
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
165 170 175
Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
180 185 190
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
195 200 205
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
210 215 220
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 34
<211> 305
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 34
Met Ala Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His
35 40 45
Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu
50 55 60
Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His
85 90 95
Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn
290 295 300
Ser
305
<210> 35
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 35
Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr
115 120 125
Val Ile Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
130 135 140
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
165 170 175
Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
180 185 190
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
195 200 205
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
210 215 220
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 36
<211> 305
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 36
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His
35 40 45
Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu
50 55 60
Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His
85 90 95
Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn
290 295 300
Ser
305
<210> 37
<211> 247
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 37
Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp
1 5 10 15
Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe
20 25 30
Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp
35 40 45
Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu
50 55 60
Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln
65 70 75 80
Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly Asn
85 90 95
Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro Asn Ile
100 105 110
Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln
115 120 125
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val
130 135 140
Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu
145 150 155 160
Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser
165 170 175
Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala
180 185 190
Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys
195 200 205
Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile
210 215 220
Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
225 230 235 240
Thr Leu Arg Leu Trp Ser Ser
245
<210> 38
<211> 287
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 38
Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met Gly Met
1 5 10 15
Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His Asn Ala
20 25 30
Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu Met Phe
35 40 45
Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro Ser Arg
50 55 60
Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His Leu His
65 70 75 80
Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg
85 90 95
Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
100 105 110
Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
115 120 125
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
130 135 140
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
145 150 155 160
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
165 170 175
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
180 185 190
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
195 200 205
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
210 215 220
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
225 230 235 240
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
245 250 255
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
260 265 270
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
275 280 285
<210> 39
<211> 600
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 39
Met Ala Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His
35 40 45
Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu
50 55 60
Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His
85 90 95
Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser
130 135 140
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
180 185 190
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
225 230 235 240
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser
260 265 270
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
275 280 285
Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn
290 295 300
Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
305 310 315 320
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Gly Ile
325 330 335
Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp Trp Val Ser Arg
340 345 350
Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly
355 360 365
Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr
370 375 380
Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile
385 390 395 400
Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val
405 410 415
Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr
420 425 430
Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly
435 440 445
Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro Asn
450 455 460
Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser
465 470 475 480
Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn
485 490 495
Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val
500 505 510
Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp
515 520 525
Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn
530 535 540
Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu
545 550 555 560
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val
565 570 575
Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu
580 585 590
Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 40
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 40
Val Ser Gly Asn Pro Tyr
1 5
<210> 41
<211> 8
<212> PRT
<213> 智人 (Homo sapiens)
<400> 41
Tyr Ile Thr Gly Asp Asn Leu Val
1 5
<210> 42
<211> 16
<212> PRT
<213> 智人 (Homo sapiens)
<400> 42
Cys Ala Val Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe
1 5 10 15
<210> 43
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 43
Asp Phe Gln Ala Thr Thr
1 5
<210> 44
<211> 7
<212> PRT
<213> 智人 (Homo sapiens)
<400> 44
Ser Asn Glu Gly Ser Lys Ala
1 5
<210> 45
<211> 15
<212> PRT
<213> 智人 (Homo sapiens)
<400> 45
Cys Ser Ala Ile Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe
1 5 10 15
<210> 46
<211> 115
<212> PRT
<213> 智人 (Homo sapiens)
<400> 46
Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly Asn
1 5 10 15
Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr Leu
20 25 30
Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu Lys
35 40 45
Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu Ala
50 55 60
Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser Ala
65 70 75 80
Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro Thr
85 90 95
Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys
100 105 110
Val Leu Ala
115
<210> 47
<211> 116
<212> PRT
<213> 智人 (Homo sapiens)
<400> 47
Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr
1 5 10 15
Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met
20 25 30
Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr
35 40 45
Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp
50 55 60
Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val
65 70 75 80
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile
85 90 95
Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg
100 105 110
Leu Leu Val Leu
115
<210> 48
<211> 135
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 48
Met His Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser
1 5 10 15
Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val
20 25 30
Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly
35 40 45
Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln
50 55 60
Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys
85 90 95
Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val
100 105 110
Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly
115 120 125
Thr Arg Leu Lys Val Leu Ala
130 135
<210> 49
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 49
Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala
1 5 10 15
Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser
20 25 30
Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe
35 40 45
Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser
50 55 60
Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys
65 70 75 80
Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr
85 90 95
Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg
100 105 110
Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Leu Val Leu
130
<210> 50
<211> 135
<212> PRT
<213> 智人 (Homo sapiens)
<400> 50
Met Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser
1 5 10 15
Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val
20 25 30
Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly
35 40 45
Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln
50 55 60
Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys
85 90 95
Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val
100 105 110
Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly
115 120 125
Thr Arg Leu Lys Val Leu Ala
130 135
<210> 51
<211> 131
<212> PRT
<213> 智人 (Homo sapiens)
<400> 51
Met Leu Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala
1 5 10 15
Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser
20 25 30
Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe
35 40 45
Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser
50 55 60
Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys
65 70 75 80
Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr
85 90 95
Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg
100 105 110
Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Leu Val Leu
130
<210> 52
<211> 272
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 52
Met His Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser
1 5 10 15
Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val
20 25 30
Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly
35 40 45
Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln
50 55 60
Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys
85 90 95
Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val
100 105 110
Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly
115 120 125
Thr Arg Leu Lys Val Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val
130 135 140
Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe
145 150 155 160
Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly
165 170 175
Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser
180 185 190
Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys
195 200 205
Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val
210 215 220
Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn
225 230 235 240
Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu
245 250 255
Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 53
<211> 304
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 53
Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala
1 5 10 15
Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser
20 25 30
Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe
35 40 45
Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser
50 55 60
Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys
65 70 75 80
Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr
85 90 95
Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg
100 105 110
Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
195 200 205
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
210 215 220
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
225 230 235 240
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
245 250 255
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
260 265 270
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
275 280 285
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 54
<211> 272
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 54
Met Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser
1 5 10 15
Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val
20 25 30
Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly
35 40 45
Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln
50 55 60
Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys
85 90 95
Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val
100 105 110
Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly
115 120 125
Thr Arg Leu Lys Val Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val
130 135 140
Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe
145 150 155 160
Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly
165 170 175
Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser
180 185 190
Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys
195 200 205
Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val
210 215 220
Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn
225 230 235 240
Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu
245 250 255
Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 55
<211> 304
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 55
Met Leu Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala
1 5 10 15
Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser
20 25 30
Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe
35 40 45
Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser
50 55 60
Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys
65 70 75 80
Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr
85 90 95
Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg
100 105 110
Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
195 200 205
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
210 215 220
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
225 230 235 240
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
245 250 255
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
260 265 270
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
275 280 285
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 56
<211> 252
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 56
Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly Asn
1 5 10 15
Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr Leu
20 25 30
Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu Lys
35 40 45
Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu Ala
50 55 60
Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser Ala
65 70 75 80
Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro Thr
85 90 95
Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys
100 105 110
Val Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
115 120 125
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
130 135 140
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
145 150 155 160
Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
165 170 175
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
180 185 190
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
195 200 205
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
210 215 220
Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
225 230 235 240
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
245 250
<210> 57
<211> 289
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 57
Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr
1 5 10 15
Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met
20 25 30
Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr
35 40 45
Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp
50 55 60
Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val
65 70 75 80
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile
85 90 95
Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg
100 105 110
Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser
115 120 125
Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr
130 135 140
Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser
145 150 155 160
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro
165 170 175
Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu
180 185 190
Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys
195 200 205
Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly
210 215 220
Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg
225 230 235 240
Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser
245 250 255
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
260 265 270
Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn
275 280 285
Ser
<210> 58
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 58
Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala
1 5 10 15
Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser
20 25 30
Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe
35 40 45
Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser
50 55 60
Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys
65 70 75 80
Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr
85 90 95
Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg
100 105 110
Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
130 135 140
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
180 185 190
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
195 200 205
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
210 215 220
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
225 230 235 240
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
245 250 255
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
260 265 270
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
275 280 285
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
305 310 315 320
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Ser Ala Pro
325 330 335
Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser Gly Leu Arg Ala Gln
340 345 350
Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly Asn Pro
355 360 365
Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr Leu Phe
370 375 380
Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu Lys Tyr
385 390 395 400
Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu Ala Glu
405 410 415
Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser Ala Leu
420 425 430
Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro Thr Val
435 440 445
Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val
450 455 460
Leu Ala Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
465 470 475 480
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
485 490 495
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
500 505 510
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
515 520 525
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
530 535 540
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
545 550 555 560
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
565 570 575
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 59
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 59
Asn Thr Ala Phe Asp Tyr
1 5
<210> 60
<211> 7
<212> PRT
<213> 智人 (Homo sapiens)
<400> 60
Ile Arg Pro Asp Val Ser Glu
1 5
<210> 61
<211> 14
<212> PRT
<213> 智人 (Homo sapiens)
<400> 61
Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe
1 5 10
<210> 62
<211> 5
<212> PRT
<213> 智人 (Homo sapiens)
<400> 62
Ser Gly His Thr Ala
1 5
<210> 63
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 63
Phe Gln Gly Asn Ser Ala
1 5
<210> 64
<211> 14
<212> PRT
<213> 智人 (Homo sapiens)
<400> 64
Cys Ala Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe
1 5 10
<210> 65
<211> 120
<212> PRT
<213> 智人 (Homo sapiens)
<400> 65
Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val Lys Gln Ser Pro Gln
1 5 10 15
Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile Ile Asn Cys Ala Tyr
20 25 30
Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr Gln Gln Phe Pro Gly
35 40 45
Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro Asp Val Ser Glu Lys
50 55 60
Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys Ser Ala Lys Gln Phe
65 70 75 80
Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp Ser Ala Thr Tyr Phe
85 90 95
Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe Gly Lys
100 105 110
Gly Thr Lys Leu Thr Val Asn Pro
115 120
<210> 66
<211> 112
<212> PRT
<213> 智人 (Homo sapiens)
<400> 66
Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp
1 5 10 15
Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp
20 25 30
Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln
35 40 45
Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser
50 55 60
Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln Arg Thr
65 70 75 80
Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Gly Gly
85 90 95
Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu
100 105 110
<210> 67
<211> 141
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 67
Met His Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu
1 5 10 15
Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val
20 25 30
Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile
35 40 45
Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr
50 55 60
Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro
65 70 75 80
Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys
85 90 95
Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp
100 105 110
Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys
115 120 125
Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro
130 135 140
<210> 68
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 68
Met Ala Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu
130
<210> 69
<211> 141
<212> PRT
<213> 智人 (Homo sapiens)
<400> 69
Met Asp Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu
1 5 10 15
Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val
20 25 30
Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile
35 40 45
Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr
50 55 60
Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro
65 70 75 80
Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys
85 90 95
Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp
100 105 110
Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys
115 120 125
Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro
130 135 140
<210> 70
<211> 133
<212> PRT
<213> 智人 (Homo sapiens)
<400> 70
Met Gly Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu
130
<210> 71
<211> 278
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 71
Met His Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu
1 5 10 15
Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val
20 25 30
Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile
35 40 45
Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr
50 55 60
Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro
65 70 75 80
Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys
85 90 95
Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp
100 105 110
Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys
115 120 125
Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln
130 135 140
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
145 150 155 160
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
165 170 175
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
180 185 190
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
195 200 205
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
210 215 220
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
225 230 235 240
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
245 250 255
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
260 265 270
Leu Arg Leu Trp Ser Ser
275
<210> 72
<211> 306
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 72
Met Ala Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
290 295 300
Asn Ser
305
<210> 73
<211> 278
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 73
Met Asp Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu
1 5 10 15
Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val
20 25 30
Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile
35 40 45
Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr
50 55 60
Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro
65 70 75 80
Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys
85 90 95
Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp
100 105 110
Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys
115 120 125
Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln
130 135 140
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
145 150 155 160
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
165 170 175
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
180 185 190
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
195 200 205
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
210 215 220
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
225 230 235 240
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
245 250 255
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
260 265 270
Leu Arg Leu Trp Ser Ser
275
<210> 74
<211> 306
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 74
Met Gly Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
290 295 300
Asn Ser
305
<210> 75
<211> 257
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 75
Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val Lys Gln Ser Pro Gln
1 5 10 15
Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile Ile Asn Cys Ala Tyr
20 25 30
Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr Gln Gln Phe Pro Gly
35 40 45
Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro Asp Val Ser Glu Lys
50 55 60
Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys Ser Ala Lys Gln Phe
65 70 75 80
Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp Ser Ala Thr Tyr Phe
85 90 95
Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe Gly Lys
100 105 110
Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala
115 120 125
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
130 135 140
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
145 150 155 160
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
165 170 175
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
180 185 190
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
195 200 205
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
210 215 220
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
225 230 235 240
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
245 250 255
Ser
<210> 76
<211> 285
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 76
Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp
1 5 10 15
Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp
20 25 30
Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln
35 40 45
Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser
50 55 60
Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln Arg Thr
65 70 75 80
Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Gly Gly
85 90 95
Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu
100 105 110
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
115 120 125
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
130 135 140
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
145 150 155 160
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
165 170 175
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
180 185 190
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
195 200 205
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
210 215 220
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
225 230 235 240
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
245 250 255
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
260 265 270
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
275 280 285
<210> 77
<211> 611
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 77
Met Ala Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
290 295 300
Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu
305 310 315 320
Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Lys
325 330 335
Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu Cys Trp Val
340 345 350
Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val Lys Gln Ser
355 360 365
Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile Ile Asn Cys
370 375 380
Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr Gln Gln Phe
385 390 395 400
Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro Asp Val Ser
405 410 415
Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys Ser Ala Lys
420 425 430
Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp Ser Ala Thr
435 440 445
Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys Leu Val Phe
450 455 460
Gly Lys Gly Thr Lys Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu
465 470 475 480
Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu
485 490 495
Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met
500 505 510
Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala
515 520 525
Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser
530 535 540
Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser
545 550 555 560
Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr
565 570 575
Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile
580 585 590
Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu
595 600 605
Trp Ser Ser
610
<210> 78
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 78
Asn Ser Ala Ser Asp Tyr
1 5
<210> 79
<211> 7
<212> PRT
<213> 智人 (Homo sapiens)
<400> 79
Ile Arg Ser Asn Met Asp Lys
1 5
<210> 80
<211> 14
<212> PRT
<213> 智人 (Homo sapiens)
<400> 80
Cys Ala Glu Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe
1 5 10
<210> 81
<211> 5
<212> PRT
<213> 智人 (Homo sapiens)
<400> 81
Ser Gly His Thr Ala
1 5
<210> 82
<211> 6
<212> PRT
<213> 智人 (Homo sapiens)
<400> 82
Phe Gln Gly Thr Gly Ala
1 5
<210> 83
<211> 14
<212> PRT
<213> 智人 (Homo sapiens)
<400> 83
Cys Ala Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe
1 5 10
<210> 84
<211> 112
<212> PRT
<213> 智人 (Homo sapiens)
<400> 84
Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp
1 5 10 15
Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe
20 25 30
Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp
35 40 45
Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu
50 55 60
Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln
65 70 75 80
Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg Gly Gly
85 90 95
Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro
100 105 110
<210> 85
<211> 112
<212> PRT
<213> 智人 (Homo sapiens)
<400> 85
Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Tyr
1 5 10 15
Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp
20 25 30
Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr Phe Gln
35 40 45
Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg Phe Phe
50 55 60
Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln Arg Thr
65 70 75 80
Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Pro Gly Gly
85 90 95
Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu
100 105 110
<210> 86
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 86
Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys
115 120 125
Leu Thr Val Asn Pro
130
<210> 87
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 87
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu
130
<210> 88
<211> 133
<212> PRT
<213> 智人 (Homo sapiens)
<400> 88
Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys
115 120 125
Leu Thr Val Asn Pro
130
<210> 89
<211> 133
<212> PRT
<213> 智人 (Homo sapiens)
<400> 89
Met Gly Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu
130
<210> 90
<211> 270
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 90
Met His Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys
115 120 125
Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln
130 135 140
Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe
165 170 175
Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser
180 185 190
Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp
195 200 205
Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys
210 215 220
Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val
245 250 255
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 91
<211> 306
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 91
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
290 295 300
Asn Ser
305
<210> 92
<211> 270
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 92
Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys
115 120 125
Leu Thr Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln
130 135 140
Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe
165 170 175
Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser
180 185 190
Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp
195 200 205
Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys
210 215 220
Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val
245 250 255
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 93
<211> 306
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 93
Met Gly Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
290 295 300
Asn Ser
305
<210> 94
<211> 249
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 94
Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly Asp
1 5 10 15
Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr Phe
20 25 30
Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile Asp
35 40 45
Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val Leu
50 55 60
Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr Gln
65 70 75 80
Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg Gly Gly
85 90 95
Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro
100 105 110
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
115 120 125
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
130 135 140
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
145 150 155 160
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
165 170 175
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
180 185 190
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
195 200 205
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
210 215 220
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
225 230 235 240
Leu Met Thr Leu Arg Leu Trp Ser Ser
245
<210> 95
<211> 285
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 95
Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Tyr
1 5 10 15
Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp
20 25 30
Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr Phe Gln
35 40 45
Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg Phe Phe
50 55 60
Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln Arg Thr
65 70 75 80
Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Pro Gly Gly
85 90 95
Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu
100 105 110
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
115 120 125
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
130 135 140
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
145 150 155 160
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
165 170 175
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
180 185 190
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
195 200 205
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
210 215 220
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
225 230 235 240
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
245 250 255
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
260 265 270
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
275 280 285
<210> 96
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 96
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
130 135 140
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
180 185 190
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
195 200 205
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
210 215 220
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
225 230 235 240
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
245 250 255
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
260 265 270
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
275 280 285
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
290 295 300
Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu
305 310 315 320
Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Gly
325 330 335
Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp Trp Val Ser
340 345 350
Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu
355 360 365
Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp
370 375 380
Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile
385 390 395 400
Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr
405 410 415
Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala
420 425 430
Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg
435 440 445
Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val
450 455 460
Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
465 470 475 480
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
485 490 495
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
500 505 510
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
515 520 525
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
530 535 540
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
545 550 555 560
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
565 570 575
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 97
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 97
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
100 105 110
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 98
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 98
Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
100 105 110
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 99
<211> 173
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 99
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
1 5 10 15
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
50 55 60
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
65 70 75 80
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
85 90 95
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
100 105 110
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
115 120 125
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
130 135 140
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
145 150 155 160
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
165 170
<210> 100
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 100
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
1 5 10 15
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
20 25
<210> 101
<211> 341
<212> PRT
<213> 智人 (Homo sapiens)
<400> 101
Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu
20 25 30
Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp
35 40 45
Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro
50 55 60
Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro
65 70 75 80
Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser
85 90 95
Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly
100 105 110
Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro
115 120 125
Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln
130 135 140
Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met
145 150 155 160
Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys
165 170 175
Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln
180 185 190
His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp
195 200 205
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu
210 215 220
Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser
225 230 235 240
Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr
245 250 255
Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val
260 265 270
Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn
275 280 285
Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr
290 295 300
Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys
305 310 315 320
Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Asp Gln Thr Ser Phe
325 330 335
Gln Lys Glu Asn Cys
340
<210> 102
<211> 346
<212> PRT
<213> 智人 (Homo sapiens)
<400> 102
Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln
1 5 10 15
Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu
20 25 30
Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp
35 40 45
Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro
50 55 60
Arg Met Pro Glu Ala Ala Pro Pro Val Ala Pro Ala Pro Ala Ala Pro
65 70 75 80
Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser
85 90 95
Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly
100 105 110
Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro
115 120 125
Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln
130 135 140
Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met
145 150 155 160
Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys
165 170 175
Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln
180 185 190
His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp
195 200 205
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu
210 215 220
Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser
225 230 235 240
Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr
245 250 255
Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val
260 265 270
Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn
275 280 285
Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr
290 295 300
Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys
305 310 315 320
Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Met Leu Leu Asp Leu
325 330 335
Arg Trp Cys Tyr Phe Leu Ile Asn Ser Ser
340 345
<210> 103
<211> 354
<212> PRT
<213> 智人 (Homo sapiens)
<400> 103
Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr
1 5 10 15
Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro
20 25 30
Pro Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro
35 40 45
Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr
50 55 60
Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala
65 70 75 80
Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys
85 90 95
Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro
100 105 110
Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln
115 120 125
His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser
130 135 140
Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly
145 150 155 160
Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser
165 170 175
Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr
180 185 190
Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn
195 200 205
Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn
210 215 220
Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly
225 230 235 240
Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro
245 250 255
His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn
260 265 270
Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr
275 280 285
Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe Arg Glu
290 295 300
Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Glu Pro
305 310 315 320
Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys Lys Gly Gln
325 330 335
Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly Pro Asp
340 345 350
Ser Asp
<210> 104
<211> 302
<212> PRT
<213> 智人 (Homo sapiens)
<400> 104
Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr
1 5 10 15
Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro
20 25 30
Pro Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro
35 40 45
Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr
50 55 60
Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala
65 70 75 80
Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys
85 90 95
Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro
100 105 110
Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln
115 120 125
His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser
130 135 140
Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly
145 150 155 160
Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser
165 170 175
Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr
180 185 190
Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn
195 200 205
Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn
210 215 220
Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly
225 230 235 240
Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro
245 250 255
His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn
260 265 270
Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr
275 280 285
Phe Thr Leu Gln Asp Gln Thr Ser Phe Gln Lys Glu Asn Cys
290 295 300
<210> 105
<211> 307
<212> PRT
<213> 智人 (Homo sapiens)
<400> 105
Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr
1 5 10 15
Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro
20 25 30
Pro Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro
35 40 45
Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr
50 55 60
Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala
65 70 75 80
Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys
85 90 95
Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro
100 105 110
Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln
115 120 125
His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser
130 135 140
Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly
145 150 155 160
Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser
165 170 175
Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr
180 185 190
Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn
195 200 205
Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn
210 215 220
Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly
225 230 235 240
Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro
245 250 255
His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn
260 265 270
Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr
275 280 285
Phe Thr Leu Gln Met Leu Leu Asp Leu Arg Trp Cys Tyr Phe Leu Ile
290 295 300
Asn Ser Ser
305
<210> 106
<211> 261
<212> PRT
<213> 智人 (Homo sapiens)
<400> 106
Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp
1 5 10 15
Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys
20 25 30
Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu
35 40 45
Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg
50 55 60
Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe
65 70 75 80
Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp
85 90 95
Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly
100 105 110
Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser
115 120 125
Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala
130 135 140
Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys
145 150 155 160
Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu
165 170 175
Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp
180 185 190
Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met
195 200 205
Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly
210 215 220
Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys
225 230 235 240
Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu
245 250 255
Gly Pro Asp Ser Asp
260
<210> 107
<211> 209
<212> PRT
<213> 智人 (Homo sapiens)
<400> 107
Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp
1 5 10 15
Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys
20 25 30
Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu
35 40 45
Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg
50 55 60
Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe
65 70 75 80
Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp
85 90 95
Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly
100 105 110
Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser
115 120 125
Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala
130 135 140
Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys
145 150 155 160
Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu
165 170 175
Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp
180 185 190
Gly Glu Tyr Phe Thr Leu Gln Asp Gln Thr Ser Phe Gln Lys Glu Asn
195 200 205
Cys
<210> 108
<211> 214
<212> PRT
<213> 智人 (Homo sapiens)
<400> 108
Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp
1 5 10 15
Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys
20 25 30
Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu
35 40 45
Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg
50 55 60
Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe
65 70 75 80
Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp
85 90 95
Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly
100 105 110
Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser
115 120 125
Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala
130 135 140
Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys
145 150 155 160
Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu
165 170 175
Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp
180 185 190
Gly Glu Tyr Phe Thr Leu Gln Met Leu Leu Asp Leu Arg Trp Cys Tyr
195 200 205
Phe Leu Ile Asn Ser Ser
210
<210> 109
<211> 1797
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 109
atggcgcccc agctgctggg ctacgtggtg ctgtgcctgc tgggagcagg accactggag 60
gcacaggtga cccagaaccc cagatatctg atcaccgtga caggcaagaa gctgaccgtg 120
acatgttccc agaacatgaa tcacgagtac atgtcttggt ataggcagga ccctggcctg 180
ggcctgaggc agatctacta ttctatgaat gtggaggtga cagacaaggg cgatgtgcct 240
gagggctaca aggtgagccg gaaggagaag agaaacttcc cactgatcct ggagtctccc 300
agccctaatc agaccagcct gtatttctgc gccagctcct ttatctccaa ccagccccag 360
cactttggcg atggcacaag gctgtccatc ctggaggatc tccggaatgt gacaccccct 420
aaggtgtctc tgttcgagcc aagcaaggcc gagatcgcca acaagcagaa ggccaccctg 480
gtgtgcctgg ccagaggctt ctttcccgat cacgtggagc tgtcctggtg ggtgaatggc 540
aaggaggtgc actctggcgt gtgcaccgac cctcaggcct ataaggagtc caactactct 600
tattgtctga gctcccggct gagagtgtcc gccacattct ggcacaatcc cagaaaccac 660
ttcagatgcc aggtgcagtt tcacggcctg tccgaggagg ataagtggcc tgagggctct 720
ccaaagcccg tgacccagaa tatcagcgcc gaggcatggg gaagggcaga ctgtggaatc 780
acctccgcct cttaccagca gggcgtgctg agcgccacaa tcctgtatga gatcctgctg 840
ggcaaggcca ccctgtacgc cgtgctggtg agcacactgg tggtcatggc tatggtgaag 900
aggaagaaca gccgggccaa gcgcagcggc tccggcgcaa ccaacttctc tctgctgaag 960
caggcaggcg acgtggagga gaatcctggc ccaatgcata agagcctgcg ggtgctgctg 1020
gtcatcctgt ggctccagct gtcttgggtg tggagccagc agaaggaggt ggagcaggac 1080
cccggccctc tgagcgtgcc tgagggagcc atcgtgtccc tgaactgcac ctactccaat 1140
tctgccttcc agtacttcat gtggtacagg cagtacagcc ggaagggccc cgagctgctg 1200
atgtacacct atagctccgg caacaaggag gacggcaggt tcacagccca ggtggataag 1260
tctagcaagt acatctccct gtttatccgc gactctcagc caagcgattc cgccacctac 1320
ctgtgcgcag gaggatccta tggcaagctg acattcggcc agggcaccat cctgacagtg 1380
caccccaata ttcagaatcc cgagcccgcg gtataccagc tgaaggaccc ccggagccag 1440
gatagcaccc tgtgcctgtt cacagacttt gattctcaga tcaacgtgcc caagacaatg 1500
gagagcggca cctttatcac agacaagtgc gtgctggaca tgaaggctat ggactctaag 1560
agcaatggcg ccatcgcctg gtccaaccag acctctttca catgccagga tatctttaag 1620
gagacaaatg ccacataccc cagctccgac gtgccttgtg atgccaccct gacagagaag 1680
agcttcgaga cagacatgaa tctgaacttt cagaacctgc tggtcatcgt gctgagaatc 1740
ctgctgctga aagtggctgg cttcaacctg ctgatgaccc tgcggctgtg gagtagc 1797
<210> 110
<211> 1800
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 110
atggcgtgcc ggctgctgtg ctgtgccgtg ctgtgcctgc tgggagcagt gccaatggag 60
accggagtga cccagacacc caggcacctg gtcatgggca tgacaaacaa gaagtctctg 120
aagtgcgagc agcacctggg ccacaatgcc atgtactggt ataagcagtc cgccaagaag 180
cctctggagc tgatgttcgt gtactctctg gaggagcggg tggagaacaa ttccgtgcca 240
agccggttca gccccgagtg ccctaacagc tcccacctgt ttctgcacct gcacaccctc 300
cagccagagg acagcgccct gtacctgtgc gcctctagca gggtggaggg ctccgataca 360
cagtattttg gccctggcac ccgcctgaca gtgctggagg atctccggaa tgtgacaccc 420
cctaaggtgt ctctgttcga gccaagcaag gccgagatcg ccaacaagca gaaggccacc 480
ctggtgtgcc tggccagagg cttctttccc gatcacgtgg agctgtcctg gtgggtgaat 540
ggcaaggagg tgcactctgg cgtgtgcacc gaccctcagg cctataagga gtccaactac 600
tcttattgtc tgagctcccg gctgagagtg tccgccacat tctggcacaa tcccagaaac 660
cacttcagat gccaggtgca gtttcacggc ctgtccgagg aggataagtg gcctgagggc 720
tctccaaagc ccgtgaccca gaatatcagc gccgaggcat ggggaagggc agactgtgga 780
atcacctccg cctcttacca gcagggcgtg ctgagcgcca caatcctgta tgagatcctg 840
ctgggcaagg ccaccctgta cgccgtgctg gtgagcacac tggtggtcat ggctatggtg 900
aagaggaaga acagccgggc caagcgcagc ggctccggcg caaccaactt ctctctgctg 960
aagcaggcag gcgacgtgga ggagaatcct ggcccaatgc atggcatcag ggccctgttc 1020
atgtacctgt ggctccagct ggactgggtg agccggggcg agtccgtggg actgcacctg 1080
ccaaccctgt ctgtgcagga gggcgacaac agcatcatca attgcgccta tagcaactcc 1140
gcctctgatt acttcatctg gtataagcag gagagcggca agggccccca gtttatcatc 1200
gacatccggt ccaacatgga taagcggcag ggccagagag tgaccgtgct gctgaataag 1260
acagtgaagc acctgtctct ccagatcgca gcaacacagc ccggcgattc cgccgtgtac 1320
ttttgtgccg agaagtctac cggcaatcag ttctattttg gcaccggcac aagcctgaca 1380
gtgatcccta atattcagaa tcccgagccc gcggtatacc agctgaagga cccccggagc 1440
caggatagca ccctgtgcct gttcacagac tttgattctc agatcaacgt gcccaagaca 1500
atggagagcg gcacctttat cacagacaag tgcgtgctgg acatgaaggc tatggactct 1560
aagagcaatg gcgccatcgc ctggtccaac cagacctctt tcacatgcca ggatatcttt 1620
aaggagacaa atgccacata ccccagctcc gacgtgcctt gtgatgccac cctgacagag 1680
aagagcttcg agacagacat gaatctgaac tttcagaacc tgctggtcat cgtgctgaga 1740
atcctgctgc tgaaagtggc tggcttcaac ctgctgatga ccctgcggct gtggagtagc 1800
<210> 111
<211> 1809
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 111
atggcgctgc tgctgctgct gctgggccct ggctctggcc tgggagcagt ggtgtcccag 60
caccctagca gagtgatctg caagtctggc acaagcgtga agatcgagtg taggagcctg 120
gacttccagg ccaccacaat gttctggtac cgccagtttc ccaagcagtc cctgatgctg 180
atggccacaa gcaacgaggg ctccaaggcc acctatgagc agggcgtgga gaaggataag 240
tttctgatca atcacgcctc tctgaccctg agcaccctga cagtgacctc cgcccaccca 300
gaggacagct ccttctacat ctgctccgcc atccgggata gatctggcgg cgagacacag 360
tattttggcc ctggcaccag gctgctggtg ctggaggatc tccggaatgt gacaccccct 420
aaggtgtctc tgttcgagcc aagcaaggcc gagatcgcca acaagcagaa ggccaccctg 480
gtgtgcctgg ccagaggctt ctttcccgat cacgtggagc tgtcctggtg ggtgaatggc 540
aaggaggtgc actctggcgt gtgcaccgac cctcaggcct ataaggagtc caactactct 600
tattgtctga gctcccggct gagagtgtcc gccacattct ggcacaatcc cagaaaccac 660
ttcagatgcc aggtgcagtt tcacggcctg tccgaggagg ataagtggcc tgagggctct 720
ccaaagcccg tgacccagaa tatcagcgcc gaggcatggg gaagggcaga ctgtggaatc 780
acctccgcct cttaccagca gggcgtgctg agcgccacaa tcctgtatga gatcctgctg 840
ggcaaggcca ccctgtacgc cgtgctggtg agcacactgg tggtcatggc tatggtgaag 900
aggaagaaca gccgggccaa gcgcagcggc tccggcgcaa ccaacttctc tctgctgaag 960
caggcaggcg acgtggagga gaatcctggc ccaatgcata gcgcccccat ctccatgctg 1020
gccatgctgt ttaccctgtc tggcctgagg gcacagagcg tggcacagcc agaggaccag 1080
gtgaacgtgg ccgagggcaa tcccctgacc gtgaagtgca catacagcgt gtccggcaac 1140
ccctatctgt tctggtacgt gcagtatcct aatcggggcc tccagttcct gctgaagtac 1200
atcaccggcg ataacctggt gaagggcagc tatggcttcg aggccgagtt taataagtcc 1260
cagacatctt tccacctgaa gaagccttcc gccctggtgt ctgacagcgc cctgtacttt 1320
tgtgccgtgc gggatccaac cgtgtctggc acatacaagt atatcttcgg caccggcaca 1380
agactgaagg tgctggccaa tattcagaat cccgagcccg cggtatacca gctgaaggac 1440
ccccggagcc aggatagcac cctgtgcctg ttcacagact ttgattctca gatcaacgtg 1500
cccaagacaa tggagagcgg cacctttatc acagacaagt gcgtgctgga catgaaggct 1560
atggactcta agagcaatgg cgccatcgcc tggtccaacc agacctcttt cacatgccag 1620
gatatcttta aggagacaaa tgccacatac cccagctccg acgtgccttg tgatgccacc 1680
ctgacagaga agagcttcga gacagacatg aatctgaact ttcagaacct gctggtcatc 1740
gtgctgagaa tcctgctgct gaaagtggct ggcttcaacc tgctgatgac cctgcggctg 1800
tggagtagc 1809
<210> 112
<211> 1833
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 112
atggcgaccc ggctgctgtt ctgggtggca ttttgcctgc tgggagcaga ccacaccgga 60
gcaggcgtgt cccagtctcc aagcaacaag gtgacagaga agggcaagga cgtggagctg 120
aggtgtgatc ccatcagcgg ccacacagcc ctgtactggt ataggcagtc cctgggacag 180
ggcctggagt tcctgatcta ctttcagggc aattctgccc ccgacaagag cggcctgcct 240
tccgatcggt tctctgccga gagaaccggc ggctccgtgt ctaccctgac aatccagcgg 300
acacagcagg aggattccgc cgtgtacctg tgcgccagct ccctgggagg atctagcgag 360
acccagtatt ttggccctgg cacaaggctg ctggtgctgg aggatctccg gaatgtgaca 420
ccccctaagg tgtctctgtt cgagccaagc aaggccgaga tcgccaacaa gcagaaggcc 480
accctggtgt gcctggccag aggcttcttt cccgatcacg tggagctgtc ctggtgggtg 540
aatggcaagg aggtgcactc tggcgtgtgc accgaccctc aggcctataa ggagtccaac 600
tactcttatt gtctgagctc ccggctgaga gtgtccgcca cattctggca caatcccaga 660
aaccacttca gatgccaggt gcagtttcac ggcctgtccg aggaggataa gtggcctgag 720
ggctctccaa agcccgtgac ccagaatatc agcgccgagg catggggaag ggcagactgt 780
ggaatcacct ccgcctctta ccagcagggc gtgctgagcg ccacaatcct gtatgagatc 840
ctgctgggca aggccaccct gtacgccgtg ctggtgagca cactggtggt catggctatg 900
gtgaagagga agaacagccg ggccaagcgc agcggctccg gcgcaaccaa cttctctctg 960
ctgaagcagg caggcgacgt ggaggagaat cctggcccaa tgcataagat cctgggcgcc 1020
tccttcctgg tgctgtggct ccagctgtgc tgggtgagcg gccagcagaa ggagaagtcc 1080
gaccagcagc aggtgaagca gagcccccag tccctgatcg tgcagaaggg cggcatctct 1140
atcatcaact gtgcctacga gaataccgcc ttcgactact ttccctggta tcagcagttc 1200
cccggcaagg gacctgccct gctgatcgca atccggcccg acgtgagcga gaagaaggag 1260
ggcagattca ccatctcttt taacaagagc gccaagcagt ttagcctgca catcatggac 1320
tcccagcctg gcgattctgc cacatatttc tgcgcagcaa agaggcaggg aggaagcgag 1380
aagctggtgt ttggcaaggg caccaagctg acagtgaatc caaatattca gaatcccgag 1440
cccgcggtat accagctgaa ggacccccgg agccaggata gcaccctgtg cctgttcaca 1500
gactttgatt ctcagatcaa cgtgcccaag acaatggaga gcggcacctt tatcacagac 1560
aagtgcgtgc tggacatgaa ggctatggac tctaagagca atggcgccat cgcctggtcc 1620
aaccagacct ctttcacatg ccaggatatc tttaaggaga caaatgccac ataccccagc 1680
tccgacgtgc cttgtgatgc caccctgaca gagaagagct tcgagacaga catgaatctg 1740
aactttcaga acctgctggt catcgtgctg agaatcctgc tgctgaaagt ggctggcttc 1800
aacctgctga tgaccctgcg gctgtggagt agc 1833
<210> 113
<211> 1809
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 113
atggcgacca ggctgctgtg ctgggccgcc ctgtgcctgc tgggagcaga ccacacagga 60
gcaggcgtgt cccagacccc ttctaacaag gtgacagaga agggcaagta cgtggagctg 120
cggtgcgatc caatcagcgg ccacaccgcc ctgtactggt atagacagtc cctgggacag 180
ggccccgagt tcctgatcta ttttcaggga acaggagccg ccgacgattc cggcctgccc 240
aatgacaggt tctttgccgt gcgccctgag ggatctgtga gcaccctgaa gatccagcgg 300
acagagagag gcgatagcgc cgtgtacctg tgcgccagct ccccaggcgg aagccaggag 360
acccagtatt tcggccctgg cacaagactg ctggtgctgg aggatctccg gaatgtgaca 420
ccccctaagg tgtctctgtt cgagccaagc aaggccgaga tcgccaacaa gcagaaggcc 480
accctggtgt gcctggccag aggcttcttt cccgatcacg tggagctgtc ctggtgggtg 540
aatggcaagg aggtgcactc tggcgtgtgc accgaccctc aggcctataa ggagtccaac 600
tactcttatt gtctgagctc ccggctgaga gtgtccgcca cattctggca caatcccaga 660
aaccacttca gatgccaggt gcagtttcac ggcctgtccg aggaggataa gtggcctgag 720
ggctctccaa agcccgtgac ccagaatatc agcgccgagg catggggaag ggcagactgt 780
ggaatcacct ccgcctctta ccagcagggc gtgctgagcg ccacaatcct gtatgagatc 840
ctgctgggca aggccaccct gtacgccgtg ctggtgagca cactggtggt catggctatg 900
gtgaagagga agaacagccg ggccaagcgc agcggctccg gcgcaaccaa cttctctctg 960
ctgaagcagg caggcgacgt ggaggagaat cctggcccaa tgcatggcat ccgggccctg 1020
ttcatgtacc tgtggctcca gctggactgg gtgagcaggg gcgagtccgt gggactgcac 1080
ctgccaaccc tgtctgtgca ggagggcgac aacagcatca tcaattgcgc ctatagcaac 1140
tccgcctctg attacttcat ctggtataag caggagagcg gcaagggccc ccagtttatc 1200
atcgacatcc ggtccaacat ggataagagg cagggacaga gggtgaccgt gctgctgaat 1260
aagacagtga agcacctgtc cctccagatc gcagcaacac agcccggcga ttctgccgtg 1320
tacttctgtg ccgagaagcg gagaggcggc tctgagaagc tggtgtttgg caagggcacc 1380
aagctgacag tgaatcctaa tattcagaat cccgagcccg cggtatacca gctgaaggac 1440
ccccggagcc aggatagcac cctgtgcctg ttcacagact ttgattctca gatcaacgtg 1500
cccaagacaa tggagagcgg cacctttatc acagacaagt gcgtgctgga catgaaggct 1560
atggactcta agagcaatgg cgccatcgcc tggtccaacc agacctcttt cacatgccag 1620
gatatcttta aggagacaaa tgccacatac cccagctccg acgtgccttg tgatgccacc 1680
ctgacagaga agagcttcga gacagacatg aatctgaact ttcagaacct gctggtcatc 1740
gtgctgagaa tcctgctgct gaaagtggct ggcttcaacc tgctgatgac cctgcggctg 1800
tggagtagc 1809
<210> 114
<211> 25
<212> PRT
<213> 智人 (Homo sapiens)
<400> 114
Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro
1 5 10 15
Glu Val Gly Ser Asp Cys Thr Thr Ile
20 25
<210> 115
<211> 25
<212> PRT
<213> 智人 (Homo sapiens)
<400> 115
Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Cys Glu Pro Pro
1 5 10 15
Glu Val Gly Ser Asp Cys Thr Thr Ile
20 25
<210> 116
<211> 25
<212> PRT
<213> 智人 (Homo sapiens)
<400> 116
Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala
1 5 10 15
Cys Pro Gly Arg Asp Arg Arg Thr Glu
20 25
<210> 117
<211> 25
<212> PRT
<213> 智人 (Homo sapiens)
<400> 117
Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Cys Val Cys Ala
1 5 10 15
Cys Pro Gly Arg Asp Arg Arg Thr Glu
20 25
<210> 118
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 118
Arg Ala Lys Arg
1
<210> 119
<211> 109
<212> PRT
<213> 智人 (Homo sapiens)
<400> 119
Gln Lys Glu Val Glu Gln Asp Pro Gly Pro Leu Ser Val Pro Glu Gly
1 5 10 15
Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser Asn Ser Ala Phe Gln Tyr
20 25 30
Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys Gly Pro Glu Leu Leu Met
35 40 45
Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp Gly Arg Phe Thr Ala Gln
50 55 60
Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu Phe Ile Arg Asp Ser Gln
65 70 75 80
Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Gly Gly Ser Tyr Gly Lys
85 90 95
Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr Val His Pro
100 105
<210> 120
<211> 112
<212> PRT
<213> 智人 (Homo sapiens)
<400> 120
Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly
1 5 10 15
Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met
20 25 30
Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr
35 40 45
Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr
50 55 60
Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser
65 70 75 80
Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Phe Ile
85 90 95
Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu
100 105 110
<210> 121
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 121
Met Ala Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Gly Gly Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly Thr Ile Leu Thr
115 120 125
Val His Pro
130
<210> 122
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 122
Met His Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Phe Ile Ser Asn Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu
115 120 125
Ser Ile Leu
130
<210> 123
<211> 111
<212> PRT
<213> 智人 (Homo sapiens)
<400> 123
Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly
1 5 10 15
Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr
20 25 30
Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile
35 40 45
Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val
50 55 60
Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr
65 70 75 80
Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Ser Thr Gly
85 90 95
Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro
100 105 110
<210> 124
<211> 113
<212> PRT
<213> 智人 (Homo sapiens)
<400> 124
Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met Gly Met Thr
1 5 10 15
Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His Asn Ala Met
20 25 30
Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu Met Phe Val
35 40 45
Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro Ser Arg Phe
50 55 60
Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His Leu His Thr
65 70 75 80
Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg Val
85 90 95
Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
100 105 110
Leu
<210> 125
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 125
Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Ser Thr Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr
115 120 125
Val Ile Pro
130
<210> 126
<211> 132
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 126
Met His Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Met Glu Thr Gly Val Thr Gln Thr Pro Arg His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Leu Gly His
35 40 45
Asn Ala Met Tyr Trp Tyr Lys Gln Ser Ala Lys Lys Pro Leu Glu Leu
50 55 60
Met Phe Val Tyr Ser Leu Glu Glu Arg Val Glu Asn Asn Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser His Leu Phe Leu His
85 90 95
Leu His Thr Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Val Glu Gly Ser Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu
130
<210> 127
<211> 116
<212> PRT
<213> 智人 (Homo sapiens)
<400> 127
Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu Gly
1 5 10 15
Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro Tyr
20 25 30
Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu Leu
35 40 45
Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe Glu
50 55 60
Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro Ser
65 70 75 80
Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp Pro
85 90 95
Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu
100 105 110
Lys Val Leu Ala
115
<210> 128
<211> 117
<212> PRT
<213> 智人 (Homo sapiens)
<400> 128
Gly Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly
1 5 10 15
Thr Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr
20 25 30
Met Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala
35 40 45
Thr Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys
50 55 60
Asp Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr
65 70 75 80
Val Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala
85 90 95
Ile Arg Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr
100 105 110
Arg Leu Leu Val Leu
115
<210> 129
<211> 135
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 129
Met Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser
1 5 10 15
Gly Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val
20 25 30
Ala Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly
35 40 45
Asn Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln
50 55 60
Phe Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys
85 90 95
Lys Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val
100 105 110
Arg Asp Pro Thr Val Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly
115 120 125
Thr Arg Leu Lys Val Leu Ala
130 135
<210> 130
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 130
Met His Leu Leu Leu Leu Leu Leu Gly Pro Gly Ser Gly Leu Gly Ala
1 5 10 15
Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser
20 25 30
Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe
35 40 45
Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser
50 55 60
Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys
65 70 75 80
Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr
85 90 95
Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ile Arg
100 105 110
Asp Arg Ser Gly Gly Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Leu Val Leu
130
<210> 131
<211> 113
<212> PRT
<213> 智人 (Homo sapiens)
<400> 131
Gln Gln Gln Val Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly
1 5 10 15
Gly Ile Ser Ile Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr
20 25 30
Phe Pro Trp Tyr Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile
35 40 45
Ala Ile Arg Pro Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile
50 55 60
Ser Phe Asn Lys Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser
65 70 75 80
Gln Pro Gly Asp Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly
85 90 95
Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn
100 105 110
Pro
<210> 132
<211> 114
<212> PRT
<213> 智人 (Homo sapiens)
<400> 132
Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly
1 5 10 15
Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu
20 25 30
Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr
35 40 45
Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg
50 55 60
Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln
65 70 75 80
Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu
85 90 95
Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu
100 105 110
Val Leu
<210> 133
<211> 141
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 133
Met Ala Lys Ile Leu Gly Ala Ser Phe Leu Val Leu Trp Leu Gln Leu
1 5 10 15
Cys Trp Val Ser Gly Gln Gln Lys Glu Lys Ser Asp Gln Gln Gln Val
20 25 30
Lys Gln Ser Pro Gln Ser Leu Ile Val Gln Lys Gly Gly Ile Ser Ile
35 40 45
Ile Asn Cys Ala Tyr Glu Asn Thr Ala Phe Asp Tyr Phe Pro Trp Tyr
50 55 60
Gln Gln Phe Pro Gly Lys Gly Pro Ala Leu Leu Ile Ala Ile Arg Pro
65 70 75 80
Asp Val Ser Glu Lys Lys Glu Gly Arg Phe Thr Ile Ser Phe Asn Lys
85 90 95
Ser Ala Lys Gln Phe Ser Leu His Ile Met Asp Ser Gln Pro Gly Asp
100 105 110
Ser Ala Thr Tyr Phe Cys Ala Ala Lys Arg Gln Gly Gly Ser Glu Lys
115 120 125
Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn Pro
130 135 140
<210> 134
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 134
Met His Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Asp Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly Gly Ser Val Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gly Ser Ser Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu
130
<210> 135
<211> 113
<212> PRT
<213> 智人 (Homo sapiens)
<400> 135
Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser Val Gln Glu Gly
1 5 10 15
Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser Ala Ser Asp Tyr
20 25 30
Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro Gln Phe Ile Ile
35 40 45
Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln Arg Val Thr Val
50 55 60
Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln Ile Ala Ala Thr
65 70 75 80
Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu Lys Arg Arg Gly
85 90 95
Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys Leu Thr Val Asn
100 105 110
Pro
<210> 136
<211> 114
<212> PRT
<213> 智人 (Homo sapiens)
<400> 136
Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr Glu Lys Gly
1 5 10 15
Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu
20 25 30
Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr
35 40 45
Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg
50 55 60
Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu Lys Ile Gln
65 70 75 80
Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Pro
85 90 95
Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu
100 105 110
Val Leu
<210> 137
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 137
Met Ala Gly Ile Arg Ala Leu Phe Met Tyr Leu Trp Leu Gln Leu Asp
1 5 10 15
Trp Val Ser Arg Gly Glu Ser Val Gly Leu His Leu Pro Thr Leu Ser
20 25 30
Val Gln Glu Gly Asp Asn Ser Ile Ile Asn Cys Ala Tyr Ser Asn Ser
35 40 45
Ala Ser Asp Tyr Phe Ile Trp Tyr Lys Gln Glu Ser Gly Lys Gly Pro
50 55 60
Gln Phe Ile Ile Asp Ile Arg Ser Asn Met Asp Lys Arg Gln Gly Gln
65 70 75 80
Arg Val Thr Val Leu Leu Asn Lys Thr Val Lys His Leu Ser Leu Gln
85 90 95
Ile Ala Ala Thr Gln Pro Gly Asp Ser Ala Val Tyr Phe Cys Ala Glu
100 105 110
Lys Arg Arg Gly Gly Ser Glu Lys Leu Val Phe Gly Lys Gly Thr Lys
115 120 125
Leu Thr Val Asn Pro
130
<210> 138
<211> 133
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 138
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Thr Pro Ser Asn Lys Val Thr
20 25 30
Glu Lys Gly Lys Tyr Val Glu Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Thr Ala Leu Tyr Trp Tyr Arg Gln Ser Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Ile Tyr Phe Gln Gly Thr Gly Ala Ala Asp Asp Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Phe Ala Val Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Glu Arg Gly Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Pro Gly Gly Ser Gln Glu Thr Gln Tyr Phe Gly Pro Gly Thr
115 120 125
Arg Leu Leu Val Leu
130
<210> 139
<211> 137
<212> PRT
<213> 小鼠( Mus musculus)
<400> 139
Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser
100 105 110
Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 140
<211> 173
<212> PRT
<213> 小鼠( Mus musculus)
<400> 140
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
1 5 10 15
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Ala Tyr Lys
50 55 60
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
65 70 75 80
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
85 90 95
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
100 105 110
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
115 120 125
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
130 135 140
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
145 150 155 160
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
165 170
<210> 141
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> X是 Asn, Asp, His, 或Tyr
<220>
<221> MISC_FEATURE
<222> (48)..(48)
<223> X是Thr 或 Cys
<220>
<221> MISC_FEATURE
<222> (112)..(112)
<223> X是Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, 或Trp
<220>
<221> MISC_FEATURE
<222> (114)..(114)
<223> X是Met, Ala, Val, Leu, Ile, Pro, Phe, 或Trp
<220>
<221> MISC_FEATURE
<222> (115)..(115)
<223> X是Gly, Ala, Val, Leu, Ile, Pro, Phe, Met,或 Trp
<400> 141
Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Xaa
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Xaa
100 105 110
Val Xaa Xaa Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 142
<211> 173
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (57)..(57)
<223> X是Ser或Cys
<400> 142
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
1 5 10 15
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
20 25 30
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
35 40 45
Gly Lys Glu Val His Ser Gly Val Xaa Thr Asp Pro Gln Ala Tyr Lys
50 55 60
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
65 70 75 80
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
85 90 95
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
100 105 110
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
115 120 125
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
130 135 140
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
145 150 155 160
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
165 170
<210> 143
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> X是 Asn, Asp, His,或Tyr
<400> 143
Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
100 105 110
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 144
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> X 是Asn, Asp, His, 或Tyr
<400> 144
Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
100 105 110
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 145
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 145
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
100 105 110
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 146
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 146
Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Thr
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
100 105 110
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 147
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> X 是Asn, Asp, His, 或Tyr
<400> 147
Xaa Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser
100 105 110
Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 148
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 148
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser
100 105 110
Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 149
<211> 137
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 149
Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
1 5 10 15
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
20 25 30
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
35 40 45
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
50 55 60
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
65 70 75 80
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
85 90 95
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Ser
100 105 110
Val Met Gly Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
115 120 125
Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135
<210> 150
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> X 是α-氨基丁酸(AABA)
<400> 150
Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro
1 5 10 15
Glu Val Gly Ser Asp Xaa Thr Thr Ile
20 25
<210> 151
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> X 是α-氨基丁酸(AABA)
<220>
<221> MISC_FEATURE
<222> (22)..(22)
<223> X 是α-氨基丁酸(AABA)
<400> 151
Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Xaa Glu Pro Pro
1 5 10 15
Glu Val Gly Ser Asp Xaa Thr Thr Ile
20 25
Claims (49)
1.分离或纯化的T细胞受体(TCR),其对人类p53R273C或人类p53Y220C氨基酸序列具有抗原特异性,其中所述TCR包含以下的氨基酸序列:
(1)SEQ ID NO:2-7的全部;
(2)SEQ ID NO:21-26的全部;
(3)SEQ ID NO:40-45的全部;
(4)SEQ ID NO:59-64的全部;或
(5)SEQ ID NO:78-83的全部。
2.如权利要求1所述的TCR,其中所述TCR包含:
(1)与氨基酸序列SEQ ID NO:8至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:9至少95%一致的氨基酸序列两者;
(2)与氨基酸序列SEQ ID NO:10至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:11至少95%一致的氨基酸序列两者;
(3)与氨基酸序列SEQ ID NO:12至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:13至少95%一致的氨基酸序列两者;
(4)与氨基酸序列SEQ ID NO:12至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:11至少95%一致的氨基酸序列两者;
(5)与氨基酸序列SEQ ID NO:121至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:13至少95%一致的氨基酸序列两者;
(6)与氨基酸序列SEQ ID NO:121至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:122至少95%一致的氨基酸序列两者;
(7)与氨基酸序列SEQ ID NO:8至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:120至少95%一致的氨基酸序列两者;
(8)与氨基酸序列SEQ ID NO:119至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:9至少95%一致的氨基酸序列两者;
(9)与氨基酸序列SEQ ID NO:119至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:120至少95%一致的氨基酸序列两者;
(10)与氨基酸序列SEQ ID NO:27至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:28至少95%一致的氨基酸序列两者;
(11)与氨基酸序列SEQ ID NO:29至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:30至少95%一致的氨基酸序列两者;
(12)与氨基酸序列SEQ ID NO:31至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:32至少95%一致的氨基酸序列两者;
(13)与氨基酸序列SEQ ID NO:31至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:30至少95%一致的氨基酸序列两者;
(14)与氨基酸序列SEQ ID NO:125至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:32至少95%一致的氨基酸序列两者;
(15)与氨基酸序列SEQ ID NO:125至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:126至少95%一致的氨基酸序列两者;
(16)与氨基酸序列SEQ ID NO:27至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:124至少95%一致的氨基酸序列两者;
(17)与氨基酸序列SEQ ID NO:123至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:28至少95%一致的氨基酸序列两者;
(18)与氨基酸序列SEQ ID NO:123至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:124至少95%一致的氨基酸序列两者;
(19)与氨基酸序列SEQ ID NO:46至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:47至少95%一致的氨基酸序列两者;
(20)与氨基酸序列SEQ ID NO:48至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:49至少95%一致的氨基酸序列两者;
(21)与氨基酸序列SEQ ID NO:50至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:51至少95%一致的氨基酸序列两者;
(22)与氨基酸序列SEQ ID NO:50至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:49至少95%一致的氨基酸序列两者;
(23)与氨基酸序列SEQ ID NO:129至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:51至少95%一致的氨基酸序列两者;
(24)与氨基酸序列SEQ ID NO:129至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:130至少95%一致的氨基酸序列两者;
(25)与氨基酸序列SEQ ID NO:46至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:128至少95%一致的氨基酸序列两者;
(26)与氨基酸序列SEQ ID NO:127至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:47至少95%一致的氨基酸序列两者;
(27)与氨基酸序列SEQ ID NO:127至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:128至少95%一致的氨基酸序列两者;
(28)与氨基酸序列SEQ ID NO:65至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:66至少95%一致的氨基酸序列两者;
(29)与氨基酸序列SEQ ID NO:67至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:68至少95%一致的氨基酸序列两者;
(30)与氨基酸序列SEQ ID NO:69至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:70至少95%一致的氨基酸序列两者;
(31)与氨基酸序列SEQ ID NO:69至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:68至少95%一致的氨基酸序列两者;
(32)与氨基酸序列SEQ ID NO:133至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:70至少95%一致的氨基酸序列两者;
(33)与氨基酸序列SEQ ID NO:133至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:134至少95%一致的氨基酸序列两者;
(34)与氨基酸序列SEQ ID NO:65至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:132至少95%一致的氨基酸序列两者;
(35)与氨基酸序列SEQ ID NO:131至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:66至少95%一致的氨基酸序列两者;
(36)与氨基酸序列SEQ ID NO:131至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:132至少95%一致的氨基酸序列两者;
(37)与氨基酸序列SEQ ID NO:84至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:85至少95%一致的氨基酸序列两者;
(38)与氨基酸序列SEQ ID NO:86至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:87至少95%一致的氨基酸序列两者;
(39)与氨基酸序列SEQ ID NO:88至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:89至少95%一致的氨基酸序列两者;
(40)与氨基酸序列SEQ ID NO:88至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:87至少95%一致的氨基酸序列两者;
(41)与氨基酸序列SEQ ID NO:137至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:89至少95%一致的氨基酸序列两者;
(42)与氨基酸序列SEQ ID NO:137至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:138至少95%一致的氨基酸序列两者;
(43)与氨基酸序列SEQ ID NO:84至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:136至少95%一致的氨基酸序列两者;
(44)与氨基酸序列SEQ ID NO:135至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:85至少95%一致的氨基酸序列两者;或
(45)与氨基酸序列SEQ ID NO:135至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:136至少95%一致的氨基酸序列两者。
3.如权利要求1所述的TCR,其中所述TCR包含以下的氨基酸序列:
(1)SEQ ID NO:8以及9两者;
(2)SEQ ID NO:10以及11两者;
(3)SEQ ID NO:12以及13两者;
(4)SEQ ID NO:12以及11两者;
(5)SEQ ID NO:121以及13两者;
(6)SEQ ID NO:121以及122两者;
(7)SEQ ID NO:8以及120两者;
(8)SEQ ID NO:119以及9两者;
(9)SEQ ID NO:119以及120两者;
(10)SEQ ID NO:27以及28两者;
(11)SEQ ID NO:29以及30两者;
(12)SEQ ID NO:31以及32两者;
(13)SEQ ID NO:31以及30两者;
(14)SEQ ID NO:125以及32两者;
(15)SEQ ID NO:125以及126两者;
(16)SEQ ID NO:27以及124两者;
(17)SEQ ID NO:123以及28两者;
(18)SEQ ID NO:123以及124两者;
(19)SEQ ID NO:46以及47两者;
(20)SEQ ID NO:48以及49两者;
(21)SEQ ID NO:50以及51两者;
(22)SEQ ID NO:50以及49两者;
(23)SEQ ID NO:129以及51两者;
(24)SEQ ID NO:129以及130两者;
(25)SEQ ID NO:46以及128两者;
(26)SEQ ID NO:127以及47两者;
(27)SEQ ID NO:127以及128两者;
(28)SEQ ID NO:65以及66两者;
(29)SEQ ID NO:67以及68两者;
(30)SEQ ID NO:69以及70两者;
(31)SEQ ID NO:69以及68两者;
(32)SEQ ID NO:133以及70两者;
(33)SEQ ID NO:133以及134两者;
(34)SEQ ID NO:65以及132两者;
(35)SEQ ID NO:131以及66两者;
(36)SEQ ID NO:131以及132两者;
(37)SEQ ID NO:84以及85两者;
(38)SEQ ID NO:86以及87两者;
(39)SEQ ID NO:88以及89两者;
(40)SEQ ID NO:88以及87两者;
(41)SEQ ID NO:137以及89两者;
(42)SEQ ID NO:137以及138两者;
(43)SEQ ID NO:84以及136两者;
(44)SEQ ID NO:135以及85两者;或
(45)SEQ ID NO:135以及136两者。
4.如权利要求1至3中任一项所述的TCR,其还包含:
(a)α链恒定区,其包含与氨基酸序列SEQ ID NO:141至少95%一致的氨基酸序列,其中:
(i)SEQ ID NO:141的位置1处的X为Asn、Asp、His或Tyr;
(ii)SEQ ID NO:141的位置48处的X为Thr或Cys;
(iii)SEQ ID NO:141的位置112处的X为Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
(iv)SEQ ID NO:141的位置114处的X为Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且
(v)SEQ ID NO:141的位置115处的X为Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
其中任选地,所述α链恒定区包含与氨基酸序列SEQ ID NO:97或145至少95%一致的氨基酸序列;
(b)β链恒定区,其包含与氨基酸序列SEQ ID NO:142至少95%一致的氨基酸序列,其中SEQ ID NO:142的位置57处的X为Ser或Cys;
其中任选地,所述β链恒定区包含与氨基酸序列SEQ ID NO:99或140至少95%一致的氨基酸序列;或
(c)(a)以及(b)两者。
5.如权利要求1至3中任一项所述的TCR,其还包含:
(a)α链恒定区,其包含氨基酸序列SEQ ID NO:141,其中:
(i)SEQ ID NO:141的位置1处的X为Asn、Asp、His或Tyr;
(ii)SEQ ID NO:141的位置48处的X为Thr或Cys;
(iii)SEQ ID NO:141的位置112处的X为Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
(iv)SEQ ID NO:141的位置114处的X为Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且
(v)SEQ ID NO:141的位置115处的X为Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
其中任选地,所述α链恒定区包含氨基酸序列SEQ ID NO:97或145;
(b)β链恒定区,其包含氨基酸序列SEQ ID NO:142,其中SEQ ID NO:142的位置57处的X为Ser或Cys;
其中任选地,所述β链恒定区包含氨基酸序列SEQ ID NO:99或140;或
(c)(a)以及(b)两者。
6.如权利要求1至5中任一项所述的TCR,其中所述TCR包含:
(1)与氨基酸序列SEQ ID NO:14至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:15至少95%一致的氨基酸序列两者;
(2)与氨基酸序列SEQ ID NO:16至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:17至少95%一致的氨基酸序列两者;
(3)与氨基酸序列SEQ ID NO:18至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:19至少95%一致的氨基酸序列两者;
(4)与氨基酸序列SEQ ID NO:33至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:34至少95%一致的氨基酸序列两者;
(5)与氨基酸序列SEQ ID NO:35至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:36至少95%一致的氨基酸序列两者;
(6)与氨基酸序列SEQ ID NO:37至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:38至少95%一致的氨基酸序列两者;
(7)与氨基酸序列SEQ ID NO:52至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:53至少95%一致的氨基酸序列两者;
(8)与氨基酸序列SEQ ID NO:54至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:55至少95%一致的氨基酸序列两者;
(9)与氨基酸序列SEQ ID NO:56至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:57至少95%一致的氨基酸序列两者;
(10)与氨基酸序列SEQ ID NO:71至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:72至少95%一致的氨基酸序列两者;
(11)与氨基酸序列SEQ ID NO:73至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:74至少95%一致的氨基酸序列两者;
(12)与氨基酸序列SEQ ID NO:75至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:76至少95%一致的氨基酸序列两者;
(13)与氨基酸序列SEQ ID NO:90至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:91至少95%一致的氨基酸序列两者;
(14)与氨基酸序列SEQ ID NO:92至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:93至少95%一致的氨基酸序列两者;或
(15)与氨基酸序列SEQ ID NO:94至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:95至少95%一致的氨基酸序列两者。
7.如权利要求1至5中任一项所述的TCR,其中所述TCR包含以下的氨基酸序列:
(1)SEQ ID NO:14以及15两者;
(2)SEQ ID NO:16以及17两者;
(3)SEQ ID NO:18以及19两者;
(4)SEQ ID NO:33以及34两者;
(5)SEQ ID NO:35以及36两者;
(6)SEQ ID NO:37以及38两者;
(7)SEQ ID NO:52以及53两者;
(8)SEQ ID NO:54以及55两者;
(9)SEQ ID NO:56以及57两者;
(10)SEQ ID NO:71以及72两者;
(11)SEQ ID NO:73以及74两者;
(12)SEQ ID NO:75以及76两者;
(13)SEQ ID NO:90以及91两者;
(14)SEQ ID NO:92以及93两者;或
(15)SEQ ID NO:94以及95两者。
8.如权利要求1至7中任一项所述的TCR,其中所述人类p53R273C氨基酸序列为SGNLLGRNSFEVCVCACPGRDRRTE(SEQ ID NO:117)。
9.如权利要求1至7中任一项所述的TCR,其中所述人类p53Y220C氨基酸序列为DRNTFRHSVVVPCEPPEVGSDCTTI(SEQ ID NO:115)。
10.如权利要求1至8中任一项所述的TCR,其中所述TCR对野生型人类p53氨基酸序列SGNLLGRNSFEVRVCACPGRDRRTE(SEQ ID NO:116)不具有抗原特异性。
11.如权利要求1至7以及9中任一项所述的TCR,其中所述TCR对野生型人类p53氨基酸序列DRNTFRHSVVVPYEPPEVGSDCTTI(SEQ ID NO:114)不具有抗原特异性。
12.分离或纯化的多肽,其包含如权利要求1至11中任一项所述的TCR的功能部分,其中所述多肽包含以下的氨基酸序列:
(1)SEQ ID NO:2-7的全部;
(2)SEQ ID NO:21-26的全部;
(3)SEQ ID NO:40-45的全部;
(4)SEQ ID NO:59-64的全部;或
(5)SEQ ID NO:78-83的全部。
13.如权利要求12的多肽,其中所述多肽包含:
(1)与氨基酸序列SEQ ID NO:8至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:9至少95%一致的氨基酸序列两者;
(2)与氨基酸序列SEQ ID NO:10至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:11至少95%一致的氨基酸序列两者;
(3)与氨基酸序列SEQ ID NO:12至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:13至少95%一致的氨基酸序列两者;
(4)与氨基酸序列SEQ ID NO:12至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:11至少95%一致的氨基酸序列两者;
(5)与氨基酸序列SEQ ID NO:121至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:13至少95%一致的氨基酸序列两者;
(6)与氨基酸序列SEQ ID NO:121至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:122至少95%一致的氨基酸序列两者;
(7)与氨基酸序列SEQ ID NO:8至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:120至少95%一致的氨基酸序列两者;
(8)与氨基酸序列SEQ ID NO:119至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:9至少95%一致的氨基酸序列两者;
(9)与氨基酸序列SEQ ID NO:119至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:120至少95%一致的氨基酸序列两者;
(10)与氨基酸序列SEQ ID NO:27至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:28至少95%一致的氨基酸序列两者;
(11)与氨基酸序列SEQ ID NO:29至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:30至少95%一致的氨基酸序列两者;
(12)与氨基酸序列SEQ ID NO:31至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:32至少95%一致的氨基酸序列两者;
(13)与氨基酸序列SEQ ID NO:31至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:30至少95%一致的氨基酸序列两者;
(14)与氨基酸序列SEQ ID NO:125至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:32至少95%一致的氨基酸序列两者;
(15)与氨基酸序列SEQ ID NO:125至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:126至少95%一致的氨基酸序列两者;
(16)与氨基酸序列SEQ ID NO:27至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:124至少95%一致的氨基酸序列两者;
(17)与氨基酸序列SEQ ID NO:123至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:28至少95%一致的氨基酸序列两者;
(18)与氨基酸序列SEQ ID NO:123至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:124至少95%一致的氨基酸序列两者;
(19)与氨基酸序列SEQ ID NO:46至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:47至少95%一致的氨基酸序列两者;
(20)与氨基酸序列SEQ ID NO:48至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:49至少95%一致的氨基酸序列两者;
(21)与氨基酸序列SEQ ID NO:50至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:51至少95%一致的氨基酸序列两者;
(22)与氨基酸序列SEQ ID NO:50至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:49至少95%一致的氨基酸序列两者;
(23)与氨基酸序列SEQ ID NO:129至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:51至少95%一致的氨基酸序列两者;
(24)与氨基酸序列SEQ ID NO:129至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:130至少95%一致的氨基酸序列两者;
(25)与氨基酸序列SEQ ID NO:46至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:128至少95%一致的氨基酸序列两者;
(26)与氨基酸序列SEQ ID NO:127至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:47至少95%一致的氨基酸序列两者;
(27)与氨基酸序列SEQ ID NO:127至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:128至少95%一致的氨基酸序列两者;
(28)与氨基酸序列SEQ ID NO:65至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:66至少95%一致的氨基酸序列两者;
(29)与氨基酸序列SEQ ID NO:67至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:68至少95%一致的氨基酸序列两者;
(30)与氨基酸序列SEQ ID NO:69至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:70至少95%一致的氨基酸序列两者;
(31)与氨基酸序列SEQ ID NO:69至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:68至少95%一致的氨基酸序列两者;
(32)与氨基酸序列SEQ ID NO:133至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:70至少95%一致的氨基酸序列两者;
(33)与氨基酸序列SEQ ID NO:133至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:134至少95%一致的氨基酸序列两者;
(34)与氨基酸序列SEQ ID NO:65至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:132至少95%一致的氨基酸序列两者;
(35)与氨基酸序列SEQ ID NO:131至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:66至少95%一致的氨基酸序列两者;
(36)与氨基酸序列SEQ ID NO:131至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:132至少95%一致的氨基酸序列两者;
(37)与氨基酸序列SEQ ID NO:84至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:85至少95%一致的氨基酸序列两者;
(38)与氨基酸序列SEQ ID NO:86至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:87至少95%一致的氨基酸序列两者;
(39)与氨基酸序列SEQ ID NO:88至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:89至少95%一致的氨基酸序列两者;
(40)与氨基酸序列SEQ ID NO:88至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:87至少95%一致的氨基酸序列两者;
(41)与氨基酸序列SEQ ID NO:137至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:89至少95%一致的氨基酸序列两者;
(42)与氨基酸序列SEQ ID NO:137至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:138至少95%一致的氨基酸序列两者;
(43)与氨基酸序列SEQ ID NO:84至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:136至少95%一致的氨基酸序列两者;
(44)与氨基酸序列SEQ ID NO:135至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:85至少95%一致的氨基酸序列两者;或
(45)与氨基酸序列SEQ ID NO:135至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:136至少95%一致的氨基酸序列两者。
14.如权利要求12所述的多肽,其中所述多肽包含以下的氨基酸序列:
(1)SEQ ID NO:8以及9两者;
(2)SEQ ID NO:10以及11两者;
(3)SEQ ID NO:12以及13两者;
(4)SEQ ID NO:12以及11两者;
(5)SEQ ID NO:121以及13两者;
(6)SEQ ID NO:121以及122两者;
(7)SEQ ID NO:8以及120两者;
(8)SEQ ID NO:119以及9两者;
(9)SEQ ID NO:119以及120两者;
(10)SEQ ID NO:27以及28两者;
(11)SEQ ID NO:29以及30两者;
(12)SEQ ID NO:31以及32两者;
(13)SEQ ID NO:31以及30两者;
(14)SEQ ID NO:125以及32两者;
(15)SEQ ID NO:125以及126两者;
(16)SEQ ID NO:27以及124两者;
(17)SEQ ID NO:123以及28两者;
(18)SEQ ID NO:123以及124两者;
(19)SEQ ID NO:46以及47两者;
(20)SEQ ID NO:48以及49两者;
(21)SEQ ID NO:50以及51两者;
(22)SEQ ID NO:50以及49两者;
(23)SEQ ID NO:129以及51两者;
(24)SEQ ID NO:129以及130两者;
(25)SEQ ID NO:46以及128两者;
(26)SEQ ID NO:127以及47两者;
(27)SEQ ID NO:127以及128两者;
(28)SEQ ID NO:65以及66两者;
(29)SEQ ID NO:67以及68两者;
(30)SEQ ID NO:69以及70两者;
(31)SEQ ID NO:69以及68两者;
(32)SEQ ID NO:133以及70两者;
(33)SEQ ID NO:133以及134两者;
(34)SEQ ID NO:65以及132两者;
(35)SEQ ID NO:131以及66两者;
(36)SEQ ID NO:131以及132两者;
(37)SEQ ID NO:84以及85两者;
(38)SEQ ID NO:86以及87两者;
(39)SEQ ID NO:88以及89两者;
(40)SEQ ID NO:88以及87两者;
(41)SEQ ID NO:137以及89两者;
(42)SEQ ID NO:137以及138两者;
(43)SEQ ID NO:84以及136两者;
(44)SEQ ID NO:135以及85两者;或
(45)SEQ ID NO:135以及136两者。
15.如权利要求12至14中任一项所述的多肽,其还包含:
(a)α链恒定区,其包含与氨基酸序列SEQ ID NO:141至少95%一致的氨基酸序列,其中:
(i)SEQ ID NO:141的位置1处的X为Asn、Asp、His或Tyr;
(ii)SEQ ID NO:141的位置48处的X为Thr或Cys;
(iii)SEQ ID NO:141的位置112处的X为Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
(iv)SEQ ID NO:141的位置114处的X为Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且
(v)SEQ ID NO:141的位置115处的X为Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
其中任选地,所述α链恒定区包含与氨基酸序列SEQ ID NO:97或145至少95%一致的氨基酸序列;
(b)β链恒定区,其包含与氨基酸序列SEQ ID NO:142至少95%一致的氨基酸序列,其中SEQ ID NO:142的位置57处的X为Ser或Cys;
其中任选地,所述β链恒定区包含与氨基酸序列SEQ ID NO:99或140至少95%一致的氨基酸序列;或
(c)(a)以及(b)两者。
16.如权利要求12至14中任一项所述的多肽,其还包含:
(a)α链恒定区,其包含氨基酸序列SEQ ID NO:141,其中:
(i)SEQ ID NO:141的位置1处的X为Asn、Asp、His或Tyr;
(ii)SEQ ID NO:141的位置48处的X为Thr或Cys;
(iii)SEQ ID NO:141的位置112处的X为Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
(iv)SEQ ID NO:141的位置114处的X为Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且
(v)SEQ ID NO:141的位置115处的X为Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
其中任选地,所述α链恒定区包含氨基酸序列SEQ ID NO:97或145;
(b)β链恒定区,其包含氨基酸序列SEQ ID NO:142,其中SEQ ID NO:142的位置57处的X为Ser或Cys;
其中任选地,所述β链恒定区包含氨基酸序列SEQ ID NO:99或140;或
(c)(a)以及(b)两者。
17.如权利要求12至16中任一项所述的多肽,其中所述多肽包含:
(1)与氨基酸序列SEQ ID NO:14至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:15至少95%一致的氨基酸序列两者;
(2)与氨基酸序列SEQ ID NO:16至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:17至少95%一致的氨基酸序列两者;
(3)与氨基酸序列SEQ ID NO:18至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:19至少95%一致的氨基酸序列两者;
(4)与氨基酸序列SEQ ID NO:33至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:34至少95%一致的氨基酸序列两者;
(5)与氨基酸序列SEQ ID NO:35至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:36至少95%一致的氨基酸序列两者;
(6)与氨基酸序列SEQ ID NO:37至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:38至少95%一致的氨基酸序列两者;
(7)与氨基酸序列SEQ ID NO:52至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:53至少95%一致的氨基酸序列两者;
(8)与氨基酸序列SEQ ID NO:54至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:55至少95%一致的氨基酸序列两者;
(9)与氨基酸序列SEQ ID NO:56至少95%一致的氨基酸序列以及与氨基酸序列SEQ IDNO:57至少95%一致的氨基酸序列两者;
(10)与氨基酸序列SEQ ID NO:71至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:72至少95%一致的氨基酸序列两者;
(11)与氨基酸序列SEQ ID NO:73至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:74至少95%一致的氨基酸序列两者;
(12)与氨基酸序列SEQ ID NO:75至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:76至少95%一致的氨基酸序列两者;
(13)与氨基酸序列SEQ ID NO:90至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:91至少95%一致的氨基酸序列两者;
(14)与氨基酸序列SEQ ID NO:92至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:93至少95%一致的氨基酸序列两者;或
(15)与氨基酸序列SEQ ID NO:94至少95%一致的氨基酸序列以及与氨基酸序列SEQID NO:95至少95%一致的氨基酸序列两者。
18.如权利要求12至16中任一项所述的多肽,其中所述多肽包含以下的氨基酸序列:
(1)SEQ ID NO:14以及15两者;
(2)SEQ ID NO:16以及17两者;
(3)SEQ ID NO:18以及19两者;
(4)SEQ ID NO:33以及34两者;
(5)SEQ ID NO:35以及36两者;
(6)SEQ ID NO:37以及38两者;
(7)SEQ ID NO:52以及53两者;
(8)SEQ ID NO:54以及55两者;
(9)SEQ ID NO:56以及57两者;
(10)SEQ ID NO:71以及72两者;
(11)SEQ ID NO:73以及74两者;
(12)SEQ ID NO:75以及76两者;
(13)SEQ ID NO:90以及91两者;
(14)SEQ ID NO:92以及93两者;或
(15)SEQ ID NO:94以及95两者。
19.分离或纯化的蛋白质,其包含:
(1)包含氨基酸序列SEQ ID NO:2-4全部的第一多肽链以及包含氨基酸序列SEQ IDNO:5-7全部的第二多肽链;
(2)包含氨基酸序列SEQ ID NO:21-23全部的第一多肽链以及包含氨基酸序列SEQ IDNO:24-26全部的第二多肽链;
(3)包含氨基酸序列SEQ ID NO:40-42全部的第一多肽链以及包含氨基酸序列SEQ IDNO:43-45全部的第二多肽链;
(4)包含氨基酸序列SEQ ID NO:59-61全部的第一多肽链以及包含氨基酸序列SEQ IDNO:62-64全部的第二多肽链;或
(5)包含氨基酸序列SEQ ID NO:78-80全部的第一多肽链以及包含氨基酸序列SEQ IDNO:81-83全部的第二多肽链。
20.如权利要求19所述的蛋白质,其中:
(1)第一多肽链包含与氨基酸序列SEQ ID NO:8至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:9至少95%一致的氨基酸序列;
(2)第一多肽链包含与氨基酸序列SEQ ID NO:10至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:11至少95%一致的氨基酸序列;
(3)第一多肽链包含与氨基酸序列SEQ ID NO:12至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:13至少95%一致的氨基酸序列;
(4)第一多肽链包含与氨基酸序列SEQ ID NO:12至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:11至少95%一致的氨基酸序列;
(5)第一多肽链包含与氨基酸序列SEQ ID NO:121至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:13至少95%一致的氨基酸序列;
(6)第一多肽链包含与氨基酸序列SEQ ID NO:121至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:122至少95%一致的氨基酸序列;
(7)第一多肽链包含与氨基酸序列SEQ ID NO:8至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:120至少95%一致的氨基酸序列;
(8)第一多肽链包含与氨基酸序列SEQ ID NO:119至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:9至少95%一致的氨基酸序列;
(9)第一多肽链包含与氨基酸序列SEQ ID NO:119至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:120至少95%一致的氨基酸序列;
(10)第一多肽链包含与氨基酸序列SEQ ID NO:27至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:28至少95%一致的氨基酸序列;
(11)第一多肽链包含与氨基酸序列SEQ ID NO:29至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:30至少95%一致的氨基酸序列;
(12)第一多肽链包含与氨基酸序列SEQ ID NO:31至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:32至少95%一致的氨基酸序列;
(13)第一多肽链包含与氨基酸序列SEQ ID NO:31至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:30至少95%一致的氨基酸序列;
(14)第一多肽链包含与氨基酸序列SEQ ID NO:125至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:32至少95%一致的氨基酸序列;
(15)第一多肽链包含与氨基酸序列SEQ ID NO:125至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:126至少95%一致的氨基酸序列;
(16)第一多肽链包含与氨基酸序列SEQ ID NO:27至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:124至少95%一致的氨基酸序列;
(17)第一多肽链包含与氨基酸序列SEQ ID NO:123至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:28至少95%一致的氨基酸序列;
(18)第一多肽链包含与氨基酸序列SEQ ID NO:123至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:124至少95%一致的氨基酸序列;
(19)第一多肽链包含与氨基酸序列SEQ ID NO:46至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:47至少95%一致的氨基酸序列;
(20)第一多肽链包含与氨基酸序列SEQ ID NO:48至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:49至少95%一致的氨基酸序列;
(21)第一多肽链包含与氨基酸序列SEQ ID NO:50至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:51至少95%一致的氨基酸序列;
(22)第一多肽链包含与氨基酸序列SEQ ID NO:50至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:49至少95%一致的氨基酸序列;
(23)第一多肽链包含与氨基酸序列SEQ ID NO:129至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:51至少95%一致的氨基酸序列;
(24)第一多肽链包含与氨基酸序列SEQ ID NO:129至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:130至少95%一致的氨基酸序列;
(25)第一多肽链包含与氨基酸序列SEQ ID NO:46至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:128至少95%一致的氨基酸序列;
(26)第一多肽链包含与氨基酸序列SEQ ID NO:127至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:47至少95%一致的氨基酸序列;
(27)第一多肽链包含与氨基酸序列SEQ ID NO:127至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:128至少95%一致的氨基酸序列;
(28)第一多肽链包含与氨基酸序列SEQ ID NO:65至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:66至少95%一致的氨基酸序列;
(29)第一多肽链包含与氨基酸序列SEQ ID NO:67至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:68至少95%一致的氨基酸序列;
(30)第一多肽链包含与氨基酸序列SEQ ID NO:69至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:70至少95%一致的氨基酸序列;
(31)第一多肽链包含与氨基酸序列SEQ ID NO:69至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:68至少95%一致的氨基酸序列;
(32)第一多肽链包含与氨基酸序列SEQ ID NO:133至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:70至少95%一致的氨基酸序列;
(33)第一多肽链包含与氨基酸序列SEQ ID NO:133至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:134至少95%一致的氨基酸序列;
(34)第一多肽链包含与氨基酸序列SEQ ID NO:65至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:132至少95%一致的氨基酸序列;
(35)第一多肽链包含与氨基酸序列SEQ ID NO:131至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:66至少95%一致的氨基酸序列;
(36)第一多肽链包含与氨基酸序列SEQ ID NO:131至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:132至少95%一致的氨基酸序列;
(37)第一多肽链包含与氨基酸序列SEQ ID NO:84至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:85至少95%一致的氨基酸序列;
(38)第一多肽链包含与氨基酸序列SEQ ID NO:86至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:87至少95%一致的氨基酸序列;
(39)第一多肽链包含与氨基酸序列SEQ ID NO:88至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:89至少95%一致的氨基酸序列;
(40)第一多肽链包含与氨基酸序列SEQ ID NO:88至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:87至少95%一致的氨基酸序列;
(41)第一多肽链包含与氨基酸序列SEQ ID NO:137至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:89至少95%一致的氨基酸序列;
(42)第一多肽链包含与氨基酸序列SEQ ID NO:137至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:138至少95%一致的氨基酸序列;
(43)第一多肽链包含与氨基酸序列SEQ ID NO:84至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:136至少95%一致的氨基酸序列;
(44)第一多肽链包含与氨基酸序列SEQ ID NO:135至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:85至少95%一致的氨基酸序列;或
(45)第一多肽链包含与氨基酸序列SEQ ID NO:135至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:136至少95%一致的氨基酸序列。
21.如权利要求19所述的蛋白质,其中:
(1)第一多肽链包含氨基酸序列SEQ ID NO:8以及第二多肽链包含氨基酸序列SEQ IDNO:9;
(2)第一多肽链包含氨基酸序列SEQ ID NO:10以及第二多肽链包含氨基酸序列SEQ IDNO:11;
(3)第一多肽链包含氨基酸序列SEQ ID NO:12以及第二多肽链包含氨基酸序列SEQ IDNO:13;
(4)第一多肽链包含氨基酸序列SEQ ID NO:12以及第二多肽链包含氨基酸序列SEQ IDNO:11;
(5)第一多肽链包含氨基酸序列SEQ ID NO:121以及第二多肽链包含氨基酸序列SEQID NO:13;
(6)第一多肽链包含氨基酸序列SEQ ID NO:121以及第二多肽链包含氨基酸序列SEQID NO:122;
(7)第一多肽链包含氨基酸序列SEQ ID NO:8以及第二多肽链包含氨基酸序列SEQ IDNO:120;
(8)第一多肽链包含氨基酸序列SEQ ID NO:119以及第二多肽链包含氨基酸序列SEQID NO:9;
(9)第一多肽链包含氨基酸序列SEQ ID NO:119以及第二多肽链包含氨基酸序列SEQID NO:120;
(10)第一多肽链包含氨基酸序列SEQ ID NO:27以及第二多肽链包含氨基酸序列SEQID NO:28;
(11)第一多肽链包含氨基酸序列SEQ ID NO:29以及第二多肽链包含氨基酸序列SEQID NO:30;
(12)第一多肽链包含氨基酸序列SEQ ID NO:31以及第二多肽链包含氨基酸序列SEQID NO:32;
(13)第一多肽链包含氨基酸序列SEQ ID NO:31以及第二多肽链包含氨基酸序列SEQID NO:30;
(14)第一多肽链包含氨基酸序列SEQ ID NO:125以及第二多肽链包含氨基酸序列SEQID NO:32;
(15)第一多肽链包含氨基酸序列SEQ ID NO:125以及第二多肽链包含氨基酸序列SEQID NO:126;
(16)第一多肽链包含氨基酸序列SEQ ID NO:27以及第二多肽链包含氨基酸序列SEQID NO:124;
(17)第一多肽链包含氨基酸序列SEQ ID NO:123以及第二多肽链包含氨基酸序列SEQID NO:28;
(18)第一多肽链包含氨基酸序列SEQ ID NO:123以及第二多肽链包含氨基酸序列SEQID NO:124;
(19)第一多肽链包含氨基酸序列SEQ ID NO:46以及第二多肽链包含氨基酸序列SEQID NO:47;
(20)第一多肽链包含氨基酸序列SEQ ID NO:48以及第二多肽链包含氨基酸序列SEQID NO:49;
(21)第一多肽链包含氨基酸序列SEQ ID NO:50以及第二多肽链包含氨基酸序列SEQID NO:51;
(22)第一多肽链包含氨基酸序列SEQ ID NO:50以及第二多肽链包含氨基酸序列SEQID NO:49;
(23)第一多肽链包含氨基酸序列SEQ ID NO:129以及第二多肽链包含氨基酸序列SEQID NO:51;
(24)第一多肽链包含氨基酸序列SEQ ID NO:129以及第二多肽链包含氨基酸序列SEQID NO:130;
(25)第一多肽链包含氨基酸序列SEQ ID NO:46以及第二多肽链包含氨基酸序列SEQID NO:128;
(26)第一多肽链包含氨基酸序列SEQ ID NO:127以及第二多肽链包含氨基酸序列SEQID NO:47;
(27)第一多肽链包含氨基酸序列SEQ ID NO:127以及第二多肽链包含氨基酸序列SEQID NO:128;
(28)第一多肽链包含氨基酸序列SEQ ID NO:65以及第二多肽链包含氨基酸序列SEQID NO:66;
(29)第一多肽链包含氨基酸序列SEQ ID NO:67以及第二多肽链包含氨基酸序列SEQID NO:68;
(30)第一多肽链包含氨基酸序列SEQ ID NO:69以及第二多肽链包含氨基酸序列SEQID NO:70;
(31)第一多肽链包含氨基酸序列SEQ ID NO:69以及第二多肽链包含氨基酸序列SEQID NO:68;
(32)第一多肽链包含氨基酸序列SEQ ID NO:133以及第二多肽链包含氨基酸序列SEQID NO:70;
(33)第一多肽链包含氨基酸序列SEQ ID NO:133以及第二多肽链包含氨基酸序列SEQID NO:134;
(34)第一多肽链包含氨基酸序列SEQ ID NO:65以及第二多肽链包含氨基酸序列SEQID NO:132;
(35)第一多肽链包含氨基酸序列SEQ ID NO:131以及第二多肽链包含氨基酸序列SEQID NO:66;
(36)第一多肽链包含氨基酸序列SEQ ID NO:131以及第二多肽链包含氨基酸序列SEQID NO:132;
(37)第一多肽链包含氨基酸序列SEQ ID NO:84以及第二多肽链包含氨基酸序列SEQID NO:85;
(38)第一多肽链包含氨基酸序列SEQ ID NO:86以及第二多肽链包含氨基酸序列SEQID NO:87;
(39)第一多肽链包含氨基酸序列SEQ ID NO:88以及第二多肽链包含氨基酸序列SEQID NO:89;
(40)第一多肽链包含氨基酸序列SEQ ID NO:88以及第二多肽链包含氨基酸序列SEQID NO:87;
(41)第一多肽链包含氨基酸序列SEQ ID NO:137以及第二多肽链包含氨基酸序列SEQID NO:89;
(42)第一多肽链包含氨基酸序列SEQ ID NO:137以及第二多肽链包含氨基酸序列SEQID NO:138;
(43)第一多肽链包含氨基酸序列SEQ ID NO:84以及第二多肽链包含氨基酸序列SEQID NO:136;
(44)第一多肽链包含氨基酸序列SEQ ID NO:135以及第二多肽链包含氨基酸序列SEQID NO:85;或
(45)第一多肽链包含氨基酸序列SEQ ID NO:135以及第二多肽链包含氨基酸序列SEQID NO:136。
22.如权利要求19至21中任一项所述的蛋白质,其中:
(a)第一多肽链包含含有与氨基酸序列SEQ ID NO:141至少95%一致的氨基酸序列的α链恒定区,其中:
(i)SEQ ID NO:141的位置1处的X为Asn、Asp、His或Tyr;
(ii)SEQ ID NO:141的位置48处的X为Thr或Cys;
(iii)SEQ ID NO:141的位置112处的X为Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
(iv)SEQ ID NO:141的位置114处的X为Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且
(v)SEQ ID NO:141的位置115处的X为Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
其中任选地,所述第一多肽链包含含有与氨基酸序列SEQ ID NO:97或145至少95%一致的氨基酸序列的α链恒定区;且
(b)第二多肽链包含含有与氨基酸序列SEQ ID NO:142至少95%一致的氨基酸序列的β链恒定区,其中SEQ ID NO:142的位置57处的X为Ser或Cys;
其中任选地,所述第二多肽链包含含有与氨基酸序列SEQ ID NO:99或140至少95%一致的氨基酸序列的β链恒定区。
23.如权利要求19至21中任一项所述的蛋白质,其还包含:
(a)第一多肽链,其包含含有氨基酸序列SEQ ID NO:141的α链恒定区,其中:
(i)SEQ ID NO:141的位置1处的X为Asn、Asp、His或Tyr;
(ii)SEQ ID NO:141的位置48处的X为Thr或Cys;
(iii)SEQ ID NO:141的位置112处的X为Ser、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
(iv)SEQ ID NO:141的位置114处的X为Met、Ala、Val、Leu、Ile、Pro、Phe或Trp;且
(v)SEQ ID NO:141的位置115处的X为Gly、Ala、Val、Leu、Ile、Pro、Phe、Met或Trp;
其中任选地,所述第一多肽链包含含有氨基酸序列SEQ ID NO:97或145的α链恒定区;以及
(b)第二多肽链,其包含含有氨基酸序列SEQ ID NO:142的β链恒定区,其中SEQ ID NO:142的位置57处的X为Ser或Cys;
其中任选地,所述第二多肽链包含含有氨基酸序列SEQ ID NO:99或140的β链恒定区。
24.如权利要求19至23中任一项所述的蛋白质,其中:
(1)第一多肽链包含与氨基酸序列SEQ ID NO:14至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:15至少95%一致的氨基酸序列;
(2)第一多肽链包含与氨基酸序列SEQ ID NO:16至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:17至少95%一致的氨基酸序列;
(3)第一多肽链包含与氨基酸序列SEQ ID NO:18至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:19至少95%一致的氨基酸序列;
(4)第一多肽链包含与氨基酸序列SEQ ID NO:33至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:34至少95%一致的氨基酸序列;
(5)第一多肽链包含与氨基酸序列SEQ ID NO:35至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:36至少95%一致的氨基酸序列;
(6)第一多肽链包含与氨基酸序列SEQ ID NO:37至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:38至少95%一致的氨基酸序列;
(7)第一多肽链包含与氨基酸序列SEQ ID NO:52至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:53至少95%一致的氨基酸序列;
(8)第一多肽链包含与氨基酸序列SEQ ID NO:54至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:55至少95%一致的氨基酸序列;
(9)第一多肽链包含与氨基酸序列SEQ ID NO:56至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:57至少95%一致的氨基酸序列;
(10)第一多肽链包含与氨基酸序列SEQ ID NO:71至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:72至少95%一致的氨基酸序列;
(11)第一多肽链包含与氨基酸序列SEQ ID NO:73至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:74至少95%一致的氨基酸序列;
(12)第一多肽链包含与氨基酸序列SEQ ID NO:75至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:76至少95%一致的氨基酸序列;
(13)第一多肽链包含与氨基酸序列SEQ ID NO:90至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:91至少95%一致的氨基酸序列;
(14)第一多肽链包含与氨基酸序列SEQ ID NO:92至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:93至少95%一致的氨基酸序列;或
(15)第一多肽链包含与氨基酸序列SEQ ID NO:94至少95%一致的氨基酸序列以及第二多肽链包含与氨基酸序列SEQ ID NO:95至少95%一致的氨基酸序列。
25.如权利要求19至23中任一项所述的蛋白质,其中:
(1)第一多肽链包含氨基酸序列SEQ ID NO:14以及第二多肽链包含氨基酸序列SEQ IDNO:15;
(2)第一多肽链包含氨基酸序列SEQ ID NO:16以及第二多肽链包含氨基酸序列SEQ IDNO:17;
(3)第一多肽链包含氨基酸序列SEQ ID NO:18以及第二多肽链包含氨基酸序列SEQ IDNO:19;
(4)第一多肽链包含氨基酸序列SEQ ID NO:33以及第二多肽链包含氨基酸序列SEQ IDNO:34;
(5)第一多肽链包含氨基酸序列SEQ ID NO:35以及第二多肽链包含氨基酸序列SEQ IDNO:36;
(6)第一多肽链包含氨基酸序列SEQ ID NO:37以及第二多肽链包含氨基酸序列SEQ IDNO:38;
(7)第一多肽链包含氨基酸序列SEQ ID NO:52以及第二多肽链包含氨基酸序列SEQ IDNO:53;
(8)第一多肽链包含氨基酸序列SEQ ID NO:54以及第二多肽链包含氨基酸序列SEQ IDNO:55;
(9)第一多肽链包含氨基酸序列SEQ ID NO:56以及第二多肽链包含氨基酸序列SEQ IDNO:57;
(10)第一多肽链包含氨基酸序列SEQ ID NO:71以及第二多肽链包含氨基酸序列SEQID NO:72;
(11)第一多肽链包含氨基酸序列SEQ ID NO:73以及第二多肽链包含氨基酸序列SEQID NO:74;
(12)第一多肽链包含氨基酸序列SEQ ID NO:75以及第二多肽链包含氨基酸序列SEQID NO:76;
(13)第一多肽链包含氨基酸序列SEQ ID NO:90以及第二多肽链包含氨基酸序列SEQID NO:91;
(14)第一多肽链包含氨基酸序列SEQ ID NO:92以及第二多肽链包含氨基酸序列SEQID NO:93;或
(15)第一多肽链包含氨基酸序列SEQ ID NO:94以及第二多肽链包含氨基酸序列SEQID NO:95。
26.分离或纯化的核酸,其包含编码以下的核苷酸序列:如权利要求1至11中任一项所述的TCR、如权利要求12至18中任一项所述的多肽或如权利要求19至25中任一项所述的蛋白质。
27.分离或纯化的核酸,其自5'至3'包含第一核苷酸序列以及第二核苷酸序列,其中所述第一和第二核苷酸序列分别编码以下的氨基酸序列:SEQ ID NO:8和9;9和8;10和11;11和10;12和13;13和12;12和11;11和12;121和13;13和121;121和122;122和121;8和120;120和8;119和9;9和119;119和120;120和119;14和15;15和14;16和17;17和16;18和19;19和18;27和28;28和27;29和30;30和29;31和32;32和31;31和30;30和31;125和32;32和125;125和126;126和125;27和124;124和27;123和28;28和123;123和124;124和123;33和34;34和33;35和36;36和35;37和38;38和37;46和47;47和46;48和49;49和48;50和51;51和50;50和49;49和50;129和51;51和129;129和130;130和129;46和128;128和46;127和47;
47和127;127和128;128和127;52和53;53和52;54和55;55和54;56和57;57和56;65和66;66和65;67和68;68和67;69和70;70和69;69和68;68和69;133和70;70和133;133和134;134和133;65和132;132和65;131和66;66和131;131和132;132和131;71和72;72和71;73和74;74和73;75和76;76和75;84和85;85和84;86和87;87和86;88和89;89和88;88和87;87和88;137和89;89和137;137和138;138和137;84和136;136和84;135和85;85和135;135和136;136和135;90和91;91和90;92和93;93和92;94和95;或95和94。
28.如权利要求27所述的分离或纯化的核酸,其还包含插入所述第一与第二核苷酸序列之间的第三核苷酸序列,其中所述第三核苷酸序列编码可切割的接头肽。
29.如权利要求28所述的分离或纯化的核酸,其中所述可切割的接头肽包含氨基酸序列RAKRSGSGATNFSLLKQAGDVEENPGP(SEQ ID NO:100)。
30.如权利要求29的分离或纯化核酸,其编码选自以下的氨基酸序列:SEQ ID NO:20、39、58、77以及96。
31.重组表达载体,其包含如权利要求26至30中任一项所述的核酸。
32.如权利要求31所述的重组表达载体,其为转座子或慢病毒载体。
33.分离或纯化的TCR、多肽或蛋白质,其由如权利要求26至30中任一项所述的核酸或如权利要求31或32所述的载体编码。
34.分离或纯化的TCR、多肽或蛋白质,其由权利要求26至30中任一项所述的核酸或权利要求31或32所述的载体在细胞中的表达所产生。
35.产生表达TCR的宿主细胞的方法,所述TCR对肽DRNTFRHSVVVPCEPPEVGSDCTTI(SEQID NO:115)或SGNLLGRNSFEVCVCACPGRDRRTE(SEQ ID NO:117)具有抗原特异性,所述方法包括使细胞与权利要求31或32所述的载体在允许将所述载体导入所述细胞中的条件下接触。
36.分离或纯化的宿主细胞,其包含如权利要求26至30中任一项所述的核酸、或如权利要求31或32所述的重组表达载体。
37.如权利要求36所述的宿主细胞,其中所述细胞为人类淋巴细胞。
38.如权利要求36所述的宿主细胞,其中所述细胞选自T细胞、自然杀伤T(NKT)细胞、恒定自然杀伤T(iNKT)细胞以及自然杀伤(NK)细胞。
39.分离或纯化的细胞群,其包含如权利要求36至38中任一项所述的宿主细胞。
40.产生如权利要求1至11、33或34中任一项所述的TCR,如权利要求12至18、33或34中任一项所述的多肽或如权利要求19至25、33或34中任一项所述的蛋白质的方法,所述方法包括培养如权利要求36至38中任一项所述的宿主细胞或如权利要求39所述的宿主细胞群,以使得产生所述TCR、多肽或蛋白质。
41.药物组合物,其包含:(a)如权利要求1至11、33或34中任一项所述的TCR,如权利要求12至18、33或34中任一项所述的多肽,如权利要求19至25、33或34中任一项所述的蛋白质,如权利要求26至30中任一项所述的核酸,如权利要求31或32所述的重组表达载体,如权利要求36至38中任一项所述的宿主细胞,或如权利要求39所述的细胞群;以及(b)药学上可接受的载体。
42.检测哺乳动物中癌症的存在的方法,所述方法包括:
(a)使包含所述癌症的细胞的样本与以下接触从而形成复合物:如权利要求1至11、33或34中任一项所述的TCR,如权利要求12至18、33或34中任一项所述的多肽,如权利要求19至25、33或34中任一项所述的蛋白质,如权利要求26至30中任一项所述的核酸,如权利要求31或32所述的重组表达载体,如权利要求36至38中任一项所述的宿主细胞,如权利要求39所述的细胞群,或如权利要求41所述的药物组合物;以及
(b)检测所述复合物,
其中所述复合物的测出指示所述哺乳动物中癌症的存在。
43.如权利要求1至11、33或34中任一项所述的TCR,如权利要求12至18、33或34中任一项所述的多肽,如权利要求19至25、33或34中任一项所述的蛋白质,如权利要求26至30中任一项所述的核酸,如权利要求31或32所述的重组表达载体,如权利要求36至38中任一项所述的宿主细胞、如权利要求39所述的细胞群或如权利要求41所述的药物组合物,其用于诱导针对哺乳动物的癌症的免疫反应的用途。
44.如权利要求1至11、33或34中任一项所述的TCR、如权利要求12至18、33或34中任一项所述的多肽、如权利要求19至25、33或34中任一项所述的蛋白质、如权利要求26至30中任一项所述的核酸、如权利要求31或32所述的重组表达载体、如权利要求36至38中任一项所述的宿主细胞、如权利要求39所述的细胞群或如权利要求41所述的药物组合物,其用于治疗或预防哺乳动物的癌症的用途。
45.如权利要求43或44所述的用途的细胞群或包含所述细胞群的药物组合物,其中所述细胞群对于所述哺乳动物为自体的。
46.如权利要求43或44所述的用途的细胞群或包含所述细胞群的药物组合物,其中所述细胞群对于所述哺乳动物为同种异体的。
47.如权利要求42所述的方法或者如权利要求43至46中任一项所述的用途的TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞、细胞群或药物组合物,其中所述癌症为上皮癌。
48.如权利要求42所述的方法或者如权利要求43至46中任一项所述的用途的TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞、细胞群或药物组合物,其中所述癌症为胆管癌、黑色素瘤、结肠癌、直肠癌、卵巢癌、子宫内膜癌、非小细胞肺癌(NSCLC)、胶质母细胞瘤、子宫颈癌、头颈癌、乳腺癌、胰脏癌或膀胱癌。
49.如权利要求42所述的方法或者如权利要求43至48中任一项所述的用途的TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞、细胞群或药物组合物,其中已知所述癌症包含人类p53中的R273C或Y220C突变。
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