CN111386282A - 识别突变的p53的T细胞受体 - Google Patents
识别突变的p53的T细胞受体 Download PDFInfo
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- CN111386282A CN111386282A CN201880074539.8A CN201880074539A CN111386282A CN 111386282 A CN111386282 A CN 111386282A CN 201880074539 A CN201880074539 A CN 201880074539A CN 111386282 A CN111386282 A CN 111386282A
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Abstract
本申请公开了对突变的人p53具有抗原特异性的分离或纯化的T细胞受体(TCR)。本申请还提供了相关多肽和蛋白质以及相关核酸、重组表达载体、宿主细胞、细胞群和药物组合物。本申请还公开了检测哺乳动物中是否存在癌症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
本专利申请要求于2017年9月29日提交的美国临时专利申请号62/565,383的权益，其通过引用整体并入本文。
关于联邦政府资助的研究和开发的声明
本发明是由美国国立卫生研究院国家癌症研究所(National Institutes ofHealth,National Cancer Institute)在政府支持下完成的，项目号为BC010985。政府拥有本发明的某些权利。
通过引用并入以电子方式提交的材料
通过引用整体并入本文的是与此同时提交并且标识如下的计算机可读核苷酸/氨基酸序列表:日期为2018年9月7日的一个名为“739980_ST25.txt”的687,555字节ASCII(文本)文件。
发明背景
某些癌症的治疗选择可能非常有限，尤其是当癌症转移且无法切除时。尽管例如手术、化疗和放射治疗等治疗取得了进展，但许多癌症(例如胰腺、结直肠、肺、子宫内膜、卵巢和前列腺癌)的预后可能较差。因此，对癌症额外治疗的需求尚未得到满足。
发明简述
本发明的一个实施方案提供对突变的人p53具有抗原特异性的分离或纯化T细胞受体(TCR)。
本发明的其它实施方案提供涉及本发明TCR的相关多肽和蛋白质以及相关核酸、重组表达载体、宿主细胞、细胞群以及药物组合物。
本发明的另外实施方案提供了检测哺乳动物中癌症存在的方法以及治疗或预防哺乳动物中癌症的方法。
若干附图视图的简述
图1是显示与用所指示的浓度(μg/mL)渐低的WTp53-G245肽(wt)(无阴影条)或突变型p53-G245S肽(mut)(阴影条)脉冲的自体树突状细胞(DC)共培养后，在与用来自患者4127的一个指定TCR转导的自体PBL共培养后测量的IFN-γ(pg/mL)浓度的图。
图2是显示在将用来自患者4127的一个所示TCR转导的自体PBL与用所指示的浓度(μg/mL)渐低的WTp53-G245肽(wt)(无阴影条)或突变型p53-G245S肽(mut)(阴影条)脉冲的自体树突状细胞(DC)共培养后，检测到的4-1BB阳性细胞的百分比(％CD4+mTCRβ+)的图。
图3是显示在将用来自患者4127的一个所示TCR转导的自体PBL与用表A所示的一种肽脉冲的自体DC共培养后，检测到的4-1BB阳性细胞的百分比(％CD4+mTCRβ+)的图。
图4是显示在将来自患者4127的TIL或用一个所示TCR转导的T细胞与COS7细胞共培养后测量的IFN-γ(pg/mL)浓度的图，所述COS7细胞用一种所示HLA等位基因转导并且用DMSO或一种所示肽脉冲。
图5是显示在将来自患者4127的TIL或用一个所示TCR转导的T细胞与COS7细胞共培养后检测到的4-1BB阳性细胞(CD4+mTCRβ+的％)的百分比的图，所述COS7细胞用一种所示HLA等位基因转导并且用DMSO或一种所示肽脉冲。
图6是显示在共培养来自患者4127的TIL与同种异体的(DRB3*01:01:01或DRB3*02:02:01)APC之后测量的每2x104个效应细胞的斑点的数量的图，所述同种异体的(DRB3*01:01:01或DRB3*02:02:01)APC(1)用由无关(IRR；左侧斜线空条)、WT p53(p53-WT；左侧斜线灰条)或突变的p53(p53-MUT；灰条)序列组成的TMG电穿孔或(2)用肽媒介物(DMSO；右侧斜线空条)或由WT p53-G245序列(LP-p53-wt-G245；右侧斜线灰条)或突变的p53-G245S(LP-p53-mut-G245S；黑条)序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲。
图7是显示在共培养表达4127-TCR1的细胞与同种异体的(DRB3*01:01:01或DRB3*02:02:01)APC之后测量的每2x104个效应细胞的斑点的数量的图，所述同种异体的(DRB3*01:01:01或DRB3*02:02:01)APC(1)用由无关(IRR；左侧斜线空条)、WT p53(p53-WT；左侧斜线灰条)或经突变的p53(p53-MUT；灰条)序列组成的TMG电穿孔或(2)用肽媒介物(DMSO；右侧斜线空条)或由WT p53-G245序列(LP-p53-wt-G245；右侧斜线灰条)或经突变的p53-G245S(LP-p53-mut-G245S；黑条)序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲。
图8A是显示将来自用于治疗患者4196的输注袋的TIL与转染了TMG1的质粒和指定HLA等位基因的Cos7细胞共培养后测量的IFN-γ分泌(斑点/2×104个细胞)的图。
图8B是显示将来自用于治疗患者4196的输注袋的TIL与用候选最小表位(HMTEVVRHC(SEQ ID NO:530)或(SQHMTEVRH(SEQ ID NO:531))脉冲的自体DC共培养后测量的IFN-γ分泌(斑点/2×104个细胞)的图。单独培养的T细胞作为对照。
图9A-9D是显示用指示浓度(μg/mL)的最小WT(圆圈)或突变的(mut)(方块)表位脉冲的DC与使用以下TCR之一转导的细胞共同培养后检测到的mTCRβ+CD8+41BB+细胞的百分比的图:AV12/BV6-1(A)，AV2/BV6-1(B)、AV6/BV11(C)或AV38/BV10-3(D)。将脉冲DCs与未转导(UT)细胞(三角形)共培养作为对照。显示的结果代表了两次实验。
图10A-10B是显示用指示浓度(μg/mL)的最小突变的表位脉冲的T2细胞与使用以下TCR之一转导的细胞共同培养后测得的IFN-γ分泌(pg/mL)(A)和4-1BB阳性细胞百分比(％，mTCRβ+)(B)的图:AV12/BV6-1(实心三角形)，AV6/BV11(圆形)或AV38/BV10-3(方形)。将脉冲的T2细胞与未转导(UT)细胞(空心三角形)共培养作为对照。
图11是显示将TCR转导细胞与指定靶细胞系共培养后，检测到的每2X104个效应细胞的IFN-γ阳性斑点数的图。用AV12/BV6-1(黑色条)、AV6/BV11(条纹条)或AV38/BV10-3(灰色条)转导效应细胞。HLA-A*02:01转导的靶细胞由LS123-A2、CCRF-CEM-A2和AU-565-A2指示。肽脉冲的靶细胞表示为(+)。未用肽脉冲的靶细胞用(-)表示。使用与靶细胞系共培养的未转导效应细胞(无阴影条)作为对照。
图12是显示在患者4238 TIL片段F1-F24(n＝24)与用由不相关的(IRR；空心条)或突变型p53(p53-MUT；黑条)序列组成的TMG电穿孔的自体APC共培养后，检测到的每2X104个效应细胞的IFN-γ阳性斑点数的图。
图13是显示在患者4238TIL片段F1-F24(n＝24)与用肽媒介物(DMSO；空心条)或突变p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的纯化(HPLC法>95％)的25个氨基酸的肽脉冲的自体APC共培养后，检测到的每2X104个效应细胞的IFN-γ阳性斑点数的图。
图14是显示患者4238TIL片段F1-F24(n＝24)与用不相关的(IRR；空心条)或突变型p53(p53-MUT；黑条)序列组成的TMG电穿孔的自体APC共培养后，检测到的CD8+4-1BB+细胞的百分比的图。
图15是显示4238TIL片段F1-F24(n＝24)与用肽媒介物(DMSO；空心条)或突变p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的纯化(HPLC法>95％)的25个氨基酸的肽脉冲的自体APC共培养后，检测到的CD8+4-1BB+细胞的百分比的图。
图16是显示在共培养来自患者4253的TIL片段(F1-F24，n＝24)与自体APC之后测量的每2x104个效应细胞的IFN-γ-阳性点的数量的图，所述自体APC(1)用肽媒介物(DMSO；空条)脉冲，(2)用由突变的p53R248W(LP-p53R248W-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲，(3)用无关TMG电穿孔(TMG-IRR；灰斜线条)、或(4)含突变p53-R248W序列的p53-mut-TMG电穿孔。
图17是显示在共培养来自患者4273的TIL片段(F1-F24，n＝24)与自体APC之后测量的每2x104个效应细胞的IFN-γ-阳性点的数量的图，所述自体APC用由无关(IRR；空条)、WT p53(p53-WT；灰条)或经突变的p53(p53-MUT；黑条)序列组成的TMG电穿孔。
图18是显示在共培养来自患者4273的TIL片段(F1-F24，n＝24)与自体APC之后检测的CD4+4-1BB+细胞的百分比的图，所述自体APC用由无关(IRR；空条)、WT p53(p53-WT；灰条)或经突变的p53(p53-MUT；黑条)序列组成的TMG电穿孔。
图19是显示在共培养来自患者4273的TIL片段(F1-F24，n＝24)与自体APC之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用肽媒介物(DMSO；空条)或由WT p53-R248序列(LP-p53-R248-WT；灰条)或经突变的p53-R248W(LP-p53-R248W-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图20显示在共培养来自患者4273的TIL片段(F1-F24，n＝24)与自体APC之后检测的CD4+4-1BB+细胞的百分比的图，所述自体APC用肽媒介物(DMSO；空条)或由WT p53-R248序列(LP-p53-R248-WT；灰条)或经突变的p53-R248W(LP-p53-R248W-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图21是显示在共培养来自患者4149的自体PBL(经4149-TCRa2b1或4149-TCRa2b2转座)与自体APC之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC(1)用由无关的(IRR，右侧斜线黑条)、WT p53(p53-wt-TMG,左侧斜线黑条)或经突变的p53(p53-mut-TMG，灰条)序列组成的TMG电穿孔，或(2)用肽媒介物(DMSO，空心条)或由WTp53-Y220序列(LP-p53-Y220-WT，水平阴影黑条)或经突变的p53-Y220C(LP-p53-Y220C-MUT，黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。佛波醇12-肉豆蔻酸13-乙酸酯(PMA)和离子霉素(Iono)为阳性对照(灰色条)。
图22是显示在共培养来自患者4149的自体PBL(其用TCR(4149-TCRa2b1或4149-TCRa2b2)转座)与自体APC共培养之后检测的CD4+4-1BB+细胞的百分比的图，所述自体APC(1)用由无关的(IRR，右侧斜线黑条)、WT p53(p53-wt-TMG,左侧斜线黑条)或经突变的p53(p53-mut-TMG，灰条)序列组成的TMG电穿孔，或(2)用肽媒介物(DMSO，空心条)或由WT p53-Y220序列(LP-p53-Y220-WT，水平阴影黑条)或经突变的p53-Y220C(LP-p53-Y220C-MUT，黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。PMA和Iono为阳性对照(灰色条)。
图23是显示来自患者4149的TIL与用表F的其中一个肽脉冲的自体DC共同培养后检测到的4-1BB+细胞的百分比(CD4+T细胞百分比)的图。
图24是显示4149-TCRa2b2转座的T细胞与用单个HLA等位基因+/-TMG共转染的Cos7细胞共培养后的IFN-γ分泌(pg/mL)的图。未转染TMG的细胞用p53Y220C 15-mer肽脉冲。脉冲的靶细胞用阴影条表示。用无阴影条指示TMG转染的靶细胞。
图25是显示患者4213的TIL片段(F2和F24)与自体APC共培养之后检测的CD8+4-1BB+细胞的百分比的图，所述自体APC用肽媒介物(DMSO，空心条)或由突变的p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图26是患者4213的TIL片段(F2和F24)与自体APC共培养之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用肽媒介物(DMSO，空心条)或由突变的p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。IFN-γ的分泌由空心条表示。4-1BB的表达由实心条显示。
图27是患者4268的TIL片段(F1-F24，n＝24)与自体APC共培养之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用由无关的(IRR，空心条)、WTp53(p53-WT,灰条)或经突变的p53(p53-MUT，黑条)序列组成的TMG电穿孔。
图28是显示患者4268的TIL片段(F1-F24，n＝24)与自体APC共培养之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用肽媒介物(DMSO，空心条)或由WTp53-R248序列(LP-p53-R248-WT；灰色条)或突变的p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图29是显示患者4268的TIL片段(F1-F24，n＝24)与自体APC共培养之后检测的CD4+4-1BB+细胞的百分比的图，所述自体APC用肽媒介物(DMSO，空心条)或由WTp53-R248序列(LP-p53-R248-WT；灰色条)或突变的p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图30是显示患者4268的TIL片段(F1-F24，n＝24)与自体APC共培养之后检测的CD8+4-1BB+细胞的百分比的图，所述自体APC用肽媒介物(DMSO，空心条)或由WTp53-R248序列(LP-p53-R248-WT；灰色条)或突变的p53-R248Q(LP-p53-R248Q-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图31是显示在来自患者4266的TIL片段(F1-F24，n＝24)与自体APC共培养之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用由无关的(IRR，空心条)、WT p53(p53-WT，灰条)或经突变的p53(p53-MUT，黑条)序列组成的TMG电穿孔。
图32是显示在来自患者4266的TIL片段(F1-F24，n＝24)与自体APC共培养之后检测的CD8+4-1BB+细胞的百分比的图，所述自体APC用由无关的(IRR，空心条)、WT p53(p53-WT，灰条)或经突变的p53(p53-MUT，黑条)序列组成的TMG电穿孔。
图33是显示在来自患者4266的TIL片段(F1-F24，n＝24)与自体APC共培养之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用肽媒介物(DMSO，空心条)或由WTp53-R248序列(LP-p53-R248-WT；灰色条)或突变的p53-R248W(LP-p53-R248W-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图34是显示在来自患者4266的TIL片段(F1-F24，n＝24)与自体APC共培养之后检测的CD8+4-1BB+细胞的百分比的图，所述自体APC用肽媒介物(DMSO，空心条)或由WTp53-R248序列(LP-p53-R248-WT；灰色条)或突变的p53-R248W(LP-p53-R248W-MUT；黑条)序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。
图35显示了九种p53剪接变体的氨基酸序列的比对。SP|P04637|P53_HUMAN(SEQID NO:1)；SP|P04637-2|P53_HUMAN(SEQ ID NO:535)；SP|P04637-3|P53_HUMAN(SEQ IDNO:536)；SP|P04637-4|P53_HUMAN(SEQ ID NO:537)；SP|P04637-5|P53_HUMAN(SEQ ID NO:538)；SP|P04637-6|P53_HUMAN(SEQ ID NO:539)；SP|P04637-7|P53_HUMAN(SEQ ID NO:540)；SP|P04637-8|P53_HUMAN(SEQ ID NO:541)；和SP|P04637-9|P53_HUMAN(SEQ ID NO:542)。
图36是显示在与4127-O37-TCR转导的T细胞与自体APC共培养后检测到的4-1BB阳性细胞百分比(mTCRβ+的％)的图，所述APC用对应于WT(空心圆)或突变(实心方形)p53–G245S序列的浓度渐低的25个氨基酸的肽脉冲。
图37A-37C是显示在将4127-O37-TCR(A)、4127-TP31-G245S-TCR1(B)或4127-O102-TCR(C)转导的T细胞与COS7细胞共同培养后测量的4-1BB阳性细胞百分比(mTCRβ+的％)(左y轴；斜线条)和IFN-γ(pg/mL)(右y轴；黑条)的图，所述COS7细胞用一种所示的HLA等位基因进行共转染并用25-氨基酸的p53-G245S肽脉冲。
图38是显示在将患者4141的TIL(片段培养物12)与自体APC共培养后测量的4-1BB阳性细胞百分比(％CD8+)的图形(右y轴；黑条)和IFN-γ(斑点数/2X104个细胞)(左y轴；斜线条)的图，所述APC用编码无关突变(TMG-IRR)、WTp53序列(TP53-wt-TMG)或突变p53序列(包括R175H)(TP53-mut-TMG)的TMG转染。单独的培养基以及PMA和离子霉素分别为阴性和阳性对照。
图39为显示将患者4141的TIL(片段培养物12)与Cos7细胞共培养之后测量的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述Cos7细胞用所示的HLA等位基因并无额外基因(仅HLA；空心条)共转染、或者用WT TP53TMG(灰色阴影条)或含有p53-R175H序列的突变(黑色条)TP53 TMG共转染。
图40为显示将表达模拟物(无TCR)或4141-TCR1a2的T细胞与T2肿瘤细胞(表达HLA-A*02:01)共培养后测定的IFN-γ浓度(pg/mL)的图。T2细胞用肽媒介物(DMSO；灰色条)或纯化(HPLC法>95％)的由WT p53-R175肽(阴影灰色条)或突变p53-R175H肽(黑色条)组成的肽脉冲。仅培养基(空心条)以及PMA和离子霉素(格状条)分别为阴性和阳性对照。数据为平均值±SEM(n＝3)。
图41是显示将表达4141-TCR1a2的T细胞与Saos2细胞(p53-NULL和HLA-A*02:01+)共培养后阳性表达一种所示标记物的细胞百分比的图，这些细胞要么未经处理(无阴影条)，要么被使得过度表达全长p53R-175H蛋白(阴影条)。数据为平均值±SEM(n＝3)。对两种细胞系之间的每种细胞因子进行Student双尾t检验，以进行统计分析(***p<0.001)。
图42是显示在将TIL(来自患者4259的片段培养物6)与自体APC共培养后检测到的CD4+4-1BB阳性细胞的百分比的图，所述APC或者(1)用由无关的(TMG-IRR)、WT p53(TMG-p53-WT)或经突变的p53(TMG-p53-MUT)序列组成的TMG电穿孔，或者(2)用肽媒介物(DMSO)或由WTp53-Y220序列(LP-p53-Y220-WT)或突变的p53-Y220C(LP-p53-Y220C-MUT)序列组成的纯化的(HPLC法>95％)25-氨基酸肽脉冲。
图43是显示将来自患者4259的TIL片段培养物(no.6)与自体APC共培养后检测到的CD4+4-1BB阳性细胞的百分比的图，所述APC用对应于WT p53序列(空心圆)或突变的p53-Y220C(实心方形)的浓度逐渐降低的25-氨基酸肽在37oC下脉冲2小时。
图44是显示患者4259的TIL与用DMSO、WTp53-Y220肽或突变p53-Y220C肽脉冲的自体APC共培养后检测到的CD4+4-1BB阳性细胞的百分比的图。
图45是显示将来自患者4259的TIL片段培养物(no.6)与Cos7细胞共培养后检测到的4-1BB阳性细胞百分比(CD4+％)的图，所述Cos7细胞用来自患者4259的所示HLA等位基因共转染，并用DMSO(空心条)或p53-Y220C肽(实心条)脉冲。
图46是TC#4259靶细胞(内源性表达p53Y220C和HLA-DRB1*04:01:01)与表达模拟物(无TCR，空心条)或p53-Y220C特异性TCR(4259-F6-TCR；黑条)的效应T细胞(105)共培养后检测到的4-1BB+细胞百分比的图。将TC#4259细胞不与任何物质孵育、或将TC#4259细胞与W6/32泛-HLA I类特异性阻断抗体、IVA12泛-HLA II类特异性阻断抗体或经突变的p53-Y220C肽孵育。单独的培养基(无TC)及PMA和离子霉素分别是阴性对照和阳性对照。数据是平均值±SEM(n＝3)。在指定的组之间进行学生双尾t检验用于统计分析(**p<0.01和***p<0.001)。
图47是显示将来自患者4285的TIL片段(F1-F22和F24，n＝23)与自体APC共培养之后检测的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述自体APC用由无关的(IRR，空心条)、WT p53(p53-WT，灰条)或经突变的p53(p53-MUT，黑条)序列组成的TMG电穿孔。
图48是显示将来自患者4285的TIL片段(F1-F22和F24，n＝23)与自体APC共培养之后检测的每2x104个效应细胞的IFN-γ-阳性斑点的数量的图，所述APC用肽媒介物(DMSO；空心条)或由WTp53-R175序列(LP-p53-R175-WT；灰色条)或突变型p53-R175H(LP-p53-R175H-MUT；黑条)组成的经纯化(HPLC法>95％)的25个氨基酸的肽脉冲。
图49是显示将来自患者4285的TIL片段(F1-F22和F24，n＝23)与自体APC共培养之后检测的CD4+4-1BB阳性细胞的百分比的图，所述自体APC用由无关的(IRR，空心条)、WTp53(p53-WT，灰条)或经突变的p53(p53-MUT，黑条)序列组成的TMG电穿孔。。
图50是显示将来自患者4285的TIL片段(F1-F22和F24，n＝23)与自体APC共培养之后检测的CD4+4-1BB阳性细胞的百分比的图，所述APC用肽媒介物(DMSO；空心条)或由WTp53-R175序列(LP-p53-R175-WT；灰色条)或突变型p53-R175H(LP-p53-R175H-MUT；黑条)组成的经纯化(HPLC法>95％)的25个氨基酸的肽脉冲。
图51是显示在共培养TIL片段培养物4285-F6、4285-F9和4285-F10与Cos7细胞之后检测的4-1BB+细胞的百分比(CD4+百分比)的图，所述Cos7细胞用指定HLA等位基因转染并用DMSO(肽媒介物；灰和黑斜线条)或突变的p53-R175H肽(灰、格子和黑条)脉冲。
图52是显示在共培养用4285-TCR1转座的T细胞与自体APC之后检测的4-1BB+细胞的百分比(CD4+百分比)的图，所述自体APC用降低浓度的25-个或15-个氨基酸的肽(对应于WT(空心环和方块)或经突变的(实心环和方块)p53-R175H序列)脉冲。
图53是显示在共培养来自患者4266的TIL与Cos7细胞之后检测的4-1BB+细胞的百分比(CD8+百分比)的图，所述Cos7细胞用来自患者4266的单独HLA等位基因共转染以及用无肽(空条)、DMSO(肽媒介物；灰条)、WT p53-R248肽(灰斜线条)或经突变的p53-R248W肽(黑条)脉冲。数据是平均值±SEM(n＝3)。
图54是显示在共培养表达模拟物(无TCR)、4266-TCR1、4266-TCR2、4266-TCR3或4266-TCR4的T细胞与自体APC之后检测的4-1BB+细胞的百分比(CD8+百分比)的图，所述自体APC用肽媒介物(DMSO；灰条)或由WT p53-R248序列(斜线灰条)或经突变的p53-R248W(黑条)序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲。单独的培养基(空条)及PMA和离子霉素(格条)分别是阴性对照和阳性对照。
图55是显示在共培养表达模拟物(无TCR)或p53-R248W-特异性TCR(4266-TCR2、4266-TCR3或4266-TCR4)的T细胞与从由患者4266切除的异种移植的肿瘤碎片建立然后通过免疫受损小鼠(TC#4266)连续传代的肿瘤细胞(TC)系之后检测的4-1BB+细胞的百分比(CD8+百分比)的图。将TC#4266细胞不与任何物质孵育(黑条)、或将TC#4266细胞与W6/32泛-HLA I类特异性阻断抗体(右侧灰斜线条)、IVA12泛-HLA II类特异性阻断抗体(灰条)或突变的p53-R248W肽(左侧灰斜线条)孵育。单独的培养基(无TC；空条)及PMA和离子霉素(灰格条)分别是阴性对照和阳性对照。
图56是显示在来自患者4273的TIL与自体APC共培养后检测到的CD4+4-1BB+细胞的百分比的图，所述APC用编码不相关突变(灰色条)、野生型p53序列(灰色斜线条)或包括p53-R248W的突变p53序列(黑色条)的TMG转染。单独的培养基(空心条)以及PMA和离子霉素(格状条)分别为阴性和阳性对照。
图57是显示患者4273的TIL与自体APC共培养后检测到的CD4+4-1BB+细胞百分比的图，所述APC用对应于野生型(空心环)的25个氨基酸的肽或来自p53-R248W新表位的突变(实心方形)的25个氨基酸的肽脉冲。DMSO为肽媒介物。
图58是显示患者4273的TIL与自体APC共培养后检测到的CD4+4-1BB+细胞的百分比的图，所述APC用重叠14个氨基酸的来自p53-R248W新表位的15个氨基酸肽脉冲(以粗体表示氨基酸取代)。DMSO为肽媒介物，单独的培养基(仅T细胞)，以及PMA和离子霉素为对照。25个氨基酸肽(wtp53-R248和突变的p53-R248W)是15个氨基酸肽的额外对照。肽为:
图59是显示来自患者4273的TIL与Cos7细胞共培养之后分泌的IFN-γ(pg/mL)的浓度的图，所述Cos7细胞用来自患者4273的单独HLA等位基因以及分别在有或无p53-R248W新抗原的情况下的WT(空条)或突变的(黑条)TP53TMG共转染。
图60是显示在表达模拟物(无TCR)或4273-TCR1a2的T细胞与自体APC的共培养之后测量的每2x104个细胞的IFN-γ-点的数量的图，所述自体APC用肽媒介物(DMSO；灰条)或由WT p53-R248序列(斜线灰条)或经突变的p53-R248W(黑条)序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲。单独的培养基(空条)及PMA和离子霉素(格条)分别是阴性对照和阳性对照。
发明详述
肿瘤蛋白P53(也称为“TP53”或“p53”)通过例如调节细胞分裂而作为肿瘤遏制物。p53蛋白位于细胞核中，在那里其直接结合至DNA。当DNA受损时，p53蛋白参与确定DNA是否会被修复或受损的细胞是否会发生凋亡。如果DNA可以被修复，则p53激活其他基因以恢复损伤。如果DNA无法被修复，则p53蛋白阻止细胞分裂并向其发出进行凋亡的信号。通过阻止具有突变或受损DNA的细胞分裂，p53有助于预防肿瘤发展。野生型(WT)全长p53包含SEQ IDNO:1的氨基酸序列。
p53蛋白中的突变可降低或消除p53蛋白的肿瘤遏制功能。可替代地或另外地，p53突变可以是通过以显性负性方式干扰野生型p53的功能获得性突变。经突变的p53蛋白可以在多种人类癌症中的任一种中表达，诸如例如，胆管癌、黑素瘤、结肠癌、直肠癌、卵巢癌、子宫内膜癌、非小细胞肺癌(NSCLC)、成胶质细胞瘤、子宫颈癌、头颈癌、乳房癌、胰腺癌或膀胱癌。
本发明的一个实施方案提供一种对突变的人p53具有抗原性特异性的分离或纯化的T细胞受体(TCR)(下文称为“突变的p53”)。下文中，除非另有规定，否则提及“TCR”亦指TCR的功能部分及功能变体。p53的突变在本文中通过参考全长氨基酸酸序列WT p53(SEQID NO:1)来定义。因此，p53的突变在本文中通过参考在特定位置存在的氨基酸残基，然后是位置编号，然后是在所讨论的特定突变中取代此残基的氨基酸来描述。例如，当位置如由SEQ ID NO:1所定义时，术语“R175”是指存在于SEQ ID NO:1的位置175处的精氨酸，“R175H”表示存在于SEQ ID NO:1的位置175处的精氨酸被组氨酸替代，而“G245S”表示存在于SEQ ID NO:1的位置245处的甘氨酸已经被丝氨酸替代。P53具有九种已知的剪接变体。本文所述的p53突变在所有九种p53剪接变体中是保守的。图35中显示了9种p53剪接变体的比对。因此，通过本发明的方法分离的T细胞可对由九种p53剪接变体中任一种编码的本文所述的任何经突变的p53氨基酸序列具有抗原特异性。当位置如SEQ ID NO:1所定义时，则p53的特定剪接变体的氨基酸序列的实际位置是相对于SEQ ID NO:1的相应位置来定义的，并且如由SEQ ID NO:1定义的位置可与特定剪接变体中的实际位置不同。因此，例如，突变是指对应于SEQ ID NO:1的393个氨基酸的序列的指定位置的p53的特定剪接变体的氨基酸序列中的氨基酸残基的替代，要理解剪接变体中的实际位置可有所不同。
在本发明的一个实施方案中，TCR对在SEQ ID NO:1的位置175、220、245、248、249、273或282处具有突变的人p53具有抗原特异性。TCR可对在SEQ ID NO:1的位置175、220、245或248具有突变的人p53具有抗原特异性。p53突变可能是任何错义突变。因此，SEQ ID NO:1的位置175、220、245、248、249、273或282处的突变可以是SEQ ID NO:1的位置175、220、245、248、249、273或282处存在的天然(WT)氨基酸残基的取代，其中在所讨论的特定位置处存在除天然(WT)氨基酸残基以外的任何氨基酸残基。在本发明的一个实施方案中，TCR对具有以下一种人p53突变的人p53具有抗原性特异性:R175H、Y220C、G245D、G245S、R248L、R248Q、R248W、R249S、R273H、R273C、R273L或R282W。SEQ ID NOSEQ ID NOTCR可对具有以下一种人p53突变的人p53具有抗原特异性:R175H、Y220C、G245S、R248Q或R248W。例如，本发明TCR可对选自SEQ ID NO:2-13的突变型p53氨基酸序列具有抗原特异性。
在本发明的一个实施方案中，本发明TCR可以能够以HLA(人类白细胞抗原)分子依赖性方式识别突变型p53。本文使用的“HLA-分子依赖性方式”意指TCR在HLA分子背景下结合突变型p53时产生免疫应答，HLA分子由从中分离出TCR的患者表达。本发明TCR可以能够识别由适用的HLA分子呈递的突变型p53，且除突变型p53外还可与HLA分子结合。
本发明的TCR提供许多优点，包括当由用于过继细胞转移的细胞表达时。突变型p53由肿瘤细胞表达，而不是由正常的非癌细胞表达。在不约束于特定理论或机制的情况下，认为本发明TCR有利地靶向破坏癌细胞，同时尽可能减少或消除正常非癌细胞的破坏，从而例如通过最小化或消除毒性而减少毒性。此外，有利地，本发明TCR可成功地治疗或预防对其他类型的治疗(例如，化疗、手术或辐射)无响应的突变p53阳性癌症。此外，本发明TCR可提供对突变p53的高亲和识别，其可提供识别未经处理的肿瘤细胞的能力(例如，未经干扰素(IFN)-γ处理的肿瘤细胞，未用编码一种或两种突变p53和适用的HLA分子的载体转染的肿瘤细胞，未用带有p53突变的p53肽脉冲的肿瘤细胞，或其组合)。大约一半的肿瘤携带p53突变，其中约一半为错义突变，约30％的错义突变发生在以下“热点”残基:R175H、Y220C、G245D、G245S、R248L、R248Q、R248W、R249S、R273C、R273L、R273H和R282W。此外，相同的p53“热点”突变(例如，R175H、Y220C、G245D、G245S、R248L、R248Q、R248W、R249S、R273H、R273C、R273L或R282W)常发生于无关人群的肿瘤中(累积约30％的p53错义突变)。因此，本发明TCR可以增加可能适合免疫疗法治疗的患者人数。
如本文所使用的短语“抗原特异性”意指TCR可特异性结合并免疫识别具有高亲和力的突变p53。例如，如果表达TCR的约1x 104至约1x 105T细胞与以下抗原阴性、适用HLA分子阳性的靶细胞共培养时分泌至少约200pg/mL或更高(例如，200pg/mL或更高、300pg/mL或更高、400pg/mL或更高、500pg/mL或更高、600pg/mL或更高、700pg/mL或更高、1000pg/mL或更高、5,000pg/mL或更高、7,000pg/mL或更高、10,000pg/mL或更高、20,000pg/mL或更高，或由前述值中的任两个所限定的范围)的IFN-γ，则所述TCR被视为对突变的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，或由前述值中的任两个定义的范围)脉冲的抗原阴性的、适用HLA分子阳性的靶细胞，或(b)已引入编码突变p53的核苷酸序列以使靶细胞表达突变p53的抗原阴性、适用的HLA分子阳性的靶细胞。表达本发明TCR的细胞也可在与用较高浓度的突变p53肽脉冲的抗原阴性、适用HLA分子阳性靶细胞共培养时分泌IFN-γ。
可选地或者另外地，如果与阴性对照表达IFN-γ的量相比，表达TCR的T细胞与(a)用低浓度突变型p53肽脉冲的抗原阴性、适用HLA分子阳性的靶细胞或(b)已引入编码突变型p53的核苷酸序列以使靶细胞表达突变p53的的抗原阴性、适用HLA分子阳性的靶细胞共同培养时分泌至少两倍的IFN-γ，则TCR可被视为对突变型p53具有“抗原特异性”。阴性对照可以是，例如(i)与以下靶细胞共培养的表达TCR的T细胞:(a)用相同浓度的不相关的肽(例如，与突变型p53肽具有不同序列的一些其他肽)脉冲的抗原阴性、适用HLA分子阳性的靶细胞或(b)已引入编码不相关肽的核苷酸序列以使靶细胞表达不相关肽的抗原阴性、适用HLA分子阳性的靶细胞，或(ii)与以下靶细胞共培养的未转导的T细胞(例如来自PBMC，其不表达TCR):(a)与相同浓度的突变p53肽脉冲的抗原阴性、适用HLA分子阳性靶细胞或(b)已引入编码突变p53的核苷酸序列以使靶细胞表达突变的p53的抗原阴性、适用HLA分子阳性的靶细胞。IFN-γ分泌可藉由本领域已知的方法(例如，酶联免疫吸附测定(ELISA))来测量。
可选地或者另外地，如果与分泌IFN-γ的阴性对照T细胞的数量相比，至少两倍数量的表达TCR的T细胞与以下靶细胞共培养时分泌IFN-γ，则所述TCR可被视为对突变型p53具有“抗原特异性”:(a)用低浓度突变型p53肽脉冲的抗原阴性、适用HLA分子阳性靶细胞或(b)已引入编码突变型p53的核苷酸序列以使靶细胞表达突变的p53的抗原阴性、适用HLA分子阳性的靶细胞。肽和阴性对照的浓度可如本文关于本发明的其它方面所述。可藉由本领域的已知方法(例如，酶联免疫斑点(ELISOT)分析)来测量分泌IFN-γ的细胞的数量。
可选地或者另外地，如果在与(a)用低浓度突变型p53肽脉冲的抗原阴性、适用HLA分子阳性的靶细胞或(b)已引入编码突变型p53的核苷酸序列以使靶细胞表达突变的p53的抗原阴性、适用HLA分子阳性的靶细胞共同培养时，通过ELISPOT检测到表达TCR的T细胞的的至少两倍的斑点，则TCR可被视为对突变型p53具有“抗原特异性”，其中上述斑点数是与通过ELISPOT检测的与相同靶细胞共培养的阴性对照T细胞的斑点数相比。肽和阴性对照的浓度可如本文结合关于本发明的其它方面所述。
可选地或者另外地，如果对于与以下靶细胞共培养的表达TCR的T细胞而言通过ELISPOT检测到大于约50个斑点，则TCR可被视为对突变型p53具有“抗原特异性”:(a)用低浓度突变型p53肽脉冲的抗原阴性、适用HLA分子阳性的靶细胞或(b)已将编码突变型p53的核苷酸序列引入以便靶细胞表达突变型p53的抗原阴性、适用HLA分子阳性的靶细胞，。肽的浓度可如本文关于本发明的其它方面所述。
可选地或者另外地，如果表达TCR的T细胞上调4-1BB和OX40的一种或两种表达(例如在用表达突变p53的靶细胞刺激后通过流式细胞术测量)，则TCR可被视为对突变p53具有“抗原特异性”。
本发明提供包含两个多肽(即多肽链)的TCR，例如TCR的alpha(α)链、TCR的beta(β)链、TCR的gamma(γ)链、TCR的delta(δ)链或其组合。本发明TCR的多肽可包含任何氨基酸序列，前提是TCR对突变的p53具有抗原特异性。
在本发明的一个实施方案中，TCR包含两条多肽链，每条多肽链均包含包含TCR的互补决定区(CDR)1、CDR2及CDR3的可变区。在本发明的一个实施方案中，TCR包含第一多肽链和第二多肽链，第一多肽链包含α链CDR1(CDR1α)、α链CDR2(CDR2α)和α链CDR3(CDR3α)的，以及第二多肽链包含β链CDR1(CDR1β)、β链CDR2(CDR2β)和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)所有SEQ ID NO:27-32；(2)所有SEQ ID NO:37-42；(3)所有SEQ ID NO:47-52；(4)所有SEQ ID NO:57-62；(5)所有SEQ ID NO:67-72；(6)所有SEQ ID NO:77-82；(7)所有SEQ ID NO:87-92；(8)所有SEQ ID NO:97-102；(9)所有SEQ ID NO:107-112；(10)所有SEQ ID NO:117-122；(11)所有SEQ ID NO:127-132；(12)所有SEQ ID NO:137-142；(13)所有SEQ ID NO:147-152；(14)所有SEQ ID NO:157-162；(15)所有SEQ ID NO:167-172；(16)所有SEQ ID NO:177-182；(17)所有SEQ ID NO:187-192；(18)所有SEQ ID NO:197-202；(19)所有SEQ ID NO:207-212；(20)所有SEQ ID NO:217-222；(21)所有SEQ ID NO:227-232；(22)所有SEQ ID NO:237-242；(23)所有SEQ ID NO:247-252；(24)所有SEQ ID NO:257-262；(25)所有SEQ ID NO:267-272；(26)所有SEQ IDNO:277-282；(27)所有SEQ ID NO:287-292；(28)所有SEQ ID NO:297-302；(29)所有SEQ IDNO:307-312；(30)所有SEQ ID NO:317-322；(31)所有SEQ ID NO:327-332；(32)所有SEQ IDNO:337-342；(33)所有SEQ ID NO:347-352；(34)所有SEQ ID NO:357-362；(35)所有SEQ IDNO:367-372；(36)所有SEQ ID NO:377-382；(37)所有SEQ ID NO:387-392；(38)所有SEQ IDNO:397-402；(39)所有SEQ ID NO:407-412；(40)所有SEQ ID NO:417-422；(41)所有SEQ IDNO:427-432；(42)所有SEQ ID NO:437-442；(43)所有SEQ ID NO:447-452；(44)所有SEQ IDNO:457-462；(45)所有SEQ ID NO:467-472；(46)所有SEQ ID NO:477-482；或(47)所有SEQID NO:487-492。本段中前述47个氨基酸序列集合中的每一个列出了对突变人p53具有抗原特异性的47个不同TCR的每一个的6个CDR区域。每一集合中的6个氨基酸序列分别对应于TCR的CDR1α、CDR2α、CDR3α、CDR1β、CDR2β和CDR3β。
在本发明的一个实施方案中，TCR包含α链可变区氨基酸序列及β链可变区氨基酸序列，其共同包含上述CDR集合之一。在这方面，TCR可包含以下氨基酸序列:(1)SEQ ID NO:33-34两者；(2)SEQ ID NO:43-44两者；(3)SEQ ID NO:53-54两者；(4)SEQ ID NO:63-64两者；(5)SEQ ID NO:73-74两者；(6)SEQ ID NO:83-84两者；(7)SEQ ID NO:93-94两者；(8)SEQ ID NO:103-104两者；(9)SEQ ID NO:113-114两者；(10)SEQ ID NO:123-124两者；(11)SEQ ID NO:133-134两者；(12)SEQ ID NO:143-144两者；(13)SEQ ID NO:153-154两者；(14)SEQ ID NO:163-164两者；(15)SEQ ID NO:173-174两者；(16)SEQ ID NO:183-184两者；(17)SEQ ID NO:193-194两者；(18)SEQ ID NO:203-204两者；(19)SEQ ID NO:213-214两者；(20)SEQ ID NO:223-224两者；(21)SEQ ID NO:233-234两者；(22)SEQ ID NO:243-244两者；(23)SEQ ID NO:253-254两者；(24)SEQ ID NO:263-264两者；(25)SEQ ID NO:273-274两者；(26)SEQ ID NO:283-284两者；(27)SEQ ID NO:293-294两者；(28)SEQ IDNO:303-304两者；(29)SEQ ID NO:313-314两者；(30)SEQ ID NO:323-324两者；(31)SEQ IDNO:333-334两者；(32)SEQ ID NO:343-344两者；(33)SEQ ID NO:353-354；(34)SEQ ID NO:363-364；(35)SEQ ID NO:373-374两者；(36)SEQ ID NO:383-384两者；(37)SEQ ID NO:393-394两者；(38)SEQ ID NO:403-404两者；(39)SEQ ID NO:413-414两者；(40)SEQ IDNO:423-424两者；(41)SEQ ID NO:433-434两者；(42)SEQ ID NO:443-444两者；(43)SEQ IDNO:453-454两者；(44)SEQ ID NO:463-464两者；(45)SEQ ID NO:473-474两者；(46)SEQ IDNO:483-484两者；或(47)SEQ ID NO:493-494两者。本段中的前述47个氨基酸序列集合中的每一个列出了对突变人p53具有抗原特异性的47个不同TCR的每一个的两个可变区域。每个集合中的两个氨基酸序列分别对应于TCR的α链的可变区和β链的可变区。
本发明TCR可进一步包含恒定区。恒定区可衍生自任何适宜物种(例如人或小鼠)。在本发明的一个实施方案中，TCR进一步包含鼠恒定区。如本文所使用，当提及本文所述的TCR或TCR的任何组分时(例如，互补决定区(CDR)、可变区、恒定区、α链和/或β链)，术语“鼠”或“人”意指分别衍生自小鼠或人的TCR(或其组分)，即，分别起源自或曾经由小鼠T细胞或人T细胞表达的TCR。在本发明的一个实施方案中，TCR可包含鼠α链恒定区及鼠β链恒定区。鼠α链恒定区可是被修饰的或未被修饰的。如例如US2017/0145070中所述，修饰的鼠α链恒定区可以是例如半胱氨酸取代的、LVL修饰的、或同时半胱氨酸取代和LVL修饰的。鼠β链恒定区可以是修饰的或未修饰的。修饰的鼠β链恒定区可以是例如半胱氨酸取代的，如例如US2017/0145070中所述。在本发明的一个实施方案中，TCR包含半胱氨酸取代的、LVL修饰的鼠α链恒定区，其包含SEQ ID NO:23或24的氨基酸序列。在本发明的一个实施方案中，TCR包含包含SEQ ID NO:25的氨基酸序列的经半胱氨酸取代的鼠β链恒定区。
在本发明的一个实施方案中，本发明TCR可包含TCR的α链及TCR的β链。TCR的α链可包含α链的可变区和α链的恒定区。这种类型的α链可与TCR的任何β链配对。β链可包含β链的可变区及β链的恒定区。在本发明的一个实施方案中，TCR包含以下氨基酸序列:(1)SEQ IDNO:35-36两者；(2)SEQ ID NO:45-46两者；(3)SEQ ID NO:55-56两者；(4)SEQ ID NO:65-66两者；(5)SEQ ID NO:75-76两者；(6)SEQ ID NO:85-86两者；(7)SEQ ID NO:95-96两者；(8)SEQ ID NO:105-106两者；(9)SEQ ID NO:115-116两者；(10)SEQ ID NO:125-126两者；(11)SEQ ID NO:135-136两者；(12)SEQ ID NO:145-146两者；(13)SEQ ID NO:155-156两者；(14)SEQ ID NO:165-166两者；(15)SEQ ID NO:175-176两者；(16)SEQ ID NO:185-186两者；(17)SEQ ID NO:195-196两者；(18)SEQ ID NO:205-206两者；(19)SEQ ID NO:215-216两者；(20)SEQ ID NO:225-226两者；(21)SEQ ID NO:235-236两者；(22)SEQ ID NO:245-246两者；(23)SEQ ID NO:255-256两者；(24)SEQ ID NO:265-266两者；(25)SEQ ID NO:275-276两者；(26)SEQ ID NO:285-286两者；(27)SEQ ID NO:295-296两者；(28)SEQ IDNO:305-306两者；(29)SEQ ID NO:315-316两者；(30)SEQ ID NO:325-326两者；(31)SEQ IDNO:335-336两者；(32)SEQ ID NO:345-346两者；(33)SEQ ID NO:355-356两者；(34)SEQ IDNO:365-366两者；(35)SEQ ID NO:375-376两者；(36)SEQ ID NO:385-386两者；(37)SEQ IDNO:395-396两者；(38)SEQ ID NO:405-406两者；(39)SEQ ID NO:415-416两者；(40)SEQ IDNO:425-426两者；(41)SEQ ID NO:435-436两者；(42)SEQ ID NO:445-446两者；(43)SEQ IDNO:455-456两者；(44)SEQ ID NO:465-466两者；(45)SEQ ID NO:475-476两者；(46)SEQ IDNO:485-486两者；或(47)SEQ ID NO:495-496两者本段中的上述47个氨基酸序列集合中的每一个列出了对突变人p53具有抗原特异性的47个不同TCR的每一个的α链和β链。每个集合中的两个氨基酸序列分别对应于TCR的α链和β链。
本发明范围包括本文所述的本发明TCR的功能性变体。如本文所使用的术语“功能性变体”是指与母体TCR、多肽或蛋白质具有实质性或显著序列同一性或相似性的TCR、多肽或蛋白质，该功能性变体保留其为变体的TCR、多肽或蛋白质的生物活性。例如，功能性变体包括本文所述的TCR、多肽或蛋白质(母体TCR、多肽或蛋白质)的那些变体，其保留与母体TCR、多肽或蛋白质具有相似程度、相同程度或更高程度的特异性结合突变p53的能力，所述母体TCR对所述突变p53具有抗原特异性、或所述母体多肽或蛋白质特异性结合所述突变p53。就母体TCR、多肽或蛋白质而言，功能性变体可以例如在氨基酸序列中分别与母体TCR、多肽或蛋白质至少约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％或更多相同。
例如，功能性变体可包含具有至少一个保守氨基酸取代的母体TCR、多肽或蛋白质的氨基酸序列。保守氨基酸取代为本领域已知，并且包括氨基酸取代，其中具有某些物理和/或化学性质的一个氨基酸交换为具有相同化学或物理性质的另一个氨基酸。例如，保守氨基酸取代可为酸性氨基酸取代另一酸性氨基酸(例如，Asp或Glu)，具有非极性侧链的氨基酸取代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)，碱性氨基酸被另一种碱性氨基酸(Lys、Arg等)取代，具有极性侧链的氨基酸取代另一具有极性侧链的氨基酸(Asn、Cys、Gln、Ser、Thr、Tyr等)，等等。
可选地或者另外地，功能性变体可包含具有至少一个非保守氨基酸取代的母体TCR、多肽或蛋白质的氨基酸序列。在这种情况下，优选非保守氨基酸取代不干扰或抑制功能性变体的生物活性。优选地，非保守氨基酸取代增强功能性变体的生物活性，使得与母体TCR、多肽或蛋白质相比，功能性变体的生物活性增加。
TCR、多肽或蛋白质基本上可由本文所述的指定氨基酸序列或序列组成，使得TCR、多肽或蛋白质的其他组分，例如其他氨基酸，不会实质性地改变TCR、多肽或蛋白质的生物活性。
本发明还提供包含本文所述的任一TCR的功能部分的多肽。如本文所使用的术语“多肽”包括寡肽并且是指通过一个或多个肽键连接的氨基酸的单链。
关于本发明的多肽，功能部分可以是包含为TCR的一部分的TCR的邻接氨基酸的任何部分，前提是功能部分特异性地结合到突变型p53。当在提及TCR时使用时，术语“功能部分”是指本发明的TCR的任何部分或片段，该部分或片段保留其为其一部分的TCR的生物活性(母体TCR)。例如，功能部分包含TCR的那些部分，其保留与突变p53特异性结合的能力(例如，以适用的HLA分子依赖性方式)，或检测、治疗或预防癌症的能力，程度与母体TCR相似、相同或更高。就母体TCR而言，功能部分可包含例如母体TCR的约10％、约25％、约30％、约50％、约68％、约80％、约90％、约95％或更多。
上述功能部分可包含该部分的氨基末端或羧基末端或两末端的额外氨基酸，所述额外氨基酸不存在于母体TCR的氨基酸序列中。理想的是，所述额外氨基酸不会干扰功能部分的生物功能，例如，特异性结合突变的p53；和/或能够检测癌症、治疗或预防癌症等。更理想的是，与母体TCR的生物活性相比，所述额外氨基酸增强了生物活性。
所述多肽可包含本发明TCR的α链和β链之一或两者的功能部分，例如包含本发明TCR的α链和/或β链的可变区的CDR1、CDR2和CDR3中的一个或多个的功能部分。在本发明的一个实施方案中，多肽可包含的功能部分包含以下氨基酸序列:(1)SEQ ID NO:27-32的全部；(2)SEQ ID NO:37-42的全部；(3)SEQ ID NO:47-52的全部；(4)SEQ ID NO:57-62的全部；(5)SEQ ID NO:67-72的全部；(6)SEQ ID NO:77-82的全部；(7)SEQ ID NO:87-92的全部；(8)SEQ ID NO:97-102的全部；(9)SEQ ID NO:107-112的全部；(10)SEQ ID NO:117-122的全部；(11)SEQ ID NO:127-132的全部；(12)SEQ ID NO:137-142的全部；(13)SEQ ID NO:147-152的全部；(14)SEQ ID NO:157-162的全部；(15)SEQ ID NO:167-172的全部；(16)SEQID NO:177-182的全部；(17)SEQ ID NO:187-192的全部；(18)SEQ ID NO:197-202的全部；(19)SEQ ID NO:207-212的全部；(20)SEQ ID NO:217-222的全部；(21)SEQ ID NO:227-232的全部；(22)所有SEQ ID NO:237-242的全部；(23)SEQ ID NO:247-252的全部；(24)SEQ IDNO:257-262的全部；(25)SEQ ID NO:267-272的全部；(26)SEQ ID NO:277-282的全部；(27)SEQ ID NO:287-292的全部；(28)SEQ ID NO:297-302的全部；(29)SEQ ID NO:307-312的全部；(30)SEQ ID NO:317-322的全部；(31)SEQ ID NO:327-332的全部；(32)SEQ ID NO:337-342的全部；(33)SEQ ID NO:347-352的全部；(34)SEQ ID NO:357-362的全部；(35)SEQ IDNO:367-372的全部；(36)SEQ ID NO:377-382的全部；(37)SEQ ID NO:387-392的全部；(38)SEQ ID NO:397-402的全部；(39)所有SEQ ID NO:407-412的全部；(40)SEQ ID NO:417-422的全部；(41)SEQ ID NO:427-432的全部；(42)SEQ ID NO:437-442的全部；(43)SEQ ID NO:447-452的全部；(44)SEQ ID NO:457-462的全部；(45)SEQ ID NO:467-472的全部；(46)SEQID NO:477-482的全部；或(47)SEQ ID NO:487-492的全部。
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TCR的可变区，其包含上述CDR区之组合。在这方面，多肽可包含以下氨基酸序列:(1)SEQ ID NO:33-34两者；(2)SEQ ID NO:43-44两者；(3)SEQ ID NO:53-54两者；(4)SEQ ID NO:63-64两者；(5)SEQID NO:73-74两者；(6)SEQ ID NO:83-84两者；(7)SEQ ID NO:93-94两者；(8)SEQ ID NO:103-104两者；(9)SEQ ID NO:113-114两者；(10)SEQ ID NO:123-124两者；(11)SEQ ID NO:133-134两者；(12)SEQ ID NO:143-144两者；(13)SEQ ID NO:153-154两者；(14)SEQ IDNO:163-164两者；(15)SEQ ID NO:173-174两者；(16)SEQ ID NO:183-184两者；(17)SEQ IDNO:193-194两者；(18)SEQ ID NO:203-204两者；(19)SEQ ID NO:213-214两者；(20)SEQ IDNO:223-224两者；(21)SEQ ID NO:233-234两者；(22)SEQ ID NO:243-244两者；(23)SEQ IDNO:253-254两者；(24)SEQ ID NO:263-264两者；(25)SEQ ID NO:273-274两者；(26)SEQ IDNO:283-284两者；(27)SEQ ID NO:293-294两者；(28)SEQ ID NO:303-304两者；(29)SEQ IDNO:313-314两者；(30)SEQ ID NO:323-324两者；(31)SEQ ID NO:333-334两者；(32)SEQ IDNO:343-344两者；(33)SEQ ID NO:353-354两者；(34)SEQ ID NO:363-364两者；(35)SEQ IDNO:373-374两者；(36)SEQ ID NO:383-384两者；(37)SEQ ID NO:393-394两者；(38)SEQ IDNO:403-404两者；(39)SEQ ID NO:413-414两者；(40)SEQ ID NO:423-424；(41)SEQ ID NO:433-434两者；(42)SEQ ID NO:443-444两者；(43)SEQ ID NO:453-454两者；(44)SEQ IDNO:463-464两者；(45)SEQ ID NO:473-474两者；(46)SEQ ID NO:483-484两者；或(47)SEQID NO:493-494两者。
在本发明的一个实施方案中，本发明多肽可进一步包含上述本发明TCR的恒定区。在这方面，多肽可包含(i)SEQ ID NO:23-25之一或(ii)SEQ ID NO:25和SEQ ID NO:23-24之一的氨基酸序列。
在本发明的一个实施方案中，本发明多肽可包含本发明TCR的α链及β链。在这方面，多肽可包含以下氨基酸序列:(1)SEQ ID NO:35-36两者；(2)SEQ ID NO:45-46两者；(3)SEQ ID NO:55-56两者；(4)SEQ ID NO:65-66两者；(5)SEQ ID NO:75-76两者；(6)SEQ IDNO:85-86两者；(7)SEQ ID NO:95-96两者；(8)SEQ ID NO:105-106两者；(9)SEQ ID NO:115-116两者；(10)SEQ ID NO:125-126两者；(11)SEQ ID NO:135-136两者；(12)SEQ IDNO:145-146两者；(13)SEQ ID NO:155-156两者；(14)SEQ ID NO:165-166两者；(15)SEQ IDNO:175-176两者；(16)SEQ ID NO:185-186两者；(17)SEQ ID NO:195-196两者；(18)SEQ IDNO:205-206两者；(19)SEQ ID NO:215-216两者；(20)SEQ ID NO:225-226两者；(21)SEQ IDNO:235-236两者；(22)SEQ ID NO:245-246两者；(23)SEQ ID NO:255-256两者；(24)SEQ IDNO:265-266；(25)SEQ ID NO:275-276两者；(26)SEQ ID NO:285-286两者；(27)SEQ ID NO:295-296两者；(28)SEQ ID NO:305-306两者；(29)SEQ ID NO:315-316两者；(30)SEQ IDNO:325-326两者；(31)SEQ ID NO:335-336两者；(32)SEQ ID NO:345-346两者；(33)SEQ IDNO:355-356两者；(34)SEQ ID NO:365-366两者；(35)SEQ ID NO:375-376两者；(36)SEQ IDNO:385-386两者；(37)SEQ ID NO:395-396两者；(38)SEQ ID NO:405-406两者；(39)SEQ IDNO:415-416两者；(40)SEQ ID NO:425-426两者；(41)SEQ ID NO:435-436两者；(42)SEQ IDNO:445-446两者；(43)SEQ ID NO:455-456；(44)SEQ ID NO:465-466两者；(45)SEQ ID NO:475-476两者；(46)SEQ ID NO:485-486两者；或(47)SEQ ID NO:495-496两者。
本发明进一步提供包含本文所述的至少一种多肽的蛋白质。“蛋白质”意指包含一个或多个多肽链的分子。在一个实施方案中，本发明的蛋白质可包含:(1)包含SEQ ID NO:27-29全部的氨基酸序列的第一多肽链及包含所有SEQ ID NO:30-32的氨基酸序列的第二多肽链；(2)包含SEQ ID NO:37-39全部的氨基酸序列的第一多肽链和包含SEQ ID NO:40-42全部的氨基酸序列的第二多肽链；(3)包含SEQ ID NO:47-49全部的氨基酸序列的第一多肽链和包含SEQ ID NO:50-52全部的氨基酸序列的第二多肽链；(4)包含SEQ ID NO:57-59全部的氨基酸序列的第一多肽链和包含SEQ ID NO:60-62全部的氨基酸序列的第二多肽链；(5)包含SEQ ID NO:67-69全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:70-72全部的氨基酸序列的第二多肽链；(6)包含SEQ ID NO:77-79全部的氨基酸序列的第一多肽链和包含SEQ ID NO:80-82全部的氨基酸序列的第二多肽链；(7)包含SEQ ID NO:87-89全部的氨基酸序列的第一多肽链和包含SEQ ID NO:90-92全部的氨基酸序列的第二多肽链；(8)包含SEQ ID NO:97-99全部的氨基酸序列的第一多肽链和包含SEQ ID NO:100-102全部的氨基酸序列的第二多肽链；(9)包含SEQ ID NO:107-109全部的氨基酸序列的第一多肽链和包含SEQ ID NO:110-112全部的氨基酸序列的第二多肽链；(10)包含SEQ ID NO:117-119全部的氨基酸序列的第一多肽链和包含SEQ ID NO:120-122全部的氨基酸序列的第二多肽链；(11)包含SEQ ID NO:127-129全部的氨基酸序列的第一多肽链和包含SEQ ID NO:130-132全部的氨基酸序列的第二多肽链；(12)包含SEQ ID NO:137-139全部的氨基酸序列的第一多肽链和包含SEQ ID NO:140-142全部的氨基酸序列的第二多肽链；(13)第一多肽链，其包含SEQ ID NO:147-149全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:150-152全部的氨基酸序列；(14)第一多肽链，其包含SEQ ID NO:157-159全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:160-162全部的氨基酸序列；(15)包含SEQ ID NO:167-169全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:170-172全部的氨基酸序列的第二多肽链；(16)包含SEQ ID NO:177-179全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:180-182全部的氨基酸序列的第二多肽链；(17)第一多肽链，其包含SEQ ID NO:187-189全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:190-192全部的氨基酸序列；(18)第一多肽链，其包含SEQ ID NO:197-199全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:200-202全部的氨基酸序列；(19)第一多肽链，其包含SEQ ID NO:207-209全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:210-212全部的氨基酸序列；(20)第一多肽链，其包含SEQ IDNO:217-219全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:220-222全部的氨基酸序列；(21)包含SEQ ID NO:227-229全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:230-232全部的氨基酸序列的第二多肽链；(22)包含SEQ ID NO:237-239全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:240-242全部的氨基酸序列的第二多肽链；(23)第一多肽链，其包含SEQ ID NO:247-249全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:250-252全部的氨基酸序列；(24)第一多肽链，其包含SEQ ID NO:257-259全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:260-262全部的氨基酸序列；(25)第一多肽链，其包含SEQ IDNO:267-269全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:270-272全部的氨基酸序列；(26)第一多肽链，其包含SEQ ID NO:277-279全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:280-282全部的氨基酸序列；(27)第一多肽链，其包含SEQ ID NO:287-289全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:290-292全部的氨基酸序列；(28)第一多肽链，其包含SEQ ID NO:297-299全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:300-302全部的氨基酸序列；(29)第一多肽链，其包含SEQ ID NO:307-309全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:310-312全部的氨基酸序列；(30)包含SEQ ID NO:317-319全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:320-322全部的氨基酸序列的第二多肽链；(31)包含SEQ ID NO:327-329全部的氨基酸序列的第一多肽链，和包含SEQ IDNO:330-332全部的氨基酸序列的第二多肽链；(32)第一多肽链，其包含SEQ ID NO:337-339全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:340-342全部的氨基酸序列；(33)第一多肽链，其包含SEQ ID NO:347-349全部的氨基酸序列，和第二多肽链，其包含SEQ IDNO:350-352全部的氨基酸序列；(34)包含SEQ ID NO:357-359全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:360-362全部的氨基酸序列的第二多肽链；(35)包含SEQ ID NO:367-369全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:370-372全部的氨基酸序列的第二多肽链；(36)第一多肽链，其包含SEQ ID NO:377-379全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:380-382全部的氨基酸序列；(37)第一多肽链，其包含SEQ ID NO:387-389全部的氨基酸序列和第二多肽链，其包含SEQ ID NO:390-392全部的氨基酸序列；(38)包含SEQ ID NO:397-399全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:400-402全部的氨基酸序列的第二多肽链；(39)包含SEQ ID NO:407-409全部的氨基酸序列的第一多肽链和包含SEQ ID NO:410-412全部的氨基酸序列的第二多肽链；(40)包含SEQ ID NO:417-419全部的氨基酸序列的第一多肽链和包含SEQ ID NO:420-422全部的氨基酸序列的第二多肽链；(41)第一多肽链，其包含SEQ ID NO:427-429全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:430-432全部的氨基酸序列；(42)第一多肽链，其包含SEQ ID NO:437-439全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:440-442全部的氨基酸序列；(43)第一多肽链，其包含SEQ ID NO:447-449全部的氨基酸序列，和第二多肽链，其包含SEQID NO:450-452全部的氨基酸序列；(44)包含SEQ ID NO:457-459全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:460-462全部的氨基酸序列的第二多肽链；(45)第一多肽链，其包含SEQ ID NO:467-469全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:470-472全部的氨基酸序列；(46)第一多肽链，其包含SEQ ID NO:477-479全部的氨基酸序列，和第二多肽链，其包含SEQ ID NO:480-482全部的氨基酸序列；或(47)包含SEQ ID NO:487-489全部的氨基酸序列的第一多肽链，和包含SEQ ID NO:490-492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:33的氨基酸序列的第一多肽链及包含SEQ ID NO:34的氨基酸序列的第二多肽链；(2)包含SEQ ID NO:43的氨基酸序列的第一多肽链和包含SEQ ID NO:44的氨基酸序列的第二多肽链；(3)包含SEQ IDNO:53的氨基酸序列的第一多肽链和包含SEQ ID NO:54的氨基酸序列的第二多肽链；(4)包含SEQ ID NO:63的氨基酸序列的第一多肽链和包含SEQ ID NO:64的氨基酸序列的第二多肽链；(5)包含SEQ ID NO:73的氨基酸序列的第一多肽链和包含SEQ ID NO:74的氨基酸序列的第二多肽链；(6)包含SEQ ID NO:83的氨基酸序列的第一多肽链和包含SEQ ID NO:84的氨基酸序列的第二多肽链；(7)包含SEQ ID NO:93的氨基酸序列的第一多肽链和包含SEQID NO:94的氨基酸序列的第二多肽链；(8)包含SEQ ID NO:103的氨基酸序列的第一多肽链和包含SEQ ID NO:104的氨基酸序列的第二多肽链；(9)包含SEQ ID NO:113的氨基酸序列的第一多肽链和包含SEQ ID NO:114的氨基酸序列的第二多肽链；(10)包含SEQ ID NO:123的氨基酸序列的第一多肽链和包含SEQ ID NO:124的氨基酸序列的第二多肽链；(11)包含SEQ ID NO:133的氨基酸序列的第一多肽链和包含SEQ ID NO:134的氨基酸序列的第二多肽链；(12)包含SEQ ID NO:143的氨基酸序列的第一多肽链和包含SEQ ID NO:144的氨基酸序列的第二多肽链；(13)包含SEQ ID NO:153的氨基酸序列的第一多肽链和包含SEQ IDNO:154的氨基酸序列的第二多肽链；(14)包含SEQ ID NO:163的氨基酸序列的第一多肽链和包含SEQ ID NO:164的氨基酸序列的第二多肽链；(15)包含SEQ ID NO:173的氨基酸序列的第一多肽链和包含SEQ ID NO:174的氨基酸序列的第二多肽链；(16)包含SEQ ID NO:183的氨基酸序列的第一多肽链和包含SEQ ID NO:184的氨基酸序列的第二多肽链；(17)包含SEQ ID NO:193的氨基酸序列的第一多肽链和包含SEQ ID NO:194的氨基酸序列的第二多肽链；(18)包含SEQ ID NO:203的氨基酸序列的第一多肽链和包含SEQ ID NO:204的氨基酸序列的第二多肽链；(19)包含SEQ ID NO:213的氨基酸序列的第一多肽链和包含SEQ IDNO:214的氨基酸序列的第二多肽链；(20)包含SEQ ID NO:223的氨基酸序列的第一多肽链和包含SEQ ID NO:224的氨基酸序列的第二多肽链；(21)包含SEQ ID NO:233的氨基酸序列的第一多肽链和包含SEQ ID NO:234的氨基酸序列的第二多肽链；(22)包含SEQ ID NO:243的氨基酸序列的第一多肽链和包含SEQ ID NO:244的氨基酸序列的第二多肽链；(23)包含SEQ ID NO:253的氨基酸序列的第一多肽链和包含SEQ ID NO:254的氨基酸序列的第二多肽链；(24)包含SEQ ID NO:263的氨基酸序列的第一多肽链和包含SEQ ID NO:264的氨基酸序列的第二多肽链；(25)包含SEQ ID NO:273的氨基酸序列的第一多肽链和包含SEQ IDNO:274的氨基酸序列的第二多肽链；(26)包含SEQ ID NO:283的氨基酸序列的第一多肽链和包含SEQ ID NO:284的氨基酸序列的第二多肽链；(27)包含SEQ ID NO:293的氨基酸序列的第一多肽链和包含SEQ ID NO:294的氨基酸序列的第二多肽链；(28)包含SEQ ID NO:303的氨基酸序列的第一多肽链和包含SEQ ID NO:304的氨基酸序列的第二多肽链；(29)包含SEQ ID NO:313的氨基酸序列的第一多肽链和包含SEQ ID NO:314的氨基酸序列的第二多肽链；(30)包含SEQ ID NO:323的氨基酸序列的第一多肽链和包含SEQ ID NO:324的氨基酸序列的第二多肽链；(31)包含SEQ ID NO:333的氨基酸序列的第一多肽链和包含SEQ IDNO:334的氨基酸序列的第二多肽链；(32)包含SEQ ID NO:343的氨基酸序列的第一多肽链和包含SEQ ID NO:344的氨基酸序列的第二多肽链；(33)包含SEQ ID NO:353的氨基酸序列的第一多肽链和包含SEQ ID NO:354的氨基酸序列的第二多肽链；(34)包含SEQ ID NO:363的氨基酸序列的第一多肽链和包含SEQ ID NO:364的氨基酸序列的第二多肽链；(35)包含SEQ ID NO:373的氨基酸序列的第一多肽链和包含SEQ ID NO:374的氨基酸序列的第二多肽链；(36)包含SEQ ID NO:383的氨基酸序列的第一多肽链和包含SEQ ID NO:384的氨基酸序列的第二多肽链；(37)包含SEQ ID NO:393的氨基酸序列的第一多肽链和包含SEQ IDNO:394的氨基酸序列的第二多肽链；(38)包含SEQ ID NO:403的氨基酸序列的第一多肽链和包含SEQ ID NO:404的氨基酸序列的第二多肽链；(39)包含SEQ ID NO:413的氨基酸序列的第一多肽链和包含SEQ ID NO:414的氨基酸序列的第二多肽链；(40)包含SEQ ID NO:423的氨基酸序列的第一多肽链和包含SEQ ID NO:424的氨基酸序列的第二多肽链；(41)包含SEQ ID NO:433的氨基酸序列的第一多肽链和包含SEQ ID NO:434的氨基酸序列的第二多肽链；(42)包含SEQ ID NO:443的氨基酸序列的第一多肽链和包含SEQ ID NO:444的氨基酸序列的第二多肽链；(43)包含SEQ ID NO:453的氨基酸序列的第一多肽链和包含SEQ IDNO:454的氨基酸序列的第二多肽链；(44)包含SEQ ID NO:463的氨基酸序列的第一多肽链和包含SEQ ID NO:464的氨基酸序列的第二多肽链；(45)包含SEQ ID NO:473的氨基酸序列的第一多肽链和包含SEQ ID NO:474的氨基酸序列的第二多肽链；(46)包含SEQ ID NO:483的氨基酸序列的第一多肽链和包含SEQ ID NO:484的氨基酸序列的第二多肽链；或(47)包含SEQ ID NO:493的氨基酸序列的第一多肽链和包含SEQ ID NO:494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:35的氨基酸序列的第一多肽链及包含SEQ ID NO:36的氨基酸序列的第二多肽链；(2)包含SEQ ID NO:45的氨基酸序列的第一多肽链和包含SEQ ID NO:46的氨基酸序列的第二多肽链；(3)包含SEQ IDNO:55的氨基酸序列的第一多肽链和包含SEQ ID NO:56的氨基酸序列的第二多肽链；(4)包含SEQ ID NO:65的氨基酸序列的第一多肽链和包含SEQ ID NO:66的氨基酸序列的第二多肽链；(5)包含SEQ ID NO:75的氨基酸序列的第一多肽链和包含SEQ ID NO:76的氨基酸序列的第二多肽链；(6)包含SEQ ID NO:85的氨基酸序列的第一多肽链和包含SEQ ID NO:86的氨基酸序列的第二多肽链；(7)包含SEQ ID NO:95的氨基酸序列的第一多肽链和包含SEQID NO:96的氨基酸序列的第二多肽链；(8)包含SEQ ID NO:105的氨基酸序列的第一多肽链和包含SEQ ID NO:106的氨基酸序列的第二多肽链；(9)包含SEQ ID NO:115的氨基酸序列的第一多肽链和包含SEQ ID NO:116的氨基酸序列的第二多肽链；(10)包含SEQ ID NO:125的氨基酸序列的第一多肽链和包含SEQ ID NO:126的氨基酸序列的第二多肽链；(11)包含SEQ ID NO:135的氨基酸序列的第一多肽链和包含SEQ ID NO:136的氨基酸序列的第二多肽链；(12)包含SEQ ID NO:145的氨基酸序列的第一多肽链和包含SEQ ID NO:146的氨基酸序列的第二多肽链；(13)包含SEQ ID NO:155的氨基酸序列的第一多肽链和包含SEQ IDNO:156的氨基酸序列的第二多肽链；(14)包含SEQ ID NO:165的氨基酸序列的第一多肽链和包含SEQ ID NO:166的氨基酸序列的第二多肽链；(15)包含SEQ ID NO:175的氨基酸序列的第一多肽链和包含SEQ ID NO:176的氨基酸序列的第二多肽链；(16)包含SEQ ID NO:185的氨基酸序列的第一多肽链和包含SEQ ID NO:186的氨基酸序列的第二多肽链；(17)包含SEQ ID NO:195的氨基酸序列的第一多肽链和包含SEQ ID NO:196的氨基酸序列的第二多肽链；(18)包含SEQ ID NO:205的氨基酸序列的第一多肽链和包含SEQ ID NO:206的氨基酸序列的第二多肽链；(19)包含SEQ ID NO:215的氨基酸序列的第一多肽链和包含SEQ IDNO:216的氨基酸序列的第二多肽链；(20)包含SEQ ID NO:225的氨基酸序列的第一多肽链和包含SEQ ID NO:226的氨基酸序列的第二多肽链；(21)包含SEQ ID NO:235的氨基酸序列的第一多肽链和包含SEQ ID NO:236的氨基酸序列的第二多肽链；(22)包含SEQ ID NO:245的氨基酸序列的第一多肽链和包含SEQ ID NO:246的氨基酸序列的第二多肽链；(23)包含SEQ ID NO:255的氨基酸序列的第一多肽链和包含SEQ ID NO:256的氨基酸序列的第二多肽链；(24)包含SEQ ID NO:265的氨基酸序列的第一多肽链和包含SEQ ID NO:266的氨基酸序列的第二多肽链；(25)包含SEQ ID NO:275的氨基酸序列的第一多肽链和包含SEQ IDNO:276的氨基酸序列的第二多肽链；(26)包含SEQ ID NO:285的氨基酸序列的第一多肽链和包含SEQ ID NO:286的氨基酸序列的第二多肽链；(27)包含SEQ ID NO:295的氨基酸序列的第一多肽链和包含SEQ ID NO:296的氨基酸序列的第二多肽链；(28)包含SEQ ID NO:305的氨基酸序列的第一多肽链和包含SEQ ID NO:306的氨基酸序列的第二多肽链；(29)包含SEQ ID NO:315的氨基酸序列的第一多肽链和包含SEQ ID NO:316的氨基酸序列的第二多肽链；(30)包含SEQ ID NO:325的氨基酸序列的第一多肽链和包含SEQ ID NO:326的氨基酸序列的第二多肽链；(31)包含SEQ ID NO:335的氨基酸序列的第一多肽链和包含SEQ IDNO:336的氨基酸序列的第二多肽链；(32)包含SEQ ID NO:345的氨基酸序列的第一多肽链和包含SEQ ID NO:346的氨基酸序列的第二多肽链；(33)包含SEQ ID NO:355的氨基酸序列的第一多肽链和包含SEQ ID NO:356的氨基酸序列的第二多肽链；(34)包含SEQ ID NO:365的氨基酸序列的第一多肽链和包含SEQ ID NO:366的氨基酸序列的第二多肽链；(35)包含SEQ ID NO:375的氨基酸序列的第一多肽链和包含SEQ ID NO:376的氨基酸序列的第二多肽链；(36)包含SEQ ID NO:385的氨基酸序列的第一多肽链和包含SEQ ID NO:386的氨基酸序列的第二多肽链；(37)包含SEQ ID NO:395的氨基酸序列的第一多肽链和包含SEQ IDNO:396的氨基酸序列的第二多肽链；(38)包含SEQ ID NO:405的氨基酸序列的第一多肽链和包含SEQ ID NO:406的氨基酸序列的第二多肽链；(39)包含SEQ ID NO:415的氨基酸序列的第一多肽链和包含SEQ ID NO:416的氨基酸序列的第二多肽链；(40)包含SEQ ID NO:425的氨基酸序列的第一多肽链和包含SEQ ID NO:426的氨基酸序列的第二多肽链；(41)包含SEQ ID NO:435的氨基酸序列的第一多肽链和包含SEQ ID NO:436的氨基酸序列的第二多肽链；(42)包含SEQ ID NO:445的氨基酸序列的第一多肽链和包含SEQ ID NO:446的氨基酸序列的第二多肽链；(43)包含SEQ ID NO:455的氨基酸序列的第一多肽链和包含SEQ IDNO:456的氨基酸序列的第二多肽链；(44)包含SEQ ID NO:465的氨基酸序列的第一多肽链和包含SEQ ID NO:466的氨基酸序列的第二多肽链；(45)包含SEQ ID NO:475的氨基酸序列的第一多肽链和包含SEQ ID NO:476的氨基酸序列的第二多肽链；(46)包含SEQ ID NO:485的氨基酸序列的第一多肽链和包含SEQ ID NO:486的氨基酸序列的第二多肽链；或(47)包含SEQ ID NO:495的氨基酸序列的第一多肽链和包含SEQ ID NO:496的氨基酸序列的第二多肽链。
本发明的蛋白质可以是TCR。或者，如果蛋白质的第一和/或第二多肽链还包含其他氨基酸序列，例如编码免疫球蛋白或其一部分的氨基酸序列，那么本发明的蛋白质可以是融合蛋白。在这方面，本发明还提供包含本文所述的至少一种本发明多肽以及至少一种其它多肽的融合蛋白。其他多肽可作为融合蛋白的单独多肽存在，或可作为多肽存在，其与本文所述的一种本发明多肽同框(串联)表达。其他多肽可编码任何肽或蛋白质分子或其一部分，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多肽的一个或多个拷贝和/或其他多肽的一或多个拷贝。例如，融合蛋白可包含本发明多肽和/或其他多肽的1个、2个、3个、4个、5个或更多个拷贝。制备融合蛋白的适宜方法是本领域已知的，且包括(例如)重组方法。
在本发明的一些实施方案中，本发明的TCR、多肽和蛋白质可表达为包含连接α链和β链的连接肽的单一蛋白质。在这方面，本发明的TCR、多肽和蛋白质可进一步包含连接子肽。连接肽可有利地促进重组TCR、多肽和/或蛋白在宿主细胞中的表达。连接肽可包含任何适宜的氨基酸序列。例如，连接肽可包含SEQ ID NO:26的氨基酸序列。通过宿主细胞表达包括连接肽在内的构建体时，连接肽可能被裂解，从而产生分开的α和β链。在本发明的一个实施方案中，TCR、多肽或蛋白质可包含包含全长α链、全长β链、及位于α与β链之间的连接肽的氨基酸序列。
本发明的蛋白质可为重组抗体或其抗原结合部分，其包含本文所述的至少一种本发明的多肽。如本文所用，“重组抗体”是指包含本发明的至少一种多肽和抗体的多肽链或其抗原结合部分的重组(例如，基因工程化的)蛋白。抗体的多肽或其抗原结合部分可为重链、轻链、重链或轻链的可变区或恒定区、单链可变区片段(scFv)或抗体的Fc、Fab或F(ab)2’片段等。抗体的多肽链或其抗原结合部分可作为重组抗体的单独多肽存在。或者，抗体的多肽链或其抗原结合部分可作为多肽存在，其与本发明的多肽同框(串联)表达。抗体的多肽或其抗原结合部分可以是任何抗体或任何抗体片段的多肽，包括本文所述的任何抗体和抗体片段。
本发明的TCR、多肽和蛋白质可具有任何长度，即可包含任何数量的氨基酸，前提是TCR、多肽或蛋白质保持其生物活性，例如特异性结合突变p53的能力、检测哺乳动物中癌症的能力、或治疗或预防哺乳动物中的癌症的能力等。例如，多肽可在约50至约5000个氨基酸长度范围内，例如50、70、75、100、125、150、175、200、300、400、500、600、700、800、900、1000或更多个氨基酸。在这方面，本发明的多肽也包括寡肽。
本发明的TCR、多肽和蛋白质可包含合成氨基酸替代一种或多种天然存在的氨基酸。此类合成氨基酸在本领域内是已知的，并且包括例如氨基环己烷羧酸、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-和反式-4-羟基脯氨酸、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-苯丝氨酸β-羟基苯丙氨酸、苯甘氨酸、α-萘丙氨酸、环己基丙氨酸、环己基甘氨酸、吲哚-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸、氨基马来酸、氨基马来酸单酰胺，N’-苄基-N’-甲基-赖氨酸，N’，N’-二苄基-赖氨酸，6-羟基赖氨酸，鸟氨酸，α-氨基环戊烷羧酸，α-氨基环己烷羧酸，α-氨基环庚烷羧酸，α-(2-氨基-2-正硼烷)-羧酸，α，β-二氨基丁酸，α，β--二氨基丙酸，同苯丙氨酸和α-叔丁基甘氨酸。
本发明的TCR、多肽和蛋白质可被糖基化、酰胺化、羧基化、磷酸化、酯化、N-酰化、例如经二硫键环化、或转化为酸加成盐和/或任选地二聚的或聚合的、或共轭的。
本发明的TCR、多肽、和/或蛋白质可藉由本领域已知方法(例如，从头合成)获得。此外，可使用本文所述核酸使用标准重组方法重组产生多肽和蛋白质。例如，参见Greenand Sambrook,Molecular Cloning:A Laboratory Manual,4th ed.,Cold Spring HarborPress,Cold Spring Harbor,NY(2012)。可选地，本文所述的TCR、多肽和/或蛋白质可由诸如Synpep(Dublin,CA)、PeptideTechnologiesCorp.(Gaithersburg,MD)和多肽系统(SanDiego,CA)等公司商业化合成。在这方面，本发明TCR、多肽和蛋白质可为合成、重组、分离和/或纯化的。
本发明的一个实施方案提供包含编码本文所述的任何TCR、多肽或蛋白质的核苷酸序列的核酸。如本文所使用的“核酸”包括“多核苷酸”、“寡核苷酸”和“核酸分子”，并且通常意指DNA或RNA的聚合物，其可为单链或双链，其可含有天然、非天然或改变的核苷酸，并且可含有天然、非天然或改变的核苷酸间链接，例如磷酰胺酯链接或硫代磷酸酯链接，而不是未修饰寡核苷酸的核苷酸之间发现的磷酸二酯。在一个实施方案中，核酸包含互补DNA(cDNA)。通常优选地，核酸不包含任何插入、缺失、倒置和/或取代。然而，在一些实例中，如本文所讨论，其可适用于核酸包含一个或多个插入、删除、倒置和/或取代。
优选地，本发明的核酸是重组的。如本文所用，术语“重组”是指(i)通过将天然或合成核酸片段连接到可在活细胞中复制的核酸分子而在活细胞外构建的分子，或(ii)由上文(i)中所述的那些复制产生的分子。出于本文的目的，复制可以是体外复制或体内复制。
核酸可使用本领域已知程序基于化学合成和/或酶连接反应构建。例如，参见Green和Sambrook等人，同上。例如，核酸可使用天然存在的核苷酸或设计用于增加分子的生物稳定性或提高杂交后形成的双链体的物理稳定性的各种修饰的核苷酸(例如，硫代磷酸酯衍生物和吖啶取代的核苷酸)进行化学合成。可用于产生核酸的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-(羧羟甲基)尿嘧啶、5-羧甲基氨基甲基-2-硫脲嘧啶、5-羧甲基氨基甲基尿嘧啶、二氢尿嘧啶、β-D-半乳糖喹啉、肌苷、N6-异戊烯基腺嘌呤、1-甲基鸟嘌呤、1-甲基亚麻苷、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、N6-取代的腺嘌呤、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧氨基甲基-2-硫尿嘧啶、β-D-甘露糖苷、5'-甲氧羧甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-异戊烯基腺嘌呤、尿嘧啶-5-氧乙酸(v)、wybutoxosine、假性尿嘧啶、queosine、2-硫代胞嘧啶、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-羟乙酸甲酯、3-(3-氨基-3-N-2-羧丙基)尿嘧啶和2,6-二氨基嘌呤。或者，本发明的一种或多种核酸可购自诸如MacromolecularResources(Fort Collins,CO)和Synthegen(Houston,TX)等公司。
在本发明的一个实施方案中，核酸包含编码本文所述的任何TCR、多肽或蛋白质的密码子优化核苷酸序列。在不受任何特定理论或机制约束的情况下，核苷酸序列的密码子优化被认为提高了mRNA转录本的翻译效率。核苷酸序列的密码子优化可能涉及将天然密码子替换为编码相同氨基酸的另一密码子，但可通过在细胞内更容易获得的tRNA进行翻译，从而提高翻译效率。核苷酸序列的优化也可减少干扰翻译的次级mRNA结构，从而提高翻译效率。
本发明还提供包含与本文所述的任何核酸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述的任何核酸的核苷酸序列杂交的核苷酸序列的核酸。
在严格条件下杂交的核苷酸序列最好在高严格条件下杂交。所述“高严格条件”意指核苷酸序列以比非特异性杂交可更强检测的量特异性地杂交至目标序列(本文所述的任何核酸的核苷酸序列)。高严格性条件包括能够将具有精确互补序列或仅包含几个分散不匹配的多核苷酸与随机序列区分的条件，所述随机序列恰好有几个与核苷酸序列匹配的小区域(例如，3-10个碱基)。这种互补的小区域比14-17碱基或更多碱基的全长互补物更容易熔融，高严格性杂交使它们容易区分。相对较高的严格条件将包括(例如)在约50-70℃的温度下由约0.02-0.1MNaCl或其等效物提供的低盐和/或高温条件。此等高严格条件耐受核苷酸序列与模板或靶链之间的极少不匹配(如有的话)，并且尤其适于检测任何本发明TCR的表达。通常可以理解，通过增加甲酰胺的量可以使条件变得更加严格。
本发明还提供包含与本文所述的任一核酸具有至少约70％或更多，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％等同的核苷酸序列的核酸于。在这方面，核酸可以基本上由本文所述的任何核苷酸序列组成。
本发明的核酸可并入重组表达载体中。在这方面，本发明提供包含本发明的任何核酸的重组表达载体。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链和连接肽的核苷酸序列。
出于本文的目的，术语“重组表达载体”意指基因修饰的寡核苷酸或多核苷酸构建体，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接触细胞时，所述构建体允许宿主细胞表达RNA、蛋白质、多肽或肽。本发明的载体作为整体并非自然存在的。然而，载体的部分可以是自然存在的。本发明的重组表达载体可包含任何类型的核苷酸，包括但不限于DNA和RNA，其可以是部分由天然来源获得或合成的单链或双链，并且可含有天然、非天然或改变的核苷酸。重组表达载体可包含自然存在的、非自然存在的核苷酸间链接或两种类型的链接。优选地，非自然存在或改变的核苷酸或核苷酸间链接不妨碍载体的转录或复制。
本发明的重组表达载体可以是任何合适的重组表达载体，并且可以用于转化或转染任何合适的宿主细胞。合适的载体包括那些设计用于增殖和扩增或用于表达或用于上述两者的载体，例如质粒和病毒。载体可选自转座子/转座酶系列、pUC系列(FermentasLifeSciences)、pBluescript系列(Stratagene，LaJolla，CA)、pET系列(Novagen，Madison，WI)、pGEX系列(PharmaciaBiotech，Uppsala，瑞典)、以及pEX系列(Clontech,PaloAlto,CA)。也可使用噬菌体载体，如λGT10、λGT11、λZapII(Stratagene)、λEMBL4和λNM1149。植物表达载体的实例包括pBI01、pBI101.2、pBI101.3、pBI121和pBIN19(Clontech)。动物表达载体的实例包括PEUK-Cl、pMAM和pMAMneo(Clontech)。优选地，重组表达载体是转座子载体或病毒载体，例如逆转录病毒载体。
本发明的重组表达载体可使用例如Green和Sambrook等人(同上述)所述的标准重组DNA技术制备。可制备环形或线性表达载体的构建体，以包含在原核或真核宿主细胞中发挥功能的复制系统。复制系统可衍生自ColEl、2μ质粒、λ、SV40、牛乳头瘤病毒等。
理想的是，重组表达载体包含调节序列，例如转录和翻译起始和终止密码子，所述调控序列对要将载体引入的宿主细胞类型(例如，细菌、真菌、植物或动物)具有特异性，视情况并考虑载体是基于DNA还是基于RNA。
重组表达载体可包括一个或多个标记基因，可用于选择转化或转染的宿主细胞。标记基因包括杀生物剂耐药性，例如抗生素耐药性、重金属等。在营养缺陷型宿主细胞中互补以提供原养性等。适于本发明表达载体的标记基因包括(例如)新霉素/G418抗性基因、潮霉素抗性基因、组氨酸抗性基因、四环素抗性基因及氨苄西林抗性基因。
重组表达载体可包含可操作地连接到编码TCR、多肽或蛋白质的核苷酸序列或与编码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。启动子的选择，例如，强、弱、可诱导、组织特异性和发育特异性启动子，在本领域普通技术范围内。类似地，核苷酸序列与启动子的组合也在本领域技术范围内。启动子可为非病毒启动子，例如人延伸因子-1α启动子，或病毒启动子，例如巨细胞病毒(CMV)启动子、SV40启动子、RSV启动子和在鼠干细胞病毒的长末端重复序列中发现的启动子。
本发明重组表达载体可设计用于瞬时表达、稳定表达或两者。此外，重组表达载体可用于组成型表达或诱导型表达。
此外，可制备重组表达载体以包括自杀基因。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。自杀基因可以是使基因表达的细胞对药剂(例如药物)敏感的基因，并且当细胞接触或暴露于该药剂时使细胞死亡。自杀基因在本领域是已知的，并且包括(例如)单纯疱疹病毒(HSV)胸苷激酶(TK)基因、胞嘧啶脱氨酶、嘌呤核苷磷酸化酶和硝基还原酶。
本发明的另一实施方案进一步提供包含本文所述的任何重组表达载体的宿主细胞。如本文所用，术语“宿主细胞”是指可包含本发明重组表达载体的任何类型的细胞。宿主细胞可以是真核细胞，例如植物、动物、真菌或藻类，或者可以是原核细胞，例如细菌或原生动物。宿主细胞可为培养细胞或原代细胞，即直接从生物体(例如人)中分离的。宿主细胞可以是贴壁细胞或悬浮细胞，即悬浮生长的细胞。合适的宿主细胞是本领域已知的并且包括例如DH5α大肠杆菌细胞、中国仓鼠卵巢细胞、猴VERO细胞、COS细胞、HEK293细胞等。为了扩增或复制重组表达载体，宿主细胞优选原核细胞，例如DH5细胞。为了产生重组TCR、多肽或蛋白质，宿主细胞优选哺乳动物细胞。最优选地，宿主细胞是人类细胞。虽然宿主细胞可以是任何细胞类型，可以来自任何类型的组织，并且可以是任何发育阶段的细胞，但宿主细胞优选是外周血淋巴细胞(PBL)或外周血单核细胞(PBMC)。更优选地，宿主细胞是T细胞。
出于本文的目的，T细胞可以是任何T细胞，例如培养的T细胞，例如原代T细胞；或来自培养的T细胞系的T细胞，例如Jurkat、SupT1等；或从哺乳动物获得的T细胞。如果从哺乳动物获得，T细胞可以从多种来源获得，包括但不限于血液、骨髓、淋巴结、胸腺或其他组织或液体。T细胞也可以富集或纯化。优选地，该T细胞是人类T细胞。T细胞可以是任何类型的T细胞并且可以是任何发育阶段的T细胞，包括但不限于CD4+/CD8+双阳性T细胞、CD4+辅助T细胞例如Th1和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(TILs)、记忆性T细胞(例如中心记忆性T细胞和效应记忆性T细胞)、初始T细胞等。
本发明还提供包含本文所述至少一种宿主细胞的细胞群。细胞群可为异质性群体，其包含包含所述的任何重组表达载体的宿主细胞以及至少一种其他细胞，例如不包含任何重组表达载体的宿主细胞(例如T细胞)或除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，细胞群可以是基本上均质的群体，其中群体主要包含宿主细胞(例如，基本上由其组成)，所述宿主细胞包含重组表达载体。该群体还可以是细胞的克隆群体，其中该群体的所有细胞均为包含重组表达载体的单一宿主细胞的克隆，使得该群体的所有细胞均包含重组表达载体。在本发明的一个实施方案中，细胞群是包含宿主细胞的克隆群，所述宿主细胞包含如本文所述的重组表达载体。
在本发明的一个实施方案中，该群体中细胞的数量可快速扩大。T细胞的数量可通过所属领域内已知的任何一种方法来实现扩增，例如，美国专利8,034,334；美国专利8,383,099；美国专利申请公开第2012/0244133号；Dudley et al.,J.Immunother.,26:332-42(2003)；and Riddell et al.,J.Immunol.Methods,128:189-201(1990)。在一个实施方案中，通过用OKT3抗体、IL-2和饲养PBMC(例如，经辐照的同种异体PBMC)培养T细胞来扩大T细胞的数量。
本发明的TCR、多肽、蛋白质、核酸、重组表达载体和宿主细胞(包括其群体)可以是分离的和/或纯化的。本文所用术语“分离的”意指已从其自然环境中移除。本文所用术语“纯化的”意指已增加纯度，其中“纯度”是相对术语，且不必解释为绝对纯度。例如，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TCR、多肽、蛋白质、核酸、重组表达载体和宿主细胞(包括其群体)，其在下文中统称为“本发明TCR材料”，可被配制为组合物，例如药物组合物。在这方面，本发明提供包含本文所述的TCR、多肽、蛋白质、核酸、表达载体和宿主细胞(包括其群体)中的任一种和药学上可接受的载体的药物组合物。含有任一本发明TCR材料的本发明药物组合物可包含一种以上本发明TCR材料，例如多肽和核酸，或两种或多种不同TCR。或者，药物组合物可包含与另一种药物活性剂或药物组合的本发明TCR材料，所述另一种药物活性剂或药物例如化学治疗剂，例如天冬酰胺酶、白消安、卡铂、顺铂、柔红霉素、阿霉素、氟尿嘧啶、吉西他滨、羟基脲、甲氨蝶呤、紫杉醇、利妥昔单抗、长春碱、长春新碱等
优选地，该载体是医药上可接受的载体。关于药物组合物，载体可以是常规用于所考虑的特定本发明TCR材料的任何载体。制备可施用组合物的方法为本领域技术人员已知或显而易见且更详细地阐述于例如Remington:TheScienceandPracticeofPharmacy,22ndEd.，PharmaceuticalPress(2012)。优选地，医学上可接受的载体是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TCR材料以及用于施用与本发明TCR材料的特定方法决定。因此，存在本发明的药物组合物的各种适宜调配物。适宜调配物可包括用于肠外、皮下、静脉内、肌内、动脉内、鞘内、瘤内或腹膜间施用的任何调配物。一种以上途径可用于施用本发明TCR材料，且在某些情况下，特定途径可提供比另一途径更立即且更有效的响应。
优选地，通过例如静脉注射施用本发明TCR材料。当本发明TCR材料是表达本发明TCR的宿主细胞时，注射用细胞的药学可接受的载体可包括任何等渗载体，例如生理盐水(约0.90％w/vNaCl水溶液、约300mOsm/LNaCl水溶液或约9.0gNaCl/升水)、Normosol R电解质溶液(Abbott，芝加哥，IL)、PLASMA-LYTEA(Baxter，Deerfield，IL)、约5％葡萄糖水溶液或林格乳酸盐。在一个实施例中，用所述药学上可接受的载体添加了人血清蛋白。
出于本发明的目的，施用的本发明TCR材料的量或剂量(例如，当本发明TCR材料为一个或多个细胞时的细胞数量)应足以在合理的时间范围内对个体或动物产生治疗或预防反应。例如，本发明TCR材料的剂量应足以与癌症抗原(例如突变的p53)结合，或在自施用时起约2小时或更长时间(例如12至24小时或更长时间)内检测、治疗或预防癌症。在某些实施例中，时间周期甚至可能更长。剂量将通过特定本发明TCR材料的有效性和动物(例如人)的状况以及待处理动物(例如人)的体重确定。
确定给药剂量的许多分析是本领域已知的。出于本发明的目的，一种包括以下的分析可用于确定向哺乳动物施用的起始剂量:在一组哺乳动物中，每一只给予不同剂量的T细胞，比较当将给定剂量的所述T细胞给予哺乳动物时，靶细胞裂解的程度，或者表达本发明TCR、多肽或蛋白质的T细胞分泌IFN-γ的程度。可藉由本领域已知方法来分析施用特定剂量时靶细胞裂解的程度或所分泌的IFN-γ的程度。
本发明TCR材料的剂量还通过施用特定的本发明TCR材料时可能伴随的任何不良副作用的存在、性质及程度来确定。通常，主治医生将决定用于治疗每例个体患者的本发明TCR材料的剂量，考虑各种因素，例如年龄、体重、一般健康状况、饮食、性别、拟给予的本发明TCR材料、给药途径和所治疗癌症的严重程度。在其中本发明TCR材料是细胞群的一个实施方案中，每次输注施用的细胞数量可变化，例如约1x106到约1x1012个细胞或更多。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，本发明的发明TCR材料可以任何多种方式修饰，以便通过修饰来提高本发明TCR材料的治疗或预防效果。例如，本发明TCR材料可直接或间接通过桥接与化学治疗剂偶联。将化合物偶联到化学治疗剂的实践在本领域是已知的。本领域普通技术人员认识到，对于本发明TCR材料的功能而言不必需的本发明TCR材料上的部位是连接桥接和/或化学治疗剂的理想部位，前提是桥接和/或化学治疗剂一旦连接到本发明TCR材料上，就不会干扰本发明TCR材料的功能，即与突变型p53结合或检测、治疗或预防癌症的能力。
预期本发明的药物组合物、TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞或细胞群可用于治疗或预防癌症的方法。在不约束于特定理论的情况下，认为本发明的TCR特异性结合于突变的p53，使得当由细胞表达时，TCR(或相关的本发明的多肽或蛋白质)能够介导对表达突变p53的靶细胞的免疫应答。在这方面，本发明的实施方案提供治疗或预防哺乳动物中的癌症的方法，其包含以有效治疗或预防哺乳动物中癌症的量向哺乳动物施用本文所述的任一种药物组合物、TCR、多肽或蛋白质、包含编码本文所述的任一TCR、多肽或蛋白质的核苷酸序列的任何核酸或重组表达载体、或者任何宿主细胞或细胞群，其包含编码本文所述的任一TCR、多肽或蛋白质的重组载体。
本发明的实施方案提供本文所述的任何药物组合物、TCR、多肽或蛋白质、包含编码本文所述的任何TCR、多肽、蛋白质的核苷酸序列的任何核酸或重组表达载体、或包含编码本文所述的任何TCR、多肽或蛋白质的重组载体的任何宿主细胞或细胞群，其用于治疗或预防哺乳动物中的癌症。
如本文所使用的术语“治疗”和“预防”以及由此产生的词语不一定意味着100％或完全治疗或预防。而是存在不同程度的治疗或预防，本领域技术人员认识到其具有潜在的益处或治疗效果。在这方面，本发明方法可在哺乳动物中提供任何水平的癌症治疗或预防。此外，本发明方法提供的治疗或预防可包括对正在治疗或预防的癌症的一种或多种病况或症状的治疗或预防。例如，治疗或预防可包括促进肿瘤消退。此外，出于本文之目的，“预防”可包括延迟癌症或其症状或状况的发作。可选地或者另外地，“预防”可包括预防或延迟癌症或其症状或状况的复发。
本发明实施方案还提供了检测哺乳动物中是否存在癌症的方法。该方法包括(i)使包含来自哺乳动物的一或多个细胞的样品与本文所述的任何本发明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接触，由此形成复合物，并检测所述复合物，其中所述复合物的检测指示所述哺乳动物中存在癌症。
关于在哺乳动物中检测癌症的本发明方法，细胞样本可以是包含全细胞、其裂解物或全细胞裂解物的部分，例如，核或细胞质部分、全蛋白部分或核酸部分的样品。
出于本发明检测方法的目的，对于哺乳动物，可在体外或体内进行接触。优选地，该接触是在体外。
此外，可通过本领域已知的任何多种方式来检测该复合物。例如，本文所述的本发明的TCR、多肽、蛋白质、核酸、重组表达载体、宿主细胞或细胞群，可以用可检测的标签标记，例如，放射性同位素、荧光团(例如，异硫氰酸荧光素(FITC)、藻红蛋白(PE))，酶(例如碱性磷酸酶、辣根过氧化物酶)和元素颗粒(例如金颗粒)。
出于本发明方法的目的，其中施用宿主细胞或细胞群，所述细胞可以是哺乳动物同种异体或自体的。优选地，细胞是哺乳动物自体的。
就本发明方法而言，癌症可为任何癌症，包括急性淋巴细胞癌、急性髓性白血病、肺泡横纹肌肉瘤、骨癌、脑癌、乳腺癌、肛门癌、肛管或肛门直肠癌、眼癌、肝内胆管癌、关节癌、颈部癌、胆囊或胸膜癌、鼻、鼻腔或中耳癌、口腔癌、阴道癌、外阴癌、慢性淋巴细胞性白血病、慢性髓系癌、结肠癌、结直肠癌、子宫内膜癌、食管癌、子宫颈癌、胃肠道类癌、胶质瘤、霍奇金淋巴瘤、下咽癌、肾癌、喉癌、肝癌、肺癌、恶性间皮瘤、黑色素瘤、多发性骨髓瘤、鼻咽癌、非霍奇金淋巴瘤、口咽癌、卵巢癌、阴茎癌、胰腺癌、腹膜、网膜和肠系膜癌、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、输尿管癌和膀胱癌。在一个优选的实施方案中，该癌症是表达突变p53的癌症。癌症可在SEQ ID NO:1的位置175、220、245、248、249、273和282中的任何一个或多个处表达具有突变的p53。癌症可表达具有以下一种或多种人类p53突变的p53:R175H、Y220C、G245D、G245S、R248L、R248Q、R248W、R249S、R273H、R273C、R273L和R282W。优选地，癌症是上皮癌或胆管癌、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、胰腺癌或膀胱癌。
本发明方法中提及的哺乳动物可以是任何哺乳动物。如本文所使用，术语“哺乳动物”是指任何哺乳动物，包括但不限于啮齿目的哺乳动物，例如小鼠和仓鼠，和兔形目的哺乳动物，例如兔。优选哺乳动物来自食肉目，包括猫(猫)和犬(犬)。更优选的是，哺乳动物来自偶蹄目，包括Bovines(奶牛)和Swines(猪)；或来自Persodactyla目，包括Equines(马)。最优选地，哺乳动物属于灵长动物目，Ceboids，或Simoids(猴子)或类人猿目(人类和类人猿)。特别优选的哺乳动物是人类。
以下实例进一步说明本发明，但当然不应以任何方式解释为限制其范围。
实施例
在以下实施例中所述的实验中使用表1-3中列出的氨基酸序列。在表
1-2中，“LP”代表“长肽”。在表3中，“TMG”代表“串联微基因”。
表1
表2列出了表1的肽的野生型形式。
表2
表3
实施例1
该实施例证实了来自患者4127的4个抗突变p53的TCR的分离和特异的反应性。
结合图1-7、36和37A-37C所述对患者4127进行实验。通过美国专利申请号2017/0224800(“Tran方法”)中描述的方法鉴别该患者的突变p53反应性T细胞。分离单个TCR的方法如下所述。
使用图1中所示的其中一种TCR转导自体PBL，并在2周后进行检测。将自体DC细胞以3x 104个细胞/孔铺板，并用逐渐降低浓度的WT p53-G245肽(wt)或突变型p53-G245S肽(mut)脉冲过夜。每孔添加3x 104个转导的T细胞并且在37℃下共培养过夜。收获上清液，用于IFN-γELISA。IFN-γELISA结果见图1。通过FACS设门测定4-1BB表达:淋巴细胞\PI(neg)CD3+\CD3+MTCR+\CD8(neg)CD4+。FACS结果见图2。
用图3中所示的一种TCR转导自体PBL，并按照图2中所述的实验进行共培养，但DCs用DMSO(肽媒介物)或表A中所示的具有重叠的14个氨基酸的15-mer p53-G245S肽之一脉冲。如图2所述进行4-1BB表达。结果见图3。
表A
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。20小时后，将细胞用单独的HLA等位基因共转染。20小时后，将细胞用10μg/mL的p53G245S-15-mer肽在37℃下脉冲3小时。洗涤后，将T细胞(105)加入孔中，并于37℃共培养过夜(20小时)。通过ELISA法检测IFN-γ的分泌。通过NetMHCIIpan预测:cbs.dtu.dk/services/NetMHCIIpan/。通过FACS测量4-1BB表达。FACS设门:淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4+(4127-TIL)或CD4+mTCR+(TCR转导的T细胞)。结果显示在图4-5和表B中。
表B
在NCI HLA数据库中，3719例DRB_型患者中有1367例(37％)表达DRB3*02，在NCI-SB(美国国家癌症研究所外科分会)的子宫内膜癌和卵巢癌患者中有5/9(56％)表达DRB3*02。根据allelefrequencies.net website，报告的DRB3*02等位基因频率非常高。例如，本网站报告DRB3*02等位基因的频率是美国NMDP中东或非洲北海岸人口的0.3447。
来自患者4127的TIL与同种异体(DRB3*01:01:01或DRB3*02:02:01)抗原呈递细胞(APC)共培养，所述抗原呈递细胞(1)用由无关、WT p53或突变的p53序列组成的串联微型基因(TMG)电穿孔，或者(2)用肽媒介物(DMSO)或由WT p53-G245S序列或突变的p53-G245S序列组成的经纯化的(>95％，通过高效液相色谱(HPLC))25个氨基酸的肽脉冲。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果示于图6中。
对p53-G245S特异的、表达4127-TCR1的T细胞与同种异体APC共培养，如图6实验所述。结果示于图7中。
自体APC用浓度逐渐降低的对应于WT p53-G245或突变型p53-G245S序列的25个氨基酸的肽脉冲。用来自患者4127的4127-O37-TCR转导的T细胞与肽脉冲的APC在37℃共培养过夜。对于淋巴细胞→单细胞→活细胞)→CD3+MTCR+设门后，通过流式细胞术评价4-1BB的表达。结果见图36。
将Cos7细胞(2.5x104/孔)铺在平底96孔板的孔上。第二天，将细胞与来自患者4127的单个HLA等位基因共转染。第二天，在转染的Cos7细胞上脉冲25个氨基酸的p53-G245S肽。洗去过量的肽。T细胞用来自患者4127的一种TCR转导。向与Cos7细胞共培养物中加入转导的T细胞(2X 104个细胞/孔)。共培养物在37℃下孵育过夜。采用ELISA法评价IFN-γ的分泌。对于淋巴细胞→单细胞→活细胞)→CD3+MTCR+设门后，通过流式细胞术评价4-1BB的表达。结果见图37A-37C。
从患者4127中分离的TCR 4127-TP53-G245S-TCR1的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1β(SEQ ID NO:30)，第二个下划线区域为CDR2β(SEQ ID NO:31)，第三个下划线区域为CDR3β(SEQ ID NO:32)，第四个下划线区域为CDR1α(SEQ ID NO:27)，第五个下划线区域为CDR2α(SEQ ID NO:28)，第六个下划线区域为CDR3α(SEQ ID NO:29)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQ ID NO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:23)。β链可变区(SEQ ID NO:34)包括从氨基末端开始并且就在β链恒定区开始之前结束的序列。α链可变区(SEQ ID NO:33)包括连接子后立即开始并且就在α链恒定区开始之前结束的序列。全长β链(SEQ ID NO:36)包括从氨基末端开始并且就连接子开始前结束的序列。全长α链(SEQ ID NO:35)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。如下所述分离TCR。
TCR名称:4127-TP 53-G245S-TCR1
P53突变的识别:G245S
方法:Tran法
共培养以鉴定TCR:与G245S长肽共培养4127-F10 TIL片段，分选CD4+41BB+TIL细胞(仅单细胞RT-PCR)
鉴定TCR的方法:单细胞RT-PCR(见下文)，适应性Pairseq(4127-F10片段)，来自TIL克隆O71的5'RACE
所有配对TCR中TCR的丰度:31.3％(在16对中观察到5次)
TCR方向:β-α
表达载体:γ-逆转录病毒
患者4127的TCR 4127-TP53-G245S-TCR1的统计数据如下表4所示。
表4
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α型 | 6 | 6.3％ |
| CDR3β | 13 | 13.5％ |
| 4127-TP3-G245S-TCR1对 | 5 | 5.2％ |
| 总配对的TCR | 16 | 16.7％ |
从患者4127中分离的TCR 4127-TP53-G245S-TCR4的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1β(SEQ ID NO:40)，第二个下划线区域为CDR2β(SEQ ID NO:41)，第三个下划线区域为CDR3β(SEQ ID NO:42)，第四个下划线区域为CDR1α(SEQ ID NO:37)，第五个下划线区域为CDR2α(SEQ ID NO:38)，第六个下划线区域为CDR3α(SEQ ID NO:39)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQ ID NO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:23)。β链可变区(SEQ ID NO:44)包括从氨基末端开始并且就在β链恒定区开始前结束的序列。α链可变区(SEQ ID NO:43)包括在连接子后立即开始并且就在α链恒定区开始前结束的序列。全长β链(SEQ ID NO:46)包括从氨基末端开始并且就在连接子开始前结束的序列。全长α链(SEQ ID NO:45)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。如下所述分离TCR。
TCR名称:4127-TP 53-G245S-TCR4
P53突变的识别:G245S
方法:Tran法
共培养以鉴定TCR:与G245S长肽共培养4127-F10TIL片段，分选CD4+41BB+TIL细胞(仅单细胞RT-PCR)
鉴定TCR的方法:单细胞RT-PCR(见下文)，适应性Pairseq(4127-F10片段)
所有配对TCR中TCR的丰度:12.5％(在16对中观察到2次)
TCR方向:β-α
表达载体:γ-逆转录病毒
患者4127的TCR 4127-TP53-G245S-TCR4统计数据见下表5。
表5
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α基因 | 2 | 2.1％ |
| CDR3β基因 | 39 | 40.6％ |
| 4127-TP53-G245S-TCR4对 | 2 | 2.1％ |
| 总配对的TCR | 16 | 16.7％ |
从患者4127中分离的TCR 4127_O102_TCR的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1β(SEQ ID NO:50)，第二个下划线区域为CDR2β(SEQ ID NO:51)，第三个下划线区域为CDR3β(SEQ ID NO:52)，第四个下划线区域为CDR1α(SEQ ID NO:47)，第五个下划线区域为CDR2α(SEQ ID NO:48)，第六个下划线区域为CDR3α(SEQ ID NO:49)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQ IDNO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:23)。β链可变区(SEQ ID NO:54)包括从氨基末端开始并在β链恒定区开始前结束的序列。α链可变区(SEQ ID NO:53)包括连接子后立即开始并且就在α链恒定区开始前即结束的序列。全长β链(SEQ ID NO:56)包括从氨基末端开始并且在连接子开始前即结束的序列。全长α链(SEQ ID NO:55)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述确定癌症反应性T细胞。如下所述，分离TCR。
TCR名称:4127_O102_TCR
p53突变的识别:G245S
方法:Tran法
共培养以鉴定TCR:未进行。使用5'RACE由T细胞克隆(O102)的RNA直接鉴定TCR。通过分选OX 40+T细胞以及通过有限稀释确立T细胞克隆来发展克隆，使用Tran方法筛选T细胞克隆。
鉴定TCR的方法:5’RACE，从TIL克隆O102
所有配对的TCR中的TCR的丰度:100％T细胞克隆(不适用)
TCR取向:α-β
表达载体:γ-逆转录病毒
从患者4127中分离的TCR 4127-O37-TCR的序列如下所述。从氨基末端开始，第一个带下划线的区域是CDR1β(SEQ ID NO:460)，第二个带下划线的区域是CDR2β(SEQ ID NO:461)，第三个带下划线的区域是CDR3β(SEQ ID NO:462)，第四个带下划线的区域是CDR1α(SEQ ID NO:457)，第五个下划线区域为CDR2α(SEQ ID NO:458)，第六个下划线区域为CDR3α(SEQ ID NO:459)。
粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQ ID NO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:23)。β链可变区(SEQ ID NO:464)包括从氨基末端开始并在β链恒定区开始前结束的序列。α链可变区(SEQ ID NO:463)包括连接子后立即开始并在α链恒定区开始前即结束的序列。全长β链(SEQ ID NO:466)包括从氨基末端开始到连接子开始前即结束的序列。全长α链(SEQ ID NO:465)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述确定癌症反应性T细胞。如下所述，分离TCR。
TCR名称:4127-O37-TCR
识别p53突变的识别:G245S
方法:Tran法
共培养以鉴别TCR:未进行。使用适应性TCRAD和TCRB测量法(下一代测序(NGS)平台)从T细胞克隆(O37)的基因组DNA中直接鉴别TCR。通过分选OX40+T细胞以及通过有限稀释确立T细胞克隆来发展O37克隆。使用Tran方法筛选T细胞克隆。
鉴别TCR的方法:TIL克隆O37的适应性TCR测序(NGS)
所有配对TCR中的TCR丰度:100％T细胞克隆(n/a)
TCR方向:β-α
表达载体:γ-逆转录病毒
实施例2
该实施例证实了来自患者4196的3种抗突变p53TCR的分离及特异性反应性。
按照图8-11所述，对患者4196进行实验。如美国专利申请号2017/0224800所述，通过Tran方法鉴定该患者的p53反应性T细胞。使用Fluidigm方法分离单独TCR。患者4196的统计数据见表D。
p53反应性细胞的特征:鉴定最小表位的挑战:第一个具有突变氨基酸p53 R 175H的预测肽如表C所示。
表C
| HLA | HLA-A0201 |
| 肽 | HMTEVVRHC(SEQ ID NO:530) |
| 核心 | HMTEVVRHC(SEQ ID NO:530) |
| 亲和力(nM) | 7826.06 |
| ％等级 | 13.00 |
MG1 vs 4196-Rx1 TIL:COS7细胞用质粒转染TMG1和HLA等位基因。细胞与4196Rx1 TIL输液袋共培养20小时(h)。结果见图8A。
使用候选最小表位(HMTEVVRHC(SEQ ID NO:530)或(SQHMTEVRH(SEQ ID NO:531))脉冲P53-R175H最小肽versus 4196-Rx1 TIL:第4天自体DCs 2小时。清洗细胞并用4196Rx1 TIL输液袋共培养20小时。结果见图8B。
A*02:01限制性TP 53四聚体可用于从TIL输液袋中分离TP 53反应性细胞:与TP53肽共同培养后使用4-1BB+分选分离TP 53反应性细胞的技术有限。为分离TP 53反应性细胞，生成A*02:01-TP 53四聚体。生成不相关四聚体(A*02:01-gp 100)作为对照。对活CD3+、CD8+细胞设门进行FACS分析。对于A*02:01-TP 53四聚体，检测到14.9％的p53四聚体+细胞。对于A*02:01-gp 100四聚体，检测到0.7％的p53四聚体+细胞。
TP 53反应性细胞的分离和表征:TP 53反应性细胞的分离和表征策略如下:(1)如上所述使用FACS对四聚体阳性细胞进行分选。(2)进行单细胞PCR。(3)进行Vβ渗出序列测定。
使用单细胞PCR鉴定了TP 53 TCR的几个候选克隆，如表D所示。TCR-1a和TCR-1b是可选候选克隆。
表D
用MSGV1载体克隆编码候选TCR的质粒。使用逆转录病毒转导将TCR引入供体淋巴细胞中。
第4天，在A*02:01 DC上，对HPLC级最小表位脉冲2小时。DC细胞与TCR转导的细胞共培养20h。结果见图9A-9D。鉴定了三种不同的A*02:01限制性TP 53受体。
将T2细胞解冻并静置24小时，然后用浓度逐渐降低的HPLC最小表位脉冲2小时。然后洗涤细胞并与TP 53 TCR转导的细胞共培养17小时。结果见图10A-10B。
使用HLA-A*02:01转导以下亲代肿瘤细胞系:结肠系–LS 123(ATCC CCL-255)，有R175H，但HLA-A2状态未知；白血病细胞系:CCRF-CEM(ATCC CRM-CCL-119，白血病)，有R175H，但HLA-A2状态未知；乳腺系:AU-565(ATCC CRL-2351，乳腺腺癌)，有R175H，但HLA-A2状态未知；黑色素瘤细胞系:MEL 624，内源性表达HLA-A2和wtR 175。
在共同培养的早上收获靶向转导的肿瘤细胞并铺板(1x 105个细胞/孔)。在靶细胞上，脉冲R 175H最小表位(HPLC，5μg/mL)2h。洗涤细胞两次，并与2x 104TP 53TCR转导的细胞共培养20小时(患者4196)。使用IFN-γELISPOT读取应答。结果见图11。关于本实施例的靶细胞HLA-A2和TP 53表达和TCR反应性的其他实验数据在实施例15中提供。
从患者4196中分离的TCR 4196_AV12-1_with_BV6-1如下所述。从氨基末端开始，第一个下划线区域为CDR1β(SEQ ID NO:70)，第二个下划线区域为CDR2β(SEQ ID NO:71)，第三个下划线区域为CDR3β(SEQ ID NO:72)，第四个下划线区域为CDR1α(SEQ ID NO:67)，第五个下划线区域为CDR2α(SEQ ID NO:68)，第六个下划线区域为CDR3α(SEQ ID NO:69)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQID NO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:24)。β链可变区(SEQ ID NO:74)包括从氨基末端开始并在β链恒定区开始前即结束的序列。α链可变区(SEQ ID NO:73)包括连接子后立即开始并在α链恒定区开始前即结束的序列。全长β链(SEQ ID NO:76)包括从氨基末端开始到连接子开始前即结束的序列。全长α链(SEQ ID NO:75)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。
TCR名称:4196_AV12-1_with_BV6-1
p53突变的识别:R175H
方法:Tran法
从患者4196中分离的TCR 4196_AV38-1_with_BV10-3如下所述。从氨基末端开始，第一个下划线区域为CDR1β(SEQ ID NO:80)，第二个下划线区域为CDR2β(SEQ ID NO:81)，第三个下划线区域为CDR3β(SEQ ID NO:82)，第四个下划线区域为CDR1α(SEQ ID NO:77)，第五个下划线区域为CDR2α(SEQ ID NO:78)，第六个下划线区域为CDR3α(SEQ ID NO:79)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQID NO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:24)。β链可变区(SEQ ID NO:84)包括从氨基末端开始并在β链恒定区开始即前结束的序列。α链可变区(SEQ ID NO:83)包括连接子后立即开始和α链恒定区开始前即结束的序列。全长β链(SEQ ID NO:86)包括从氨基末端开始到连接子开始前即结束的序列。全长α链(SEQ ID NO:85)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。
TCR名称:4196_AV38-1_with_BV10-3
p53突变的识别:R175H
方法:Tran法
从患者4196中分离的TCR 4196_AV6_with_BV11-2如下所述。从氨基末端开始，第一个下划线区域为CDR1β(SEQ ID NO:90)，第二个下划线区域为CDR2β(SEQ ID NO:91)，第三个下划线区域为CDR3β(SEQ ID NO:92)，第四个下划线区域为CDR1α(SEQ ID NO:87)，第五个下划线区域为CDR2α(SEQ ID NO:88)，第六个下划线区域为CDR3α(SEQ ID NO:89)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是β链恒定区(SEQ IDNO:25)，第二个斜体区域是α链恒定区(SEQ ID NO:24)。β链可变区(SEQ ID NO:94)包括从氨基末端开始并在β链恒定区开始前即结束的序列。α链可变区(SEQ ID NO:93)包括连接子后立即开始且α链恒定区开始前即结束的序列。全长β链(SEQ ID NO:96)包括从氨基末端开始到连接子开始前即结束的序列。全长α链(SEQ ID NO:95)包括在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。
TCR名称:4196_AV6_with_BV11-2
识别p53突变:R175H
方法:Tran法
实施例3
该实例证实了来自患者4238的11个抗突变p53 TCR的分离。
如对于图12-15所述对患者4238进行实验。
患者4238的TIL片段(F1-F24,n＝24)与由不相关或突变的p53序列组成的TMG电穿孔的自体APC共培养。共培养物在37℃下培养过夜。使用ELISPOT试验评估IFN-γ的分泌。结果见图12。对淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果见图14。
患者4238的TIL片段(F1-F24，n＝24)与自体APC共培养，所述自体APC用肽媒介物(DMSO)脉冲或用由突变型p53-R248Q序列组成的纯化的25个氨基酸的肽(HPLC法>95％)脉冲。共培养物在37℃下培养过夜。使用ELISPOT试验评估IFN-γ的分泌。结果见图13。对淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果见图15。
TIL片段F10、F11和F17是CD8+41 BB+F17分选后TCR的来源。
从患者4238中分离的TCR 4238-F10-TCR1的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:207)，第二个下划线区域为CDR2α(SEQ ID NO:208)，第三个下划线区域为CDR3α(SEQ ID NO:209)，第四个下划线区域为CDR1β(SEQ ID NO:210)，第五个下划线区域为CDR2β(SEQ ID NO:211)，第六个下划线区域为CDR3β(SEQ ID NO:212)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:213)包括从氨基末端开始并在α链恒定区开始前结束的序列。β链可变区(SEQ ID NO:214)包括连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:215)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:216)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选法鉴定癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F10-TCR1
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248 Q长肽共培养4238-F10，分选CD8+41 BB+NMT
鉴定TCR的方法:单细胞逆转录酶聚合酶链反应(RT-PCR)
所有配对的TCR中的TCR的丰度:25.0％(在12对中观察到3次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F10-TCR1统计见下表6。
表6
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 4 | 4.2％ |
| CDR3β | 4 | 4.2％ |
| 4238-F10-TCR1对 | 3 | 3.1％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F10-TCR2的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:217)，第二个下划线区域为CDR2α(SEQ ID NO:218)，第三个下划线区域为CDR3α(SEQ ID NO:219)，第四个下划线区域为CDR1β(SEQ ID NO:220)，第五个下划线区域为CDR2β(SEQ ID NO:221)，第六个下划线区域为CDR3β(SEQ ID NO:222)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:223)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:224)包括在连接子之后立即开始并在β链恒定区开始之前即结束的序列。全长α链(SEQ IDNO:225)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:226)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴定癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F10-TCR2
识别p53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F10，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:25.0％(在12对中观察到3次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F10-TCR2统计见下表7。
表7
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 4 | 4.2％ |
| CDR3β | 4 | 4.2％ |
| 4238-F10-TCR2对 | 3 | 3.1％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F10-TCR3的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:227)，第二个下划线区域为CDR2α(SEQ ID NO:228)，第三个下划线区域为CDR3α(SEQ ID NO:229)，第四个下划线区域为CDR1β(SEQ ID NO:230)，第五个下划线区域为CDR2β(SEQ ID NO:231)，第六个下划线区域为CDR3β(SEQ ID NO:232)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:233)包括从氨基末端开始并在α链恒定区开始前结束的序列。β链可变区(SEQ ID NO:234)包括在连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:235)包括从氨基末端开始并在连接子开始前即结束的序列。全长β链(SEQ ID NO:236)包括在连接子后立即开始并以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F10-TCR3
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248 Q长肽共培养4238-F10，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:58.3.0％(在12对中观察到7次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F10-TCR3统计见下表8。
表8
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 16 | 16.7％ |
| CDR3β | 26 | 27.1％ |
| 4238-F10-TCR3对 | 7 | 7.3％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F10-TCR4的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:237)，第二个下划线区域为CDR2α(SEQ ID NO:238)，第三个下划线区域为CDR3α(SEQ ID NO:239)，第四个下划线区域为CDR1β(SEQ ID NO:240)，第五个下划线区域为CDR2β(SEQ ID NO:241)，第六个下划线区域为CDR3β(SEQ ID NO:242)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:243)包括从氨基末端开始到α链恒定区开始之前即结束的序列。β链可变区(SEQ ID NO:244)包括在连接子之后立即开始并在β链恒定区开始之前即结束的序列。全长α链(SEQ IDNO:245)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:246)包括在连接子后立即开始并以羧基末端结束的序列。
使用下述筛选方法鉴定癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F10-TCR4
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F10，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:58.3.0％(在12对中观察到7次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F10-TCR4统计见下表9。
表9
从患者4238中分离的TCR 4238-F11-TCR1的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:247)，第二个下划线区域为CDR2α(SEQ ID NO:248)，第三个下划线区域为CDR3α(SEQ ID NO:249)，第四个下划线区域为CDR1β(SEQ ID NO:250)，第五个下划线区域为CDR2β(SEQ ID NO:251)，第六个下划线区域为CDR3β(SEQ ID NO:252)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:253)包括从氨基末端开始并在α链恒定区开始前结束的序列。β链可变区(SEQ ID NO:254)包括连接子后立即开始并β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:255)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:256)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴定癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F11-TCR1
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F10，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:25.0％(在12对中观察到3次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F11-TCR1统计见下表10。
表10
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 5 | 5.2％ |
| CDR3β | 3 | 3.1％ |
| 4238-F11-TCR1对 | 3 | 3.1％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F11-TCR2的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:257)，第二个下划线区域为CDR2α(SEQ ID NO:258)，第三个下划线区域为CDR3α(SEQ ID NO:259)，第四个下划线区域为CDR1β(SEQ ID NO:260)，第五个下划线区域为CDR2β(SEQ ID NO:261)，第六个下划线区域为CDR3β(SEQ ID NO:262)。粗体区域为连接子(SEQ ID NO:262)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:263)包括从氨基末端开始并在α链恒定区开始前结束的序列。β链可变区(SEQ ID NO:264)包括连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:265)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:266)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F11-TCR2
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248 Q长肽共培养4238-F11，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:25.0％(在12对中观察到3次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F11-TCR2统计见下表11。
表11
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 5 | 5.2％ |
| CDR3β | 8 | 8.3％ |
| 4238-F11-TCR2对 | 3 | 3.1％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F11-TCR3的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:267)，第二个下划线区域为CDR2α(SEQ ID NO:268)，第三个下划线区域为CDR3α(SEQ ID NO:269)，第四个下划线区域为CDR1β(SEQ ID NO:270)，第五个下划线区域为CDR2β(SEQ ID NO:271)，第六个下划线区域为CDR3β(SEQ ID NO:272)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:273)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:274)包括连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:275)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:276)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F11-TCR3
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F11，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:16.7％(在12对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F11-TCR3统计见下表12。
表12
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 4 | 4.2％ |
| CDR3β | 2 | 2.1％ |
| 4238-F11-TCR3对 | 2 | 2.1％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F11-TCR4的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:277)，第二个下划线区域为CDR2α(SEQ ID NO:278)，第三个下划线区域为CDR3α(SEQ ID NO:279)，第四个下划线区域为CDR1β(SEQ ID NO:280)，第五个下划线区域为CDR2β(SEQ ID NO:281)，第六个下划线区域为CDR3β(SEQ ID NO:282)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:283)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:284)包括连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:285)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:286)包括在连接子之后立即开始并以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F11-TCR4
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F11，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:16.7％(在12对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F11-TCR4统计见下表13。
表13
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 4 | 4.2％ |
| CDR3β | 2 | 2.1％ |
| 4238-F11-TCR4对 | 2 | 2.1％ |
| 总配对TCR | 12 | 12.5％ |
从患者4238中分离的TCR 4238-F17-TCR1的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:287)，第二个下划线区域为CDR2α(SEQ ID NO:288)，第三个下划线区域为CDR3α(SEQ ID NO:289)，第四个下划线区域为CDR1β(SEQ ID NO:290)，第五个下划线区域为CDR2β(SEQ ID NO:291)，第六个下划线区域为CDR3β(SEQ ID NO:292)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:293)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:294)包括在连接子之后立即开始并在β链恒定区开始之前即结束的序列。全长α链(SEQ IDNO:295)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:296)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F17-TCR1
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F11，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:33.3％(在6对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F17-TCR1统计见下表14。
表14
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 3 | 3.1％ |
| CDR3β | 2 | 2.1％ |
| 4238-F17-TCR1对 | 2 | 2.1％ |
| 总配对TCR | 6 | 6.3％ |
从患者4238中分离的TCR 4238-F17-TCR2的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:297)，第二个下划线区域为CDR2α(SEQ ID NO:298)，第三个下划线区域为CDR3α(SEQ ID NO:299)，第四个下划线区域为CDR1β(SEQ ID NO:300)，第五个下划线区域为CDR2β(SEQ ID NO:301)，第六个下划线区域为CDR3β(SEQ ID NO:302)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:303)包括从氨基末端开始并在α链恒定区开始之前即结束的序列。β链可变区(SEQ ID NO:304)包括在连接子之后立即开始并在β链恒定区开始之前即结束的序列。全长α链(SEQ IDNO:305)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:306)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F17-TCR2
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F11，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:33.3％(在6对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F17-TCR2统计见下表15。
表15
| 参数 | # | 频率 |
| 总孔数 | 96 | 100％ |
| CDR3α | 6 | 6.3％ |
| CDR3β | 2 | 2.1％ |
| 4238-F17-TCR2对 | 2 | 2.1％ |
| 总配对TCR | 6 | 6.3％ |
从患者4238中分离的TCR 4238-F17-TCR3的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:307)，第二个下划线区域为CDR2α(SEQ ID NO:308)，第三个下划线区域为CDR3α(SEQ ID NO:309)，第四个下划线区域为CDR1β(SEQ ID NO:310)，第五个下划线区域为CDR2β(SEQ ID NO:311)，第六个下划线区域为CDR3β(SEQ ID NO:312)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:313)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:314)包括在连接子之后立即开始并在β链恒定区开始之前即结束的序列。全长α链(SEQ IDNO:315)包括从氨基末端开始并在连接子开始之前即结束的序列。全长β链(SEQ ID NO:316)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4238-F17-TCR3
p53突变的识别:R248Q
筛选法:p53“热点”突变通用筛选
共培养以鉴定TCR:与R248Q长肽共培养4238-F11，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:33.3％(在6对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4238的TCR 4238-F17-TCR3统计见下表16。
表16
实施例4
该实施例证实了从患者4253中分离出两种抗突变p53 TCR。
按照图16所述，对患者4253进行实验。
来自患者的TIL片段(F1-F24；n＝24)与自体APC共培养，所述自体APC(1)用肽媒介物(DMSO)脉冲,(2)用由突变的p53-R248W序列组成的25个氨基酸的纯化肽(HPLC法>95％)脉冲，(3)用不相关的TMG电穿孔或(4)用含有突变的p53-R248W序列的p53-mut-TMG电穿孔。共培养物在37℃下培养过夜。通过ELISPOT评估IFN-γ的分泌。结果见图16。选择F15用于TCR的分选，因为它对p53-mut-TMG和p53-R248W长肽都有反应。
从患者4253中分离的TCR 4253-TIL-TCR1的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:187)，第二个下划线区域为CDR2α(SEQ ID NO:188)，第三个下划线区域为CDR3α(SEQ ID NO:189)，第四个下划线区域为CDR1β(SEQ ID NO:190)，第五个下划线区域为CDR2β(SEQ ID NO:191)，第六个下划线区域为CDR3β(SEQ ID NO:192)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:193)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:194)包括在连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:195)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:196)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4253-TIL-TCR1
p53突变的识别:R248W
方法:简略的p53“热点”突变通用筛选(仅评价突变TMG和R248W长肽)
共培养以鉴定TCR:与p53-R248W长肽共培养4253-F15，分选CD3+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:5.6％(36对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4253的TCR 4253-TIL-TCR1统计见下表17。
表17
| 参数 | # | 频率 |
| 总孔数 | 55 | 100％ |
| CDR3α | 3 | 5.5％ |
| CDR3β | 2 | 3.6％ |
| 4253-TIL-TCR1对 | 2 | 3.6％ |
| 总配对TCR | 36 | 65.5％ |
从患者4253中分离的TCR 4253-TIL-TCR2的序列如下所述。从氨基末端开始，第一个下划线区域为CDR1α(SEQ ID NO:197)，第二个下划线区域为CDR2α(SEQ ID NO:198)，第三个下划线区域为CDR3α(SEQ ID NO:199)，第四个下划线区域为CDR1β(SEQ ID NO:200)，第五个下划线区域为CDR2β(SEQ ID NO:201)，第六个下划线区域为CDR3β(SEQ ID NO:202)。粗体区域为连接子(SEQ ID NO:26)。从氨基末端开始，第一个斜体区域是α链恒定区(SEQ ID NO:23)，第二个斜体区域是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:203)包括从氨基末端开始并在α链恒定区开始前即结束的序列。β链可变区(SEQ ID NO:204)包括在连接子后立即开始并在β链恒定区开始前即结束的序列。全长α链(SEQ ID NO:205)包括从氨基末端开始到连接子开始前即结束的序列。全长β链(SEQ ID NO:206)包括在连接子之后立即开始并且以羧基末端结束的序列。
使用下述筛选方法鉴别癌症反应性T细胞。用于分离TCR的方法如下所述。
TCR名称:4253-TIL-TCR2
p53突变的识别:R248W
方法:简略的p53“热点”突变通用筛选(仅评价突变TMG和R248W长肽)
共培养以鉴定TCR:与p53-R248W长肽共培养4253-F15，分选CD3+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:91.7％(36对中观察到33次)
TCR取向:α-β
表达载体:SB转座子
患者4253的TCR 4253-TIL-TCR2统计见下表18。
表18
| 参数 | # | 频率 |
| 总孔数 | 55 | 100％ |
| CDR3α | 35 | 63.6％ |
| CDR3β | 33 | 60.0％ |
| 4253-TIL-TCR2对 | 33 | 60.0％ |
| 总配对TCR | 36 | 65.5％ |
实施例5
本实施例通过在自体T细胞内共培养经诱导以表达突变型p53的自体APC(“p53热点突变通用筛选”)来鉴定患者4273中的抗突变型p53 T细胞。该实施例还证实从患者4273中分离出两种抗突变p53 TCR。
按照图17-20和56-60所述，对患者4273进行实验。
将来自患者4273的TIL片段(F1-F24，n＝24)与用由不相关的、WT p53或突变型p53序列组成的TMG电穿孔的自体APC共培养。共培养物在37℃下培养过夜。使用ELISPOT试验评估IFN-γ的分泌。结果见图17。对淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后通过流式细胞术评价4-1BB的表达。结果见图18。
患者4273的TIL片段(F1-F24,n＝24)与自体APC共培养，所述APC用肽媒介物(DMSO)脉冲或者用由WT p53-R248序列或突变型p53-R248W序列组成的纯化(HPLC法>95％)的25个氨基酸的肽脉冲。共培养物在37℃下过夜培养。使用ELISPOT试验评估IFN-γ的分泌。结果见图19。对淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后通过流式细胞术评价4-1BB的表达。结果见图20。
对于患者4273，F15是最具反应性的片段，F15对LP和TMG的应答相当，主要是CD4 T细胞。所以将4273-F15与用R248W LP脉冲的APC共培养，并在第二天将CD4+41BB+T细胞作为单细胞分选至96孔PCR板的孔中，每孔一个细胞。PCR板在每个孔中有RT-PCR溶液，可扩增相同溶液中的TCRα和βCDR3区域。然后将微孔板分成两个96孔PCR板，并进行第二次PCR反应以扩增CDR3α或CDR3β作为单独反应。通过Sanger测序对各孔的PCR产物(共192个PCR产物映射至各孔-α或β)进行测序。将核苷酸序列输入IMGT/V-QUEST(imgt.org/iView/vest)livret＝0&Option＝Human TcR),IgBlast(ncbi.nlm.nih.gov/igblast/igblast.cgi？CMD＝Web和SEARCH_TYPE＝TCR和LINK_LOC＝igtab)，并由Expasy翻译(web.exasy.org/transf/)。根据翻译序列确定变量家族并融合至CDR3和接合区(J或DJ)。可变序列融合至鼠恒定序列，并且重构的TCRα和TCRβ通过弗林蛋白酶-柔性-P2A(RAKR-SGSG-ATNFSLLKQAGDVEENPGP)(SEQID NO:26)连接。然后将该序列从头合成为DNA，并克隆至表达载体(γ逆转录病毒或SLEEPING BEAUTY(SB)转座子(University of Minnesota,Minneapolis,MN))中。然后使用标准病毒转导或非病毒转座方案使T细胞表达TCR，并针对推定的肽测试表达鼠源化TCR的T细胞(如通过小鼠TCRβ恒定链检测)。
用编码无关突变、WT p53序列或经突变的p53序列(包括p53-R248W)的TMG转染自体APC。单独的培养基及PMA和离子霉素分别为阴性对照和阳性对照。将来自患者4273的TIL(片段培养物8和15)与TMG转染的APC在37℃下共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图56中。
将自体APC在37℃下用对应于WT或经突变的p53-R248W新表位的25个氨基酸的肽脉冲2小时。将来自患者4273的对p53-R248W具有特异性的TIL(片段培养物15)与肽-脉冲的APC在37℃下共培养过夜。DMSO是肽媒介物。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)，设门后，通过流式细胞术评价4-1BB的表达。结果示于图57中。
将自体APC用来自p53-R248W新表位的重叠14个氨基酸的15个氨基酸的肽脉冲。将来自患者4273的对p53-R248W具有特异性的TIL(片段培养物15)与肽-脉冲的APC在37℃下共培养过夜。DMSO是肽媒介物，单独的培养基(仅T细胞)及PMA和离子霉素是对照。25个氨基酸的肽(wt p53-R248和经突变的p53-R248W)是15个氨基酸的肽的另外对照。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4+CD8-设门后，通过流式细胞术评价4-1BB的表达。结果示于图58中。
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。第二天，将细胞分别与来自患者4273的单独的HLA等位基因以及有或无p53-R248W新抗原的WT或经突变的TP53 TMG共转染。第二天，将来自患者4273的对p53-R248W具有特异性的TIL(片段培养物15)与转染的Cos7细胞在37℃下共培养过夜。通过ELISA评价IFN-γ的分泌。结果示于图59中。
将表达模拟物(无TCR)或4273-TCR1a2的T细胞与自体APC共培养，所述自体APC用肽媒介物(DMSO)或由野生型p53-R248序列或经突变的p53-R248W序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲。单独的培养基及PMA和离子霉素分别为阴性对照和阳性对照。在37℃下进行共培养过夜。通过ELISPOT评价IFN-γ的分泌。结果示于图60中。
从患者4273分离的TCR 4273-TP53-R248W-TCR1a1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:437)，第二加下划线区是CDR2α(SEQ ID NO:438)，第三加下划线区是CDR3α(SEQ ID NO:439)，第四加下划线区是CDR1β(SEQ ID NO:440)，第五加下划线区是CDR2β(SEQ ID NO:441)，和第六加下划线区是CDR3β(SEQ ID NO:442)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:443)包含从氨基末端开始并且就在α链恒定区开始之前即结束的序列。β链可变区(SEQ ID NO:444)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:445)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:446)包含在连接子之后立即开始并且以羧基末端结束的序列。
TCR名称:4273-TP53-R248W-TCR1a1
P53突变的识别:R248W
方法:p53“热点”突变通用筛选
从患者4273分离的TCR 4273-TP53-R248W-TCR1a2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:447)，第二加下划线区是CDR2α(SEQ ID NO:448)，第三加下划线区是CDR3α(SEQ ID NO:449)，第四加下划线区是CDR1β(SEQ ID NO:450)，第五加下划线区是CDR2β(SEQ ID NO:451)，和第六加下划线区是CDR3β(SEQ ID NO:452)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:453)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:454)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:455)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:456)包含在连接子之后立即开始并且以羧基末端结束的序列。
TCR名称:4273-TP53-R248W-TCR1a2
P53突变的识别:R248W
方法:p53“热点”突变通用筛选
下表19列出了患者4273的TCR的统计数据。在表19中，与经突变的p53蛋白(TMG或肽)共培养后，总有96个孔用41BB+T细胞分选。77个孔具有生产对(意指具有(1)序列和(2)该序列中没有终止密码子)，配对频率为80.2％。那些对中有43个是CDR3A/CDR3B组合，以构成4273-TP53-R248W-TCR1a1(生产对的55.8％)。那些对中有30个是CDR3A/CDR3B组合，以构成4273-TP53-R248W-TCR1a2(生产对的39％)。总体而言，在96个孔中，分别发现了4273-TP53-R248W-TCR1a1的CDR3A和CDR3B50次和83次。总体而言，在96个孔中，分别发现了4273-TP53-R248W-TCR1a2的CDR3A和CDR3B 33次和83次。
表19
实施例6
该实施例证实了在患者4149中抗-突变的p53 T细胞的鉴定。该实施例还证实了来自患者4149的一种抗-突变的p53 TCR的分离和特异反应性。
如图21-24针对患者4149所述进行实验。使用Tran方法发现了TCR。然后使用TCR来验证“p53热点突变通用筛选”方法。
将TCR(4149-TCRa2b1或4149-TCRa2b2)转座至来自患者4149的自体PBL中，并与自体APC共培养，所述自体APC(1)用由无关、WT p53或经突变的p53序列组成的TMG电穿孔，或(2)用肽媒介物(DMSO)或由WT p53-Y220序列或经突变的p53-Y220C序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲。PMA和离子霉素的组合是阳性对照。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果示于图21中。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4+mTCR+(TCR转座的T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图22中。
还进行了通过TCRAD深度测序和TCRB深度测序确定CD4+4-1BB+细胞的百分比。结果示于表E中。
表E
被4149-F11识别的假定p53Y220C最小表位的作图:将自体DC细胞经肽脉冲(10μg/mL)并在粒细胞-巨噬细胞集落刺激因子(GM-CSF)和IL-4中静置过夜。将TIL在500CU/mLIL-2中静置2-3天。将2x104个TIL和105个靶细胞在37℃下共培养过夜。通过ELISPOT测量IFN-γ。结果示于表10中。通过FACS用设门淋巴细胞\PI(neg)CD3+\CD3+CD4+测量4-1BB表达。结果示于图23中。
表F
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。20小时后，将细胞与单独的HLA等位基因在有或无TMG的情况下下共转染。20小时后，将自体DC细胞用TMG平行转染。将所有HLA II类等位基因在有或无TMG的情况下共转染一组孔中。将未用TMG转染的细胞在37℃下用10μg/mL的p53-Y220C 15-聚体肽脉冲2-3小时。洗涤后，将在第二REP的第14天的4149-TCRa2b2-转座的T细胞(105)添加至孔，并在37℃下共培养过夜。通过ELISA测量IFN-γ分泌。结果示于图24中。通过NetMHCIIpan进行预测(表G):cbs.dtu.dk/services/NetMHCIIpan/。
表G
在NCI HLA数据库中的3719名DRB_型患者中有1367名(37％)以及在NCI-SB的9名子宫内膜癌和卵巢癌患者中有5名(56％)检测到DRB3*02表达。DRB3*02等位基因的报道频率非常高，如实施例1所述。
从患者4149分离的TCR 4149TCRa2b2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:57)，第二加下划线区是CDR2α(SEQ ID NO:58)，第三加下划线区是CDR3α(SEQ ID NO:59)，第四加下划线区是CDR1β(SEQ ID NO:60)，第五加下划线区是CDR2β(SEQ ID NO:61)，和第六加下划线区是CDR3β(SEQ ID NO:62)。粗体区是连接子(SEQID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:63)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:64)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:65)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:66)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。该患者的p53反应性细胞通过美国申请2017/0224800描述的Transcreening方法来鉴定。
TCR名称:4149TCRa2b2
P53突变的识别:Y220C
筛选方法:用于验证p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4149-F11 TIL片段与p53-Y220C长肽，分选CD4+41BB+T细胞
鉴定TCR的方法:频率配对.将CD4+41BB+分选的T细胞在REP(快速扩增方案)中扩增并使所得的T细胞培养物经受Adaptive Biotechnologies的TCRAD(α)和TCRB(β)深度测序。在4种总TCR矩阵中，使前两种TCRα与前两种TCRβ配对。第二TCRα和第二TCRβ是反应性TCR，因此TCRa2b2命名。
所有TCR中TCR的丰度:如下
TCR取向:α-β
表达载体:SB转座子
患者4149的TCR 4149TCRa2b2的统计数据示于下表20中。
表20
实施例7
该实施例证实了通过在自体T细胞内共培养被诱导表达突变的p53的自体APC来鉴定患者4213中的抗-突变的p53 T细胞(“p53热点突变通用筛选”)。该实施例还证实了从患者4213分离12种抗-突变的p53 TCR。
如图25-26针对患者4213所述进行实验。
将来自患者4213的TIL片段(F2和F24)与用肽媒介物(DMSO)或由经突变的p53-R248Q序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图25中。将CD8+4-1BB+T细胞分选至96孔板的孔中。使用单细胞RT-PCR鉴定TCR。
CD4+T细胞来自患者4213的外周血淋巴细胞。将CD4+T细胞培养物与用肽媒介物(DMSO)或由经突变的p53-R248Q序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。IFN-γ的分泌通过ELISPOT评价。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图26中。将CD4+41BB+T细胞分选至96孔板的孔中。使用单细胞RT-PCR鉴定TCR。
从患者4213分离的4213-F2-TCR1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:317)，第二加下划线区是CDR2α(SEQ ID NO:318)，第三加下划线区是CDR3α(SEQ ID NO:319)，第四加下划线区是CDR1β(SEQ ID NO:320)，第五加下划线区是CDR2β(SEQ ID NO:321)，和第六加下划线区是CDR3β(SEQ ID NO:322)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:323)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:324)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:325)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:326)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-F2-TCR1
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4213-F2与R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:8.3％(在24对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-F2-TCR1的统计数据示于下表21中。
表21
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 3 | 3.1％ |
| CDR3β | 8 | 8.3％ |
| 4213-F2-TCR1对 | 2 | 2.1％ |
| 总配对的TCR | 24 | 25.0％ |
从患者4213分离的4213-F2-TCR2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:327)，第二加下划线区是CDR2α(SEQ ID NO:328)，第三加下划线区是CDR3α(SEQ ID NO:329)，第四加下划线区是CDR1β(SEQ ID NO:330)，第五加下划线区是CDR2β(SEQ ID NO:331)，和第六加下划线区是CDR3β(SEQ ID NO:332)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:333)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:334)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:335)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:336)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-F2-TCR2
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4213-F2与R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:12.5％(在24对中观察到3次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-F2-TCR2的统计数据示于下表22中。
表22
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 4 | 4.2％ |
| CDR3β | 4 | 4.2％ |
| 4213-F2-TCR2对 | 3 | 3.1％ |
| 总配对的TCR | 24 | 25.0％ |
从患者4213分离的4213-F2-TCR3的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:337)，第二加下划线区是CDR2α(SEQ ID NO:338)，第三加下划线区是CDR3α(SEQ ID NO:339)，第四加下划线区是CDR1β(SEQ ID NO:340)，第五加下划线区是CDR2β(SEQ ID NO:341)，并且第六加下划线区是CDR3β(SEQ ID NO:342)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:343)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:344)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:345)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:346)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-F2-TCR3
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4213-F2与R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:70.8％(在24对中观察到17次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-F2-TCR3的统计数据示于下表23中。
表23
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 19 | 19.8％ |
| CDR3β | 42 | 43.8％ |
| 4213-F2-TCR3对 | 17 | 17.7％ |
| 总配对的TCR | 24 | 25.0％ |
从患者4213分离的4213-F24-TCRa1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:347)，第二加下划线区是CDR2α(SEQ ID NO:348)，第三加下划线区是CDR3α(SEQ ID NO:349)，第四加下划线区是CDR1β(SEQ ID NO:350)，第五加下划线区是CDR2β(SEQ ID NO:351)，和第六加下划线区是CDR3β(SEQ ID NO:352)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:353)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:354)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:355)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:356)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-F24-TCRa1
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4213-F24与R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:15.9％(在44对中观察到7次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-F24-TCRa1的统计数据示于下表24中。
表24
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 7 | 7.3％ |
| CDR3β | 80 | 83.3％ |
| 4213-F24-TCRa1对 | 7 | 7.3％ |
| 总配对的TCR | 44 | 45.8％ |
从患者4213分离的4213-F24-TCRa2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:357)，第二加下划线区是CDR2α(SEQ ID NO:358)，第三加下划线区是CDR3α(SEQ ID NO:359)，第四加下划线区是CDR1β(SEQ ID NO:360)，第五加下划线区是CDR2β(SEQ ID NO:361)，和第六加下划线区是CDR3β(SEQ ID NO:362)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:363)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:364)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:365)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:366)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-F24-TCRa2
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4213-F24与R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:84.1％(在44对中观察到37次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-F24-TCRa2的统计数据示于下表25中。
表25
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 39 | 40.6％ |
| CDR3β | 80 | 83.3％ |
| 4213-F24-TCRa2对 | 37 | 38.5％ |
| 总配对的TCR | 44 | 45.8％ |
从患者4213分离的4213-PBL-TCR1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:367)，第二加下划线区是CDR2α(SEQ ID NO:368)，第三加下划线区是CDR3α(SEQ ID NO:369)，第四加下划线区是CDR1β(SEQ ID NO:370)，第五加下划线区是CDR2β(SEQ ID NO:371)，和第六加下划线区是CDR3β(SEQ ID NO:372)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:373)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:374)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:375)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:376)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR1
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养，并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:9.5％(在63对中观察到6次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR1的统计数据示于下表26中。
表26
从患者4213分离的4213-PBL-TCR2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:377)，第二加下划线区是CDR2α(SEQ ID NO:378)，第三加下划线区是CDR3α(SEQ ID NO:379)，第四加下划线区是CDR1β(SEQ ID NO:380)，第五加下划线区是CDR2β(SEQ ID NO:381)，和第六加下划线区是CDR3β(SEQ ID NO:382)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:383)包含从氨基末端开始并且在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:384)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:385)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:386)包含在连接子之后立即开始并且以羧基末端结束的序列.
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR2
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养，并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:7.9％(在63对中观察到5次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR2的统计数据示于下表27中。
表27
| 参数 | # | 频率 |
| 总孔 | 192 | 100％ |
| CDR3α | 8 | 4.2％ |
| CDR3β | 8 | 4.2％ |
| 4213-PBL-TCR2对 | 5 | 2.6％ |
| 总配对的TCR | 63 | 32.8％ |
从患者4213分离的4213-PBL-TCR3的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:387)，第二加下划线区是CDR2α(SEQ ID NO:388)，第三加下划线区是CDR3α(SEQ ID NO:389)，第四加下划线区是CDR1β(SEQ ID NO:390)，第五加下划线区是CDR2β(SEQ ID NO:391)，和第六加下划线区是CDR3β(SEQ ID NO:392)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:393)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:394)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:395)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:396)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR3
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养，并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:6.3％(在63对中观察到4次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR3的统计数据示于下表28中。
表28
从患者4213分离的4213-PBL-TCR4a1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:397)，第二加下划线区是CDR2α(SEQ ID NO:398)，第三加下划线区是CDR3α(SEQ ID NO:399)，第四加下划线区是CDR1β(SEQ ID NO:400)，第五加下划线区是CDR2β(SEQ ID NO:401)，和第六加下划线区是CDR3β(SEQ ID NO:402)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:403)包含从氨基末端开始并且就在α链恒定区的开始之前结束的序列。β链可变区(SEQ ID NO:404)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:405)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:406)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR4a1
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:3.2％(在63对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR4a1的统计数据示于下表29中。
表29
| 参数 | # | 频率 |
| 总孔 | 192 | 100％ |
| CDR3α | 2 | 1.0％ |
| CDR3β | 36 | 18.8％ |
| 4213-PBL-TCR4a1对 | 2 | 1.0％ |
| 总配对的TCR | 63 | 32.8％ |
从患者4213分离的4213-PBL-TCR4a2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:407)，第二加下划线区是CDR2α(SEQ ID NO:408)，第三加下划线区是CDR3α(SEQ ID NO:409)，第四加下划线区是CDR1β(SEQ ID NO:410)，第五加下划线区是CDR2β(SEQ ID NO:411)，和第六加下划线区是CDR3β(SEQ ID NO:412)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:413)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:414)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:415)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:416)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR4a2
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:3.2％(在63对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR4a2的统计数据示于下表30中。
表30
| 参数 | # | 频率 |
| 总孔 | 192 | 100％ |
| CDR3α | 2 | 1.0％ |
| CDR3β | 36 | 18.8％ |
| 4213-PBL-TCR4a2对 | 2 | 1.0％ |
| 总配对的TCR | 63 | 32.8％ |
从患者4213分离的4213-PBL-TCR4a3的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:417)，第二加下划线区是CDR2α(SEQ ID NO:418)，第三加下划线区是CDR3α(SEQ ID NO:419)，第四加下划线区是CDR1β(SEQ ID NO:420)，第五加下划线区是CDR2β(SEQ ID NO:421)，和第六加下划线区是CDR3β(SEQ ID NO:422)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:423)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:424)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:425)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:426)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR4a3
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:4.8％(在63对中观察到3次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR4a3的统计数据示于下表31中。
表31
| 参数 | # | 频率 |
| 总孔 | 192 | 100％ |
| CDR3α | 4 | 2.1％ |
| CDR3β | 36 | 18.8％ |
| 4213-PBL-TCR4a3对 | 3 | 1.6％ |
| 总配对的TCR | 63 | 32.8％ |
从患者4213分离的4213-PBL-TCR4a4的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:427)，第二加下划线区是CDR2α(SEQ ID NO:428)，第三加下划线区是CDR3α(SEQ ID NO:429)，第四加下划线区是CDR1β(SEQ ID NO:430)，第五加下划线区是CDR2β(SEQ ID NO:431)，和第六加下划线区是CDR3β(SEQ ID NO:432)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:433)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:434)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:435)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:436)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4213-PBL-TCR4a4
P53突变的识别:R248Q
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:将在用R248Q长肽体外致敏之后的CD4+记忆T细胞与R248Q长肽共培养并分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:3.2％(在63对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4213的TCR 4213-PBL-TCR4a4的统计数据示于下表32中。
表32
| 参数 | # | 频率 |
| 总孔 | 192 | 100％ |
| CDR3α | 2 | 1.0％ |
| CDR3β | 36 | 18.8％ |
| 4213-PBL-TCR4a3对 | 2 | 1.0％ |
| 总配对的TCR | 63 | 32.8％ |
实施例8
该实施例证实了通过在自体T细胞内共培养被诱导以表达突变的p53的自体APC来鉴定患者4268中的抗-突变的p53 T细胞(“p53热点突变通用筛选”)。该实施例还证实了从患者4268分离五种抗-突变的p53 TCR。
如针对患者4268的图27-30所述进行实验。
将来自患者4268的TIL片段(F1-F24，n＝24)与用由无关、WT p53或经突变的p53序列组成的TMG电穿孔的自体APC共培养。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果示于图27中。
将来自患者4268的TIL片段(F1-F24，n＝24)与用肽媒介物(DMSO)或由WT p53-R248序列或经突变的p53-R248Q序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果示于图28中。
将来自患者4268的TIL片段(F1-F24，n＝24)与用肽媒介物(DMSO)或由wt p53-R248序列或经突变的p53-R248Q序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图29中。TIL片段F18和F19是对CD4+41BB+T细胞进行分选后的TCR的来源。
将来自患者4268的TIL片段(F1-F24，n＝24)与用肽媒介物(DMSO)或由wt p53-R248序列或经突变的p53-R248Q序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图30中。TIL片段F7,F8和F15是对CD8+4-1BB+T细胞进行分选后的TCR的来源。
从患者4268分离的4268-TCR1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:137)，第二加下划线区是CDR2α(SEQ ID NO:138)，第三加下划线区是CDR3α(SEQ ID NO:139)，第四加下划线区是CDR1β(SEQ ID NO:140)，第五加下划线区是CDR2β(SEQ ID NO:141)，和第六加下划线区是CDR3β(SEQ ID NO:142)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:143)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:144)包含在连接子之后立即开始并且在β链恒定区开始之前就结束的序列。全长α链(SEQ ID NO:145)包含从氨基末端开始并且在连接子开始之前就结束的序列。全长β链(SEQ ID NO:146)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4268-TCR1
P53突变的识别:R248Q
方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4268-F7和4268-F8与p53-R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:78.7％(在61对中观察到48次)
TCR取向:α-β
表达载体:SB转座子
患者4268的TCR 4268-TCR1的统计数据示于下表33中。
表33
从患者4268分离的4268-TCR2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:147)，第二加下划线区是CDR2α(SEQ ID NO:148)，第三加下划线区是CDR3α(SEQ ID NO:149)，第四加下划线区是CDR1β(SEQ ID NO:150)，第五加下划线区是CDR2β(SEQ ID NO:151)，和第六加下划线区是CDR3β(SEQ ID NO:152)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:153)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:154)包含在连接子之后立即开始并且就β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:155)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:156)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4268-TCR2
P53突变的识别:R248Q
方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4268-F7和4268-F8与p53-R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:6.6％(在61对中观察到4次)
TCR取向:α-β
表达载体:SB转座子
患者4268的TCR 4268-TCR2的统计数据示于下表34中。
表34
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 6 | 6.3％ |
| CDR3β | 4 | 4.2％ |
| 4268-TCR2对 | 4 | 4.2％ |
| 总配对的TCR | 61 | 63.5％ |
从患者4268分离的4268-TCR3的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:157)，第二加下划线区是CDR2α(SEQ ID NO:158)，第三加下划线区是CDR3α(SEQ ID NO:159)，第四加下划线区是CDR1β(SEQ ID NO:160)，第五加下划线区是CDR2β(SEQ ID NO:161)，和第六加下划线区是CDR3β(SEQ ID NO:162)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:163)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:164)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:165)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:166)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4268-TCR3
P53突变的识别:R248Q
方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4268-F15与p53-R248Q长肽，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:88.6％(在35对中观察到31次)
TCR取向:α-β
表达载体:SB转座子
患者4268的TCR 4268-TCR3的统计数据示于下表35中。
表35
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 42 | 43.8％ |
| CDR3β | 37 | 38.5％ |
| 4268-TCR3对 | 31 | 32.3％ |
| 总配对的TCR | 35 | 36.5％ |
从患者4268分离的4268-TCR4的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:167)，第二加下划线区是CDR2α(SEQ ID NO:168)，第三加下划线区是CDR3α(SEQ ID NO:169)，第四加下划线区是CDR1β(SEQ ID NO:170)，第五加下划线区是CDR2β(SEQ ID NO:171)，和第六加下划线区是CDR3β(SEQ ID NO:172)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:173)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:174)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:175)包含从氨基末端开始并且在连接子开始之前就结束的序列。全长β链(SEQ ID NO:176)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4268-TCR4
P53突变的识别:R248Q
方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4268-F18与p53-R248Q长肽，分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:95.2％(在42对中观察到40次)
TCR取向:α-β
表达载体:SB转座子
患者4268的TCR 4268-TCR4的统计数据示于下表36中。
表36
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 43 | 44.8％ |
| CDR3β | 53 | 55.2％ |
| 4268-TCR4对 | 40 | 41.7％ |
| 总配对的TCR | 42 | 43.8％ |
从患者4268分离的4268-TCR5的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:177)，第二加下划线区是CDR2α(SEQ ID NO:178)，第三加下划线区是CDR3α(SEQ ID NO:179)，第四加下划线区是CDR1β(SEQ ID NO:180)，第五加下划线区是CDR2β(SEQ ID NO:181)，和第六加下划线区是CDR3β(SEQ ID NO:182)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:183)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:184)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:185)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:186)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4268-TCR5
P53突变的识别:R248Q
方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4268-F19与p53-mut-TMG，分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:11.8％(在17对中观察到2次)
TCR取向:α-β
表达载体:SB转座子
患者4268的TCR 4268-TCR5的统计数据示于下表37中。
表37
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 2 | 2.1％ |
| CDR3β | 87 | 90.6％ |
| 4268-TCR5对 | 2 | 2.1％ |
| 总配对的TCR | 17 | 17.7％ |
实施例9
该实施例证实了通过在自体T细胞内共培养被诱导以表达突变的p53的自体APC来鉴定患者4266中的抗-突变的p53 T细胞(“p53热点突变通用筛选”)。该实施例还证实了从患者4266分离四种抗-突变的p53 TCR。
如图31-34和53-55针对患者4266所述进行实验。
将来自患者4266的TIL片段(F1-F24，n＝24)与用由无关、WT p53或经突变的p53序列组成的TMG电穿孔的自体APC共培养。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果显示于图31中。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果显示于图32中。
将来自患者4266的TIL片段(F1-F24，n＝24)与用肽媒介物(DMSO)或由WT p53-R248序列或经突变的p53-R248W序列组成的经纯化的(>95％，通过HPLC)25-个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果显示于图33中。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果显示于图34中。
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。第二天，将细胞与来自患者4266的单独HLA等位基因共转染。次日，将细胞用无肽、DMSO、野生型p53-R248肽SSCMGGMNRR(SEQ ID NO:590)或经突变的p53-R248W肽SSCMGGMNWR(SEQ ID NO:591)在37℃下以1μg/mL脉冲2小时。将来自患者4266的TIL培养物(105)添加至孔并在37℃下共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4-CD8+设门后，通过流式细胞术评价4-1BB的表达。结果显示于图53中。
将对从4266-TIL鉴定的p53-R248W具有假定特异性的表达模拟物(无TCR)、4266-TCR1、4266-TCR2、4266-TCR3或4266-TCR4的T细胞与用肽媒介物(DMSO)或由WT p53-R248序列或经突变的p53-R248W序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲的自体APC共培养。单独的培养基及PMA和离子霉素分别为阴性对照和阳性对照。在37℃下进行共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4-CD8+设门后，通过流式细胞术评价4-1BB的表达。结果显示于图54中。
肿瘤细胞(TC)系由从患者4266切除的异种移植的肿瘤碎片建立，然后通过免疫受损的小鼠连续传代(TC#4266)。将TC#4266与表达模拟物(无TCR)或p53-R248W-特异性TCR(4266-TCR2、4266-TCR3或4266-TCR4)的T细胞(105)在37℃下共培养过夜。将TC#4266细胞不与任何东西孵育、或者将TC#4266细胞与W6/32泛-HLA I类特异性阻断抗体、IVA12泛-HLAII类特异性阻断抗体或突变的p53-R248W肽SSCMGGMNWR(SEQ ID NO:591)在37℃下孵育2小时。将抗体以5μg/mL的终浓度保存在共培养物中。将肽以1μg/mL孵育，并且孵育后洗涤过量肽。单独的培养基(无TC)及PMA和离子霉素分别为阴性对照和阳性对照。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4-CD8+设门后，通过流式细胞术评价4-1BB的表达。结果示于图55中。
从患者4266分离的4266-TCR1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:97)，第二加下划线区是CDR2α(SEQ ID NO:98)，第三加下划线区是CDR3α(SEQ ID NO:99)，第四加下划线区是CDR1β(SEQ ID NO:100)，第五加下划线区是CDR2β(SEQ ID NO:101)，和第六加下划线区是CDR3β(SEQ ID NO:102)。粗体区是连接子(SEQ IDNO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:103)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:104)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:105)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:106)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4266-TCR1
P53突变的识别:R248W
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4266-F1、4266-F3、4266-F5和4266-F6与p53mutTMG或R248W长肽(两次共培养均检测相同的TCR)，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:17.0％(在53对中观察到9次)
TCR取向:α-β
表达载体:SB转座子
患者4266的TCR 4266-TCR1的统计数据示于下表38中。
表38
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 9 | 9.4％ |
| CDR3β | 10 | 10.4％ |
| 4266-TCR1对 | 9 | 9.4％ |
| 总配对的TCR | 53 | 55.2％ |
从患者4266分离的4266-TCR2的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:107)，第二加下划线区是CDR2α(SEQ ID NO:108)，第三加下划线区是CDR3α(SEQ ID NO:109)，第四加下划线区是CDR1β(SEQ ID NO:110)，第五加下划线区是CDR2β(SEQ ID NO:111)，和第六加下划线区是CDR3β(SEQ ID NO:112)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:113)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:114)包含在连接子之后立即开始并且在β链恒定区开始之前就结束的序列。全长α链(SEQ ID NO:115)包含从氨基末端开始并且在连接子开始之前就结束的序列。全长β链(SEQ ID NO:116)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4266-TCR2
P53突变的识别:R248W
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4266-F1、4266-F3、4266-F5和4266-F6与p53mutTMG或R248W长肽(两次共培养均检测相同的TCR)，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:24.5％(在53对中观察到13次)
TCR取向:α-β
表达载体:SB转座子
患者4266的TCR 4266-TCR2的统计数据示于下表39中。
表39
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 21 | 21.9％ |
| CDR3β | 18 | 18.8％ |
| 4266-TCR2对 | 13 | 13.5％ |
| 总配对的TCR | 53 | 55.2％ |
从患者4266分离的4266-TCR3的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:117)，第二加下划线区是CDR2α(SEQ ID NO:118)，第三加下划线区是CDR3α(SEQ ID NO:119)，第四加下划线区是CDR1β(SEQ ID NO:120)，第五加下划线区是CDR2β(SEQ ID NO:121)，和第六加下划线区是CDR3β(SEQ ID NO:122)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:123)包含从氨基末端开始并且在α链恒定区开始之前就结束的序列。β链可变区(SEQ ID NO:124)包含在连接子之后立即开始并且在β链恒定区开始之前就结束的序列。全长α链(SEQ ID NO:125)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:126)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4266-TCR3
P53突变的识别:R248W
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4266-F1、4266-F3、4266-F5和4266-F6与p53mutTMG或R248W长肽(两次共培养均检测相同的TCR)，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:34.0％(在53对中观察到18次)
TCR取向:α-β
表达载体:SB转座子
患者4266的TCR 4266-TCR3的统计数据示于下表40中。
表40
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 19 | 19.8％ |
| CDR3β | 26 | 27.1 |
| 4266-TCR3对 | 18 | 18.8％ |
| 总配对的TCR | 53 | 55.2％ |
从患者4266分离的4266-TCR4的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:127)，第二加下划线区是CDR2α(SEQ ID NO:128)，第三加下划线区是CDR3α(SEQ ID NO:129)，第四加下划线区是CDR1β(SEQ ID NO:130)，第五加下划线区是CDR2β(SEQ ID NO:131)，和第六加下划线区是CDR3β(SEQ ID NO:132)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:133)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:134)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:135)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:136)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞使用下面列出的筛选方法进行鉴定。用于分离TCR的方法示于下文。
TCR名称:4266-TCR4
P53突变的识别:R248W
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4266-F1、4266-F3、4266-F5和4266-F6与p53mutTMG或R248W长肽(两次共培养均检测相同的TCR)，分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:9.4％(在53对中观察到5次)
TCR取向:α-β
表达载体:SB转座子
患者4266的TCR 4266-TCR4的统计数据示于下表41中。
表41
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 5 | 5.2％ |
| CDR3β | 13 | 13.5 |
| 4266-TCR3对 | 5 | 5.2％ |
| 总配对的TCR | 53 | 55.2％ |
实施例10
该实施例证实了T细胞对p53“热点”突变的响应的概述。
表42提供了T细胞对p53“热点”突变的响应的概述。表42的第1-15号是一项回顾性研究。表42的第16-33号是一项前瞻性研究。
表42
n/a＝不适用；N＝阴性；Y＝确认有反应性；TBS＝待筛选。
实施例11
该实施例证实了用p53突变-反应性TIL治疗患者。
表43提供了用p53突变-反应性TIL治疗患者的概述。
表43
NT＝未治疗；TBS＝待筛选；N.R.＝无响应；P.R.＝部分响应；**患者尚未治疗。
实施例12
该实施例证实了来自患者4141的TCR的分离和特异的反应性。
将自体APC用编码无关突变、WT p53序列或包含R175H的突变的p53序列的TMG转染。单独的培养基以及PMA和离子霉素分别为阴性对照和阳性对照。第二天，将来自患者4141的TIL(片段培养物12)与TMG-转染的APC在37℃下共培养过夜。通过ELISPOT评价IFN-γ的分泌。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)→CD4-CD8+设门后，通过流式细胞术评价4-1BB的表达。结果示于图38中。
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。第二天，将细胞用来自患者4141的单独HLA等位基因以及无额外基因、WT TP53TMG或含有p53-R175H序列的突变的TP53 TMG共转染。第二天，将来自患者4141的对p53-R175H具有特异性的TIL(片段培养物12)与转染的Cos7细胞共培养，并在37℃下孵育过夜。通过ELISPOT评价IFN-γ的分泌。结果示于图39中。
将表达模拟物(无TCR)或4141-TCR1a2的T细胞与T2肿瘤细胞(表达HLA-A*02:01)共培养。将T2细胞在37℃下用肽媒介物(DMSO)或由WT p53-R175肽HMTEVVRRC(SEQ ID NO:532)或经突变的p53-R175H肽HMTEVVRHC(SEQ ID NO:530)组成的纯化的(>95％，通过HPLC)肽脉冲。单独的培养基及PMA和离子霉素分别为阴性对照和阳性对照。在37℃下进行共培养过夜。IFN-γ的分泌通过ELISA评价。结果示于图40中。
将表达4141-TCR1a2的T细胞与Saos2细胞(p53-NULL和HLA-A*02:01+)在37℃下共培养过夜，这些细胞未经处理，或使得过表达全长p53-R175H蛋白。将分泌的抑制剂(莫能菌素和布雷菲德菌素A)添加至共培养物，以捕获T细胞内的细胞因子。共培养6小时后，将细胞固定并透化，然后针对IL-2、CD107a、IFN-γ和肿瘤坏死因子-α(TNFα)染色。流式细胞术用于基于淋巴细胞设门分析共培养物。结果示于图41中。
从患者4141分离的TCR 4141-TCR1a2的序列示于以下。从氨基末端开始，第一加下划线的区是CDR1α(SEQ ID NO:467)，第二加下划线的区是CDR2α(SEQ ID NO:468)，第三加下划线的区是CDR3α(SEQ ID NO:469)，第四加下划线的区是CDR1β(SEQ ID NO:470)，第五加下划线的区是CDR2β(SEQ ID NO:471)，并且第六加下划线的区是CDR3β(SEQ ID NO:472)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一斜体区是α链恒定区(SEQ IDNO:23)并且第二斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:473)包含从氨基末端开始并且就在α链恒定区开始前结束的序列。β链可变区(SEQ ID NO:474)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:475)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:476)包含在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。如下所述分离TCR。
TCR名称:4141-TCR1a2
P53突变的识别:R175H
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4141输液袋TIL与p53mutTMG，和分选CD8+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR，然后TA TOPO克隆试剂盒(Thermo FisherScientific,Waltham,MA)用于α链
TCR取向:α-β
表达载体:SB转座子
来自患者4141的4141-TCR1a2的统计数据示于下表44中。
表44
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 未知(TA topO克隆) | 不适用 |
| CDR3β | 58 | 60.4％ |
实施例13
该实施例证实了从患者4259分离的TCR的分离和特异的反应性。
将来自患者4259的TIL片段培养物(no.6)与自体APC共培养，所述自体APC用1)由无关的、WT p53或突变的p53序列组成的TMG电穿孔或者2)用肽媒介物(DMSO)或由WT p53-Y220序列或经突变的p53-Y220序列组成的纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲。在37℃下进行共培养过夜。对淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图42中。
将自体APC在37℃下用浓度逐渐降低的25-个氨基酸的肽(对应于WT p53-Y220或突变的p53-Y220C序列)脉冲2小时。将来自患者4259的TIL片段培养物(no.6)与肽-脉冲的APC共培养。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术测定4-1BB的表达。结果示于图43中。
将自体抗原呈递细胞在37℃下用DMSO、WT p53-Y220肽RNTFRHSVVVPYE(SEQ IDNO:533)或突变的p53-Y220C肽RNTFRHSVVVPCE(SEQ ID NO:534)脉冲2小时。将过量肽冲走。将来自患者4259的对p53-Y220C具有特异性的TIL在37℃下与肽-脉冲的APC共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图44中。
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。接下来的一天，将细胞与来自患者4259的单独的HLA等位基因共转染。次日，将DMSO或p53-Y220C肽RNTFRHSVVVPCE(SEQ ID NO:534)在经转染的Cos7细胞上脉冲2小时。将过量肽冲走。添加来自患者4259的TIL片段培养物no.6(105个细胞/孔)。将共培养物在37℃下孵育过夜。对于淋巴细胞→活→CD3+(T细胞)→CD8-CD4+设门后，通过流式细胞术测定4-1BB的表达。结果示于图45中。
将患者4259自体的APC在37℃下用对应于WT p53-Y220或经突变的p53-Y220C序列的25-个氨基酸的肽脉冲2小时。将过量肽冲走。将表达4259-F6-TCR的T细胞与肽-脉冲的APC在37℃下共培养过夜。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。通过小鼠TCRβ(mTCR)测量导入的TCR。结果示于表45中。
表45
| WT p53-Y220 | Mut p53-Y220C | |
| 4-1BB+/mTCR+ | 0.27 | 5.22 |
| 4-1BB-/mTCR- | 68.5 | 73.7 |
| 4-1BB+/mTCR- | 0.18 | 1.59 |
| 4-1BB-/mTCR+ | 31.0 | 19.5 |
肿瘤细胞(TC)系由从患者4259切除的异种移植的肿瘤碎片建立，然后通过免疫受损的小鼠连续传代(TC#4259)。将TC#4259与表达模拟物(无TCR)或p53-Y220C-特异性TCR(4259-F6-TCR)的T细胞(105)在37℃下共培养过夜。将单独的TC#4259细胞或者将TC#4259细胞与W6/32泛-HLA I类特异性阻断抗体、IVA12泛-HLA II类特异性阻断抗体或经突变的p53-Y220C肽RNTFRHSVVVPCE(SEQ ID NO:534)在37℃下孵育2小时。将抗体以5μg/mL的终浓度保存在共培养物中。将肽以10μg/mL孵育，并且孵育后洗涤过量肽。单独的培养基(无TC)及PMA和离子霉素分别为阴性对照和阳性对照。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果示于图46中。
从患者4259分离的TCR 4259-F6-TCR的序列示于以下。从氨基末端开始，第一加下划线的区域是CDR1α(SEQ ID NO:477)，第二加下划线的区域是CDR2α(SEQ ID NO:478)，第三加下划线的区域是CDR3α(SEQ ID NO:479)，第四加下划线的区域是CDR1β(SEQ ID NO:480)，第五加下划线的区域是CDR2β(SEQ ID NO:481)，和第六加下划线的区域是CDR3β(SEQID NO:482)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一斜体区是α链恒定区(SEQ ID NO:23)并且第二斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:483)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ IDNO:484)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:485)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQID NO:486)包含在连接子之后立即开始并且以羧基末端结束的序列。
如下所述鉴定癌症反应性T细胞。如下所述分离TCR。
TCR名称:4259-F6-TCR
P53突变的识别:Y220C
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4259-F6与p53-Y220C肽，和分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:81.1％(在44对中观察到36次)
TCR取向:α-β
表达载体:SB转座子
来自患者4259的4259-F6-TCR的统计数据示于下表46中。
表46
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 41 | 42.7％ |
| CDR3β | 47 | 49.0％ |
| 4259-F6-TCR对 | 36 | 37.5％ |
| 总配对的TCR | 44 | 45.8％ |
实施例14
该实施例证实了来自患者4285的TCR的分离和特异反应性。
将来自患者4285的TIL片段(F1-F22和F24，n＝23)与用由无关、WT p53或经突变的p53序列组成的TMG电穿孔的自体APC共培养。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果显示于图47中。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果显示于图49中。
将来自患者4285的TIL片段(F1-F22和F24，n＝23)与用肽媒介物(DMSO)或由WTp53-R175序列或突变的p53-R175H序列组成的经纯化的(>95％，通过HPLC)25个氨基酸的肽脉冲的自体APC共培养。在37℃下进行共培养过夜。使用ELISPOT测定评价IFN-γ的分泌。结果显示于图48中。对于淋巴细胞→活细胞(PI阴性)→CD3+(T细胞)设门后，通过流式细胞术评价4-1BB的表达。结果显示于图50中。TIL片段F6是分选CD4+41BB+T细胞后的4285-TCR1的来源。
将自体APC用来自p53-R175H序列(表45中加下划线的氨基酸取代)的重叠14个氨基酸的15个氨基酸的肽脉冲。将对p53-R175H具有特异性的来自患者4285的TIL(片段培养物10、6和9)与肽-脉冲的APC在37℃下共培养过夜。DMSO是肽媒介物。使用ELISPOT测定评价IFN-γ的分泌。结果显示于表47中。
表47
将Cos7细胞(每孔2.5x104个)涂铺在平底96孔板的孔上。第二天，将细胞与来自患者4285的单独HLA等位基因共转染。次日，将细胞用DMSO或经突变的p53-R175H肽YKQSQHMTEVVRHCPHHERCSDSDG(SEQ ID NO:2)在37℃下在10μg/mL下脉冲2小时。将来自患者4285的对p53-R175H具有特异性的选定TIL片段培养物(4285-F6、4285-F9和4285-F10)与经转染的Cos7细胞在37℃下共培养过夜。对于淋巴细胞→活→CD3+(T细胞)→CD8-CD4+设门后，通过流式细胞术测定4-1BB的表达。结果显示于图51中。
将自体APC用对应于WT或突变的p53-R175H序列的逐渐降低浓度的25-个或15-个氨基酸的肽在37℃下脉冲2小时。将来自患者4285的4285-TCR1转座的T细胞与肽-脉冲的APC在37℃下共培养过夜。对于淋巴细胞→活→CD3+(T细胞)→CD8-CD4+设门后，通过流式细胞术测定4-1BB的表达。结果显示于图52中。
从患者4285分离的4285-TCR1的序列示于下文。从氨基末端开始，第一加下划线区是CDR1α(SEQ ID NO:487)，第二加下划线区是CDR2α(SEQ ID NO:488)，第三加下划线区是CDR3α(SEQ ID NO:489)，第四加下划线区是CDR1β(SEQ ID NO:490)，第五加下划线区是CDR2β(SEQ ID NO:491)，和第六加下划线区是CDR3β(SEQ ID NO:492)。粗体区是连接子(SEQ ID NO:26)。从氨基末端开始，第一加斜体区是α链恒定区(SEQ ID NO:23)并且第二加斜体区是β链恒定区(SEQ ID NO:25)。α链可变区(SEQ ID NO:493)包含从氨基末端开始并且就在α链恒定区开始之前结束的序列。β链可变区(SEQ ID NO:494)包含在连接子之后立即开始并且就在β链恒定区开始之前结束的序列。全长α链(SEQ ID NO:495)包含从氨基末端开始并且就在连接子开始之前结束的序列。全长β链(SEQ ID NO:496)包含在连接子之后立即开始并且以羧基末端结束的序列。
癌症反应性T细胞如下所述鉴定。TCR如下所述分离。
TCR名称:4285-TCR1
P53突变的识别:R175H
筛选方法:p53“热点”突变通用筛选
共培养以鉴定TCR:共培养4285-F6与p53-R175H肽和分选CD4+41BB+T细胞
鉴定TCR的方法:单细胞RT-PCR
所有配对的TCR中的TCR的丰度:81.8％(在44对中观察到36次)
TCR取向:α-β
表达载体:SB转座子
患者4285的4285-TCR1的统计数据示于下表48中。
表48
| 参数 | # | 频率 |
| 总孔 | 96 | 100％ |
| CDR3α | 37 | 39.8％ |
| CDR3β | 39 | 40.6％ |
| 4285-TCR1对 | 36 | 37.5％ |
| 总配对的TCR | 44 | 45.8％ |
实施例15
该实施例验证了来自实施例2的患者4196的三种抗突变p53 TCR的特异反应性。
不同靶细胞系的HLA-A*0201和p53 R 175 H的表达如表49所示。
表49
将表49中的靶细胞与用实施例2中的一种TCR转导的细胞共培养。使用模拟转导细胞(无TCR)作为对照效应细胞。测定IFN-γ分泌(pg/mL)(表50)和4-1BB表达(％4-1BB(mTCRβ+的))(表51)。
表50
表51
实施例16
该实施例证实了实施例1-15的TCR的反应性的概述。
将表52的TCR分离，在T细胞中表达并针对相关抗原进行了测试。结果概述显示于表52中。
表52
本文引用的所有参考文献，包括出版物、专利申请和专利，均通过引用并入本文，其程度如同每篇参考文献均被单独且具体地指示为通过引用并入本文并在本文中整体阐述。
在描述本发明的上下文中(尤其是在所附权利要求的上下文中)术语“一个”和“一种”和“该”和“至少一种”以及类似指代物的使用应被解释为涵盖了单数和复数两种，除非本文另有说明或与上下文明显矛盾。术语“至少一种”之后是一项或多项的列表(例如，“A和B中的至少一种”)的使用应理解为意指选自所列项(A或B)的一项或所列项(A和B)的两种或多种的任何组合，除非本文另有说明或与上下文明显矛盾。除非另有说明，否则术语“包含”、“具有”、“包括”和“含有”应被解释为开放式术语(即，意指“包括但不限于”)。除非在本文中另外指出，否则本文中数值范围的叙述仅旨在用作分别指代落入该范围内的每个单独值的简写方法，并且每个单独值都被并入说明书中，就好像它在本文中被单独叙述一样。除非本文另外指出或另外与上下文明显矛盾，否则本文描述的所有方法可以以任何适合的顺序执行。除非另外要求保护，否则本文提供的任何和所有示例或示例性语言(如，“诸如”)的使用仅旨在更好地阐明本发明，并且不对本发明的范围构成限制。说明书中的任何语言都不应解释为指示任何未要求保护的要素对于实施本发明必不可少。
本文描述了本发明的优选实施方案，包括发明人已知的用于实施本发明的最佳模式。在阅读前述说明书之后，那些优选实施方案的变型对于本领域普通技术人员而言将变得显而易见。本发明人期望熟练的技术人员适当地采用这样的变型，并且本发明人有意以不同于本文具体描述的方式来实践本发明。因此，本发明包括适用法律所允许的所附权利要求书中记载的主题的所有修改和等同物。此外，除非本文另外指出或另外与上下文明显矛盾，否则本发明涵盖上述要素在其所有可能的变型中的任何组合。
序列表
<110> THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE
SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
<120> 识别突变的p53的T细胞受体
<130> 739980
<150> US 62/565,383
<151> 2017-09-29
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Gly Phe Glu Ala Glu Phe Ile Lys Ser Lys Phe Ser Phe Asn Leu Arg
85 90 95
Lys Pro Ser Val Gln Trp Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Lys Gly Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val
115 120 125
Arg Ala
130
<210> 34
<211> 131
<212> PRT
<213> 人
<400> 34
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
115 120 125
Thr Val Val
130
<210> 35
<211> 267
<212> PRT
<213> 人
<400> 35
Met Leu Leu Leu Leu Ile Pro Val Leu Gly Met Ile Phe Ala Leu Arg
1 5 10 15
Asp Ala Arg Ala Gln Ser Val Ser Gln His Asn His His Val Ile Leu
20 25 30
Ser Glu Ala Ala Ser Leu Glu Leu Gly Cys Asn Tyr Ser Tyr Gly Gly
35 40 45
Thr Val Asn Leu Phe Trp Tyr Val Gln Tyr Pro Gly Gln His Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Phe Ser Gly Asp Pro Leu Val Lys Gly Ile Lys
65 70 75 80
Gly Phe Glu Ala Glu Phe Ile Lys Ser Lys Phe Ser Phe Asn Leu Arg
85 90 95
Lys Pro Ser Val Gln Trp Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Lys Gly Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val
115 120 125
Arg Ala Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 36
<211> 304
<212> PRT
<213> 人
<400> 36
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
115 120 125
Thr Val Val 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> 37
<211> 7
<212> PRT
<213> 人
<400> 37
Thr Arg Asp Thr Thr Tyr Tyr
1 5
<210> 38
<211> 8
<212> PRT
<213> 人
<400> 38
Arg Asn Ser Phe Asp Glu Gln Asn
1 5
<210> 39
<211> 14
<212> PRT
<213> 人
<400> 39
Cys Ala Leu Ser Glu Gly Gly Ser Asn Tyr Lys Leu Thr Phe
1 5 10
<210> 40
<211> 5
<212> PRT
<213> 人
<400> 40
Leu Asn His Asn Val
1 5
<210> 41
<211> 6
<212> PRT
<213> 人
<400> 41
Tyr Tyr Asp Lys Asp Phe
1 5
<210> 42
<211> 14
<212> PRT
<213> 人
<400> 42
Cys Ala Thr Ser Arg Glu Leu Arg Gly Asn Glu Gln Phe Phe
1 5 10
<210> 43
<211> 135
<212> PRT
<213> 人
<400> 43
Met Leu Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly
115 120 125
Thr Leu Leu Thr Val Asn Pro
130 135
<210> 44
<211> 132
<212> PRT
<213> 人
<400> 44
Met Ala Pro Gly Leu Leu His Trp Met Ala Leu Cys Leu Leu Gly Thr
1 5 10 15
Gly His Gly Asp Ala Met Val Ile Gln Asn Pro Arg Tyr Gln Val Thr
20 25 30
Gln Phe Gly Lys Pro Val Thr Leu Ser Cys Ser Gln Thr Leu Asn His
35 40 45
Asn Val Met Tyr Trp Tyr Gln Gln Lys Ser Ser Gln Ala Pro Lys Leu
50 55 60
Leu Phe His Tyr Tyr Asp Lys Asp Phe Asn Asn Glu Ala Asp Thr Pro
65 70 75 80
Asp Asn Phe Gln Ser Arg Arg Pro Asn Thr Ser Phe Cys Phe Leu Asp
85 90 95
Ile Arg Ser Pro Gly Leu Gly Asp Ala Ala Met Tyr Leu Cys Ala Thr
100 105 110
Ser Arg Glu Leu Arg Gly Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu
130
<210> 45
<211> 272
<212> PRT
<213> 人
<400> 45
Met Leu Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly
115 120 125
Thr Leu Leu Thr Val Asn Pro 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> 46
<211> 305
<212> PRT
<213> 人
<400> 46
Met Ala Pro Gly Leu Leu His Trp Met Ala Leu Cys Leu Leu Gly Thr
1 5 10 15
Gly His Gly Asp Ala Met Val Ile Gln Asn Pro Arg Tyr Gln Val Thr
20 25 30
Gln Phe Gly Lys Pro Val Thr Leu Ser Cys Ser Gln Thr Leu Asn His
35 40 45
Asn Val Met Tyr Trp Tyr Gln Gln Lys Ser Ser Gln Ala Pro Lys Leu
50 55 60
Leu Phe His Tyr Tyr Asp Lys Asp Phe Asn Asn Glu Ala Asp Thr Pro
65 70 75 80
Asp Asn Phe Gln Ser Arg Arg Pro Asn Thr Ser Phe Cys Phe Leu Asp
85 90 95
Ile Arg Ser Pro Gly Leu Gly Asp Ala Ala Met Tyr Leu Cys Ala Thr
100 105 110
Ser Arg Glu Leu Arg Gly Asn Glu Gln Phe 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> 47
<211> 6
<212> PRT
<213> 人
<400> 47
Thr Ser Gly Phe Asn Gly
1 5
<210> 48
<211> 6
<212> PRT
<213> 人
<400> 48
Asn Val Leu Asp Gly Leu
1 5
<210> 49
<211> 13
<212> PRT
<213> 人
<400> 49
Cys Ala Val Lys Trp Thr Gly Gly Phe Lys Thr Ile Phe
1 5 10
<210> 50
<211> 5
<212> PRT
<213> 人
<400> 50
Met Asn His Glu Tyr
1 5
<210> 51
<211> 6
<212> PRT
<213> 人
<400> 51
Ser Val Gly Ala Gly Ile
1 5
<210> 52
<211> 14
<212> PRT
<213> 人
<400> 52
Cys Ala Ser Ser Tyr Arg Glu Ser His Tyr Gly Tyr Thr Phe
1 5 10
<210> 53
<211> 127
<212> PRT
<213> 人
<400> 53
Met Trp Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Lys Trp Thr Gly Gly
100 105 110
Phe Lys Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala
115 120 125
<210> 54
<211> 134
<212> PRT
<213> 人
<400> 54
Met Ala Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu
1 5 10 15
Trp Ala Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln
20 25 30
Val Leu Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met
35 40 45
Asn His Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu
50 55 60
Arg Leu Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu
65 70 75 80
Val Pro Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro
85 90 95
Leu Arg Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys
100 105 110
Ala Ser Ser Tyr Arg Glu Ser His Tyr Gly Tyr Thr Phe Gly Ser Gly
115 120 125
Thr Arg Leu Thr Val Val
130
<210> 55
<211> 264
<212> PRT
<213> 人
<400> 55
Met Trp Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Lys Trp Thr Gly Gly
100 105 110
Phe Lys Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala Asn
115 120 125
Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser
130 135 140
Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn
145 150 155 160
Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val
165 170 175
Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp
180 185 190
Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn
195 200 205
Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu
210 215 220
Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val
225 230 235 240
Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu
245 250 255
Met Thr Leu Arg Leu Trp Ser Ser
260
<210> 56
<211> 307
<212> PRT
<213> 人
<400> 56
Met Ala Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu
1 5 10 15
Trp Ala Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln
20 25 30
Val Leu Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met
35 40 45
Asn His Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu
50 55 60
Arg Leu Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu
65 70 75 80
Val Pro Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro
85 90 95
Leu Arg Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys
100 105 110
Ala Ser Ser Tyr Arg Glu Ser His Tyr Gly Tyr Thr Phe Gly Ser Gly
115 120 125
Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 57
<211> 6
<212> PRT
<213> 人
<400> 57
Val Ser Gly Asn Pro Tyr
1 5
<210> 58
<211> 8
<212> PRT
<213> 人
<400> 58
Tyr Ile Thr Gly Asp Asn Leu Val
1 5
<210> 59
<211> 12
<212> PRT
<213> 人
<400> 59
Cys Ala Val Arg Val Trp Asp Tyr Lys Leu Ser Phe
1 5 10
<210> 60
<211> 5
<212> PRT
<213> 人
<400> 60
Leu Asn His Asp Ala
1 5
<210> 61
<211> 6
<212> PRT
<213> 人
<400> 61
Ser Gln Ile Val Asn Asp
1 5
<210> 62
<211> 14
<212> PRT
<213> 人
<400> 62
Cys Ala Ser Ser Ile Ser Ala Gly Gly Asp Gly Tyr Thr Phe
1 5 10
<210> 63
<211> 131
<212> PRT
<213> 人
<400> 63
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 Val Trp Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr
115 120 125
Val Arg Ala
130
<210> 64
<211> 132
<212> PRT
<213> 人
<400> 64
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Ala
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Thr
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Phe Tyr Leu Cys Ala Ser
100 105 110
Ser Ile Ser Ala Gly Gly Asp Gly Tyr Thr Phe Gly Ser Gly Thr Arg
115 120 125
Leu Thr Val Val
130
<210> 65
<211> 268
<212> PRT
<213> 人
<400> 65
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 Val Trp Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr
115 120 125
Val Arg Ala 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> 66
<211> 305
<212> PRT
<213> 人
<400> 66
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Ala
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Thr
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Phe Tyr Leu Cys Ala Ser
100 105 110
Ser Ile Ser Ala Gly Gly Asp Gly Tyr Thr Phe Gly Ser Gly Thr Arg
115 120 125
Leu Thr Val Val 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> 67
<211> 6
<212> PRT
<213> 人
<400> 67
Asn Ser Ala Ser Gln Ser
1 5
<210> 68
<211> 6
<212> PRT
<213> 人
<400> 68
Val Tyr Ser Ser Gly Asn
1 5
<210> 69
<211> 13
<212> PRT
<213> 人
<400> 69
Cys Val Val Gln Pro Gly Gly Tyr Gln Lys Val Thr Phe
1 5 10
<210> 70
<211> 5
<212> PRT
<213> 人
<400> 70
Met Asn His Asn Ser
1 5
<210> 71
<211> 6
<212> PRT
<213> 人
<400> 71
Ser Ala Ser Glu Gly Thr
1 5
<210> 72
<211> 16
<212> PRT
<213> 人
<400> 72
Cys Ala Ser Ser Glu Gly Leu Trp Gln Val Gly Asp Glu Gln Tyr Phe
1 5 10 15
<210> 73
<211> 131
<212> PRT
<213> 人
<400> 73
Met Ile Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Arg Lys Glu Val Glu Gln Asp Pro Gly Pro Phe
20 25 30
Asn Val Pro Glu Gly Ala Thr Val Ala Phe Asn Cys Thr Tyr Ser Asn
35 40 45
Ser Ala Ser Gln Ser Phe Phe Trp Tyr Arg Gln Asp Cys Arg Lys Glu
50 55 60
Pro Lys Leu Leu Met Ser Val Tyr Ser Ser Gly Asn Glu Asp Gly Arg
65 70 75 80
Phe Thr Ala Gln Leu Asn Arg Ala Ser Gln Tyr Ile Ser Leu Leu Ile
85 90 95
Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Val Val Gln
100 105 110
Pro Gly Gly Tyr Gln Lys Val Thr Phe Gly Thr Gly Thr Lys Leu Gln
115 120 125
Val Ile Pro
130
<210> 74
<211> 134
<212> PRT
<213> 人
<400> 74
Met Ala Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Glu Gly Leu Trp Gln Val Gly Asp Glu Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Thr
130
<210> 75
<211> 268
<212> PRT
<213> 人
<400> 75
Met Ile Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Arg Lys Glu Val Glu Gln Asp Pro Gly Pro Phe
20 25 30
Asn Val Pro Glu Gly Ala Thr Val Ala Phe Asn Cys Thr Tyr Ser Asn
35 40 45
Ser Ala Ser Gln Ser Phe Phe Trp Tyr Arg Gln Asp Cys Arg Lys Glu
50 55 60
Pro Lys Leu Leu Met Ser Val Tyr Ser Ser Gly Asn Glu Asp Gly Arg
65 70 75 80
Phe Thr Ala Gln Leu Asn Arg Ala Ser Gln Tyr Ile Ser Leu Leu Ile
85 90 95
Arg Asp Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Val Val Gln
100 105 110
Pro Gly Gly Tyr Gln Lys Val Thr Phe Gly Thr Gly Thr Lys Leu Gln
115 120 125
Val Ile Pro Asp 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> 76
<211> 307
<212> PRT
<213> 人
<400> 76
Met Ala Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Glu Gly Leu Trp Gln Val Gly Asp Glu Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 77
<211> 7
<212> PRT
<213> 人
<400> 77
Thr Ser Glu Asn Asn Tyr Tyr
1 5
<210> 78
<211> 8
<212> PRT
<213> 人
<400> 78
Gln Glu Ala Tyr Lys Gln Gln Asn
1 5
<210> 79
<211> 16
<212> PRT
<213> 人
<400> 79
Cys Ala Phe Met Gly Tyr Ser Gly Ala Gly Ser Tyr Gln Leu Thr Phe
1 5 10 15
<210> 80
<211> 5
<212> PRT
<213> 人
<400> 80
Glu Asn His Arg Tyr
1 5
<210> 81
<211> 6
<212> PRT
<213> 人
<400> 81
Ser Tyr Gly Val Lys Asp
1 5
<210> 82
<211> 15
<212> PRT
<213> 人
<400> 82
Cys Ala Ile Ser Glu Leu Val Thr Gly Asp Ser Pro Leu His Phe
1 5 10 15
<210> 83
<211> 137
<212> PRT
<213> 人
<400> 83
Met Thr Arg Val Ser Leu Leu Trp Ala Val Val Val Ser Thr Cys Leu
1 5 10 15
Glu Ser Gly Met Ala Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser
20 25 30
Val Gln Glu Ala Glu Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser
35 40 45
Glu Asn Asn Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln
50 55 60
Met Ile Leu Val Ile Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr
65 70 75 80
Glu Asn Arg Phe Ser Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser
85 90 95
Leu Lys Ile Ser Asp Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys
100 105 110
Ala Phe Met Gly Tyr Ser Gly Ala Gly Ser Tyr Gln Leu Thr Phe Gly
115 120 125
Lys Gly Thr Lys Leu Ser Val Ile Pro
130 135
<210> 84
<211> 133
<212> PRT
<213> 人
<400> 84
Met Ala Thr Arg Leu Phe Phe Tyr Val Ala Leu Cys Leu Leu Trp Thr
1 5 10 15
Gly His Met Asp Ala Gly Ile Thr Gln Ser Pro Arg His Lys Val Thr
20 25 30
Glu Thr Gly Thr Pro Val Thr Leu Arg Cys His Gln Thr Glu Asn His
35 40 45
Arg Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly His Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Tyr Gly Val Lys Asp Thr Asp Lys Gly Glu Val Ser
65 70 75 80
Asp Gly Tyr Ser Val Ser Arg Ser Lys Thr Glu Asp Phe Leu Leu Thr
85 90 95
Leu Glu Ser Ala Thr Ser Ser Gln Thr Ser Val Tyr Phe Cys Ala Ile
100 105 110
Ser Glu Leu Val Thr Gly Asp Ser Pro Leu His Phe Gly Asn Gly Thr
115 120 125
Arg Leu Thr Val Thr
130
<210> 85
<211> 274
<212> PRT
<213> 人
<400> 85
Met Thr Arg Val Ser Leu Leu Trp Ala Val Val Val Ser Thr Cys Leu
1 5 10 15
Glu Ser Gly Met Ala Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser
20 25 30
Val Gln Glu Ala Glu Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser
35 40 45
Glu Asn Asn Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln
50 55 60
Met Ile Leu Val Ile Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr
65 70 75 80
Glu Asn Arg Phe Ser Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser
85 90 95
Leu Lys Ile Ser Asp Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys
100 105 110
Ala Phe Met Gly Tyr Ser Gly Ala Gly Ser Tyr Gln Leu Thr Phe Gly
115 120 125
Lys Gly Thr Lys Leu Ser Val Ile Pro Asp Ile Gln Asn Pro Glu Pro
130 135 140
Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys
145 150 155 160
Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu
165 170 175
Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met
180 185 190
Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe
195 200 205
Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser
210 215 220
Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu
245 250 255
Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp
260 265 270
Ser Ser
<210> 86
<211> 306
<212> PRT
<213> 人
<400> 86
Met Ala Thr Arg Leu Phe Phe Tyr Val Ala Leu Cys Leu Leu Trp Thr
1 5 10 15
Gly His Met Asp Ala Gly Ile Thr Gln Ser Pro Arg His Lys Val Thr
20 25 30
Glu Thr Gly Thr Pro Val Thr Leu Arg Cys His Gln Thr Glu Asn His
35 40 45
Arg Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly His Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Tyr Gly Val Lys Asp Thr Asp Lys Gly Glu Val Ser
65 70 75 80
Asp Gly Tyr Ser Val Ser Arg Ser Lys Thr Glu Asp Phe Leu Leu Thr
85 90 95
Leu Glu Ser Ala Thr Ser Ser Gln Thr Ser Val Tyr Phe Cys Ala Ile
100 105 110
Ser Glu Leu Val Thr Gly Asp Ser Pro Leu His Phe Gly Asn Gly Thr
115 120 125
Arg Leu Thr Val Thr 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> 87
<211> 6
<212> PRT
<213> 人
<400> 87
Asn Tyr Ser Pro Ala Tyr
1 5
<210> 88
<211> 7
<212> PRT
<213> 人
<400> 88
Ile Arg Glu Asn Glu Lys Glu
1 5
<210> 89
<211> 12
<212> PRT
<213> 人
<400> 89
Cys Ala Leu Asp Ile Tyr Pro His Asp Met Arg Phe
1 5 10
<210> 90
<211> 5
<212> PRT
<213> 人
<400> 90
Ser Gly His Ala Thr
1 5
<210> 91
<211> 6
<212> PRT
<213> 人
<400> 91
Phe Gln Asn Asn Gly Val
1 5
<210> 92
<211> 15
<212> PRT
<213> 人
<400> 92
Cys Ala Ser Ser Leu Asp Pro Gly Asp Thr Gly Glu Leu Phe Phe
1 5 10 15
<210> 93
<211> 131
<212> PRT
<213> 人
<400> 93
Met Glu Ser Phe Leu Gly Gly Val Leu Leu Ile Leu Trp Leu Gln Val
1 5 10 15
Asp Trp Val Lys Ser Gln Lys Ile Glu Gln Asn Ser Glu Ala Leu Asn
20 25 30
Ile Gln Glu Gly Lys Thr Ala Thr Leu Thr Cys Asn Tyr Thr Asn Tyr
35 40 45
Ser Pro Ala Tyr Leu Gln Trp Tyr Arg Gln Asp Pro Gly Arg Gly Pro
50 55 60
Val Phe Leu Leu Leu Ile Arg Glu Asn Glu Lys Glu Lys Arg Lys Glu
65 70 75 80
Arg Leu Lys Val Thr Phe Asp Thr Thr Leu Lys Gln Ser Leu Phe His
85 90 95
Ile Thr Ala Ser Gln Pro Ala Asp Ser Ala Thr Tyr Leu Cys Ala Leu
100 105 110
Asp Ile Tyr Pro His Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr
115 120 125
Val Lys Pro
130
<210> 94
<211> 134
<212> PRT
<213> 人
<400> 94
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Asp Pro Gly Asp Thr Gly Glu Leu Phe Phe Gly Glu Gly
115 120 125
Ser Arg Leu Thr Val Leu
130
<210> 95
<211> 268
<212> PRT
<213> 人
<400> 95
Met Glu Ser Phe Leu Gly Gly Val Leu Leu Ile Leu Trp Leu Gln Val
1 5 10 15
Asp Trp Val Lys Ser Gln Lys Ile Glu Gln Asn Ser Glu Ala Leu Asn
20 25 30
Ile Gln Glu Gly Lys Thr Ala Thr Leu Thr Cys Asn Tyr Thr Asn Tyr
35 40 45
Ser Pro Ala Tyr Leu Gln Trp Tyr Arg Gln Asp Pro Gly Arg Gly Pro
50 55 60
Val Phe Leu Leu Leu Ile Arg Glu Asn Glu Lys Glu Lys Arg Lys Glu
65 70 75 80
Arg Leu Lys Val Thr Phe Asp Thr Thr Leu Lys Gln Ser Leu Phe His
85 90 95
Ile Thr Ala Ser Gln Pro Ala Asp Ser Ala Thr Tyr Leu Cys Ala Leu
100 105 110
Asp Ile Tyr Pro His Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr
115 120 125
Val Lys Pro Asp 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> 96
<211> 307
<212> PRT
<213> 人
<400> 96
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Asp Pro Gly Asp Thr Gly Glu Leu Phe Phe Gly Glu Gly
115 120 125
Ser Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 97
<211> 6
<212> PRT
<213> 人
<400> 97
Ser Ser Val Ser Val Tyr
1 5
<210> 98
<211> 8
<212> PRT
<213> 人
<400> 98
Tyr Leu Ser Gly Ser Thr Leu Val
1 5
<210> 99
<211> 14
<212> PRT
<213> 人
<400> 99
Cys Ala Val Ser Asp Leu Val Arg Asp Asp Lys Ile Ile Phe
1 5 10
<210> 100
<211> 5
<212> PRT
<213> 人
<400> 100
Met Asn His Asn Ser
1 5
<210> 101
<211> 6
<212> PRT
<213> 人
<400> 101
Ser Ala Ser Glu Gly Thr
1 5
<210> 102
<211> 11
<212> PRT
<213> 人
<400> 102
Cys Ala Ser Ile Gly Gly Phe Glu Ala Phe Phe
1 5 10
<210> 103
<211> 133
<212> PRT
<213> 人
<400> 103
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Ser Asp Leu Val Arg Asp Asp Lys Ile Ile Phe Gly Lys Gly Thr Arg
115 120 125
Leu His Ile Leu Pro
130
<210> 104
<211> 129
<212> PRT
<213> 人
<400> 104
Met His Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ile Gly Gly Phe Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val
115 120 125
Val
<210> 105
<211> 270
<212> PRT
<213> 人
<400> 105
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Ser Asp Leu Val Arg Asp Asp Lys Ile Ile Phe Gly Lys Gly Thr Arg
115 120 125
Leu His Ile Leu 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> 106
<211> 302
<212> PRT
<213> 人
<400> 106
Met His Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ile Gly Gly Phe Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val
115 120 125
Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu
130 135 140
Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys
145 150 155 160
Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val
165 170 175
Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr
180 185 190
Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser
195 200 205
Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln
210 215 220
Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys
225 230 235 240
Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys
245 250 255
Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile
260 265 270
Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val
275 280 285
Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 107
<211> 6
<212> PRT
<213> 人
<400> 107
Thr Ser Gly Phe Asn Gly
1 5
<210> 108
<211> 6
<212> PRT
<213> 人
<400> 108
Asn Val Leu Asp Gly Leu
1 5
<210> 109
<211> 12
<212> PRT
<213> 人
<400> 109
Cys Ala Val Tyr Thr Gly Gly Phe Lys Thr Ile Phe
1 5 10
<210> 110
<211> 5
<212> PRT
<213> 人
<400> 110
Ser Gly His Ala Thr
1 5
<210> 111
<211> 6
<212> PRT
<213> 人
<400> 111
Phe Gln Asn Asn Gly Val
1 5
<210> 112
<211> 15
<212> PRT
<213> 人
<400> 112
Cys Ala Ser Asn Leu Gly Gly Gly Ser Thr Asp Thr Gln Tyr Phe
1 5 10 15
<210> 113
<211> 126
<212> PRT
<213> 人
<400> 113
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Tyr Thr Gly Gly Phe
100 105 110
Lys Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala
115 120 125
<210> 114
<211> 134
<212> PRT
<213> 人
<400> 114
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Asn Leu Gly Gly Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 115
<211> 263
<212> PRT
<213> 人
<400> 115
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Tyr Thr Gly Gly Phe
100 105 110
Lys Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala Asn Ile
115 120 125
Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln
130 135 140
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val
145 150 155 160
Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu
165 170 175
Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser
180 185 190
Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala
195 200 205
Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys
210 215 220
Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile
225 230 235 240
Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
245 250 255
Thr Leu Arg Leu Trp Ser Ser
260
<210> 116
<211> 307
<212> PRT
<213> 人
<400> 116
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Asn Leu Gly Gly Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 117
<211> 6
<212> PRT
<213> 人
<400> 117
Thr Ser Gly Phe Asn Gly
1 5
<210> 118
<211> 6
<212> PRT
<213> 人
<400> 118
Asn Val Leu Asp Gly Leu
1 5
<210> 119
<211> 14
<212> PRT
<213> 人
<400> 119
Cys Ala Phe Tyr Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10
<210> 120
<211> 5
<212> PRT
<213> 人
<400> 120
Ser Gly His Val Ser
1 5
<210> 121
<211> 6
<212> PRT
<213> 人
<400> 121
Phe Gln Asn Glu Ala Gln
1 5
<210> 122
<211> 15
<212> PRT
<213> 人
<400> 122
Cys Ala Ser Ser Phe Gly Ser Gly Ser Thr Asp Thr Gln Tyr Phe
1 5 10 15
<210> 123
<211> 128
<212> PRT
<213> 人
<400> 123
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Phe Tyr Tyr Gly Gly Ser
100 105 110
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
115 120 125
<210> 124
<211> 134
<212> PRT
<213> 人
<400> 124
Met His Thr Arg Leu Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Ala
20 25 30
Lys Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Val Ser Leu Phe Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Phe Ala Glu Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Phe Gly Ser Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 125
<211> 265
<212> PRT
<213> 人
<400> 125
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Phe Tyr Tyr Gly Gly Ser
100 105 110
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 126
<211> 307
<212> PRT
<213> 人
<400> 126
Met His Thr Arg Leu Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Ala
20 25 30
Lys Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Val Ser Leu Phe Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Asp Lys Ser Gly Leu Pro
65 70 75 80
Ser Asp Arg Phe Phe Ala Glu Arg Pro Glu Gly Ser Val Ser Thr Leu
85 90 95
Lys Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Phe Gly Ser Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 127
<211> 6
<212> PRT
<213> 人
<400> 127
Thr Ser Gly Phe Asn Gly
1 5
<210> 128
<211> 6
<212> PRT
<213> 人
<400> 128
Asn Val Leu Asp Gly Leu
1 5
<210> 129
<211> 14
<212> PRT
<213> 人
<400> 129
Cys Ala Val Tyr Pro Gly Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10
<210> 130
<211> 5
<212> PRT
<213> 人
<400> 130
Ser Gly His Ala Thr
1 5
<210> 131
<211> 6
<212> PRT
<213> 人
<400> 131
Phe Gln Asn Asn Gly Val
1 5
<210> 132
<211> 15
<212> PRT
<213> 人
<400> 132
Cys Ala Ser Ser Leu Gly Thr Gly Ser Thr Asp Thr Gln Tyr Phe
1 5 10 15
<210> 133
<211> 128
<212> PRT
<213> 人
<400> 133
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Tyr Pro Gly Gly Ser
100 105 110
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
115 120 125
<210> 134
<211> 134
<212> PRT
<213> 人
<400> 134
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Thr Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 135
<211> 265
<212> PRT
<213> 人
<400> 135
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Tyr Pro Gly Gly Ser
100 105 110
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 136
<211> 307
<212> PRT
<213> 人
<400> 136
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Thr Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 137
<211> 6
<212> PRT
<213> 人
<400> 137
Asp Arg Gly Ser Gln Ser
1 5
<210> 138
<211> 6
<212> PRT
<213> 人
<400> 138
Ile Tyr Ser Asn Gly Asp
1 5
<210> 139
<211> 11
<212> PRT
<213> 人
<400> 139
Cys Ala Val Ser Trp Tyr Ser Thr Leu Thr Phe
1 5 10
<210> 140
<211> 5
<212> PRT
<213> 人
<400> 140
Trp Ser His Ser Tyr
1 5
<210> 141
<211> 6
<212> PRT
<213> 人
<400> 141
Ser Ala Ala Ala Asp Ile
1 5
<210> 142
<211> 13
<212> PRT
<213> 人
<400> 142
Cys Ala Ser Ser Gly Ser Arg Thr Asp Thr Gln Tyr Phe
1 5 10
<210> 143
<211> 130
<212> PRT
<213> 人
<400> 143
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Ser Trp Tyr Ser Thr Leu Thr Phe Gly Lys Gly Thr Met Leu Leu Val
115 120 125
Ser Pro
130
<210> 144
<211> 131
<212> PRT
<213> 人
<400> 144
Met His Thr Arg Leu Phe Phe Tyr Val Ala Leu Cys Leu Leu Trp Ala
1 5 10 15
Gly His Arg Asp Ala Gly Ile Thr Gln Ser Pro Arg Tyr Lys Ile Thr
20 25 30
Glu Thr Gly Arg Gln Val Thr Leu Met Cys His Gln Thr Trp Ser His
35 40 45
Ser Tyr Met Phe Trp Tyr Arg Gln Asp Leu Gly His Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ala Ala Asp Ile Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asp Gly Tyr Val Val Ser Arg Ser Lys Thr Glu Asn Phe Pro Leu Thr
85 90 95
Leu Glu Ser Ala Thr Arg Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Gly Ser Arg Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Leu
130
<210> 145
<211> 267
<212> PRT
<213> 人
<400> 145
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Ser Trp Tyr Ser Thr Leu Thr Phe Gly Lys Gly Thr Met Leu Leu Val
115 120 125
Ser Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 146
<211> 304
<212> PRT
<213> 人
<400> 146
Met His Thr Arg Leu Phe Phe Tyr Val Ala Leu Cys Leu Leu Trp Ala
1 5 10 15
Gly His Arg Asp Ala Gly Ile Thr Gln Ser Pro Arg Tyr Lys Ile Thr
20 25 30
Glu Thr Gly Arg Gln Val Thr Leu Met Cys His Gln Thr Trp Ser His
35 40 45
Ser Tyr Met Phe Trp Tyr Arg Gln Asp Leu Gly His Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ala Ala Asp Ile Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asp Gly Tyr Val Val Ser Arg Ser Lys Thr Glu Asn Phe Pro Leu Thr
85 90 95
Leu Glu Ser Ala Thr Arg Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Gly Ser Arg Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr 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> 147
<211> 5
<212> PRT
<213> 人
<400> 147
Ser Val Phe Ser Ser
1 5
<210> 148
<211> 7
<212> PRT
<213> 人
<400> 148
Val Val Thr Gly Gly Glu Val
1 5
<210> 149
<211> 12
<212> PRT
<213> 人
<400> 149
Cys Ala Gly Glu Phe Ala Gly Asn Gln Phe Tyr Phe
1 5 10
<210> 150
<211> 5
<212> PRT
<213> 人
<400> 150
Met Gly His Arg Ala
1 5
<210> 151
<211> 6
<212> PRT
<213> 人
<400> 151
Tyr Ser Tyr Glu Lys Leu
1 5
<210> 152
<211> 14
<212> PRT
<213> 人
<400> 152
Cys Ala Ser Ser Gln Val Gly Leu Thr Tyr Glu Gln Tyr Phe
1 5 10
<210> 153
<211> 128
<212> PRT
<213> 人
<400> 153
Met Ala Leu Lys Phe Ser Val Ser Ile Leu Trp Ile Gln Leu Ala Trp
1 5 10 15
Val Ser Thr Gln Leu Leu Glu Gln Ser Pro Gln Phe Leu Ser Ile Gln
20 25 30
Glu Gly Glu Asn Leu Thr Val Tyr Cys Asn Ser Ser Ser Val Phe Ser
35 40 45
Ser Leu Gln Trp Tyr Arg Gln Glu Pro Gly Glu Gly Pro Val Leu Leu
50 55 60
Val Thr Val Val Thr Gly Gly Glu Val Lys Lys Leu Lys Arg Leu Thr
65 70 75 80
Phe Gln Phe Gly Asp Ala Arg Lys Asp Ser Ser Leu His Ile Thr Ala
85 90 95
Ala Gln Pro Gly Asp Thr Gly Leu Tyr Leu Cys Ala Gly Glu Phe Ala
100 105 110
Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro
115 120 125
<210> 154
<211> 132
<212> PRT
<213> 人
<400> 154
Met His Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gln Val Gly Leu Thr Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr
130
<210> 155
<211> 265
<212> PRT
<213> 人
<400> 155
Met Ala Leu Lys Phe Ser Val Ser Ile Leu Trp Ile Gln Leu Ala Trp
1 5 10 15
Val Ser Thr Gln Leu Leu Glu Gln Ser Pro Gln Phe Leu Ser Ile Gln
20 25 30
Glu Gly Glu Asn Leu Thr Val Tyr Cys Asn Ser Ser Ser Val Phe Ser
35 40 45
Ser Leu Gln Trp Tyr Arg Gln Glu Pro Gly Glu Gly Pro Val Leu Leu
50 55 60
Val Thr Val Val Thr Gly Gly Glu Val Lys Lys Leu Lys Arg Leu Thr
65 70 75 80
Phe Gln Phe Gly Asp Ala Arg Lys Asp Ser Ser Leu His Ile Thr Ala
85 90 95
Ala Gln Pro Gly Asp Thr Gly Leu Tyr Leu Cys Ala Gly Glu Phe Ala
100 105 110
Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 156
<211> 305
<212> PRT
<213> 人
<400> 156
Met His Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gln Val Gly Leu Thr Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr 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> 157
<211> 6
<212> PRT
<213> 人
<400> 157
Val Ser Gly Asn Pro Tyr
1 5
<210> 158
<211> 8
<212> PRT
<213> 人
<400> 158
Tyr Ile Thr Gly Asp Asn Leu Val
1 5
<210> 159
<211> 16
<212> PRT
<213> 人
<400> 159
Cys Ala Val Arg Asp Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe
1 5 10 15
<210> 160
<211> 5
<212> PRT
<213> 人
<400> 160
Ser Gly His Ala Thr
1 5
<210> 161
<211> 6
<212> PRT
<213> 人
<400> 161
Phe Gln Asn Asn Gly Val
1 5
<210> 162
<211> 13
<212> PRT
<213> 人
<400> 162
Cys Ala Ser Ser Leu Gly Gln Gly Gln Thr Gln Tyr Phe
1 5 10
<210> 163
<211> 135
<212> PRT
<213> 人
<400> 163
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 Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly
115 120 125
Thr Leu Leu Thr Val Asn Pro
130 135
<210> 164
<211> 132
<212> PRT
<213> 人
<400> 164
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gln Gly Gln Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Leu Val Leu
130
<210> 165
<211> 272
<212> PRT
<213> 人
<400> 165
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 Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly
115 120 125
Thr Leu Leu Thr Val Asn Pro 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> 166
<211> 305
<212> PRT
<213> 人
<400> 166
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Gly Gln Gly Gln Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Leu 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> 167
<211> 6
<212> PRT
<213> 人
<400> 167
Ser Ser Val Ser Val Tyr
1 5
<210> 168
<211> 8
<212> PRT
<213> 人
<400> 168
Tyr Leu Ser Gly Ser Thr Leu Val
1 5
<210> 169
<211> 14
<212> PRT
<213> 人
<400> 169
Cys Ala Val Arg Gly Ser Ser Gly Thr Tyr Lys Tyr Ile Phe
1 5 10
<210> 170
<211> 5
<212> PRT
<213> 人
<400> 170
Met Asp His Glu Asn
1 5
<210> 171
<211> 6
<212> PRT
<213> 人
<400> 171
Ser Tyr Asp Val Lys Met
1 5
<210> 172
<211> 13
<212> PRT
<213> 人
<400> 172
Cys Ala Ser Lys Gly Asp Gln Asn Thr Glu Ala Phe Phe
1 5 10
<210> 173
<211> 133
<212> PRT
<213> 人
<400> 173
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Arg Gly Ser Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg
115 120 125
Leu Lys Val Leu Ala
130
<210> 174
<211> 131
<212> PRT
<213> 人
<400> 174
Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Lys Gly Asp Gln Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
115 120 125
Thr Val Val
130
<210> 175
<211> 270
<212> PRT
<213> 人
<400> 175
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Arg Gly Ser Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg
115 120 125
Leu Lys Val Leu Ala 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> 176
<211> 304
<212> PRT
<213> 人
<400> 176
Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Lys Gly Asp Gln Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
115 120 125
Thr Val Val 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> 177
<211> 6
<212> PRT
<213> 人
<400> 177
Thr Ser Gly Phe Asn Gly
1 5
<210> 178
<211> 6
<212> PRT
<213> 人
<400> 178
Asn Val Leu Asp Gly Leu
1 5
<210> 179
<211> 15
<212> PRT
<213> 人
<400> 179
Cys Ala Val Arg Asp Leu Gln Thr Gly Ala Asn Asn Leu Phe Phe
1 5 10 15
<210> 180
<211> 5
<212> PRT
<213> 人
<400> 180
Met Asp His Glu Asn
1 5
<210> 181
<211> 6
<212> PRT
<213> 人
<400> 181
Ser Tyr Asp Val Lys Met
1 5
<210> 182
<211> 14
<212> PRT
<213> 人
<400> 182
Cys Ala Ser Ser Leu Thr Phe Gly Thr Thr Glu Ala Phe Phe
1 5 10
<210> 183
<211> 129
<212> PRT
<213> 人
<400> 183
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Arg Asp Leu Gln Thr
100 105 110
Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu Thr Val Ile
115 120 125
Pro
<210> 184
<211> 132
<212> PRT
<213> 人
<400> 184
Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Ser Leu Thr Phe Gly Thr Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val
130
<210> 185
<211> 266
<212> PRT
<213> 人
<400> 185
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Arg Asp Leu Gln Thr
100 105 110
Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu Thr Val Ile
115 120 125
Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro
130 135 140
Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys
165 170 175
Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile
180 185 190
Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu
195 200 205
Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu
210 215 220
Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu
225 230 235 240
Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
245 250 255
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 186
<211> 305
<212> PRT
<213> 人
<400> 186
Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Ser Leu Thr Phe Gly Thr Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val 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> 187
<211> 6
<212> PRT
<213> 人
<400> 187
Val Thr Asn Phe Arg Ser
1 5
<210> 188
<211> 7
<212> PRT
<213> 人
<400> 188
Leu Thr Ser Ser Gly Ile Glu
1 5
<210> 189
<211> 15
<212> PRT
<213> 人
<400> 189
Cys Ala Gly Gln Asn Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe
1 5 10 15
<210> 190
<211> 5
<212> PRT
<213> 人
<400> 190
Ser Asn His Leu Tyr
1 5
<210> 191
<211> 6
<212> PRT
<213> 人
<400> 191
Phe Tyr Asn Asn Glu Ile
1 5
<210> 192
<211> 12
<212> PRT
<213> 人
<400> 192
Cys Ala Ser Arg Asp Pro Ala Tyr Glu Gln Tyr Phe
1 5 10
<210> 193
<211> 134
<212> PRT
<213> 人
<400> 193
Met Ala Lys Cys Pro Gln Ala Leu Leu Ala Ile Phe Trp Leu Leu Leu
1 5 10 15
Ser Trp Val Ser Ser Glu Asp Lys Val Val Gln Ser Pro Leu Ser Leu
20 25 30
Val Val His Glu Gly Asp Thr Val Thr Leu Asn Cys Ser Tyr Glu Val
35 40 45
Thr Asn Phe Arg Ser Leu Leu Trp Tyr Lys Gln Glu Lys Lys Ala Pro
50 55 60
Thr Phe Leu Phe Met Leu Thr Ser Ser Gly Ile Glu Lys Lys Ser Gly
65 70 75 80
Arg Leu Ser Ser Ile Leu Asp Lys Lys Glu Leu Ser Ser Ile Leu Asn
85 90 95
Ile Thr Ala Thr Gln Thr Gly Asp Ser Ala Ile Tyr Leu Cys Ala Gly
100 105 110
Gln Asn Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr
115 120 125
Lys Leu Ser Val Lys Pro
130
<210> 194
<211> 131
<212> PRT
<213> 人
<400> 194
Met His Thr Trp Leu Val Cys Trp Ala Ile Phe Ser Leu Leu Lys Ala
1 5 10 15
Gly Leu Thr Glu Pro Glu Val Thr Gln Thr Pro Ser His Gln Val Thr
20 25 30
Gln Met Gly Gln Glu Val Ile Leu Arg Cys Val Pro Ile Ser Asn His
35 40 45
Leu Tyr Phe Tyr Trp Tyr Arg Gln Ile Leu Gly Gln Lys Val Glu Phe
50 55 60
Leu Val Ser Phe Tyr Asn Asn Glu Ile Ser Glu Lys Ser Glu Ile Phe
65 70 75 80
Asp Asp Gln Phe Ser Val Glu Arg Pro Asp Gly Ser Asn Phe Thr Leu
85 90 95
Lys Ile Arg Ser Thr Lys Leu Glu Asp Ser Ala Met Tyr Phe Cys Ala
100 105 110
Ser Arg Asp Pro Ala Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr
130
<210> 195
<211> 271
<212> PRT
<213> 人
<400> 195
Met Ala Lys Cys Pro Gln Ala Leu Leu Ala Ile Phe Trp Leu Leu Leu
1 5 10 15
Ser Trp Val Ser Ser Glu Asp Lys Val Val Gln Ser Pro Leu Ser Leu
20 25 30
Val Val His Glu Gly Asp Thr Val Thr Leu Asn Cys Ser Tyr Glu Val
35 40 45
Thr Asn Phe Arg Ser Leu Leu Trp Tyr Lys Gln Glu Lys Lys Ala Pro
50 55 60
Thr Phe Leu Phe Met Leu Thr Ser Ser Gly Ile Glu Lys Lys Ser Gly
65 70 75 80
Arg Leu Ser Ser Ile Leu Asp Lys Lys Glu Leu Ser Ser Ile Leu Asn
85 90 95
Ile Thr Ala Thr Gln Thr Gly Asp Ser Ala Ile Tyr Leu Cys Ala Gly
100 105 110
Gln Asn Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr
115 120 125
Lys Leu Ser Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 196
<211> 304
<212> PRT
<213> 人
<400> 196
Met His Thr Trp Leu Val Cys Trp Ala Ile Phe Ser Leu Leu Lys Ala
1 5 10 15
Gly Leu Thr Glu Pro Glu Val Thr Gln Thr Pro Ser His Gln Val Thr
20 25 30
Gln Met Gly Gln Glu Val Ile Leu Arg Cys Val Pro Ile Ser Asn His
35 40 45
Leu Tyr Phe Tyr Trp Tyr Arg Gln Ile Leu Gly Gln Lys Val Glu Phe
50 55 60
Leu Val Ser Phe Tyr Asn Asn Glu Ile Ser Glu Lys Ser Glu Ile Phe
65 70 75 80
Asp Asp Gln Phe Ser Val Glu Arg Pro Asp Gly Ser Asn Phe Thr Leu
85 90 95
Lys Ile Arg Ser Thr Lys Leu Glu Asp Ser Ala Met Tyr Phe Cys Ala
100 105 110
Ser Arg Asp Pro Ala Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr 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> 197
<211> 6
<212> PRT
<213> 人
<400> 197
Asp Arg Gly Ser Gln Ser
1 5
<210> 198
<211> 6
<212> PRT
<213> 人
<400> 198
Ile Tyr Ser Asn Gly Asp
1 5
<210> 199
<211> 16
<212> PRT
<213> 人
<400> 199
Cys Ala Val Asn Pro Pro Val Lys Thr Ser Tyr Asp Lys Val Ile Phe
1 5 10 15
<210> 200
<211> 5
<212> PRT
<213> 人
<400> 200
Ser Gly His Val Ser
1 5
<210> 201
<211> 6
<212> PRT
<213> 人
<400> 201
Phe Asn Tyr Glu Ala Gln
1 5
<210> 202
<211> 15
<212> PRT
<213> 人
<400> 202
Cys Ala Ser Ser His Arg Glu Pro His Thr Gly Glu Leu Phe Phe
1 5 10 15
<210> 203
<211> 135
<212> PRT
<213> 人
<400> 203
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Asn Pro Pro Val Lys Thr Ser Tyr Asp Lys Val Ile Phe Gly Pro Gly
115 120 125
Thr Ser Leu Ser Val Ile Pro
130 135
<210> 204
<211> 134
<212> PRT
<213> 人
<400> 204
Met His Thr Ser Leu Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Thr
20 25 30
Lys Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Val Ser Leu Tyr Trp Tyr Arg Gln Ala Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Asn Tyr Glu Ala Gln Gln Asp Lys Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Ser Ala Glu Arg Pro Glu Gly Ser Ile Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Glu Gln Arg Asp Ser Ala Met Tyr Arg Cys Ala
100 105 110
Ser Ser His Arg Glu Pro His Thr Gly Glu Leu Phe Phe Gly Glu Gly
115 120 125
Ser Arg Leu Thr Val Leu
130
<210> 205
<211> 272
<212> PRT
<213> 人
<400> 205
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Asn Pro Pro Val Lys Thr Ser Tyr Asp Lys Val Ile Phe Gly Pro Gly
115 120 125
Thr Ser Leu Ser Val Ile Pro 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> 206
<211> 307
<212> PRT
<213> 人
<400> 206
Met His Thr Ser Leu Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr
1 5 10 15
Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Thr
20 25 30
Lys Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His
35 40 45
Val Ser Leu Tyr Trp Tyr Arg Gln Ala Leu Gly Gln Gly Pro Glu Phe
50 55 60
Leu Thr Tyr Phe Asn Tyr Glu Ala Gln Gln Asp Lys Ser Gly Leu Pro
65 70 75 80
Asn Asp Arg Phe Ser Ala Glu Arg Pro Glu Gly Ser Ile Ser Thr Leu
85 90 95
Thr Ile Gln Arg Thr Glu Gln Arg Asp Ser Ala Met Tyr Arg Cys Ala
100 105 110
Ser Ser His Arg Glu Pro His Thr Gly Glu Leu Phe Phe Gly Glu Gly
115 120 125
Ser Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 207
<211> 7
<212> PRT
<213> 人
<400> 207
Thr Arg Asp Thr Thr Tyr Tyr
1 5
<210> 208
<211> 8
<212> PRT
<213> 人
<400> 208
Arg Asn Ser Phe Asp Glu Gln Asn
1 5
<210> 209
<211> 15
<212> PRT
<213> 人
<400> 209
Cys Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe
1 5 10 15
<210> 210
<211> 5
<212> PRT
<213> 人
<400> 210
Ser Gly Asp Leu Ser
1 5
<210> 211
<211> 6
<212> PRT
<213> 人
<400> 211
Tyr Tyr Asn Gly Glu Glu
1 5
<210> 212
<211> 16
<212> PRT
<213> 人
<400> 212
Cys Ala Ser Ser Val Gly Ser Ser Ser Ser Thr Asp Thr Gln Tyr Phe
1 5 10 15
<210> 213
<211> 136
<212> PRT
<213> 人
<400> 213
Met Ala Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe Gly Lys
115 120 125
Gly Thr Arg Leu Ser Val Ile Ala
130 135
<210> 214
<211> 134
<212> PRT
<213> 人
<400> 214
Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Val Gly Ser Ser Ser Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 215
<211> 273
<212> PRT
<213> 人
<400> 215
Met Ala Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe Gly Lys
115 120 125
Gly Thr Arg Leu Ser Val Ile Ala Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser
<210> 216
<211> 307
<212> PRT
<213> 人
<400> 216
Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Val Gly Ser Ser Ser Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 217
<211> 7
<212> PRT
<213> 人
<400> 217
Thr Arg Asp Thr Thr Tyr Tyr
1 5
<210> 218
<211> 8
<212> PRT
<213> 人
<400> 218
Arg Asn Ser Phe Asp Glu Gln Asn
1 5
<210> 219
<211> 15
<212> PRT
<213> 人
<400> 219
Cys Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe
1 5 10 15
<210> 220
<211> 5
<212> PRT
<213> 人
<400> 220
Ser Gly Asp Leu Ser
1 5
<210> 221
<211> 6
<212> PRT
<213> 人
<400> 221
Tyr Tyr Asn Gly Glu Glu
1 5
<210> 222
<211> 16
<212> PRT
<213> 人
<400> 222
Cys Ala Ser Ser Val Gly Ser Ser Ser Ser Thr Asp Thr Gln Tyr Phe
1 5 10 15
<210> 223
<211> 136
<212> PRT
<213> 人
<400> 223
Met Ala Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe Gly Lys
115 120 125
Gly Thr Arg Leu Ser Val Ile Ala
130 135
<210> 224
<211> 134
<212> PRT
<213> 人
<400> 224
Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile His Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Val Gly Ser Ser Ser Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 225
<211> 273
<212> PRT
<213> 人
<400> 225
Met Ala Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe Gly Lys
115 120 125
Gly Thr Arg Leu Ser Val Ile Ala Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser
<210> 226
<211> 307
<212> PRT
<213> 人
<400> 226
Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile His Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Val Gly Ser Ser Ser Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 227
<211> 6
<212> PRT
<213> 人
<400> 227
Asn Ser Ala Phe Gln Tyr
1 5
<210> 228
<211> 6
<212> PRT
<213> 人
<400> 228
Thr Tyr Ser Ser Gly Asn
1 5
<210> 229
<211> 14
<212> PRT
<213> 人
<400> 229
Cys Ala Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe
1 5 10
<210> 230
<211> 6
<212> PRT
<213> 人
<400> 230
Asp Phe Gln Ala Thr Thr
1 5
<210> 231
<211> 7
<212> PRT
<213> 人
<400> 231
Ser Asn Glu Gly Ser Lys Ala
1 5
<210> 232
<211> 13
<212> PRT
<213> 人
<400> 232
Cys Ser Gly Gly Leu Glu Glu Ala Ala Arg Gln Phe Ile
1 5 10
<210> 233
<211> 134
<212> PRT
<213> 人
<400> 233
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
Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr
115 120 125
Arg Leu Thr Val Lys Pro
130
<210> 234
<211> 140
<212> PRT
<213> 人
<400> 234
Met His Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Gly Gly Leu Glu Glu Ala Ala Arg
115 120 125
Gln Phe Ile Gly Pro Gly Thr Arg Leu Thr Val Leu
130 135 140
<210> 235
<211> 271
<212> PRT
<213> 人
<400> 235
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
Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr
115 120 125
Arg Leu Thr Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 236
<211> 313
<212> PRT
<213> 人
<400> 236
Met His Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Gly Gly Leu Glu Glu Ala Ala Arg
115 120 125
Gln Phe Ile Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg
130 135 140
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
145 150 155 160
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
165 170 175
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
180 185 190
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
195 200 205
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
210 215 220
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
225 230 235 240
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
245 250 255
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
260 265 270
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
275 280 285
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
290 295 300
Met Ala Met Val Lys Arg Lys Asn Ser
305 310
<210> 237
<211> 6
<212> PRT
<213> 人
<400> 237
Asn Ser Ala Phe Gln Tyr
1 5
<210> 238
<211> 6
<212> PRT
<213> 人
<400> 238
Thr Tyr Ser Ser Gly Asn
1 5
<210> 239
<211> 14
<212> PRT
<213> 人
<400> 239
Cys Ala Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe
1 5 10
<210> 240
<211> 6
<212> PRT
<213> 人
<400> 240
Asp Phe Gln Ala Thr Thr
1 5
<210> 241
<211> 7
<212> PRT
<213> 人
<400> 241
Ser Asn Glu Gly Ser Lys Ala
1 5
<210> 242
<211> 13
<212> PRT
<213> 人
<400> 242
Cys Ser Gly Gly Leu Glu Glu Ala Ala Arg Gln Phe Ile
1 5 10
<210> 243
<211> 134
<212> PRT
<213> 人
<400> 243
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
Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr
115 120 125
Arg Leu Thr Val Lys Pro
130
<210> 244
<211> 130
<212> PRT
<213> 人
<400> 244
Met His Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ser Gly Leu Gly
1 5 10 15
Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr
20 25 30
Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met
35 40 45
Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr
50 55 60
Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp
65 70 75 80
Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val
85 90 95
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Gly Gly
100 105 110
Leu Glu Glu Ala Ala Arg Gln Phe Ile Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Leu
130
<210> 245
<211> 271
<212> PRT
<213> 人
<400> 245
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
Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr
115 120 125
Arg Leu Thr Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 246
<211> 303
<212> PRT
<213> 人
<400> 246
Met His Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ser Gly Leu Gly
1 5 10 15
Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr
20 25 30
Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met
35 40 45
Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr
50 55 60
Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp
65 70 75 80
Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val
85 90 95
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Gly Gly
100 105 110
Leu Glu Glu Ala Ala Arg Gln Phe Ile Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 247
<211> 7
<212> PRT
<213> 人
<400> 247
Thr Ile Ser Gly Asn Glu Tyr
1 5
<210> 248
<211> 5
<212> PRT
<213> 人
<400> 248
Gly Leu Lys Asn Asn
1 5
<210> 249
<211> 11
<212> PRT
<213> 人
<400> 249
Cys Ile Val Pro Asn Asp Tyr Lys Leu Ser Phe
1 5 10
<210> 250
<211> 5
<212> PRT
<213> 人
<400> 250
Met Asp His Glu Asn
1 5
<210> 251
<211> 6
<212> PRT
<213> 人
<400> 251
Ser Tyr Asp Val Lys Met
1 5
<210> 252
<211> 16
<212> PRT
<213> 人
<400> 252
Cys Ala Ser Ser Phe Gly Thr Gly Ser Ile Gln Glu Thr Gln Tyr Phe
1 5 10 15
<210> 253
<211> 125
<212> PRT
<213> 人
<400> 253
Met Ala Leu Val Ala Arg Val Thr Val Phe Leu Thr Phe Gly Thr Ile
1 5 10 15
Ile Asp Ala Lys Thr Thr Gln Pro Pro Ser Met Asp Cys Ala Glu Gly
20 25 30
Arg Ala Ala Asn Leu Pro Cys Asn His Ser Thr Ile Ser Gly Asn Glu
35 40 45
Tyr Val Tyr Trp Tyr Arg Gln Ile His Ser Gln Gly Pro Gln Tyr Ile
50 55 60
Ile His Gly Leu Lys Asn Asn Glu Thr Asn Glu Met Ala Ser Leu Ile
65 70 75 80
Ile Thr Glu Asp Arg Lys Ser Ser Thr Leu Ile Leu Pro His Ala Thr
85 90 95
Leu Arg Asp Thr Ala Val Tyr Tyr Cys Ile Val Pro Asn Asp Tyr Lys
100 105 110
Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg Ala
115 120 125
<210> 254
<211> 134
<212> PRT
<213> 人
<400> 254
Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Ser Phe Gly Thr Gly Ser Ile Gln Glu Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Leu Val Leu
130
<210> 255
<211> 262
<212> PRT
<213> 人
<400> 255
Met Ala Leu Val Ala Arg Val Thr Val Phe Leu Thr Phe Gly Thr Ile
1 5 10 15
Ile Asp Ala Lys Thr Thr Gln Pro Pro Ser Met Asp Cys Ala Glu Gly
20 25 30
Arg Ala Ala Asn Leu Pro Cys Asn His Ser Thr Ile Ser Gly Asn Glu
35 40 45
Tyr Val Tyr Trp Tyr Arg Gln Ile His Ser Gln Gly Pro Gln Tyr Ile
50 55 60
Ile His Gly Leu Lys Asn Asn Glu Thr Asn Glu Met Ala Ser Leu Ile
65 70 75 80
Ile Thr Glu Asp Arg Lys Ser Ser Thr Leu Ile Leu Pro His Ala Thr
85 90 95
Leu Arg Asp Thr Ala Val Tyr Tyr Cys Ile Val Pro Asn Asp Tyr Lys
100 105 110
Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg Ala Asn Ile Gln
115 120 125
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
130 135 140
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
145 150 155 160
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
165 170 175
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
180 185 190
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
195 200 205
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
210 215 220
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
225 230 235 240
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
245 250 255
Leu Arg Leu Trp Ser Ser
260
<210> 256
<211> 307
<212> PRT
<213> 人
<400> 256
Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Ser Phe Gly Thr Gly Ser Ile Gln Glu Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 257
<211> 6
<212> PRT
<213> 人
<400> 257
Ala Thr Gly Tyr Pro Ser
1 5
<210> 258
<211> 7
<212> PRT
<213> 人
<400> 258
Ala Thr Lys Ala Asp Asp Lys
1 5
<210> 259
<211> 17
<212> PRT
<213> 人
<400> 259
Cys Ala Leu Asn Pro Asn Ala Gly Gly Thr Ser Tyr Gly Lys Leu Thr
1 5 10 15
Phe
<210> 260
<211> 5
<212> PRT
<213> 人
<400> 260
Ser Gly His Thr Ser
1 5
<210> 261
<211> 6
<212> PRT
<213> 人
<400> 261
Tyr Asp Glu Gly Glu Glu
1 5
<210> 262
<211> 20
<212> PRT
<213> 人
<400> 262
Cys Ala Ser Ser Ser Pro Gly Ala Thr Ser Gly Gly Ala Asn Thr Gly
1 5 10 15
Glu Leu Phe Phe
20
<210> 263
<211> 135
<212> PRT
<213> 人
<400> 263
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Asn
100 105 110
Pro Asn Ala Gly Gly Thr Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly
115 120 125
Thr Ile Leu Thr Val His Pro
130 135
<210> 264
<211> 138
<212> PRT
<213> 人
<400> 264
Met His Pro Arg Leu Leu Phe Trp Ala Leu Leu Cys Leu Leu Gly Thr
1 5 10 15
Gly Pro Val Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Ala Thr Leu Arg Cys Ser Pro Ile Ser Gly His
35 40 45
Thr Ser Val Tyr Trp Tyr Gln Gln Ala Leu Gly Leu Gly Leu Gln Phe
50 55 60
Leu Leu Trp Tyr Asp Glu Gly Glu Glu Arg Asn Arg Gly Asn Phe Pro
65 70 75 80
Pro Arg Phe Ser Gly Arg Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn
85 90 95
Val Asn Ala Leu Glu Leu Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Ser Pro Gly Ala Thr Ser Gly Gly Ala Asn Thr Gly Glu Leu Phe
115 120 125
Phe Gly Glu Gly Ser Arg Leu Thr Val Leu
130 135
<210> 265
<211> 272
<212> PRT
<213> 人
<400> 265
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Asn
100 105 110
Pro Asn Ala Gly Gly Thr Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly
115 120 125
Thr Ile Leu Thr Val His Pro 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> 266
<211> 311
<212> PRT
<213> 人
<400> 266
Met His Pro Arg Leu Leu Phe Trp Ala Leu Leu Cys Leu Leu Gly Thr
1 5 10 15
Gly Pro Val Glu Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Ala Thr Leu Arg Cys Ser Pro Ile Ser Gly His
35 40 45
Thr Ser Val Tyr Trp Tyr Gln Gln Ala Leu Gly Leu Gly Leu Gln Phe
50 55 60
Leu Leu Trp Tyr Asp Glu Gly Glu Glu Arg Asn Arg Gly Asn Phe Pro
65 70 75 80
Pro Arg Phe Ser Gly Arg Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn
85 90 95
Val Asn Ala Leu Glu Leu Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Ser Pro Gly Ala Thr Ser Gly Gly Ala Asn Thr Gly Glu Leu Phe
115 120 125
Phe Gly Glu Gly Ser Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val
130 135 140
Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala
145 150 155 160
Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro
165 170 175
Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser
180 185 190
Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu
225 230 235 240
Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
260 265 270
Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
275 280 285
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala
290 295 300
Met Val Lys Arg Lys Asn Ser
305 310
<210> 267
<211> 6
<212> PRT
<213> 人
<400> 267
Asp Ser Ser Ser Thr Tyr
1 5
<210> 268
<211> 7
<212> PRT
<213> 人
<400> 268
Ile Phe Ser Asn Met Asp Met
1 5
<210> 269
<211> 17
<212> PRT
<213> 人
<400> 269
Cys Ala Glu Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr
1 5 10 15
Phe
<210> 270
<211> 6
<212> PRT
<213> 人
<400> 270
Asp Phe Gln Ala Thr Thr
1 5
<210> 271
<211> 7
<212> PRT
<213> 人
<400> 271
Ser Asn Glu Gly Ser Lys Ala
1 5
<210> 272
<211> 14
<212> PRT
<213> 人
<400> 272
Cys Ser Ala Arg Asp Leu Gln Arg Ser Tyr Glu Gln Tyr Phe
1 5 10
<210> 273
<211> 136
<212> PRT
<213> 人
<400> 273
Met Ala Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro
130 135
<210> 274
<211> 141
<212> PRT
<213> 人
<400> 274
Met His Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Ala Arg Asp Leu Gln Arg Ser Tyr
115 120 125
Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr
130 135 140
<210> 275
<211> 273
<212> PRT
<213> 人
<400> 275
Met Ala Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser
<210> 276
<211> 314
<212> PRT
<213> 人
<400> 276
Met His Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Ala Arg Asp Leu Gln Arg Ser Tyr
115 120 125
Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu
130 135 140
Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala
145 150 155 160
Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly
165 170 175
Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu
180 185 190
Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn
195 200 205
Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp
210 215 220
His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu
225 230 235 240
Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln
245 250 255
Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser
260 265 270
Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile
275 280 285
Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val
290 295 300
Val Met Ala Met Val Lys Arg Lys Asn Ser
305 310
<210> 277
<211> 6
<212> PRT
<213> 人
<400> 277
Asp Ser Ser Ser Thr Tyr
1 5
<210> 278
<211> 7
<212> PRT
<213> 人
<400> 278
Ile Phe Ser Asn Met Asp Met
1 5
<210> 279
<211> 17
<212> PRT
<213> 人
<400> 279
Cys Ala Glu Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr
1 5 10 15
Phe
<210> 280
<211> 6
<212> PRT
<213> 人
<400> 280
Asp Phe Gln Ala Thr Thr
1 5
<210> 281
<211> 7
<212> PRT
<213> 人
<400> 281
Ser Asn Glu Gly Ser Lys Ala
1 5
<210> 282
<211> 14
<212> PRT
<213> 人
<400> 282
Cys Ser Ala Arg Asp Leu Gln Arg Ser Tyr Glu Gln Tyr Phe
1 5 10
<210> 283
<211> 136
<212> PRT
<213> 人
<400> 283
Met Ala Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro
130 135
<210> 284
<211> 131
<212> PRT
<213> 人
<400> 284
Met His Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ser Gly Leu Gly
1 5 10 15
Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr
20 25 30
Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met
35 40 45
Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr
50 55 60
Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp
65 70 75 80
Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val
85 90 95
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Arg
100 105 110
Asp Leu Gln Arg Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr
130
<210> 285
<211> 273
<212> PRT
<213> 人
<400> 285
Met Ala Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser
<210> 286
<211> 304
<212> PRT
<213> 人
<400> 286
Met His Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ser Gly Leu Gly
1 5 10 15
Ala Val Val Ser Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr
20 25 30
Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met
35 40 45
Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr
50 55 60
Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp
65 70 75 80
Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val
85 90 95
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Arg
100 105 110
Asp Leu Gln Arg Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr 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> 287
<211> 6
<212> PRT
<213> 人
<400> 287
Asn Ser Ala Ser Asp Tyr
1 5
<210> 288
<211> 7
<212> PRT
<213> 人
<400> 288
Ile Arg Ser Asn Met Asp Lys
1 5
<210> 289
<211> 16
<212> PRT
<213> 人
<400> 289
Cys Ala Glu Pro Val Gly Gly Leu Asn Ser Gly Tyr Ala Leu Asn Phe
1 5 10 15
<210> 290
<211> 5
<212> PRT
<213> 人
<400> 290
Ser Gly His Lys Ser
1 5
<210> 291
<211> 6
<212> PRT
<213> 人
<400> 291
Tyr Tyr Glu Lys Glu Glu
1 5
<210> 292
<211> 16
<212> PRT
<213> 人
<400> 292
Cys Ala Ser Ser Gly Gly Arg Thr Ser Gly Ala Tyr Glu Gln Phe Phe
1 5 10 15
<210> 293
<211> 135
<212> PRT
<213> 人
<400> 293
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
Pro Val Gly Gly Leu Asn Ser Gly Tyr Ala Leu Asn Phe Gly Lys Gly
115 120 125
Thr Ser Leu Leu Val Thr Pro
130 135
<210> 294
<211> 134
<212> PRT
<213> 人
<400> 294
Met His Pro Gly Leu Leu Cys Trp Val Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Ile Ser Gly His
35 40 45
Lys Ser Val Ser Trp Tyr Gln Gln Val Leu Gly Gln Gly Pro Gln Phe
50 55 60
Ile Phe Gln Tyr Tyr Glu Lys Glu Glu Arg Gly Arg Gly Asn Phe Pro
65 70 75 80
Asp Arg Phe Ser Ala Arg Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn
85 90 95
Val Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gly Gly Arg Thr Ser Gly Ala Tyr Glu Gln Phe Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 295
<211> 272
<212> PRT
<213> 人
<400> 295
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
Pro Val Gly Gly Leu Asn Ser Gly Tyr Ala Leu Asn Phe Gly Lys Gly
115 120 125
Thr Ser Leu Leu Val Thr Pro 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> 296
<211> 307
<212> PRT
<213> 人
<400> 296
Met His Pro Gly Leu Leu Cys Trp Val Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Ile Ser Gly His
35 40 45
Lys Ser Val Ser Trp Tyr Gln Gln Val Leu Gly Gln Gly Pro Gln Phe
50 55 60
Ile Phe Gln Tyr Tyr Glu Lys Glu Glu Arg Gly Arg Gly Asn Phe Pro
65 70 75 80
Asp Arg Phe Ser Ala Arg Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn
85 90 95
Val Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gly Gly Arg Thr Ser Gly Ala Tyr Glu Gln Phe Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 297
<211> 6
<212> PRT
<213> 人
<400> 297
Val Ser Gly Leu Arg Gly
1 5
<210> 298
<211> 7
<212> PRT
<213> 人
<400> 298
Leu Tyr Ser Ala Gly Glu Glu
1 5
<210> 299
<211> 16
<212> PRT
<213> 人
<400> 299
Cys Ala Val Thr Ala His Arg Gly Ser Thr Leu Gly Arg Leu Tyr Phe
1 5 10 15
<210> 300
<211> 5
<212> PRT
<213> 人
<400> 300
Ser Gly His Asp Thr
1 5
<210> 301
<211> 6
<212> PRT
<213> 人
<400> 301
Tyr Tyr Glu Glu Glu Glu
1 5
<210> 302
<211> 15
<212> PRT
<213> 人
<400> 302
Cys Ala Ser Ser Arg Arg Gly Gly Ala Tyr Asn Glu Gln Phe Phe
1 5 10 15
<210> 303
<211> 134
<212> PRT
<213> 人
<400> 303
Met Ala Lys Met Leu Glu Cys Ala Phe Ile Val Leu Trp Leu Gln Leu
1 5 10 15
Gly Trp Leu Ser Gly Glu Asp Gln Val Thr Gln Ser Pro Glu Ala Leu
20 25 30
Arg Leu Gln Glu Gly Glu Ser Ser Ser Leu Asn Cys Ser Tyr Thr Val
35 40 45
Ser Gly Leu Arg Gly Leu Phe Trp Tyr Arg Gln Asp Pro Gly Lys Gly
50 55 60
Pro Glu Phe Leu Phe Thr Leu Tyr Ser Ala Gly Glu Glu Lys Glu Lys
65 70 75 80
Glu Arg Leu Lys Ala Thr Leu Thr Lys Lys Glu Ser Phe Leu His Ile
85 90 95
Thr Ala Pro Lys Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Val Thr
100 105 110
Ala His Arg Gly Ser Thr Leu Gly Arg Leu Tyr Phe Gly Arg Gly Thr
115 120 125
Gln Leu Thr Val Trp Pro
130
<210> 304
<211> 133
<212> PRT
<213> 人
<400> 304
Met His Pro Gly Leu Leu Cys Trp Ala Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Leu Val Asp Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His
35 40 45
Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe
50 55 60
Ile Phe Gln Tyr Tyr Glu Glu Glu Glu Arg Gln Arg Gly Asn Phe Pro
65 70 75 80
Asp Arg Phe Ser Gly His Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn
85 90 95
Val Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Arg Gly Gly Ala Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr
115 120 125
Arg Leu Thr Val Leu
130
<210> 305
<211> 271
<212> PRT
<213> 人
<400> 305
Met Ala Lys Met Leu Glu Cys Ala Phe Ile Val Leu Trp Leu Gln Leu
1 5 10 15
Gly Trp Leu Ser Gly Glu Asp Gln Val Thr Gln Ser Pro Glu Ala Leu
20 25 30
Arg Leu Gln Glu Gly Glu Ser Ser Ser Leu Asn Cys Ser Tyr Thr Val
35 40 45
Ser Gly Leu Arg Gly Leu Phe Trp Tyr Arg Gln Asp Pro Gly Lys Gly
50 55 60
Pro Glu Phe Leu Phe Thr Leu Tyr Ser Ala Gly Glu Glu Lys Glu Lys
65 70 75 80
Glu Arg Leu Lys Ala Thr Leu Thr Lys Lys Glu Ser Phe Leu His Ile
85 90 95
Thr Ala Pro Lys Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Val Thr
100 105 110
Ala His Arg Gly Ser Thr Leu Gly Arg Leu Tyr Phe Gly Arg Gly Thr
115 120 125
Gln Leu Thr Val Trp Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 306
<211> 306
<212> PRT
<213> 人
<400> 306
Met His Pro Gly Leu Leu Cys Trp Ala Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Leu Val Asp Ala Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Arg Cys Ser Pro Lys Ser Gly His
35 40 45
Asp Thr Val Ser Trp Tyr Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe
50 55 60
Ile Phe Gln Tyr Tyr Glu Glu Glu Glu Arg Gln Arg Gly Asn Phe Pro
65 70 75 80
Asp Arg Phe Ser Gly His Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn
85 90 95
Val Asn Ala Leu Leu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Arg Arg Gly Gly Ala Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr
115 120 125
Arg Leu Thr 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> 307
<211> 6
<212> PRT
<213> 人
<400> 307
Ser Ser Asn Phe Tyr Ala
1 5
<210> 308
<211> 7
<212> PRT
<213> 人
<400> 308
Met Thr Leu Asn Gly Asp Glu
1 5
<210> 309
<211> 13
<212> PRT
<213> 人
<400> 309
Cys Ala Ser Val Gly Gly Gly Ala Asp Gly Leu Thr Phe
1 5 10
<210> 310
<211> 5
<212> PRT
<213> 人
<400> 310
Ser Gly His Thr Ala
1 5
<210> 311
<211> 6
<212> PRT
<213> 人
<400> 311
Phe Gln Gly Asn Ser Ala
1 5
<210> 312
<211> 15
<212> PRT
<213> 人
<400> 312
Cys Ala Ser Thr Trp Asp Arg Gly Ser Tyr Asn Glu Gln Phe Phe
1 5 10 15
<210> 313
<211> 134
<212> PRT
<213> 人
<400> 313
Met Ala Lys Asn Pro Leu Ala Ala Pro Leu Leu Ile Leu Trp Phe His
1 5 10 15
Leu Asp Cys Val Ser Ser Ile Leu Asn Val Glu Gln Ser Pro Gln Ser
20 25 30
Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro
35 40 45
Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu Thr Ala Lys
50 55 60
Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp Glu Lys Lys
65 70 75 80
Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr
85 90 95
Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys
100 105 110
Ala Ser Val Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys Gly Thr
115 120 125
His Leu Ile Ile Gln Pro
130
<210> 314
<211> 134
<212> PRT
<213> 人
<400> 314
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 Thr Trp Asp Arg Gly Ser Tyr Asn Glu Gln Phe Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu
130
<210> 315
<211> 271
<212> PRT
<213> 人
<400> 315
Met Ala Lys Asn Pro Leu Ala Ala Pro Leu Leu Ile Leu Trp Phe His
1 5 10 15
Leu Asp Cys Val Ser Ser Ile Leu Asn Val Glu Gln Ser Pro Gln Ser
20 25 30
Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro
35 40 45
Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu Thr Ala Lys
50 55 60
Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp Glu Lys Lys
65 70 75 80
Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr
85 90 95
Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys
100 105 110
Ala Ser Val Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys Gly Thr
115 120 125
His Leu Ile Ile Gln Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 316
<211> 307
<212> PRT
<213> 人
<400> 316
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 Thr Trp Asp Arg Gly Ser Tyr Asn Glu Gln Phe Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 317
<211> 6
<212> PRT
<213> 人
<400> 317
Asn Ser Met Phe Asp Tyr
1 5
<210> 318
<211> 7
<212> PRT
<213> 人
<400> 318
Ile Ser Ser Ile Lys Asp Lys
1 5
<210> 319
<211> 11
<212> PRT
<213> 人
<400> 319
Cys Ala Ala Asn Thr Gly Asn Gln Phe Tyr Phe
1 5 10
<210> 320
<211> 5
<212> PRT
<213> 人
<400> 320
Ser Gly His Ala Thr
1 5
<210> 321
<211> 6
<212> PRT
<213> 人
<400> 321
Phe Gln Asn Asn Gly Val
1 5
<210> 322
<211> 16
<212> PRT
<213> 人
<400> 322
Cys Ala Ser Ser His Leu Ala Gly Glu Phe Tyr Asn Glu Gln Phe Phe
1 5 10 15
<210> 323
<211> 136
<212> PRT
<213> 人
<400> 323
Met Ala Met Leu Leu Gly Ala Ser Val Leu Ile Leu Trp Leu Gln Pro
1 5 10 15
Asp Trp Val Asn Ser Gln Gln Lys Asn Asp Asp Gln Gln Val Lys Gln
20 25 30
Asn Ser Pro Ser Leu Ser Val Gln Glu Gly Arg Ile Ser Ile Leu Asn
35 40 45
Cys Asp Tyr Thr Asn Ser Met Phe Asp Tyr Phe Leu Trp Tyr Lys Lys
50 55 60
Tyr Pro Ala Glu Gly Pro Thr Phe Leu Ile Ser Ile Ser Ser Ile Lys
65 70 75 80
Asp Lys Asn Glu Asp Gly Arg Phe Thr Val Phe Leu Asn Lys Ser Ala
85 90 95
Lys His Leu Ser Leu His Ile Val Pro Ser Gln Pro Gly Asp Ser Ala
100 105 110
Val Tyr Phe Cys Ala Ala Asn Thr Gly Asn Gln Phe Tyr Phe Gly Thr
115 120 125
Gly Thr Ser Leu Thr Val Ile Pro
130 135
<210> 324
<211> 135
<212> PRT
<213> 人
<400> 324
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser His Leu Ala Gly Glu Phe Tyr Asn Glu Gln Phe Phe Gly Pro
115 120 125
Gly Thr Arg Leu Thr Val Leu
130 135
<210> 325
<211> 273
<212> PRT
<213> 人
<400> 325
Met Ala Met Leu Leu Gly Ala Ser Val Leu Ile Leu Trp Leu Gln Pro
1 5 10 15
Asp Trp Val Asn Ser Gln Gln Lys Asn Asp Asp Gln Gln Val Lys Gln
20 25 30
Asn Ser Pro Ser Leu Ser Val Gln Glu Gly Arg Ile Ser Ile Leu Asn
35 40 45
Cys Asp Tyr Thr Asn Ser Met Phe Asp Tyr Phe Leu Trp Tyr Lys Lys
50 55 60
Tyr Pro Ala Glu Gly Pro Thr Phe Leu Ile Ser Ile Ser Ser Ile Lys
65 70 75 80
Asp Lys Asn Glu Asp Gly Arg Phe Thr Val Phe Leu Asn Lys Ser Ala
85 90 95
Lys His Leu Ser Leu His Ile Val Pro Ser Gln Pro Gly Asp Ser Ala
100 105 110
Val Tyr Phe Cys Ala Ala Asn Thr Gly Asn Gln Phe Tyr Phe Gly Thr
115 120 125
Gly Thr Ser Leu Thr Val Ile Pro Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser
<210> 326
<211> 308
<212> PRT
<213> 人
<400> 326
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser His Leu Ala Gly Glu Phe Tyr Asn Glu Gln Phe Phe Gly Pro
115 120 125
Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro
130 135 140
Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys
180 185 190
Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp
225 230 235 240
Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys
290 295 300
Arg Lys Asn Ser
305
<210> 327
<211> 6
<212> PRT
<213> 人
<400> 327
Thr Ser Gly Phe Tyr Gly
1 5
<210> 328
<211> 6
<212> PRT
<213> 人
<400> 328
Asn Ala Leu Asp Gly Leu
1 5
<210> 329
<211> 11
<212> PRT
<213> 人
<400> 329
Cys Ala Phe Ala Tyr Gly Gln Asn Phe Val Phe
1 5 10
<210> 330
<211> 5
<212> PRT
<213> 人
<400> 330
Ser Gly Asp Leu Ser
1 5
<210> 331
<211> 6
<212> PRT
<213> 人
<400> 331
Tyr Tyr Asn Gly Glu Glu
1 5
<210> 332
<211> 15
<212> PRT
<213> 人
<400> 332
Cys Ala Ser Ser Pro Leu Gly Asp Ser Gly Asn Thr Ile Tyr Phe
1 5 10 15
<210> 333
<211> 125
<212> PRT
<213> 人
<400> 333
Met Ala Gly Ala Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Ala Gly Gln Ser Leu Glu Gln Pro Ser Glu Val Thr Ala Val Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Tyr Gly
35 40 45
Leu Ser Trp Tyr Gln Gln His Asp Gly Gly Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Ala Leu Asp Gly Leu Glu Glu Thr Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Asp Ser Tyr Gly Tyr Leu Leu Leu Gln Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Phe Cys Ala Phe Ala Tyr Gly Gln Asn
100 105 110
Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro
115 120 125
<210> 334
<211> 133
<212> PRT
<213> 人
<400> 334
Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Pro Leu Gly Asp Ser Gly Asn Thr Ile Tyr Phe Gly Glu Gly Ser
115 120 125
Trp Leu Thr Val Val
130
<210> 335
<211> 262
<212> PRT
<213> 人
<400> 335
Met Ala Gly Ala Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Ala Gly Gln Ser Leu Glu Gln Pro Ser Glu Val Thr Ala Val Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Tyr Gly
35 40 45
Leu Ser Trp Tyr Gln Gln His Asp Gly Gly Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Ala Leu Asp Gly Leu Glu Glu Thr Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Asp Ser Tyr Gly Tyr Leu Leu Leu Gln Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Phe Cys Ala Phe Ala Tyr Gly Gln Asn
100 105 110
Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro Asn Ile Gln
115 120 125
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
130 135 140
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
145 150 155 160
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
165 170 175
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
180 185 190
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
195 200 205
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
210 215 220
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
225 230 235 240
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
245 250 255
Leu Arg Leu Trp Ser Ser
260
<210> 336
<211> 306
<212> PRT
<213> 人
<400> 336
Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Pro Leu Gly Asp Ser Gly Asn Thr Ile Tyr Phe Gly Glu Gly Ser
115 120 125
Trp Leu Thr Val Val 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> 337
<211> 5
<212> PRT
<213> 人
<400> 337
Thr Ser Ile Asn Asn
1 5
<210> 338
<211> 7
<212> PRT
<213> 人
<400> 338
Ile Arg Ser Asn Glu Arg Glu
1 5
<210> 339
<211> 12
<212> PRT
<213> 人
<400> 339
Cys Ala Thr Asp Ala Trp Asn Asn Asp Met Arg Phe
1 5 10
<210> 340
<211> 5
<212> PRT
<213> 人
<400> 340
Met Asn His Asn Ser
1 5
<210> 341
<211> 6
<212> PRT
<213> 人
<400> 341
Ser Ala Ser Glu Gly Thr
1 5
<210> 342
<211> 14
<212> PRT
<213> 人
<400> 342
Cys Ala Ser Ser Glu Ser Gln Gly Asn Thr Glu Ala Phe Phe
1 5 10
<210> 343
<211> 130
<212> PRT
<213> 人
<400> 343
Met Ala Thr Leu Leu Gly Val Ser Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp Pro Gln Ala Leu Ser
20 25 30
Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys Ser Tyr Lys Thr Ser
35 40 45
Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser Gly Arg Gly Leu Val
50 55 60
His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu Lys His Ser Gly Arg
65 70 75 80
Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser Ser Ser Leu Leu Ile
85 90 95
Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr Phe Cys Ala Thr Asp
100 105 110
Ala Trp Asn Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val
115 120 125
Lys Pro
130
<210> 344
<211> 132
<212> PRT
<213> 人
<400> 344
Met His Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Glu Ser Gln Gly Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val
130
<210> 345
<211> 267
<212> PRT
<213> 人
<400> 345
Met Ala Thr Leu Leu Gly Val Ser Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp Pro Gln Ala Leu Ser
20 25 30
Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys Ser Tyr Lys Thr Ser
35 40 45
Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser Gly Arg Gly Leu Val
50 55 60
His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu Lys His Ser Gly Arg
65 70 75 80
Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser Ser Ser Leu Leu Ile
85 90 95
Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr Phe Cys Ala Thr Asp
100 105 110
Ala Trp Asn Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val
115 120 125
Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 346
<211> 305
<212> PRT
<213> 人
<400> 346
Met His Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Glu Ser Gln Gly Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val 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> 347
<211> 6
<212> PRT
<213> 人
<400> 347
Val Ser Pro Phe Ser Asn
1 5
<210> 348
<211> 7
<212> PRT
<213> 人
<400> 348
Met Thr Phe Ser Glu Asn Thr
1 5
<210> 349
<211> 10
<212> PRT
<213> 人
<400> 349
Cys Val Val Ser Ser Tyr Lys Ile Ile Phe
1 5 10
<210> 350
<211> 5
<212> PRT
<213> 人
<400> 350
Ser Gly His Thr Ala
1 5
<210> 351
<211> 6
<212> PRT
<213> 人
<400> 351
Phe Gln Gly Asn Ser Ala
1 5
<210> 352
<211> 15
<212> PRT
<213> 人
<400> 352
Cys Ala Ser Ser Pro Ile Gln Gly Glu Asn Ser Pro Leu His Phe
1 5 10 15
<210> 353
<211> 130
<212> PRT
<213> 人
<400> 353
Met Ala Lys His Leu Thr Thr Phe Leu Val Ile Leu Trp Leu Tyr Phe
1 5 10 15
Tyr Arg Gly Asn Gly Lys Asn Gln Val Glu Gln Ser Pro Gln Ser Leu
20 25 30
Ile Ile Leu Glu Gly Lys Asn Cys Thr Leu Gln Cys Asn Tyr Thr Val
35 40 45
Ser Pro Phe Ser Asn Leu Arg Trp Tyr Lys Gln Asp Thr Gly Arg Gly
50 55 60
Pro Val Ser Leu Thr Ile Met Thr Phe Ser Glu Asn Thr Lys Ser Asn
65 70 75 80
Gly Arg Tyr Thr Ala Thr Leu Asp Ala Asp Thr Lys Gln Ser Ser Leu
85 90 95
His Ile Thr Ala Ser Gln Leu Ser Asp Ser Ala Ser Tyr Ile Cys Val
100 105 110
Val Ser Ser Tyr Lys Ile Ile Phe Gly Thr Gly Thr Arg Leu His Val
115 120 125
Phe Pro
130
<210> 354
<211> 134
<212> PRT
<213> 人
<400> 354
Met His Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Tyr 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 Arg 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 Glu 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 Pro Ile Gln Gly Glu Asn Ser Pro Leu His Phe Gly Asn Gly
115 120 125
Thr Arg Leu Thr Val Thr
130
<210> 355
<211> 267
<212> PRT
<213> 人
<400> 355
Met Ala Lys His Leu Thr Thr Phe Leu Val Ile Leu Trp Leu Tyr Phe
1 5 10 15
Tyr Arg Gly Asn Gly Lys Asn Gln Val Glu Gln Ser Pro Gln Ser Leu
20 25 30
Ile Ile Leu Glu Gly Lys Asn Cys Thr Leu Gln Cys Asn Tyr Thr Val
35 40 45
Ser Pro Phe Ser Asn Leu Arg Trp Tyr Lys Gln Asp Thr Gly Arg Gly
50 55 60
Pro Val Ser Leu Thr Ile Met Thr Phe Ser Glu Asn Thr Lys Ser Asn
65 70 75 80
Gly Arg Tyr Thr Ala Thr Leu Asp Ala Asp Thr Lys Gln Ser Ser Leu
85 90 95
His Ile Thr Ala Ser Gln Leu Ser Asp Ser Ala Ser Tyr Ile Cys Val
100 105 110
Val Ser Ser Tyr Lys Ile Ile Phe Gly Thr Gly Thr Arg Leu His Val
115 120 125
Phe Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 356
<211> 307
<212> PRT
<213> 人
<400> 356
Met His Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Tyr 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 Arg 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 Glu 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 Pro Ile Gln Gly Glu Asn Ser Pro Leu His Phe Gly Asn Gly
115 120 125
Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 357
<211> 6
<212> PRT
<213> 人
<400> 357
Val Ser Pro Phe Ser Asn
1 5
<210> 358
<211> 7
<212> PRT
<213> 人
<400> 358
Met Thr Phe Ser Glu Asn Thr
1 5
<210> 359
<211> 11
<212> PRT
<213> 人
<400> 359
Ile Cys Val Val Ser Ser Tyr Lys Leu Ile Phe
1 5 10
<210> 360
<211> 5
<212> PRT
<213> 人
<400> 360
Ser Gly His Thr Ala
1 5
<210> 361
<211> 6
<212> PRT
<213> 人
<400> 361
Phe Gln Gly Asn Ser Ala
1 5
<210> 362
<211> 15
<212> PRT
<213> 人
<400> 362
Cys Ala Ser Ser Pro Ile Gln Gly Glu Asn Ser Pro Leu His Phe
1 5 10 15
<210> 363
<211> 130
<212> PRT
<213> 人
<400> 363
Met Ala Lys His Leu Thr Thr Phe Leu Val Ile Leu Trp Leu Tyr Phe
1 5 10 15
Tyr Arg Gly Asn Gly Lys Asn Gln Val Glu Gln Ser Pro Gln Ser Leu
20 25 30
Ile Ile Leu Glu Gly Lys Asn Cys Thr Leu Gln Cys Asn Tyr Thr Val
35 40 45
Ser Pro Phe Ser Asn Leu Arg Trp Tyr Lys Gln Asp Thr Gly Arg Gly
50 55 60
Pro Val Ser Leu Thr Ile Met Thr Phe Ser Glu Asn Thr Lys Ser Asn
65 70 75 80
Gly Arg Tyr Thr Ala Thr Leu Asp Ala Asp Thr Lys Gln Ser Ser Leu
85 90 95
His Ile Thr Ala Ser Gln Leu Ser Asp Ser Ala Ser Tyr Ile Cys Val
100 105 110
Val Ser Ser Tyr Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln Val
115 120 125
Phe Pro
130
<210> 364
<211> 134
<212> PRT
<213> 人
<400> 364
Met His Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Tyr 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 Arg 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 Glu 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 Pro Ile Gln Gly Glu Asn Ser Pro Leu His Phe Gly Asn Gly
115 120 125
Thr Arg Leu Thr Val Thr
130
<210> 365
<211> 267
<212> PRT
<213> 人
<400> 365
Met Ala Lys His Leu Thr Thr Phe Leu Val Ile Leu Trp Leu Tyr Phe
1 5 10 15
Tyr Arg Gly Asn Gly Lys Asn Gln Val Glu Gln Ser Pro Gln Ser Leu
20 25 30
Ile Ile Leu Glu Gly Lys Asn Cys Thr Leu Gln Cys Asn Tyr Thr Val
35 40 45
Ser Pro Phe Ser Asn Leu Arg Trp Tyr Lys Gln Asp Thr Gly Arg Gly
50 55 60
Pro Val Ser Leu Thr Ile Met Thr Phe Ser Glu Asn Thr Lys Ser Asn
65 70 75 80
Gly Arg Tyr Thr Ala Thr Leu Asp Ala Asp Thr Lys Gln Ser Ser Leu
85 90 95
His Ile Thr Ala Ser Gln Leu Ser Asp Ser Ala Ser Tyr Ile Cys Val
100 105 110
Val Ser Ser Tyr Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln Val
115 120 125
Phe Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 366
<211> 307
<212> PRT
<213> 人
<400> 366
Met His Thr Arg Leu Leu Phe Trp Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Tyr 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 Arg 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 Glu 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 Pro Ile Gln Gly Glu Asn Ser Pro Leu His Phe Gly Asn Gly
115 120 125
Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 367
<211> 6
<212> PRT
<213> 人
<400> 367
Ser Ser Val Ser Val Tyr
1 5
<210> 368
<211> 8
<212> PRT
<213> 人
<400> 368
Tyr Leu Ser Gly Ser Thr Leu Val
1 5
<210> 369
<211> 14
<212> PRT
<213> 人
<400> 369
Cys Ala Val Ser Lys Gly Thr Gly Ala Gln Lys Leu Val Phe
1 5 10
<210> 370
<211> 5
<212> PRT
<213> 人
<400> 370
Leu Asn His Asp Ala
1 5
<210> 371
<211> 6
<212> PRT
<213> 人
<400> 371
Ser Gln Ile Val Asn Asp
1 5
<210> 372
<211> 7
<212> PRT
<213> 人
<400> 372
Cys Ala Ser Glu Ala Phe Phe
1 5
<210> 373
<211> 133
<212> PRT
<213> 人
<400> 373
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Ser Lys Gly Thr Gly Ala Gln Lys Leu Val Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Ile Asn Pro
130
<210> 374
<211> 125
<212> PRT
<213> 人
<400> 374
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Ala
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Ile
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Ser Tyr Leu Cys Ala Ser
100 105 110
Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val
115 120 125
<210> 375
<211> 270
<212> PRT
<213> 人
<400> 375
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Ser Lys Gly Thr Gly Ala Gln Lys Leu Val Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Ile 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> 376
<211> 298
<212> PRT
<213> 人
<400> 376
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Ala
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Ile
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Ser Tyr Leu Cys Ala Ser
100 105 110
Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu
115 120 125
Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala
130 135 140
Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly
145 150 155 160
Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu
165 170 175
Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn
180 185 190
Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp
195 200 205
His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu
210 215 220
Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln
225 230 235 240
Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser
245 250 255
Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile
260 265 270
Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val
275 280 285
Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295
<210> 377
<211> 7
<212> PRT
<213> 人
<400> 377
Thr Ile Ser Gly Thr Asp Tyr
1 5
<210> 378
<211> 5
<212> PRT
<213> 人
<400> 378
Gly Leu Thr Ser Asn
1 5
<210> 379
<211> 14
<212> PRT
<213> 人
<400> 379
Cys Ile Leu Ala Ser Gly Ala Gly Ser Tyr Gln Leu Thr Phe
1 5 10
<210> 380
<211> 5
<212> PRT
<213> 人
<400> 380
Leu Gly His Asp Thr
1 5
<210> 381
<211> 6
<212> PRT
<213> 人
<400> 381
Tyr Asn Asn Lys Glu Leu
1 5
<210> 382
<211> 14
<212> PRT
<213> 人
<400> 382
Cys Ala Ser Arg Thr Ile Gly Tyr Asn Thr Glu Ala Phe Phe
1 5 10
<210> 383
<211> 128
<212> PRT
<213> 人
<400> 383
Met Ala Leu Val Thr Ser Ile Thr Val Leu Leu Ser Leu Gly Ile Met
1 5 10 15
Gly Asp Ala Lys Thr Thr Gln Pro Asn Ser Met Glu Ser Asn Glu Glu
20 25 30
Glu Pro Val His Leu Pro Cys Asn His Ser Thr Ile Ser Gly Thr Asp
35 40 45
Tyr Ile His Trp Tyr Arg Gln Leu Pro Ser Gln Gly Pro Glu Tyr Val
50 55 60
Ile His Gly Leu Thr Ser Asn Val Asn Asn Arg Met Ala Ser Leu Ala
65 70 75 80
Ile Ala Glu Asp Arg Lys Ser Ser Thr Leu Ile Leu His Arg Ala Thr
85 90 95
Leu Arg Asp Ala Ala Val Tyr Tyr Cys Ile Leu Ala Ser Gly Ala Gly
100 105 110
Ser Tyr Gln Leu Thr Phe Gly Lys Gly Thr Lys Leu Ser Val Ile Pro
115 120 125
<210> 384
<211> 132
<212> PRT
<213> 人
<400> 384
Met His Cys Arg Leu Leu Cys Cys Val Val Phe Cys Leu Leu Gln Ala
1 5 10 15
Gly Pro Leu Asp Thr Ala Val Ser Gln Thr Pro Lys Tyr Leu Val Thr
20 25 30
Gln Met Gly Asn Asp Lys Ser Ile Lys Cys Glu Gln Asn Leu Gly His
35 40 45
Asp Thr Met Tyr Trp Tyr Lys Gln Asp Ser Lys Lys Phe Leu Lys Ile
50 55 60
Met Phe Ser Tyr Asn Asn Lys Glu Leu Ile Ile Asn Glu Thr Val Pro
65 70 75 80
Asn Arg Phe Ser Pro Lys Ser Pro Asp Lys Ala His Leu Asn Leu His
85 90 95
Ile Asn Ser Leu Glu Leu Gly Asp Ser Ala Val Tyr Phe Cys Ala Ser
100 105 110
Arg Thr Ile Gly Tyr Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val
130
<210> 385
<211> 265
<212> PRT
<213> 人
<400> 385
Met Ala Leu Val Thr Ser Ile Thr Val Leu Leu Ser Leu Gly Ile Met
1 5 10 15
Gly Asp Ala Lys Thr Thr Gln Pro Asn Ser Met Glu Ser Asn Glu Glu
20 25 30
Glu Pro Val His Leu Pro Cys Asn His Ser Thr Ile Ser Gly Thr Asp
35 40 45
Tyr Ile His Trp Tyr Arg Gln Leu Pro Ser Gln Gly Pro Glu Tyr Val
50 55 60
Ile His Gly Leu Thr Ser Asn Val Asn Asn Arg Met Ala Ser Leu Ala
65 70 75 80
Ile Ala Glu Asp Arg Lys Ser Ser Thr Leu Ile Leu His Arg Ala Thr
85 90 95
Leu Arg Asp Ala Ala Val Tyr Tyr Cys Ile Leu Ala Ser Gly Ala Gly
100 105 110
Ser Tyr Gln Leu Thr Phe Gly Lys Gly Thr Lys Leu Ser Val Ile Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 386
<211> 305
<212> PRT
<213> 人
<400> 386
Met His Cys Arg Leu Leu Cys Cys Val Val Phe Cys Leu Leu Gln Ala
1 5 10 15
Gly Pro Leu Asp Thr Ala Val Ser Gln Thr Pro Lys Tyr Leu Val Thr
20 25 30
Gln Met Gly Asn Asp Lys Ser Ile Lys Cys Glu Gln Asn Leu Gly His
35 40 45
Asp Thr Met Tyr Trp Tyr Lys Gln Asp Ser Lys Lys Phe Leu Lys Ile
50 55 60
Met Phe Ser Tyr Asn Asn Lys Glu Leu Ile Ile Asn Glu Thr Val Pro
65 70 75 80
Asn Arg Phe Ser Pro Lys Ser Pro Asp Lys Ala His Leu Asn Leu His
85 90 95
Ile Asn Ser Leu Glu Leu Gly Asp Ser Ala Val Tyr Phe Cys Ala Ser
100 105 110
Arg Thr Ile Gly Tyr Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val 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> 387
<211> 5
<212> PRT
<213> 人
<400> 387
Val Gly Ile Ser Ala
1 5
<210> 388
<211> 5
<212> PRT
<213> 人
<400> 388
Leu Ser Ser Gly Lys
1 5
<210> 389
<211> 13
<212> PRT
<213> 人
<400> 389
Cys Ala Ala Leu Ser Tyr Asn Thr Asp Lys Leu Ile Phe
1 5 10
<210> 390
<211> 5
<212> PRT
<213> 人
<400> 390
Ser Gly His Thr Ala
1 5
<210> 391
<211> 6
<212> PRT
<213> 人
<400> 391
Phe Gln Gly Thr Gly Ala
1 5
<210> 392
<211> 15
<212> PRT
<213> 人
<400> 392
Cys Ala Ser Ser Leu Ser Gly Leu Leu Gln Glu Thr Gln Tyr Phe
1 5 10 15
<210> 393
<211> 131
<212> PRT
<213> 人
<400> 393
Met Ala Lys Ile Arg Gln Phe Leu Leu Ala Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Cys Val Ser Ala Ala Lys Asn Glu Val Glu Gln Ser Pro Gln Asn
20 25 30
Leu Thr Ala Gln Glu Gly Glu Phe Ile Thr Ile Asn Cys Ser Tyr Ser
35 40 45
Val Gly Ile Ser Ala Leu His Trp Leu Gln Gln His Pro Gly Gly Gly
50 55 60
Ile Val Ser Leu Phe Met Leu Ser Ser Gly Lys Lys Lys His Gly Arg
65 70 75 80
Leu Ile Ala Thr Ile Asn Ile Gln Glu Lys His Ser Ser Leu His Ile
85 90 95
Thr Ala Ser His Pro Arg Asp Ser Ala Val Tyr Ile Cys Ala Ala Leu
100 105 110
Ser Tyr Asn Thr Asp Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln
115 120 125
Val Phe Pro
130
<210> 394
<211> 134
<212> PRT
<213> 人
<400> 394
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 Leu Ser Gly Leu Leu Gln Glu Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Leu Val Leu
130
<210> 395
<211> 268
<212> PRT
<213> 人
<400> 395
Met Ala Lys Ile Arg Gln Phe Leu Leu Ala Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Cys Val Ser Ala Ala Lys Asn Glu Val Glu Gln Ser Pro Gln Asn
20 25 30
Leu Thr Ala Gln Glu Gly Glu Phe Ile Thr Ile Asn Cys Ser Tyr Ser
35 40 45
Val Gly Ile Ser Ala Leu His Trp Leu Gln Gln His Pro Gly Gly Gly
50 55 60
Ile Val Ser Leu Phe Met Leu Ser Ser Gly Lys Lys Lys His Gly Arg
65 70 75 80
Leu Ile Ala Thr Ile Asn Ile Gln Glu Lys His Ser Ser Leu His Ile
85 90 95
Thr Ala Ser His Pro Arg Asp Ser Ala Val Tyr Ile Cys Ala Ala Leu
100 105 110
Ser Tyr Asn Thr Asp Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln
115 120 125
Val Phe 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> 396
<211> 307
<212> PRT
<213> 人
<400> 396
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 Leu Ser Gly Leu Leu Gln Glu Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 397
<211> 6
<212> PRT
<213> 人
<400> 397
Ala Thr Gly Tyr Pro Ser
1 5
<210> 398
<211> 7
<212> PRT
<213> 人
<400> 398
Ala Thr Lys Ala Asp Asp Lys
1 5
<210> 399
<211> 16
<212> PRT
<213> 人
<400> 399
Cys Ala Leu Ser His Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe
1 5 10 15
<210> 400
<211> 5
<212> PRT
<213> 人
<400> 400
Ser Gly His Ala Thr
1 5
<210> 401
<211> 6
<212> PRT
<213> 人
<400> 401
Phe Gln Asn Asn Gly Val
1 5
<210> 402
<211> 15
<212> PRT
<213> 人
<400> 402
Cys Ala Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe
1 5 10 15
<210> 403
<211> 134
<212> PRT
<213> 人
<400> 403
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
His Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro
130
<210> 404
<211> 134
<212> PRT
<213> 人
<400> 404
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu
130
<210> 405
<211> 271
<212> PRT
<213> 人
<400> 405
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
His Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 406
<211> 307
<212> PRT
<213> 人
<400> 406
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 407
<211> 6
<212> PRT
<213> 人
<400> 407
Ala Thr Gly Tyr Pro Ser
1 5
<210> 408
<211> 7
<212> PRT
<213> 人
<400> 408
Ala Thr Lys Ala Asp Asp Lys
1 5
<210> 409
<211> 16
<212> PRT
<213> 人
<400> 409
Cys Ala Leu Ser Gln Thr Gly Ser Ser Lys Thr Gly Lys Leu Ile Phe
1 5 10 15
<210> 410
<211> 5
<212> PRT
<213> 人
<400> 410
Ser Gly His Ala Thr
1 5
<210> 411
<211> 6
<212> PRT
<213> 人
<400> 411
Phe Gln Asn Asn Gly Val
1 5
<210> 412
<211> 15
<212> PRT
<213> 人
<400> 412
Cys Ala Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe
1 5 10 15
<210> 413
<211> 134
<212> PRT
<213> 人
<400> 413
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Gln Thr Gly Ser Ser Lys Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro
130
<210> 414
<211> 134
<212> PRT
<213> 人
<400> 414
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu
130
<210> 415
<211> 271
<212> PRT
<213> 人
<400> 415
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Gln Thr Gly Ser Ser Lys Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 416
<211> 307
<212> PRT
<213> 人
<400> 416
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 417
<211> 6
<212> PRT
<213> 人
<400> 417
Ala Thr Gly Tyr Pro Ser
1 5
<210> 418
<211> 7
<212> PRT
<213> 人
<400> 418
Ala Thr Lys Ala Asp Asp Lys
1 5
<210> 419
<211> 16
<212> PRT
<213> 人
<400> 419
Cys Ala Leu Ser Gln Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe
1 5 10 15
<210> 420
<211> 5
<212> PRT
<213> 人
<400> 420
Ser Gly His Ala Thr
1 5
<210> 421
<211> 6
<212> PRT
<213> 人
<400> 421
Phe Gln Asn Asn Gly Val
1 5
<210> 422
<211> 15
<212> PRT
<213> 人
<400> 422
Cys Ala Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe
1 5 10 15
<210> 423
<211> 134
<212> PRT
<213> 人
<400> 423
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Gln Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro
130
<210> 424
<211> 134
<212> PRT
<213> 人
<400> 424
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu
130
<210> 425
<211> 271
<212> PRT
<213> 人
<400> 425
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Gln Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 426
<211> 307
<212> PRT
<213> 人
<400> 426
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 427
<211> 6
<212> PRT
<213> 人
<400> 427
Ala Thr Gly Tyr Pro Ser
1 5
<210> 428
<211> 7
<212> PRT
<213> 人
<400> 428
Ala Thr Lys Ala Asp Asp Lys
1 5
<210> 429
<211> 16
<212> PRT
<213> 人
<400> 429
Cys Ala Leu Ser Thr Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe
1 5 10 15
<210> 430
<211> 5
<212> PRT
<213> 人
<400> 430
Ser Gly His Ala Thr
1 5
<210> 431
<211> 6
<212> PRT
<213> 人
<400> 431
Phe Gln Asn Asn Gly Val
1 5
<210> 432
<211> 15
<212> PRT
<213> 人
<400> 432
Cys Ala Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe
1 5 10 15
<210> 433
<211> 134
<212> PRT
<213> 人
<400> 433
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Thr Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Thr Leu Gln Val Lys Pro
130
<210> 434
<211> 134
<212> PRT
<213> 人
<400> 434
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu
130
<210> 435
<211> 271
<212> PRT
<213> 人
<400> 435
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Thr Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Thr Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 436
<211> 307
<212> PRT
<213> 人
<400> 436
Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Thr Gly Gly Gly Arg His Gln Pro Gln His Phe Gly Asp Gly
115 120 125
Thr Arg Leu Ser Ile Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser
305
<210> 437
<211> 6
<212> PRT
<213> 人
<400> 437
Asp Arg Gly Ser Gln Ser
1 5
<210> 438
<211> 6
<212> PRT
<213> 人
<400> 438
Ile Tyr Ser Asn Gly Asp
1 5
<210> 439
<211> 14
<212> PRT
<213> 人
<400> 439
Cys Ala Val Thr Leu Cys Gly Gly Tyr Asn Lys Leu Ile Phe
1 5 10
<210> 440
<211> 5
<212> PRT
<213> 人
<400> 440
Leu Asn His Asp Ala
1 5
<210> 441
<211> 6
<212> PRT
<213> 人
<400> 441
Ser Gln Ile Val Asn Asp
1 5
<210> 442
<211> 12
<212> PRT
<213> 人
<400> 442
Cys Ala Ser Ser Ser Arg Asp Tyr Glu Gln Tyr Phe
1 5 10
<210> 443
<211> 133
<212> PRT
<213> 人
<400> 443
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Thr Leu Cys Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg
115 120 125
Leu Ala Val His Pro
130
<210> 444
<211> 130
<212> PRT
<213> 人
<400> 444
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Val
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Thr
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Phe Tyr Leu Cys Ala Ser
100 105 110
Ser Ser Arg Asp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Thr
130
<210> 445
<211> 270
<212> PRT
<213> 人
<400> 445
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Thr Leu Cys Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg
115 120 125
Leu Ala Val His 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> 446
<211> 303
<212> PRT
<213> 人
<400> 446
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Val
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Thr
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Phe Tyr Leu Cys Ala Ser
100 105 110
Ser Ser Arg Asp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Thr Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 447
<211> 6
<212> PRT
<213> 人
<400> 447
Asp Arg Gly Ser Gln Ser
1 5
<210> 448
<211> 6
<212> PRT
<213> 人
<400> 448
Ile Tyr Ser Asn Gly Asp
1 5
<210> 449
<211> 14
<212> PRT
<213> 人
<400> 449
Cys Ala Val Thr Leu Ser Gly Gly Tyr Asn Lys Leu Ile Phe
1 5 10
<210> 450
<211> 5
<212> PRT
<213> 人
<400> 450
Leu Asn His Asp Ala
1 5
<210> 451
<211> 6
<212> PRT
<213> 人
<400> 451
Ser Gln Ile Val Asn Asp
1 5
<210> 452
<211> 12
<212> PRT
<213> 人
<400> 452
Cys Ala Ser Ser Ser Arg Asp Tyr Glu Gln Tyr Phe
1 5 10
<210> 453
<211> 133
<212> PRT
<213> 人
<400> 453
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Thr Leu Ser Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg
115 120 125
Leu Ala Val His Pro
130
<210> 454
<211> 130
<212> PRT
<213> 人
<400> 454
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Val
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Thr
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Phe Tyr Leu Cys Ala Ser
100 105 110
Ser Ser Arg Asp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Thr
130
<210> 455
<211> 270
<212> PRT
<213> 人
<400> 455
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Thr Leu Ser Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg
115 120 125
Leu Ala Val His 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> 456
<211> 303
<212> PRT
<213> 人
<400> 456
Met His Asn Gln Val Leu Cys Cys Val Val Leu Cys Phe Leu Gly Ala
1 5 10 15
Asn Thr Val Asp Gly Gly Ile Thr Gln Ser Pro Lys Tyr Leu Phe Arg
20 25 30
Lys Glu Gly Gln Asn Val Thr Leu Ser Cys Glu Gln Asn Leu Asn His
35 40 45
Asp Ala Met Tyr Trp Tyr Arg Gln Asp Pro Gly Gln Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Gln Ile Val Asn Asp Phe Gln Lys Gly Asp Ile Val
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Ser Phe Pro Leu Thr
85 90 95
Val Thr Ser Ala Gln Lys Asn Pro Thr Ala Phe Tyr Leu Cys Ala Ser
100 105 110
Ser Ser Arg Asp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Thr Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
130 135 140
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
180 185 190
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
195 200 205
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
210 215 220
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
225 230 235 240
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
245 250 255
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
260 265 270
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
275 280 285
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
290 295 300
<210> 457
<211> 6
<212> PRT
<213> 人
<400> 457
Asp Arg Gly Ser Gln Ser
1 5
<210> 458
<211> 6
<212> PRT
<213> 人
<400> 458
Ile Tyr Ser Asn Gly Asp
1 5
<210> 459
<211> 12
<212> PRT
<213> 人
<400> 459
Cys Ala Val Asn Asp Ala Gly Asn Met Leu Thr Phe
1 5 10
<210> 460
<211> 6
<212> PRT
<213> 人
<400> 460
Asp Phe Gln Ala Thr Thr
1 5
<210> 461
<211> 7
<212> PRT
<213> 人
<400> 461
Ser Asn Glu Gly Ser Lys Ala
1 5
<210> 462
<211> 13
<212> PRT
<213> 人
<400> 462
Cys Ser Ala Ala Gly Gln Ala Asn Thr Glu Ala Phe Phe
1 5 10
<210> 463
<211> 131
<212> PRT
<213> 人
<400> 463
Met His Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Asn Asp Ala Gly Asn Met Leu Thr Phe Gly Gly Gly Thr Arg Leu Met
115 120 125
Val Lys Pro
130
<210> 464
<211> 140
<212> PRT
<213> 人
<400> 464
Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ala Gly Gln Ala Asn Thr Glu
115 120 125
Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val
130 135 140
<210> 465
<211> 268
<212> PRT
<213> 人
<400> 465
Met His Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Asn Asp Ala Gly Asn Met Leu Thr Phe Gly Gly Gly Thr Arg Leu Met
115 120 125
Val Lys 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> 466
<211> 313
<212> PRT
<213> 人
<400> 466
Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ala Gly Gln Ala Asn Thr Glu
115 120 125
Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg
130 135 140
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
145 150 155 160
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
165 170 175
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
180 185 190
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
195 200 205
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
210 215 220
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
225 230 235 240
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
245 250 255
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
260 265 270
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
275 280 285
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
290 295 300
Met Ala Met Val Lys Arg Lys Asn Ser
305 310
<210> 467
<211> 6
<212> PRT
<213> 人
<400> 467
Asp Ser Ala Ser Asn Tyr
1 5
<210> 468
<211> 7
<212> PRT
<213> 人
<400> 468
Ile Arg Ser Asn Val Gly Glu
1 5
<210> 469
<211> 18
<212> PRT
<213> 人
<400> 469
Cys Ala Ala Ser Lys Ser Ala Ile Met Val Val Leu Gln Thr Ser Ser
1 5 10 15
Ser Leu
<210> 470
<211> 5
<212> PRT
<213> 人
<400> 470
Met Asn His Glu Tyr
1 5
<210> 471
<211> 6
<212> PRT
<213> 人
<400> 471
Ser Met Asn Val Glu Val
1 5
<210> 472
<211> 14
<212> PRT
<213> 人
<400> 472
Cys Ala Ser Ser Ile Gln Gln Gly Ala Asp Thr Gln Tyr Phe
1 5 10
<210> 473
<211> 137
<212> PRT
<213> 人
<400> 473
Met Ala Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala Ser
100 105 110
Lys Ser Ala Ile Met Val Val Leu Gln Thr Ser Ser Ser Leu Glu Leu
115 120 125
Ala Leu Cys Leu Leu Ser Ser Gln Val
130 135
<210> 474
<211> 132
<212> PRT
<213> 人
<400> 474
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 Ile Gln Gln Gly Ala Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu
130
<210> 475
<211> 274
<212> PRT
<213> 人
<400> 475
Met Ala Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala Ser
100 105 110
Lys Ser Ala Ile Met Val Val Leu Gln Thr Ser Ser Ser Leu Glu Leu
115 120 125
Ala Leu Cys Leu Leu Ser Ser Gln Val Asn Ile Gln Asn Pro Glu Pro
130 135 140
Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys
145 150 155 160
Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu
165 170 175
Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met
180 185 190
Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe
195 200 205
Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser
210 215 220
Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu
245 250 255
Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp
260 265 270
Ser Ser
<210> 476
<211> 305
<212> PRT
<213> 人
<400> 476
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 Ile Gln Gln Gly Ala 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> 477
<211> 6
<212> PRT
<213> 人
<400> 477
Asp Arg Gly Ser Gln Ser
1 5
<210> 478
<211> 6
<212> PRT
<213> 人
<400> 478
Ile Tyr Ser Asn Gly Asp
1 5
<210> 479
<211> 14
<212> PRT
<213> 人
<400> 479
Cys Ala Trp Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe
1 5 10
<210> 480
<211> 5
<212> PRT
<213> 人
<400> 480
Met Asn His Glu Tyr
1 5
<210> 481
<211> 6
<212> PRT
<213> 人
<400> 481
Ser Val Gly Glu Gly Thr
1 5
<210> 482
<211> 15
<212> PRT
<213> 人
<400> 482
Cys Ala Ser Ser Tyr Ser Gln Ala Trp Gly Gln Pro Gln His Phe
1 5 10 15
<210> 483
<211> 133
<212> PRT
<213> 人
<400> 483
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Trp
100 105 110
Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly Thr Leu
115 120 125
Leu Thr Val Asn Pro
130
<210> 484
<211> 133
<212> PRT
<213> 人
<400> 484
Met His Leu Gly Leu Leu Cys Cys Gly Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro
65 70 75 80
Asp Gly Tyr Asn Val Ser Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Ser Gln Ala Trp Gly Gln Pro Gln His Phe Gly Asp Gly Thr
115 120 125
Arg Leu Ser Ile Leu
130
<210> 485
<211> 270
<212> PRT
<213> 人
<400> 485
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Trp
100 105 110
Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly Thr Leu
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> 486
<211> 306
<212> PRT
<213> 人
<400> 486
Met His Leu Gly Leu Leu Cys Cys Gly Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro
65 70 75 80
Asp Gly Tyr Asn Val Ser Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Tyr Ser Gln Ala Trp Gly Gln Pro Gln His Phe Gly Asp Gly Thr
115 120 125
Arg Leu Ser Ile 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> 487
<211> 6
<212> PRT
<213> 人
<400> 487
Ser Ser Asn Phe Tyr Ala
1 5
<210> 488
<211> 7
<212> PRT
<213> 人
<400> 488
Met Thr Leu Asn Gly Asp Glu
1 5
<210> 489
<211> 13
<212> PRT
<213> 人
<400> 489
Cys Ala Leu Ile Thr Gly Gly Gly Asn Lys Leu Thr Phe
1 5 10
<210> 490
<211> 5
<212> PRT
<213> 人
<400> 490
Met Asn His Glu Tyr
1 5
<210> 491
<211> 6
<212> PRT
<213> 人
<400> 491
Ser Val Gly Glu Gly Thr
1 5
<210> 492
<211> 14
<212> PRT
<213> 人
<400> 492
Cys Ala Ser Arg Leu Gln Gly Trp Asn Ser Pro Leu His Phe
1 5 10
<210> 493
<211> 134
<212> PRT
<213> 人
<400> 493
Met Ala Lys Asn Pro Leu Ala Ala Pro Leu Leu Ile Leu Trp Phe His
1 5 10 15
Leu Asp Cys Val Ser Ser Ile Leu Asn Val Glu Gln Ser Pro Gln Ser
20 25 30
Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro
35 40 45
Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu Thr Ala Lys
50 55 60
Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp Glu Lys Lys
65 70 75 80
Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr
85 90 95
Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys
100 105 110
Ala Leu Ile Thr Gly Gly Gly Asn Lys Leu Thr Phe Gly Thr Gly Thr
115 120 125
Gln Leu Lys Val Glu Leu
130
<210> 494
<211> 132
<212> PRT
<213> 人
<400> 494
Met His Leu Gly Leu Leu Cys Cys Gly Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro
65 70 75 80
Asp Gly Tyr Asn Val Ser Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Arg Leu Gln Gly Trp Asn Ser Pro Leu His Phe Gly Asn Gly Thr Arg
115 120 125
Leu Thr Val Thr
130
<210> 495
<211> 271
<212> PRT
<213> 人
<400> 495
Met Ala Lys Asn Pro Leu Ala Ala Pro Leu Leu Ile Leu Trp Phe His
1 5 10 15
Leu Asp Cys Val Ser Ser Ile Leu Asn Val Glu Gln Ser Pro Gln Ser
20 25 30
Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro
35 40 45
Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu Thr Ala Lys
50 55 60
Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp Glu Lys Lys
65 70 75 80
Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr
85 90 95
Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys
100 105 110
Ala Leu Ile Thr Gly Gly Gly Asn Lys Leu Thr Phe Gly Thr Gly Thr
115 120 125
Gln Leu Lys Val Glu Leu Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265 270
<210> 496
<211> 305
<212> PRT
<213> 人
<400> 496
Met His Leu Gly Leu Leu Cys Cys Gly Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Arg Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Leu Cys Ala Gln Asp Met Asn His
35 40 45
Glu Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Glu Gly Thr Thr Ala Lys Gly Glu Val Pro
65 70 75 80
Asp Gly Tyr Asn Val Ser Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Arg Leu Gln Gly Trp Asn Ser Pro Leu His Phe Gly Asn Gly Thr Arg
115 120 125
Leu Thr Val Thr 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> 497
<211> 15
<212> PRT
<213> 人
<400> 497
His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Ser Met Asn
1 5 10 15
<210> 498
<211> 15
<212> PRT
<213> 人
<400> 498
Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Ser Met Asn Arg
1 5 10 15
<210> 499
<211> 15
<212> PRT
<213> 人
<400> 499
Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Ser Met Asn Arg Arg
1 5 10 15
<210> 500
<211> 15
<212> PRT
<213> 人
<400> 500
Tyr Met Cys Asn Ser Ser Cys Met Gly Ser Met Asn Arg Arg Pro
1 5 10 15
<210> 501
<211> 15
<212> PRT
<213> 人
<400> 501
Met Cys Asn Ser Ser Cys Met Gly Ser Met Asn Arg Arg Pro Ile
1 5 10 15
<210> 502
<211> 15
<212> PRT
<213> 人
<400> 502
Cys Asn Ser Ser Cys Met Gly Ser Met Asn Arg Arg Pro Ile Leu
1 5 10 15
<210> 503
<211> 15
<212> PRT
<213> 人
<400> 503
Asn Ser Ser Cys Met Gly Ser Met Asn Arg Arg Pro Ile Leu Thr
1 5 10 15
<210> 504
<211> 15
<212> PRT
<213> 人
<400> 504
Ser Ser Cys Met Gly Ser Met Asn Arg Arg Pro Ile Leu Thr Ile
1 5 10 15
<210> 505
<211> 15
<212> PRT
<213> 人
<400> 505
Ser Cys Met Gly Ser Met Asn Arg Arg Pro Ile Leu Thr Ile Ile
1 5 10 15
<210> 506
<211> 15
<212> PRT
<213> 人
<400> 506
Cys Met Gly Ser Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr
1 5 10 15
<210> 507
<211> 15
<212> PRT
<213> 人
<400> 507
Met Gly Ser Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu
1 5 10 15
<210> 508
<211> 15
<212> PRT
<213> 人
<400> 508
Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Cys Glu Pro
1 5 10 15
<210> 509
<211> 15
<212> PRT
<213> 人
<400> 509
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Cys Glu Pro Pro
1 5 10 15
<210> 510
<211> 15
<212> PRT
<213> 人
<400> 510
Asn Thr Phe Arg His Ser Val Val Val Pro Cys Glu Pro Pro Glu
1 5 10 15
<210> 511
<211> 15
<212> PRT
<213> 人
<400> 511
Thr Phe Arg His Ser Val Val Val Pro Cys Glu Pro Pro Glu Val
1 5 10 15
<210> 512
<211> 15
<212> PRT
<213> 人
<400> 512
Phe Arg His Ser Val Val Val Pro Cys Glu Pro Pro Glu Val Gly
1 5 10 15
<210> 513
<211> 15
<212> PRT
<213> 人
<400> 513
Arg His Ser Val Val Val Pro Cys Glu Pro Pro Glu Val Gly Ser
1 5 10 15
<210> 514
<211> 15
<212> PRT
<213> 人
<400> 514
His Ser Val Val Val Pro Cys Glu Pro Pro Glu Val Gly Ser Asp
1 5 10 15
<210> 515
<211> 15
<212> PRT
<213> 人
<400> 515
Ser Val Val Val Pro Cys Glu Pro Pro Glu Val Gly Ser Asp Cys
1 5 10 15
<210> 516
<211> 15
<212> PRT
<213> 人
<400> 516
Val Val Val Pro Cys Glu Pro Pro Glu Val Gly Ser Asp Cys Thr
1 5 10 15
<210> 517
<211> 15
<212> PRT
<213> 人
<400> 517
Val Val Pro Cys Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr
1 5 10 15
<210> 518
<211> 15
<212> PRT
<213> 人
<400> 518
Val Pro Cys Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr Ile
1 5 10 15
<210> 519
<211> 15
<212> PRT
<213> 人
<400> 519
Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg His Cys Pro
1 5 10 15
<210> 520
<211> 15
<212> PRT
<213> 人
<400> 520
Lys Gln Ser Gln His Met Thr Glu Val Val Arg His Cys Pro His
1 5 10 15
<210> 521
<211> 15
<212> PRT
<213> 人
<400> 521
Gln Ser Gln His Met Thr Glu Val Val Arg His Cys Pro His His
1 5 10 15
<210> 522
<211> 15
<212> PRT
<213> 人
<400> 522
Ser Gln His Met Thr Glu Val Val Arg His Cys Pro His His Glu
1 5 10 15
<210> 523
<211> 15
<212> PRT
<213> 人
<400> 523
Gln His Met Thr Glu Val Val Arg His Cys Pro His His Glu Arg
1 5 10 15
<210> 524
<211> 15
<212> PRT
<213> 人
<400> 524
His Met Thr Glu Val Val Arg His Cys Pro His His Glu Arg Cys
1 5 10 15
<210> 525
<211> 15
<212> PRT
<213> 人
<400> 525
Met Thr Glu Val Val Arg His Cys Pro His His Glu Arg Cys Ser
1 5 10 15
<210> 526
<211> 15
<212> PRT
<213> 人
<400> 526
Thr Glu Val Val Arg His Cys Pro His His Glu Arg Cys Ser Asp
1 5 10 15
<210> 527
<211> 15
<212> PRT
<213> 人
<400> 527
Glu Val Val Arg His Cys Pro His His Glu Arg Cys Ser Asp Ser
1 5 10 15
<210> 528
<211> 15
<212> PRT
<213> 人
<400> 528
Val Val Arg His Cys Pro His His Glu Arg Cys Ser Asp Ser Asp
1 5 10 15
<210> 529
<211> 15
<212> PRT
<213> 人
<400> 529
Val Arg His Cys Pro His His Glu Arg Cys Ser Asp Ser Asp Gly
1 5 10 15
<210> 530
<211> 9
<212> PRT
<213> 人
<400> 530
His Met Thr Glu Val Val Arg His Cys
1 5
<210> 531
<211> 10
<212> PRT
<213> 人
<400> 531
Ser Gln His Met Thr Glu Val Val Arg His
1 5 10
<210> 532
<211> 9
<212> PRT
<213> 人
<400> 532
His Met Thr Glu Val Val Arg Arg Cys
1 5
<210> 533
<211> 13
<212> PRT
<213> 人
<400> 533
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu
1 5 10
<210> 534
<211> 13
<212> PRT
<213> 人
<400> 534
Arg Asn Thr Phe Arg His Ser Val Val Val Pro Cys Glu
1 5 10
<210> 535
<211> 341
<212> PRT
<213> 人
<400> 535
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> 536
<211> 346
<212> PRT
<213> 人
<400> 536
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> 537
<211> 354
<212> PRT
<213> 人
<400> 537
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> 538
<211> 302
<212> PRT
<213> 人
<400> 538
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> 539
<211> 307
<212> PRT
<213> 人
<400> 539
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> 540
<211> 261
<212> PRT
<213> 人
<400> 540
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> 541
<211> 209
<212> PRT
<213> 人
<400> 541
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> 542
<211> 214
<212> PRT
<213> 人
<400> 542
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> 543
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 543
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Val Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
115 120 125
Thr Val Val 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 Leu Leu Leu Leu
325 330 335
Ile Pro Val Leu Gly Met Ile Phe Ala Leu Arg Asp Ala Arg Ala Gln
340 345 350
Ser Val Ser Gln His Asn His His Val Ile Leu Ser Glu Ala Ala Ser
355 360 365
Leu Glu Leu Gly Cys Asn Tyr Ser Tyr Gly Gly Thr Val Asn Leu Phe
370 375 380
Trp Tyr Val Gln Tyr Pro Gly Gln His Leu Gln Leu Leu Leu Lys Tyr
385 390 395 400
Phe Ser Gly Asp Pro Leu Val Lys Gly Ile Lys Gly Phe Glu Ala Glu
405 410 415
Phe Ile Lys Ser Lys Phe Ser Phe Asn Leu Arg Lys Pro Ser Val Gln
420 425 430
Trp Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val Lys Gly Asp Tyr Lys
435 440 445
Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg Ala Asn Ile Gln
450 455 460
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
465 470 475 480
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
485 490 495
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
500 505 510
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
515 520 525
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
530 535 540
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
545 550 555 560
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
565 570 575
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
580 585 590
Leu Arg Leu Trp Ser Ser
595
<210> 544
<211> 604
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 544
Met Ala Pro Gly Leu Leu His Trp Met Ala Leu Cys Leu Leu Gly Thr
1 5 10 15
Gly His Gly Asp Ala Met Val Ile Gln Asn Pro Arg Tyr Gln Val Thr
20 25 30
Gln Phe Gly Lys Pro Val Thr Leu Ser Cys Ser Gln Thr Leu Asn His
35 40 45
Asn Val Met Tyr Trp Tyr Gln Gln Lys Ser Ser Gln Ala Pro Lys Leu
50 55 60
Leu Phe His Tyr Tyr Asp Lys Asp Phe Asn Asn Glu Ala Asp Thr Pro
65 70 75 80
Asp Asn Phe Gln Ser Arg Arg Pro Asn Thr Ser Phe Cys Phe Leu Asp
85 90 95
Ile Arg Ser Pro Gly Leu Gly Asp Ala Ala Met Tyr Leu Cys Ala Thr
100 105 110
Ser Arg Glu Leu Arg Gly Asn Glu Gln Phe 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 Leu Thr Ala
325 330 335
Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val Val Ser Ser Met
340 345 350
Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser Val Val Glu Lys
355 360 365
Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg Asp Thr Thr Tyr
370 375 380
Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu Leu Val Phe Leu
385 390 395 400
Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile Ser Gly Arg Tyr
405 410 415
Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn Phe Thr Ile Thr
420 425 430
Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser Glu
435 440 445
Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly Thr Leu Leu Thr
450 455 460
Val Asn Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys
465 470 475 480
Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp
485 490 495
Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr
500 505 510
Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly
515 520 525
Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe
530 535 540
Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala
545 550 555 560
Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln
565 570 575
Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly
580 585 590
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 545
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 545
Met Ala Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu
1 5 10 15
Trp Ala Gly Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln
20 25 30
Val Leu Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met
35 40 45
Asn His Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu
50 55 60
Arg Leu Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu
65 70 75 80
Val Pro Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro
85 90 95
Leu Arg Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys
100 105 110
Ala Ser Ser Tyr Arg Glu Ser His Tyr Gly Tyr Thr Phe Gly Ser Gly
115 120 125
Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser
305 310 315 320
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Trp
325 330 335
Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr Thr Gly
340 345 350
Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly Ala Ile
355 360 365
Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly Leu Phe
370 375 380
Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser Tyr Asn
385 390 395 400
Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe Leu Ser
405 410 415
Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln Met Lys
420 425 430
Asp Ser Ala Ser Tyr Leu Cys Ala Val Lys Trp Thr Gly Gly Phe Lys
435 440 445
Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala Asn Ile Gln
450 455 460
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
465 470 475 480
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
485 490 495
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
500 505 510
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
515 520 525
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
530 535 540
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
545 550 555 560
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
565 570 575
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
580 585 590
Leu Arg Leu Trp Ser Ser
595
<210> 546
<211> 608
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 546
Met Ala Leu Leu Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu
1 5 10 15
Pro Gly Ser Leu Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
20 25 30
Pro Ser Trp Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
35 40 45
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
50 55 60
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
65 70 75 80
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
85 90 95
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
100 105 110
Asp Ser Ser Phe Tyr Ile Cys Ser Ala Ala Gly Gln Ala Asn Thr Glu
115 120 125
Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg
130 135 140
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
145 150 155 160
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
165 170 175
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
180 185 190
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
195 200 205
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
210 215 220
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
225 230 235 240
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
245 250 255
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
260 265 270
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
275 280 285
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
290 295 300
Met Ala Met Val Lys Arg Lys Asn Ser Arg Ala Lys Arg Ser Gly Ser
305 310 315 320
Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu
325 330 335
Asn Pro Gly Pro Met His Ser Leu Arg Val Leu Leu Val Ile Leu Trp
340 345 350
Leu Gln Leu Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn
355 360 365
Ser Gly Pro Leu Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys
370 375 380
Thr Tyr Ser Asp Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr
385 390 395 400
Ser Gly Lys Ser Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp
405 410 415
Lys Glu Asp Gly Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr
420 425 430
Val Ser Leu Leu Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr
435 440 445
Leu Cys Ala Val Asn Asp Ala Gly Asn Met Leu Thr Phe Gly Gly Gly
450 455 460
Thr Arg Leu Met Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val
465 470 475 480
Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe
485 490 495
Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly
500 505 510
Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser
515 520 525
Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys
530 535 540
Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val
545 550 555 560
Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn
565 570 575
Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu
580 585 590
Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600 605
<210> 547
<211> 602
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 547
Met Ala Ile Gly Leu Leu Cys Cys Val Ala Phe Ser Leu Leu Trp Ala
1 5 10 15
Ser Pro Val Asn Ala Gly Val Thr Gln Thr Pro Lys Phe Gln Val Leu
20 25 30
Lys Thr Gly Gln Ser Met Thr Leu Gln Cys Ala Gln Asp Met Asn His
35 40 45
Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr Asp Lys Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys Arg Glu Phe Ser Leu Arg
85 90 95
Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Glu Gly Leu Trp Gln Val Gly Asp Glu Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser
305 310 315 320
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ile
325 330 335
Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser Trp Val
340 345 350
Trp Ser Gln Arg Lys Glu Val Glu Gln Asp Pro Gly Pro Phe Asn Val
355 360 365
Pro Glu Gly Ala Thr Val Ala Phe Asn Cys Thr Tyr Ser Asn Ser Ala
370 375 380
Ser Gln Ser Phe Phe Trp Tyr Arg Gln Asp Cys Arg Lys Glu Pro Lys
385 390 395 400
Leu Leu Met Ser Val Tyr Ser Ser Gly Asn Glu Asp Gly Arg Phe Thr
405 410 415
Ala Gln Leu Asn Arg Ala Ser Gln Tyr Ile Ser Leu Leu Ile Arg Asp
420 425 430
Ser Lys Leu Ser Asp Ser Ala Thr Tyr Leu Cys Val Val Gln Pro Gly
435 440 445
Gly Tyr Gln Lys Val Thr Phe Gly Thr Gly Thr Lys Leu Gln Val Ile
450 455 460
Pro Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro
465 470 475 480
Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln
485 490 495
Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys
500 505 510
Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile
515 520 525
Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu
530 535 540
Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu
545 550 555 560
Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu
565 570 575
Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
580 585 590
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 548
<211> 607
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 548
Met Ala Thr Arg Leu Phe Phe Tyr Val Ala Leu Cys Leu Leu Trp Thr
1 5 10 15
Gly His Met Asp Ala Gly Ile Thr Gln Ser Pro Arg His Lys Val Thr
20 25 30
Glu Thr Gly Thr Pro Val Thr Leu Arg Cys His Gln Thr Glu Asn His
35 40 45
Arg Tyr Met Tyr Trp Tyr Arg Gln Asp Pro Gly His Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Tyr Gly Val Lys Asp Thr Asp Lys Gly Glu Val Ser
65 70 75 80
Asp Gly Tyr Ser Val Ser Arg Ser Lys Thr Glu Asp Phe Leu Leu Thr
85 90 95
Leu Glu Ser Ala Thr Ser Ser Gln Thr Ser Val Tyr Phe Cys Ala Ile
100 105 110
Ser Glu Leu Val Thr Gly Asp Ser Pro Leu His Phe Gly Asn Gly Thr
115 120 125
Arg Leu Thr Val Thr 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 Thr Arg
325 330 335
Val Ser Leu Leu Trp Ala Val Val Val Ser Thr Cys Leu Glu Ser Gly
340 345 350
Met Ala Gln Thr Val Thr Gln Ser Gln Pro Glu Met Ser Val Gln Glu
355 360 365
Ala Glu Thr Val Thr Leu Ser Cys Thr Tyr Asp Thr Ser Glu Asn Asn
370 375 380
Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Arg Gln Met Ile Leu
385 390 395 400
Val Ile Arg Gln Glu Ala Tyr Lys Gln Gln Asn Ala Thr Glu Asn Arg
405 410 415
Phe Ser Val Asn Phe Gln Lys Ala Ala Lys Ser Phe Ser Leu Lys Ile
420 425 430
Ser Asp Ser Gln Leu Gly Asp Thr Ala Met Tyr Phe Cys Ala Phe Met
435 440 445
Gly Tyr Ser Gly Ala Gly Ser Tyr Gln Leu Thr Phe Gly Lys Gly Thr
450 455 460
Lys Leu Ser Val Ile Pro Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr
465 470 475 480
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
485 490 495
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
500 505 510
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
515 520 525
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
530 535 540
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
545 550 555 560
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
565 570 575
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
580 585 590
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600 605
<210> 549
<211> 602
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 549
Met Ala Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala
1 5 10 15
Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile
20 25 30
Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His
35 40 45
Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu
50 55 60
Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro
65 70 75 80
Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala
100 105 110
Ser Ser Leu Asp Pro Gly Asp Thr Gly Glu Leu Phe Phe Gly Glu Gly
115 120 125
Ser Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
130 135 140
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
180 185 190
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
225 230 235 240
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
290 295 300
Lys Asn Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser
305 310 315 320
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu
325 330 335
Ser Phe Leu Gly Gly Val Leu Leu Ile Leu Trp Leu Gln Val Asp Trp
340 345 350
Val Lys Ser Gln Lys Ile Glu Gln Asn Ser Glu Ala Leu Asn Ile Gln
355 360 365
Glu Gly Lys Thr Ala Thr Leu Thr Cys Asn Tyr Thr Asn Tyr Ser Pro
370 375 380
Ala Tyr Leu Gln Trp Tyr Arg Gln Asp Pro Gly Arg Gly Pro Val Phe
385 390 395 400
Leu Leu Leu Ile Arg Glu Asn Glu Lys Glu Lys Arg Lys Glu Arg Leu
405 410 415
Lys Val Thr Phe Asp Thr Thr Leu Lys Gln Ser Leu Phe His Ile Thr
420 425 430
Ala Ser Gln Pro Ala Asp Ser Ala Thr Tyr Leu Cys Ala Leu Asp Ile
435 440 445
Tyr Pro His Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys
450 455 460
Pro Asp Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro
465 470 475 480
Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln
485 490 495
Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys
500 505 510
Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile
515 520 525
Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu
530 535 540
Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu
545 550 555 560
Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu
565 570 575
Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
580 585 590
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 550
<211> 607
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 550
Met Ala Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe Gly Lys
115 120 125
Gly Thr Arg Leu Ser Val Ile Ala Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
275 280 285
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Phe Arg
290 295 300
Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala Gly Pro Val Asp
305 310 315 320
Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr Ala Thr Gly Gln
325 330 335
Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp Leu Ser Val Tyr
340 345 350
Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe Leu Ile Gln Tyr
355 360 365
Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu Glu Arg Phe Ser
370 375 380
Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn Leu Ser Ser Leu
385 390 395 400
Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Val Gly Ser
405 410 415
Ser Ser Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
420 425 430
Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
435 440 445
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
450 455 460
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
465 470 475 480
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
485 490 495
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
500 505 510
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
515 520 525
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
530 535 540
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
545 550 555 560
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
565 570 575
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
580 585 590
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 551
<211> 607
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 551
Met Ala Thr Ala Ser Leu Leu Arg Ala Val Ile Ala Ser Ile Cys Val
1 5 10 15
Val Ser Ser Met Ala Gln Lys Val Thr Gln Ala Gln Thr Glu Ile Ser
20 25 30
Val Val Glu Lys Glu Asp Val Thr Leu Asp Cys Val Tyr Glu Thr Arg
35 40 45
Asp Thr Thr Tyr Tyr Leu Phe Trp Tyr Lys Gln Pro Pro Ser Gly Glu
50 55 60
Leu Val Phe Leu Ile Arg Arg Asn Ser Phe Asp Glu Gln Asn Glu Ile
65 70 75 80
Ser Gly Arg Tyr Ser Trp Asn Phe Gln Lys Ser Thr Ser Ser Phe Asn
85 90 95
Phe Thr Ile Thr Ala Ser Gln Val Val Asp Ser Ala Val Tyr Phe Cys
100 105 110
Ala Leu Ser Glu Val Asp Ser Gly Asn Thr Pro Leu Val Phe Gly Lys
115 120 125
Gly Thr Arg Leu Ser Val Ile Ala Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
275 280 285
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Phe Arg
290 295 300
Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala Gly Pro Val Asp
305 310 315 320
Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr Ala Thr Gly Gln
325 330 335
Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp Leu Ser Val Tyr
340 345 350
Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe Leu Ile His Tyr
355 360 365
Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu Glu Arg Phe Ser
370 375 380
Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn Leu Ser Ser Leu
385 390 395 400
Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Val Gly Ser
405 410 415
Ser Ser Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
420 425 430
Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe
435 440 445
Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val
450 455 460
Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp
465 470 475 480
Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala
485 490 495
Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val
500 505 510
Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val
515 520 525
Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro
530 535 540
Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp
545 550 555 560
Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
565 570 575
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
580 585 590
Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 552
<211> 611
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 552
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
Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr
115 120 125
Arg Leu Thr Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Leu Leu Leu Leu
290 295 300
Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu Pro Gly Ser Leu Ala Gly
305 310 315 320
Ser Gly Leu Gly Ala Val Val Ser Gln His Pro Ser Trp Val Ile Cys
325 330 335
Lys Ser Gly Thr Ser Val Lys Ile Glu Cys Arg Ser Leu Asp Phe Gln
340 345 350
Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser Leu Met
355 360 365
Leu Met Ala Thr Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu Gln Gly
370 375 380
Val Glu Lys Asp Lys Phe Leu Ile Asn His Ala Ser Leu Thr Leu Ser
385 390 395 400
Thr Leu Thr Val Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr Ile
405 410 415
Cys Ser Gly Gly Leu Glu Glu Ala Ala Arg Gln Phe Ile Gly Pro Gly
420 425 430
Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
435 440 445
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
450 455 460
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
465 470 475 480
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
485 490 495
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
500 505 510
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
515 520 525
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
530 535 540
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
545 550 555 560
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
565 570 575
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
580 585 590
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
595 600 605
Lys Asn Ser
610
<210> 553
<211> 601
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 553
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
Met Thr Ser Pro Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr
115 120 125
Arg Leu Thr Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Leu Leu Leu Leu
290 295 300
Leu Leu Gly Pro Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His
305 310 315 320
Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys
325 330 335
Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe
340 345 350
Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys
355 360 365
Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His
370 375 380
Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu
385 390 395 400
Asp Ser Ser Phe Tyr Ile Cys Ser Gly Gly Leu Glu Glu Ala Ala Arg
405 410 415
Gln Phe Ile Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg
420 425 430
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
435 440 445
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
450 455 460
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
465 470 475 480
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
485 490 495
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
500 505 510
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
515 520 525
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
530 535 540
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
545 550 555 560
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
565 570 575
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
580 585 590
Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 554
<211> 596
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 554
Met Ala Leu Val Ala Arg Val Thr Val Phe Leu Thr Phe Gly Thr Ile
1 5 10 15
Ile Asp Ala Lys Thr Thr Gln Pro Pro Ser Met Asp Cys Ala Glu Gly
20 25 30
Arg Ala Ala Asn Leu Pro Cys Asn His Ser Thr Ile Ser Gly Asn Glu
35 40 45
Tyr Val Tyr Trp Tyr Arg Gln Ile His Ser Gln Gly Pro Gln Tyr Ile
50 55 60
Ile His Gly Leu Lys Asn Asn Glu Thr Asn Glu Met Ala Ser Leu Ile
65 70 75 80
Ile Thr Glu Asp Arg Lys Ser Ser Thr Leu Ile Leu Pro His Ala Thr
85 90 95
Leu Arg Asp Thr Ala Val Tyr Tyr Cys Ile Val Pro Asn Asp Tyr Lys
100 105 110
Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg Ala Asn Ile Gln
115 120 125
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
130 135 140
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
145 150 155 160
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
165 170 175
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
180 185 190
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
195 200 205
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
210 215 220
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
225 230 235 240
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
245 250 255
Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr
260 265 270
Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly
275 280 285
Pro Met His Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala
290 295 300
Val Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val
305 310 315 320
Lys Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp
325 330 335
His Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg
340 345 350
Leu Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile
355 360 365
Pro Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu
370 375 380
Ile Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala
385 390 395 400
Ser Ser Phe Gly Thr Gly Ser Ile Gln Glu Thr Gln Tyr Phe Gly Pro
405 410 415
Gly Thr Arg Leu Leu Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro
420 425 430
Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln
435 440 445
Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val
450 455 460
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys
465 470 475 480
Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser
485 490 495
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His
500 505 510
Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp
515 520 525
Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala
530 535 540
Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly
545 550 555 560
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
565 570 575
Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys
580 585 590
Arg Lys Asn Ser
595
<210> 555
<211> 610
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 555
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Asn
100 105 110
Pro Asn Ala Gly Gly Thr Ser Tyr Gly Lys Leu Thr Phe Gly Gln Gly
115 120 125
Thr Ile Leu Thr Val His Pro 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
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
275 280 285
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Pro Arg Leu
290 295 300
Leu Phe Trp Ala Leu Leu Cys Leu Leu Gly Thr Gly Pro Val Glu Ala
305 310 315 320
Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly Gln Gln
325 330 335
Ala Thr Leu Arg Cys Ser Pro Ile Ser Gly His Thr Ser Val Tyr Trp
340 345 350
Tyr Gln Gln Ala Leu Gly Leu Gly Leu Gln Phe Leu Leu Trp Tyr Asp
355 360 365
Glu Gly Glu Glu Arg Asn Arg Gly Asn Phe Pro Pro Arg Phe Ser Gly
370 375 380
Arg Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn Val Asn Ala Leu Glu
385 390 395 400
Leu Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Ser Pro Gly Ala
405 410 415
Thr Ser Gly Gly Ala Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser
420 425 430
Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val
435 440 445
Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala
450 455 460
Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu
465 470 475 480
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp
485 490 495
Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg
500 505 510
Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg
515 520 525
Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu
530 535 540
Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly
545 550 555 560
Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu
565 570 575
Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr
580 585 590
Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys
595 600 605
Asn Ser
610
<210> 556
<211> 614
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 556
Met Ala Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
275 280 285
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Leu Leu
290 295 300
Leu Leu Leu Leu Gly Pro Gly Ile Ser Leu Leu Leu Pro Gly Ser Leu
305 310 315 320
Ala Gly Ser Gly Leu Gly Ala Val Val Ser Gln His Pro Ser Trp Val
325 330 335
Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys Arg Ser Leu Asp
340 345 350
Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe Pro Lys Gln Ser
355 360 365
Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys Ala Thr Tyr Glu
370 375 380
Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His Ala Ser Leu Thr
385 390 395 400
Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu Asp Ser Ser Phe
405 410 415
Tyr Ile Cys Ser Ala Arg Asp Leu Gln Arg Ser Tyr Glu Gln Tyr Phe
420 425 430
Gly Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn Val Thr
435 440 445
Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn
450 455 460
Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp
465 470 475 480
His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly
485 490 495
Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys
500 505 510
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg
515 520 525
Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp
530 535 540
Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala
545 550 555 560
Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln
565 570 575
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
580 585 590
Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met
595 600 605
Val Lys Arg Lys Asn Ser
610
<210> 557
<211> 604
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 557
Met Ala Thr Phe Ala Gly Phe Ser Phe Leu Phe Leu Trp Leu Gln Leu
1 5 10 15
Asp Cys Met Ser Arg Gly Glu Asp Val Glu Gln Ser Leu Phe Leu Ser
20 25 30
Val Arg Glu Gly Asp Ser Ser Val Ile Asn Cys Thr Tyr Thr Asp Ser
35 40 45
Ser Ser Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu
50 55 60
Gln Leu Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln
65 70 75 80
Arg Leu Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg
85 90 95
Ile Ala Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu
100 105 110
Ile Pro Arg Asp Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
275 280 285
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Leu Leu
290 295 300
Leu Leu Leu Leu Gly Pro Ala Gly Ser Gly Leu Gly Ala Val Val Ser
305 310 315 320
Gln His Pro Ser Arg Val Ile Cys Lys Ser Gly Thr Ser Val Lys Ile
325 330 335
Glu Cys Arg Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg
340 345 350
Gln Phe Pro Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly
355 360 365
Ser Lys Ala Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile
370 375 380
Asn His Ala Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His
385 390 395 400
Pro Glu Asp Ser Ser Phe Tyr Ile Cys Ser Ala Arg Asp Leu Gln Arg
405 410 415
Ser Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu
420 425 430
Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser
435 440 445
Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala
450 455 460
Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
465 470 475 480
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu
485 490 495
Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr
500 505 510
Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His
515 520 525
Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val
530 535 540
Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile
545 550 555 560
Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr
565 570 575
Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr
580 585 590
Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 558
<211> 606
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 558
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
Pro Val Gly Gly Leu Asn Ser Gly Tyr Ala Leu Asn Phe Gly Lys Gly
115 120 125
Thr Ser Leu Leu Val Thr Pro 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
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
275 280 285
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Pro Gly Leu
290 295 300
Leu Cys Trp Val Leu Leu Cys Leu Leu Gly Ala Gly Pro Val Asp Ala
305 310 315 320
Gly Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly Gln Gln
325 330 335
Val Thr Leu Arg Cys Ser Pro Ile Ser Gly His Lys Ser Val Ser Trp
340 345 350
Tyr Gln Gln Val Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln Tyr Tyr
355 360 365
Glu Lys Glu Glu Arg Gly Arg Gly Asn Phe Pro Asp Arg Phe Ser Ala
370 375 380
Arg Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn Val Asn Ala Leu Leu
385 390 395 400
Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Gly Gly Arg Thr
405 410 415
Ser Gly Ala Tyr Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val
420 425 430
Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu
435 440 445
Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys
450 455 460
Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val
465 470 475 480
Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr
485 490 495
Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser
500 505 510
Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln
515 520 525
Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys
530 535 540
Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys
545 550 555 560
Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile
565 570 575
Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val
580 585 590
Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 559
<211> 604
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 559
Met Ala Lys Met Leu Glu Cys Ala Phe Ile Val Leu Trp Leu Gln Leu
1 5 10 15
Gly Trp Leu Ser Gly Glu Asp Gln Val Thr Gln Ser Pro Glu Ala Leu
20 25 30
Arg Leu Gln Glu Gly Glu Ser Ser Ser Leu Asn Cys Ser Tyr Thr Val
35 40 45
Ser Gly Leu Arg Gly Leu Phe Trp Tyr Arg Gln Asp Pro Gly Lys Gly
50 55 60
Pro Glu Phe Leu Phe Thr Leu Tyr Ser Ala Gly Glu Glu Lys Glu Lys
65 70 75 80
Glu Arg Leu Lys Ala Thr Leu Thr Lys Lys Glu Ser Phe Leu His Ile
85 90 95
Thr Ala Pro Lys Pro Glu Asp Ser Ala Thr Tyr Leu Cys Ala Val Thr
100 105 110
Ala His Arg Gly Ser Thr Leu Gly Arg Leu Tyr Phe Gly Arg Gly Thr
115 120 125
Gln Leu Thr Val Trp Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Pro Gly Leu Leu
290 295 300
Cys Trp Ala Leu Leu Cys Leu Leu Gly Ala Gly Leu Val Asp Ala Gly
305 310 315 320
Val Thr Gln Ser Pro Thr His Leu Ile Lys Thr Arg Gly Gln Gln Val
325 330 335
Thr Leu Arg Cys Ser Pro Lys Ser Gly His Asp Thr Val Ser Trp Tyr
340 345 350
Gln Gln Ala Leu Gly Gln Gly Pro Gln Phe Ile Phe Gln Tyr Tyr Glu
355 360 365
Glu Glu Glu Arg Gln Arg Gly Asn Phe Pro Asp Arg Phe Ser Gly His
370 375 380
Gln Phe Pro Asn Tyr Ser Ser Glu Leu Asn Val Asn Ala Leu Leu Leu
385 390 395 400
Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser Ser Arg Arg Gly Gly Ala
405 410 415
Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu
420 425 430
Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser
435 440 445
Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala
450 455 460
Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
465 470 475 480
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu
485 490 495
Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr
500 505 510
Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His
515 520 525
Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val
530 535 540
Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile
545 550 555 560
Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr
565 570 575
Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr
580 585 590
Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 560
<211> 605
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 560
Met Ala Lys Asn Pro Leu Ala Ala Pro Leu Leu Ile Leu Trp Phe His
1 5 10 15
Leu Asp Cys Val Ser Ser Ile Leu Asn Val Glu Gln Ser Pro Gln Ser
20 25 30
Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro
35 40 45
Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu Thr Ala Lys
50 55 60
Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp Glu Lys Lys
65 70 75 80
Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr
85 90 95
Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys
100 105 110
Ala Ser Val Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys Gly Thr
115 120 125
His Leu Ile Ile Gln Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu
290 295 300
Phe Trp Val Ala Phe Cys Leu Leu Gly Ala Asp His Thr Gly Ala Gly
305 310 315 320
Val Ser Gln Ser Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp Val
325 330 335
Glu Leu Arg Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp Tyr
340 345 350
Arg Gln Ser Leu Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln Gly
355 360 365
Asn Ser Ala Pro Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser Ala
370 375 380
Glu Arg Thr Gly Gly Ser Val Ser Thr Leu Thr Ile Gln Arg Thr Gln
385 390 395 400
Gln Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Thr Trp Asp Arg Gly
405 410 415
Ser Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val Leu
420 425 430
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
435 440 445
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
450 455 460
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
465 470 475 480
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
485 490 495
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
500 505 510
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
515 520 525
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
530 535 540
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
545 550 555 560
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
565 570 575
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
580 585 590
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 561
<211> 602
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 561
Met Ala Lys Cys Pro Gln Ala Leu Leu Ala Ile Phe Trp Leu Leu Leu
1 5 10 15
Ser Trp Val Ser Ser Glu Asp Lys Val Val Gln Ser Pro Leu Ser Leu
20 25 30
Val Val His Glu Gly Asp Thr Val Thr Leu Asn Cys Ser Tyr Glu Val
35 40 45
Thr Asn Phe Arg Ser Leu Leu Trp Tyr Lys Gln Glu Lys Lys Ala Pro
50 55 60
Thr Phe Leu Phe Met Leu Thr Ser Ser Gly Ile Glu Lys Lys Ser Gly
65 70 75 80
Arg Leu Ser Ser Ile Leu Asp Lys Lys Glu Leu Ser Ser Ile Leu Asn
85 90 95
Ile Thr Ala Thr Gln Thr Gly Asp Ser Ala Ile Tyr Leu Cys Ala Gly
100 105 110
Gln Asn Tyr Gly Gly Ser Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr
115 120 125
Lys Leu Ser Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Trp Leu Val
290 295 300
Cys Trp Ala Ile Phe Ser Leu Leu Lys Ala Gly Leu Thr Glu Pro Glu
305 310 315 320
Val Thr Gln Thr Pro Ser His Gln Val Thr Gln Met Gly Gln Glu Val
325 330 335
Ile Leu Arg Cys Val Pro Ile Ser Asn His Leu Tyr Phe Tyr Trp Tyr
340 345 350
Arg Gln Ile Leu Gly Gln Lys Val Glu Phe Leu Val Ser Phe Tyr Asn
355 360 365
Asn Glu Ile Ser Glu Lys Ser Glu Ile Phe Asp Asp Gln Phe Ser Val
370 375 380
Glu Arg Pro Asp Gly Ser Asn Phe Thr Leu Lys Ile Arg Ser Thr Lys
385 390 395 400
Leu Glu Asp Ser Ala Met Tyr Phe Cys Ala Ser Arg Asp Pro Ala Tyr
405 410 415
Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu
420 425 430
Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala
435 440 445
Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly
450 455 460
Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu
465 470 475 480
Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn
485 490 495
Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp
500 505 510
His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu
515 520 525
Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln
530 535 540
Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser
545 550 555 560
Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile
565 570 575
Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val
580 585 590
Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 562
<211> 606
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 562
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Asn Pro Pro Val Lys Thr Ser Tyr Asp Lys Val Ile Phe Gly Pro Gly
115 120 125
Thr Ser Leu Ser Val Ile Pro 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
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
275 280 285
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Ser Leu
290 295 300
Leu Cys Trp Val Val Leu Gly Phe Leu Gly Thr Asp His Thr Gly Ala
305 310 315 320
Gly Val Ser Gln Ser Pro Arg Tyr Lys Val Thr Lys Arg Gly Gln Asp
325 330 335
Val Ala Leu Arg Cys Asp Pro Ile Ser Gly His Val Ser Leu Tyr Trp
340 345 350
Tyr Arg Gln Ala Leu Gly Gln Gly Pro Glu Phe Leu Thr Tyr Phe Asn
355 360 365
Tyr Glu Ala Gln Gln Asp Lys Ser Gly Leu Pro Asn Asp Arg Phe Ser
370 375 380
Ala Glu Arg Pro Glu Gly Ser Ile Ser Thr Leu Thr Ile Gln Arg Thr
385 390 395 400
Glu Gln Arg Asp Ser Ala Met Tyr Arg Cys Ala Ser Ser His Arg Glu
405 410 415
Pro His Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu Thr Val
420 425 430
Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu
435 440 445
Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys
450 455 460
Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val
465 470 475 480
Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr
485 490 495
Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser
500 505 510
Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln
515 520 525
Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys
530 535 540
Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys
545 550 555 560
Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile
565 570 575
Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val
580 585 590
Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 563
<211> 600
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 563
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Thr Leu Cys Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg
115 120 125
Leu Ala Val His 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 Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Asn Gln Val Leu Cys
290 295 300
Cys Val Val Leu Cys Phe Leu Gly Ala Asn Thr Val Asp Gly Gly Ile
305 310 315 320
Thr Gln Ser Pro Lys Tyr Leu Phe Arg Lys Glu Gly Gln Asn Val Thr
325 330 335
Leu Ser Cys Glu Gln Asn Leu Asn His Asp Ala Met Tyr Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Gln Gly Leu Arg Leu Ile Tyr Tyr Ser Gln Ile Val
355 360 365
Asn Asp Phe Gln Lys Gly Asp Ile Val Glu Gly Tyr Ser Val Ser Arg
370 375 380
Glu Lys Lys Glu Ser Phe Pro Leu Thr Val Thr Ser Ala Gln Lys Asn
385 390 395 400
Pro Thr Ala Phe Tyr Leu Cys Ala Ser Ser Ser Arg Asp Tyr Glu Gln
405 410 415
Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn
420 425 430
Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile
435 440 445
Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe
450 455 460
Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His
465 470 475 480
Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser
485 490 495
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn
500 505 510
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu
515 520 525
Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile
530 535 540
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser
545 550 555 560
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
565 570 575
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met
580 585 590
Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 564
<211> 600
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 564
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Thr Leu Ser Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg
115 120 125
Leu Ala Val His 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 Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Asn Gln Val Leu Cys
290 295 300
Cys Val Val Leu Cys Phe Leu Gly Ala Asn Thr Val Asp Gly Gly Ile
305 310 315 320
Thr Gln Ser Pro Lys Tyr Leu Phe Arg Lys Glu Gly Gln Asn Val Thr
325 330 335
Leu Ser Cys Glu Gln Asn Leu Asn His Asp Ala Met Tyr Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Gln Gly Leu Arg Leu Ile Tyr Tyr Ser Gln Ile Val
355 360 365
Asn Asp Phe Gln Lys Gly Asp Ile Val Glu Gly Tyr Ser Val Ser Arg
370 375 380
Glu Lys Lys Glu Ser Phe Pro Leu Thr Val Thr Ser Ala Gln Lys Asn
385 390 395 400
Pro Thr Ala Phe Tyr Leu Cys Ala Ser Ser Ser Arg Asp Tyr Glu Gln
405 410 415
Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn
420 425 430
Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile
435 440 445
Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe
450 455 460
Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His
465 470 475 480
Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser
485 490 495
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn
500 505 510
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu
515 520 525
Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile
530 535 540
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser
545 550 555 560
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
565 570 575
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met
580 585 590
Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 565
<211> 600
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 565
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 Val Trp Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr
115 120 125
Val Arg Ala 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 Arg Ala Lys Arg
260 265 270
Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp
275 280 285
Val Glu Glu Asn Pro Gly Pro Met His Asn Gln Val Leu Cys Cys Val
290 295 300
Val Leu Cys Phe Leu Gly Ala Asn Thr Val Asp Gly Gly Ile Thr Gln
305 310 315 320
Ser Pro Lys Tyr Leu Phe Arg Lys Glu Gly Gln Asn Val Thr Leu Ser
325 330 335
Cys Glu Gln Asn Leu Asn His Asp Ala Met Tyr Trp Tyr Arg Gln Asp
340 345 350
Pro Gly Gln Gly Leu Arg Leu Ile Tyr Tyr Ser Gln Ile Val Asn Asp
355 360 365
Phe Gln Lys Gly Asp Ile Ala Glu Gly Tyr Ser Val Ser Arg Glu Lys
370 375 380
Lys Glu Ser Phe Pro Leu Thr Val Thr Ser Ala Gln Lys Asn Pro Thr
385 390 395 400
Ala Phe Tyr Leu Cys Ala Ser Ser Ile Ser Ala Gly Gly Asp Gly Tyr
405 410 415
Thr Phe Gly Ser Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn
420 425 430
Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile
435 440 445
Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe
450 455 460
Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His
465 470 475 480
Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser
485 490 495
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn
500 505 510
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu
515 520 525
Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile
530 535 540
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser
545 550 555 560
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
565 570 575
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met
580 585 590
Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 566
<211> 608
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 566
Met Ala Met Leu Leu Gly Ala Ser Val Leu Ile Leu Trp Leu Gln Pro
1 5 10 15
Asp Trp Val Asn Ser Gln Gln Lys Asn Asp Asp Gln Gln Val Lys Gln
20 25 30
Asn Ser Pro Ser Leu Ser Val Gln Glu Gly Arg Ile Ser Ile Leu Asn
35 40 45
Cys Asp Tyr Thr Asn Ser Met Phe Asp Tyr Phe Leu Trp Tyr Lys Lys
50 55 60
Tyr Pro Ala Glu Gly Pro Thr Phe Leu Ile Ser Ile Ser Ser Ile Lys
65 70 75 80
Asp Lys Asn Glu Asp Gly Arg Phe Thr Val Phe Leu Asn Lys Ser Ala
85 90 95
Lys His Leu Ser Leu His Ile Val Pro Ser Gln Pro Gly Asp Ser Ala
100 105 110
Val Tyr Phe Cys Ala Ala Asn Thr Gly Asn Gln Phe Tyr Phe Gly Thr
115 120 125
Gly Thr Ser Leu Thr Val Ile Pro Asn Ile Gln Asn Pro Glu Pro Ala
130 135 140
Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser
165 170 175
Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp
180 185 190
Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr
195 200 205
Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp
210 215 220
Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu
245 250 255
Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser
260 265 270
Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu
275 280 285
Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg
290 295 300
Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala Glu Leu Thr Glu
305 310 315 320
Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln
325 330 335
Ser Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr
340 345 350
Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe
355 360 365
Gln Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe
370 375 380
Ser Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro
385 390 395 400
Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser His Leu
405 410 415
Ala Gly Glu Phe Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu
420 425 430
Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu
435 440 445
Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu
450 455 460
Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
465 470 475 480
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln
485 490 495
Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg
500 505 510
Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln
515 520 525
Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser
530 535 540
Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala
545 550 555 560
Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala
565 570 575
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
580 585 590
Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 567
<211> 595
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 567
Met Ala Gly Ala Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Ala Gly Gln Ser Leu Glu Gln Pro Ser Glu Val Thr Ala Val Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Tyr Gly
35 40 45
Leu Ser Trp Tyr Gln Gln His Asp Gly Gly Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Ala Leu Asp Gly Leu Glu Glu Thr Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Asp Ser Tyr Gly Tyr Leu Leu Leu Gln Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Phe Cys Ala Phe Ala Tyr Gly Gln Asn
100 105 110
Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu Pro Asn Ile Gln
115 120 125
Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp
130 135 140
Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro
145 150 155 160
Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp
165 170 175
Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn
180 185 190
Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr
195 200 205
Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser
210 215 220
Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val
225 230 235 240
Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr
245 250 255
Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr
260 265 270
Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly
275 280 285
Pro Met His Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly
290 295 300
Ala Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile
305 310 315 320
Thr Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly
325 330 335
Asp Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln
340 345 350
Phe Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile
355 360 365
Leu Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu
370 375 380
Asn Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala
385 390 395 400
Ser Ser Pro Leu Gly Asp Ser Gly Asn Thr Ile Tyr Phe Gly Glu Gly
405 410 415
Ser Trp Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
420 425 430
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
435 440 445
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
450 455 460
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
465 470 475 480
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
485 490 495
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
500 505 510
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
515 520 525
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
530 535 540
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
545 550 555 560
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
565 570 575
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
580 585 590
Lys Asn Ser
595
<210> 568
<211> 599
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 568
Met Ala Thr Leu Leu Gly Val Ser Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ala Arg Val Asn Ser Gln Gln Gly Glu Glu Asp Pro Gln Ala Leu Ser
20 25 30
Ile Gln Glu Gly Glu Asn Ala Thr Met Asn Cys Ser Tyr Lys Thr Ser
35 40 45
Ile Asn Asn Leu Gln Trp Tyr Arg Gln Asn Ser Gly Arg Gly Leu Val
50 55 60
His Leu Ile Leu Ile Arg Ser Asn Glu Arg Glu Lys His Ser Gly Arg
65 70 75 80
Leu Arg Val Thr Leu Asp Thr Ser Lys Lys Ser Ser Ser Leu Leu Ile
85 90 95
Thr Ala Ser Arg Ala Ala Asp Thr Ala Ser Tyr Phe Cys Ala Thr Asp
100 105 110
Ala Trp Asn Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val
115 120 125
Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser
260 265 270
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
275 280 285
Glu Glu Asn Pro Gly Pro Met His Ile Gly Leu Leu Cys Cys Val Ala
290 295 300
Phe Ser Leu Leu Trp Ala Ser Pro Val Asn Ala Gly Val Thr Gln Thr
305 310 315 320
Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser Met Thr Leu Gln Cys
325 330 335
Ala Gln Asp Met Asn His Asn Ser Met Tyr Trp Tyr Arg Gln Asp Pro
340 345 350
Gly Met Gly Leu Arg Leu Ile Tyr Tyr Ser Ala Ser Glu Gly Thr Thr
355 360 365
Asp Lys Gly Glu Val Pro Asn Gly Tyr Asn Val Ser Arg Leu Asn Lys
370 375 380
Arg Glu Phe Ser Leu Arg Leu Glu Ser Ala Ala Pro Ser Gln Thr Ser
385 390 395 400
Val Tyr Phe Cys Ala Ser Ser Glu Ser Gln Gly Asn Thr Glu Ala Phe
405 410 415
Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val
420 425 430
Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala
435 440 445
Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro
450 455 460
Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser
465 470 475 480
Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr
485 490 495
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro
500 505 510
Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu
515 520 525
Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser
530 535 540
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
545 550 555 560
Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
565 570 575
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala
580 585 590
Met Val Lys Arg Lys Asn Ser
595
<210> 569
<211> 601
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 569
Met Ala Lys His Leu Thr Thr Phe Leu Val Ile Leu Trp Leu Tyr Phe
1 5 10 15
Tyr Arg Gly Asn Gly Lys Asn Gln Val Glu Gln Ser Pro Gln Ser Leu
20 25 30
Ile Ile Leu Glu Gly Lys Asn Cys Thr Leu Gln Cys Asn Tyr Thr Val
35 40 45
Ser Pro Phe Ser Asn Leu Arg Trp Tyr Lys Gln Asp Thr Gly Arg Gly
50 55 60
Pro Val Ser Leu Thr Ile Met Thr Phe Ser Glu Asn Thr Lys Ser Asn
65 70 75 80
Gly Arg Tyr Thr Ala Thr Leu Asp Ala Asp Thr Lys Gln Ser Ser Leu
85 90 95
His Ile Thr Ala Ser Gln Leu Ser Asp Ser Ala Ser Tyr Ile Cys Val
100 105 110
Val Ser Ser Tyr Lys Ile Ile Phe Gly Thr Gly Thr Arg Leu His Val
115 120 125
Phe Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser
260 265 270
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
275 280 285
Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu Phe Trp Val Ala
290 295 300
Phe Cys Leu Leu Gly Ala Tyr His Thr Gly Ala Gly Val Ser Gln Ser
305 310 315 320
Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp Val Glu Leu Arg Cys
325 330 335
Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp Tyr Arg Gln Arg Leu
340 345 350
Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro
355 360 365
Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly
370 375 380
Glu Ser Val Ser Thr Leu Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser
385 390 395 400
Ala Val Tyr Leu Cys Ala Ser Ser Pro Ile Gln Gly Glu Asn Ser Pro
405 410 415
Leu His Phe Gly Asn Gly Thr Arg Leu Thr Val Thr Glu Asp Leu Arg
420 425 430
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
435 440 445
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
450 455 460
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
465 470 475 480
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
485 490 495
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
500 505 510
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
515 520 525
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
530 535 540
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
545 550 555 560
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
565 570 575
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
580 585 590
Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 570
<211> 601
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 570
Met Ala Lys His Leu Thr Thr Phe Leu Val Ile Leu Trp Leu Tyr Phe
1 5 10 15
Tyr Arg Gly Asn Gly Lys Asn Gln Val Glu Gln Ser Pro Gln Ser Leu
20 25 30
Ile Ile Leu Glu Gly Lys Asn Cys Thr Leu Gln Cys Asn Tyr Thr Val
35 40 45
Ser Pro Phe Ser Asn Leu Arg Trp Tyr Lys Gln Asp Thr Gly Arg Gly
50 55 60
Pro Val Ser Leu Thr Ile Met Thr Phe Ser Glu Asn Thr Lys Ser Asn
65 70 75 80
Gly Arg Tyr Thr Ala Thr Leu Asp Ala Asp Thr Lys Gln Ser Ser Leu
85 90 95
His Ile Thr Ala Ser Gln Leu Ser Asp Ser Ala Ser Tyr Ile Cys Val
100 105 110
Val Ser Ser Tyr Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln Val
115 120 125
Phe Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser
260 265 270
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
275 280 285
Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu Phe Trp Val Ala
290 295 300
Phe Cys Leu Leu Gly Ala Tyr His Thr Gly Ala Gly Val Ser Gln Ser
305 310 315 320
Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Asp Val Glu Leu Arg Cys
325 330 335
Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp Tyr Arg Gln Arg Leu
340 345 350
Gly Gln Gly Leu Glu Phe Leu Ile Tyr Phe Gln Gly Asn Ser Ala Pro
355 360 365
Asp Lys Ser Gly Leu Pro Ser Asp Arg Phe Ser Ala Glu Arg Thr Gly
370 375 380
Glu Ser Val Ser Thr Leu Thr Ile Gln Arg Thr Gln Gln Glu Asp Ser
385 390 395 400
Ala Val Tyr Leu Cys Ala Ser Ser Pro Ile Gln Gly Glu Asn Ser Pro
405 410 415
Leu His Phe Gly Asn Gly Thr Arg Leu Thr Val Thr Glu Asp Leu Arg
420 425 430
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
435 440 445
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
450 455 460
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
465 470 475 480
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
485 490 495
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
500 505 510
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
515 520 525
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
530 535 540
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
545 550 555 560
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
565 570 575
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
580 585 590
Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 571
<211> 595
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 571
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Ser Lys Gly Thr Gly Ala Gln Lys Leu Val Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Ile 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 Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Asn Gln Val Leu Cys
290 295 300
Cys Val Val Leu Cys Phe Leu Gly Ala Asn Thr Val Asp Gly Gly Ile
305 310 315 320
Thr Gln Ser Pro Lys Tyr Leu Phe Arg Lys Glu Gly Gln Asn Val Thr
325 330 335
Leu Ser Cys Glu Gln Asn Leu Asn His Asp Ala Met Tyr Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Gln Gly Leu Arg Leu Ile Tyr Tyr Ser Gln Ile Val
355 360 365
Asn Asp Phe Gln Lys Gly Asp Ile Ala Glu Gly Tyr Ser Val Ser Arg
370 375 380
Glu Lys Lys Glu Ser Phe Pro Leu Ile Val Thr Ser Ala Gln Lys Asn
385 390 395 400
Pro Thr Ala Ser Tyr Leu Cys Ala Ser Glu Ala Phe Phe Gly Gln Gly
405 410 415
Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro Pro Lys
420 425 430
Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys
435 440 445
Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu
450 455 460
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Cys Thr
465 470 475 480
Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser
485 490 495
Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn His Phe
500 505 510
Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro
515 520 525
Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp
530 535 540
Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val
545 550 555 560
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
565 570 575
Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val Lys Arg
580 585 590
Lys Asn Ser
595
<210> 572
<211> 597
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 572
Met Ala Leu Val Thr Ser Ile Thr Val Leu Leu Ser Leu Gly Ile Met
1 5 10 15
Gly Asp Ala Lys Thr Thr Gln Pro Asn Ser Met Glu Ser Asn Glu Glu
20 25 30
Glu Pro Val His Leu Pro Cys Asn His Ser Thr Ile Ser Gly Thr Asp
35 40 45
Tyr Ile His Trp Tyr Arg Gln Leu Pro Ser Gln Gly Pro Glu Tyr Val
50 55 60
Ile His Gly Leu Thr Ser Asn Val Asn Asn Arg Met Ala Ser Leu Ala
65 70 75 80
Ile Ala Glu Asp Arg Lys Ser Ser Thr Leu Ile Leu His Arg Ala Thr
85 90 95
Leu Arg Asp Ala Ala Val Tyr Tyr Cys Ile Leu Ala Ser Gly Ala Gly
100 105 110
Ser Tyr Gln Leu Thr Phe Gly Lys Gly Thr Lys Leu Ser Val Ile Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser
260 265 270
Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu
275 280 285
Asn Pro Gly Pro Met His Cys Arg Leu Leu Cys Cys Val Val Phe Cys
290 295 300
Leu Leu Gln Ala Gly Pro Leu Asp Thr Ala Val Ser Gln Thr Pro Lys
305 310 315 320
Tyr Leu Val Thr Gln Met Gly Asn Asp Lys Ser Ile Lys Cys Glu Gln
325 330 335
Asn Leu Gly His Asp Thr Met Tyr Trp Tyr Lys Gln Asp Ser Lys Lys
340 345 350
Phe Leu Lys Ile Met Phe Ser Tyr Asn Asn Lys Glu Leu Ile Ile Asn
355 360 365
Glu Thr Val Pro Asn Arg Phe Ser Pro Lys Ser Pro Asp Lys Ala His
370 375 380
Leu Asn Leu His Ile Asn Ser Leu Glu Leu Gly Asp Ser Ala Val Tyr
385 390 395 400
Phe Cys Ala Ser Arg Thr Ile Gly Tyr Asn Thr Glu Ala Phe Phe Gly
405 410 415
Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr Pro
420 425 430
Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys
435 440 445
Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His
450 455 460
Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val
465 470 475 480
Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu
485 490 495
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn
500 505 510
His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys
515 520 525
Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu
530 535 540
Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln
545 550 555 560
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
565 570 575
Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val
580 585 590
Lys Arg Lys Asn Ser
595
<210> 573
<211> 602
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 573
Met Ala Lys Ile Arg Gln Phe Leu Leu Ala Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Cys Val Ser Ala Ala Lys Asn Glu Val Glu Gln Ser Pro Gln Asn
20 25 30
Leu Thr Ala Gln Glu Gly Glu Phe Ile Thr Ile Asn Cys Ser Tyr Ser
35 40 45
Val Gly Ile Ser Ala Leu His Trp Leu Gln Gln His Pro Gly Gly Gly
50 55 60
Ile Val Ser Leu Phe Met Leu Ser Ser Gly Lys Lys Lys His Gly Arg
65 70 75 80
Leu Ile Ala Thr Ile Asn Ile Gln Glu Lys His Ser Ser Leu His Ile
85 90 95
Thr Ala Ser His Pro Arg Asp Ser Ala Val Tyr Ile Cys Ala Ala Leu
100 105 110
Ser Tyr Asn Thr Asp Lys Leu Ile Phe Gly Thr Gly Thr Arg Leu Gln
115 120 125
Val Phe 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 Arg Ala Lys Arg
260 265 270
Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp
275 280 285
Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu Cys Trp Ala
290 295 300
Ala Leu Cys Leu Leu Gly Ala Asp His Thr Gly Ala Gly Val Ser Gln
305 310 315 320
Thr Pro Ser Asn Lys Val Thr Glu Lys Gly Lys Tyr Val Glu Leu Arg
325 330 335
Cys Asp Pro Ile Ser Gly His Thr Ala Leu Tyr Trp Tyr Arg Gln Ser
340 345 350
Leu Gly Gln Gly Pro Glu Phe Leu Ile Tyr Phe Gln Gly Thr Gly Ala
355 360 365
Ala Asp Asp Ser Gly Leu Pro Asn Asp Arg Phe Phe Ala Val Arg Pro
370 375 380
Glu Gly Ser Val Ser Thr Leu Lys Ile Gln Arg Thr Glu Arg Gly Asp
385 390 395 400
Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Ser Gly Leu Leu Gln Glu
405 410 415
Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu Glu Asp Leu
420 425 430
Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala
435 440 445
Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly
450 455 460
Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu
465 470 475 480
Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn
485 490 495
Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp
500 505 510
His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu
515 520 525
Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln
530 535 540
Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser
545 550 555 560
Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile
565 570 575
Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val
580 585 590
Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 574
<211> 605
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 574
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
His Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu
290 295 300
Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala Glu Leu Thr Glu Ala Gly
305 310 315 320
Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln Ser Val
325 330 335
Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr Trp Tyr
340 345 350
Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe Gln Asn
355 360 365
Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe Ser Ala
370 375 380
Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro Ala Lys
385 390 395 400
Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Thr Gly Gly Gly
405 410 415
Arg His Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu
420 425 430
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
435 440 445
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
450 455 460
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
465 470 475 480
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
485 490 495
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
500 505 510
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
515 520 525
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
530 535 540
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
545 550 555 560
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
565 570 575
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
580 585 590
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 575
<211> 605
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 575
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Gln Thr Gly Ser Ser Lys Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu
290 295 300
Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala Glu Leu Thr Glu Ala Gly
305 310 315 320
Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln Ser Val
325 330 335
Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr Trp Tyr
340 345 350
Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe Gln Asn
355 360 365
Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe Ser Ala
370 375 380
Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro Ala Lys
385 390 395 400
Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Thr Gly Gly Gly
405 410 415
Arg His Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu
420 425 430
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
435 440 445
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
450 455 460
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
465 470 475 480
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
485 490 495
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
500 505 510
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
515 520 525
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
530 535 540
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
545 550 555 560
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
565 570 575
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
580 585 590
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 576
<211> 605
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 576
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Gln Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Arg Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu
290 295 300
Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala Glu Leu Thr Glu Ala Gly
305 310 315 320
Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln Ser Val
325 330 335
Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr Trp Tyr
340 345 350
Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe Gln Asn
355 360 365
Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe Ser Ala
370 375 380
Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro Ala Lys
385 390 395 400
Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Thr Gly Gly Gly
405 410 415
Arg His Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu
420 425 430
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
435 440 445
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
450 455 460
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
465 470 475 480
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
485 490 495
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
500 505 510
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
515 520 525
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
530 535 540
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
545 550 555 560
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
565 570 575
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
580 585 590
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 577
<211> 605
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 577
Met Ala Tyr Ser Pro Gly Leu Val Ser Leu Ile Leu Leu Leu Leu Gly
1 5 10 15
Arg Thr Arg Gly Asn Ser Val Thr Gln Met Glu Gly Pro Val Thr Leu
20 25 30
Ser Glu Glu Ala Phe Leu Thr Ile Asn Cys Thr Tyr Thr Ala Thr Gly
35 40 45
Tyr Pro Ser Leu Phe Trp Tyr Val Gln Tyr Pro Gly Glu Gly Leu Gln
50 55 60
Leu Leu Leu Lys Ala Thr Lys Ala Asp Asp Lys Gly Ser Asn Lys Gly
65 70 75 80
Phe Glu Ala Thr Tyr Arg Lys Glu Thr Thr Ser Phe His Leu Glu Lys
85 90 95
Gly Ser Val Gln Val Ser Asp Ser Ala Val Tyr Phe Cys Ala Leu Ser
100 105 110
Thr Thr Gly Ser Ser Asn Thr Gly Lys Leu Ile Phe Gly Gln Gly Thr
115 120 125
Thr Leu Gln Val Lys Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Leu
290 295 300
Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala Glu Leu Thr Glu Ala Gly
305 310 315 320
Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln Ser Val
325 330 335
Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr Trp Tyr
340 345 350
Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe Gln Asn
355 360 365
Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe Ser Ala
370 375 380
Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro Ala Lys
385 390 395 400
Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Thr Gly Gly Gly
405 410 415
Arg His Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu
420 425 430
Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro
435 440 445
Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu
450 455 460
Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
465 470 475 480
Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys
485 490 495
Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala
500 505 510
Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe
515 520 525
His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro
530 535 540
Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly
545 550 555 560
Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu
565 570 575
Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser
580 585 590
Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 578
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 578
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val
100 105 110
Ser Trp Tyr Ser Thr Leu Thr Phe Gly Lys Gly Thr Met Leu Leu Val
115 120 125
Ser Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp
130 135 140
Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp
165 170 175
Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala
180 185 190
Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys
195 200 205
Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr
210 215 220
Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn
225 230 235 240
Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
245 250 255
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser
260 265 270
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
275 280 285
Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu Phe Phe Tyr Val Ala
290 295 300
Leu Cys Leu Leu Trp Ala Gly His Arg Asp Ala Gly Ile Thr Gln Ser
305 310 315 320
Pro Arg Tyr Lys Ile Thr Glu Thr Gly Arg Gln Val Thr Leu Met Cys
325 330 335
His Gln Thr Trp Ser His Ser Tyr Met Phe Trp Tyr Arg Gln Asp Leu
340 345 350
Gly His Gly Leu Arg Leu Ile Tyr Tyr Ser Ala Ala Ala Asp Ile Thr
355 360 365
Asp Lys Gly Glu Val Pro Asp Gly Tyr Val Val Ser Arg Ser Lys Thr
370 375 380
Glu Asn Phe Pro Leu Thr Leu Glu Ser Ala Thr Arg Ser Gln Thr Ser
385 390 395 400
Val Tyr Phe Cys Ala Ser Ser Gly Ser Arg Thr Asp Thr Gln Tyr Phe
405 410 415
Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr
420 425 430
Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn
435 440 445
Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp
450 455 460
His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly
465 470 475 480
Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys
485 490 495
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg
500 505 510
Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp
515 520 525
Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala
530 535 540
Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln
545 550 555 560
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
565 570 575
Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met
580 585 590
Val Lys Arg Lys Asn Ser
595
<210> 579
<211> 597
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 579
Met Ala Leu Lys Phe Ser Val Ser Ile Leu Trp Ile Gln Leu Ala Trp
1 5 10 15
Val Ser Thr Gln Leu Leu Glu Gln Ser Pro Gln Phe Leu Ser Ile Gln
20 25 30
Glu Gly Glu Asn Leu Thr Val Tyr Cys Asn Ser Ser Ser Val Phe Ser
35 40 45
Ser Leu Gln Trp Tyr Arg Gln Glu Pro Gly Glu Gly Pro Val Leu Leu
50 55 60
Val Thr Val Val Thr Gly Gly Glu Val Lys Lys Leu Lys Arg Leu Thr
65 70 75 80
Phe Gln Phe Gly Asp Ala Arg Lys Asp Ser Ser Leu His Ile Thr Ala
85 90 95
Ala Gln Pro Gly Asp Thr Gly Leu Tyr Leu Cys Ala Gly Glu Phe Ala
100 105 110
Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val Ile Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser
260 265 270
Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu
275 280 285
Asn Pro Gly Pro Met His Cys Arg Leu Leu Cys Cys Ala Val Leu Cys
290 295 300
Leu Leu Gly Ala Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys
305 310 315 320
His Leu Val Met Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln
325 330 335
His Met Gly His Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys
340 345 350
Pro Pro Glu Leu Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn
355 360 365
Glu Ser Val Pro Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu
370 375 380
Leu Asn Leu His Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr
385 390 395 400
Leu Cys Ala Ser Ser Gln Val Gly Leu Thr Tyr Glu Gln Tyr Phe Gly
405 410 415
Pro Gly Thr Arg Leu Thr Val Thr Glu Asp Leu Arg Asn Val Thr Pro
420 425 430
Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys
435 440 445
Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His
450 455 460
Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val
465 470 475 480
Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu
485 490 495
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn
500 505 510
His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys
515 520 525
Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu
530 535 540
Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln
545 550 555 560
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
565 570 575
Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val
580 585 590
Lys Arg Lys Asn Ser
595
<210> 580
<211> 604
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 580
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 Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly
115 120 125
Thr Leu Leu Thr Val Asn Pro 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
Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
275 280 285
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Thr Arg Leu
290 295 300
Leu Cys Trp Ala Ala Leu Cys Leu Leu Gly Ala Glu Leu Thr Glu Ala
305 310 315 320
Gly Val Ala Gln Ser Pro Arg Tyr Lys Ile Ile Glu Lys Arg Gln Ser
325 330 335
Val Ala Phe Trp Cys Asn Pro Ile Ser Gly His Ala Thr Leu Tyr Trp
340 345 350
Tyr Gln Gln Ile Leu Gly Gln Gly Pro Lys Leu Leu Ile Gln Phe Gln
355 360 365
Asn Asn Gly Val Val Asp Asp Ser Gln Leu Pro Lys Asp Arg Phe Ser
370 375 380
Ala Glu Arg Leu Lys Gly Val Asp Ser Thr Leu Lys Ile Gln Pro Ala
385 390 395 400
Lys Leu Glu Asp Ser Ala Val Tyr Leu Cys Ala Ser Ser Leu Gly Gln
405 410 415
Gly Gln Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Leu Val Leu Glu
420 425 430
Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser
435 440 445
Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala
450 455 460
Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
465 470 475 480
Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu
485 490 495
Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr
500 505 510
Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His
515 520 525
Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val
530 535 540
Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile
545 550 555 560
Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr
565 570 575
Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr
580 585 590
Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 581
<211> 601
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 581
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Arg Gly Ser Ser Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg
115 120 125
Leu Lys Val Leu Ala 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 Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Ile Arg Leu Leu Cys
290 295 300
Arg Val Ala Phe Cys Phe Leu Ala Val Gly Leu Val Asp Val Lys Val
305 310 315 320
Thr Gln Ser Ser Arg Tyr Leu Val Lys Arg Thr Gly Glu Lys Val Phe
325 330 335
Leu Glu Cys Val Gln Asp Met Asp His Glu Asn Met Phe Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Leu Gly Leu Arg Leu Ile Tyr Phe Ser Tyr Asp Val
355 360 365
Lys Met Lys Glu Lys Gly Asp Ile Pro Glu Gly Tyr Ser Val Ser Arg
370 375 380
Glu Lys Lys Glu Arg Phe Ser Leu Ile Leu Glu Ser Ala Ser Thr Asn
385 390 395 400
Gln Thr Ser Met Tyr Leu Cys Ala Ser Lys Gly Asp Gln Asn Thr Glu
405 410 415
Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg
420 425 430
Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu
435 440 445
Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe
450 455 460
Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val
465 470 475 480
His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr
485 490 495
Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His
500 505 510
Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser
515 520 525
Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn
530 535 540
Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala
545 550 555 560
Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu
565 570 575
Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val
580 585 590
Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 582
<211> 598
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 582
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Arg Asp Leu Gln Thr
100 105 110
Gly Ala Asn Asn Leu Phe Phe Gly Thr Gly Thr Arg Leu Thr Val Ile
115 120 125
Pro Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro
130 135 140
Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys
165 170 175
Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile
180 185 190
Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu
195 200 205
Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu
210 215 220
Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu
225 230 235 240
Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn
245 250 255
Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly
260 265 270
Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu
275 280 285
Glu Asn Pro Gly Pro Met His Ile Arg Leu Leu Cys Arg Val Ala Phe
290 295 300
Cys Phe Leu Ala Val Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser
305 310 315 320
Arg Tyr Leu Val Lys Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val
325 330 335
Gln Asp Met Asp His Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly
340 345 350
Leu Gly Leu Arg Leu Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu
355 360 365
Lys Gly Asp Ile Pro Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu
370 375 380
Arg Phe Ser Leu Ile Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met
385 390 395 400
Tyr Leu Cys Ala Ser Ser Leu Thr Phe Gly Thr Thr Glu Ala Phe Phe
405 410 415
Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val Thr
420 425 430
Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn
435 440 445
Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp
450 455 460
His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly
465 470 475 480
Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys
485 490 495
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg
500 505 510
Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp
515 520 525
Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala
530 535 540
Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln
545 550 555 560
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
565 570 575
Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met
580 585 590
Val Lys Arg Lys Asn Ser
595
<210> 583
<211> 599
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 583
Met Ala Leu Leu Leu Val Pro Ala Phe Gln Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Asp Ser Gln Val Pro Val
20 25 30
Phe Glu Glu Ala Pro Val Glu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Ser Val Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Leu Ser Gly Ser Thr Leu Val Glu Ser Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Arg
85 90 95
Lys Pro Ser Val His Ile Ser Asp Thr Ala Glu Tyr Phe Cys Ala Val
100 105 110
Ser Asp Leu Val Arg Asp Asp Lys Ile Ile Phe Gly Lys Gly Thr Arg
115 120 125
Leu His Ile Leu 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 Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Ile Gly Leu Leu Cys
290 295 300
Cys Val Ala Phe Ser Leu Leu Trp Ala Ser Pro Val Asn Ala Gly Val
305 310 315 320
Thr Gln Thr Pro Lys Phe Gln Val Leu Lys Thr Gly Gln Ser Met Thr
325 330 335
Leu Gln Cys Ala Gln Asp Met Asn His Asn Ser Met Tyr Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Met Gly Leu Arg Leu Ile Tyr Tyr Ser Ala Ser Glu
355 360 365
Gly Thr Thr Asp Lys Gly Glu Val Pro Asn Gly Tyr Asn Val Ser Arg
370 375 380
Leu Asn Lys Arg Glu Phe Ser Leu Arg Leu Glu Ser Ala Ala Pro Ser
385 390 395 400
Gln Thr Ser Val Tyr Phe Cys Ala Ser Ile Gly Gly Phe Glu Ala Phe
405 410 415
Phe Gly Gln Gly Thr Arg Leu Thr Val Val Glu Asp Leu Arg Asn Val
420 425 430
Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala
435 440 445
Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro
450 455 460
Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser
465 470 475 480
Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr
485 490 495
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro
500 505 510
Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu
515 520 525
Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser
530 535 540
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
545 550 555 560
Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
565 570 575
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala
580 585 590
Met Val Lys Arg Lys Asn Ser
595
<210> 584
<211> 597
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 584
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Tyr Thr Gly Gly Phe
100 105 110
Lys Thr Ile Phe Gly Ala Gly Thr Arg Leu Phe Val Lys Ala Asn Ile
115 120 125
Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln
130 135 140
Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val
145 150 155 160
Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu
165 170 175
Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser
180 185 190
Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala
195 200 205
Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys
210 215 220
Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile
225 230 235 240
Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
245 250 255
Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala
260 265 270
Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro
275 280 285
Gly Pro Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys Leu Leu
290 295 300
Gly Ala Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg Tyr Lys
305 310 315 320
Ile Ile Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro Ile Ser
325 330 335
Gly His Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln Gly Pro
340 345 350
Lys Leu Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp Ser Gln
355 360 365
Leu Pro Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val Asp Ser
370 375 380
Thr Leu Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val Tyr Leu
385 390 395 400
Cys Ala Ser Asn Leu Gly Gly Gly Ser Thr Asp Thr Gln Tyr Phe Gly
405 410 415
Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val Thr Pro
420 425 430
Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala Asn Lys
435 440 445
Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro Asp His
450 455 460
Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val
465 470 475 480
Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr Cys Leu
485 490 495
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro Arg Asn
500 505 510
His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu Asp Lys
515 520 525
Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser Ala Glu
530 535 540
Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr Gln Gln
545 550 555 560
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
565 570 575
Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala Met Val
580 585 590
Lys Arg Lys Asn Ser
595
<210> 585
<211> 599
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 585
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Phe Tyr Tyr Gly Gly Ser
100 105 110
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser
260 265 270
Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu
275 280 285
Asn Pro Gly Pro Met His Thr Arg Leu Leu Cys Trp Val Val Leu Gly
290 295 300
Phe Leu Gly Thr Asp His Thr Gly Ala Gly Val Ser Gln Ser Pro Arg
305 310 315 320
Tyr Lys Val Ala Lys Arg Gly Gln Asp Val Ala Leu Arg Cys Asp Pro
325 330 335
Ile Ser Gly His Val Ser Leu Phe Trp Tyr Gln Gln Ala Leu Gly Gln
340 345 350
Gly Pro Glu Phe Leu Thr Tyr Phe Gln Asn Glu Ala Gln Leu Asp Lys
355 360 365
Ser Gly Leu Pro Ser Asp Arg Phe Phe Ala Glu Arg Pro Glu Gly Ser
370 375 380
Val Ser Thr Leu Lys Ile Gln Arg Thr Gln Gln Glu Asp Ser Ala Val
385 390 395 400
Tyr Leu Cys Ala Ser Ser Phe Gly Ser Gly Ser Thr Asp Thr Gln Tyr
405 410 415
Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val
420 425 430
Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala
435 440 445
Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro
450 455 460
Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser
465 470 475 480
Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr
485 490 495
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro
500 505 510
Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu
515 520 525
Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser
530 535 540
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
545 550 555 560
Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
565 570 575
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala
580 585 590
Met Val Lys Arg Lys Asn Ser
595
<210> 586
<211> 599
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 586
Met Ala Gly Val Phe Leu Leu Tyr Val Ser Met Lys Met Gly Gly Thr
1 5 10 15
Thr Gly Gln Asn Ile Asp Gln Pro Thr Glu Met Thr Ala Thr Glu Gly
20 25 30
Ala Ile Val Gln Ile Asn Cys Thr Tyr Gln Thr Ser Gly Phe Asn Gly
35 40 45
Leu Phe Trp Tyr Gln Gln His Ala Gly Glu Ala Pro Thr Phe Leu Ser
50 55 60
Tyr Asn Val Leu Asp Gly Leu Glu Glu Lys Gly Arg Phe Ser Ser Phe
65 70 75 80
Leu Ser Arg Ser Lys Gly Tyr Ser Tyr Leu Leu Leu Lys Glu Leu Gln
85 90 95
Met Lys Asp Ser Ala Ser Tyr Leu Cys Ala Val Tyr Pro Gly Gly Ser
100 105 110
Gln Gly Asn Leu Ile Phe Gly Lys Gly Thr Lys Leu Ser Val Lys Pro
115 120 125
Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr Gln Leu Lys Asp Pro Arg
130 135 140
Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr Asp Phe Asp Ser Gln Ile
145 150 155 160
Asn Val Pro Lys Thr Met Glu Ser Gly Thr Phe Ile Thr Asp Lys Cys
165 170 175
Val Leu Asp Met Lys Ala Met Asp Ser Lys Ser Asn Gly Ala Ile Ala
180 185 190
Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln Asp Ile Phe Lys Glu Thr
195 200 205
Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro Cys Asp Ala Thr Leu Thr
210 215 220
Glu Lys Ser Phe Glu Thr Asp Met Asn Leu Asn Phe Gln Asn Leu Leu
225 230 235 240
Val Ile Val Leu Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
245 250 255
Leu Met Thr Leu Arg Leu Trp Ser Ser Arg Ala Lys Arg Ser Gly Ser
260 265 270
Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu
275 280 285
Asn Pro Gly Pro Met His Thr Arg Leu Leu Cys Trp Ala Ala Leu Cys
290 295 300
Leu Leu Gly Ala Glu Leu Thr Glu Ala Gly Val Ala Gln Ser Pro Arg
305 310 315 320
Tyr Lys Ile Ile Glu Lys Arg Gln Ser Val Ala Phe Trp Cys Asn Pro
325 330 335
Ile Ser Gly His Ala Thr Leu Tyr Trp Tyr Gln Gln Ile Leu Gly Gln
340 345 350
Gly Pro Lys Leu Leu Ile Gln Phe Gln Asn Asn Gly Val Val Asp Asp
355 360 365
Ser Gln Leu Pro Lys Asp Arg Phe Ser Ala Glu Arg Leu Lys Gly Val
370 375 380
Asp Ser Thr Leu Lys Ile Gln Pro Ala Lys Leu Glu Asp Ser Ala Val
385 390 395 400
Tyr Leu Cys Ala Ser Ser Leu Gly Thr Gly Ser Thr Asp Thr Gln Tyr
405 410 415
Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Arg Asn Val
420 425 430
Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys Ala Glu Ile Ala
435 440 445
Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg Gly Phe Phe Pro
450 455 460
Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser
465 470 475 480
Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser Asn Tyr Ser Tyr
485 490 495
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp His Asn Pro
500 505 510
Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly Leu Ser Glu Glu
515 520 525
Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr Gln Asn Ile Ser
530 535 540
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr Ser Ala Ser Tyr
545 550 555 560
Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly
565 570 575
Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu Val Val Met Ala
580 585 590
Met Val Lys Arg Lys Asn Ser
595
<210> 587
<211> 606
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 587
Met Ala Ser Ile Arg Ala Val Phe Ile Phe Leu Trp Leu Gln Leu Asp
1 5 10 15
Leu Val Asn Gly Glu Asn Val Glu Gln His Pro Ser Thr Leu Ser Val
20 25 30
Gln Glu Gly Asp Ser Ala Val Ile Lys Cys Thr Tyr Ser Asp Ser Ala
35 40 45
Ser Asn Tyr Phe Pro Trp Tyr Lys Gln Glu Leu Gly Lys Gly Pro Gln
50 55 60
Leu Ile Ile Asp Ile Arg Ser Asn Val Gly Glu Lys Lys Asp Gln Arg
65 70 75 80
Ile Ala Val Thr Leu Asn Lys Thr Ala Lys His Phe Ser Leu His Ile
85 90 95
Thr Glu Thr Gln Pro Glu Asp Ser Ala Val Tyr Phe Cys Ala Ala Ser
100 105 110
Lys Ser Ala Ile Met Val Val Leu Gln Thr Ser Ser Ser Leu Glu Leu
115 120 125
Ala Leu Cys Leu Leu Ser Ser Gln Val Asn Ile Gln Asn Pro Glu Pro
130 135 140
Ala Val Tyr Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys
145 150 155 160
Leu Phe Thr Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu
165 170 175
Ser Gly Thr Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met
180 185 190
Asp Ser Lys Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe
195 200 205
Thr Cys Gln Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser
210 215 220
Asp Val Pro Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Met Asn Leu Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu
245 250 255
Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp
260 265 270
Ser Ser Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu
275 280 285
Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Pro
290 295 300
Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala Gly Pro Leu
305 310 315 320
Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr Val Thr Gly
325 330 335
Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His Glu Tyr Met
340 345 350
Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln Ile Tyr Tyr
355 360 365
Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro Glu Gly Tyr
370 375 380
Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile Leu Glu Ser
385 390 395 400
Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser Ser Ile Gln
405 410 415
Gln Gly Ala Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val
420 425 430
Leu Glu Asp Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu
435 440 445
Pro Ser Lys Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys
450 455 460
Leu Ala Arg Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val
465 470 475 480
Asn Gly Lys Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr
485 490 495
Lys Glu Ser Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser
500 505 510
Ala Thr Phe Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln
515 520 525
Phe His Gly Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys
530 535 540
Pro Val Thr Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys
545 550 555 560
Gly Ile Thr Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile
565 570 575
Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val
580 585 590
Ser Thr Leu Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600 605
<210> 588
<211> 603
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 588
Met Ala Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu Ser
1 5 10 15
Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asn Ser Gly Pro Leu
20 25 30
Ser Val Pro Glu Gly Ala Ile Ala Ser Leu Asn Cys Thr Tyr Ser Asp
35 40 45
Arg Gly Ser Gln Ser Phe Phe Trp Tyr Arg Gln Tyr Ser Gly Lys Ser
50 55 60
Pro Glu Leu Ile Met Phe Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly
65 70 75 80
Arg Phe Thr Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu
85 90 95
Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Trp
100 105 110
Asn Ser Gly Gly Ser Asn Tyr Lys Leu Thr Phe Gly Lys Gly Thr Leu
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 Arg Ala
260 265 270
Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala
275 280 285
Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Leu Gly Leu Leu Cys
290 295 300
Cys Gly Ala Phe Ser Leu Leu Trp Ala Gly Pro Val Asn Ala Gly Val
305 310 315 320
Thr Gln Thr Pro Lys Phe Arg Val Leu Lys Thr Gly Gln Ser Met Thr
325 330 335
Leu Leu Cys Ala Gln Asp Met Asn His Glu Tyr Met Tyr Trp Tyr Arg
340 345 350
Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val Gly Glu
355 360 365
Gly Thr Thr Ala Lys Gly Glu Val Pro Asp Gly Tyr Asn Val Ser Arg
370 375 380
Leu Lys Lys Gln Asn Phe Leu Leu Gly Leu Glu Ser Ala Ala Pro Ser
385 390 395 400
Gln Thr Ser Val Tyr Phe Cys Ala Ser Ser Tyr Ser Gln Ala Trp Gly
405 410 415
Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu Glu Asp
420 425 430
Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys
435 440 445
Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg
450 455 460
Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys
465 470 475 480
Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser
485 490 495
Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe
500 505 510
Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly
515 520 525
Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr
530 535 540
Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr
545 550 555 560
Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu
565 570 575
Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu
580 585 590
Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 589
<211> 603
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 589
Met Ala Lys Asn Pro Leu Ala Ala Pro Leu Leu Ile Leu Trp Phe His
1 5 10 15
Leu Asp Cys Val Ser Ser Ile Leu Asn Val Glu Gln Ser Pro Gln Ser
20 25 30
Leu His Val Gln Glu Gly Asp Ser Thr Asn Phe Thr Cys Ser Phe Pro
35 40 45
Ser Ser Asn Phe Tyr Ala Leu His Trp Tyr Arg Trp Glu Thr Ala Lys
50 55 60
Ser Pro Glu Ala Leu Phe Val Met Thr Leu Asn Gly Asp Glu Lys Lys
65 70 75 80
Lys Gly Arg Ile Ser Ala Thr Leu Asn Thr Lys Glu Gly Tyr Ser Tyr
85 90 95
Leu Tyr Ile Lys Gly Ser Gln Pro Glu Asp Ser Ala Thr Tyr Leu Cys
100 105 110
Ala Leu Ile Thr Gly Gly Gly Asn Lys Leu Thr Phe Gly Thr Gly Thr
115 120 125
Gln Leu Lys Val Glu Leu Asn Ile Gln Asn Pro Glu Pro Ala Val Tyr
130 135 140
Gln Leu Lys Asp Pro Arg Ser Gln Asp Ser Thr Leu Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Ile Asn Val Pro Lys Thr Met Glu Ser Gly Thr
165 170 175
Phe Ile Thr Asp Lys Cys Val Leu Asp Met Lys Ala Met Asp Ser Lys
180 185 190
Ser Asn Gly Ala Ile Ala Trp Ser Asn Gln Thr Ser Phe Thr Cys Gln
195 200 205
Asp Ile Phe Lys Glu Thr Asn Ala Thr Tyr Pro Ser Ser Asp Val Pro
210 215 220
Cys Asp Ala Thr Leu Thr Glu Lys Ser Phe Glu Thr Asp Met Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Leu Val Ile Val Leu Arg Ile Leu Leu Leu Lys
245 250 255
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser Arg
260 265 270
Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln
275 280 285
Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met His Leu Gly Leu Leu
290 295 300
Cys Cys Gly Ala Phe Ser Leu Leu Trp Ala Gly Pro Val Asn Ala Gly
305 310 315 320
Val Thr Gln Thr Pro Lys Phe Arg Val Leu Lys Thr Gly Gln Ser Met
325 330 335
Thr Leu Leu Cys Ala Gln Asp Met Asn His Glu Tyr Met Tyr Trp Tyr
340 345 350
Arg Gln Asp Pro Gly Met Gly Leu Arg Leu Ile His Tyr Ser Val Gly
355 360 365
Glu Gly Thr Thr Ala Lys Gly Glu Val Pro Asp Gly Tyr Asn Val Ser
370 375 380
Arg Leu Lys Lys Gln Asn Phe Leu Leu Gly Leu Glu Ser Ala Ala Pro
385 390 395 400
Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser Arg Leu Gln Gly Trp Asn
405 410 415
Ser Pro Leu His Phe Gly Asn Gly Thr Arg Leu Thr Val Thr Glu Asp
420 425 430
Leu Arg Asn Val Thr Pro Pro Lys Val Ser Leu Phe Glu Pro Ser Lys
435 440 445
Ala Glu Ile Ala Asn Lys Gln Lys Ala Thr Leu Val Cys Leu Ala Arg
450 455 460
Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys
465 470 475 480
Glu Val His Ser Gly Val Cys Thr Asp Pro Gln Ala Tyr Lys Glu Ser
485 490 495
Asn Tyr Ser Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe
500 505 510
Trp His Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe His Gly
515 520 525
Leu Ser Glu Glu Asp Lys Trp Pro Glu Gly Ser Pro Lys Pro Val Thr
530 535 540
Gln Asn Ile Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Ile Thr
545 550 555 560
Ser Ala Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu
565 570 575
Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Thr Leu
580 585 590
Val Val Met Ala Met Val Lys Arg Lys Asn Ser
595 600
<210> 590
<211> 10
<212> PRT
<213> 人
<400> 590
Ser Ser Cys Met Gly Gly Met Asn Arg Arg
1 5 10
<210> 591
<211> 10
<212> PRT
<213> 人
<400> 591
Ser Ser Cys Met Gly Gly Met Asn Trp Arg
1 5 10
<210> 592
<211> 15
<212> PRT
<213> 人
<400> 592
Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn Trp Arg Pro
1 5 10 15
<210> 593
<211> 15
<212> PRT
<213> 人
<400> 593
Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn Trp Arg Pro Ile
1 5 10 15
<210> 594
<211> 15
<212> PRT
<213> 人
<400> 594
Cys Asn Ser Ser Cys Met Gly Gly Met Asn Trp Arg Pro Ile Leu
1 5 10 15
<210> 595
<211> 15
<212> PRT
<213> 人
<400> 595
Asn Ser Ser Cys Met Gly Gly Met Asn Trp Arg Pro Ile Leu Thr
1 5 10 15
<210> 596
<211> 15
<212> PRT
<213> 人
<400> 596
Ser Ser Cys Met Gly Gly Met Asn Trp Arg Pro Ile Leu Thr Ile
1 5 10 15
<210> 597
<211> 15
<212> PRT
<213> 人
<400> 597
Ser Cys Met Gly Gly Met Asn Trp Arg Pro Ile Leu Thr Ile Ile
1 5 10 15
<210> 598
<211> 15
<212> PRT
<213> 人
<400> 598
Cys Met Gly Gly Met Asn Trp Arg Pro Ile Leu Thr Ile Ile Thr
1 5 10 15
<210> 599
<211> 15
<212> PRT
<213> 人
<400> 599
Met Gly Gly Met Asn Trp Arg Pro Ile Leu Thr Ile Ile Thr Leu
1 5 10 15
<210> 600
<211> 15
<212> PRT
<213> 人
<400> 600
Gly Gly Met Asn Trp Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu
1 5 10 15
<210> 601
<211> 15
<212> PRT
<213> 人
<400> 601
Gly Met Asn Trp Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp
1 5 10 15
<210> 602
<211> 15
<212> PRT
<213> 人
<400> 602
Met Asn Trp Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser
1 5 10 15
Claims (23)
1.对突变的人p53具有抗原特异性的分离或纯化的T细胞受体(TCR)。
2.如权利要求1所述的TCR，其中所述TCR对在SEQ ID NO:1的第175、220、245或248位置处具有突变的人p53具有抗原特异性。
3.如权利要求1所述的TCR，其中所述TCR对具有以下一个人p53突变的人p53具有抗原性特异性:R175H、Y220C、G245S、R248Q或R248W。
4.如权利要求1-3中任一项所述的TCR，其中所述TCR包含以下氨基酸序列:
(1)所有SEQ ID NO:27-32；
(2)所有SEQ ID NO:37-42；
(3)所有SEQ ID NO:47-52；
(4)所有SEQ ID NO:57-62；
(5)所有SEQ ID NO:67-72；
(6)所有SEQ ID NO:77-82；
(7)所有SEQ ID NO:87-92；
(8)所有SEQ ID NO:97-102；
(9)所有SEQ ID NO:107-112；
(10)所有SEQ ID NO:117-122；
(11)所有SEQ ID NO:127-132；
(12)所有SEQ ID NO:137-142；
(13)所有SEQ ID NO:147-152；
(14)所有SEQ ID NO:157-162；
(15)所有SEQ ID NO:167-172；
(16)所有SEQ ID NO:177-182；
(17)所有SEQ ID NO:187-192；
(18)所有SEQ ID NO:197-202；
(19)所有SEQ ID NO:207-212；
(20)所有SEQ ID NO:217-222；
(21)所有SEQ ID NO:227-232；
(22)所有SEQ ID NO:237-242；
(23)所有SEQ ID NO:247-252；
(24)所有SEQ ID NO:257-262；
(25)所有SEQ ID NO:267-272；
(26)所有SEQ ID NO:277-282；
(27)所有SEQ ID NO:287-292；
(28)所有SEQ ID NO:297-302；
(29)所有SEQ ID NO:307-312；
(30)所有SEQ ID NO:317-322；
(31)所有SEQ ID NO:327-332；
(32)所有SEQ ID NO:337-342；
(33)所有SEQ ID NO:347-352；
(34)所有SEQ ID NO:357-362；
(35)所有SEQ ID NO:367-372；
(36)所有SEQ ID NO:377-382；
(37)所有SEQ ID NO:387-392；
(38)所有SEQ ID NO:397-402；
(39)所有SEQ ID NO:407-412；
(40)所有SEQ ID NO:417-422；
(41)所有SEQ ID NO:427-432；
(42)所有SEQ ID NO:437-442；
(43)所有SEQ ID NO:447-452；
(44)所有SEQ ID NO:457-462；
(45)所有SEQ ID NO:467-472；
(46)所有SEQ ID NO:477-482；或
(47)所有SEQ ID NO:487-492。
5.如权利要求1-4中任一项所述的TCR，其中所述TCR包含以下氨基酸序列:
(1)SEQ ID NO:33-34两者；
(2)SEQ ID NO:43-44两者；
(3)SEQ ID NO:53-54两者；
(4)SEQ ID NO:63-64两者；
(5)SEQ ID NO:73-74两者；
(6)SEQ ID NO:83-84两者；
(7)SEQ ID NO:93-94两者；
(8)SEQ ID NO:103-104两者；
(9)SEQ ID NO:113-114两者；
(10)SEQ ID NO:123-124两者；
(11)SEQ ID NO:133-134两者；
(12)SEQ ID NO:143-144两者；
(13)SEQ ID NO:153-154两者；
(14)SEQ ID NO:163-164两者；
(15)SEQ ID NO:173-174两者；
(16)SEQ ID NO:183-184两者；
(17)SEQ ID NO:193-194两者；
(18)SEQ ID NO:203-204两者；
(19)SEQ ID NO:213-214两者；
(20)SEQ ID NO:223-224两者；
(21)SEQ ID NO:233-234两者；
(22)SEQ ID NO:243-244两者；
(23)SEQ ID NO:253-254两者；
(24)SEQ ID NO:263-264两者；
(25)SEQ ID NO:273-274两者；
(26)SEQ ID NO:283-284两者；
(27)SEQ ID NO:293-294两者；
(28)SEQ ID NO:303-304两者；
(29)SEQ ID NO:313-314两者；
(30)SEQ ID NO:323-324两者；
(31)SEQ ID NO:333-334两者；
(32)SEQ ID NO:343-344两者；
(33)SEQ ID NO:353-354两者；
(34)SEQ ID NO:363-364两者；
(35)SEQ ID NO:373-374两者；
(36)SEQ ID NO:383-384两者；
(37)SEQ ID NO:393-394两者；
(38)SEQ ID NO:403-404两者；
(39)SEQ ID NO:413-414两者；
(40)SEQ ID NO:423-424两者；
(41)SEQ ID NO:433-434两者；
(42)SEQ ID NO:443-444两者；
(43)SEQ ID NO:453-454两者；
(44)SEQ ID NO:463-464两者；
(45)SEQ ID NO:473-474两者；
(46)SEQ ID NO:483-484两者；或
(47)SEQ ID NO:493-494两者。
6.如权利要求1-5中任一项所述的TCR，其中所述TCR包含以下氨基酸序列:
(1)SEQ ID NO:35-36两者；
(2)SEQ ID NO:45-46两者；
(3)SEQ ID NO:55-56两者；
(4)SEQ ID NO:65-66两者；
(5)SEQ ID NO:75-76两者；
(6)SEQ ID NO:85-86两者；
(7)SEQ ID NO:95-96两者；
(8)SEQ ID NO:105-106两者；
(9)SEQ ID NO:115-116两者；
(10)SEQ ID NO:125-126两者；
(11)SEQ ID NO:135-136两者；
(12)SEQ ID NO:145-146两者；
(13)SEQ ID NO:155-156两者；
(14)SEQ ID NO:165-166两者；
(15)SEQ ID NO:175-176两者；
(16)SEQ ID NO:185-186两者；
(17)SEQ ID NO:195-196两者；
(18)SEQ ID NO:205-206两者；
(19)SEQ ID NO:215-216两者；
(20)SEQ ID NO:225-226两者；
(21)SEQ ID NO:235-236两者；
(22)SEQ ID NO:245-246两者；
(23)SEQ ID NO:255-256两者；
(24)SEQ ID NO:265-266两者；
(25)SEQ ID NO:275-276两者；
(26)SEQ ID NO:285-286两者；
(27)SEQ ID NO:295-296两者；
(28)SEQ ID NO:305-306两者；
(29)SEQ ID NO:315-316两者；
(30)SEQ ID NO:325-326两者；
(31)SEQ ID NO:335-336两者；
(32)SEQ ID NO:345-346两者；
(33)SEQ ID NO:355-356两者；
(34)SEQ ID NO:365-366两者；
(35)SEQ ID NO:375-376两者；
(36)SEQ ID NO:385-386两者；
(37)SEQ ID NO:395-396两者；
(38)SEQ ID NO:405-406两者；
(39)SEQ ID NO:415-416两者；
(40)SEQ ID NO:425-426两者；
(41)SEQ ID NO:435-436两者；
(42)SEQ ID NO:445-446两者；
(43)SEQ ID NO:455-456两者；
(44)SEQ ID NO:465-466两者；
(45)SEQ ID NO:475-476两者；
(46)SEQ ID NO:485-486两者；或
(47)SEQ ID NO:495-496两者。
7.分离或纯化的多肽，其包含权利要求1-6中任一项所述的TCR的功能部分，其中所述多肽包含以下氨基酸序列:
(1)所有SEQ ID NO:27-32；
(2)所有SEQ ID NO:37-42；
(3)所有SEQ ID NO:47-52；
(4)所有SEQ ID NO:57-62；
(5)所有SEQ ID NO:67-72；
(6)所有SEQ ID NO:77-82；
(7)所有SEQ ID NO:87-92；
(8)所有SEQ ID NO:97-102；
(9)所有SEQ ID NO:107-112；
(10)所有SEQ ID NO:117-122；
(11)所有SEQ ID NO:127-132；
(12)所有SEQ ID NO:137-142；
(13)所有SEQ ID NO:147-152；
(14)所有SEQ ID NO:157-162；
(15)所有SEQ ID NO:167-172；
(16)所有SEQ ID NO:177-182；
(17)所有SEQ ID NO:187-192；
(18)所有SEQ ID NO:197-202；
(19)所有SEQ ID NO:207-212；
(20)所有SEQ ID NO:217-222；
(21)所有SEQ ID NO:227-232；
(22)所有SEQ ID NO:237-242；
(23)所有SEQ ID NO:247-252；
(24)所有SEQ ID NO:257-262；
(25)所有SEQ ID NO:267-272；
(26)所有SEQ ID NO:277-282；
(27)所有SEQ ID NO:287-292；
(28)所有SEQ ID NO:297-302；
(29)所有SEQ ID NO:307-312；
(30)所有SEQ ID NO:317-322；
(31)所有SEQ ID NO:327-332；
(32)所有SEQ ID NO:337-342；
(33)所有SEQ ID NO:347-352；
(34)所有SEQ ID NO:357-362；
(35)所有SEQ ID NO:367-372；
(36)所有SEQ ID NO:377-382；
(37)所有SEQ ID NO:387-392；
(38)所有SEQ ID NO:397-402；
(39)所有SEQ ID NO:407-412；
(40)所有SEQ ID NO:417-422；
(41)所有SEQ ID NO:427-432；
(42)所有SEQ ID NO:437-442；
(43)所有SEQ ID NO:447-452；
(44)所有SEQ ID NO:457-462；
(45)所有SEQ ID NO:467-472；
(46)所有SEQ ID NO:477-482；或
(47)所有SEQ ID NO:487-492。
8.如权利要求7所述的多肽，其中所述多肽包含以下氨基酸序列:
(1)SEQ ID NO:33-34两者；
(2)SEQ ID NO:43-44两者；
(3)SEQ ID NO:53-54两者；
(4)SEQ ID NO:63-64两者；
(5)SEQ ID NO:73-74两者；
(6)SEQ ID NO:83-84两者；
(7)SEQ ID NO:93-94两者；
(8)SEQ ID NO:103-104两者；
(9)SEQ ID NO:113-114两者；
(10)SEQ ID NO:123-124两者；
(11)SEQ ID NO:133-134两者；
(12)SEQ ID NO:143-144两者；
(13)SEQ ID NO:153-154两者；
(14)SEQ ID NO:163-164两者；
(15)SEQ ID NO:173-174两者；
(16)SEQ ID NO:183-184两者；
(17)SEQ ID NO:193-194两者；
(18)SEQ ID NO:203-204两者；
(19)SEQ ID NO:213-214两者；
(20)SEQ ID NO:223-224两者；
(21)SEQ ID NO:233-234两者；
(22)SEQ ID NO:243-244两者；
(23)SEQ ID NO:253-254两者；
(24)SEQ ID NO:263-264两者；
(25)SEQ ID NO:273-274两者；
(26)SEQ ID NO:283-284两者；
(27)SEQ ID NO:293-294两者；
(28)SEQ ID NO:303-304两者；
(29)SEQ ID NO:313-314两者；
(30)SEQ ID NO:323-324两者；
(31)SEQ ID NO:333-334两者；
(32)SEQ ID NO:343-344两者；
(33)SEQ ID NO:353-354两者；
(34)SEQ ID NO:363-364两者；
(35)SEQ ID NO:373-374两者；
(36)SEQ ID NO:383-384两者；
(37)SEQ ID NO:393-394两者；
(38)SEQ ID NO:403-404两者；
(39)SEQ ID NO:413-414两者；
(40)SEQ ID NO:423-424两者；
(41)SEQ ID NO:433-434两者；
(42)SEQ ID NO:443-444两者；
(43)SEQ ID NO:453-454两者；
(44)SEQ ID NO:463-464两者；
(45)SEQ ID NO:473-474两者；
(46)SEQ ID NO:483-484两者；或
(47)SEQ ID NO:493-494两者。
9.如权利要求7或8所述的多肽，其中所述多肽包含以下氨基酸序列:
(1)SEQ ID NO:35-36两者；
(2)SEQ ID NO:45-46两者；
(3)SEQ ID NO:55-56两者；
(4)SEQ ID NO:65-66两者；
(5)SEQ ID NO:75-76两者；
(6)SEQ ID NO:85-86两者；
(7)SEQ ID NO:95-96两者；
(8)SEQ ID NO:105-106两者；
(9)SEQ ID NO:115-116两者；
(10)SEQ ID NO:125-126两者；
(11)SEQ ID NO:135-136两者；
(12)SEQ ID NO:145-146两者；
(13)SEQ ID NO:155-156两者；
(14)SEQ ID NO:165-166两者；
(15)SEQ ID NO:175-176两者；
(16)SEQ ID NO:185-186两者；
(17)SEQ ID NO:195-196两者；
(18)SEQ ID NO:205-206两者；
(19)SEQ ID NO:215-216两者；
(20)SEQ ID NO:225-226两者；
(21)SEQ ID NO:235-236两者；
(22)SEQ ID NO:245-246两者；
(23)SEQ ID NO:255-256两者；
(24)SEQ ID NO:265-266两者；
(25)SEQ ID NO:275-276两者；
(26)SEQ ID NO:285-286两者；
(27)SEQ ID NO:295-296两者；
(28)SEQ ID NO:305-306两者；
(29)SEQ ID NO:315-316两者；
(30)SEQ ID NO:325-326两者；
(31)SEQ ID NO:335-336两者；
(32)SEQ ID NO:345-346两者；
(33)SEQ ID NO:355-356两者；
(34)SEQ ID NO:365-366两者；
(35)SEQ ID NO:375-376两者；
(36)SEQ ID NO:385-386两者；
(37)SEQ ID NO:395-396两者；
(38)SEQ ID NO:405-406两者；
(39)SEQ ID NO:415-416两者；
(40)SEQ ID NO:425-426两者；
(41)SEQ ID NO:435-436两者；
(42)SEQ ID NO:445-446两者；
(43)SEQ ID NO:455-456两者；
(44)SEQ ID NO:465-466两者；
(45)SEQ ID NO:475-476两者；
(46)SEQ ID NO:485-486两者；或
(47)SEQ ID NO:495-496两者；
10.分离或纯化的蛋白，其包含:
(1)包含所有SEQ ID NO:27-29的氨基酸序列的第一多肽链和包含所有SEQ ID NO:30-32的氨基酸序列的第二多肽链；
(2)包含所有SEQ ID NO:37-39的氨基酸序列的第一多肽链和包含所有SEQ ID NO:40-42的氨基酸序列的第二多肽链；
(3)包含所有SEQ ID NO:47-49的氨基酸序列的第一多肽链和包含所有SEQ ID NO:50-52的氨基酸序列的第二多肽链；
(4)包含所有SEQ ID NO:57-59的氨基酸序列的第一多肽链和包含所有SEQ ID NO:60-62的氨基酸序列的第二多肽链；
(5)包含所有SEQ ID NO:67-69的氨基酸序列的第一多肽链和包含所有SEQ ID NO:70-72的氨基酸序列的第二多肽链；
(6)包含所有SEQ ID NO:77-79的氨基酸序列的第一多肽链和包含所有SEQ ID NO:80-82的氨基酸序列的第二多肽链；
(7)包含所有SEQ ID NO:87-89的氨基酸序列的第一多肽链和包含所有SEQ ID NO:90-92的氨基酸序列的第二多肽链；
(8)包含所有SEQ ID NO:97-99的氨基酸序列的第一多肽链和包含所有SEQ ID NO:100-102的氨基酸序列的第二多肽链；
(9)包含所有SEQ ID NO:107-109的氨基酸序列的第一多肽链和包含所有SEQ ID NO:110-112的氨基酸序列的第二多肽链；
(10)包含所有SEQ ID NO:117-119的氨基酸序列的第一多肽链和包含所有SEQ ID NO:120-122的氨基酸序列的第二多肽链；
(11)包含所有SEQ ID NO:127-129的氨基酸序列的第一多肽链和包含所有SEQ ID NO:130-132的氨基酸序列的第二多肽链；
(12)包含所有SEQ ID NO:137-139的氨基酸序列的第一多肽链和包含所有SEQ ID NO:140-142的氨基酸序列的第二多肽链；
(13)包含所有SEQ ID NO:147-149的氨基酸序列的第一多肽链和包含所有SEQ ID NO:150-152的氨基酸序列的第二多肽链；
(14)包含所有SEQ ID NO:157-159的氨基酸序列的第一多肽链和包含所有SEQ ID NO:160-162的氨基酸序列的第二多肽链；
(15)包含所有SEQ ID NO:167-169的氨基酸序列的第一多肽链和包含所有SEQ ID NO:170-172的氨基酸序列的第二多肽链；
(16)包含所有SEQ ID NO:177-179的氨基酸序列的第一多肽链和包含所有SEQ ID NO:180-182的氨基酸序列的第二多肽链；
(17)包含所有SEQ ID NO:187-189的氨基酸序列的第一多肽链和包含所有SEQ ID NO:190-192的氨基酸序列的第二多肽链；
(18)包含所有SEQ ID NO:197-199的氨基酸序列的第一多肽链和包含所有SEQ ID NO:200-202的氨基酸序列的第二多肽链；
(19)包含所有SEQ ID NO:207-209的氨基酸序列的第一多肽链和包含所有SEQ ID NO:210-212的氨基酸序列的第二多肽链；
(20)包含所有SEQ ID NO:217-219的氨基酸序列的第一多肽链和包含所有SEQ ID NO:220-222的氨基酸序列的第二多肽链；
(21)包含所有SEQ ID NO:227-229的氨基酸序列的第一多肽链和包含所有SEQ ID NO:230-232的氨基酸序列的第二多肽链；
(22)包含所有SEQ ID NO:237-239的氨基酸序列的第一多肽链和包含所有SEQ ID NO:240-242的氨基酸序列的第二多肽链；
(23)包含所有SEQ ID NO:247-249的氨基酸序列的第一多肽链和包含所有SEQ ID NO:250-252的氨基酸序列的第二多肽链；
(24)包含所有SEQ ID NO:257-259的氨基酸序列的第一多肽链和包含所有SEQ ID NO:260-262的氨基酸序列的第二多肽链；
(25)包含所有SEQ ID NO:267-269的氨基酸序列的第一多肽链和包含所有SEQ ID NO:270-272的氨基酸序列的第二多肽链；
(26)包含所有SEQ ID NO:277-279的氨基酸序列的第一多肽链和包含所有SEQ ID NO:280-282的氨基酸序列的第二多肽链；
(27)包含所有SEQ ID NO:287-289的氨基酸序列的第一多肽链和包含所有SEQ ID NO:290-292的氨基酸序列的第二多肽链；
(28)包含所有SEQ ID NO:297-299的氨基酸序列的第一多肽链和包含所有SEQ ID NO:300-302的氨基酸序列的第二多肽链；
(29)包含所有SEQ ID NO:307-309的氨基酸序列的第一多肽链和包含所有SEQ ID NO:310-312的氨基酸序列的第二多肽链；
(30)包含所有SEQ ID NO:317-319的氨基酸序列的第一多肽链和包含所有SEQ ID NO:320-322的氨基酸序列的第二多肽链；
(31)包含所有SEQ ID NO:327-329的氨基酸序列的第一多肽链和包含所有SEQ ID NO:330-332的氨基酸序列的第二多肽链；
(32)包含所有SEQ ID NO:337-339的氨基酸序列的第一多肽链和包含所有SEQ ID NO:340-342的氨基酸序列的第二多肽链；
(33)包含所有SEQ ID NO:347-349的氨基酸序列的第一多肽链和包含所有SEQ ID NO:350-352的氨基酸序列的第二多肽链；
(34)包含所有SEQ ID NO:357-359的氨基酸序列的第一多肽链和包含所有SEQ ID NO:360-362的氨基酸序列的第二多肽链；
(35)包含所有SEQ ID NO:367-369的氨基酸序列的第一多肽链和包含所有SEQ ID NO:370-372的氨基酸序列的第二多肽链；
(36)包含所有SEQ ID NO:377-379的氨基酸序列的第一多肽链和包含所有SEQ ID NO:380-382的氨基酸序列的第二多肽链；
(37)包含所有SEQ ID NO:387-389的氨基酸序列的第一多肽链和包含所有SEQ ID NO:390-392的氨基酸序列的第二多肽链；
(38)包含所有SEQ ID NO:397-399的氨基酸序列的第一多肽链和包含所有SEQ ID NO:400-402的氨基酸序列的第二多肽链；
(39)包含所有SEQ ID NO:407-409的氨基酸序列的第一多肽链和包含所有SEQ ID NO:410-412的氨基酸序列的第二多肽链；
(40)包含所有SEQ ID NO:417-419的氨基酸序列的第一多肽链和包含所有SEQ ID NO:420-422的氨基酸序列的第二多肽链；
(41)包含所有SEQ ID NO:427-429的氨基酸序列的第一多肽链和包含所有SEQ ID NO:430-432的氨基酸序列的第二多肽链；
(42)包含所有SEQ ID NO:437-439的氨基酸序列的第一多肽链和包含所有SEQ ID NO:440-442的氨基酸序列的第二多肽链；
(43)包含所有SEQ ID NO:447-449的氨基酸序列的第一多肽链和包含所有SEQ ID NO:450-452的氨基酸序列的第二多肽链；
(44)包含所有SEQ ID NO:457-459的氨基酸序列的第一多肽链和包含所有SEQ ID NO:460-462的氨基酸序列的第二多肽链；
(45)包含所有SEQ ID NO:467-469的氨基酸序列的第一多肽链和包含所有SEQ ID NO:470-472的氨基酸序列的第二多肽链；
(46)包含所有SEQ ID NO:477-479的氨基酸序列的第一多肽链和包含所有SEQ ID NO:480-482的氨基酸序列分人第二多肽链；或
(47)包含所有SEQ ID NO:487-489的氨基酸序列的第一多肽链和包含所有SEQ ID NO:490-492的氨基酸序列的第二多肽链。
11.如权利要求10所述的蛋白，其中所述蛋白包含:
(1)包含SEQ ID NO:33的氨基酸序列的第一多肽链和包含SEQ ID NO:34的氨基酸序列的第二多肽链；
(2)包含SEQ ID NO:43的氨基酸序列的第一多肽链和包含SEQ ID NO:44的氨基酸序列的第二多肽链；
(3)包含SEQ ID NO:53的氨基酸序列的第一多肽链和包含SEQ ID NO:54的氨基酸序列的第二多肽链；
(4)包含SEQ ID NO:63的氨基酸序列的第一多肽链和包含SEQ ID NO:64的氨基酸序列的第二多肽链；
(5)包含SEQ ID NO:73的氨基酸序列的第一多肽链和包含SEQ ID NO:74的氨基酸序列的第二多肽链；
(6)包含SEQ ID NO:83的氨基酸序列的第一多肽链和包含SEQ ID NO:84的氨基酸序列的第二多肽链；
(7)包含SEQ ID NO:93的氨基酸序列的第一多肽链和包含SEQ ID NO:94的氨基酸序列的第二多肽链；
(8)包含SEQ ID NO:103的氨基酸序列的第一多肽链和包含SEQ ID NO:104的氨基酸序列的第二多肽链；
(9)包含SEQ ID NO:113的氨基酸序列的第一多肽链和包含SEQ ID NO:114的氨基酸序列的第二多肽链；
(10)包含SEQ ID NO:123的氨基酸序列的第一多肽链和包含SEQ ID NO:124的氨基酸序列的第二多肽链；
(11)包含SEQ ID NO:133的氨基酸序列的第一多肽链和包含SEQ ID NO:134的氨基酸序列的第二多肽链；
(12)包含SEQ ID NO:143的氨基酸序列的第一多肽链和包含SEQ ID NO:144的氨基酸序列的第二多肽链；
(13)包含SEQ ID NO:153的氨基酸序列的第一多肽链和包含SEQ ID NO:154的氨基酸序列的第二多肽链；
(14)包含SEQ ID NO:163的氨基酸序列的第一多肽链和包含SEQ ID NO:164的氨基酸序列的第二多肽链；
(15)包含SEQ ID NO:173的氨基酸序列的第一多肽链和包含SEQ ID NO:174的氨基酸序列的第二多肽链；
(16)包含SEQ ID NO:183的氨基酸序列的第一多肽链和包含SEQ ID NO:184的氨基酸序列的第二多肽链；
(17)包含SEQ ID NO:193的氨基酸序列的第一多肽链和包含SEQ ID NO:194的氨基酸序列的第二多肽链；
(18)包含SEQ ID NO:203的氨基酸序列的第一多肽链和包含SEQ ID NO:204的氨基酸序列的第二多肽链；
(19)包含SEQ ID NO:213的氨基酸序列的第一多肽链和包含SEQ ID NO:214的氨基酸序列的第二多肽链；
(20)包含SEQ ID NO:223的氨基酸序列的第一多肽链和包含SEQ ID NO:224的氨基酸序列的第二多肽链；
(21)包含SEQ ID NO:233的氨基酸序列的第一多肽链和包含SEQ ID NO:234的氨基酸序列的第二多肽链；
(22)包含SEQ ID NO:243的氨基酸序列的第一多肽链和包含SEQ ID NO:244的氨基酸序列的第二多肽链；
(23)包含SEQ ID NO:253的氨基酸序列的第一多肽链和包含SEQ ID NO:254的氨基酸序列的第二多肽链；
(24)包含SEQ ID NO:263的氨基酸序列的第一多肽链和包含SEQ ID NO:264的氨基酸序列的第二多肽链；
(25)包含SEQ ID NO:273的氨基酸序列的第一多肽链和包含SEQ ID NO:274的氨基酸序列的第二多肽链；
(26)包含SEQ ID NO:283的氨基酸序列的第一多肽链和包含SEQ ID NO:284的氨基酸序列的第二多肽链；
(27)包含SEQ ID NO:293的氨基酸序列的第一多肽链和包含SEQ ID NO:294的氨基酸序列的第二多肽链；
(28)包含SEQ ID NO:303的氨基酸序列的第一多肽链和包含SEQ ID NO:304的氨基酸序列的第二多肽链；
(29)包含SEQ ID NO:313的氨基酸序列的第一多肽链和包含SEQ ID NO:314的氨基酸序列的第二多肽链；
(30)包含SEQ ID NO:323的氨基酸序列的第一多肽链和包含SEQ ID NO:324的氨基酸序列的第二多肽链；
(31)包含SEQ ID NO:333的氨基酸序列的第一多肽链和包含SEQ ID NO:334的氨基酸序列的第二多肽链；
(32)包含SEQ ID NO:343的氨基酸序列的第一多肽链和包含SEQ ID NO:344的氨基酸序列的第二多肽链；
(33)包含SEQ ID NO:353的氨基酸序列的第一多肽链和包含SEQ ID NO:354的氨基酸序列的第二多肽链；
(34)包含SEQ ID NO:363的氨基酸序列的第一多肽链和包含SEQ ID NO:364的氨基酸序列的第二多肽链；
(35)包含SEQ ID NO:373的氨基酸序列的第一多肽链和包含SEQ ID NO:374的氨基酸序列的第二多肽链；
(36)包含SEQ ID NO:383的氨基酸序列的第一多肽链和包含SEQ ID NO:384的氨基酸序列的第二多肽链；
(37)包含SEQ ID NO:393的氨基酸序列的第一多肽链和包含SEQ ID NO:394的氨基酸序列的第二多肽链；
(38)包含SEQ ID NO:403的氨基酸序列的第一多肽链和包含SEQ ID NO:404的氨基酸序列的第二多肽链；
(39)包含SEQ ID NO:413的氨基酸序列的第一多肽链和包含SEQ ID NO:414的氨基酸序列的第二多肽链；
(40)包含SEQ ID NO:423的氨基酸序列的第一多肽链和包含SEQ ID NO:424的氨基酸序列的第二多肽链；
(41)包含SEQ ID NO:433的氨基酸序列的第一多肽链和包含SEQ ID NO:434的氨基酸序列的第二多肽链；
(42)包含SEQ ID NO:443的氨基酸序列的第一多肽链和包含SEQ ID NO:444的氨基酸序列的第二多肽链；
(43)包含SEQ ID NO:453的氨基酸序列的第一多肽链和包含SEQ ID NO:454的氨基酸序列的第二多肽链；
(44)包含SEQ ID NO:463的氨基酸序列的第一多肽链和包含SEQ ID NO:464的氨基酸序列的第二多肽链；
(45)包含SEQ ID NO:473的氨基酸序列的第一多肽链和包含SEQ ID NO:474的氨基酸序列的第二多肽链；
(46)包含SEQ ID NO:483的氨基酸序列的第一多肽链和包含SEQ ID NO:484的氨基酸序列的第二多肽链；或
(47)包含SEQ ID NO:493的氨基酸序列的第一多肽链和包含SEQ ID NO:494的氨基酸序列的第二多肽链。
12.如权利要求10或11所述的蛋白，其中所述蛋白包含:
(1)包含SEQ ID NO:35的氨基酸序列的第一多肽链和包含SEQ ID NO:36的氨基酸序列的第二多肽链；
(2)包含SEQ ID NO:45的氨基酸序列的第一多肽链和包含SEQ ID NO:46的氨基酸序列的第二多肽链；
(3)包含SEQ ID NO:55的氨基酸序列的第一多肽链和包含SEQ ID NO:56的氨基酸序列的第二多肽链；
(4)包含SEQ ID NO:65的氨基酸序列的第一多肽链和包含SEQ ID NO:66的氨基酸序列的第二多肽链；
(5)包含SEQ ID NO:75的氨基酸序列的第一多肽链和包含SEQ ID NO:76的氨基酸序列的第二多肽链；
(6)包含SEQ ID NO:85的氨基酸序列的第一多肽链和包含SEQ ID NO:86的氨基酸序列的第二多肽链；
(7)包含SEQ ID NO:95的氨基酸序列的第一多肽链和包含SEQ ID NO:96的氨基酸序列的第二多肽链；
(8)包含SEQ ID NO:105的氨基酸序列的第一多肽链和包含SEQ ID NO:106的氨基酸序列的第二多肽链；
(9)包含SEQ ID NO:115的氨基酸序列的第一多肽链和包含SEQ ID NO:116的氨基酸序列的第二多肽链；
(10)包含SEQ ID NO:125的氨基酸序列的第一多肽链和包含SEQ ID NO:126的氨基酸序列的第二多肽链；
(11)包含SEQ ID NO:135的氨基酸序列的第一多肽链和包含SEQ ID NO:136的氨基酸序列的第二多肽链；
(12)包含SEQ ID NO:145的氨基酸序列的第一多肽链和包含SEQ ID NO:146的氨基酸序列的第二多肽链；
(13)包含SEQ ID NO:155的氨基酸序列的第一多肽链和包含SEQ ID NO:156的氨基酸序列的第二多肽链；
(14)包含SEQ ID NO:165的氨基酸序列的第一多肽链和包含SEQ ID NO:166的氨基酸序列的第二多肽链；
(15)包含SEQ ID NO:175的氨基酸序列的第一多肽链和包含SEQ ID NO:176的氨基酸序列的第二多肽链；
(16)包含SEQ ID NO:185的氨基酸序列的第一多肽链和包含SEQ ID NO:186的氨基酸序列的第二多肽链；
(17)包含SEQ ID NO:195的氨基酸序列的第一多肽链和包含SEQ ID NO:196的氨基酸序列的第二多肽链；
(18)包含SEQ ID NO:205的氨基酸序列的第一多肽链和包含SEQ ID NO:206的氨基酸序列的第二多肽链；
(19)包含SEQ ID NO:215的氨基酸序列的第一多肽链和包含SEQ ID NO:216的氨基酸序列的第二多肽链；
(20)包含SEQ ID NO:225的氨基酸序列的第一多肽链和包含SEQ ID NO:226的氨基酸序列的第二多肽链；
(21)包含SEQ ID NO:235的氨基酸序列的第一多肽链和包含SEQ ID NO:236的氨基酸序列的第二多肽链；
(22)包含SEQ ID NO:245的氨基酸序列的第一多肽链和包含SEQ ID NO:246的氨基酸序列的第二多肽链；
(23)包含SEQ ID NO:255的氨基酸序列的第一多肽链和包含SEQ ID NO:256的氨基酸序列的第二多肽链；
(24)包含SEQ ID NO:265的氨基酸序列的第一多肽链和包含SEQ ID NO:266的氨基酸序列的第二多肽链；
(25)包含SEQ ID NO:275的氨基酸序列的第一多肽链和包含SEQ ID NO:276的氨基酸序列的第二多肽链；
(26)包含SEQ ID NO:285的氨基酸序列的第一多肽链和包含SEQ ID NO:286的氨基酸序列的第二多肽链；
(27)包含SEQ ID NO:295的氨基酸序列的第一多肽链和包含SEQ ID NO:296的氨基酸序列的第二多肽链；
(28)包含SEQ ID NO:305的氨基酸序列的第一多肽链和包含SEQ ID NO:306的氨基酸序列的第二多肽链；
(29)包含SEQ ID NO:315的氨基酸序列的第一多肽链和包含SEQ ID NO:316的氨基酸序列的第二多肽链；
(30)包含SEQ ID NO:325的氨基酸序列的第一多肽链和包含SEQ ID NO:326的氨基酸序列的第二多肽链；
(31)包含SEQ ID NO:335的氨基酸序列的第一多肽链和包含SEQ ID NO:336的氨基酸序列的第二多肽链；
(32)包含SEQ ID NO:345的氨基酸序列的第一多肽链和包含SEQ ID NO:346的氨基酸序列的第二多肽链；
(33)包含SEQ ID NO:355的氨基酸序列的第一多肽链和包含SEQ ID NO:356的氨基酸序列的第二多肽链；
(34)包含SEQ ID NO:365的氨基酸序列的第一多肽链和包含SEQ ID NO:366的氨基酸序列的第二多肽链；
(35)包含SEQ ID NO:375的氨基酸序列的第一多肽链和包含SEQ ID NO:376的氨基酸序列的第二多肽链；
(36)包含SEQ ID NO:385的氨基酸序列的第一多肽链和包含SEQ ID NO:386的氨基酸序列的第二多肽链；
(37)包含SEQ ID NO:395的氨基酸序列的第一多肽链和包含SEQ ID NO:396的氨基酸序列的第二多肽链；
(38)包含SEQ ID NO:405的氨基酸序列的第一多肽链和包含SEQ ID NO:406的氨基酸序列的第二多肽链；
(39)包含SEQ ID NO:415的氨基酸序列的第一多肽链和包含SEQ ID NO:416的氨基酸序列的第二多肽链；
(40)包含SEQ ID NO:425的氨基酸序列的第一多肽链和包含SEQ ID NO:426的氨基酸序列的第二多肽链；
(41)包含SEQ ID NO:435的氨基酸序列的第一多肽链和包含SEQ ID NO:436的氨基酸序列的第二多肽链；
(42)包含SEQ ID NO:445的氨基酸序列的第一多肽链和包含SEQ ID NO:446的氨基酸序列的第二多肽链；
(43)包含SEQ ID NO:455的氨基酸序列的第一多肽链和包含SEQ ID NO:456的氨基酸序列的第二多肽链；
(44)包含SEQ ID NO:465的氨基酸序列的第一多肽链和包含SEQ ID NO:466的氨基酸序列的第二多肽链；
(45)包含SEQ ID NO:475的氨基酸序列的第一多肽链和包含SEQ ID NO:476的氨基酸序列的第二多肽链；
(46)包含SEQ ID NO:485的氨基酸序列的第一多肽链和包含SEQ ID NO:486的氨基酸序列的第二多肽链；或
(47)包含SEQ ID NO:495的氨基酸序列的第一多肽链和包含SEQ ID NO:496的氨基酸序列的第二多肽链。
13.分离或纯化的核酸，其包含编码如权利要求1至6任一项所述的TCR、如权利要求7至9任一项所述的多肽或如权利要求10至12任一项所述的蛋白的核苷酸序列。
14.重组表达载体，其包含权利要求13所述的核酸。
15.分离或纯化的宿主细胞，其包含权利要求14所述的重组表达载体。
16.分离或纯化的细胞群，其包含权利要求15所述的宿主细胞。
17.药物组合物，其包含(a)权利要求1-6任一项所述的TCR、权利要求7-9任一项所述的多肽、权利要求10-12任一项所述的蛋白、权利要求13所述的核酸、权利要求14所述的重组表达载体、权利要求15所述的宿主细胞或权利要求16所述的细胞群，以及(b)药学上可接受的载体。
18.检测哺乳动物中存在癌症的方法，所述方法包括:
(a)将包含所述癌症的细胞的样品与权利要求1-6任一项所述的TCR、权利要求7-9任一项所述的多肽、权利要求10-12任一项所述的蛋白、权利要求13所述的核酸、权利要求14所述的重组表达载体、权利要求15所述的宿主细胞、权利要求16所述的细胞群、或权利要求17所述的药物组合物接触，由此形成复合物；以及
(b)检测所述复合物。
其中，检测到所述复合物指示哺乳动物中存在癌症。
19.如权利要求1-6任一项所述的TCR、如权利要求7-9任一项所述的多肽、如权利要求10-12任一项所述的蛋白、如权利要求13所述的核酸、如权利要求14所述的重组表达载体、如权利要求15所述的宿主细胞、如权利要求16所述的细胞群或如权利要求17所述的药物组合物，其用于治疗或预防哺乳动物中的癌症的用途。
20.如权利要求19所述的用于所述用途的细胞群，其中所述细胞群是所述哺乳动物自体的。
21.如权利要求19所述的用于所述用途的细胞群，其中所述细胞群是所述哺乳动物同种异体的。
22.如权利要求18所述的方法，或如权利要求19-21任一权利要求所述的用于所述用途的TCR、多肽、蛋白、核酸、重组表达载体、宿主细胞、细胞群或药物组合物，其中所述癌症是上皮癌。
23.如权利要求18所述的方法，或如权利要求19-21任一权利要求所述的用于所述用途的TCR、多肽、蛋白、核酸、重组表达载体、宿主细胞、细胞群或药物组合物，其中所述癌症是胆管癌、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、胰腺癌或膀胱癌。
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| MX2020003504A (es) | 2020-09-14 |
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| US11939365B2 (en) | 2024-03-26 |
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| KR20200064110A (ko) | 2020-06-05 |
| MX2024005678A (es) | 2024-06-11 |
| IL273515A (en) | 2020-05-31 |
| CN111386282B (zh) | 2024-09-06 |
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