CN113874516A - 病毒载体及其在细胞过继疗法中的用途 - Google Patents
病毒载体及其在细胞过继疗法中的用途 Download PDFInfo
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Abstract
一种载体,其包含编码蛋白质Z1的第一核苷酸序列S1、编码蛋白质Z2的第二核苷酸序列S2、编码蛋白质Y1的第三核苷酸序列S3和编码Y2蛋白质的第四核苷酸序列S4,其中Z1和Z2形成第一二聚体、Y1和Y2形成第二二聚体,其中第一二聚体Z1Z2与第二二聚体Y1Y2不同。
Description
相关申请的交叉引用
这是一项根据专利合作条约的国际申请,要求于2019年5月27日提交的美国临时专利申请号62/853,123的优先权,其内容透过引用整体并入本文。
对电子方式提交的序列表的引用
序列表的正式副本通过EFS-Web以ASCII格式序列表电子提交,其文件名为“3000011-013977_SEQLIST_ST25.txt”,创建于2020年5月26日,大小为313,426字节,与说明书同时提交。此ASCII格式的文档中包含的序列表是说明书的一部分,在此以引用的方式全文并入。
背景
1.领域
本公开涉及T细胞制造。一方面,本公开涉及使用一种单个载体中表达多种蛋白质用多顺反子盒的T细胞制造。更具体来说,本公开涉及共表达TCRαβ和CD8αβ的T细胞的T细胞制造及其在过继细胞疗法中的用途。
2.背景
人淋巴细胞基因工程改造为遗传性、获得性或传染性疾病的潜在疗法需要有效转移和表达转基因。在癌症过继免疫疗法的情况下,天然和/或重组抗肿瘤T细胞受体(TCR)已用于向正常T细胞或肿瘤浸润淋巴细胞赋予抗肿瘤反应性。
Morgan et al.(J Immunol.2003 September 15;171(6):3287–32percent)公开了一种由双顺反子RNA表达的抗gp100 TCR,其中编码TCRβ链的第一个基因表达由长末端重复序列(LTR)控制,而编码TCRα链的第二个基因由内部核糖体进入位点(IRES)控制。用这种抗gp100 TCR基因改造的CD4+ T细胞具有抗原反应性。
Cohen et al.(J Immunol.2005 November 1;175(9):5799–5808)公开了一种双顺反子逆转录病毒载体,用于共表达与p53表位结合的TCRα链和TCRβ链。编码TCRα链的第一个基因表达由LTR控制,编码TCRβ链的第二个基因由IRES控制。p53TCR转导的淋巴细胞能够以高亲和力特异性识别肽脉冲处理的APC以及以野生型或突变型p53蛋白转染的HLA-A2.1+细胞。
Hughes et al.(Hum Gene Ther.2005 April;16(4):457–472)公开了用于共表达抗MART-1 TCR的各种双顺反子逆转录病毒载体。编码TCRα链的第一个基因表达由LTR控制,编码TCRβ链的第二个基因由IRES控制,反之亦然。此外,编码TCRα链的第一个基因表达由LTR控制,编码TCRβ链的第二个基因由PGK启动子控制,反之亦然。用这些载体转导的T细胞显示了出高度活跃的T细胞效应子功能。
Zhao et al.(J Immunol.2005 April 1;174(7):4415-4423)公开了用于共表达NY-ESO-1 TCR的双顺反子逆转录病毒载体。编码TCRα链的第一个基因表达由LTR控制,编码TCRβ链的第二个基因由IRES控制,或编码TCRα链的第一个基因表达由LTR控制,编码TCRβ链的第二个基因由PGK启动子控制。转导的淋巴细胞可有效识别和杀灭HLA-A2和NY-ESO-1阳性黑色素瘤细胞系。
Morgan et al.(Gene Therapy(2008)15,1411–1423)公开了双顺反子慢病毒载体,其与弗林蛋白酶切割位点和氨基酸间隔区(GSG或SGSG(SEQ ID NO:8))结合,然后与2A核糖体跳跃肽结合,以表达抗gp100 TCR或抗MART-1 TCR。当通过添加合成V5肽标签序列来增强间隔序列时,蛋白质加工得到加强,从而产生能够在转导淋巴细胞中介导高水平TCR表达的慢病毒载体。
过继细胞疗法中仍需要安全有效地表达转基因的基因递送系统。
简要概述
一方面,本公开提供了一种基因递送系统,其包括包含编码蛋白质Z1的第一核苷酸序列S1、编码蛋白质Z2的第二核苷酸序列S2、编码蛋白质Y1的第三核苷酸序列S3和编码Y2蛋白质的第四核苷酸序列S4,其中Z1和Z2形成第一二聚体、Y1和Y2形成第二二聚体,其中第一二聚体Z1Z2与第二二聚体Y1Y2不同,并且其中基因递送系统用于适应性细胞疗法。
另一方面,S1、S2、S3和S4可以以选自S1-S2-S3-S4、S1-S2-S4-S3、S1-S3-S2-S4、S1-S3-S4-S2、S1-S4-S3-S2、S1-S4-S2-S3、S2-S1-S3-S4、S2-S1-S4-S3、S2-S3-S1-S4、S2-S3-S4-S1、S2-S4-S3-S1、S2-S4-S1-S3、S3-S1-S2-S4、S3-S1-S4-S2、S3-S2-S1-S4、S3-S2-S4-S1、S3-S4-S1-S2、S3-S4-S2-S1、S4-S1-S2-S3、S4-S1-S3-S2、S4-S2-S1-S3、S4-S2-S3-S1、S4-S3-S1-S2或S4-S3-S2-S1的5'至3'方向串联排列。
另一方面,载体可以进一步包括编码2A肽的第五核苷酸序列S5和编码连接子肽的第六核苷酸序列S6,其中S5和S6位于S1和S2、S1和S3、S1和S4、S2和S3、S2和S4和/或S3和S4之间。
另一方面,2A肽可以选自P2A(SEQ ID NO:3)、T2A(SEQ ID NO:4)、E2A(SEQ ID NO:5)或F2A(SEQ ID NO:6)。
另一方面,连接子肽可以为GSG或SGSG(SEQ ID NO:8)。
另一方面,所述载体可以包括编码弗林蛋白酶肽(SEQ ID NO:2)的第七核苷酸序列S7,其中S7位于S1和S2、S1和S3、S1和S4、S2和S3、S2和S4和/或S3和S4之间。
另一方面,载体可进一步包括选自土拨鼠PRE(WPRE)或乙型肝炎病毒(HBV)PRE(HPRE)的转录后调控元件(PRE)序列。
另一方面,载体可以进一步包括控制S1、S2、S3、S4、S5、S6和/或S7转录的启动子序列,其中所述启动子序列选自巨细胞病毒(CMV)启动子、磷酸甘油酸酯激酶(PGK)启动子、髓磷脂碱性蛋白(MBP)启动子、神经胶质纤维酸性蛋白(GFAP)启动子、包含骨髓增生性肉瘤病毒增强剂(MNDU3)的修饰MoMuLV LTR、泛素C启动子、EF-1α启动子或鼠干细胞病毒(MSCV)启动子。
另一方面,第一二聚体ZlZ2可选自SEQ ID NO:13和14、15和16、17和18、19和20、21和22、23和24、25和26、27和28、29和30、31和32、33和34、35和36、37和38、39和40、41和42、43和44、45和46、47和48、49和50、51和52、53和54、55和56、57和58、59和60、61和62、63和64、65和66、67和68、69和70、71和72、73和74、75和76、77和78、79和80、81和82、83和84、85和86、87和88或89和90。
另一方面,第二二聚体Y1和Y2在SEQ ID NO:11和12中列出。
另一方面,方向为S2-S1-S4-S3。
另一方面,载体具有选自PTE WPRE(SEQ ID NO:91)、TPE WPRE(SEQ ID NO:92)或PTE fn WPRE(SEQ ID NO:93)的序列。
另一方面,方向为S4-S3-S2-S1。
另一方面,载体具有序列PTE CD8 TCR WPRE(SEQ ID NO:94)。
另一方面,病毒载体选自腺病毒、痘病毒、α病毒、晕病毒、黄病毒、弹状病毒、逆转录病毒、慢病毒、疱疹病毒、副粘病毒或微小核糖核酸病毒。
另一方面,载体用病毒的包膜蛋白进行假型化处理,所述病毒选自天然猫内源性病毒(RD114)、RD114的嵌合版本(RD114TR)、长臂猿白血病病毒(GALV)、GALV的嵌合版本(GALV-TR)、两栖鼠白血病病毒(MLV 4070A)、杆状病毒(GP64)、水疱性口炎病毒(VSV-G)、猫瘟病毒(FPV)、埃博拉病毒(EboV)、狒狒逆转录病毒包膜糖蛋白(BaEV)或淋巴细胞性脉络膜脑膜炎病毒(LCMV)。
另一方面,载体可以用水泡性口炎病毒(VSV-G)的包膜蛋白进行假型化处理。
一方面,本公开涉及一种制备用于免疫疗法的T细胞的方法,包括从人受试者的血液样本中分离T细胞、在存在氨基二膦酸盐的情况下激活分离的T细胞、用本文所述的载体转导激活的T细胞、扩增转导的T细胞。
另一方面,可以从白细胞分离术人样本中分离T细胞。
另一方面,氨基二膦酸盐可选自帕米膦酸、阿仑膦酸、唑来膦酸、利塞膦酸、伊班膦酸、恩加膦酸、其盐和/或其水合物。
另一方面,所述激活可以进一步在存在人重组白介素2(IL-2)和人重组白介素15(IL-15)的情况下进行。
另一方面,扩增可以在存在IL-2和IL-15的情况下进行。
另一方面,T细胞可以为γδT细胞。
另一方面,第一二聚体ZlZ2和第二二聚体Y1Y2在扩增的T细胞表面上共表达。
另一方面,本公开涉及通过以上方面的方法制备的扩增T细胞群。
一方面,本公开涉及一种治疗癌症患者的方法,其包括向所述患者施用包含本文所述扩增T细胞群体的组合物,其中所述T细胞杀灭提呈与表面MHC分子复合的肽的癌细胞,其中所述肽选自SEQ ID NO:98-255中的任何一个,其中所述癌症选自非小细胞肺癌、小细胞肺癌、黑色素瘤、肝癌、乳腺癌、子宫癌、默克尔细胞癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、膀胱癌、肾癌、白血病、卵巢癌、食道癌、脑癌、胃癌和前列腺癌。
另一方面,所述组合物进一步包括佐剂。
另一方面、佐剂选自抗-CD40抗体、咪喹莫特、雷西喹莫特、GM-CSF、环磷酰胺、舒尼替尼、贝伐单抗、阿特珠单抗、干扰素-α、干扰素-β、CpG寡核苷酸和衍生物、聚(I:C)和衍生物、RNA、西地那非、含有聚(丙交酯-共-乙交酯)(PLG)的颗粒制剂、病毒体、白介素(IL)-1、IL-2、IL-4、IL-7、IL-12、IL-13、IL-15、IL-21和IL-23中的一种或多种。
一方面,本公开涉及一种在癌症患者中引发免疫应答的方法,其包括向所述患者施用包含本文所述扩增T细胞群体的组合物,其中所述T细胞杀灭提呈与表面MHC分子复合的肽的癌细胞,其中所述肽选自SEQ ID NO:98-255中的任何一个,其中所述癌症选自非小细胞肺癌、小细胞肺癌、黑色素瘤、肝癌、乳腺癌、子宫癌、默克尔细胞癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、膀胱癌、肾癌、白血病、卵巢癌、食道癌、脑癌、胃癌和前列腺癌。
另一方面,免疫应答包含细胞毒性T细胞应答。
一方面,本公开提出了通过在本文描述的方法中利用他汀类药物制备T细胞的方法。另一方面,本公开提出了在存在他汀类药物的情况下通过激活T细胞来制备T细胞的方法。
再一方面,本公开涉及一种制备用于免疫疗法的T细胞的方法,包括在存在他汀类药物的情况下激活T细胞,用本公开的载体转导激活的T细胞(其中所述载体可以用水疱性口炎病毒(VSV-G)的包膜蛋白进行假型化处理),并扩增转导的T细胞。
另一方面,T细胞可包括αβT细胞、γδT细胞和/或自然杀伤T细胞。
另一方面,他汀类药物可以选自阿托伐他汀、西立伐他汀、达伐他汀、氟吲他汀、氟伐他汀、美伐他汀、普伐他汀、辛伐他汀、维洛他汀和瑞舒伐他汀。
一方面,本公开涉及一种制备用于免疫疗法的T细胞的方法,包括激活T细胞、用本公开内容的载体转导激活的T细胞以及扩增转导的T细胞。
另一方面,所述激活可以在存在抗CD3抗体和抗CD28抗体的情况下进行。
另一方面,扩增可以在存在IL-7和IL-15的情况下进行。
附图简要说明
图1显示了根据本公开一个实施方案的γδT细胞制造工艺。γδT细胞的制造可能包括收集或获得白细胞或PBMC(例如,白细胞去除产物),从PBMC或白细胞分离术产物中消耗αβT细胞,然后激活、转导和扩增γδT细胞。
图2显示了根据本公开一些实施方案具有开放阅读框(ORF)改组的转导策略。
图3显示了根据本公开一些实施方案的慢病毒构建体。
图4显示了用RD114TR假型化处理的慢病毒,其用于在用唑来膦酸盐、IL-2和IL-15激活后第3天或第6天转导γδT细胞。通过流式细胞术,使用TCR(Vβ8)和CD8(CD8α)特异性抗体评估转导效率。
图5A显示了根据本公开一实施方案的构建体。
图5B显示了根据本公开另一实施方案的构建体。
图5C显示了根据本公开另一实施方案的构建体。
图5D显示了根据本公开另一实施方案的构建体。
图6A显示了根据本公开另一实施方案的构建体。
图6B显示了根据本公开另一实施方案的构建体。
图7显示了根据本公开一些实施方案的构建体示意图。
图8A显示了根据本公开一实施方案的构建体。
图8B显示了根据本公开另一实施方案的构建体。
图8C显示了根据本公开另一实施方案的构建体。
图8D显示了根据本公开另一实施方案的构建体。
图9A显示了根据本公开一些实施方案的构建体示意图。
图9B显示了根据本公开一些实施方案的构建体示意图。
图10显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的%CD8+TCR+γδT细胞。非转导(NT)细胞作为对照。
图11显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的γδT细胞中CD8和TCR的中值荧光强度(MFI)。非转导(NT)细胞作为对照。
图12显示了从用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的供体3中获得的γδT细胞在高抗原表达肿瘤细胞系(例如,UACC257(上图))或在低抗原表达肿瘤细胞系(例如,U2OS(下图))中的肿瘤杀伤活性,如通过Incucyte细胞毒性测定法测得。仅靶细胞和非转导细胞作为对照。
图13A-13C显示了从用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的供体3中获得的γδT细胞在高抗原表达肿瘤细胞系(例如,UACC257(图13A))、在低抗原表达肿瘤细胞系(例如,U2OS(图13B))或在抗原阴性肿瘤细胞系(例如,MCF-7(图13C)中的干扰素(IFN)-γ分泌量。未转导的细胞作为对照。
图14显示了从用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的供体4中获得的γδT细胞在高抗原表达肿瘤细胞系(例如,UACC257(上图))或在低抗原表达肿瘤细胞系(例如,U2OS(下图))中的肿瘤杀伤活性,如通过Incucyte细胞毒性测定法测得。仅靶细胞和非转导细胞作为对照。
图15A-15C显示了从用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的供体4中获得的γδT细胞在高抗原表达肿瘤细胞系(例如,UACC257(图15A))、在低抗原表达肿瘤细胞系(例如,U2OS(图15B))或在抗原阴性肿瘤细胞系(例如,MCF-7(图15C)中的IFN-γ分泌量。未转导的细胞作为对照。
图16显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的γδT细胞中病毒载体拷贝数。非转导细胞作为对照。
图17A和17B显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的供体3(图17A)或供体4(图17B)中获得的γδT细胞倍数扩增。非转导(NT)细胞作为对照。
图18A显示了根据本公开一些实施方案通过流式细胞术测定的γδT细胞的记忆表型。
图18B显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、PTE.Fn.WPRE或TPE.WPRE的病毒载体转导的γδT细胞记忆表型。非转导(NT)细胞作为对照。
图19显示了用含有PTE.CD8.TCR.WPRE(图B(120μl)和图C(240μl))的单个慢病毒载体(LV)转导或用以下两种单独慢病毒载体转导的γδT细胞之间的转导效率比较:一种含有R11KE.WPRE,另一种含有CD8,WPRE(图D和E),伴随病毒载体量增加,例如,R11KE.WPRE和CD8,WPRE各120μl(图D),R11KE.WPRE和CD8,WPRE各240μl(图E)。未转导(NT)细胞作为对照。
图20显示了用增加量的含有PTE.CD8.TCR.WPRE(例如30μl、120μl和240μl)的病毒载体转导的γδT细胞中转导效率增强。未转导的细胞作为对照。
图21显示了使用表达本公开的4合1构建体(例如LV-PTE.CD8.TCR.WPRE)的慢病毒载体(LV)各种稀释液从供体5和供体6获得的CD4+ T细胞中CD8强制表达情况。
图22显示了使用表达本公开的4合1构建体(例如LV-PTE.CD8.TCR.WPRE)的LV各种稀释液检测CD4+ T细胞中TCR表达情况。
图23显示了使用表达本公开的4合1构建体(例如LV-PTE.CD8.TCR.WPRE)转导的供体5(上图)和供体6(下图)中获得的CD4+和/或CD8+ T细胞中的%靶肽/MHC复合体Dextramer203(Dex203)+。
图24显示了使用表达本公开的4合1构建体(例如LV-PTE.CD8.TCR.WPRE)转导的供体5(上图)和供体6(下图)中获得的CD4+和/或CD8+ T细胞中的Dex203MFI。
图25显示了用根据本公开一实施方案所述4合1构建体或仅TCR构建体转导的T细胞检测功能的实验设计。
图26显示了用含有R11KE.WPRE(LV-TCR)(TCR)的慢病毒载体或含有PTE.CD8.TCR.WPRE(LV-CD8.TCR)(TCR+CD8)的慢病毒载体转导、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD4-CD8α+T细胞中%IFN-γ阳性细胞增加(上图)和IFN-γMFI(下图)(TCR)增加情况。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=4)。
图27显示了用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD4-CD8α+T细胞中%颗粒酶B阳性细胞增加(上图)和颗粒酶B MFI增加(下图)情况。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=3)。
图28显示了用LV-CD8.TCR(TCR+CD8)转导或不进行转导(NT)、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD4+CD8α+T细胞中%IFN-γ阳性细胞增加(上图)和IFN-γMFI增加(下图)情况。(效应细胞与靶细胞之比=2:1,供体分组N=4)。
图29显示了用LV-CD8.TCR(TCR+CD8)转导或不进行转导(NT)、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD4+CD8α+T细胞中%颗粒酶B阳性细胞增加(上图)和颗粒酶B MFI增加(下图)情况。(效应细胞与靶细胞之比=2:1,供体分组N=4)。
图30显示了用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD3+ T细胞中%IFN-γ阳性细胞增加(上图)和IFN-γMFI增加(下图)情况。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=4)。
图31显示了用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD3+ T细胞中%颗粒酶B阳性细胞增加(上图)和颗粒酶B MFI增加(下图)情况。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=3)。
图32显示了用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的分组供体中获得的CD3+ T细胞中IFN-γ分泌增加情况。非转导(NT)细胞、UACC257细胞和MCF7细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=4)。
图33显示了用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导、然后用高靶标表达UACC257细胞共培养与非靶标表达细胞MCF7共培养相比较的个体供体5、6、7和8中获得的CD3+ T细胞中IFN-γ分泌增加情况。非转导(NT)细胞、仅UACC257细胞和仅MCF7细胞作为对照。(效应细胞与靶细胞之比=2:1)。
图34显示了用阿托伐他汀、普伐他汀或瑞舒伐他汀处理的CD3+CD4+ T细胞中的%CD25+细胞(上图)、%CD69+细胞(中图)和%人低密度脂蛋白受体(hLDLR)+细胞(下图)。预激活细胞、未用他汀类药物或DMSO激活的细胞(对照)和DMSO作为对照。
图35显示了用阿托伐他汀、普伐他汀或瑞舒伐他汀处理的CD3+CD8+ T细胞中的%CD25+细胞(上图)、%CD69+细胞(中图)和%hLDLR+细胞(下图)。预激活细胞、未用他汀类药物或DMSO激活的细胞(对照)和DMSO作为对照。
图36显示了根据本公开一实施方案所述的慢病毒载体滴度。
图37显示了根据本公开一实施方案所述的T细胞制造工艺。
详细描述
如本文所用,术语“自裂解2A肽”系指通过阻止甘氨酸和最后一个脯氨酸之间的肽键结合的形成而共同翻译作用的相对较短肽(长约20个氨基酸的量级,取决于来源的病毒),导致核糖体跳至下一个密码子,而新生肽在Gly和Pro之间裂解。裂解后,短的2A肽仍与“上游”蛋白的C端融合,而脯氨酸被添加至“下游”蛋白的N端。自裂解2A肽可以选自猪破伤风病毒1(P2A)、马鼻炎A病毒(E2A)、明脉扁刺蛾β四体病毒(T2A)、口蹄疫病毒(F2A)或其任意组合(参见例如,Kim et al.,PLOS One 6:e18556,2011,其内容包括2A核酸和氨基酸序列,通过引用整体并入本文)。通过在自裂解2A序列之前添加连接子序列(GSG或SGSG(SEQID NO:8)),这可以使生物活性蛋白(例如TCR)有效合成。
如本文所用,术语“启动子”系指通常位于允许基因转录的基因上游(朝向有义链的5'区域)的DNA的调节区。启动子包含称为转录因子的蛋白质识别的特定DNA序列和应答元件。这些因子与启动子序列结合,募集RNA聚合酶——从基因编码区合成RNA的酶。例如,本文使用的启动子序列可以选自巨细胞病毒(CMV)启动子、磷酸甘油酸酯激酶(PGK)启动子、髓磷脂碱性蛋白(MBP)启动子、神经胶质纤维酸性蛋白(GFAP)启动子、包含骨髓增生性肉瘤病毒增强剂(MNDU3)的修饰MoMuLV LTR、泛素C启动子、EF-1α启动子或鼠干细胞病毒(MSCV)启动子。
本文使用的术语“组成型启动子”可包括大多数时间内在大多数细胞或组织中指导基因转录的调控序列。在一些非限制性实施方案中,组成型启动子可以选自由MSCV启动子、泛素C(Ubc)启动子、CMV启动子、EF-1α启动子、PGK启动子、β-肌动蛋白启动子和ROSA26启动子组成的组。
在一些实施方案中,启动子可以为诱导型启动子。诱导型启动子的活性可以增加或减少以对信号作出响应。例如,诱导型启动子可促进转录以对存在信号作出响应,例如T细胞激活或异丙基β-D-1-硫代吡喃半乳糖苷(IPTG)。诱导型启动子可促进转录,以对信号(例如磷酸盐)的缺失作出响应。在这两种情况中的任一情况下,转录量可能与信号量或其不足成正比,也可能不成正比。适用于原核宿主细胞的诱导型启动子实例可包括但不限于NFAT、CD69、lac、tac、trc、trp、pho、recA、tetA、nar、噬菌体PL、cspA、T7和PBAD启动子(参见Terpe K.2006Appl.Microbiol.Biotechnol.72:211;其内容通过引用整体并入)。
在一些实施方案中,诱导型启动子可包括激活T细胞的核因子(NFAT)/AP1转录反应元件(TRE)。在识别同源肽/MHC1复合体后,NFAT可进行Ca2+依赖性易位至细胞核,在细胞核中,其促进含有NFAT TRE的基因的转录。合适的NFAT TRE是本领域熟知的,包括人IL2启动子NFAT TRE(Macian et al(2001)Oncogene,2001 Apr.30;20(19):2476-89)。Zhang etal.(“Tumor-Infiltrating Lymphocytes Genetically Engineered with an InducibleGene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma,”Clin.Cancer Res.21:2278-2288,2015)描述了经基因改造分泌单链IL12(其表达由诱导型NFAT启动子驱动)的人肿瘤浸润淋巴细胞(TIL)在临床试验中的用途。这些引用文献内容通过引用整体并入本文。
在一些实施方案中,诱导型启动子可包括CD69启动子,例如,如美国专利5,759,805中所披露;其内容通过引用整体并入。CD69可能为激活T细胞上诱导的这些新合成细胞表面激活分子中最早的分子之一。在T细胞刺激后60分钟内可观察到CD69表达,但在静息细胞上可能不存在。CD69表达也在胸腺细胞、B细胞、自然杀伤(NK)细胞和中性粒细胞上诱导。位于小鼠CD69启动子上游50kb内称为CNS1-4的四个非编码区可能有助于T细胞和B细胞中CD69激活的发育和时间控制。CNS2区域可充当有效增强子的功能。Kulemzin et al.(“Design and analysis of stably integrated reporters for inducible transgeneexpression in human T cells and chimeric antigen receptor(CAR)NK cell lines,”BMC Medical Genomics 2019,12(Suppl 2):44,88-95;其内容以引用方式整体并入)描述了在原代T细胞背景下,激活诱导型CD69启动子变体提供了最高倍数诱导。.因此,该启动子可用于在被激活但非静息人T或CAR T细胞中表达蛋白质。
在一些实施方案中,诱导型启动子可以为IPTG诱导型启动子。IPTG诱导型启动子可指任何多核苷酸序列,其以响应于IPTG或可促进从lac操纵子(例如异乳糖)转录的任何其他乳糖衍生物的方式来促进转录。IPTG诱导型启动子的许多实例为本领域已知,包括但不限于tac(例如,tacI、tacII等)启动子、lac启动子及其衍生物(例如,lacUV5、taclac等)。
一方面,包含编码CD8α链、CD8β链、TCRα链和TCRβ链的序列的4合1病毒载体(例如慢病毒载体)表达可以由组成型或诱导型启动子驱动。例如,图5A显示了包含PTE CD8 TCRWPRE(SEQ ID NO:94)的4合1病毒载体,其具有位于编码TCR的序列(例如TCR R11KEα链(SEQID NO:13)和R11KEβ链(SEQ ID NO:14)并由组成型MSCV启动子(SEQ ID NO:1)驱动)上游的编码CD8α(SEQ ID NO:12)和CD8β(SEQ ID NO:13)的密码子优化序列。上述相同的编码序列也可由诱导型启动子(例如NFAT、CD69或IPTG启动子)驱动。
另一方面,包含编码融合蛋白、TCRα链和TCRβ链的序列的3合1病毒载体表达可以由组成型或诱导型启动子驱动。例如,图5B显示了包含CD8aCD4Fusion.TCR WPRE(SEQ IDNO:256)的病毒载体,其具有编码融合蛋白的密码子优化序列(其中CD8α胞外结构域与CD4跨膜结构域和CD4胞内结构域融合)以及编码TCR R11KEα链(SEQ ID NO:13)和R11KEβ链(SEQ ID NO:14)并由MSCV启动子(SEQ ID NO:1)驱动的序列。图5C显示了包含CD8bCD4Fusion.TCR WPRE(SEQ ID NO:257)的病毒载体,其具有编码融合蛋白的密码子优化序列(其中CD8β胞外结构域与CD4跨膜结构域和CD4胞内结构域融合)以及编码TCR R11KEα链(SEQ ID NO:13)和R11KEβ链(SEQ ID NO:14)并由MSCV启动子(SEQ ID NO:1)驱动的序列。图5D显示了包含CD8bCD8aFusion.TCR WPRE(SEQ ID NO:258)的病毒载体,其具有编码融合蛋白的序列(其中CD8β胞外结构域与CD8α跨膜结构域和CD8α胞内结构域融合)以及编码TCR R11KEα链(SEQ ID NO:13)和R11KEβ链(SEQ ID NO:14)并由MSCV启动子(SEQ ID NO:1)驱动的序列。上述相同的编码序列也可由诱导型启动子(例如NFAT、CD69或IPTG启动子)驱动。
一方面,本公开的4合1病毒载体表达可以由双向组成型和/或诱导型启动子驱动。例如,图6A显示了包含PGK.CD8.EF1a.TCR(SEQ ID NO:259)的4合1病毒载体,其具有位于编码TCR R11KEα链和R11KEβ链的序列上游的编码CD8α链和CD8β链的密码子优化序列,其中编码CD8α链和CD8β链的序列与编码TCR R11KEα链和R11KEβ链的序列可以由双向启动子(例如PGK启动子和EF-1α启动子)分开。PGK启动子可以位于编码CD8α链和CD8β链的密码子优化序列3'端,以驱动CD8α链和CD8β链表达。EF-1α启动子可位于编码TCR R11KEα链和R11KEβ链的序列5'端,以驱动TCR R11KEα链和R11KEβ链表达。
图6B显示了包含PGK.TCR.EF1a.CD8(SEQ ID NO:260)的4合1病毒载体,其具有位于编码CD8α链和CD8β链的密码子优化序列上游的编码TCR R11KEα链和R11KEβ链的序列,其中编码TCR R11KEα链和R11KEβ链的序列与编码CD8α链和CD8β链的序列可以由双向启动子(例如PGK启动子和EF-1α启动子)分开。PGK启动子可位于编码TCR R11KEα链和R11KEβ链的序列3'端,以驱动TCR R11KEα链和R11KEβ链表达。EF-1α启动子可以位于编码CD8α链和CD8β链的密码子优化序列5'端,以驱动CD8α链和CD8β链表达。
本公开的一些实施方案可以包括病毒载体,其含有编码TCRα链和TCRβ链的序列和编码其他蛋白质的序列,所述其他蛋白质有例如,细胞因子(包括但不限于IL-1、IL-2、IL-6、IL-7、IL-10、IL-12、IL-15、IL-18和IL-21)、IL-15/IL-15受体(IL-15R)融合蛋白、显性负性TGFβ受体(DN TGFbRII)和/或转化生长因子β受体的细胞外结构域。在一些实施方案中,这些编码序列可以由启动子或双向启动子驱动。
图7显示了包含位于编码细胞因子的序列上游的编码TCRα链和TCRβ链的序列的病毒载体,其中编码TCRα链和TCRβ链的序列和编码细胞因子的序列可以由双向启动子分开。双向启动子可以自5'至3'方向、组成型-组成型、组成型-诱导型、诱导型-组成型或诱导型-诱导型方向排列。例如,组成型启动子(例如MSCV、PGK或EF1α启动子)可位于编码TCRα链和TCRβ链的序列的3’端,以驱动TCRα链和TCRβ链表达。诱导型启动子(例如NFAT、CD69或IPTG启动子)可位于编码细胞因子的序列5'端以驱动细胞因子表达。图8A显示了具有位于编码IL-12(例如,IL-12α(p35)/IL-12β(p40)融合蛋白(SEQ ID NO:261))的序列5'端最小IL-2启动子的诱导型NFAT启动子,以驱动12α(p35)/IL-12β(p40)融合蛋白在病毒载体中表达,如图7所示。图8B显示了具有位于编码IL-12(例如,IL-12α(p35)/IL-12β(p40)融合蛋白(SEQ ID NO:262))的序列5'端CNS1和CNS2增强子元件的诱导型CD69启动子,以驱动12α(p35)/IL-12β(p40)融合蛋白在病毒载体中表达,如图7所示。图8C显示了具有位于编码IL-18(例如,IL-18变体1(SEQ ID NO:263))的序列5'端最小IL-2启动子的诱导型NFAT启动子,以驱动IL-18变体1在病毒载体中表达,如图7所示。图8D显示了具有位于编码IL-18(例如,IL-18变体1(SEQ ID NO:264))的序列5'端CNS1和CNS2增强子元件的诱导型CD69启动子,以驱动IL-18变体1在病毒载体中表达,如图7所示。
一方面,本公开提出了具有CD8β-CD8α-TCRβ-TCRα的5'端至3'端方向的4合1构建体。另一方面,本公开提出了具有CD8β-CD8α-TCRα-TCRβ的5'端至3'端方向的4合1构建体。另一方面,本公开提出了具有CD8α-CD8β-TCRβ-TCRα的5'端至3'端方向的4合1构建体。另一方面,本公开提出了具有CD8α-CD8β-TCRα-TCRβ的5'端至3'端方向的4合1构建体。
一方面,本公开提出的具有5'端至3'端方向的4合1构建体不包括TCRβ-TCRα-CD8α-CD8β。另一方面,本公开提出的具有5'端至3'端方向的4合1构建体不包括TCRβ-TCRα-CD8β-CD8α。另一方面,本公开提出的具有5'端至3'端方向的4合1构建体不包括TCRα-TCRβ-CD8α-CD8β。另一方面,本公开提出的具有5'端至3'端方向的4合1构建体不包括TCRα-TCRβ-CD8β-CD8α。
一方面,本公开提出了具有CD8β-CD8α-TCRβ-TCRα的5'端至3'端方向的4合1构建体。在一非限制性方面,本公开提出的具有5'端至3'端方向的4合1构建体不包括TCRβ-TCRα-CD8α-CD8β。
在一些实施方案中,本公开的病毒载体可包含编码TCRα链和TCRβ链的序列和编码TGF-β抑制剂(例如,显性负性TGFβ受体(DN TGFbRII))的序列和/或细胞外转化生长因子β受体结构域。图9A显示了包含位于编码DN TGFbRII的序列上游的编码TCRα链和TCRβ链的序列的病毒载体,其中编码TCRα链和TCRβ链的序列和编码DN TGFbRII的序列可由双向启动子分开。例如,图9A显示组成型启动子(例如MSCV、Ubc、CMV、EF-1α和PGK启动子)可位于编码TCRα链和TCRβ链的序列的3’端,以驱动TCRα链和TCRβ链表达;另一组成型启动子可位于编码DN TGFbRII的序列的5'端,以驱动DN TGFbRII表达。
或者,图9B显示了包含组成型启动子(例如MSCV、Ubc、CMV、EF-1α和PGK启动子)的病毒载体,其位于编码TCRα链和TCRβ链的序列上游的编码DN TGFbRII的序列5'末端,以驱动DN TGFbRII、TCRα链和TCRβ链表达。上述相同的编码序列也可由诱导型启动子(例如NFAT、CD69或IPTG启动子)驱动。
本文所用的术语“顺反子”系指DNA分子的一部分,其指定一条多肽链的形成,即编码一条多肽链。例如,“双顺反子”系指DNA分子的两个部分,其指定两条多肽链的形成,即编码两条多肽链。“三顺反子”系指DNA分子的三个部分,其指定三个多肽链的形成,即编码三个多肽链;以此类推。
本文所用的术语“多顺反子RNA”或“多顺反子mRNA”系指包含基因信息以翻译成几种蛋白质的RNA。相反,单顺反子RNA包含仅翻译单个蛋白质的基因信息。在本公开背景下,从实施例2-4中慢病毒转录的多顺反子RNA可翻译为四种蛋白质(4合1):TCRα链、TCRβ链、CD8α链和CD8β链;或翻译为两种蛋白质(2合1):TCRα链和TCRβ链或CD8α链和CD8β链。
本文所用的术语“串联排列”系指基因在核酸序列上的单个文件中相邻、一个在另一个之后或后面排列。基因在核酸序列上相邻连接在一起,每个基因的编码链(有义链)在核酸序列上连接在一起。
本文所用的术语“有义链”系指被翻译或可翻译成蛋白质的基因DNA链。当基因相对于核酸序列中的启动子沿“有义方向”定向时,“有义链”位于启动子下游的5'端,其中编码蛋白质的核酸的第一个密码子位于启动子的近端,而最后一个密码子位于启动子的远端。
本文所用的术语“病毒载体”系指核酸载体构建体,其包括至少一种病毒来源的元件,有被包装入病毒载体颗粒的能力,并编码至少一种外源核酸。载体和/或颗粒可用于在体外或体内将任何核酸转移至细胞之目的。多种形式的病毒载体为本领域已知。术语“病毒体”指单个感染性病毒颗粒。“病毒载体”、“病毒载体颗粒”和“病毒颗粒”也指具有其DNA或RNA核心和蛋白质外壳的完整病毒颗粒,因为该病毒存在于细胞外部。例如,病毒载体可选自腺病毒、痘病毒、α病毒、晕病毒、黄病毒、弹状病毒、逆转录病毒、慢病毒、疱疹病毒、副粘病毒或微小核糖核酸病毒。
术语“T细胞”或“T淋巴细胞”是本领域公认的,包括胸腺细胞、幼稚T淋巴细胞、未成熟T淋巴细胞、成熟T淋巴细胞、静置T淋巴细胞或激活T淋巴细胞。适用于特定实施方案的示例性T细胞群包括但不限于辅助性T细胞(HTL;CD4+ T细胞)、细胞毒性T细胞(CTL;CD8+ T细胞)、CD4+CD8+ T细胞、CD4-CD8-T细胞、自然杀伤T细胞、表达αβTCR的T细胞(αβT细胞)、表达γδTCR的T细胞(γδT细胞)或任何其他T细胞亚群。适用于特定实施方案的其他示例性T细胞群包括但不限于表达以下一种或多种标志物的T细胞:CD3、CD4、CD8、CD27、CD28、CD45RA、CD45RO、CD62L、CD127、CD197和HLA-DR,如果需要,可透过阳性或阴性选择技术进一步分离。
术语“他汀类药物”、“伐他汀类药物”或在本文中可互换使用的“3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂”系指抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)的药剂。该酶参与HMG-CoA转化为甲羟戊酸,这是胆固醇生物合成的步骤之一。此类抑制很容易根据本领域技术人员众所周知的标准测定方法确定。
可根据本公开使用的优选他汀类药物包括:阿托伐他汀,其公开于美国专利号4,681,893;阿托伐他汀钙,公开于美国专利号5,273,995;西伐他汀,公开于美国专利号5,502,199;达伐他汀,公开于美国专利号5,316,765;氟吲他汀,公开于美国专利号4,915,954;氟伐他汀,公开于美国专利号4,739,073;洛伐他汀,公开于美国专利号4,231,938;美伐他汀,公开于美国专利号3,983,140;普伐他汀,公开于美国专利号4,346,227;辛伐他汀,公开于美国专利号4,444,784;维洛他汀,公开于美国专利号4,448,784和美国专利号4,450,171;瑞舒伐他汀,公开于美国专利号6,858,618和美国专利号7,511,140,这些参考文献中的每一项内容均通过引用整体并入本文。代表性3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂可包括阿托伐他汀、阿托伐他汀钙(也称为)、洛伐他汀(也称为)、普伐他汀(也称为)、辛伐他汀(也称为 )和瑞舒伐他汀。
一方面,本公开涉及可用于转基因表达的T细胞(例如肿瘤浸润淋巴细胞、CD8+T细胞、CD4+ T细胞和γδT细胞)的激活、转导和/或扩增。另一方面,本公开内容涉及γδT细胞的激活、转导和表达,同时消耗α-和/或β-TCR阳性细胞。
一方面,γδT细胞可从体外培养的复杂样本中分离。另一方面,在没有预先消耗特定细胞群(例如,单核细胞、αβT细胞、B细胞和NK细胞)的情况下可激活和扩增全部的PBMC群。另一方面,可以在特异性激活和扩增之前产生富集的γδT细胞群。另一方面,可以在不存在天然或工程化APC的情况下进行γδT细胞的激活和扩增。另一方面,可以使用固定的γδT细胞有丝分裂原(包括γδTCR特异的抗体)和其他γδTCR激活剂(包括凝集素)对来自肿瘤样本的γδT细胞进行分离和扩增。另一方面,可以在没有γδT细胞有丝分裂原(包括γδTCR特异的抗体)和其他γδTCR激活剂(包括凝集素)的情况下对来自肿瘤样本的γδT细胞进行分离和扩增。
一方面,γδT细胞分离自受试者(例如人受试者)的白细胞分离产物。另一方面,γδT细胞不是从外周血单核细胞(PBMC)中分离的。
一方面,分离的γδT细胞可以快速扩增,以应对与一种或多种抗原接触。一些γδT细胞(例如Vγ9Vδ2+ T细胞)可以在组织培养期间在体外快速扩增,以应对与一些抗原(如:异戊二烯基焦磷酸酯、烷基胺和代谢物或微生物提取物)接触。刺激的γδT细胞可以表现出许多抗原呈递、共刺激和黏附分子,其可以促进从复杂样本中分离γδT细胞。复合样本中的γδT细胞可以用至少一种抗原在体外刺激1天、2天、3天、4天、5天、6天、7天或其他合适的时间段。用合适的抗原刺激γδT细胞可以在体外扩增γδT细胞群。
可用于在体外刺激复杂样本中γδT细胞扩增的抗原非限制性实例可包括异戊烯-焦磷酸盐,例如异戊烯焦磷酸盐(IPP)、烷基胺、人微生物病原体代谢物、共生细菌代谢物、甲基-3-丁烯基-1-焦磷酸(2M3B1PP)、(E)-4-羟基-3-甲基-丁-2-烯基焦磷酸盐(HMB-PP)、焦磷酸乙酯(EPP)、法呢基焦磷酸盐(FPP)、二甲基烯丙基磷酸盐(DMAP)、二甲基烯丙基焦磷酸盐(DMAPP)、乙基三磷酸腺苷(EPPPA)、香叶基焦磷酸盐(GPP)、香叶基香叶基焦磷酸盐(GGPP)、异戊烯基三磷酸腺苷(IPPPA)、磷酸单乙基酯(MEP)、焦磷酸单乙酯(MEPP)、3-甲酰基-1-丁基焦磷酸盐(TUBAg 1)、X-焦磷酸盐(TUBAg 2)、3-甲酰基-1-丁基-尿苷三磷酸盐(TUBAg 3)、3-甲酰基-1-丁基-脱氧胸苷三磷酸(TUBAg 4)、单乙基烷基胺、烯丙基焦磷酸盐、焦磷酰基吡啶、二甲基烯丙基-γ-尿苷三磷酸盐、甲酰基-γ-尿苷三磷酸盐、烯丙基-γ-尿苷三磷酸盐、乙胺、异丁胺、仲丁胺、异戊胺和含氮二膦酸盐。
可以使用本文所述的激活和共刺激剂进行γδT细胞的激活和扩增,以触发特异性γδT细胞增殖和持久性群体。一方面,来自不同培养物的γδT细胞的激活和扩增可以实现不同的克隆或混合多克隆群体亚群。另一方面,不同的激动剂可用于鉴定提供特异性γδ激活信号的药剂。另一方面,提供特异性γδ激活信号的试剂可以是针对γδTCR的不同单克隆抗体(MAb)。另一方面,可以使用伴随共刺激剂以帮助触发特异性γδT细胞增殖而不诱导细胞能量和细胞凋亡。这些共刺激剂可包括与γδ细胞上表达的受体结合的配体,如NKG2D、CD161、CD70、JAML、DNAX辅助分子-1(DNAM-1)、ICOS、CD27、CD137、CD30、HVEM、SLAM、CD122、DAP和CD28。另一方面,共刺激剂可以是对CD2和CD3分子上的独特表位特异的抗体。当在αβ或γδT细胞上表达时,CD2和CD3可具有不同的构象结构。另一方面,CD3和CD2的特异性抗体可导致γδT细胞的不同激活。
在γδT细胞改造之前,可以离体扩增γδT细胞群。可用于促进体外γδT细胞群扩增的试剂非限制性实例可能包括抗CD3或抗CD2、抗CD27、抗CD30、抗CD70、抗OX40抗体、IL-2、IL-15、IL-12、IL-9、IL-33、IL-18或IL-21、CD70(CD27配体)、植物血凝素(PHA)、刀豆蛋白A(ConA)、商陆(PWM)、蛋白质花生凝集素(PNA)、大豆凝集素(SBA)、扁豆凝集素(LCA)、豌豆凝集素(PSA)、蜗牛凝集素(HPA)、蚕豆凝集素(VGA)或其他能够刺激T细胞增殖的合适有丝分裂原。
通过γδT细胞的基因改造可以增强γδT细胞识别广谱抗原的能力。一方面,可以改造γδT细胞以提供识别体内选择抗原的通用同种异体疗法。γδT细胞的基因改造可能包括稳定整合表达肿瘤识别部分的构建体,例如:αβTCR、γδTCR、嵌合抗原受体(CAR),其将抗原结合和T细胞激活功能组合为单一的受体、其抗原结合片段或淋巴细胞激活结构域组合为分离γδT细胞、细胞因子(例如,IL-15、IL-12、IL-2、IL-7、IL-21、IL-
18、IL-19、IL-33、IL-4、IL-9、IL-23或IL1β)的基因组,以在体外和体内增强T细胞增殖、存活和功能。分离γδT细胞的基因改造还可能包括从分离γδT细胞(例如,MHC基因座)的基因组中的一个或多个内源基因中删除或破坏基因表达。
可用各种方法产生改造γδT细胞。例如,编码包含肿瘤识别或其他类型识别部分的表达盒的多核苷酸可通过转座子/转座酶系统或基于病毒的基因转移系统(例如,慢病毒或逆转录病毒系统)或其他合适的方法,如:转染、电穿孔、转导、脂质转染、磷酸钙(CaPO4)、纳米改造物质(如Ormosil),病毒传递方法,包括腺病毒、逆转录病毒、慢病毒、腺相关病毒或其他合适的方法稳定地引入γδT细胞。许多病毒方法已用于人基因治疗,例如WO1993020221中描述的方法,其内容通过引用整体并入本文。可用于改造γδT细胞的病毒方法的非限制性实例可包括γ-逆转录病毒、腺病毒、慢病毒、单纯疱疹病毒、痘苗病毒、痘病毒或腺病毒相关病毒方法。
一方面,本文所述的构建体和载体与2018年11月26日提交的美国专利16/200,308中描述的方法一起使用,其内容通过引用整体并入本文。
一方面,病毒系指天然存在的病毒以及人造病毒。根据本公开一些实施方案的病毒可能是包膜病毒或无包膜病毒。细小病毒(例如AAV)是无包膜病毒的实例。在一优选实施方案中,病毒可能是包膜病毒。在优选实施方案中,病毒可能是逆转录病毒,特别是慢病毒。可以促进真核细胞病毒感染的病毒包膜蛋白可能包括HIV-1衍生慢病毒载体(LV),这些载体用水疱性口炎病毒(VSV-G)的包膜糖蛋白(GP)、修饰的猫内源性逆转录病毒(RD114TR)(SEQ ID NO:97)和修饰的长臂猿白血病病毒(GALVTR)处理成为假型。这些包膜蛋白可以有效地促进其他病毒的进入,例如细小病毒,包括腺相关病毒(AAV),从而证明它们的广泛效率。例如,可使用其他病毒包膜蛋白,包括莫洛尼鼠白血病病毒(MLV)4070env(如Merten etal.,J.Virol.79:834-840,2005一文中所述;其内容通过引用并入本文)、RD114env、嵌合包膜蛋白RD114pro或RDpro(通过用HIV-1基质/衣壳(MA/CA)切割序列取代RD114的R肽切割序列构建的RD114-HIV嵌合体,如Bell et al.Experimental Biology and Medicine 2010;235:1269–1276一文中所述;其内容通过引用并入本文)、杆状病毒GP64env(如Wang etal.J.Virol.81:10869-10878,2007一文中所述;其内容通过引用并入本文)或GALV env(如Merten et al.,J.Virol.79:834-840,2005一文中所述;其内容通过引用并入本文)或其衍生物。
本公开的实施方案基于以下发现:单个慢病毒盒可用于产生单个慢病毒载体,其表达来自单个多顺反子mRNA的两个不同二聚体的至少四个个体单体蛋白,从而在细胞表面上共表达二聚体。例如,整合单拷贝慢病毒载体可足以转化γδT细胞,以共表达TCRαβ和CD8αβ。
一方面,本公开涉及在单个载体内包含多顺反子盒的载体,其能够表达多于一个、多于两个、多于三个、多于四个基因、多于五个基因或多于六个基因,其中这些基因编码的多肽可以彼此相互作用,或可以形成二聚体。二聚体可以为同二聚体(即形成二聚体的两种相同的蛋白质),或异二聚体(即形成二聚体的两种结构上不同的蛋白质)。
一方面,慢病毒载体可包含编码蛋白质Z1的第一核苷酸序列S1、编码蛋白质Z2的第二核苷酸序列S2、编码蛋白质Y1的第三核苷酸序列S3和编码Y2蛋白质的第四核苷酸序列S4,其中Z1和Z2形成第一二聚体、Y1和Y2形成第二二聚体,其中第一二聚体Z1Z2与第二二聚体Y1Y2不同。
一方面,第一个慢病毒载体可包含编码二聚体ZlZ2的双顺反子盒(2合1),第二个慢病毒载体可包含编码二聚体Y1Y2的双顺反子盒(2合1)。在2合1载体中,S1和S2可以按S1-S2或S2-S1的5'至3'方向串联排列。同样,在2合1载体中,S3和S4可以按S3-S4或S4-S3的5'至3'方向串联排列。Z1和Z2或Y1和Y2可以被一个或多个自裂解2A肽分开。
另一方面,单个慢病毒载体(4合1)可以编码不同的二聚体Z1Z2和Y1Y2,其中Z1、Z2、Y1和Y2可以被一个或多个自裂解2A肽分开。例如,S1、S2、S3和S4可以以选自S1-S2-S3-S4、S1-S2-S4-S3、S1-S3-S2-S4、S1-S3-S4-S2、S1-S4-S3-S2、S1-S4-S2-S3、S2-S1-S3-S4、S2-S1-S4-S3、S2-S3-S1-S4、S2-S3-S4-S1、S2-S4-S3-S1、S2-S4-S1-S3、S3-S1-S2-S4、S3-S1-S4-S2、S3-S2-S1-S4、S3-S2-S4-S1、S3-S4-S1-S2、S3-S4-S2-S1、S4-S1-S2-S3、S4-S1-S3-S2、S4-S2-S1-S3、S4-S2-S3-S1、S4-S3-S1-S2或S4-S3-S2-S1的5'至3'方向串联排列。
一方面,二聚体Z1Z2可以为具有TCRα链和TCRβ链的TCR。
一方面,能够与本文所述的构建体、方法和实施方案一起使用的TCR和抗原结合蛋白包括,例如,表2中列出的那些(SEQ ID NO:13-90)以及美国专利公开号20170267738、美国专利公开号20170312350、美国专利公开号20180051080、美国专利公开号20180164315、美国专利公开号20180161396、美国专利公开号20180162922、美国专利公开号20180273602、美国专利公开号20190016801、美国专利公开号20190002556、美国专利公开号20190135914,U.S.Patent 10,538,573,U.S.Patent 10,626,160、美国专利公开号20190321478、美国专利公开号20190256572、美国专利号10,550,182、美国专利号10,526,407、美国专利公开号20190284276、美国专利公开号20190016802和美国专利号10,583,573中描述的那些TCR和抗原结合蛋白,这些这些专利公开内容及其中描述的序列表通过引用整体并入本文。
另一方面,二聚体Z1Z2可以为选自R11KEA(SEQ ID NO:13和14)、R20P1H7(SEQ IDNO:15和16)、R7P1D5(SEQ ID NO:17和18)、R10P2G12(SEQ ID NO:19和20)、R10P1A7(SEQ IDNO:21和22)、R4P1D10(SEQ ID NO:23和24)、R4P3F9(SEQ ID NO:25和26)、R4P3H3(SEQ IDNO:27和28)、R36P3F9(SEQ ID NO:29和30)、R52P2G11(SEQ ID NO:31和32)、R53P2A9(SEQID NO:33和34)、R26P1A9(SEQ ID NO:35和36)、R26P2A6(SEQ ID NO:37和38)、R26P3H1(SEQID NO:39和40)、R35P3A4(SEQ ID NO:41和42)、R37P1C9(SEQ ID NO:43和44)、R37P1H1(SEQID NO:45和46)、R42P3A9(SEQ ID NO:47和48)、R43P3F2(SEQ ID NO:49和50)、R43P3G5(SEQID NO:51和52)、R59P2E7(SEQ ID NO:53和54)、R11P3D3(SEQ ID NO:55和56)、R16P1C10(SEQ ID NO:57和58)、R16P1E8(SEQ ID NO:59和60)、R17P1A9(SEQ ID NO:61和62)、R17P1D7(SEQ ID NO:63和64)、R17P1G3(SEQ ID NO:65和66)、R17P2B6(SEQ ID NO:67和68)、R11P3D3KE(SEQ ID NO:69和70)、R39P1C12(SEQ ID NO:71和72)、R39P1F5(SEQ ID NO:73和74)、R40P1C2(SEQ ID NO:75和76)、R41P3E6(SEQ ID NO:77和78)、R43P3G4(SEQ IDNO:79和80)、R44P3B3(SEQ ID NO:81和82)、R44P3E7(SEQ ID NO:83和84)、R49P2B7(SEQ IDNO:85和86)、R55P1G7(SEQ ID NO:87和88)或R59P2A7(SEQ ID NO:89和90)的TCRα链和TCRβ链。一方面,序列展示SEQ ID NO:13-90中任一个的至少约90%、至少约95%或至少约98%。
表1显示了肽与MHC分子复合时,与哪些TCR结合的肽的实例。
表1
一方面,能够与本文所述的方法和实施方案一起使用的肿瘤相关抗原(TAA)肽包括,例如,表3中所列的那些以及美国专利公开号20160187351、美国专利公开号20170165335、美国专利公开号20170035807、美国专利公开号20160280759、美国专利公开号20160287687、美国专利公开号20160346371、美国专利公开号20160368965、美国专利公开号20170022251、美国专利公开号20170002055、美国专利公开号20170029486、美国专利公开号20170037089、美国专利公开号20170136108、美国专利公开号20170101473、美国专利公开号20170096461、美国专利公开号20170165337、美国专利公开号20170189505、美国专利公开号20170173132、美国专利公开号20170296640、美国专利公开号20170253633、美国专利公开号20170260249、美国专利公开号20180051080,U.S.PublicationNo.20180164315、美国专利公开号20180291082、美国专利公开号20180291083、美国专利公开号20190255110、美国专利号9,717,774、美国专利号9,895,415、美国专利公开号20190247433、美国专利公开号20190292520、美国专利公开号20200085930、美国专利号10,336,809、美国专利号10,131,703、美国专利号10,081,664、美国专利号10,081,664、美国专利号10,093,715、10,583,573和US20200085930所述的那些TAA肽,每个这些专利公开内容和序列表透过引用整体并入本文。
另一方面,二聚体Z1Z2可以为T细胞二聚体信号传导模块,例如CD3δ/ε、CD3γ/ε和CD247ζ/ζ或ζ/η、TCRα可变区(Vα)和TCRβ可变区(Vβ)的二聚体、免疫球蛋白重链可变区(VH)和免疫球蛋白轻链可变区(VL)的二聚体、Vα和VH的二聚体、Vα和VL的二聚体、Vβ和VH的二聚体或Vβ和VL的二聚体。
另一方面,Y1Y2可以为CD8α链和CD8β链,或任何其他合适的二聚膜受体,优选为CD8+ T细胞和/或CD4+ T细胞中表达的那些。
弗林蛋白酶为普遍存在的枯草杆菌蛋白酶样前蛋白转化酶,其天然底物包括某些血清蛋白和生长因子受体,例如胰岛素样生长因子受体。弗林蛋白酶裂解的共有序列为RXXR(SEQ ID NO:7),但是实际裂解的潜力取决于底物三级结构和识别位点紧邻的氨基酸。添加弗林蛋白酶裂解位点加上连接子序列(GSG或SGSG(SEQ ID NO:8))可以实现高效的基因表达。
一方面,串联排列的弗林蛋白酶-连接子-2A肽的核苷酸序列可以位于Z1和Z2之间、Z1和Y1之间、Z1和Y2之间、Z2和Y1之间、Z2和Y2之间和/或Y1和Y2之间。弗林蛋白酶可以具有RXXR(SEQ ID NO:7)的共有序列,例如RAKR(SEQ ID NO:2)。连接子序列可以为GSG或SGSG(SEQ ID NO:8)。2A肽可以选自P2A(SEQ ID NO:3)、T2A(SEQ ID NO:4)、E2A(SEQ IDNO:5)、F2A(SEQ ID NO:6)或其任何组合。
另一方面,串联排列的连接子-2A肽的核苷酸序列可以位于Z1和Z2之间、Z1和Y1之间、Z1和Y2之间、Z2和Y1之间、Z2和Y2之间和/或Y1和Y2之间。连接子序列可以为GSG或SGSG(SEQ ID NO:8)。2A肽可以选自P2A(SEQ ID NO:3)、T2A(SEQ ID NO:4)、E2A(SEQ ID NO:5)、F2A(SEQ ID NO:6)或其任何组合。
一方面,改造(或转导)的γδT细胞可以离体扩增而不受抗原呈递细胞或氨基二膦酸盐的刺激。本公开的抗原反应性改造T细胞可以离体和体内扩增。另一方面,本公开内容的改造γδT细胞的活性群体可以离体扩增,而无需抗原呈递细胞、抗原肽、非肽分子或小分子化合物(例如,氨基二膦酸盐)的抗原刺激,但是使用某些抗体、细胞因子、有丝分裂原或融合蛋白,例如:IL-17Fc融合、MICA Fc融合和CD70Fc融合。可用于扩增γδT细胞群抗体实例可能包括抗CD3、抗CD27、抗CD30、抗CD70、抗OX40、抗NKG2D或抗CD2抗体,细胞因子的实例可能包括IL-2、IL-15、IL-12、IL-21、IL-18、IL-9、IL-7和/或IL-33,有丝分裂原的实例可能包括CD70人CD27的配体、植物血凝素(PHA)、刀豆蛋白A(ConA)、商陆有丝分裂原(PWM)、蛋白质花生凝集素(PNA)、大豆凝集素(SBA)、扁豆凝集素(LCA)、豌豆凝集素(PSA)、蜗牛凝集素(HPA)、蚕豆凝集素(VGA)或其他能够刺激T细胞增殖的合适有丝分裂原。另一方面,改造γδT细胞群可在少于60天、少于48天、小于36天、少于24天、少于12天或少于6天内扩增。另一方面,工程化改造γδT细胞群可扩增约7天至约49天、约7天至约42天、约7天至约35天、约7天至约28天、约7天至约21天或约7天至约14天。
另一方面,本公开内容提供了用于过继扩增用于过继转移疗法的改造γδT细胞群的方法。本公开内容的改造γδT细胞可离体扩增。本公开内容的改造γδT细胞可在体外扩增而不经APC激活或不与APC和氨基磷酸盐共培养。
治疗方法
可以给予含有本文所述的改造γδT细胞的组合物用于预防性和/或治疗性治疗。在治疗应用中,药物组合物可以以足以治愈或至少部分阻止疾病或病症症状的量给予已患有疾病或病症的受试者。还可给予改造γδT细胞以减少病症发展、感染或恶化的可能性。用于治疗用途的有效量改造γδT细胞群可能根据疾病或病症的严重程度和病程、先前疗法、受试者的健康状况、体重和/或对药物的反应和/或治疗医师的判断而不同。
本公开的组合物还可包含一种或多种佐剂。佐剂是那些非特异性地增强或加强免疫反应的物质(例如,通过CD8-阳性T细胞和辅助T(TH)细胞介导的对一种抗原的免疫应答,因此被视为对本发明的药剂有用。适合的佐剂包括(但不仅限于)1018ISS、铝盐、AS15、BCG、CP-870,893、CpG7909、CyaA、dSLIM、鞭毛蛋白或鞭毛蛋白衍生的TLR5配体、FLT3配体、GM-CSF、IC30、IC31、咪喹莫特resiquimod、ImuFactIMP321、白细胞介素IL-2、IL-13、IL-21、干扰素α或β,或其聚乙二醇衍生物、IS Patch、ISS、ISCOMATRIX、ISCOMs、LipoVac、MALP2、MF59、单磷酰脂A、Montanide IMS1312、Montanide ISA 206、Montanide ISA50V、Montanide ISA-51、水包油和油包水乳状液、OK-432、OM-174、OM-197-MP-EC、ONTAK、OspA、载体系统、基于聚丙交酯复合乙交酯[PLG]和右旋糖苷微粒、重组人乳铁传递蛋白SRL172、病毒颗粒和其他病毒样颗粒、YF-17D、VEGF trap、R848、β-葡聚糖、Pam3Cys、源自皂角苷、分支杆菌提取物和细菌细胞壁合成模拟物的Aquila公司的QS21刺激子,以及其他专有佐剂,如:Ribi's Detox、Quil或Superfos。优选佐剂为弗氏佐剂或GM-CSF。前人对一些树突状细胞特异性免疫佐剂(如MF59)及其制备方法进行了描述(Allison and Krummel,1995)。也可使用细胞因子。一些细胞因子直接影响树突状细胞向淋巴组织迁移(如,TNF-),加速树突状细胞成熟为T淋巴细胞的有效抗原提呈细胞(如,GM-CSF、IL-1和IL-4)(美国5849589号专利,特别以其完整引用形式并入本文),并充当免疫佐剂(如IL-12、IL-15、IL-23、IL-7、IFN-α、IFN-β)(Gabrilovichet al.,1996)。
据报告,CpG免疫刺激寡核苷酸可提高佐剂在疫苗中的作用。如果没有理论的约束,CpG寡核苷酸可通过Toll样受体(TLR)(主要为TLR9)激活先天(非适应性)免疫系统从而起作用。CpG引发的TLR9激活作用提高了对各种抗原的抗原特异性体液和细胞反应,这些抗原包括肽或蛋白抗原、活病毒或被杀死的病毒、树突状细胞疫苗、自体细胞疫苗以及预防性和治疗性疫苗中的多糖结合物。更重要的是,它会增强树突状细胞的成熟和分化,导致TH1细胞的激活增强以及细胞毒性T淋巴细胞(CTL)生成加强,甚至CD4T细胞帮助的缺失。甚至有疫苗佐剂的存在也能维持TLR9激活作用诱发的TH1偏移,这些佐剂如:正常促进TH2偏移的明矾或弗氏不完全佐剂(IFA)。CpG寡核苷酸与以下其他佐剂或配方一起制备或联合给药时,表现出更强的佐剂活性,如微粒、纳米粒子、脂肪乳或类似制剂,当抗原相对较弱时,这些对诱发强反应尤为必要。它们还能加速免疫反应,使抗原剂量减少约两个数量级,在有些实验中,对不含CpG的全剂量疫苗也能产生类似的抗体反应(Krieg,2006)。美国6406705B1号专利对CpG寡核苷酸、非核酸佐剂和抗原结合使用促使抗原特异性免疫反应进行了描述。一种CpG TLR9拮抗剂为Mologen公司(德国柏林)的dSLIM(双干环免疫调节剂),这是本发明药物组合物的优选成分。也可使用其他如TLR结合分子,如:RNA结合TLR7、TLR8和/或TLR9。
其他有用的佐剂例子包括(但不限于)化学修饰性CpG(如CpR、Idera)、dsRNA模拟物,如,Poly(I:C)及其衍生物(如:多聚-(ICLC)、多聚(IC-R)、多聚(I:C12U))、非CpG细菌性DNA或RNA以及免疫活性小分子和抗体,如:环磷酰胺、舒尼替单抗、免疫检查点抑制剂(包括ipilimumab、nivolumab、pembrolizumab、atezolizumab、avelumab、durvalumab和cemiplimab)、西乐葆、NCX-4016、西地那非、他达拉非、伐地那非、索拉非尼、替莫唑胺、替西罗莫司、XL-999、CP-547632、帕唑帕尼、VEGF Trap、ZD2171、AZD2171、抗-CTLA4、免疫系统的其他抗体靶向性主要结构(如:抗-CD40、抗-TGFβ、抗-TNFα受体)和SC58175,这些药物都可能有治疗作用和/或充当佐剂。技术人员无需过度进行不当实验就很容易确定本发明中有用的佐剂和添加剂的数量和浓度。
优选的佐剂为抗-CD40、咪喹莫特、雷西喹莫特、GM-CSF、环磷酰胺、舒尼替尼、贝伐单抗、阿特珠单抗、干扰素-α、干扰素-β、CpG寡核苷酸和衍生物、聚(I:C)和衍生物、RNA、西地那非、含聚聚(丙交酯-共-乙交酯)(PLG)的颗粒制剂、病毒体、白介素(IL)-1、IL-2、IL-4、IL-7、IL-12、IL-13、IL-15、IL-21和IL-23。
本发明药物组合物的一个优选实施方案中,佐剂从含集落刺激因子制剂中选择,如粒细胞巨噬细胞集落刺激因子(GM-CSF,沙格司亭)、环磷酰胺、咪喹莫特、resiquimod和干扰素-α。
本发明药物组合物的一个优选实施方案中,佐剂从含集落刺激因子制剂中选择,如粒细胞巨噬细胞集落刺激因子(GM-CSF,沙格司亭)、环磷酰胺、咪喹莫特和resimiquimod。在本发明药物组合物的一个优选实施方案中,佐剂为环磷酰胺、咪喹莫特或resiquimod。更优选的佐剂是Montanide IMS 1312、Montanide ISA 206、Montanide ISA50V、Montanide ISA-51、聚-ICLC和抗CD40mAB或其组合物。
本公开内容的改造γδT细胞可用于治疗需要治疗病症(例如,本文所述的癌症)的受试者。
用γδT细胞治疗受试者病症(例如,疾病)的方法可能包括给予受试者治疗有效量的改造γδT细胞。本公开内容的γδT细胞可以以各种方案(例如,时间、浓度、剂量、治疗之间的间隔和/或制剂)施用。在接受本公开的改造γδT细胞之前,还可以用,例如,化学疗法、放射疗法或两者的组合对受试者进行预处理。在施用于受试者之前,还可以冷冻或冷冻保存改造的γδT细胞群。改造的γδT细胞群可包括表达相同、不同或相同和不同肿瘤识别部分组合的两种或更多种细胞。例如,改造的γδT细胞群可包括几种不同的改造γδT细胞,其被设计用于识别不同抗原或相同抗原的不同表位。
本公开内容的γδT细胞可用于治疗各种病症。一方面,本公开内容的改造γδT细胞可用于治疗癌症,包括实体瘤和恶性血液病。癌症的非限制性实例包括:急性淋巴细胞白血病、急性髓性白血病、肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、阑尾癌、星形细胞瘤、神经母细胞瘤、基底细胞癌、胆管癌、膀胱癌、骨癌、脑肿瘤(如:小脑星形细胞瘤、脑星形细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤、视觉通路和下丘脑胶质瘤)、乳腺癌、支气管腺瘤、伯基特淋巴瘤、原发性未知癌、中枢神经系统淋巴瘤、小脑星形细胞瘤、宫颈癌、儿童癌症、慢性淋巴细胞白血病、慢性粒细胞白血病、慢性骨髓增生性疾病、结肠癌、皮肤T细胞淋巴瘤、增生性小圆细胞瘤、子宫内膜癌、室管膜瘤、食道癌、尤因氏肉瘤、生殖细胞肿瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质瘤、胶质瘤、毛细胞白血病、头颈癌、心脏癌、肝细胞癌(肝癌)、霍奇金淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞癌、卡波西肉瘤、肾癌、喉癌、唇癌和口腔癌、脂肪肉瘤、肝癌、肺癌(如:非小细胞和小细胞肺癌)、淋巴瘤、白血病、巨球蛋白血症、骨恶性纤维组织细胞瘤/骨肉瘤、成神经管细胞瘤、黑色素瘤、间皮瘤、原发灶隐匿的转移性鳞状颈癌、口腔癌、多发性内分泌肿瘤综合征、骨髓增生异常综合征、骨髓性白血病、鼻腔和副鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔癌、口咽癌、骨肉瘤/骨恶性纤维组织细胞瘤、卵巢癌、卵巢上皮癌、卵巢生殖细胞肿瘤、胰腺癌、胰腺癌胰岛细胞、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、松果体星形细胞瘤、松果体生殖细胞瘤、垂体腺瘤、胸膜肺母细胞瘤、浆细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌、肾盂和输尿管移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉瘤、皮肤癌、默克尔细胞皮肤癌、小肠癌、软组织肉瘤、鳞状细胞癌、胃癌、T细胞淋巴瘤、咽喉癌、胸腺瘤、胸腺癌、甲状腺癌、滋养细胞肿瘤(妊娠)、原发部位未知癌、尿道癌、子宫肉瘤、阴道癌、外阴癌、瓦尔登斯特伦巨球蛋白血症和肾母细胞瘤。
一方面,本公开内容的改造γδT细胞可用于治疗传染病。另一方面,本公开内容的改造γδT细胞可用于治疗传染病,传染病可由病毒引起。再一方面,本公开内容的改造γδT细胞可用于治疗免疫疾病,例如,自身免疫疾病。
可以在病症临床发作之前、发作期间和发作之后向受试者提供本公开内容的γδT细胞治疗。在疾病临床发作后1天、1周、6个月、12个月或2年后,可向受试者提供治疗。在疾病临床发作后可能提供给受试者治疗超过1天、1周、1个月、6个月、12个月、2年、3年、4年、5年、6年、7年、8年、9年、10年或更长时间。在疾病临床发作后可能提供给受试者治疗少于1天、1周、1个月、6个月、12个月或2年。治疗还可能包括在临床试验中治疗人受试者。治疗可包括向受试者施用包含本公开内容的改造γδT细胞的药物组合物。
另一方面,向受试者施用本公开内容的改造γδT细胞可以调节受试者体内内源性淋巴细胞的活性。另一方面,向受试者施用改造γδT细胞可以向内源性T细胞提供抗原并且可增强免疫应答。另一方面,记忆T细胞可以为CD4+ T细胞。另一方面,记忆T细胞可以为CD8+ T细胞。另一方面,向受试者施用本公开内容的改造γδT细胞可激活另一种免疫细胞的细胞毒性。另一方面,其他免疫细胞可以为CD8+ T细胞。另一方面,其他免疫细胞可以为天然杀伤T细胞。另一方面,向受试者施用本公开内容的改造γδT细胞可抑制调节性T细胞。另一方面,调节性T细胞可以为FOX3+ Treg细胞。另一方面,调节性T细胞可以为FOX3-Treg细胞。其活性可通过本公开内容的改造γδT细胞调节的细胞非限制性实例可能包括:造血干细胞;B细胞;CD4;CD8;红血球;白血球;树突细胞,包括树突抗原呈递细胞;白细胞;巨噬细胞;记忆B细胞;记忆T细胞;单核细胞;自然杀伤细胞;中性粒细胞;T辅助细胞;和T杀伤细胞。
在大多数骨髓移植期间,环磷酰胺与全身照射组合可常规用于防止受试者免疫系统对移植体的造血干细胞(HSC)产生排斥。一方面,可以进行供体骨髓与白细胞介素-2(IL-2)离体孵育以增强供体骨髓中杀伤性淋巴细胞的产生。白细胞介素-2(IL-2)是野生型淋巴细胞生长、增殖和分化所必需的细胞因子。目前关于将γδT细胞过继转移到人体中的研究可能需要共同施用γδT细胞和白细胞介素-2。然而,低剂量和高剂量的IL-2都可能具有高度的毒副作用。IL-2毒性可在多个器官/系统中表现出来,最显著的是心脏、肺、肾和中枢神经系统。另一方面,本公开内容提供了用于向受试者施用改造γδT细胞而不共同施用天然细胞因子或其修饰形式(例如IL-2、IL-15、IL-12、IL-21)的方法。另一方面,改造的γδT细胞可以在不与IL-2共同施用的情况下施用于受试者。另一方面,改造的γδT细胞可以在手术期间施用于受试者,例如,骨髓移植而不共同施用IL-2。
给药方法
可以以任何顺序或同时向受试者施用一种或多种改造的γδT细胞群。如果同时施用,多重改造的γδT细胞可以为单次统一的剂量,例如:静脉内注射,或以多剂量提供,
例如,多次静脉内输注、皮下注射、注射或丸剂。改造的γδT细胞可以一起包装或单独包装,在单个包装中或在多个包装中包装。可以以多剂量给予一种或所有改造的γδT细胞。如果不是同时施用,多次剂量之间的时间间隔可能为大约一周、一个月、两个月、三个月、四个月、五个月、六个月或大约一年。另一方面,改造的γδT细胞可以在施用于受试者后在受试者体内扩增。可以冷冻改造γδT细胞以提供细胞以相同的细胞制剂进行多次治疗。本公开内容的改造γδT细胞和包含该细胞的药物组合物可以作为套件包装。套件可包括改造γδT细胞和包含该细胞的组合物的使用说明书(例如,书面说明书)。
另一方面,治疗癌症的方法包括向受试者施用治疗有效量的改造γδT细胞,其中所述给药治疗癌症。在另一实施方案中,治疗有效量的改造γδT细胞可以施用至少约10秒、30秒、1分钟、10分钟、30分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、24小时、2天、3天、4天、5天、6天、1周、2周、3周、1个月、2个月、3个月、4个月、5个月、6个月或1年。另一方面,治疗有效量的改造γδT细胞可以施用至少一周。另一方面,治疗有效量的改造γδT细胞可以施用至少二周。
本文所述的改造γδT细胞可以在疾病或病症发生之前、发生期间或发生之后施用,并且施用含有改造γδT细胞的药物组合物的时间可能不同。例如,改造的γδT细胞可以用作预防剂,并且可以连续给予有病症或疾病倾向的受试者,以减少疾病或病症发生的可能性。可以在症状发作期间或尽可能快地给予受试者改造的γδT细胞。改造γδT细胞可以在症状发作后立即、症状发作的前3小时内、症状发作的前6小时内、症状发作的前24小时内、症状发作的前48小时内或症状发作后的任何一段时间内立即给予。初始施用可通过任何实用的途径,例如:通过本文描述的任何途径使用本文描述的任何制剂给予。另一方面,本公开内容的改造γδT细胞可以是静脉内施用。一种或多种剂量的改造γδT细胞可在癌症、传染病、免疫疾病、败血症或骨髓移植开始后尽快施用,并持续一段时间用于治疗免疫疾病,例如,从约24小时到约48小时、从约48小时到约1周、从约1周到约2周、从约2周到约1个月、从约1个月到约3个月。对于癌症治疗,可以在癌症发作后数年和其他治疗之前或之后施用一剂或多剂量的改造γδT细胞。另一方面,改造的γδT细胞可以施用至少约10分钟、30分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、24小时、至少48小时、至少72小时、至少96小时、至少1周、至少2周、至少3周、至少4周、至少1个月、至少2个月、至少3个月、至少4个月、至少5个月、至少6个月、至少7个月、至少8个月、至少9个月、至少10个月、至少11个月、至少12个月、至少1年、至少2年、至少3年、至少4年或至少5年。每个受试者的治疗时间可能不同。
保存
一方面,γδT细胞可以在冷冻介质中配制并置于低温储存装置(例如:液氮冷冻器(-196℃)或超低温冷冻器(-65℃、-80℃、-120℃或-150℃)中长期储存至少约1个月、2个月、3个月、4个月、5个月、6个月、1年、2年、3年或至少5年。冷冻培养基可以含有二甲基亚砜(DMSO)和/或氯化钠(NaCl)和/或右旋糖和/或硫酸葡聚糖和/或羟乙基淀粉(HES)以及生理pH缓冲剂,以将pH保持在约6.0至约6.5、约6.5至约7.0、约7.0至约7.5、约7.5至约8.0或约6.5至约7.5之间。冷冻保存的γδT细胞可以解冻并通过用本文所述的抗体、蛋白质、肽和/或细胞因子刺激进行进一步加工。冷冻保存的γδT细胞可以解冻并用本文所述的病毒载体(包括逆转录病毒、腺相关病毒(AAV)和慢病毒载体)或非病毒手段(包括RNA、DNA,例如转座子和蛋白质)进行基因修饰。可以进一步冷冻保存修饰的γδT细胞以产生至少约1、5、10、100、150、200、500个小瓶量的细胞库,冷冻介质浓度为至少约101、102、103、104、105、106、107、108、109或至少1010个细胞/mL。冷冻保存的细胞库可以保留其功能并且可以解冻并进一步刺激和扩增。另一方面,可以在合适的封闭容器(例如:细胞培养袋和/或生物反应器)中刺激和扩增解冻的细胞,以产生大量细胞作为同种异体细胞产物。冷冻保存的γδT细胞可以在低温储存条件下维持其生物学功能至少约6个月、7个月、8个月、9个月、10个月、11个月、12个月、13个月、15个月、18个月、20个月、24个月、30个月、36个月、40个月、50个月或至少约60个月。另一方面,制剂中不使用防腐剂。冷冻保存的γδT细胞可以解冻并作为同种异体现成的细胞产物输注到多个患者中。
一方面,本文所述的改造γδT细胞可能存在于组合物中,含量为至少1×103个细胞/ml、至少2×103个细胞/ml、至少3×103个细胞/ml、至少4×103个细胞/ml、至少5×103个细胞/ml、至少6×103个细胞/ml、至少7×103个细胞/ml、至少8×103个细胞/ml、至少9×103个细胞/ml、至少1×104个细胞/ml、至少2×104个细胞/ml、至少3×104个细胞/ml、至少4×104个细胞/ml、至少5×104个细胞/ml、至少6×104个细胞/ml、至少7×104个细胞/ml、至少8×104个细胞/ml、至少9×104个细胞/ml、至少1×105个细胞/ml、至少2×105个细胞/ml、至少3×105个细胞/ml、至少4×105个细胞/ml、至少5×105个细胞/ml、至少6×105个细胞/ml、至少7×105个细胞/ml、至少8×105个细胞/ml、至少9×105个细胞/ml、至少1×106个细胞/ml、至少2×106个细胞/ml、至少3×106个细胞/ml、至少4×106个细胞/ml、至少5×106个细胞/ml、至少6×106个细胞/ml、至少7×106个细胞/ml、至少8×106个细胞/ml、至少9×106个细胞/ml、至少1×107个细胞/ml、至少2×107个细胞/ml、至少3×107个细胞/ml、至少4×107个细胞/ml、至少5×107个细胞/ml、至少6×107个细胞/ml、至少7×107个细胞/ml、至少8×107个细胞/ml、至少9×107个细胞/ml、至少1×108个细胞/ml、至少2×108个细胞/ml、至少3×108个细胞/ml、至少4×108个细胞/ml、至少5×108个细胞/ml、至少6×108个细胞/ml、至少7×108个细胞/ml、至少8×108个细胞/ml、至少9×108个细胞/ml、至少1×109个细胞/ml或更多、从约1×103个细胞/ml至约至少1×108个细胞/ml、从约1×105个细胞/ml至约至少1×108个细胞/ml或从约1×106个细胞/ml至约至少1×108个细胞/ml。
一方面,根据本公开内容的一个方面,本文描述的方法可以用于产生自体或同种异体产物。
一方面,本文所述的载体、构建体或序列可包含SEQ ID NO:1–97和265-266中任何一个的约80%、约85%、约90%、约95%、约96%、约97%、约98%或约99%。“与参考序列至少85%相同”的序列系指其全长与参考序列全长具有85%或更高序列同一性,特别是90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性的序列。
在本申请的背景下,使用整体成对比对法来计算“同一性百分比”(即,比较两个序列的全长)。比较两个或更多个序列同一性的方法是本领域所周知的。例如,可使用《针具》程序,其使用Needleman-Wunsch整体比对算法(Needleman and Wunsch,1970J.Mol.Biol.48:443-453)以找到两个序列(考虑其全长)的最佳比对方法(包括间隙)。例如,针头程序可从ebi.ac.uk万维网上下载,并在以下出版物中进一步描述(EMBOSS:TheEuropean Molecular Biology Open Software Suite(2000)Rice,P.Longden,I.andBleasby,A.Trends in Genetics 16,(6)pp.276—277).根据本发明,两个多肽之间同一性百分比的计算方法为:EMBOSS:针具(整体)程序,“Gap Open”参数等于10.0、“Gap Extend”参数等于0.5、矩阵为Blosum62。
由与参考序列“至少80%、85%、90%、95%、96%、97%、98%或99%相同”的氨基酸序列组成的蛋白可能包含相对于参考序列的突变,例如缺失、插入和/或取代。在发生取代时,由与参考序列至少80%、85%、90%、95%、96%、97%、98%或99%相同的氨基酸序列组成的蛋白可能对应于衍生自其他物种的同源序列(不同于参考序列)。
“氨基酸取代”可以是保守的也可以是非保守的。优选情况是,取代为保守取代,其中一个氨基酸被具有相似结构和/或化学性质的另一氨基酸所取代。
在一实施方案中,保守取代可能包括由Dayhoff在“The Atlas of ProteinSequence and Structure.Vol.5”Natl.Biomedical Research中所述的取代,其内容通过引用整体并入本文。例如,一方面,属于以下组之一的氨基酸可彼此交换,因此构成保守交换:第1组:丙氨酸(A)、脯氨酸(P)、甘氨酸(G)、天冬酰胺(N)、丝氨酸(S)、苏氨酸(T);第2组:半胱氨酸(C)、丝氨酸(S)、酪氨酸(Y)、苏氨酸(T);第3组:缬氨酸(V)、异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、丙氨酸(A)、苯丙氨酸(F);第4组:赖氨酸(K)、精氨酸(R)、组氨酸(H);第5组:苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)、组氨酸(H);和第6组:天冬氨酸(D)、谷氨酸(E)。一方面,保守氨基酸取代可选自以下取代:T→A、G→A、A→I、T→V、A→M、T→I、A→V、T→G和/或T→S。
在另一实施方案中,保守氨基酸取代可包括用相同类别的另一个氨基酸取代一种氨基酸,例如,(1)非极性:Ala、Val、Leu、Ile、Pro、Met、Phe、Trp;(2)不带电的极性:Gly、Ser、Thr、Cys、Tyr、Asn、Gln;(3)酸性:Asp、Glu;和(4)碱性:Lys、Arg、His。其他保守氨基酸取代也可以按如下进行:(1)芳香族:Phe、Tyr、His;(2)质子供体:Asn、Gln、Lys、Arg、His、Trp;和(3)质子受体:Glu、Asp、Thr、Ser、Tyr、Asn、Gln(参见美国专利号10,106,805,其内容通过引用整体并入本文)。
在另一实施方案中,保守取代可以根据表1进行。用于预测蛋白质修饰耐受性的方法可参加,例如,Guo et al.,Proc.Natl.Acad.Sci.,USA,101(25):9205-9210(2004),其内容通过引用整体并入。
表A:保守的氨基酸取代
一方面,本文所述的序列可包括1、2、3、4、5、10、15、20、25或30个氨基酸或核苷酸突变、取代、删除。一方面,SEQ ID NO:1–97和265-266中的任何一个均可包括1、2、3、4、5、10、15、20、25或30个突变、取代、删除。再一方面,突变或取代为保守氨基酸取代。
在另一实施方案中,保守取代可能为表B中“保守取代”标题下所示的取代。如果此类取代导致生物活性改变,则可能引入表B中称为“代表性取代”的重大改变,并且在需要时筛选产品。
表B:氨基酸取代
实施例1
表2.DNA和蛋白质序列
表3.TAA肽序列
实施例2
γδT细胞制造
为了分离γδT细胞,一方面,γδT细胞可从受试者或受试者的复杂样本中分离。一方面,复杂样本可能是外周血样本、脐带血样本、肿瘤、干细胞前体、肿瘤活组织检查物、组织、淋巴,或直接接触外部环境的受试者的上皮部位样本或源自干前体细胞的样本。γδT细胞可能直接从受试者的复杂样本中分离,例如,通过用流式细胞术技术分选表达一种或多种细胞表面标志物的γδT细胞。野生型γδT细胞可表现出许多可与γδT细胞相关的抗原识别、抗原呈递、共刺激和黏附分子。一种或多种细胞表面标志物,例如,特异性γδTCR、抗原识别、抗原呈递、配体、黏附分子或共刺激分子可用于从复杂样本中分离野生型γδT细胞。与γδT细胞相关或由其表达的各种分子可用于从复杂样本中分离γδT细胞,例如,分离Vδ1+、Vδ2+、Vδ3+细胞或其任何组合的混合群。
例如,可从受试者中收集外周血单核细胞,例如,采用血液成分单采机(包括Ficoll-PaqueTM PLUS(GE Healthcare)系统或其他合适的装置/系统。例如,可采用流式细胞术技术从收集的样本中纯化γδT细胞或所需亚群的γδT细胞。脐带血细胞也可在受试者出生期间从脐带血中获得。
在收集的γδT细胞上表达的细胞表面标志物的阳性和/或阴性选择可用于直接分离γδT细胞或来自外周血样本、脐带血样本、肿瘤、肿瘤活组织检查、组织、淋巴或来自受试者上皮样本的表达相似细胞表面标志物的γδT细胞群。例如,可以基于CD2、CD3、CD4、CD8、CD24、CD25、CD44、Kit、TCRα、TCRβ、TCRα、TCRδ、NKG2D、CD70、CD27、CD30、CD16、CD337(NKp30)、CD336(NKp46)、OX40、CD46、CCR7和其他合适的细胞表面标志物的阳性或阴性表达从复杂样本中分离γδT细胞。
图1显示了根据本公开内容实施方案的γδT细胞制造。此过程可能包括从白细胞分离术产物中收集或获得白细胞或PBMC。白细胞分离术可能包括从供体收集全血并使用血液成分单采机分离组分。血液成分单采机分离出所需的血液组分,并将其余部分返回供体的血液循环。例如,可以使用血液成分单采设备收集白细胞、血浆和血小板,并将红细胞和中性粒细胞返回供体的血液循环。市售白细胞分离术产品可用于该程序。另一种方法是从血沉棕黄层获得白细胞。为了分离血沉棕黄层,从供体获得抗凝全血并离心。离心后,将血液分离成血浆、红细胞和血沉棕黄层。血沉棕黄层是位于血浆和红细胞层之间的层。与血沉棕黄层收集相比,白细胞分离术收集可以获得更高的纯度和显著增加的单核细胞含量。白细胞分离术可能获得的单核细胞含量通常比血沉棕黄层获得的单核细胞含量高20倍。为了富集单核细胞,可能需要使用Ficoll梯度进行进一步分离。
为了从PBMC中消耗αβT细胞,可通过磁分离将表达αβTCR的细胞与PBMC分离,例如,使用涂覆有抗αβTCR抗体的磁珠,然后冷冻保存αβTCR-T细胞消耗的PBMC。为了制造“现成的”T细胞产品,可在存在氨基二膦酸盐(例如,唑来膦酸盐)和/或异戊烯焦磷酸盐(IPP)和/或细胞因子(例如白细胞介素2(IL-2)、白细胞介素15(IL-15)和/或白细胞介素18(IL-18))和/或其他激活剂(例如,Toll样受体2(TLR2)配体)的情况下小/中等规模(例如,在24至4-6孔板或T75/T175烧瓶中)或大规模(例如,在50ml-100升袋中)解冻和激活冷冻保存的αβTCR-T细胞消耗的PBMC,持续1-10天,例如2-7天。
图1显示了激活T细胞可以通过用病毒载体(例如:慢病毒载体)转导,将相关外源基因(例如:针对特定癌抗原和CD8的αβTCR)表达到分离γδT细胞中来进行改造。转导可以进行一次或多次以实现小规模(例如24至4-6孔板)或中/大规模的稳定转基因表达1/2至5天,例如1天。
图1进一步显示了转导或改造的γδT细胞的扩增可在存在细胞因子(例如:IL-2、IL-15、IL-18等)的情况下以小/中等规模(例如:烧瓶/G-Rex)或大规模(例如:50ml-100升袋)进行,持续7-35天,例如7-28天。然后可将扩增转导的T细胞产物冷冻保存为“现成的”T细胞产物,用于输注到患者体内。
实施例3
慢病毒性病毒载体
本文使用的慢病毒载体包含之前显示可增强载体功能的几种元件,包括用于改善复制和核输入的中央多嘌呤道(cPPT)、来自鼠干细胞病毒(MSCV)的启动子(SEQ ID NO:1)(其已被证明可以减少某些细胞类型的载体沉寂)、用于改善转录终止的土拨鼠肝炎病毒转录后反应元件(WPRE)(SEQ ID NO:9),并且骨架具有删除的3'-LTR自灭活(SIN)载体设计,可以提高安全性,维持基因表达和抗沉寂特性(Yang et al.Gene Therapy(2008)15,1411–1423),其内容通过引用整体并入本文。
一方面,本文所述的载体、构建体或序列包含突变形式的WPRE。另一方面,本文所述的序列或载体包含WPRE版本1(例如WPREmut1(SEQ ID NO:265))或WPRE版本2(例如WPREmut2(SEQ ID NO:266))中的突变。一方面,WPRE突变体包含至多一个突变、至多两个突变、至多三个突变、至少四个突变或至多五个突变。一方面,本文所述的载体、构建体或序列不包含WPRE。另一方面,本公开提出了SEQ ID NO:91-96之一中的一个、两个、三个、四个、五个、十个或20个取代。
另一方面,本文所述的载体、构建体或序列不包括X蛋白启动子。
为了在转导γδT细胞中获得TCRαβ和CD8αβ的最佳共表达水平,产生了具有各种设计的慢病毒载体。图2显示,可以用表达TCRαβ或CD8αβ的两个单独的慢病毒载体(2合1)和共表达TCRαβ和CD8αβ的单个慢病毒载体(4合1)转导T细胞。在4合1载体中,编码TCRα链、TCRβ链、CD8α链和CD8β链的核苷酸可以按各种顺序进行改组。由此产生的各种4合1载体可用于转导γδT细胞,然后使用本领域已知的技术(例如流式细胞术)测量转导细胞的TCR/CD8共表达水平。
为了产生共表达TCRαβ和CD8αβ的慢病毒载体,编码弗林蛋白酶连接子(GSG或SGSG(SEQ ID NO:8))-2A肽的核苷酸可以位于TCRα链和TCRβ链之间、CD8α链和CD8β链之间以及TCR链和CD8链之间,以实现高效的基因表达。2A肽可以选自P2A(SEQ ID NO:3)、T2A(SEQ IDNO:4)、E2A(SEQ ID NO:5)或F2A(SEQ ID NO:6)。
慢病毒性病毒载体还可含有转录后调控元件(PRE),例如:土拨鼠PRE(WPRE)(SEQID NO:9),以通过增加细胞核和细胞质mRNA水平来增强转基因的表达。还可使用一种或多种调节元件,包括小鼠RNA转运元件(RTE)、猿猴逆转录病毒1型(SRV-1)的组成型转运元件(CTE)和人热休克蛋白70的5'非翻译区(Hsp70 5′UTR)和/或与WPRE组合使用以增加转基因表达。
慢病毒载体可以用RD114TR(SEQ ID NO:97)进行假型化处理,而RD114TR是一种嵌合糖蛋白,其含有与鼠白血病病毒的细胞质尾(TR)融合的猫内源病毒(RD114)的细胞外和跨膜结构域。还可以使用其他病毒包膜蛋白,例如VSV-G env、MLV 4070A env、RD114env、嵌合包膜蛋白RD114pro、杆状病毒GP64env或GALV env或其衍生物。
图3显示了四种不同的4合1载体,即共表达TCRαβ(R11KEA)和CD8αβ的PTE WPRE(SEQ ID NO:91)、TPE WPRE(SEQ ID NO:92)、PTE fn WPRE(SEQ ID NO:93)和PTE CD8 TCRWPRE(SEQ ID NO:94),以及两个2合1载体,即表达TCRαβ(R11KEA)的R11KE WPRE(SEQ IDNO:95)和表达CD8αβ的CD8WPRE(SEQ ID NO:96)。TCRαβ(R11KEA)在与MHC分子复合体中与PRAME-004(SLLQHLIGL)(SEQ ID NO:147)结合。
实施例4
TCR和CD8共表达
从供体1和供体2获得的γδT细胞通过图1中所示的工艺制造。在用唑来膦酸盐、IL2和IL15激活后第3天或第6天,用慢病毒转导γδT细胞,用RD114TR(PTE WPRE(SEQ IDNO:91)、TPE WPRE(SEQ ID NO:92)、PTE fn WPRE(SEQ ID NO:93)和PTE CD8 TCR WPRE(SEQID NO:94))进行假型化处理,然后使用流式细胞术测量R11KEA和CD8的共表达水平。通过流式细胞术,使用TCR(Vβ8)和CD8(CD8α)特异性抗体评估转导效率。
图4显示,在来自供体1的γδT细胞中,PTE CD8 TCR WPRE转导导致的R11KEA和CD8的共表达水平,即40.5%(第3天)和18.5%(第6天),高于PTE WPRE(29.6%(第3天)、16.2%(第6天))、TPE WPRE(30.8%(第3天)、11.0%(第6天))和PTE fn WPRE(33.0%(第3天)、15.0%(第6天))转导的水平。在来自供体2的γδT细胞中,激活后第6天由PTE WPRE转导导致的R11KEA和CD8的共表达水平,即18.8%,高于TPE WPRE(14.2%)、PTE fn WPRE(14.7%)和PTE CD8 TCR WPRE(17.2%)转导的水平。作为对照,在用2合1载体(即TCRαβ(R11KEA)或CD8WPRE)分别转导的γδT细胞中检测了R11KEA和CD8的背景水平。
实施例5
对4合1病毒载体(例如慢病毒载体,包含编码CD8αβ链的序列和位于载体不同位置的编码TCRαβ链的序列)的转基因表达和功能性的影响。
WO 2019/204662描述了表达外源性CD8αβ共受体和一种或多种外源性工程化抗原受体(例如TCR)的CD4+细胞。表4显示了WO 2019/204662中描述的4合1构建体以及根据本公开各方面所述的4合1构建体之间的比较。
表4
本公开核酸分子的开放阅读框(ORF)可至少部分地进行密码子优化。密码子优化基于以下发现:翻译效率可由细胞中出现转移RNA(tRNA)的不同频率决定。因此,与相应野生型编码区相比,本公开核酸分子的开放阅读框可被修饰,使得编码tRNA(在细胞中相对稀有)的野生型序列的至少一个密码子可以交换密码子(该密码子编码tRNA,在细胞中比较常见,并且可能携带与相对稀有tRNA相同的氨基酸)。通过这种修饰,本公开核酸分子的开放阅读框可以被修饰,使得频繁出现tRNA可用的密码子可以替换对应于稀有tRNA的密码子。换言之,根据本公开,通过这种修饰,编码稀有tRNA的野生型开放阅读框的所有密码子可以交换密码子(该密码子编码tRNA,在细胞中比较常见,并且携带与稀有tRNA相同的氨基酸)。本领域技术人员已知哪些tRNA在细胞中相对频繁出现,而哪些相对很少出现;例如,Akashi,Curr.Opin.Genet.Dev.2001,11(6):660-666,其内容通过引用整体并入。在一些实施方案中,本公开核酸分子的开放阅读框可进行密码子优化,优选为关于本公开核酸分子将在其中表达的系统,优选为关于本公开核酸分子将在其中被翻译的系统。优选地,本公开核酸分子的开放阅读框的密码子使用可以根据哺乳动物密码子使用,更优选地,根据人密码子使用进行密码子优化。优选地,开放阅读框可进行密码子优化和G/C含量修饰。
为了确定哪种转基因方向可提供更好的转基因表达和功能,三个4合1病毒载体(各含有位于编码CD8αβ链——例如PTE.WPRE(SEQ ID NO:91)、TPE.WPRE(SEQ ID NO:92)和PTE.fn.WPRE(SEQ ID NO:93)的序列上游的编码TCRαβ链的序列)以及一个4合1病毒载体(其含有位于编码TCRαβ链——例如PTE.CD8.TCR.WPRE(SEQ ID NO:94)的序列上游的编码CD8αβ链的序列)被转导入γδT细胞,然后使用荧光标记抗CD8抗体和荧光标记抗TCR Vβ8(Vb8)抗体进行荧光激活细胞分选(FACS)分析,以分别检测细胞表面上的CD8和TCR表达。
图10和11显示,从供体3和供体4获得的γδT细胞用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导导致生产后第14天细胞表面上CD8和TCR的表达量最高(相较于与用含有PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体转导),根据CD8+Vb8+双阳性细胞的百分比(图10)和CD8的MFI或Vb8的MFI(图11)计算。
在用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导的γδT细胞的细胞表面上,CD8和TCR高表达与其体外杀伤活性密切相关。例如,图12显示,从用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导的供体3获得的γδT细胞对高靶肽提呈细胞系UACC257(上图)和低靶肽提呈细胞系U2OS(下图)均表现出最佳杀伤活性(相较于用含有PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体转导)。图13A-13C显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体在存在靶细胞(例如UACC257(图13A)、U2OS(图13B))和靶阴性细胞系MCF-7(图13C)的情况下所转导相应γδT细胞分泌的IFN-γ量。
图14显示,从用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导的供体4中获得的γδT细胞对UACC257(上图)和U2OS(下图)也表现出最佳杀伤活性(相较于用含有PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体转导)。图15A-15C显示了用含有PTE.CD8.TCR.WPRE、PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体在存在靶细胞(例如UACC257(图15A)、U2OS(图15B)和MCF-7(图15C)的情况下所转导相应γδT细胞分泌的IFN-γ量。
图16显示,从用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导的供体3和供体4中获得的γδT细胞导致每个细胞少于0.6拷贝整合载体,这与用PTE.WPRE、TPE.WPRE和PTE.fn.WPRE转导相似。这种每个细胞的整合载体低拷贝数在安全要求的范围内,即每个细胞整合载体少于5个拷贝数。
图17A和17B显示分别从供体3和供体4获得的γδT细胞(用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导)在制造第14天达到的细胞扩增水平与用包含PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体转导相当。
为了确定转导γδT细胞的记忆细胞表型,用别藻蓝蛋白(APC)-Cy7标记抗CD45RA抗体和BV421标记抗CCR7抗体染色细胞,然后进行FACS分析,以确定转导γδT细胞中Tcm、幼稚T细胞、TemRA和Teff的百分比。图18A显示了这种分析的一个示例。
图18B显示从供体3和供体4获得的γδT细胞(用含有PTE.CD8.TCR.WPRE的4合1病毒载体转导)在制造第14天达到的记忆T细胞表型水平与用包含PTE.WPRE、TPE.WPRE或PTE.fn.WPRE的4合1病毒载体转导相当。
实施例6
对用一种4合1病毒载体转导的细胞对比用两种2合1病毒载体转导的细胞中转基因表达的影响
图19显示,与使用含有CD8.WPRE(120μl)的2合1慢病毒载体和含有R11KE.WPRE(120μl)的2合1慢病毒载体混合物转导相比(图D,15.5%),用含有PTE.CD8.TCR.WPRE(120μl)的4合1慢病毒载体转导可产生更多的CD8+TCR+γδT细胞(图B,20.9%)。另一方面,与用含有PTE.CD8.TCR.WPRE的4合1慢病毒性病毒载体转导相比(图B,21.2%),使用含有CD8.WPRE(120μl)的2合1慢病毒载体和含有R11KE.WPRE(120μl)的2合1慢病毒载体混合物转导可产生更多的CD8+TCR-γδT细胞(图D,28.3%)。同样,与使用含有CD8.WPRE(240μl)的2合1慢病毒载体和含有R11KE.WPRE(240μl)的2合1慢病毒载体混合物转导相比(图E,21.1%),用含有PTE.CD8.TCR.WPRE(240μl)的4合1慢病毒载体转导可产生更多的CD8+TCR+γδT细胞(图C,27.7%)。另一方面,与用含有PTE.CD8.TCR.WPRE的4合1慢病毒载体转导相比(图C,24.4%),使用含有CD8.WPRE(240μl)的2合1慢病毒载体和含有R11KE.WPRE(240μl)的2合1慢病毒载体混合物转导可产生更多的CD8+TCR-γδT细胞(图E,40.2%)。未转导(NT)γδT细胞作为对照(图A)。使用APC标记抗CD8β抗体和藻红蛋白(PE)标记靶肽/MHC复合四聚体进行2色染色。这些结果表明,与用含有编码CD8αβ序列的2合1慢病毒载体(例如CD8.WPRE)和含有编码TCRαβ序列的2合1慢病毒载体(例如R11KE.WPRE)混合物转导相比,使用含有编码CD8αβ和TCRαβ序列的4合1慢病毒载体(例如PTE.CD8.TCR.WPRE)转导可产生更高数量的CD8+TCR+T细胞。另一方面,与用含有编码CD8αβ和TCRαβ序列的4合1慢病毒载体(例如PTE.CD8.TCR.WPRE)转导相比,使用含有编码CD8αβ序列的2合1慢病毒载体(例如CD8.WPRE)和含有编码TCRαβ序列的2合1慢病毒载体(例如R11KE.WPRE)混合物转导可产生更高数量的CD8+TCR-T细胞。
图20显示,增加用于转导的含有PTE.CD8.TCR.WPRE的4合1病毒载体量(例如30μl、120μl和240μl)可提高转导效率,例如CD8+TCR+γδT细胞的百分比增加,例如,30μl时增加9.6%、120μl时增加20.9%,240μl时增加27.7%。未转导γδT细胞作为对照。使用APC标记抗CD8β抗体和PE标记靶肽/MHC复合四聚体进行2色染色。
实施例7
αβT细胞中4合1构建体的表达
工程化淋巴细胞(包括表达重组蛋白的工程化αβT细胞,例如CD8αβ和/或TCRαβ)可根据US 2019/0247433中公开的方法制造,其内容通过引用整体并入本文。例如,图37显示了T细胞制造工艺370,其可包括PBMC的分离(371),其中PBMC可新鲜使用或冷冻储存直至准备使用,或者可以为白细胞分离术产品(例如leukopaks),或可用作T细胞制造和淋巴细胞群选择的起始材料(例如,αβTCR+T细胞、CD8+、CD4+或两者);将淋巴细胞解冻过夜,例如约16小时或约4-6小时(372),这可使凋亡细胞死亡并恢复T细胞功能(如果使用新鲜材料,则此步骤可能非必需);激活淋巴细胞(373),这可使用抗CD3和抗CD28抗体(可溶性或表面结合性,例如磁性或生物可降解珠、固定于培养容器上的抗体);用含有编码重组蛋白的序列的病毒载体(例如CD8αβ和/或TCRαβ多肽)进行转导(374),其中病毒载体可以为慢病毒载体或逆转录病毒载体,或者可通过非病毒方法进行转染;淋巴细胞的扩增、收获和冷冻保存(375),这可在存在细胞因子(例如IL-7和IL-15)、血清(ABS或FBS)和/或冷冻保存培养基的情况下进行。
外源性CD8表达
为了确定用含有具有编码CD8和TCR序列的4合1构建体的病毒载体转导αβT细胞中的外源CD8表达情况,从供体5和供体6中获得的T细胞用增加量的LV-PTE.CD8.TCR.WPRE转导,然后通过淋巴细胞<单细胞<活细胞<CD3+细胞群上的门控FACS检测CD4+细胞中的CD8α+细胞百分比。图21显示来自供体5的CD8α+CD4+细胞百分比从2.87%(未转导)增加至14.7%(2.5μl/1x106个细胞)、19.5%(5μl/1x106个细胞)、21.7%(7.5μl/1x106个细胞)和24.1%(10μl/1x106个细胞);来自供体6的CD8α+CD4+细胞百分比从1.93%(未转导)增加至12.5%(2.5μl/1x106个细胞)、17.2%(5μl/1x106个细胞)、19.6%(7.5μl/1x106个细胞)和20.8%(10μl/1x106个细胞)。
外源性TCR表达
为了确定用含有具有编码CD8和TCR序列的4合1构建体的病毒载体转导αβT细胞中的外源TCR表达情况,从供体5和供体6中获得的T细胞用增加量的LV-PTE.CD8.TCR.WPRE转导,然后通过淋巴细胞<单细胞<活细胞<CD3+<CD4+CD8+细胞群上的门控FACS检测CD4+CD8+细胞群中的靶肽/MHC复合体Dextramer203+(即,TCR+)细胞百分比。图22显示来自供体5的Dextramer203+细胞百分比从0.32%(未转导)增加至41.9%(2.5μl/1x106个细胞)、48.3%(5μl/1x106个细胞)、54.5%(7.5μl/1x106个细胞)和49.5%(10μl/1x106个细胞);来自供体6的Dextramer203+细胞百分比从0.19%(未转导)增加至35.5%(2.5μl/1x106个细胞)、41.2%(5μl/1x106个细胞)、44.6%(7.5μl/1x106个细胞)和44.0%(10μl/1x106个细胞)。
为了检测各种αβT细胞群中TCR表达情况,用LV-PTE.CD8.TCR.WPRE转导的αβT细胞通过淋巴细胞<单细胞<活细胞<CD3+<CD4+/-CD8+/-上的门控FACS进行分析。图23显示从供体5(上图)和供体6(下图)中获得的Dextramer203(Dex203)+(即TCR+)细胞百分比在CD4+CD8α+细胞群中通常高于CD4-CD8α+细胞群中。相比之下,CD4+CD8α-细胞群中Dex203+(即TCR+)细胞百分比最低。同样,图24显示从供体5(上图)和供体6(下图)中获得的Dextramer203(Dex203)MFI百分比在CD4+CD8α+细胞群中通常高于CD4-CD8α+细胞群中。相比之下,CD4+CD8α-细胞群中Dex203MFI百分比最低。这些结果表明,由LV-PTE.CD8.TCR.WPRE编码的外源性TCR和CD8可在CD4+T细胞和CD4-T细胞中共同表达。
实施例8
表达4合1构建体或仅含TCR构建体的αβT细胞的功能分析
图25显示了一种实验设计,其用于测试用含有4合1构建体的慢病毒载体(LV)(例如PTE.CD8.TCR.WPRE(LV-CD8.TCR)或仅含TCR的构建体(如R11KE.WPRE(LV-TCR))转导的αβT细胞功能。简言之,在第-1天,将靶细胞(例如,高抗原表达UACC257+RFP细胞系(阳性对照)和抗原阴性MCF7+GFP细胞系(阴性对照)接种于96孔板中。供体细胞产品,例如,用LV-CD8.TCR(5μl/1x106个细胞)或LV-TCR(2.5μl/1x106个细胞)转导的PBMC(从供体5、6、7和8中获得)进行解冻并静置于24孔G-透气性快速膨胀装置中过夜。在第0天,供体细胞产品(效应细胞)与靶细胞(例如UACC257+RFP和MCF7+GFP)以效应细胞与靶细胞(E/T)之比为2:1(例如200,000个效应细胞:100,000个靶细胞)下进行共培养。于37℃下孵育5小时后,将蛋白质转运抑制剂(例如GolgiStopTM(BD Biosciences)以0.5μl/孔添加至每孔中,然后于37℃下孵育4小时。然后离心细胞,收集上清液进行ELISA检测IFN-γ表达情况,并收集细胞使用细胞内细胞因子染色(ICS)板染色,例如CD3、CD4、CD8、IFN-γ、颗粒酶B和活/死细胞染色。
CD4-CD8+ T细胞群
图26显示,从用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD4-CD8α+T细胞与高靶标表达UACC257细胞共培养后,导致IFN-γ-阳性细胞(上图)和IFN-γMFI(下图)百分比均高于无转导(NT)时。相比之下,当LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的CD4-CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到IFN-γ阳性细胞和IFN-γMFI百分比存在显著差异。FACS于CD4-CD8α+IFN-γ+T细胞上进行门控。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=4)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-TCR或LV-CD8.TCR转导的CD4-CD8α+T细胞具有功能活性(例如通过表达IFN-γ),并且转导细胞对抗原阴性细胞(例如MCF7细胞)几乎无影响。
图27显示,从用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD4-CD8α+T细胞与高靶标表达UACC257细胞共培养后,导致颗粒酶B阳性细胞(上图)和颗粒酶B MFI(下图)百分比均高于无转导(NT)时。相比之下,当LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的CD4-CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到颗粒酶B阳性细胞和颗粒酶B MFI百分比存在显著差异。FACS于CD4-CD8α+颗粒酶B+T细胞上进行门控。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=3)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-TCR或LV-CD8.TCR转导的CD4-CD8α+T细胞具有功能活性(例如通过表达颗粒酶B),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
CD4+CD8+ T细胞群
图28显示,从用LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD4+CD8α+T细胞与高靶标表达UACC257细胞共培养后,导致IFN-γ-阳性细胞(上图)和IFN-γMFI(下图)百分比均高于无转导(NT)时。相比之下,当LV-CD8.TCR(TCR+CD8)转导的CD4+CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到IFN-γ阳性细胞和IFN-γMFI百分比存在显著差异。对于NT细胞,FACS在CD4+CD8α-IFN-γ+上进行门控,对于LV-CD8.TCR转导细胞,FACS在CD4+CD8α+IFN-γ+上进行门控。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=4)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-CD8.TCR转导的CD4+CD8α+T细胞具有功能活性(例如通过表达IFN-γ),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
图29显示,从用LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD4+CD8α+T细胞与高靶标表达UACC257细胞共培养后,导致颗粒酶B阳性细胞(上图)和颗粒酶B MFI(下图)百分比均高于无转导(NT)时。相比之下,当LV-CD8.TCR(TCR+CD8)转导的CD4+CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到颗粒酶B阳性细胞和颗粒酶BMFI百分比存在显著差异。对于NT细胞,FACS在CD4+CD8α-颗粒酶B+上进行门控,对于LV-CD8.TCR转导细胞,FACS在CD4+CD8α+颗粒酶B+上进行门控。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=3)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-CD8.TCR转导的CD4+CD8α+T细胞具有功能活性(例如通过表达颗粒酶B),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
CD3+ T细胞
图30显示,从用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD3+ T细胞与高靶标表达UACC257细胞共培养后,导致IFN-γ-阳性细胞(上图)和IFN-γMFI(下图)百分比均高于无转导(NT)时。相比之下,当LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的CD4-CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到IFN-γ阳性细胞和IFN-γMFI百分比存在显著差异。FACS于CD3+ T细胞上进行门控。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=4)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-TCR或LV-CD8.TCR转导的CD3+ T细胞具有功能活性(例如通过表达IFN-γ),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
图31显示,从用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD3+ T细胞与高靶标表达UACC257细胞共培养后,导致颗粒酶B阳性细胞(上图)和颗粒酶BMFI(下图)百分比均高于无转导(NT)时。相比之下,当LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的CD3+ T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到颗粒酶B阳性细胞和颗粒酶B MFI百分比存在显著差异。FACS于CD3+ T细胞上进行门控。未转导(NT)细胞作为对照。(效应细胞与靶细胞之比=2:1,供体分组N=3)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-TCR或LV-CD8.TCR转导的CD3+ T细胞具有功能活性(例如通过表达颗粒酶B),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
图32显示,从用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的分组供体中获得的CD3+ T细胞与高靶标表达UACC257细胞共培养后,导致IFN-γ分泌水平高于无转导(NT)、仅MCF7细胞和仅UACC257细胞时。相比之下,当LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的CD4-CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到IFN-γ分泌水平存在显著差异。(效应细胞与靶细胞之比=2:1,供体分组N=4)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-TCR或LV-CD8.TCR转导的CD3+ T细胞具有功能活性(例如通过分泌IFN-γ),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
图33显示,从用LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的个体供体5、6、7和8中获得的CD3+ T细胞与高靶标表达UACC257细胞共培养后,导致IFN-γ分泌水平高于无转导(NT)、仅MCF7细胞和仅UACC257细胞时。相比之下,当LV-TCR(TCR)或LV-CD8.TCR(TCR+CD8)转导的CD4-CD8α+T细胞与抗原阴性MCF7共培养时,转导和非转导细胞之间均未观察到IFN-γ分泌水平存在显著差异。(效应细胞与靶细胞之比=2:1)。这些结果表明,当接触高抗原表达靶细胞(例如UACC257细胞)时,用LV-TCR或LV-CD8.TCR转导的来自个体供体的CD3+ T细胞具有功能活性(例如通过分泌IFN-γ),并且转导细胞可能对抗原阴性细胞(例如MCF7细胞)几乎无影响。
实施例9
他汀类药物对T细胞激活标志物表达的影响
为了确定他汀类药物对T细胞激活标志物表达的影响,用他汀类药物(例如,阿托伐他汀、普伐他汀或瑞舒伐他汀)处理T细胞,然后进行FACS分析以测量T细胞激活标志物(例如,CD25、CD69和hLDLR)的表达。
CD4+ T细胞群
图34显示了用阿托伐他汀、普伐他汀或瑞舒伐他汀处理的CD3+CD4+ T细胞中的%CD25+细胞(上图)、%CD69+细胞(中图)和%hLDLR+细胞(下图)。预激活细胞、未用他汀类药物或DMSO激活的细胞(对照)和DMSO作为对照。这些结果表明,虽然阿托伐他汀、普伐他汀和瑞舒伐他汀对%CD4+CD25+细胞和%CD4+CD69+细胞几乎没有影响,但他汀类药物(例如,阿托伐他汀)可能会增加%CD4+hLDLR+细胞。FACS于淋巴细胞>单态细胞>活/死细胞>CD3+>CD4+上进行门控。
CD8+ T细胞群
图35显示了用阿托伐他汀、普伐他汀或瑞舒伐他汀处理的CD3+CD8+ T细胞中的%CD25+细胞(上图)、%CD69+细胞(中图)和%hLDLR+细胞(下图)。预激活细胞、未用他汀类药物或DMSO激活的细胞(对照)和DMSO作为对照。这些结果表明,虽然阿托伐他汀、普伐他汀和瑞舒伐他汀对%CD8+CD25+细胞和%CD8+CD69+细胞几乎没有影响,但他汀类药物(例如,阿托伐他汀)可能会增加%CD8+hLDLR+细胞。FACS于淋巴细胞>单态细胞>活/死细胞>CD3+>CD8+上进行门控。
实施例10
WPRE对慢病毒滴度的影响
为了确定WPRE对慢病毒滴度的影响,生成了包含野生型(wt)WPRE(SEQ ID NO:9)(LV-A)、无WPRE(LV-B)、WPREmutl(SEQ ID NO:265)(LV-C)或WPREmut2(SEQ ID NO:266)(LV-D)的慢病毒载体(LV)。HEK293T细胞用LV-A、LV-B、LV-C或LV-D转染,然后使用本领域已知的方法测定滴度。图36显示,这些慢病毒载体的滴度顺序为LV-C>LV-D≥LV-A>LV-B。这些结果表明WPREmut1和WPREmut2可能有助于提高慢病毒载体的产生。
本公开的优点可包括:生成在单个载体中共表达多种转基因(例如4个多肽)的病毒载体,以及生成共表达TCRαβ和CD8αβ作为安全和靶特异性“现成”T细胞产品的γδT细胞用于过继细胞疗法。
本专利说明书中引用的所有参考文献均透过引用并入本文,如同每篇参考文献被具体和单独地指出透过引用并入。任何参考文献的引用均为其在申请日之前的公开内容,不应解释为认可本公开内容无权凭借之前的发明而先于此类参考文献。
序列名单
<110> 伊玛提克斯美国公司
<120> 病毒载体及其在细胞过继疗法中的用途
<130> 3000011-013977
<150> US 62/853,123
<151> 2019-05-27
<160> 266
<170> PatentIn version 3.5
<210> 1
<211> 367
<212> DNA
<213> Artificial Sequence
<220>
<223> murine stem cell virus promoter
<400> 1
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcact 367
<210> 2
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Furin
<400> 2
Arg Ala Lys Arg
1
<210> 3
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> P2A peptide
<400> 3
Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn
1 5 10 15
Pro Gly Pro
<210> 4
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> T2A peptide
<400> 4
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 5
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> E2A peptide
<400> 5
Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp Val Glu Ser
1 5 10 15
Asn Pro Gly Pro
20
<210> 6
<211> 22
<212> PRT
<213> Artificial Sequence
<220>
<223> F2A peptide
<400> 6
Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val
1 5 10 15
Glu Ser Asn Pro Gly Pro
20
<210> 7
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Furin consensus sequence
<220>
<221> misc_feature
<222> (2)..(3)
<223> Xaa can be any naturally occurring amino acid
<400> 7
Arg Xaa Xaa Arg
1
<210> 8
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker peptide
<400> 8
Ser Gly Ser Gly
1
<210> 9
<211> 607
<212> DNA
<213> Artificial Sequence
<220>
<223> WPRE
<400> 9
cagtctgacg tacgcgtaat caacctctgg attacaaaat ttgtgaaaga ttgactggta 60
ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc 120
atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt 180
ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg 240
ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt 300
tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct 360
ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg aagctgacgt 420
cctttccatg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct 480
acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc 540
ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct 600
ccccgcc 607
<210> 10
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> X protein promoter
<400> 10
ggggaagctg acgtcctttc c 21
<210> 11
<211> 235
<212> PRT
<213> Homo sapiens
<400> 11
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ser Gln Phe Arg Val Ser Pro Leu Asp Arg Thr
20 25 30
Trp Asn Leu Gly Glu Thr Val Glu Leu Lys Cys Gln Val Leu Leu Ser
35 40 45
Asn Pro Thr Ser Gly Cys Ser Trp Leu Phe Gln Pro Arg Gly Ala Ala
50 55 60
Ala Ser Pro Thr Phe Leu Leu Tyr Leu Ser Gln Asn Lys Pro Lys Ala
65 70 75 80
Ala Glu Gly Leu Asp Thr Gln Arg Phe Ser Gly Lys Arg Leu Gly Asp
85 90 95
Thr Phe Val Leu Thr Leu Ser Asp Phe Arg Arg Glu Asn Glu Gly Tyr
100 105 110
Tyr Phe Cys Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe
115 120 125
Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg
130 135 140
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
145 150 155 160
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
165 170 175
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
180 185 190
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His
195 200 205
Arg Asn Arg Arg Arg Val Cys Lys Cys Pro Arg Pro Val Val Lys Ser
210 215 220
Gly Asp Lys Pro Ser Leu Ser Ala Arg Tyr Val
225 230 235
<210> 12
<211> 243
<212> PRT
<213> Homo sapiens
<400> 12
Met Arg Pro Arg Leu Trp Leu Leu Leu Ala Ala Gln Leu Thr Val Leu
1 5 10 15
His Gly Asn Ser Val Leu Gln Gln Thr Pro Ala Tyr Ile Lys Val Gln
20 25 30
Thr Asn Lys Met Val Met Leu Ser Cys Glu Ala Lys Ile Ser Leu Ser
35 40 45
Asn Met Arg Ile Tyr Trp Leu Arg Gln Arg Gln Ala Pro Ser Ser Asp
50 55 60
Ser His His Glu Phe Leu Ala Leu Trp Asp Ser Ala Lys Gly Thr Ile
65 70 75 80
His Gly Glu Glu Val Glu Gln Glu Lys Ile Ala Val Phe Arg Asp Ala
85 90 95
Ser Arg Phe Ile Leu Asn Leu Thr Ser Val Lys Pro Glu Asp Ser Gly
100 105 110
Ile Tyr Phe Cys Met Ile Val Gly Ser Pro Glu Leu Thr Phe Gly Lys
115 120 125
Gly Thr Gln Leu Ser Val Val Asp Phe Leu Pro Thr Thr Ala Gln Pro
130 135 140
Thr Lys Lys Ser Thr Leu Lys Lys Arg Val Cys Arg Leu Pro Arg Pro
145 150 155 160
Glu Thr Gln Lys Gly Pro Leu Cys Ser Pro Ile Thr Leu Gly Leu Leu
165 170 175
Val Ala Gly Val Leu Val Leu Leu Val Ser Leu Gly Val Ala Ile His
180 185 190
Leu Cys Cys Arg Arg Arg Arg Ala Arg Leu Arg Phe Met Lys Gln Pro
195 200 205
Gln Gly Glu Gly Ile Ser Gly Thr Phe Val Pro Gln Cys Leu His Gly
210 215 220
Tyr Tyr Ser Asn Thr Thr Thr Ser Gln Lys Leu Leu Asn Pro Trp Ile
225 230 235 240
Leu Lys Thr
<210> 13
<211> 273
<212> PRT
<213> Artificial Sequence
<220>
<223> R11KEA alpha chain
<400> 13
Met Glu 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 Lys 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 Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu
115 120 125
Thr Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 14
<211> 311
<212> PRT
<213> Artificial Sequence
<220>
<223> R11KE beta chain
<400> 14
Met Asp Ser Trp Thr Phe Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asn Ser Leu Phe Trp Tyr Arg Glu Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 15
<211> 274
<212> PRT
<213> Homo sapiens
<400> 15
Met Glu 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 Gln
100 105 110
Gly Glu Asn Ser Gly Tyr Ser Thr Leu Thr Phe Gly Lys Gly Thr Met
115 120 125
Leu Leu Val Ser Pro Asp Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 16
<211> 314
<212> PRT
<213> Homo sapiens
<400> 16
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Leu Gly Pro Gly Leu Ala Ala Tyr Asn Glu Gln Phe Phe Gly Pro
115 120 125
Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser
260 265 270
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 17
<211> 272
<212> PRT
<213> Homo sapiens
<400> 17
Met Lys 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
Tyr Ser Ser Ala Ser Lys Ile Ile Phe Gly Ser Gly Thr Arg Leu Ser
115 120 125
Ile Arg Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg
130 135 140
Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr
165 170 175
Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser
180 185 190
Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe
195 200 205
Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser
210 215 220
Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn
225 230 235 240
Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 18
<211> 310
<212> PRT
<213> Homo sapiens
<400> 18
Met Gly Ser Trp Thr Leu Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asp Tyr Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Arg Ala Asn Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu
115 120 125
Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Ser Arg Gly
305 310
<210> 19
<211> 277
<212> PRT
<213> Homo sapiens
<400> 19
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 Asn 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 Asp Pro Ala
130 135 140
Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser
165 170 175
Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp
180 185 190
Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala
195 200 205
Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe
210 215 220
Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe
225 230 235 240
Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe
245 250 255
Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu
260 265 270
Arg Leu Trp Ser Ser
275
<210> 20
<211> 313
<212> PRT
<213> Homo sapiens
<400> 20
Met Gly 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 Ser Ser Gly Ser His Gln Glu Thr Gln Tyr Phe Gly Pro Gly
115 120 125
Thr Arg Leu Leu Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu
130 135 140
Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr
180 185 190
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
225 230 235 240
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala
290 295 300
Met Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 21
<211> 271
<212> PRT
<213> Homo sapiens
<400> 21
Met Lys 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
Ser Lys Glu Thr Arg Leu Met Phe Gly Asp Gly Thr Gln Leu Val Val
115 120 125
Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
130 135 140
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
165 170 175
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
180 185 190
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
195 200 205
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
210 215 220
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 22
<211> 317
<212> PRT
<213> Homo sapiens
<400> 22
Met Leu 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 Trp Ser Gln His Pro
20 25 30
Ser Val Trp Ile Cys Lys Ser Gly Thr Ser Val Lys Ile Glu Cys Arg
35 40 45
Ser Leu Asp Phe Gln Ala Thr Thr Met Phe Trp Tyr Arg Gln Phe Pro
50 55 60
Lys Gln Ser Leu Met Leu Met Ala Thr Ser Asn Glu Gly Ser Lys Ala
65 70 75 80
Thr Tyr Glu Gln Gly Val Glu Lys Asp Lys Phe Leu Ile Asn His Ala
85 90 95
Ser Leu Thr Leu Ser Thr Leu Thr Val Thr Ser Ala His Pro Glu Asp
100 105 110
Ser Ser Phe Tyr Ile Cys Ser Ala Arg Ala Gly Gly His Glu Gln Phe
115 120 125
Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val
130 135 140
Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser
145 150 155 160
His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro
165 170 175
Asp His Val Glu Leu Ser Trp Val Trp Asn Gly Lys Glu Val His Ser
180 185 190
Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn
195 200 205
Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe
210 215 220
Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly
225 230 235 240
Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr
245 250 255
Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr
260 265 270
Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu
275 280 285
Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu
290 295 300
Val Leu Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly
305 310 315
<210> 23
<211> 271
<212> PRT
<213> Homo sapiens
<400> 23
Met Lys 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 Phe His Asp Lys Ile Ile Phe Gly Lys Gly Thr Arg Leu His Ile
115 120 125
Leu Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
130 135 140
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
165 170 175
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
180 185 190
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
195 200 205
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
210 215 220
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 24
<211> 308
<212> PRT
<213> Homo sapiens
<400> 24
Met Gly 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 Ala Ser Ala Tyr Gly Tyr Thr Phe Gly Ser Gly Thr Arg Leu
115 120 125
Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr 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 Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val 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 Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 25
<211> 274
<212> PRT
<213> Homo sapiens
<400> 25
Met Lys 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 Ala
100 105 110
Tyr Ser Gly Ala Gly Ser Tyr Gln Leu Thr Phe Gly Lys Gly Thr Lys
115 120 125
Leu Ser Val Ile Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 26
<211> 308
<212> PRT
<213> Homo sapiens
<400> 26
Met Gly 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 Glu Ser Ser Tyr Gly Tyr Thr Phe Gly Ser Gly Thr Arg Leu
115 120 125
Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr 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 Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val 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 Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 27
<211> 271
<212> PRT
<213> Homo sapiens
<400> 27
Met Lys 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
Lys Ala Gly Asn Gln Phe Tyr Phe Gly Thr Gly Thr Ser Leu Thr Val
115 120 125
Ile Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
130 135 140
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
165 170 175
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
180 185 190
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
195 200 205
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
210 215 220
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 28
<211> 314
<212> PRT
<213> Homo sapiens
<400> 28
Met Gly 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 Leu Leu Thr Ser Gly Gly Asp Asn Glu Gln Phe Phe Gly Pro
115 120 125
Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser
260 265 270
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 29
<211> 270
<212> PRT
<213> Homo sapiens
<400> 29
Met Glu 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 Val
100 105 110
Ser Asn Tyr Gln Leu Ile Trp Gly Ala Gly Thr Lys Leu Ile Ile Lys
115 120 125
Pro Asp Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
130 135 140
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
165 170 175
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
180 185 190
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
195 200 205
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys
210 215 220
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 30
<211> 314
<212> PRT
<213> Homo sapiens
<400> 30
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Ser Thr Ser Gly Gly Leu Ser Gly Glu Thr Gln Tyr Phe Gly Pro
115 120 125
Gly Thr Arg Leu Leu Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser
260 265 270
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 31
<211> 272
<212> PRT
<213> Homo sapiens
<400> 31
Met Lys 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 Ala Tyr Gly Lys Leu Gln Phe Gly Ala Gly Thr Gln Val Val
115 120 125
Val Thr Pro Asp Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg
130 135 140
Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr
165 170 175
Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser
180 185 190
Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe
195 200 205
Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser
210 215 220
Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn
225 230 235 240
Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 32
<211> 312
<212> PRT
<213> Homo sapiens
<400> 32
Met Asp Ser Trp Thr Phe Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asn Ser Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Ser Leu Gly Ser Pro Asp Gly Asn Gln Pro Gln His Phe Gly Asp
115 120 125
Gly Thr Arg Leu Ser Ile Leu Glu Asp Leu Asn Lys Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr 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 Ser
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser
260 265 270
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Phe
305 310
<210> 33
<211> 279
<212> PRT
<213> Homo sapiens
<400> 33
Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu
1 5 10 15
Glu Phe Ser 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 Ser Asp 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 Ala Ala Met Tyr Phe Cys
100 105 110
Ala Tyr Asn Ser Tyr Ala Gly Gly Thr Ser Tyr Gly Lys Leu Thr Phe
115 120 125
Gly Gln Gly Thr Ile Leu Thr Val His Pro Asn Ile Gln Asn Pro Asp
130 135 140
Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val
145 150 155 160
Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys
165 170 175
Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser
180 185 190
Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp
195 200 205
Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr
210 215 220
Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys
225 230 235 240
Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile
245 250 255
Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met
260 265 270
Thr Leu Arg Leu Trp Ser Ser
275
<210> 34
<211> 310
<212> PRT
<213> Homo sapiens
<400> 34
Met Gly 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 Leu Asp Gly Thr Ser Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Ser Arg Gly
305 310
<210> 35
<211> 271
<212> PRT
<213> Homo sapiens
<400> 35
Met Glu 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 Leu Ile Gly
100 105 110
Ala Ser Gly Ser Arg Leu Thr Phe Gly Glu Gly Thr Gln Leu Thr Val
115 120 125
Asn Pro Asp Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
130 135 140
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
165 170 175
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
180 185 190
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
195 200 205
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
210 215 220
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 36
<211> 310
<212> PRT
<213> Homo sapiens
<400> 36
Met Gly Ser Trp Thr Leu Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asp Tyr Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Ser Tyr Phe Gly Trp Asn Glu Lys Leu Phe Phe Gly Ser Gly Thr
115 120 125
Gln Leu Ser Val Leu Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val
130 135 140
Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Thr 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 Ser Thr Asp
180 185 190
Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys
195 200 205
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg
210 215 220
Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp
225 230 235 240
Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala
245 250 255
Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln
260 265 270
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
275 280 285
Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met
290 295 300
Val Lys Arg Lys Asp Phe
305 310
<210> 37
<211> 276
<212> PRT
<213> Homo sapiens
<400> 37
Met Met Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Met Ser Asp Val Ser Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly
115 120 125
Thr Arg Leu Ala Val His Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val
130 135 140
Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe
145 150 155 160
Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp
165 170 175
Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe
180 185 190
Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys
195 200 205
Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro
210 215 220
Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu
225 230 235 240
Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg
245 250 255
Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg
260 265 270
Leu Trp Ser Ser
275
<210> 38
<211> 311
<212> PRT
<213> Homo sapiens
<400> 38
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Thr Thr Pro Asp Gly Thr Asp Glu Gln Phe Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 39
<211> 274
<212> PRT
<213> Homo sapiens
<400> 39
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 Met Asn 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 Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 40
<211> 310
<212> PRT
<213> Homo sapiens
<400> 40
Met Ser 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 Arg Ala Glu Gly Gly Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Ser Arg Gly
305 310
<210> 41
<211> 273
<212> PRT
<213> Homo sapiens
<400> 41
Met Thr 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 Arg 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
Pro Thr Gly Gly Tyr Asn Lys Leu Ile Phe Gly Ala Gly Thr Arg Leu
115 120 125
Ala Val His Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 42
<211> 311
<212> PRT
<213> Homo sapiens
<400> 42
Met Ser Ile Gly Leu Leu Cys Cys Ala Ala Leu Ser Leu Leu Trp Ala
1 5 10 15
Gly 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
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Met Gly Leu Arg Leu
50 55 60
Ile His Tyr Ser Val Gly Ala Gly Ile Thr Asp Gln Gly Glu Val Pro
65 70 75 80
Asn Gly Tyr Asn Val Ser Arg Ser Thr Thr Glu Asp Phe Pro Leu Arg
85 90 95
Leu Leu Ser Ala Ala Pro Ser Gln Thr Ser Val Tyr Phe Cys Ala Ser
100 105 110
Ser Leu Gly Gly Ala Ser Gln Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 43
<211> 266
<212> PRT
<213> Homo sapiens
<400> 43
Met Lys 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 Phe Asn Phe Asn Lys
100 105 110
Phe Tyr Phe Gly Ser Gly Thr Lys Leu Asn Val Lys Pro Asn Ile Gln
115 120 125
Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp
130 135 140
Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser
145 150 155 160
Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp
165 170 175
Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn
180 185 190
Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro
195 200 205
Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu
210 215 220
Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu
225 230 235 240
Ser Val Ile Gly Phe 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> 44
<211> 309
<212> PRT
<213> Homo sapiens
<400> 44
Met Gly 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 Ser Gly Glu Thr Asn Glu Lys Leu Phe Phe Gly Ser Gly Thr Gln
115 120 125
Leu Ser Val Leu Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr 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 Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Phe
305
<210> 45
<211> 277
<212> PRT
<213> Homo sapiens
<400> 45
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 Ser 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 Gly Tyr Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys
115 120 125
Gly Thr His Leu Ile Ile Gln Pro Tyr Ile Gln Asn Pro Asp Pro Ala
130 135 140
Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser
165 170 175
Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp
180 185 190
Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala
195 200 205
Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe
210 215 220
Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe
225 230 235 240
Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe
245 250 255
Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu
260 265 270
Arg Leu Trp Ser Ser
275
<210> 46
<211> 311
<212> PRT
<213> Homo sapiens
<400> 46
Met Gly 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 Asn Glu Gly Gln Gly Trp Glu Ala Glu Ala Phe Phe Gly Gln Gly
115 120 125
Thr Arg Leu Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu
130 135 140
Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Thr 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 Ser Thr
180 185 190
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
225 230 235 240
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val 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 Ala Leu Val Leu Met Ala
290 295 300
Met Val Lys Arg Lys Asp Phe
305 310
<210> 47
<211> 268
<212> PRT
<213> Homo sapiens
<400> 47
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val His Asn Phe
100 105 110
Asn Lys Phe Tyr Phe Gly Ser Gly Thr Lys Leu Asn Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe 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> 48
<211> 322
<212> PRT
<213> Homo sapiens
<400> 48
Met Leu Ser Pro Asp Leu Pro Asp Ser Ala Trp Asn Thr Arg Leu Leu
1 5 10 15
Cys His Val Met Leu Cys Leu Leu Gly Ala Val Ser Val Ala Ala Gly
20 25 30
Val Ile Gln Ser Pro Arg His Leu Ile Lys Glu Lys Arg Glu Thr Ala
35 40 45
Thr Leu Lys Cys Tyr Pro Ile Pro Arg His Asp Thr Val Tyr Trp Tyr
50 55 60
Gln Gln Gly Pro Gly Gln Asp Pro Gln Phe Leu Ile Ser Phe Tyr Glu
65 70 75 80
Lys Met Gln Ser Asp Lys Gly Ser Ile Pro Asp Arg Phe Ser Ala Gln
85 90 95
Gln Phe Ser Asp Tyr His Ser Glu Leu Asn Met Ser Ser Leu Glu Leu
100 105 110
Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Leu Leu Gly Gln Gly
115 120 125
Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu
130 135 140
Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser
145 150 155 160
Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala
165 170 175
Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly
180 185 190
Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu
195 200 205
Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg
210 215 220
Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln
225 230 235 240
Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg
245 250 255
Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala
260 265 270
Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser Ala
275 280 285
Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val
290 295 300
Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Ser
305 310 315 320
Arg Gly
<210> 49
<211> 276
<212> PRT
<213> Homo sapiens
<400> 49
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 Asn Asn Asn Ala Gly Asn Met Leu Thr Phe Gly Gly Gly
115 120 125
Thr Arg Leu Met Val Lys Pro His Ile Gln Asn Pro Asp Pro Ala Val
130 135 140
Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe
145 150 155 160
Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp
165 170 175
Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe
180 185 190
Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys
195 200 205
Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro
210 215 220
Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu
225 230 235 240
Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg
245 250 255
Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg
260 265 270
Leu Trp Ser Ser
275
<210> 50
<211> 323
<212> PRT
<213> Homo sapiens
<400> 50
Met Leu Ser Pro Asp Leu Pro Asp Ser Ala Trp Asn Thr Arg Leu Leu
1 5 10 15
Cys His Val Met Leu Cys Leu Leu Gly Ala Val Ser Val Ala Ala Gly
20 25 30
Val Ile Gln Ser Pro Arg His Leu Ile Lys Glu Lys Arg Glu Thr Ala
35 40 45
Thr Leu Lys Cys Tyr Pro Ile Pro Arg His Asp Thr Val Tyr Trp Tyr
50 55 60
Gln Gln Gly Pro Gly Gln Asp Pro Gln Phe Leu Ile Ser Phe Tyr Glu
65 70 75 80
Lys Met Gln Ser Asp Lys Gly Ser Ile Pro Asp Arg Phe Ser Ala Gln
85 90 95
Gln Phe Ser Asp Tyr His Ser Glu Leu Asn Met Ser Ser Leu Glu Leu
100 105 110
Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Pro Thr Gly Thr Ser
115 120 125
Gly Tyr Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val Leu
130 135 140
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
145 150 155 160
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
165 170 175
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
180 185 190
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
195 200 205
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
210 215 220
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
225 230 235 240
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
245 250 255
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
260 265 270
Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser
275 280 285
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
290 295 300
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
305 310 315 320
Ser Arg Gly
<210> 51
<211> 273
<212> PRT
<213> Homo sapiens
<400> 51
Met Glu 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 Asn Arg Asp Asp Lys Ile Ile Phe Gly Lys Gly Thr Arg Leu
115 120 125
His Ile Leu Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 52
<211> 311
<212> PRT
<213> Homo sapiens
<400> 52
Met Gly 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
Arg Leu Pro Ser Arg Thr Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 53
<211> 270
<212> PRT
<213> Homo sapiens
<400> 53
Met Glu Thr Leu Leu Gly Leu Leu Ile Leu Trp Leu Gln Leu Gln Trp
1 5 10 15
Val Ser Ser Lys Gln Glu Val Thr Gln Ile Pro Ala Ala Leu Ser Val
20 25 30
Pro Glu Gly Glu Asn Leu Val Leu Asn Cys Ser Phe Thr Asp Ser Ala
35 40 45
Ile Tyr Asn Leu Gln Trp Phe Arg Gln Asp Pro Gly Lys Gly Leu Thr
50 55 60
Ser Leu Leu Leu Ile Gln Ser Ser Gln Arg Glu Gln Thr Ser Gly Arg
65 70 75 80
Leu Asn Ala Ser Leu Asp Lys Ser Ser Gly Arg Ser Thr Leu Tyr Ile
85 90 95
Ala Ala Ser Gln Pro Gly Asp Ser Ala Thr Tyr Leu Cys Ala Val Asn
100 105 110
Ser Asp Tyr Lys Leu Ser Phe Gly Ala Gly Thr Thr Val Thr Val Arg
115 120 125
Ala Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
130 135 140
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
165 170 175
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
180 185 190
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
195 200 205
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys
210 215 220
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 54
<211> 321
<212> PRT
<213> Homo sapiens
<400> 54
Met Leu Ser Pro Asp Leu Pro Asp Ser Ala Trp Asn Thr Arg Leu Leu
1 5 10 15
Cys His Val Met Leu Cys Leu Leu Gly Ala Val Ser Val Ala Ala Gly
20 25 30
Val Ile Gln Ser Pro Arg His Leu Ile Lys Glu Lys Arg Glu Thr Ala
35 40 45
Thr Leu Lys Cys Tyr Pro Ile Pro Arg His Asp Thr Val Tyr Trp Tyr
50 55 60
Gln Gln Gly Pro Gly Gln Asp Pro Gln Phe Leu Ile Ser Phe Tyr Glu
65 70 75 80
Lys Met Gln Ser Asp Lys Gly Ser Ile Pro Asp Arg Phe Ser Ala Gln
85 90 95
Gln Phe Ser Asp Tyr His Ser Glu Leu Asn Met Ser Ser Leu Glu Leu
100 105 110
Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Leu Gly Leu Gly Thr
115 120 125
Gly Asp Tyr Gly Tyr Thr Phe Gly Ser Gly Thr Arg Leu Thr Val Val
130 135 140
Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
145 150 155 160
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
165 170 175
Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
180 185 190
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
195 200 205
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
210 215 220
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
225 230 235 240
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
245 250 255
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
260 265 270
Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly Val Leu Ser
275 280 285
Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
290 295 300
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
305 310 315 320
Phe
<210> 55
<211> 273
<212> PRT
<213> Homo sapiens
<400> 55
Met Glu 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 Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu
115 120 125
Thr Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 56
<211> 311
<212> PRT
<213> Homo sapiens
<400> 56
Met Asp Ser Trp Thr Phe Cys Cys Val Ser Leu Cys Ile Leu Val Ala
1 5 10 15
Lys His Thr Asp Ala Gly Val Ile Gln Ser Pro Arg His Glu Val Thr
20 25 30
Glu Met Gly Gln Glu Val Thr Leu Arg Cys Lys Pro Ile Ser Gly His
35 40 45
Asn Ser Leu Phe Trp Tyr Arg Gln Thr Met Met Arg Gly Leu Glu Leu
50 55 60
Leu Ile Tyr Phe Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro
65 70 75 80
Glu Asp Arg Phe Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu
85 90 95
Lys Ile Gln Pro Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala
100 105 110
Ser Ser Pro Gly Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Leu Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 57
<211> 275
<212> PRT
<213> Homo sapiens
<400> 57
Met Lys 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 Ala
100 105 110
Val Ile Ser Asn Phe Gly Asn Glu Lys Leu Thr Phe Gly Thr Gly Thr
115 120 125
Arg Leu Thr Ile Ile Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr
130 135 140
Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr
145 150 155 160
Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val
165 170 175
Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys
180 185 190
Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala
195 200 205
Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser
210 215 220
Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr
225 230 235 240
Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile
245 250 255
Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu
260 265 270
Trp Ser Ser
275
<210> 58
<211> 311
<212> PRT
<213> Homo sapiens
<400> 58
Met Gly Ser Arg Leu Leu Cys Trp Val Leu Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Lys Ala Gly Val Thr Gln Thr Pro Arg Tyr Leu Ile Lys
20 25 30
Thr Arg Gly Gln Gln Val Thr Leu Ser Cys Ser Pro Ile Ser Gly His
35 40 45
Arg Ser Val Ser Trp Tyr Gln Gln Thr Pro Gly Gln Gly Leu Gln Phe
50 55 60
Leu Phe Glu Tyr Phe Ser Glu Thr Gln Arg Asn Lys Gly Asn Phe Pro
65 70 75 80
Gly Arg Phe Ser Gly Arg Gln Phe Ser Asn Ser Arg Ser Glu Met Asn
85 90 95
Val Ser Thr Leu Glu Leu Gly Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Trp Asp Ser Pro Asn Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 59
<211> 274
<212> PRT
<213> Homo sapiens
<400> 59
Met Met Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Met Ser Glu Ala Ala Gly Asn Lys Leu Thr Phe Gly Gly Gly Thr Arg
115 120 125
Val Leu Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 60
<211> 309
<212> PRT
<213> Homo sapiens
<400> 60
Met Gly 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 Tyr Thr Asn Gln Gly Glu Ala Phe Phe Gly Gln Gly Thr Arg
115 120 125
Leu Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr 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 Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Phe
305
<210> 61
<211> 273
<212> PRT
<213> Homo sapiens
<400> 61
Met Lys 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 Ser 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
Leu Asn Gln Ala Gly Thr Ala Leu Ile Phe Gly Lys Gly Thr Thr Leu
115 120 125
Ser Val Ser Ser Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 62
<211> 314
<212> PRT
<213> Homo sapiens
<400> 62
Met Gly 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 Ala Glu Thr Gly Pro Trp Leu Gly Asn Glu Gln Phe Phe Gly Pro
115 120 125
Gly Thr Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro
130 135 140
Glu Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln
145 150 155 160
Lys Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val
165 170 175
Glu Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser
180 185 190
Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg
195 200 205
Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn
210 215 220
Pro Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu
225 230 235 240
Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val
245 250 255
Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser
260 265 270
Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu
275 280 285
Gly Lys Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met
290 295 300
Ala Met Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 63
<211> 277
<212> PRT
<213> Homo sapiens
<400> 63
Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu
1 5 10 15
Glu Phe Ser 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 Ser Asp 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 Ala Ala Met Tyr Phe Cys
100 105 110
Ala Tyr Arg Trp Ala Gln Gly Gly Ser Glu Lys Leu Val Phe Gly Lys
115 120 125
Gly Thr Lys Leu Thr Val Asn Pro Tyr Ile Gln Lys Pro Asp Pro Ala
130 135 140
Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu
145 150 155 160
Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser
165 170 175
Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp
180 185 190
Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala
195 200 205
Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe
210 215 220
Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe
225 230 235 240
Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe
245 250 255
Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu
260 265 270
Arg Leu Trp Ser Ser
275
<210> 64
<211> 313
<212> PRT
<213> Homo sapiens
<400> 64
Met Thr Ile Arg Leu Leu Cys Tyr Met Gly Phe Tyr Phe Leu Gly Ala
1 5 10 15
Gly Leu Met Glu Ala Asp Ile Tyr Gln Thr Pro Arg Tyr Leu Val Ile
20 25 30
Gly Thr Gly Lys Lys Ile Thr Leu Glu Cys Ser Gln Thr Met Gly His
35 40 45
Asp Lys Met Tyr Trp Tyr Gln Gln Asp Pro Gly Met Glu Leu His Leu
50 55 60
Ile His Tyr Ser Tyr Gly Val Asn Ser Thr Glu Lys Gly Asp Leu Ser
65 70 75 80
Ser Glu Ser Thr Val Ser Arg Ile Arg Thr Glu His Phe Pro Leu Thr
85 90 95
Leu Glu Ser Ala Arg Pro Ser His Thr Ser Gln Tyr Leu Cys Ala Thr
100 105 110
Glu Leu Trp Ser Ser Gly Gly Thr Gly Glu Leu Phe Phe Gly Glu Gly
115 120 125
Ser Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu
130 135 140
Val Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys
145 150 155 160
Ala Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu
165 170 175
Leu Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr
180 185 190
Asp Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr
195 200 205
Cys Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro
210 215 220
Arg Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn
225 230 235 240
Asp Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser
245 250 255
Ala Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala
290 295 300
Met Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 65
<211> 206
<212> PRT
<213> Homo sapiens
<400> 65
Ile Met Ser Ile Tyr Ser Asn Gly Asp Lys Glu Asp Gly Arg Phe Thr
1 5 10 15
Ala Gln Leu Asn Lys Ala Ser Gln Tyr Val Ser Leu Leu Ile Arg Asp
20 25 30
Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala Val Gly Pro Ser
35 40 45
Gly Thr Tyr Lys Tyr Ile Phe Gly Thr Gly Thr Arg Leu Lys Val Leu
50 55 60
Ala Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
65 70 75 80
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
85 90 95
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
100 105 110
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
115 120 125
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
130 135 140
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys
145 150 155 160
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
165 170 175
Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val
180 185 190
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
195 200 205
<210> 66
<211> 311
<212> PRT
<213> Homo sapiens
<400> 66
Met Gly Pro Gln Leu Leu Gly Tyr Val Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Leu Glu Ala Gln Val Thr Gln Asn Pro Arg Tyr Leu Ile Thr
20 25 30
Val Thr Gly Lys Lys Leu Thr Val Thr Cys Ser Gln Asn Met Asn His
35 40 45
Glu Tyr Met Ser Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Gln
50 55 60
Ile Tyr Tyr Ser Met Asn Val Glu Val Thr Asp Lys Gly Asp Val Pro
65 70 75 80
Glu Gly Tyr Lys Val Ser Arg Lys Glu Lys Arg Asn Phe Pro Leu Ile
85 90 95
Leu Glu Ser Pro Ser Pro Asn Gln Thr Ser Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Pro Gly Gly Ser Gly Asn Glu Gln Phe Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 67
<211> 274
<212> PRT
<213> Homo sapiens
<400> 67
Met Lys 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
Val Ser Gly Gly Gly Ala Asp Gly Leu Thr Phe Gly Lys Gly Thr His
115 120 125
Leu Ile Ile Gln Pro Tyr Ile Gln Lys Pro Asp Pro Ala Val Tyr Gln
130 135 140
Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp
145 150 155 160
Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr
165 170 175
Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser
180 185 190
Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn
195 200 205
Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro
210 215 220
Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp
225 230 235 240
Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 68
<211> 319
<212> PRT
<213> Homo sapiens
<400> 68
Met Leu Ser Pro Asp Leu Pro Asp Ser Ala Trp Asn Thr Arg Leu Leu
1 5 10 15
Cys His Val Met Leu Cys Leu Leu Gly Ala Val Ser Val Ala Ala Gly
20 25 30
Val Ile Gln Ser Pro Arg His Leu Ile Lys Glu Lys Arg Glu Thr Ala
35 40 45
Thr Leu Lys Cys Tyr Pro Ile Pro Arg His Asp Thr Val Tyr Trp Tyr
50 55 60
Gln Gln Gly Pro Gly Gln Asp Pro Gln Phe Leu Ile Ser Phe Tyr Glu
65 70 75 80
Lys Met Gln Ser Asp Lys Gly Ser Ile Pro Asp Arg Phe Ser Ala Gln
85 90 95
Gln Phe Ser Asp Tyr His Ser Glu Leu Asn Met Ser Ser Leu Glu Leu
100 105 110
Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Leu Gly Arg Gly Gly
115 120 125
Gln Pro Gln His Phe Gly Asp Gly Thr Arg Leu Ser Ile Leu Glu Asp
130 135 140
Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Glu
145 150 155 160
Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr
165 170 175
Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys
180 185 190
Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu Gln
195 200 205
Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val
210 215 220
Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val
225 230 235 240
Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala
245 250 255
Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp
260 265 270
Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr
275 280 285
Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu
290 295 300
Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Phe
305 310 315
<210> 69
<211> 273
<212> PRT
<213> Artificial Sequence
<220>
<223> R11P3D3KE alpha chain
<400> 69
Met Glu 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 Lys 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 Tyr Asn Asn Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu
115 120 125
Thr Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 70
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> R11P3D3KE beta chain
<400> 70
Asn Asn Asn Val Pro Ile Asp Asp Ser Gly Met Pro Glu Asp Arg Phe
1 5 10 15
Ser Ala Lys Met Pro Asn Ala Ser Phe Ser Thr Leu Lys Ile Gln Pro
20 25 30
Ser Glu Pro Arg Asp Ser Ala Val Tyr Phe Cys Ala Ser Ser Pro Gly
35 40 45
Ser Thr Asp Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu
50 55 60
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
65 70 75 80
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
85 90 95
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
100 105 110
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
115 120 125
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
130 135 140
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
145 150 155 160
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
165 170 175
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
180 185 190
Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser
195 200 205
Ala Thr Leu Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala
210 215 220
Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
225 230 235 240
Ser Arg Gly
<210> 71
<211> 223
<212> PRT
<213> Homo sapiens
<400> 71
Thr Tyr Leu Tyr Trp Tyr Lys Gln Glu Pro Gly Ala Gly Leu Gln Leu
1 5 10 15
Leu Thr Tyr Ile Phe Ser Asn Met Asp Met Lys Gln Asp Gln Arg Leu
20 25 30
Thr Val Leu Leu Asn Lys Lys Asp Lys His Leu Ser Leu Arg Ile Ala
35 40 45
Asp Thr Gln Thr Gly Asp Ser Ala Ile Tyr Phe Cys Ala Glu Ile Asp
50 55 60
Asn Gln Gly Gly Lys Leu Ile Phe Gly Gln Gly Thr Glu Leu Ser Val
65 70 75 80
Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
85 90 95
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
100 105 110
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
115 120 125
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
130 135 140
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
145 150 155 160
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
165 170 175
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
180 185 190
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys
195 200 205
Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
210 215 220
<210> 72
<211> 307
<212> PRT
<213> Homo sapiens
<400> 72
Met Gly 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 Gln Leu Asn Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu Thr
115 120 125
Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val Phe
130 135 140
Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Thr 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 Ser Thr Asp Pro Gln Pro
180 185 190
Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
225 230 235 240
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Phe Thr Ser Val 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 Ala Leu Val Leu Met Ala Met Val Lys Arg
290 295 300
Lys Asp Phe
305
<210> 73
<211> 270
<212> PRT
<213> Homo sapiens
<400> 73
Met Lys 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 Asn Ala Arg Leu Met Phe Gly Asp Gly Thr Gln Leu Val Val Lys
115 120 125
Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
130 135 140
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
165 170 175
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
180 185 190
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
195 200 205
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys
210 215 220
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 74
<211> 311
<212> PRT
<213> Homo sapiens
<400> 74
Met Asp 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 Ser Gly Gln Gly Ala Asn Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 75
<211> 272
<212> PRT
<213> Homo sapiens
<400> 75
Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu
1 5 10 15
Glu Phe Ser 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 Ser Asp 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 Ala Ala Met Tyr Phe Cys
100 105 110
Ala Tyr Leu Asn Tyr Gln Leu Ile Trp Gly Ala Gly Thr Lys Leu Ile
115 120 125
Ile Lys Pro Asp Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg
130 135 140
Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr
165 170 175
Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser
180 185 190
Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe
195 200 205
Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser
210 215 220
Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn
225 230 235 240
Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 76
<211> 311
<212> PRT
<213> Homo sapiens
<400> 76
Met Asp 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 Ser Glu Met Thr Ala Val Gly Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 77
<211> 271
<212> PRT
<213> Homo sapiens
<400> 77
Met Lys 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 Ala
100 105 110
Phe Ser Gly Tyr Ala Leu Asn Phe Gly Lys Gly Thr Ser Leu Leu Val
115 120 125
Thr Pro His Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp
130 135 140
Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser
145 150 155 160
Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp
165 170 175
Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala
180 185 190
Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn
195 200 205
Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser
210 215 220
Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu
225 230 235 240
Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 78
<211> 310
<212> PRT
<213> Homo sapiens
<400> 78
Met Asp 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 Ser Gln Tyr Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser Arg Leu
115 120 125
Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Ser Arg Gly
305 310
<210> 79
<211> 270
<212> PRT
<213> Homo sapiens
<400> 79
Met Lys 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 Gly Gly Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys
115 120 125
Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
130 135 140
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
145 150 155 160
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
165 170 175
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
180 185 190
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
195 200 205
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys
210 215 220
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
225 230 235 240
Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 80
<211> 311
<212> PRT
<213> Homo sapiens
<400> 80
Met Asp 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 Ser Gly Gln Gly Ala Leu Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 81
<211> 281
<212> PRT
<213> Homo sapiens
<400> 81
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 Ser Gly Leu Tyr Asn Gln Gly Gly Lys Leu
115 120 125
Ile Phe Gly Gln Gly Thr Glu Leu Ser Val Lys Pro Asn Ile Gln Asn
130 135 140
Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys
145 150 155 160
Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln
165 170 175
Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met
180 185 190
Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys
195 200 205
Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu
210 215 220
Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val
225 230 235 240
Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser
245 250 255
Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu
260 265 270
Leu Met Thr Leu Arg Leu Trp Ser Ser
275 280
<210> 82
<211> 311
<212> PRT
<213> Homo sapiens
<400> 82
Met Gly 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
Ser Leu Gly Asp Arg Gly Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg
115 120 125
Leu Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala
130 135 140
Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr
145 150 155 160
Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser
165 170 175
Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro
180 185 190
Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu
195 200 205
Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn
210 215 220
His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu
225 230 235 240
Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu
245 250 255
Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln Gln
260 265 270
Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala
275 280 285
Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val
290 295 300
Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 83
<211> 272
<212> PRT
<213> Homo sapiens
<400> 83
Met Lys 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 Asn Asn Asn Ala Arg Leu Met Phe Gly Asp Gly Thr Gln Leu Val
115 120 125
Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg
130 135 140
Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp
145 150 155 160
Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr
165 170 175
Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser
180 185 190
Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe
195 200 205
Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser
210 215 220
Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn
225 230 235 240
Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 84
<211> 320
<212> PRT
<213> Homo sapiens
<400> 84
Met Leu Ser Pro Asp Leu Pro Asp Ser Ala Trp Asn Thr Arg Leu Leu
1 5 10 15
Cys His Val Met Leu Cys Leu Leu Gly Ala Val Ser Val Ala Ala Gly
20 25 30
Val Ile Gln Ser Pro Arg His Leu Ile Lys Glu Lys Arg Glu Thr Ala
35 40 45
Thr Leu Lys Cys Tyr Pro Ile Pro Arg His Asp Thr Val Tyr Trp Tyr
50 55 60
Gln Gln Gly Pro Gly Gln Asp Pro Gln Phe Leu Ile Ser Phe Tyr Glu
65 70 75 80
Lys Met Gln Ser Asp Lys Gly Ser Ile Pro Asp Arg Phe Ser Ala Gln
85 90 95
Gln Phe Ser Asp Tyr His Ser Glu Leu Asn Met Ser Ser Leu Glu Leu
100 105 110
Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser Ser Pro Pro Asp Gln Asn
115 120 125
Thr Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr Val Leu Glu Asp Leu
130 135 140
Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro Ser Glu Ala
145 150 155 160
Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu Ala Thr Gly
165 170 175
Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn Gly Lys Glu
180 185 190
Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys Glu Gln Pro
195 200 205
Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu Arg Val Ser
210 215 220
Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys Gln Val Gln
225 230 235 240
Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp Arg Ala Lys
245 250 255
Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg Ala Asp Cys
260 265 270
Gly Phe Thr Ser Glu Ser Tyr Gln Gln Gly Val Leu Ser Ala Thr Ile
275 280 285
Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val Leu Val
290 295 300
Ser Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp Ser Arg Gly
305 310 315 320
<210> 85
<211> 273
<212> PRT
<213> Homo sapiens
<400> 85
Met Leu Leu Leu Leu Val Pro Val Leu Glu Val Ile Phe Thr Leu Gly
1 5 10 15
Gly Thr Arg Ala Gln Ser Val Thr Gln Leu Gly Ser His Val Ser Val
20 25 30
Ser Glu Gly Ala Leu Val Leu Leu Arg Cys Asn Tyr Ser Ser Ser Val
35 40 45
Pro Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Gln Gly Leu Gln
50 55 60
Leu Leu Leu Lys Tyr Thr Thr Gly Ala Thr Leu Val Lys Gly Ile Asn
65 70 75 80
Gly Phe Glu Ala Glu Phe Lys Lys Ser Glu Thr Ser Phe His Leu Thr
85 90 95
Lys Pro Ser Ala His Met Ser Asp Ala Ala Glu Tyr Phe Cys Ala Val
100 105 110
Arg Ile Phe Gly Asn Glu Lys Leu Thr Phe Gly Thr Gly Thr Arg Leu
115 120 125
Thr Ile Ile Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu
130 135 140
Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe
145 150 155 160
Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile
165 170 175
Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn
180 185 190
Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala
195 200 205
Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu
210 215 220
Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr
225 230 235 240
Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe 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> 86
<211> 312
<212> PRT
<213> Homo sapiens
<400> 86
Met Gly 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 Met Gly Glu Leu Thr Gly Glu Leu Phe Phe Gly Glu Gly Ser
115 120 125
Arg Leu Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val
130 135 140
Ala Val Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala
145 150 155 160
Thr Leu Val Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu
165 170 175
Ser Trp Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp
180 185 190
Pro Gln Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys
195 200 205
Leu Ser Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg
210 215 220
Asn His Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp
225 230 235 240
Glu Trp Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala
245 250 255
Glu Ala Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu Ser Tyr Gln
260 265 270
Gln Gly Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys
275 280 285
Ala Thr Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met
290 295 300
Val Lys Arg Lys Asp Ser Arg Gly
305 310
<210> 87
<211> 276
<212> PRT
<213> Homo sapiens
<400> 87
Met Met Lys Ser Leu Arg Val Leu Leu Val Ile Leu Trp Leu Gln Leu
1 5 10 15
Ser Trp Val Trp Ser Gln Gln Lys Glu Val Glu Gln Asp Pro Gly Pro
20 25 30
Leu Ser Val Pro Glu Gly Ala Ile Val Ser Leu Asn Cys Thr Tyr Ser
35 40 45
Asn Ser Ala Phe Gln Tyr Phe Met Trp Tyr Arg Gln Tyr Ser Arg Lys
50 55 60
Gly Pro Glu Leu Leu Met Tyr Thr Tyr Ser Ser Gly Asn Lys Glu Asp
65 70 75 80
Gly Arg Phe Thr Ala Gln Val Asp Lys Ser Ser Lys Tyr Ile Ser Leu
85 90 95
Phe Ile Arg Asp Ser Gln Pro Ser Asp Ser Ala Thr Tyr Leu Cys Ala
100 105 110
Met Met Gly Asp Thr Gly Thr Ala Ser Lys Leu Thr Phe Gly Thr Gly
115 120 125
Thr Arg Leu Gln Val Thr Leu Asp Ile Gln Asn Pro Asp Pro Ala Val
130 135 140
Tyr Gln Leu Arg Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe
145 150 155 160
Thr Asp Phe Asp Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp
165 170 175
Val Tyr Ile Thr Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe
180 185 190
Lys Ser Asn Ser Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys
195 200 205
Ala Asn Ala Phe Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro
210 215 220
Ser Pro Glu Ser Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu
225 230 235 240
Thr Asp Thr Asn Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg
245 250 255
Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg
260 265 270
Leu Trp Ser Ser
275
<210> 88
<211> 309
<212> PRT
<213> Homo sapiens
<400> 88
Met Gly 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 Gly Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu Thr
115 120 125
Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe
130 135 140
Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val
145 150 155 160
Cys Leu Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp
165 170 175
Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro
180 185 190
Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser
195 200 205
Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
225 230 235 240
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala Met Val Lys Arg
290 295 300
Lys Asp Ser Arg Gly
305
<210> 89
<211> 144
<212> PRT
<213> Homo sapiens
<400> 89
Val Lys Pro Asn Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg
1 5 10 15
Asp Ser Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp
20 25 30
Ser Gln Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr
35 40 45
Asp Lys Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser
50 55 60
Ala Val Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe
65 70 75 80
Asn Asn Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser
85 90 95
Ser Cys Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn
100 105 110
Leu Asn Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu
115 120 125
Lys Val Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
130 135 140
<210> 90
<211> 307
<212> PRT
<213> Homo sapiens
<400> 90
Met Leu Cys Ser Leu Leu Ala Leu Leu Leu Gly Thr Phe Phe Gly Val
1 5 10 15
Arg Ser Gln Thr Ile His Gln Trp Pro Ala Thr Leu Val Gln Pro Val
20 25 30
Gly Ser Pro Leu Ser Leu Glu Cys Thr Val Glu Gly Thr Ser Asn Pro
35 40 45
Asn Leu Tyr Trp Tyr Arg Gln Ala Ala Gly Arg Gly Leu Gln Leu Leu
50 55 60
Phe Tyr Ser Val Gly Ile Gly Gln Ile Ser Ser Glu Val Pro Gln Asn
65 70 75 80
Leu Ser Ala Ser Arg Pro Gln Asp Arg Gln Phe Ile Leu Ser Ser Lys
85 90 95
Lys Leu Leu Leu Ser Asp Ser Gly Phe Tyr Leu Cys Ala Trp Ser Gly
100 105 110
Leu Val Ala Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu Thr Val Leu
115 120 125
Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val Phe Glu Pro
130 135 140
Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu Val Cys Leu
145 150 155 160
Ala Thr Gly Phe Tyr Pro Asp His Val Glu Leu Ser Trp Trp Val Asn
165 170 175
Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln Pro Leu Lys
180 185 190
Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser Ser Arg Leu
195 200 205
Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe Arg Cys
210 215 220
Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr Gln Asp
225 230 235 240
Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp Gly Arg
245 250 255
Ala Asp Cys Gly Phe Thr Ser Glu 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 Ala Leu Val Leu Met Ala Met Val Lys Arg Lys Asp
290 295 300
Ser Arg Gly
305
<210> 91
<211> 4445
<212> DNA
<213> Artificial Sequence
<220>
<223> PTE WPRE
<400> 91
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactcag cggccgcccc gggtcgacgc taccaccatg gactcttgga ccttctgctg 420
cgtgagcctg tgcatcctgg tggccaagca cacagacgcc ggcgtgatcc agtcccctag 480
gcacgaggtg accgagatgg gccaggaggt gacactgcgc tgtaagccaa tctctggcca 540
caacagcctg ttttggtata gggagaccat gatgcgcggc ctggagctgc tgatctactt 600
caataacaat gtgcccatcg acgattccgg catgcctgag gatcggtttt ctgccaagat 660
gcccaatgcc agcttctcca cactgaagat ccagcctagc gagccaagag actccgccgt 720
gtatttttgc gcctctagcc caggcagcac cgatacacag tacttcggac caggaaccag 780
gctgacagtg ctggaggacc tgaagaacgt gttcccccct gaggtggccg tgtttgagcc 840
ctctgaggcc gagatcagcc acacccagaa ggccaccctg gtgtgcctgg caaccggctt 900
ctatcctgat cacgtggagc tgtcctggtg ggtgaacggc aaggaggtgc acagcggcgt 960
gtccacagac ccacagcccc tgaaggagca gccagccctg aatgatagcc ggtattgcct 1020
gtcctctcgg ctgagagtgt ccgccacctt ttggcagaac ccccggaatc acttcagatg 1080
tcaggtgcag ttttacggcc tgtccgagaa cgatgagtgg acccaggacc gggccaagcc 1140
tgtgacacag atcgtgtctg ccgaggcatg gggaagagca gactgtggct tcacctctga 1200
gagctaccag cagggcgtgc tgagcgccac catcctgtat gagatcctgc tgggcaaggc 1260
cacactgtac gccgtcctgg tctccgctct ggtgctgatg gcaatggtca aaagaaaaga 1320
tagtcgggga cgggccaaga gatctggcag cggcgccacc aatttcagcc tgctgaaaca 1380
ggccggcgac gtggaagaga accctggccc catggagaag aatcccctgg ctgcccccct 1440
gctgatcctg tggtttcacc tggactgcgt gtcctctatc ctgaatgtgg aacagagccc 1500
acagagcctg cacgtgcagg agggcgactc caccaacttc acatgctctt ttcctagctc 1560
caacttctac gccctgcact ggtacagaaa ggagaccgca aagtccccag aggccctgtt 1620
cgtgatgaca ctgaacggcg atgagaagaa gaagggccgc atcagcgcca ccctgaatac 1680
aaaggagggc tactcctatc tgtacatcaa gggctcccag cctgaggact ctgccaccta 1740
tctgtgcgcc ctgtacaaca ataacgatat gcggtttggc gccggcacca gactgacagt 1800
gaagccaaac atccagaatc cagaccccgc cgtgtatcag ctgcgggaca gcaagtctag 1860
cgataagagc gtgtgcctgt tcaccgactt tgattctcag acaaacgtga gccagtccaa 1920
ggacagcgac gtgtacatca ccgacaagac agtgctggat atgagaagca tggacttcaa 1980
gtctaacagc gccgtggcct ggtccaataa gtctgatttc gcctgcgcca atgcctttaa 2040
taactccatc atccccgagg ataccttctt tccttctcca gagtcctctt gtgacgtgaa 2100
gctggtggag aagtctttcg agaccgatac aaacctgaat tttcagaacc tgagcgtgat 2160
cggcttcagg atcctgctgc tgaaggtggc cggctttaat ctgctgatga ccctgaggct 2220
gtggagctcc cgggccaaga gatctggcag cggcgagggc agaggcagcc tgctgacctg 2280
cggcgacgtg gaggagaacc ccggccccat gcgcccgaga ctgtggcttc tgctcgccgc 2340
gcaactgact gtcctgcacg gaaacagcgt gctgcagcag acaccggcct acatcaaagt 2400
gcagaccaac aagatggtca tgctgtcctg cgaggccaag atttccctct ccaacatgcg 2460
gatctattgg ttgcggcaga gacaggcgcc ttcctcggac tcccaccatg agttcttggc 2520
cctgtgggac tccgccaagg gaactattca cggcgaagaa gtggaacagg agaagatcgc 2580
cgtgtttcgc gatgcctccc gctttatact gaatctgacc tccgtgaagc ccgaagatag 2640
cgggatctac ttttgcatga ttgtgggctc acccgaactg accttcggga agggcactca 2700
gctgagcgtg gtggacttcc tccccactac cgcccaaccc actaagaagt caaccctgaa 2760
gaagcgggtt tgcagactcc cacggccgga aacgcagaag ggtccgctgt gttccccgat 2820
caccctgggg ctccttgtgg ctggagtgct ggtccttctg gtgtcccttg gcgtcgccat 2880
tcacctctgc tgccggagaa ggagggccag actgaggttc atgaagcagc ctcagggaga 2940
ggggatcagt ggcactttcg tgccacaatg cctccatggc tactattcca acaccaccac 3000
ctcgcaaaag ctgctgaacc cctggatcct gaaaacccgg gccaagagat ctggcagcgg 3060
ccagtgcacc aactacgccc tgctgaagct ggccggcgac gtggagagca accccggccc 3120
catggcgctt cccgtgaccg cactcctgtt gccccttgcc ctgctgttgc acgccgcacg 3180
accttcccaa ttccgggtgt cccctctgga tcgcacctgg aacctcgggg aaacggtgga 3240
gctcaagtgt caagtcctcc tgtcgaaccc gaccagcgga tgcagctggc tgttccagcc 3300
gagaggagct gccgcctcac ccaccttcct cctgtacttg agccagaaca agccgaaggc 3360
cgctgagggt ctggacaccc agcgcttctc gggcaaacgg ctgggagaca cttttgtgct 3420
gactctctcc gacttccggc gggagaacga gggctactac ttctgctctg cgctctccaa 3480
ttcaatcatg tacttctcac acttcgtgcc ggtgttcctg cctgccaagc ccaccactac 3540
tccggcaccc agacctccaa ctcccgctcc caccatcgcg tcccaacccc tttcgctgcg 3600
ccctgaagcg tgtcggcctg ctgctggagg agccgtgcat acccgcggtc tggacttcgc 3660
gtgcgacatc tacatttggg cccctttggc tggcacctgt ggagtgctgc tcctgtccct 3720
tgtgatcacc ctgtactgca accaccggaa taggcggaga gtctgcaagt gtccgcggcc 3780
tgtcgtgaag tcaggagata agccgagcct gtccgcacgc tacgtgtgaa ccggtccgca 3840
gtctgacgta cgcgtaatca acctctggat tacaaaattt gtgaaagatt gactggtatt 3900
cttaactatg ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat 3960
gctattgctt cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct 4020
ctttatgagg agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct 4080
gacgcaaccc ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc 4140
gctttccccc tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg 4200
acaggggctc ggctgttggg cactgacaat tccgtggtgt tgtcggggaa gctgacgtcc 4260
tttccatggc tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac 4320
gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg 4380
cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc 4440
ccgcc 4445
<210> 92
<211> 4445
<212> DNA
<213> Artificial Sequence
<220>
<223> TPE WPRE
<400> 92
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactcag cggccgcccc gggtcgacgc taccaccatg gactcttgga ccttctgctg 420
cgtgagcctg tgcatcctgg tggccaagca cacagacgcc ggcgtgatcc agtcccctag 480
gcacgaggtg accgagatgg gccaggaggt gacactgcgc tgtaagccaa tctctggcca 540
caacagcctg ttttggtata gggagaccat gatgcgcggc ctggagctgc tgatctactt 600
caataacaat gtgcccatcg acgattccgg catgcctgag gatcggtttt ctgccaagat 660
gcccaatgcc agcttctcca cactgaagat ccagcctagc gagccaagag actccgccgt 720
gtatttttgc gcctctagcc caggcagcac cgatacacag tacttcggac caggaaccag 780
gctgacagtg ctggaggacc tgaagaacgt gttcccccct gaggtggccg tgtttgagcc 840
ctctgaggcc gagatcagcc acacccagaa ggccaccctg gtgtgcctgg caaccggctt 900
ctatcctgat cacgtggagc tgtcctggtg ggtgaacggc aaggaggtgc acagcggcgt 960
gtccacagac ccacagcccc tgaaggagca gccagccctg aatgatagcc ggtattgcct 1020
gtcctctcgg ctgagagtgt ccgccacctt ttggcagaac ccccggaatc acttcagatg 1080
tcaggtgcag ttttacggcc tgtccgagaa cgatgagtgg acccaggacc gggccaagcc 1140
tgtgacacag atcgtgtctg ccgaggcatg gggaagagca gactgtggct tcacctctga 1200
gagctaccag cagggcgtgc tgagcgccac catcctgtat gagatcctgc tgggcaaggc 1260
cacactgtac gccgtcctgg tctccgctct ggtgctgatg gcaatggtca aaagaaaaga 1320
tagtcgggga cgggccaaga gatctggcag cggcgagggc agaggcagcc tgctgacctg 1380
cggcgacgtg gaggagaacc ccggccccat ggagaagaat cccctggctg cccccctgct 1440
gatcctgtgg tttcacctgg actgcgtgtc ctctatcctg aatgtggaac agagcccaca 1500
gagcctgcac gtgcaggagg gcgactccac caacttcaca tgctcttttc ctagctccaa 1560
cttctacgcc ctgcactggt acagaaagga gaccgcaaag tccccagagg ccctgttcgt 1620
gatgacactg aacggcgatg agaagaagaa gggccgcatc agcgccaccc tgaatacaaa 1680
ggagggctac tcctatctgt acatcaaggg ctcccagcct gaggactctg ccacctatct 1740
gtgcgccctg tacaacaata acgatatgcg gtttggcgcc ggcaccagac tgacagtgaa 1800
gccaaacatc cagaatccag accccgccgt gtatcagctg cgggacagca agtctagcga 1860
taagagcgtg tgcctgttca ccgactttga ttctcagaca aacgtgagcc agtccaagga 1920
cagcgacgtg tacatcaccg acaagacagt gctggatatg agaagcatgg acttcaagtc 1980
taacagcgcc gtggcctggt ccaataagtc tgatttcgcc tgcgccaatg cctttaataa 2040
ctccatcatc cccgaggata ccttctttcc ttctccagag tcctcttgtg acgtgaagct 2100
ggtggagaag tctttcgaga ccgatacaaa cctgaatttt cagaacctga gcgtgatcgg 2160
cttcaggatc ctgctgctga aggtggccgg ctttaatctg ctgatgaccc tgaggctgtg 2220
gagctcccgg gccaagagat ctggcagcgg cgccaccaat ttcagcctgc tgaaacaggc 2280
cggcgacgtg gaagagaacc ctggccccat gcgcccgaga ctgtggcttc tgctcgccgc 2340
gcaactgact gtcctgcacg gaaacagcgt gctgcagcag acaccggcct acatcaaagt 2400
gcagaccaac aagatggtca tgctgtcctg cgaggccaag atttccctct ccaacatgcg 2460
gatctattgg ttgcggcaga gacaggcgcc ttcctcggac tcccaccatg agttcttggc 2520
cctgtgggac tccgccaagg gaactattca cggcgaagaa gtggaacagg agaagatcgc 2580
cgtgtttcgc gatgcctccc gctttatact gaatctgacc tccgtgaagc ccgaagatag 2640
cgggatctac ttttgcatga ttgtgggctc acccgaactg accttcggga agggcactca 2700
gctgagcgtg gtggacttcc tccccactac cgcccaaccc actaagaagt caaccctgaa 2760
gaagcgggtt tgcagactcc cacggccgga aacgcagaag ggtccgctgt gttccccgat 2820
caccctgggg ctccttgtgg ctggagtgct ggtccttctg gtgtcccttg gcgtcgccat 2880
tcacctctgc tgccggagaa ggagggccag actgaggttc atgaagcagc ctcagggaga 2940
ggggatcagt ggcactttcg tgccacaatg cctccatggc tactattcca acaccaccac 3000
ctcgcaaaag ctgctgaacc cctggatcct gaaaacccgg gccaagagat ctggcagcgg 3060
ccagtgcacc aactacgccc tgctgaagct ggccggcgac gtggagagca accccggccc 3120
catggcgctt cccgtgaccg cactcctgtt gccccttgcc ctgctgttgc acgccgcacg 3180
accttcccaa ttccgggtgt cccctctgga tcgcacctgg aacctcgggg aaacggtgga 3240
gctcaagtgt caagtcctcc tgtcgaaccc gaccagcgga tgcagctggc tgttccagcc 3300
gagaggagct gccgcctcac ccaccttcct cctgtacttg agccagaaca agccgaaggc 3360
cgctgagggt ctggacaccc agcgcttctc gggcaaacgg ctgggagaca cttttgtgct 3420
gactctctcc gacttccggc gggagaacga gggctactac ttctgctctg cgctctccaa 3480
ttcaatcatg tacttctcac acttcgtgcc ggtgttcctg cctgccaagc ccaccactac 3540
tccggcaccc agacctccaa ctcccgctcc caccatcgcg tcccaacccc tttcgctgcg 3600
ccctgaagcg tgtcggcctg ctgctggagg agccgtgcat acccgcggtc tggacttcgc 3660
gtgcgacatc tacatttggg cccctttggc tggcacctgt ggagtgctgc tcctgtccct 3720
tgtgatcacc ctgtactgca accaccggaa taggcggaga gtctgcaagt gtccgcggcc 3780
tgtcgtgaag tcaggagata agccgagcct gtccgcacgc tacgtgtgaa ccggtccgca 3840
gtctgacgta cgcgtaatca acctctggat tacaaaattt gtgaaagatt gactggtatt 3900
cttaactatg ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat 3960
gctattgctt cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct 4020
ctttatgagg agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct 4080
gacgcaaccc ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc 4140
gctttccccc tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg 4200
acaggggctc ggctgttggg cactgacaat tccgtggtgt tgtcggggaa gctgacgtcc 4260
tttccatggc tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac 4320
gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg 4380
cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc 4440
ccgcc 4445
<210> 93
<211> 4430
<212> DNA
<213> Artificial Sequence
<220>
<223> PTE fn WPRE
<400> 93
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactcag cggccgcccc gggtcgacgc taccaccatg gactcttgga ccttctgctg 420
cgtgagcctg tgcatcctgg tggccaagca cacagacgcc ggcgtgatcc agtcccctag 480
gcacgaggtg accgagatgg gccaggaggt gacactgcgc tgtaagccaa tctctggcca 540
caacagcctg ttttggtata gggagaccat gatgcgcggc ctggagctgc tgatctactt 600
caataacaat gtgcccatcg acgattccgg catgcctgag gatcggtttt ctgccaagat 660
gcccaatgcc agcttctcca cactgaagat ccagcctagc gagccaagag actccgccgt 720
gtatttttgc gcctctagcc caggcagcac cgatacacag tacttcggac caggaaccag 780
gctgacagtg ctggaggacc tgaagaacgt gttcccccct gaggtggccg tgtttgagcc 840
ctctgaggcc gagatcagcc acacccagaa ggccaccctg gtgtgcctgg caaccggctt 900
ctatcctgat cacgtggagc tgtcctggtg ggtgaacggc aaggaggtgc acagcggcgt 960
gtccacagac ccacagcccc tgaaggagca gccagccctg aatgatagcc ggtattgcct 1020
gtcctctcgg ctgagagtgt ccgccacctt ttggcagaac ccccggaatc acttcagatg 1080
tcaggtgcag ttttacggcc tgtccgagaa cgatgagtgg acccaggacc gggccaagcc 1140
tgtgacacag atcgtgtctg ccgaggcatg gggaagagca gactgtggct tcacctctga 1200
gagctaccag cagggcgtgc tgagcgccac catcctgtat gagatcctgc tgggcaaggc 1260
cacactgtac gccgtcctgg tctccgctct ggtgctgatg gcaatggtca aaagaaaaga 1320
tagtcgggga tctggcagcg gcgccaccaa tttcagcctg ctgaaacagg ccggcgacgt 1380
ggaagagaac cctggcccca tggagaagaa tcccctggct gcccccctgc tgatcctgtg 1440
gtttcacctg gactgcgtgt cctctatcct gaatgtggaa cagagcccac agagcctgca 1500
cgtgcaggag ggcgactcca ccaacttcac atgctctttt cctagctcca acttctacgc 1560
cctgcactgg tacagaaagg agaccgcaaa gtccccagag gccctgttcg tgatgacact 1620
gaacggcgat gagaagaaga agggccgcat cagcgccacc ctgaatacaa aggagggcta 1680
ctcctatctg tacatcaagg gctcccagcc tgaggactct gccacctatc tgtgcgccct 1740
gtacaacaat aacgatatgc ggtttggcgc cggcaccaga ctgacagtga agccaaacat 1800
ccagaatcca gaccccgccg tgtatcagct gcgggacagc aagtctagcg ataagagcgt 1860
gtgcctgttc accgactttg attctcagac aaacgtgagc cagtccaagg acagcgacgt 1920
gtacatcacc gacaagacag tgctggatat gagaagcatg gacttcaagt ctaacagcgc 1980
cgtggcctgg tccaataagt ctgatttcgc ctgcgccaat gcctttaata actccatcat 2040
ccccgaggat accttctttc cttctccaga gtcctcttgt gacgtgaagc tggtggagaa 2100
gtctttcgag accgatacaa acctgaattt tcagaacctg agcgtgatcg gcttcaggat 2160
cctgctgctg aaggtggccg gctttaatct gctgatgacc ctgaggctgt ggagctcccg 2220
ggccaagaga ggcagcggcg agggcagagg cagcctgctg acctgcggcg acgtggagga 2280
gaaccccggc cccatgcgcc cgagactgtg gcttctgctc gccgcgcaac tgactgtcct 2340
gcacggaaac agcgtgctgc agcagacacc ggcctacatc aaagtgcaga ccaacaagat 2400
ggtcatgctg tcctgcgagg ccaagatttc cctctccaac atgcggatct attggttgcg 2460
gcagagacag gcgccttcct cggactccca ccatgagttc ttggccctgt gggactccgc 2520
caagggaact attcacggcg aagaagtgga acaggagaag atcgccgtgt ttcgcgatgc 2580
ctcccgcttt atactgaatc tgacctccgt gaagcccgaa gatagcggga tctacttttg 2640
catgattgtg ggctcacccg aactgacctt cgggaagggc actcagctga gcgtggtgga 2700
cttcctcccc actaccgccc aacccactaa gaagtcaacc ctgaagaagc gggtttgcag 2760
actcccacgg ccggaaacgc agaagggtcc gctgtgttcc ccgatcaccc tggggctcct 2820
tgtggctgga gtgctggtcc ttctggtgtc ccttggcgtc gccattcacc tctgctgccg 2880
gagaaggagg gccagactga ggttcatgaa gcagcctcag ggagagggga tcagtggcac 2940
tttcgtgcca caatgcctcc atggctacta ttccaacacc accacctcgc aaaagctgct 3000
gaacccctgg atcctgaaaa cccgggccaa gagatctggc agcggccagt gcaccaacta 3060
cgccctgctg aagctggccg gcgacgtgga gagcaacccc ggccccatgg cgcttcccgt 3120
gaccgcactc ctgttgcccc ttgccctgct gttgcacgcc gcacgacctt cccaattccg 3180
ggtgtcccct ctggatcgca cctggaacct cggggaaacg gtggagctca agtgtcaagt 3240
cctcctgtcg aacccgacca gcggatgcag ctggctgttc cagccgagag gagctgccgc 3300
ctcacccacc ttcctcctgt acttgagcca gaacaagccg aaggccgctg agggtctgga 3360
cacccagcgc ttctcgggca aacggctggg agacactttt gtgctgactc tctccgactt 3420
ccggcgggag aacgagggct actacttctg ctctgcgctc tccaattcaa tcatgtactt 3480
ctcacacttc gtgccggtgt tcctgcctgc caagcccacc actactccgg cacccagacc 3540
tccaactccc gctcccacca tcgcgtccca acccctttcg ctgcgccctg aagcgtgtcg 3600
gcctgctgct ggaggagccg tgcatacccg cggtctggac ttcgcgtgcg acatctacat 3660
ttgggcccct ttggctggca cctgtggagt gctgctcctg tcccttgtga tcaccctgta 3720
ctgcaaccac cggaataggc ggagagtctg caagtgtccg cggcctgtcg tgaagtcagg 3780
agataagccg agcctgtccg cacgctacgt gtgaaccggt ccgcagtctg acgtacgcgt 3840
aatcaacctc tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct 3900
ccttttacgc tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt 3960
atggctttca ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg 4020
tggcccgttg tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact 4080
ggttggggca ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct 4140
attgccacgg cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg 4200
ttgggcactg acaattccgt ggtgttgtcg gggaagctga cgtcctttcc atggctgctc 4260
gcctgtgttg ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc 4320
aatccagcgg accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt 4380
cgccttcgcc ctcagacgag tcggatctcc ctttgggccg cctccccgcc 4430
<210> 94
<211> 4445
<212> DNA
<213> Artificial Sequence
<220>
<223> PTE CD8 TCR WPRE
<400> 94
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactcag cggccgcccc gggtcgacgc taccaccatg cgcccgagac tgtggcttct 420
gctcgccgcg caactgactg tcctgcacgg aaacagcgtg ctgcagcaga caccggccta 480
catcaaagtg cagaccaaca agatggtcat gctgtcctgc gaggccaaga tttccctctc 540
caacatgcgg atctattggt tgcggcagag acaggcgcct tcctcggact cccaccatga 600
gttcttggcc ctgtgggact ccgccaaggg aactattcac ggcgaagaag tggaacagga 660
gaagatcgcc gtgtttcgcg atgcctcccg ctttatactg aatctgacct ccgtgaagcc 720
cgaagatagc gggatctact tttgcatgat tgtgggctca cccgaactga ccttcgggaa 780
gggcactcag ctgagcgtgg tggacttcct ccccactacc gcccaaccca ctaagaagtc 840
aaccctgaag aagcgggttt gcagactccc acggccggaa acgcagaagg gtccgctgtg 900
ttccccgatc accctggggc tccttgtggc tggagtgctg gtccttctgg tgtcccttgg 960
cgtcgccatt cacctctgct gccggagaag gagggccaga ctgaggttca tgaagcagcc 1020
tcagggagag gggatcagtg gcactttcgt gccacaatgc ctccatggct actattccaa 1080
caccaccacc tcgcaaaagc tgctgaaccc ctggatcctg aaaacccggg ccaagagatc 1140
tggcagcggc gccaccaatt tcagcctgct gaaacaggcc ggcgacgtgg aagagaaccc 1200
tggccccatg gcgcttcccg tgaccgcact cctgttgccc cttgccctgc tgttgcacgc 1260
cgcacgacct tcccaattcc gggtgtcccc tctggatcgc acctggaacc tcggggaaac 1320
ggtggagctc aagtgtcaag tcctcctgtc gaacccgacc agcggatgca gctggctgtt 1380
ccagccgaga ggagctgccg cctcacccac cttcctcctg tacttgagcc agaacaagcc 1440
gaaggccgct gagggtctgg acacccagcg cttctcgggc aaacggctgg gagacacttt 1500
tgtgctgact ctctccgact tccggcggga gaacgagggc tactacttct gctctgcgct 1560
ctccaattca atcatgtact tctcacactt cgtgccggtg ttcctgcctg ccaagcccac 1620
cactactccg gcacccagac ctccaactcc cgctcccacc atcgcgtccc aacccctttc 1680
gctgcgccct gaagcgtgtc ggcctgctgc tggaggagcc gtgcataccc gcggtctgga 1740
cttcgcgtgc gacatctaca tttgggcccc tttggctggc acctgtggag tgctgctcct 1800
gtcccttgtg atcaccctgt actgcaacca ccggaatagg cggagagtct gcaagtgtcc 1860
gcggcctgtc gtgaagtcag gagataagcc gagcctgtcc gcacgctacg tgcgggccaa 1920
gagatctggc agcggcgagg gcagaggcag cctgctgacc tgcggcgacg tggaggagaa 1980
ccccggcccc atggactctt ggaccttctg ctgcgtgagc ctgtgcatcc tggtggccaa 2040
gcacacagac gccggcgtga tccagtcccc taggcacgag gtgaccgaga tgggccagga 2100
ggtgacactg cgctgtaagc caatctctgg ccacaacagc ctgttttggt atagggagac 2160
catgatgcgc ggcctggagc tgctgatcta cttcaataac aatgtgccca tcgacgattc 2220
cggcatgcct gaggatcggt tttctgccaa gatgcccaat gccagcttct ccacactgaa 2280
gatccagcct agcgagccaa gagactccgc cgtgtatttt tgcgcctcta gcccaggcag 2340
caccgataca cagtacttcg gaccaggaac caggctgaca gtgctggagg acctgaagaa 2400
cgtgttcccc cctgaggtgg ccgtgtttga gccctctgag gccgagatca gccacaccca 2460
gaaggccacc ctggtgtgcc tggcaaccgg cttctatcct gatcacgtgg agctgtcctg 2520
gtgggtgaac ggcaaggagg tgcacagcgg cgtgtccaca gacccacagc ccctgaagga 2580
gcagccagcc ctgaatgata gccggtattg cctgtcctct cggctgagag tgtccgccac 2640
cttttggcag aacccccgga atcacttcag atgtcaggtg cagttttacg gcctgtccga 2700
gaacgatgag tggacccagg accgggccaa gcctgtgaca cagatcgtgt ctgccgaggc 2760
atggggaaga gcagactgtg gcttcacctc tgagagctac cagcagggcg tgctgagcgc 2820
caccatcctg tatgagatcc tgctgggcaa ggccacactg tacgccgtcc tggtctccgc 2880
tctggtgctg atggcaatgg tcaaaagaaa agatagtcgg ggacgggcca agagatctgg 2940
cagcggccag tgcaccaact acgccctgct gaagctggcc ggcgacgtgg agagcaaccc 3000
cggccccatg gagaagaatc ccctggctgc ccccctgctg atcctgtggt ttcacctgga 3060
ctgcgtgtcc tctatcctga atgtggaaca gagcccacag agcctgcacg tgcaggaggg 3120
cgactccacc aacttcacat gctcttttcc tagctccaac ttctacgccc tgcactggta 3180
cagaaaggag accgcaaagt ccccagaggc cctgttcgtg atgacactga acggcgatga 3240
gaagaagaag ggccgcatca gcgccaccct gaatacaaag gagggctact cctatctgta 3300
catcaagggc tcccagcctg aggactctgc cacctatctg tgcgccctgt acaacaataa 3360
cgatatgcgg tttggcgccg gcaccagact gacagtgaag ccaaacatcc agaatccaga 3420
ccccgccgtg tatcagctgc gggacagcaa gtctagcgat aagagcgtgt gcctgttcac 3480
cgactttgat tctcagacaa acgtgagcca gtccaaggac agcgacgtgt acatcaccga 3540
caagacagtg ctggatatga gaagcatgga cttcaagtct aacagcgccg tggcctggtc 3600
caataagtct gatttcgcct gcgccaatgc ctttaataac tccatcatcc ccgaggatac 3660
cttctttcct tctccagagt cctcttgtga cgtgaagctg gtggagaagt ctttcgagac 3720
cgatacaaac ctgaattttc agaacctgag cgtgatcggc ttcaggatcc tgctgctgaa 3780
ggtggccggc tttaatctgc tgatgaccct gaggctgtgg agctcctgaa ccggtccgca 3840
gtctgacgta cgcgtaatca acctctggat tacaaaattt gtgaaagatt gactggtatt 3900
cttaactatg ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat 3960
gctattgctt cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct 4020
ctttatgagg agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct 4080
gacgcaaccc ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc 4140
gctttccccc tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg 4200
acaggggctc ggctgttggg cactgacaat tccgtggtgt tgtcggggaa gctgacgtcc 4260
tttccatggc tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac 4320
gtcccttcgg ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg 4380
cctcttccgc gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc 4440
ccgcc 4445
<210> 95
<211> 2849
<212> DNA
<213> Artificial Sequence
<220>
<223> R11KE WPRE
<400> 95
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactcag cggccgcccc gggtcgacgc taccaccatg gactcttgga ccttctgctg 420
cgtgagcctg tgcatcctgg tggccaagca cacagacgcc ggcgtgatcc agtcccctag 480
gcacgaggtg accgagatgg gccaggaggt gacactgcgc tgtaagccaa tctctggcca 540
caacagcctg ttttggtata gggagaccat gatgcgcggc ctggagctgc tgatctactt 600
caataacaat gtgcccatcg acgattccgg catgcctgag gatcggtttt ctgccaagat 660
gcccaatgcc agcttctcca cactgaagat ccagcctagc gagccaagag actccgccgt 720
gtatttttgc gcctctagcc caggcagcac cgatacacag tacttcggac caggaaccag 780
gctgacagtg ctggaggacc tgaagaacgt gttcccccct gaggtggccg tgtttgagcc 840
ctctgaggcc gagatcagcc acacccagaa ggccaccctg gtgtgcctgg caaccggctt 900
ctatcctgat cacgtggagc tgtcctggtg ggtgaacggc aaggaggtgc acagcggcgt 960
gtccacagac ccacagcccc tgaaggagca gccagccctg aatgatagcc ggtattgcct 1020
gtcctctcgg ctgagagtgt ccgccacctt ttggcagaac ccccggaatc acttcagatg 1080
tcaggtgcag ttttacggcc tgtccgagaa cgatgagtgg acccaggacc gggccaagcc 1140
tgtgacacag atcgtgtctg ccgaggcatg gggaagagca gactgtggct tcacctctga 1200
gagctaccag cagggcgtgc tgagcgccac catcctgtat gagatcctgc tgggcaaggc 1260
cacactgtac gccgtcctgg tctccgctct ggtgctgatg gcaatggtca aaagaaaaga 1320
tagtcgggga cgggccaaga gatctggcag cggcgccacc aatttcagcc tgctgaaaca 1380
ggccggcgac gtggaagaga accctggccc catggagaag aatcccctgg ctgcccccct 1440
gctgatcctg tggtttcacc tggactgcgt gtcctctatc ctgaatgtgg aacagagccc 1500
acagagcctg cacgtgcagg agggcgactc caccaacttc acatgctctt ttcctagctc 1560
caacttctac gccctgcact ggtacagaaa ggagaccgca aagtccccag aggccctgtt 1620
cgtgatgaca ctgaacggcg atgagaagaa gaagggccgc atcagcgcca ccctgaatac 1680
aaaggagggc tactcctatc tgtacatcaa gggctcccag cctgaggact ctgccaccta 1740
tctgtgcgcc ctgtacaaca ataacgatat gcggtttggc gccggcacca gactgacagt 1800
gaagccaaac atccagaatc cagaccccgc cgtgtatcag ctgcgggaca gcaagtctag 1860
cgataagagc gtgtgcctgt tcaccgactt tgattctcag acaaacgtga gccagtccaa 1920
ggacagcgac gtgtacatca ccgacaagac agtgctggat atgagaagca tggacttcaa 1980
gtctaacagc gccgtggcct ggtccaataa gtctgatttc gcctgcgcca atgcctttaa 2040
taactccatc atccccgagg ataccttctt tccttctcca gagtcctctt gtgacgtgaa 2100
gctggtggag aagtctttcg agaccgatac aaacctgaat tttcagaacc tgagcgtgat 2160
cggcttcagg atcctgctgc tgaaggtggc cggctttaat ctgctgatga ccctgaggct 2220
gtggagctcc tgaaccggtc cgcagtctga cgtacgcgta atcaacctct ggattacaaa 2280
atttgtgaaa gattgactgg tattcttaac tatgttgctc cttttacgct atgtggatac 2340
gctgctttaa tgcctttgta tcatgctatt gcttcccgta tggctttcat tttctcctcc 2400
ttgtataaat cctggttgct gtctctttat gaggagttgt ggcccgttgt caggcaacgt 2460
ggcgtggtgt gcactgtgtt tgctgacgca acccccactg gttggggcat tgccaccacc 2520
tgtcagctcc tttccgggac tttcgctttc cccctcccta ttgccacggc ggaactcatc 2580
gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt tgggcactga caattccgtg 2640
gtgttgtcgg ggaagctgac gtcctttcca tggctgctcg cctgtgttgc cacctggatt 2700
ctgcgcggga cgtccttctg ctacgtccct tcggccctca atccagcgga ccttccttcc 2760
cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc gccttcgccc tcagacgagt 2820
cggatctccc tttgggccgc ctccccgcc 2849
<210> 96
<211> 2531
<212> DNA
<213> Artificial Sequence
<220>
<223> CD8 WPRE
<400> 96
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactcag cggccgcccc gggtcgacgc taccaccatg cgcccgagac tgtggcttct 420
gctcgccgcg caactgactg tcctgcacgg aaacagcgtg ctgcagcaga caccggccta 480
catcaaagtg cagaccaaca agatggtcat gctgtcctgc gaggccaaga tttccctctc 540
caacatgcgg atctattggt tgcggcagag acaggcgcct tcctcggact cccaccatga 600
gttcttggcc ctgtgggact ccgccaaggg aactattcac ggcgaagaag tggaacagga 660
gaagatcgcc gtgtttcgcg atgcctcccg ctttatactg aatctgacct ccgtgaagcc 720
cgaagatagc gggatctact tttgcatgat tgtgggctca cccgaactga ccttcgggaa 780
gggcactcag ctgagcgtgg tggacttcct ccccactacc gcccaaccca ctaagaagtc 840
aaccctgaag aagcgggttt gcagactccc acggccggaa acgcagaagg gtccgctgtg 900
ttccccgatc accctggggc tccttgtggc tggagtgctg gtccttctgg tgtcccttgg 960
cgtcgccatt cacctctgct gccggagaag gagggccaga ctgaggttca tgaagcagcc 1020
tcagggagag gggatcagtg gcactttcgt gccacaatgc ctccatggct actattccaa 1080
caccaccacc tcgcaaaagc tgctgaaccc ctggatcctg aaaacccggg ccaagagatc 1140
tggcagcggc gccaccaatt tcagcctgct gaaacaggcc ggcgacgtgg aagagaaccc 1200
tggccccatg gcgcttcccg tgaccgcact cctgttgccc cttgccctgc tgttgcacgc 1260
cgcacgacct tcccaattcc gggtgtcccc tctggatcgc acctggaacc tcggggaaac 1320
ggtggagctc aagtgtcaag tcctcctgtc gaacccgacc agcggatgca gctggctgtt 1380
ccagccgaga ggagctgccg cctcacccac cttcctcctg tacttgagcc agaacaagcc 1440
gaaggccgct gagggtctgg acacccagcg cttctcgggc aaacggctgg gagacacttt 1500
tgtgctgact ctctccgact tccggcggga gaacgagggc tactacttct gctctgcgct 1560
ctccaattca atcatgtact tctcacactt cgtgccggtg ttcctgcctg ccaagcccac 1620
cactactccg gcacccagac ctccaactcc cgctcccacc atcgcgtccc aacccctttc 1680
gctgcgccct gaagcgtgtc ggcctgctgc tggaggagcc gtgcataccc gcggtctgga 1740
cttcgcgtgc gacatctaca tttgggcccc tttggctggc acctgtggag tgctgctcct 1800
gtcccttgtg atcaccctgt actgcaacca ccggaatagg cggagagtct gcaagtgtcc 1860
gcggcctgtc gtgaagtcag gagataagcc gagcctgtcc gcacgctacg tgtgaaccgg 1920
tccgcagtct gacgtacgcg taatcaacct ctggattaca aaatttgtga aagattgact 1980
ggtattctta actatgttgc tccttttacg ctatgtggat acgctgcttt aatgcctttg 2040
tatcatgcta ttgcttcccg tatggctttc attttctcct ccttgtataa atcctggttg 2100
ctgtctcttt atgaggagtt gtggcccgtt gtcaggcaac gtggcgtggt gtgcactgtg 2160
tttgctgacg caacccccac tggttggggc attgccacca cctgtcagct cctttccggg 2220
actttcgctt tccccctccc tattgccacg gcggaactca tcgccgcctg ccttgcccgc 2280
tgctggacag gggctcggct gttgggcact gacaattccg tggtgttgtc ggggaagctg 2340
acgtcctttc catggctgct cgcctgtgtt gccacctgga ttctgcgcgg gacgtccttc 2400
tgctacgtcc cttcggccct caatccagcg gaccttcctt cccgcggcct gctgccggct 2460
ctgcggcctc ttccgcgtct tcgccttcgc cctcagacga gtcggatctc cctttgggcc 2520
gcctccccgc c 2531
<210> 97
<211> 559
<212> PRT
<213> Artificial Sequence
<220>
<223> RD114TR
<400> 97
Met Lys Leu Pro Thr Gly Met Val Ile Leu Cys Ser Leu Ile Ile Val
1 5 10 15
Arg Ala Gly Phe Asp Asp Pro Arg Lys Ala Ile Ala Leu Val Gln Lys
20 25 30
Gln His Gly Lys Pro Cys Glu Cys Ser Gly Gly Gln Val Ser Glu Ala
35 40 45
Pro Pro Asn Ser Ile Gln Gln Val Thr Cys Pro Gly Lys Thr Ala Tyr
50 55 60
Leu Met Thr Asn Gln Lys Trp Lys Cys Arg Val Thr Pro Lys Ile Ser
65 70 75 80
Pro Ser Gly Gly Glu Leu Gln Asn Cys Pro Cys Asn Thr Phe Gln Asp
85 90 95
Ser Met His Ser Ser Cys Tyr Thr Glu Tyr Arg Gln Cys Arg Arg Ile
100 105 110
Asn Lys Thr Tyr Tyr Thr Ala Thr Leu Leu Lys Ile Arg Ser Gly Ser
115 120 125
Leu Asn Glu Val Gln Ile Leu Gln Asn Pro Asn Gln Leu Leu Gln Ser
130 135 140
Pro Cys Arg Gly Ser Ile Asn Gln Pro Val Cys Trp Ser Ala Thr Ala
145 150 155 160
Pro Ile His Ile Ser Asp Gly Gly Gly Pro Leu Asp Thr Lys Arg Val
165 170 175
Trp Thr Val Gln Lys Arg Leu Glu Gln Ile His Lys Ala Met Thr Pro
180 185 190
Glu Leu Gln Tyr His Pro Leu Ala Leu Pro Lys Val Arg Asp Asp Leu
195 200 205
Ser Leu Asp Ala Arg Thr Phe Asp Ile Leu Asn Thr Thr Phe Arg Leu
210 215 220
Leu Gln Met Ser Asn Phe Ser Leu Ala Gln Asp Cys Trp Leu Cys Leu
225 230 235 240
Lys Leu Gly Thr Pro Thr Pro Leu Ala Ile Pro Thr Pro Ser Leu Thr
245 250 255
Tyr Ser Leu Ala Asp Ser Leu Ala Asn Ala Ser Cys Gln Ile Ile Pro
260 265 270
Pro Leu Leu Val Gln Pro Met Gln Phe Ser Asn Ser Ser Cys Leu Ser
275 280 285
Ser Pro Phe Ile Asn Asp Thr Glu Gln Ile Asp Leu Gly Ala Val Thr
290 295 300
Phe Thr Asn Cys Thr Ser Val Ala Asn Val Ser Ser Pro Leu Cys Ala
305 310 315 320
Leu Asn Gly Ser Val Phe Leu Cys Gly Asn Asn Met Ala Tyr Thr Tyr
325 330 335
Leu Pro Gln Asn Trp Thr Arg Leu Cys Val Gln Ala Ser Leu Leu Pro
340 345 350
Asp Ile Asp Ile Asn Pro Gly Asp Glu Pro Val Pro Ile Pro Ala Ile
355 360 365
Asp His Tyr Ile His Arg Pro Lys Arg Ala Val Gln Phe Ile Pro Leu
370 375 380
Leu Ala Gly Leu Gly Ile Thr Ala Ala Phe Thr Thr Gly Ala Thr Gly
385 390 395 400
Leu Gly Val Ser Val Thr Gln Tyr Thr Lys Leu Ser His Gln Leu Ile
405 410 415
Ser Asp Val Gln Val Leu Ser Gly Thr Ile Gln Asp Leu Gln Asp Gln
420 425 430
Val Asp Ser Leu Ala Glu Val Val Leu Gln Asn Arg Arg Gly Leu Asp
435 440 445
Leu Leu Thr Ala Glu Gln Gly Gly Ile Cys Leu Ala Leu Gln Glu Lys
450 455 460
Cys Cys Phe Tyr Ala Asn Lys Ser Gly Ile Val Arg Asn Lys Ile Arg
465 470 475 480
Thr Leu Gln Glu Glu Leu Gln Lys Arg Arg Glu Ser Leu Ala Ser Asn
485 490 495
Pro Leu Trp Thr Gly Leu Gln Gly Phe Leu Pro Tyr Leu Leu Pro Leu
500 505 510
Leu Gly Pro Leu Leu Thr Leu Leu Leu Ile Leu Thr Ile Gly Pro Cys
515 520 525
Val Phe Asn Arg Leu Val Gln Phe Val Lys Asp Arg Ile Ser Val Val
530 535 540
Gln Ala Leu Val Leu Thr Gln Gln Tyr His Gln Leu Lys Pro Leu
545 550 555
<210> 98
<211> 10
<212> PRT
<213> Homo sapiens
<400> 98
Tyr Leu Tyr Asp Ser Glu Thr Lys Asn Ala
1 5 10
<210> 99
<211> 9
<212> PRT
<213> Homo sapiens
<400> 99
His Leu Met Asp Gln Pro Leu Ser Val
1 5
<210> 100
<211> 9
<212> PRT
<213> Homo sapiens
<400> 100
Gly Leu Leu Lys Lys Ile Asn Ser Val
1 5
<210> 101
<211> 9
<212> PRT
<213> Homo sapiens
<400> 101
Phe Leu Val Asp Gly Ser Ser Ala Leu
1 5
<210> 102
<211> 10
<212> PRT
<213> Homo sapiens
<400> 102
Phe Leu Phe Asp Gly Ser Ala Asn Leu Val
1 5 10
<210> 103
<211> 9
<212> PRT
<213> Homo sapiens
<400> 103
Phe Leu Tyr Lys Ile Ile Asp Glu Leu
1 5
<210> 104
<211> 11
<212> PRT
<213> Homo sapiens
<400> 104
Phe Ile Leu Asp Ser Ala Glu Thr Thr Thr Leu
1 5 10
<210> 105
<211> 9
<212> PRT
<213> Homo sapiens
<400> 105
Ser Val Asp Val Ser Pro Pro Lys Val
1 5
<210> 106
<211> 8
<212> PRT
<213> Homo sapiens
<400> 106
Val Ala Asp Lys Ile His Ser Val
1 5
<210> 107
<211> 9
<212> PRT
<213> Homo sapiens
<400> 107
Ile Val Asp Asp Leu Thr Ile Asn Leu
1 5
<210> 108
<211> 9
<212> PRT
<213> Homo sapiens
<400> 108
Gly Leu Leu Glu Glu Leu Val Thr Val
1 5
<210> 109
<211> 10
<212> PRT
<213> Homo sapiens
<400> 109
Thr Leu Asp Gly Ala Ala Val Asn Gln Val
1 5 10
<210> 110
<211> 10
<212> PRT
<213> Homo sapiens
<400> 110
Ser Val Leu Glu Lys Glu Ile Tyr Ser Ile
1 5 10
<210> 111
<211> 9
<212> PRT
<213> Homo sapiens
<400> 111
Leu Leu Asp Pro Lys Thr Ile Phe Leu
1 5
<210> 112
<211> 9
<212> PRT
<213> Homo sapiens
<400> 112
Tyr Thr Phe Ser Gly Asp Val Gln Leu
1 5
<210> 113
<211> 9
<212> PRT
<213> Homo sapiens
<400> 113
Tyr Leu Met Asp Asp Phe Ser Ser Leu
1 5
<210> 114
<211> 9
<212> PRT
<213> Homo sapiens
<400> 114
Lys Val Trp Ser Asp Val Thr Pro Leu
1 5
<210> 115
<211> 11
<212> PRT
<213> Homo sapiens
<400> 115
Leu Leu Trp Gly His Pro Arg Val Ala Leu Ala
1 5 10
<210> 116
<211> 11
<212> PRT
<213> Homo sapiens
<400> 116
Lys Ile Trp Glu Glu Leu Ser Val Leu Glu Val
1 5 10
<210> 117
<211> 9
<212> PRT
<213> Homo sapiens
<400> 117
Leu Leu Ile Pro Phe Thr Ile Phe Met
1 5
<210> 118
<211> 9
<212> PRT
<213> Homo sapiens
<400> 118
Phe Leu Ile Glu Asn Leu Leu Ala Ala
1 5
<210> 119
<211> 11
<212> PRT
<213> Homo sapiens
<400> 119
Leu Leu Trp Gly His Pro Arg Val Ala Leu Ala
1 5 10
<210> 120
<211> 9
<212> PRT
<213> Homo sapiens
<400> 120
Phe Leu Leu Glu Arg Glu Gln Leu Leu
1 5
<210> 121
<211> 9
<212> PRT
<213> Homo sapiens
<400> 121
Ser Leu Ala Glu Thr Ile Phe Ile Val
1 5
<210> 122
<211> 9
<212> PRT
<213> Homo sapiens
<400> 122
Thr Leu Leu Glu Gly Ile Ser Arg Ala
1 5
<210> 123
<211> 9
<212> PRT
<213> Homo sapiens
<400> 123
Lys Ile Gln Glu Ile Leu Thr Gln Val
1 5
<210> 124
<211> 10
<212> PRT
<213> Homo sapiens
<400> 124
Val Ile Phe Glu Gly Glu Pro Met Tyr Leu
1 5 10
<210> 125
<211> 9
<212> PRT
<213> Homo sapiens
<400> 125
Ser Leu Phe Glu Ser Leu Glu Tyr Leu
1 5
<210> 126
<211> 9
<212> PRT
<213> Homo sapiens
<400> 126
Ser Leu Leu Asn Gln Pro Lys Ala Val
1 5
<210> 127
<211> 9
<212> PRT
<213> Homo sapiens
<400> 127
Gly Leu Ala Glu Phe Gln Glu Asn Val
1 5
<210> 128
<211> 9
<212> PRT
<213> Homo sapiens
<400> 128
Lys Leu Leu Ala Val Ile His Glu Leu
1 5
<210> 129
<211> 9
<212> PRT
<213> Homo sapiens
<400> 129
Thr Leu His Asp Gln Val His Leu Leu
1 5
<210> 130
<211> 11
<212> PRT
<213> Homo sapiens
<400> 130
Thr Leu Tyr Asn Pro Glu Arg Thr Ile Thr Val
1 5 10
<210> 131
<211> 9
<212> PRT
<213> Homo sapiens
<400> 131
Lys Leu Gln Glu Lys Ile Gln Glu Leu
1 5
<210> 132
<211> 10
<212> PRT
<213> Homo sapiens
<400> 132
Ser Val Leu Glu Lys Glu Ile Tyr Ser Ile
1 5 10
<210> 133
<211> 11
<212> PRT
<213> Homo sapiens
<400> 133
Arg Val Ile Asp Asp Ser Leu Val Val Gly Val
1 5 10
<210> 134
<211> 9
<212> PRT
<213> Homo sapiens
<400> 134
Val Leu Phe Gly Glu Leu Pro Ala Leu
1 5
<210> 135
<211> 9
<212> PRT
<213> Homo sapiens
<400> 135
Gly Leu Val Asp Ile Met Val His Leu
1 5
<210> 136
<211> 9
<212> PRT
<213> Homo sapiens
<400> 136
Phe Leu Asn Ala Ile Glu Thr Ala Leu
1 5
<210> 137
<211> 9
<212> PRT
<213> Homo sapiens
<400> 137
Ala Leu Leu Gln Ala Leu Met Glu Leu
1 5
<210> 138
<211> 9
<212> PRT
<213> Homo sapiens
<400> 138
Ala Leu Ser Ser Ser Gln Ala Glu Val
1 5
<210> 139
<211> 11
<212> PRT
<213> Homo sapiens
<400> 139
Ser Leu Ile Thr Gly Gln Asp Leu Leu Ser Val
1 5 10
<210> 140
<211> 9
<212> PRT
<213> Homo sapiens
<400> 140
Gln Leu Ile Glu Lys Asn Trp Leu Leu
1 5
<210> 141
<211> 9
<212> PRT
<213> Homo sapiens
<400> 141
Leu Leu Asp Pro Lys Thr Ile Phe Leu
1 5
<210> 142
<211> 9
<212> PRT
<213> Homo sapiens
<400> 142
Arg Leu His Asp Glu Asn Ile Leu Leu
1 5
<210> 143
<211> 9
<212> PRT
<213> Homo sapiens
<400> 143
Tyr Thr Phe Ser Gly Asp Val Gln Leu
1 5
<210> 144
<211> 9
<212> PRT
<213> Homo sapiens
<400> 144
Gly Leu Pro Ser Ala Thr Thr Thr Val
1 5
<210> 145
<211> 11
<212> PRT
<213> Homo sapiens
<400> 145
Gly Leu Leu Pro Ser Ala Glu Ser Ile Lys Leu
1 5 10
<210> 146
<211> 9
<212> PRT
<213> Homo sapiens
<400> 146
Lys Thr Ala Ser Ile Asn Gln Asn Val
1 5
<210> 147
<211> 9
<212> PRT
<213> Homo sapiens
<400> 147
Ser Leu Leu Gln His Leu Ile Gly Leu
1 5
<210> 148
<211> 9
<212> PRT
<213> Homo sapiens
<400> 148
Tyr Leu Met Asp Asp Phe Ser Ser Leu
1 5
<210> 149
<211> 9
<212> PRT
<213> Homo sapiens
<400> 149
Leu Met Tyr Pro Tyr Ile Tyr His Val
1 5
<210> 150
<211> 9
<212> PRT
<213> Homo sapiens
<400> 150
Lys Val Trp Ser Asp Val Thr Pro Leu
1 5
<210> 151
<211> 11
<212> PRT
<213> Homo sapiens
<400> 151
Leu Leu Trp Gly His Pro Arg Val Ala Leu Ala
1 5 10
<210> 152
<211> 9
<212> PRT
<213> Homo sapiens
<400> 152
Val Leu Asp Gly Lys Val Ala Val Val
1 5
<210> 153
<211> 9
<212> PRT
<213> Homo sapiens
<400> 153
Gly Leu Leu Gly Lys Val Thr Ser Val
1 5
<210> 154
<211> 9
<212> PRT
<213> Homo sapiens
<400> 154
Lys Met Ile Ser Ala Ile Pro Thr Leu
1 5
<210> 155
<211> 11
<212> PRT
<213> Homo sapiens
<400> 155
Gly Leu Leu Glu Thr Thr Gly Leu Leu Ala Thr
1 5 10
<210> 156
<211> 9
<212> PRT
<213> Homo sapiens
<400> 156
Thr Leu Asn Thr Leu Asp Ile Asn Leu
1 5
<210> 157
<211> 9
<212> PRT
<213> Homo sapiens
<400> 157
Val Ile Ile Lys Gly Leu Glu Glu Ile
1 5
<210> 158
<211> 9
<212> PRT
<213> Homo sapiens
<400> 158
Tyr Leu Glu Asp Gly Phe Ala Tyr Val
1 5
<210> 159
<211> 11
<212> PRT
<213> Homo sapiens
<400> 159
Lys Ile Trp Glu Glu Leu Ser Val Leu Glu Val
1 5 10
<210> 160
<211> 9
<212> PRT
<213> Homo sapiens
<400> 160
Leu Leu Ile Pro Phe Thr Ile Phe Met
1 5
<210> 161
<211> 10
<212> PRT
<213> Homo sapiens
<400> 161
Ile Ser Leu Asp Glu Val Ala Val Ser Leu
1 5 10
<210> 162
<211> 10
<212> PRT
<213> Homo sapiens
<400> 162
Lys Ile Ser Asp Phe Gly Leu Ala Thr Val
1 5 10
<210> 163
<211> 11
<212> PRT
<213> Homo sapiens
<400> 163
Lys Leu Ile Gly Asn Ile His Gly Asn Glu Val
1 5 10
<210> 164
<211> 9
<212> PRT
<213> Homo sapiens
<400> 164
Ile Leu Leu Ser Val Leu His Gln Leu
1 5
<210> 165
<211> 9
<212> PRT
<213> Homo sapiens
<400> 165
Leu Asp Ser Glu Ala Leu Leu Thr Leu
1 5
<210> 166
<211> 13
<212> PRT
<213> Homo sapiens
<400> 166
Val Leu Gln Glu Asn Ser Ser Asp Tyr Gln Ser Asn Leu
1 5 10
<210> 167
<211> 11
<212> PRT
<213> Homo sapiens
<400> 167
His Leu Leu Gly Glu Gly Ala Phe Ala Gln Val
1 5 10
<210> 168
<211> 9
<212> PRT
<213> Homo sapiens
<400> 168
Ser Leu Val Glu Asn Ile His Val Leu
1 5
<210> 169
<211> 9
<212> PRT
<213> Homo sapiens
<400> 169
Tyr Thr Phe Ser Gly Asp Val Gln Leu
1 5
<210> 170
<211> 9
<212> PRT
<213> Homo sapiens
<400> 170
Ser Leu Ser Glu Lys Ser Pro Glu Val
1 5
<210> 171
<211> 10
<212> PRT
<213> Homo sapiens
<400> 171
Ala Met Phe Pro Asp Thr Ile Pro Arg Val
1 5 10
<210> 172
<211> 9
<212> PRT
<213> Homo sapiens
<400> 172
Phe Leu Ile Glu Asn Leu Leu Ala Ala
1 5
<210> 173
<211> 9
<212> PRT
<213> Homo sapiens
<400> 173
Phe Thr Ala Glu Phe Leu Glu Lys Val
1 5
<210> 174
<211> 9
<212> PRT
<213> Homo sapiens
<400> 174
Ala Leu Tyr Gly Asn Val Gln Gln Val
1 5
<210> 175
<211> 9
<212> PRT
<213> Homo sapiens
<400> 175
Leu Phe Gln Ser Arg Ile Ala Gly Val
1 5
<210> 176
<211> 11
<212> PRT
<213> Homo sapiens
<400> 176
Ile Leu Ala Glu Glu Pro Ile Tyr Ile Arg Val
1 5 10
<210> 177
<211> 9
<212> PRT
<213> Homo sapiens
<400> 177
Phe Leu Leu Glu Arg Glu Gln Leu Leu
1 5
<210> 178
<211> 10
<212> PRT
<213> Homo sapiens
<400> 178
Leu Leu Leu Pro Leu Glu Leu Ser Leu Ala
1 5 10
<210> 179
<211> 9
<212> PRT
<213> Homo sapiens
<400> 179
Ser Leu Ala Glu Thr Ile Phe Ile Val
1 5
<210> 180
<211> 11
<212> PRT
<213> Homo sapiens
<400> 180
Ala Ile Leu Asn Val Asp Glu Lys Asn Gln Val
1 5 10
<210> 181
<211> 9
<212> PRT
<213> Homo sapiens
<400> 181
Arg Leu Phe Glu Glu Val Leu Gly Val
1 5
<210> 182
<211> 9
<212> PRT
<213> Homo sapiens
<400> 182
Tyr Leu Asp Glu Val Ala Phe Met Leu
1 5
<210> 183
<211> 11
<212> PRT
<213> Homo sapiens
<400> 183
Lys Leu Ile Asp Glu Asp Glu Pro Leu Phe Leu
1 5 10
<210> 184
<211> 9
<212> PRT
<213> Homo sapiens
<400> 184
Lys Leu Phe Glu Lys Ser Thr Gly Leu
1 5
<210> 185
<211> 11
<212> PRT
<213> Homo sapiens
<400> 185
Ser Leu Leu Glu Val Asn Glu Ala Ser Ser Val
1 5 10
<210> 186
<211> 10
<212> PRT
<213> Homo sapiens
<400> 186
Gly Val Tyr Asp Gly Arg Glu His Thr Val
1 5 10
<210> 187
<211> 10
<212> PRT
<213> Homo sapiens
<400> 187
Gly Leu Tyr Pro Val Thr Leu Val Gly Val
1 5 10
<210> 188
<211> 9
<212> PRT
<213> Homo sapiens
<400> 188
Ala Leu Leu Ser Ser Val Ala Glu Ala
1 5
<210> 189
<211> 9
<212> PRT
<213> Homo sapiens
<400> 189
Thr Leu Leu Glu Gly Ile Ser Arg Ala
1 5
<210> 190
<211> 9
<212> PRT
<213> Homo sapiens
<400> 190
Ser Leu Ile Glu Glu Ser Glu Glu Leu
1 5
<210> 191
<211> 9
<212> PRT
<213> Homo sapiens
<400> 191
Ala Leu Tyr Val Gln Ala Pro Thr Val
1 5
<210> 192
<211> 10
<212> PRT
<213> Homo sapiens
<400> 192
Lys Leu Ile Tyr Lys Asp Leu Val Ser Val
1 5 10
<210> 193
<211> 9
<212> PRT
<213> Homo sapiens
<400> 193
Ile Leu Gln Asp Gly Gln Phe Leu Val
1 5
<210> 194
<211> 9
<212> PRT
<213> Homo sapiens
<400> 194
Ser Leu Leu Asp Tyr Glu Val Ser Ile
1 5
<210> 195
<211> 9
<212> PRT
<213> Homo sapiens
<400> 195
Leu Leu Gly Asp Ser Ser Phe Phe Leu
1 5
<210> 196
<211> 10
<212> PRT
<213> Homo sapiens
<400> 196
Val Ile Phe Glu Gly Glu Pro Met Tyr Leu
1 5 10
<210> 197
<211> 9
<212> PRT
<213> Homo sapiens
<400> 197
Ala Leu Ser Tyr Ile Leu Pro Tyr Leu
1 5
<210> 198
<211> 9
<212> PRT
<213> Homo sapiens
<400> 198
Phe Leu Phe Val Asp Pro Glu Leu Val
1 5
<210> 199
<211> 11
<212> PRT
<213> Homo sapiens
<400> 199
Ser Glu Trp Gly Ser Pro His Ala Ala Val Pro
1 5 10
<210> 200
<211> 9
<212> PRT
<213> Homo sapiens
<400> 200
Ala Leu Ser Glu Leu Glu Arg Val Leu
1 5
<210> 201
<211> 9
<212> PRT
<213> Homo sapiens
<400> 201
Ser Leu Phe Glu Ser Leu Glu Tyr Leu
1 5
<210> 202
<211> 9
<212> PRT
<213> Homo sapiens
<400> 202
Lys Val Leu Glu Tyr Val Ile Lys Val
1 5
<210> 203
<211> 10
<212> PRT
<213> Homo sapiens
<400> 203
Val Leu Leu Asn Glu Ile Leu Glu Gln Val
1 5 10
<210> 204
<211> 9
<212> PRT
<213> Homo sapiens
<400> 204
Ser Leu Leu Asn Gln Pro Lys Ala Val
1 5
<210> 205
<211> 9
<212> PRT
<213> Homo sapiens
<400> 205
Lys Met Ser Glu Leu Gln Thr Tyr Val
1 5
<210> 206
<211> 11
<212> PRT
<213> Homo sapiens
<400> 206
Ala Leu Leu Glu Gln Thr Gly Asp Met Ser Leu
1 5 10
<210> 207
<211> 11
<212> PRT
<213> Homo sapiens
<400> 207
Val Ile Ile Lys Gly Leu Glu Glu Ile Thr Val
1 5 10
<210> 208
<211> 9
<212> PRT
<213> Homo sapiens
<400> 208
Lys Gln Phe Glu Gly Thr Val Glu Ile
1 5
<210> 209
<211> 9
<212> PRT
<213> Homo sapiens
<400> 209
Lys Leu Gln Glu Glu Ile Pro Val Leu
1 5
<210> 210
<211> 9
<212> PRT
<213> Homo sapiens
<400> 210
Gly Leu Ala Glu Phe Gln Glu Asn Val
1 5
<210> 211
<211> 9
<212> PRT
<213> Homo sapiens
<400> 211
Asn Val Ala Glu Ile Val Ile His Ile
1 5
<210> 212
<211> 9
<212> PRT
<213> Homo sapiens
<400> 212
Ala Leu Ala Gly Ile Val Thr Asn Val
1 5
<210> 213
<211> 12
<212> PRT
<213> Homo sapiens
<400> 213
Asn Leu Leu Ile Asp Asp Lys Gly Thr Ile Lys Leu
1 5 10
<210> 214
<211> 10
<212> PRT
<213> Homo sapiens
<400> 214
Val Leu Met Gln Asp Ser Arg Leu Tyr Leu
1 5 10
<210> 215
<211> 9
<212> PRT
<213> Homo sapiens
<400> 215
Lys Val Leu Glu His Val Val Arg Val
1 5
<210> 216
<211> 9
<212> PRT
<213> Homo sapiens
<400> 216
Leu Leu Trp Gly Asn Leu Pro Glu Ile
1 5
<210> 217
<211> 9
<212> PRT
<213> Homo sapiens
<400> 217
Ser Leu Met Glu Lys Asn Gln Ser Leu
1 5
<210> 218
<211> 9
<212> PRT
<213> Homo sapiens
<400> 218
Lys Leu Leu Ala Val Ile His Glu Leu
1 5
<210> 219
<211> 10
<212> PRT
<213> Homo sapiens
<400> 219
Ala Leu Gly Asp Lys Phe Leu Leu Arg Val
1 5 10
<210> 220
<211> 11
<212> PRT
<213> Homo sapiens
<400> 220
Phe Leu Met Lys Asn Ser Asp Leu Tyr Gly Ala
1 5 10
<210> 221
<211> 10
<212> PRT
<213> Homo sapiens
<400> 221
Lys Leu Ile Asp His Gln Gly Leu Tyr Leu
1 5 10
<210> 222
<211> 12
<212> PRT
<213> Homo sapiens
<400> 222
Gly Pro Gly Ile Phe Pro Pro Pro Pro Pro Gln Pro
1 5 10
<210> 223
<211> 9
<212> PRT
<213> Homo sapiens
<400> 223
Ala Leu Asn Glu Ser Leu Val Glu Cys
1 5
<210> 224
<211> 9
<212> PRT
<213> Homo sapiens
<400> 224
Gly Leu Ala Ala Leu Ala Val His Leu
1 5
<210> 225
<211> 9
<212> PRT
<213> Homo sapiens
<400> 225
Leu Leu Leu Glu Ala Val Trp His Leu
1 5
<210> 226
<211> 9
<212> PRT
<213> Homo sapiens
<400> 226
Ser Ile Ile Glu Tyr Leu Pro Thr Leu
1 5
<210> 227
<211> 9
<212> PRT
<213> Homo sapiens
<400> 227
Thr Leu His Asp Gln Val His Leu Leu
1 5
<210> 228
<211> 9
<212> PRT
<213> Homo sapiens
<400> 228
Ser Leu Leu Met Trp Ile Thr Gln Cys
1 5
<210> 229
<211> 11
<212> PRT
<213> Homo sapiens
<400> 229
Phe Leu Leu Asp Lys Pro Gln Asp Leu Ser Ile
1 5 10
<210> 230
<211> 10
<212> PRT
<213> Homo sapiens
<400> 230
Tyr Leu Leu Asp Met Pro Leu Trp Tyr Leu
1 5 10
<210> 231
<211> 9
<212> PRT
<213> Homo sapiens
<400> 231
Gly Leu Leu Asp Cys Pro Ile Phe Leu
1 5
<210> 232
<211> 9
<212> PRT
<213> Homo sapiens
<400> 232
Val Leu Ile Glu Tyr Asn Phe Ser Ile
1 5
<210> 233
<211> 11
<212> PRT
<213> Homo sapiens
<400> 233
Thr Leu Tyr Asn Pro Glu Arg Thr Ile Thr Val
1 5 10
<210> 234
<211> 9
<212> PRT
<213> Homo sapiens
<400> 234
Ala Val Pro Pro Pro Pro Ser Ser Val
1 5
<210> 235
<211> 9
<212> PRT
<213> Homo sapiens
<400> 235
Lys Leu Gln Glu Glu Leu Asn Lys Val
1 5
<210> 236
<211> 11
<212> PRT
<213> Homo sapiens
<400> 236
Lys Leu Met Asp Pro Gly Ser Leu Pro Pro Leu
1 5 10
<210> 237
<211> 9
<212> PRT
<213> Homo sapiens
<400> 237
Ala Leu Ile Val Ser Leu Pro Tyr Leu
1 5
<210> 238
<211> 9
<212> PRT
<213> Homo sapiens
<400> 238
Phe Leu Leu Asp Gly Ser Ala Asn Val
1 5
<210> 239
<211> 10
<212> PRT
<213> Homo sapiens
<400> 239
Ala Leu Asp Pro Ser Gly Asn Gln Leu Ile
1 5 10
<210> 240
<211> 9
<212> PRT
<213> Homo sapiens
<400> 240
Ile Leu Ile Lys His Leu Val Lys Val
1 5
<210> 241
<211> 9
<212> PRT
<213> Homo sapiens
<400> 241
Val Leu Leu Asp Thr Ile Leu Gln Leu
1 5
<210> 242
<211> 9
<212> PRT
<213> Homo sapiens
<400> 242
His Leu Ile Ala Glu Ile His Thr Ala
1 5
<210> 243
<211> 9
<212> PRT
<213> Homo sapiens
<400> 243
Ser Met Asn Gly Gly Val Phe Ala Val
1 5
<210> 244
<211> 9
<212> PRT
<213> Homo sapiens
<400> 244
Met Leu Ala Glu Lys Leu Leu Gln Ala
1 5
<210> 245
<211> 9
<212> PRT
<213> Homo sapiens
<400> 245
Tyr Met Leu Asp Ile Phe His Glu Val
1 5
<210> 246
<211> 11
<212> PRT
<213> Homo sapiens
<400> 246
Ala Leu Trp Leu Pro Thr Asp Ser Ala Thr Val
1 5 10
<210> 247
<211> 9
<212> PRT
<213> Homo sapiens
<400> 247
Gly Leu Ala Ser Arg Ile Leu Asp Ala
1 5
<210> 248
<211> 9
<212> PRT
<213> Homo sapiens
<400> 248
Ala Leu Ser Val Leu Arg Leu Ala Leu
1 5
<210> 249
<211> 9
<212> PRT
<213> Homo sapiens
<400> 249
Ser Tyr Val Lys Val Leu His His Leu
1 5
<210> 250
<211> 9
<212> PRT
<213> Homo sapiens
<400> 250
Val Tyr Leu Pro Lys Ile Pro Ser Trp
1 5
<210> 251
<211> 9
<212> PRT
<213> Homo sapiens
<400> 251
Asn Tyr Glu Asp His Phe Pro Leu Leu
1 5
<210> 252
<211> 9
<212> PRT
<213> Homo sapiens
<400> 252
Val Tyr Ile Ala Glu Leu Glu Lys Ile
1 5
<210> 253
<211> 12
<212> PRT
<213> Homo sapiens
<400> 253
Val His Phe Glu Asp Thr Gly Lys Thr Leu Leu Phe
1 5 10
<210> 254
<211> 9
<212> PRT
<213> Homo sapiens
<400> 254
Val Leu Ser Pro Phe Ile Leu Thr Leu
1 5
<210> 255
<211> 9
<212> PRT
<213> Homo sapiens
<400> 255
His Leu Leu Glu Gly Ser Val Gly Val
1 5
<210> 256
<211> 3658
<212> DNA
<213> Artificial Sequence
<220>
<223> CD8aCD4Fusion.TCR.WPRE
<400> 256
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactagc ggccgccccg ggtcgacgct accaccatgg cgcttcccgt gaccgcactc 420
ctgttgcccc ttgccctgct gttgcacgcc gcacgacctt cccaattccg ggtgtcccct 480
ctggatcgca cctggaacct cggggaaacg gtggagctca agtgtcaagt cctcctgtcg 540
aacccgacca gcggatgcag ctggctgttc cagccgagag gagctgccgc ctcacccacc 600
ttcctcctgt acttgagcca gaacaagccg aaggccgctg agggtctgga cacccagcgc 660
ttctcgggca aacggctggg agacactttt gtgctgactc tctccgactt ccggcgggag 720
aacgagggct actacttctg ctctgcgctc tccaattcaa tcatgtactt ctcacacttc 780
gtgccggtgt tcctgcctgc caagcccacc actactccgg cacccagacc tccaactccc 840
gctcccacca tcgcgtccca acccctttcg ctgcgccctg aagcgtgtcg gcctgctgct 900
ggaggagccg tgcatacccg cggtctggac ttcgcgtgcg acatggccct gattgtgctg 960
gggggcgtcg ccggcctcct gcttttcatt gggctaggca tcttcttctg tgtcaggtgc 1020
cggcaccgaa ggcgccaagc agagcggatg tctcagatca agagactcct cagtgagaag 1080
aagacctgcc agtgtcctca ccggtttcag aagacatgta gccccattcg ggccaagaga 1140
tctggcagcg gcgccaccaa tttcagcctg ctgaaacagg ccggcgacgt ggaagagaac 1200
cctggcccca tggactcttg gaccttctgc tgcgtgagcc tgtgcatcct ggtggccaag 1260
cacacagacg ccggcgtgat ccagtcccct aggcacgagg tgaccgagat gggccaggag 1320
gtgacactgc gctgtaagcc aatctctggc cacaacagcc tgttttggta tagggagacc 1380
atgatgcgcg gcctggagct gctgatctac ttcaataaca atgtgcccat cgacgattcc 1440
ggcatgcctg aggatcggtt ttctgccaag atgcccaatg ccagcttctc cacactgaag 1500
atccagccta gcgagccaag agactccgcc gtgtattttt gcgcctctag cccaggcagc 1560
accgatacac agtacttcgg accaggaacc aggctgacag tgctggagga cctgaagaac 1620
gtgttccccc ctgaggtggc cgtgtttgag ccctctgagg ccgagatcag ccacacccag 1680
aaggccaccc tggtgtgcct ggcaaccggc ttctatcctg atcacgtgga gctgtcctgg 1740
tgggtgaacg gcaaggaggt gcacagcggc gtgtccacag acccacagcc cctgaaggag 1800
cagccagccc tgaatgatag ccggtattgc ctgtcctctc ggctgagagt gtccgccacc 1860
ttttggcaga acccccggaa tcacttcaga tgtcaggtgc agttttacgg cctgtccgag 1920
aacgatgagt ggacccagga ccgggccaag cctgtgacac agatcgtgtc tgccgaggca 1980
tggggaagag cagactgtgg cttcacctct gagagctacc agcagggcgt gctgagcgcc 2040
accatcctgt atgagatcct gctgggcaag gccacactgt acgccgtcct ggtctccgct 2100
ctggtgctga tggcaatggt caaaagaaaa gatagtcggg gacgggccaa gagatctggc 2160
agcggcgagg gcagaggcag cctgctgacc tgcggcgacg tggaggagaa ccccggcccc 2220
atggagaaga atcccctggc tgcccccctg ctgatcctgt ggtttcacct ggactgcgtg 2280
tcctctatcc tgaatgtgga acagagccca cagagcctgc acgtgcagga gggcgactcc 2340
accaacttca catgctcttt tcctagctcc aacttctacg ccctgcactg gtacagaaag 2400
gagaccgcaa agtccccaga ggccctgttc gtgatgacac tgaacggcga tgagaagaag 2460
aagggccgca tcagcgccac cctgaataca aaggagggct actcctatct gtacatcaag 2520
ggctcccagc ctgaggactc tgccacctat ctgtgcgccc tgtacaacaa taacgatatg 2580
cggtttggcg ccggcaccag actgacagtg aagccaaaca tccagaatcc agaccccgcc 2640
gtgtatcagc tgcgggacag caagtctagc gataagagcg tgtgcctgtt caccgacttt 2700
gattctcaga caaacgtgag ccagtccaag gacagcgacg tgtacatcac cgacaagaca 2760
gtgctggata tgagaagcat ggacttcaag tctaacagcg ccgtggcctg gtccaataag 2820
tctgatttcg cctgcgccaa tgcctttaat aactccatca tccccgagga taccttcttt 2880
ccttctccag agtcctcttg tgacgtgaag ctggtggaga agtctttcga gaccgataca 2940
aacctgaatt ttcagaacct gagcgtgatc ggcttcagga tcctgctgct gaaggtggcc 3000
ggctttaatc tgctgatgac cctgaggctg tggagctcct gaaccggtcc gcagtctgac 3060
gtacgcgtaa tcaacctctg gattacaaaa tttgtgaaag attgactggt attcttaact 3120
atgttgctcc ttttacgcta tgtggatacg ctgctttaat gcctttgtat catgctattg 3180
cttcccgtat ggctttcatt ttctcctcct tgtataaatc ctggttgctg tctctttatg 3240
aggagttgtg gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt gctgacgcaa 3300
cccccactgg ttggggcatt gccaccacct gtcagctcct ttccgggact ttcgctttcc 3360
ccctccctat tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc tggacagggg 3420
ctcggctgtt gggcactgac aattccgtgg tgttgtcggg gaagctgacg tcctttccat 3480
ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc tacgtccctt 3540
cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg cggcctcttc 3600
cgcgtcttcg ccttcgccct cagacgagtc ggatctccct ttgggccgcc tccccgcc 3658
<210> 257
<211> 3622
<212> DNA
<213> Artificial Sequence
<220>
<223> CD8bCD4Fusion.TCR.WPRE
<400> 257
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactagc ggccgccccg ggtcgacgct accaccatgc gcccgagact gtggcttctg 420
ctcgccgcgc aactgactgt cctgcacgga aacagcgtgc tgcagcagac accggcctac 480
atcaaagtgc agaccaacaa gatggtcatg ctgtcctgcg aggccaagat ttccctctcc 540
aacatgcgga tctattggtt gcggcagaga caggcgcctt cctcggactc ccaccatgag 600
ttcttggccc tgtgggactc cgccaaggga actattcacg gcgaagaagt ggaacaggag 660
aagatcgccg tgtttcgcga tgcctcccgc tttatactga atctgacctc cgtgaagccc 720
gaagatagcg ggatctactt ttgcatgatt gtgggctcac ccgaactgac cttcgggaag 780
ggcactcagc tgagcgtggt ggacttcctc cccactaccg cccaacccac taagaagtca 840
accctgaaga agcgggtttg cagactccca cggccggaaa cgcagaaggg tccgctgtgt 900
tccccgatgg ccctgattgt gctggggggc gtcgccggcc tcctgctttt cattgggcta 960
ggcatcttct tctgtgtcag gtgccggcac cgaaggcgcc aagcagagcg gatgtctcag 1020
atcaagagac tcctcagtga gaagaagacc tgccagtgtc ctcaccggtt tcagaagaca 1080
tgtagcccca ttcgggccaa gagatctggc agcggcgcca ccaatttcag cctgctgaaa 1140
caggccggcg acgtggaaga gaaccctggc cccatggact cttggacctt ctgctgcgtg 1200
agcctgtgca tcctggtggc caagcacaca gacgccggcg tgatccagtc ccctaggcac 1260
gaggtgaccg agatgggcca ggaggtgaca ctgcgctgta agccaatctc tggccacaac 1320
agcctgtttt ggtataggga gaccatgatg cgcggcctgg agctgctgat ctacttcaat 1380
aacaatgtgc ccatcgacga ttccggcatg cctgaggatc ggttttctgc caagatgccc 1440
aatgccagct tctccacact gaagatccag cctagcgagc caagagactc cgccgtgtat 1500
ttttgcgcct ctagcccagg cagcaccgat acacagtact tcggaccagg aaccaggctg 1560
acagtgctgg aggacctgaa gaacgtgttc ccccctgagg tggccgtgtt tgagccctct 1620
gaggccgaga tcagccacac ccagaaggcc accctggtgt gcctggcaac cggcttctat 1680
cctgatcacg tggagctgtc ctggtgggtg aacggcaagg aggtgcacag cggcgtgtcc 1740
acagacccac agcccctgaa ggagcagcca gccctgaatg atagccggta ttgcctgtcc 1800
tctcggctga gagtgtccgc caccttttgg cagaaccccc ggaatcactt cagatgtcag 1860
gtgcagtttt acggcctgtc cgagaacgat gagtggaccc aggaccgggc caagcctgtg 1920
acacagatcg tgtctgccga ggcatgggga agagcagact gtggcttcac ctctgagagc 1980
taccagcagg gcgtgctgag cgccaccatc ctgtatgaga tcctgctggg caaggccaca 2040
ctgtacgccg tcctggtctc cgctctggtg ctgatggcaa tggtcaaaag aaaagatagt 2100
cggggacggg ccaagagatc tggcagcggc gagggcagag gcagcctgct gacctgcggc 2160
gacgtggagg agaaccccgg ccccatggag aagaatcccc tggctgcccc cctgctgatc 2220
ctgtggtttc acctggactg cgtgtcctct atcctgaatg tggaacagag cccacagagc 2280
ctgcacgtgc aggagggcga ctccaccaac ttcacatgct cttttcctag ctccaacttc 2340
tacgccctgc actggtacag aaaggagacc gcaaagtccc cagaggccct gttcgtgatg 2400
acactgaacg gcgatgagaa gaagaagggc cgcatcagcg ccaccctgaa tacaaaggag 2460
ggctactcct atctgtacat caagggctcc cagcctgagg actctgccac ctatctgtgc 2520
gccctgtaca acaataacga tatgcggttt ggcgccggca ccagactgac agtgaagcca 2580
aacatccaga atccagaccc cgccgtgtat cagctgcggg acagcaagtc tagcgataag 2640
agcgtgtgcc tgttcaccga ctttgattct cagacaaacg tgagccagtc caaggacagc 2700
gacgtgtaca tcaccgacaa gacagtgctg gatatgagaa gcatggactt caagtctaac 2760
agcgccgtgg cctggtccaa taagtctgat ttcgcctgcg ccaatgcctt taataactcc 2820
atcatccccg aggatacctt ctttccttct ccagagtcct cttgtgacgt gaagctggtg 2880
gagaagtctt tcgagaccga tacaaacctg aattttcaga acctgagcgt gatcggcttc 2940
aggatcctgc tgctgaaggt ggccggcttt aatctgctga tgaccctgag gctgtggagc 3000
tcctgaaccg gtccgcagtc tgacgtacgc gtaatcaacc tctggattac aaaatttgtg 3060
aaagattgac tggtattctt aactatgttg ctccttttac gctatgtgga tacgctgctt 3120
taatgccttt gtatcatgct attgcttccc gtatggcttt cattttctcc tccttgtata 3180
aatcctggtt gctgtctctt tatgaggagt tgtggcccgt tgtcaggcaa cgtggcgtgg 3240
tgtgcactgt gtttgctgac gcaaccccca ctggttgggg cattgccacc acctgtcagc 3300
tcctttccgg gactttcgct ttccccctcc ctattgccac ggcggaactc atcgccgcct 3360
gccttgcccg ctgctggaca ggggctcggc tgttgggcac tgacaattcc gtggtgttgt 3420
cggggaagct gacgtccttt ccatggctgc tcgcctgtgt tgccacctgg attctgcgcg 3480
ggacgtcctt ctgctacgtc ccttcggccc tcaatccagc ggaccttcct tcccgcggcc 3540
tgctgccggc tctgcggcct cttccgcgtc ttcgccttcg ccctcagacg agtcggatct 3600
ccctttgggc cgcctccccg cc 3622
<210> 258
<211> 3595
<212> DNA
<213> Artificial Sequence
<220>
<223> CD8bCD8aFusion.TCR.WPRE
<400> 258
tgaaagaccc cacctgtagg tttggcaagc tagcttaagt aacgccattt tgcaaggcat 60
ggaaaataca taactgagaa tagagaagtt cagatcaagg ttaggaacag agagacagca 120
gaatatgggc caaacaggat atctgtggta agcagttcct gccccggctc agggccaaga 180
acagatggtc cccagatgcg gtcccgccct cagcagtttc tagagaacca tcagatgttt 240
ccagggtgcc ccaaggacct gaaaatgacc ctgtgcctta tttgaactaa ccaatcagtt 300
cgcttctcgc ttctgttcgc gcgcttctgc tccccgagct caataaaaga gcccacaacc 360
cctcactagc ggccgccccg ggtcgacgct accaccatgc gcccgagact gtggcttctg 420
ctcgccgcgc aactgactgt cctgcacgga aacagcgtgc tgcagcagac accggcctac 480
atcaaagtgc agaccaacaa gatggtcatg ctgtcctgcg aggccaagat ttccctctcc 540
aacatgcgga tctattggtt gcggcagaga caggcgcctt cctcggactc ccaccatgag 600
ttcttggccc tgtgggactc cgccaaggga actattcacg gcgaagaagt ggaacaggag 660
aagatcgccg tgtttcgcga tgcctcccgc tttatactga atctgacctc cgtgaagccc 720
gaagatagcg ggatctactt ttgcatgatt gtgggctcac ccgaactgac cttcgggaag 780
ggcactcagc tgagcgtggt ggacttcctc cccactaccg cccaacccac taagaagtca 840
accctgaaga agcgggtttg cagactccca cggccggaaa cgcagaaggg tccgctgtgt 900
tccccgatct acatttgggc ccctttggct ggcacctgtg gagtgctgct cctgtccctt 960
gtgatcaccc tgtactgcaa ccaccggaat aggcggagag tctgcaagtg tccgcggcct 1020
gtcgtgaagt caggagataa gccgagcctg tccgcacgct acgtgcgggc caagagatct 1080
ggcagcggcg ccaccaattt cagcctgctg aaacaggccg gcgacgtgga agagaaccct 1140
ggccccatgg actcttggac cttctgctgc gtgagcctgt gcatcctggt ggccaagcac 1200
acagacgccg gcgtgatcca gtcccctagg cacgaggtga ccgagatggg ccaggaggtg 1260
acactgcgct gtaagccaat ctctggccac aacagcctgt tttggtatag ggagaccatg 1320
atgcgcggcc tggagctgct gatctacttc aataacaatg tgcccatcga cgattccggc 1380
atgcctgagg atcggttttc tgccaagatg cccaatgcca gcttctccac actgaagatc 1440
cagcctagcg agccaagaga ctccgccgtg tatttttgcg cctctagccc aggcagcacc 1500
gatacacagt acttcggacc aggaaccagg ctgacagtgc tggaggacct gaagaacgtg 1560
ttcccccctg aggtggccgt gtttgagccc tctgaggccg agatcagcca cacccagaag 1620
gccaccctgg tgtgcctggc aaccggcttc tatcctgatc acgtggagct gtcctggtgg 1680
gtgaacggca aggaggtgca cagcggcgtg tccacagacc cacagcccct gaaggagcag 1740
ccagccctga atgatagccg gtattgcctg tcctctcggc tgagagtgtc cgccaccttt 1800
tggcagaacc cccggaatca cttcagatgt caggtgcagt tttacggcct gtccgagaac 1860
gatgagtgga cccaggaccg ggccaagcct gtgacacaga tcgtgtctgc cgaggcatgg 1920
ggaagagcag actgtggctt cacctctgag agctaccagc agggcgtgct gagcgccacc 1980
atcctgtatg agatcctgct gggcaaggcc acactgtacg ccgtcctggt ctccgctctg 2040
gtgctgatgg caatggtcaa aagaaaagat agtcggggac gggccaagag atctggcagc 2100
ggcgagggca gaggcagcct gctgacctgc ggcgacgtgg aggagaaccc cggccccatg 2160
gagaagaatc ccctggctgc ccccctgctg atcctgtggt ttcacctgga ctgcgtgtcc 2220
tctatcctga atgtggaaca gagcccacag agcctgcacg tgcaggaggg cgactccacc 2280
aacttcacat gctcttttcc tagctccaac ttctacgccc tgcactggta cagaaaggag 2340
accgcaaagt ccccagaggc cctgttcgtg atgacactga acggcgatga gaagaagaag 2400
ggccgcatca gcgccaccct gaatacaaag gagggctact cctatctgta catcaagggc 2460
tcccagcctg aggactctgc cacctatctg tgcgccctgt acaacaataa cgatatgcgg 2520
tttggcgccg gcaccagact gacagtgaag ccaaacatcc agaatccaga ccccgccgtg 2580
tatcagctgc gggacagcaa gtctagcgat aagagcgtgt gcctgttcac cgactttgat 2640
tctcagacaa acgtgagcca gtccaaggac agcgacgtgt acatcaccga caagacagtg 2700
ctggatatga gaagcatgga cttcaagtct aacagcgccg tggcctggtc caataagtct 2760
gatttcgcct gcgccaatgc ctttaataac tccatcatcc ccgaggatac cttctttcct 2820
tctccagagt cctcttgtga cgtgaagctg gtggagaagt ctttcgagac cgatacaaac 2880
ctgaattttc agaacctgag cgtgatcggc ttcaggatcc tgctgctgaa ggtggccggc 2940
tttaatctgc tgatgaccct gaggctgtgg agctcctgaa ccggtccgca gtctgacgta 3000
cgcgtaatca acctctggat tacaaaattt gtgaaagatt gactggtatt cttaactatg 3060
ttgctccttt tacgctatgt ggatacgctg ctttaatgcc tttgtatcat gctattgctt 3120
cccgtatggc tttcattttc tcctccttgt ataaatcctg gttgctgtct ctttatgagg 3180
agttgtggcc cgttgtcagg caacgtggcg tggtgtgcac tgtgtttgct gacgcaaccc 3240
ccactggttg gggcattgcc accacctgtc agctcctttc cgggactttc gctttccccc 3300
tccctattgc cacggcggaa ctcatcgccg cctgccttgc ccgctgctgg acaggggctc 3360
ggctgttggg cactgacaat tccgtggtgt tgtcggggaa gctgacgtcc tttccatggc 3420
tgctcgcctg tgttgccacc tggattctgc gcgggacgtc cttctgctac gtcccttcgg 3480
ccctcaatcc agcggacctt ccttcccgcg gcctgctgcc ggctctgcgg cctcttccgc 3540
gtcttcgcct tcgccctcag acgagtcgga tctccctttg ggccgcctcc ccgcc 3595
<210> 259
<211> 5091
<212> DNA
<213> Artificial Sequence
<220>
<223> PGK.CD8.EF1a.TCR
<400> 259
tcacacgtag cgtgcggaca ggctcggctt atctcctgac ttcacgacag gccgcggaca 60
cttgcagact ctccgcctat tccggtggtt gcagtacagg gtgatcacaa gggacaggag 120
cagcactcca caggtgccag ccaaaggggc ccaaatgtag atgtcgcacg cgaagtccag 180
accgcgggta tgcacggctc ctccagcagc aggccgacac gcttcagggc gcagcgaaag 240
gggttgggac gcgatggtgg gagcgggagt tggaggtctg ggtgccggag tagtggtggg 300
cttggcaggc aggaacaccg gcacgaagtg tgagaagtac atgattgaat tggagagcgc 360
agagcagaag tagtagccct cgttctcccg ccggaagtcg gagagagtca gcacaaaagt 420
gtctcccagc cgtttgcccg agaagcgctg ggtgtccaga ccctcagcgg ccttcggctt 480
gttctggctc aagtacagga ggaaggtggg tgaggcggca gctcctctcg gctggaacag 540
ccagctgcat ccgctggtcg ggttcgacag gaggacttga cacttgagct ccaccgtttc 600
cccgaggttc caggtgcgat ccagagggga cacccggaat tgggaaggtc gtgcggcgtg 660
caacagcagg gcaaggggca acaggagtgc ggtcacggga agcgccatgg ggccagggtt 720
ctcttccacg tcgccggcct gtttcagcag gctgaaattg gtggcgccgc tgccagatct 780
cttggcccgg gttttcagga tccaggggtt cagcagcttt tgcgaggtgg tggtgttgga 840
atagtagcca tggaggcact gtggcacgaa agtgccactg atcccctctc cctgaggctg 900
cttcatgaac ctcagtctgg ccctccttct ccggcagcag aggtgaatgg cgacgccaag 960
ggacaccaga aggaccagca ctccagccac aaggagcccc agggtgatcg gggaacacag 1020
cggacccttc tgcgtttccg gccgtgggag tctgcaaacc cgcttcttca gggttgactt 1080
cttagtgggt tgggcggtag tggggaggaa gtccaccacg ctcagctgag tgcccttccc 1140
gaaggtcagt tcgggtgagc ccacaatcat gcaaaagtag atcccgctat cttcgggctt 1200
cacggaggtc agattcagta taaagcggga ggcatcgcga aacacggcga tcttctcctg 1260
ttccacttct tcgccgtgaa tagttccctt ggcggagtcc cacagggcca agaactcatg 1320
gtgggagtcc gaggaaggcg cctgtctctg ccgcaaccaa tagatccgca tgttggagag 1380
ggaaatcttg gcctcgcagg acagcatgac catcttgttg gtctgcactt tgatgtaggc 1440
cggtgtctgc tgcagcacgc tgtttccgtg caggacagtc agttgcgcgg cgagcagaag 1500
ccacagtctc gggcgcatgg tggtagcgtc gacccggggc ggccgctcga aaggcccgga 1560
gatgaggaag aggagaacag cgcggcagac gtgcgctttt gaagcgtgca gaatgccggg 1620
cctccggagg accttcgggc gcccgccccg cccctgagcc cgcccctgag cccgcccccg 1680
gacccacccc ttcccagcct ctgagcccag aaagcgaagg agcaaagctg ctattggccg 1740
ctgccccaaa ggcctacccg cttccagtgc tcagcggtgc tgtccatctg cacgagacta 1800
gtgagacgtg ctacttccat ttgtcacgtc ctgcacgacg cgagctgcgg ggcggggggg 1860
aacttcctga ctaggggagg agtagaaggt ggcgcgaagg ggccaccaaa gaacggagcc 1920
ggttggcgcc taccggtgga tgtggaatgt gtgcgaggcc agaggccact tgtgtagcgc 1980
caagtgccca gcggggctgc taaagcgcat gctccagact gccttgggaa aagcgcctcc 2040
cctacccgct ccggtgcccg tcagtgggca gagcgcacat cgcccacagt ccccgagaag 2100
ttggggggag gggtcggcaa ttgaaccggt gcctagagaa ggtggcgcgg ggtaaactgg 2160
gaaagtgatg tcgtgtactg gctccgcctt tttcccgagg gtgggggaga accgtatata 2220
agtgcagtag tcgccgtgaa cgttcttttt cgcaacgggt ttgccgccag aacacaggta 2280
agtgccgtgt gtggttcccg cgggcctggc ctctttacgg gttatggccc ttgcgtgcct 2340
tgaattactt ccacgcccct ggctgcagta cgtgattctt gatcccgagc ttcgggttgg 2400
aagtgggtgg gagagttcga ggccttgcgc ttaaggagcc ccttcgcctc gtgcttgagt 2460
tgaggcctgg cctgggcgct ggggccgccg cgtgcgaatc tggtggcacc ttcgcgcctg 2520
tctcgctgct ttcgataagt ctctagccat ttaaaatttt tgatgacctg ctgcgacgct 2580
ttttttctgg caagatagtc ttgtaaatgc gggccaagat ctgcacactg gtatttcggt 2640
ttttggggcc gcgggcggcg acggggcccg tgcgtcccag cgcacatgtt cggcgaggcg 2700
gggcctgcga gcgcggccac cgagaatcgg acgggggtag tctcaagctg gccggcctgc 2760
tctggtgcct ggcctcgcgc cgccgtgtat cgccccgccc tgggcggcaa ggctggcccg 2820
gtcggcacca gttgcgtgag cggaaagatg gccgcttccc ggccctgctg cagggagctc 2880
aaaatggagg acgcggcgct cgggagagcg ggcgggtgag tcacccacac aaaggaaaag 2940
ggcctttccg tcctcagccg tcgcttcatg tgactccacg gagtaccggg cgccgtccag 3000
gcacctcgat tagttctcga gcttttggag tacgtcgtct ttaggttggg gggaggggtt 3060
ttatgcgatg gagtttcccc acactgagtg ggtggagact gaagttaggc cagcttggca 3120
cttgatgtaa ttctccttgg aatttgccct ttttgagttt ggatcttggt tcattctcaa 3180
gcctcagaca gtggttcaaa gtttttttct tccatttcag gtgtcgtgaa gcggccgccc 3240
cgggtcgacg ctaccaccat ggactcttgg accttctgct gcgtgagcct gtgcatcctg 3300
gtggccaagc acacagacgc cggcgtgatc cagtccccta ggcacgaggt gaccgagatg 3360
ggccaggagg tgacactgcg ctgtaagcca atctctggcc acaacagcct gttttggtat 3420
agggagacca tgatgcgcgg cctggagctg ctgatctact tcaataacaa tgtgcccatc 3480
gacgattccg gcatgcctga ggatcggttt tctgccaaga tgcccaatgc cagcttctcc 3540
acactgaaga tccagcctag cgagccaaga gactccgccg tgtatttttg cgcctctagc 3600
ccaggcagca ccgatacaca gtacttcgga ccaggaacca ggctgacagt gctggaggac 3660
ctgaagaacg tgttcccccc tgaggtggcc gtgtttgagc cctctgaggc cgagatcagc 3720
cacacccaga aggccaccct ggtgtgcctg gcaaccggct tctatcctga tcacgtggag 3780
ctgtcctggt gggtgaacgg caaggaggtg cacagcggcg tgtccacaga cccacagccc 3840
ctgaaggagc agccagccct gaatgatagc cggtattgcc tgtcctctcg gctgagagtg 3900
tccgccacct tttggcagaa cccccggaat cacttcagat gtcaggtgca gttttacggc 3960
ctgtccgaga acgatgagtg gacccaggac cgggccaagc ctgtgacaca gatcgtgtct 4020
gccgaggcat ggggaagagc agactgtggc ttcacctctg agagctacca gcagggcgtg 4080
ctgagcgcca ccatcctgta tgagatcctg ctgggcaagg ccacactgta cgccgtcctg 4140
gtctccgctc tggtgctgat ggcaatggtc aaaagaaaag atagtcgggg acgggccaag 4200
agatctggca gcggcgaggg cagaggcagc ctgctgacct gcggcgacgt ggaggagaac 4260
cccggcccca tggagaagaa tcccctggct gcccccctgc tgatcctgtg gtttcacctg 4320
gactgcgtgt cctctatcct gaatgtggaa cagagcccac agagcctgca cgtgcaggag 4380
ggcgactcca ccaacttcac atgctctttt cctagctcca acttctacgc cctgcactgg 4440
tacagaaagg agaccgcaaa gtccccagag gccctgttcg tgatgacact gaacggcgat 4500
gagaagaaga agggccgcat cagcgccacc ctgaatacaa aggagggcta ctcctatctg 4560
tacatcaagg gctcccagcc tgaggactct gccacctatc tgtgcgccct gtacaacaat 4620
aacgatatgc ggtttggcgc cggcaccaga ctgacagtga agccaaacat ccagaatcca 4680
gaccccgccg tgtatcagct gcgggacagc aagtctagcg ataagagcgt gtgcctgttc 4740
accgactttg attctcagac aaacgtgagc cagtccaagg acagcgacgt gtacatcacc 4800
gacaagacag tgctggatat gagaagcatg gacttcaagt ctaacagcgc cgtggcctgg 4860
tccaataagt ctgatttcgc ctgcgccaat gcctttaata actccatcat ccccgaggat 4920
accttctttc cttctccaga gtcctcttgt gacgtgaagc tggtggagaa gtctttcgag 4980
accgatacaa acctgaattt tcagaacctg agcgtgatcg gcttcaggat cctgctgctg 5040
aaggtggccg gctttaatct gctgatgacc ctgaggctgt ggagctcctg a 5091
<210> 260
<211> 5091
<212> DNA
<213> Artificial Sequence
<220>
<223> PGK.TCR.EF1a.CD8
<400> 260
tcaggagctc cacagcctca gggtcatcag cagattaaag ccggccacct tcagcagcag 60
gatcctgaag ccgatcacgc tcaggttctg aaaattcagg tttgtatcgg tctcgaaaga 120
cttctccacc agcttcacgt cacaagagga ctctggagaa ggaaagaagg tatcctcggg 180
gatgatggag ttattaaagg cattggcgca ggcgaaatca gacttattgg accaggccac 240
ggcgctgtta gacttgaagt ccatgcttct catatccagc actgtcttgt cggtgatgta 300
cacgtcgctg tccttggact ggctcacgtt tgtctgagaa tcaaagtcgg tgaacaggca 360
cacgctctta tcgctagact tgctgtcccg cagctgatac acggcggggt ctggattctg 420
gatgtttggc ttcactgtca gtctggtgcc ggcgccaaac cgcatatcgt tattgttgta 480
cagggcgcac agataggtgg cagagtcctc aggctgggag cccttgatgt acagatagga 540
gtagccctcc tttgtattca gggtggcgct gatgcggccc ttcttcttct catcgccgtt 600
cagtgtcatc acgaacaggg cctctgggga ctttgcggtc tcctttctgt accagtgcag 660
ggcgtagaag ttggagctag gaaaagagca tgtgaagttg gtggagtcgc cctcctgcac 720
gtgcaggctc tgtgggctct gttccacatt caggatagag gacacgcagt ccaggtgaaa 780
ccacaggatc agcagggggg cagccagggg attcttctcc atggggccgg ggttctcctc 840
cacgtcgccg caggtcagca ggctgcctct gccctcgccg ctgccagatc tcttggcccg 900
tccccgacta tcttttcttt tgaccattgc catcagcacc agagcggaga ccaggacggc 960
gtacagtgtg gccttgccca gcaggatctc atacaggatg gtggcgctca gcacgccctg 1020
ctggtagctc tcagaggtga agccacagtc tgctcttccc catgcctcgg cagacacgat 1080
ctgtgtcaca ggcttggccc ggtcctgggt ccactcatcg ttctcggaca ggccgtaaaa 1140
ctgcacctga catctgaagt gattccgggg gttctgccaa aaggtggcgg acactctcag 1200
ccgagaggac aggcaatacc ggctatcatt cagggctggc tgctccttca ggggctgtgg 1260
gtctgtggac acgccgctgt gcacctcctt gccgttcacc caccaggaca gctccacgtg 1320
atcaggatag aagccggttg ccaggcacac cagggtggcc ttctgggtgt ggctgatctc 1380
ggcctcagag ggctcaaaca cggccacctc aggggggaac acgttcttca ggtcctccag 1440
cactgtcagc ctggttcctg gtccgaagta ctgtgtatcg gtgctgcctg ggctagaggc 1500
gcaaaaatac acggcggagt ctcttggctc gctaggctgg atcttcagtg tggagaagct 1560
ggcattgggc atcttggcag aaaaccgatc ctcaggcatg ccggaatcgt cgatgggcac 1620
attgttattg aagtagatca gcagctccag gccgcgcatc atggtctccc tataccaaaa 1680
caggctgttg tggccagaga ttggcttaca gcgcagtgtc acctcctggc ccatctcggt 1740
cacctcgtgc ctaggggact ggatcacgcc ggcgtctgtg tgcttggcca ccaggatgca 1800
caggctcacg cagcagaagg tccaagagtc catggtggta gcgtcgaccc ggggcggccg 1860
ctcgaaaggc ccggagatga ggaagaggag aacagcgcgg cagacgtgcg cttttgaagc 1920
gtgcagaatg ccgggcctcc ggaggacctt cgggcgcccg ccccgcccct gagcccgccc 1980
ctgagcccgc ccccggaccc accccttccc agcctctgag cccagaaagc gaaggagcaa 2040
agctgctatt ggccgctgcc ccaaaggcct acccgcttcc agtgctcagc ggtgctgtcc 2100
atctgcacga gactagtgag acgtgctact tccatttgtc acgtcctgca cgacgcgagc 2160
tgcggggcgg gggggaactt cctgactagg ggaggagtag aaggtggcgc gaaggggcca 2220
ccaaagaacg gagccggttg gcgcctaccg gtggatgtgg aatgtgtgcg aggccagagg 2280
ccacttgtgt agcgccaagt gcccagcggg gctgctaaag cgcatgctcc agactgcctt 2340
gggaaaagcg cctcccctac ccgctccggt gcccgtcagt gggcagagcg cacatcgccc 2400
acagtccccg agaagttggg gggaggggtc ggcaattgaa ccggtgccta gagaaggtgg 2460
cgcggggtaa actgggaaag tgatgtcgtg tactggctcc gcctttttcc cgagggtggg 2520
ggagaaccgt atataagtgc agtagtcgcc gtgaacgttc tttttcgcaa cgggtttgcc 2580
gccagaacac aggtaagtgc cgtgtgtggt tcccgcgggc ctggcctctt tacgggttat 2640
ggcccttgcg tgccttgaat tacttccacg cccctggctg cagtacgtga ttcttgatcc 2700
cgagcttcgg gttggaagtg ggtgggagag ttcgaggcct tgcgcttaag gagccccttc 2760
gcctcgtgct tgagttgagg cctggcctgg gcgctggggc cgccgcgtgc gaatctggtg 2820
gcaccttcgc gcctgtctcg ctgctttcga taagtctcta gccatttaaa atttttgatg 2880
acctgctgcg acgctttttt tctggcaaga tagtcttgta aatgcgggcc aagatctgca 2940
cactggtatt tcggtttttg gggccgcggg cggcgacggg gcccgtgcgt cccagcgcac 3000
atgttcggcg aggcggggcc tgcgagcgcg gccaccgaga atcggacggg ggtagtctca 3060
agctggccgg cctgctctgg tgcctggcct cgcgccgccg tgtatcgccc cgccctgggc 3120
ggcaaggctg gcccggtcgg caccagttgc gtgagcggaa agatggccgc ttcccggccc 3180
tgctgcaggg agctcaaaat ggaggacgcg gcgctcggga gagcgggcgg gtgagtcacc 3240
cacacaaagg aaaagggcct ttccgtcctc agccgtcgct tcatgtgact ccacggagta 3300
ccgggcgccg tccaggcacc tcgattagtt ctcgagcttt tggagtacgt cgtctttagg 3360
ttggggggag gggttttatg cgatggagtt tccccacact gagtgggtgg agactgaagt 3420
taggccagct tggcacttga tgtaattctc cttggaattt gccctttttg agtttggatc 3480
ttggttcatt ctcaagcctc agacagtggt tcaaagtttt tttcttccat ttcaggtgtc 3540
gtgaagcggc cgccccgggt cgacgctacc accatgcgcc cgagactgtg gcttctgctc 3600
gccgcgcaac tgactgtcct gcacggaaac agcgtgctgc agcagacacc ggcctacatc 3660
aaagtgcaga ccaacaagat ggtcatgctg tcctgcgagg ccaagatttc cctctccaac 3720
atgcggatct attggttgcg gcagagacag gcgccttcct cggactccca ccatgagttc 3780
ttggccctgt gggactccgc caagggaact attcacggcg aagaagtgga acaggagaag 3840
atcgccgtgt ttcgcgatgc ctcccgcttt atactgaatc tgacctccgt gaagcccgaa 3900
gatagcggga tctacttttg catgattgtg ggctcacccg aactgacctt cgggaagggc 3960
actcagctga gcgtggtgga cttcctcccc actaccgccc aacccactaa gaagtcaacc 4020
ctgaagaagc gggtttgcag actcccacgg ccggaaacgc agaagggtcc gctgtgttcc 4080
ccgatcaccc tggggctcct tgtggctgga gtgctggtcc ttctggtgtc ccttggcgtc 4140
gccattcacc tctgctgccg gagaaggagg gccagactga ggttcatgaa gcagcctcag 4200
ggagagggga tcagtggcac tttcgtgcca cagtgcctcc atggctacta ttccaacacc 4260
accacctcgc aaaagctgct gaacccctgg atcctgaaaa cccgggccaa gagatctggc 4320
agcggcgcca ccaatttcag cctgctgaaa caggccggcg acgtggaaga gaaccctggc 4380
cccatggcgc ttcccgtgac cgcactcctg ttgccccttg ccctgctgtt gcacgccgca 4440
cgaccttccc aattccgggt gtcccctctg gatcgcacct ggaacctcgg ggaaacggtg 4500
gagctcaagt gtcaagtcct cctgtcgaac ccgaccagcg gatgcagctg gctgttccag 4560
ccgagaggag ctgccgcctc acccaccttc ctcctgtact tgagccagaa caagccgaag 4620
gccgctgagg gtctggacac ccagcgcttc tcgggcaaac ggctgggaga cacttttgtg 4680
ctgactctct ccgacttccg gcgggagaac gagggctact acttctgctc tgcgctctcc 4740
aattcaatca tgtacttctc acacttcgtg ccggtgttcc tgcctgccaa gcccaccact 4800
actccggcac ccagacctcc aactcccgct cccaccatcg cgtcccaacc cctttcgctg 4860
cgccctgaag cgtgtcggcc tgctgctgga ggagccgtgc atacccgcgg tctggacttc 4920
gcgtgcgaca tctacatttg ggcccctttg gctggcacct gtggagtgct gctcctgtcc 4980
cttgtgatca ccctgtactg caaccaccgg aataggcgga gagtctgcaa gtgtccgcgg 5040
cctgtcgtga agtcaggaga taagccgagc ctgtccgcac gctacgtgtg a 5091
<210> 261
<211> 2749
<212> DNA
<213> Artificial Sequence
<220>
<223> NFAT.IL12
<400> 261
gtcgaccgtg gaggaaaaac tgtttcatac agaaggcgtg gaggaaaaac tgtttcatac 60
agaaggcgtg gaggaaaaac tgtttcatac agaaggcgtg gaggaaaaac tgtttcatac 120
agaaggcgtg gaggaaaaac tgtttcatac agaaggcgtg gaggaaaaac tgtttcatac 180
agaaggcgca ttttgacacc cccataatat ttttccagaa ttaacagtat aaattgcatc 240
tcttgttcaa gagttcccta tcactctctt taatcactac tcacagtaac ctcaactcct 300
gcccaagctt ggcattccgg tactgttggt aaagccacca tgtgtcacca gcagttggtc 360
atctcttggt tttccctggt ttttctggca tctcccctcg tggccatatg ggaactgaag 420
aaagatgttt atgtcgtaga attggattgg tatccggatg cccctggaga aatggtggtc 480
ctcacctgtg acacccctga agaagatggt atcacctgga ccttggacca gagcagtgag 540
gtcttaggct ctggcaaaac cctgaccatc caagtcaaag agtttggaga tgctggccag 600
tacacctgtc acaaaggagg cgaggttcta agccattcgc tcctgctgct tcacaaaaag 660
gaagatggaa tttggtccac tgatatttta aaggaccaga aagaacccaa aaataagacc 720
tttctaagat gcgaggccaa gaattattct ggacgtttca cctgctggtg gctgacgaca 780
atcagtactg atttgacatt cagtgtcaaa agcagcagag gctcttctga cccccaaggg 840
gtgacgtgcg gagctgctac actctctgca gagagagtca gaggggacaa caaggagtat 900
gagtactcag tggagtgcca ggaggacagt gcctgcccag ctgctgagga gagtctgccc 960
attgaggtca tggtggatgc cgttcacaag ctcaagtatg aaaactacac cagcagcttc 1020
ttcatcaggg acatcatcaa acctgaccca cccaagaact tgcagctgaa gccattaaag 1080
aattctcggc aggtggaggt cagctgggag taccctgaca cctggagtac tccacattcc 1140
tacttctccc tgacattctg cgttcaggtc cagggcaaga gcaagagaga aaagaaagat 1200
agagtcttca cggacaagac ctcagccacg gtcatctgcc gcaaacaagc cagcattagc 1260
gtgcgggccc aggaccgcta ctatagctca tcttggagcg agtgggcatc tgtgccctgc 1320
agtggcggcg gcggcagcgg cggcggcggc agcggcggcg gcggcagcat gtggccccct 1380
gggtcagcct cccagccacc gccctcacct gccgcggcca caggtctgca tccagcggct 1440
cgccctgtgt ccctgcagtg ccggctcagc atgtgtccag cgcgcagcct cctccttgtg 1500
gctaccctgg tcctcctgga ccacctcagt ttggccagaa acctccccgt ggccactcca 1560
gacccaggaa tgttcccatg ccttcaccac tcccaaaacc tgctgagggc cgtcagcaac 1620
atgctccaga aggccagaca aactctagaa ttttaccctt gcacttctga agagattgat 1680
catgaagata tcacaaaaga taaaaccagc acagtggagg cctgtttacc attggaatta 1740
accaagaatg agagttgcct aaattccaga gagacctctt tcataactaa tgggagttgc 1800
ctggcctcca gaaagacctc ttttatgatg gccctgtgcc ttagtagtat ttatgaagac 1860
ttgaagatgt accaggtgga gttcaagacc atgaatgcaa agcttctgat ggatcctaag 1920
aggcagatct ttctagatca aaacatgctg gcagttattg atgagctgat gcaggccctg 1980
aatttcaaca gtgagactgt gccacaaaaa tcctcccttg aagaaccgga tttttataaa 2040
actaaaatca agctctgcat acttcttcat gctttcagaa ttcgggcagt gactattgat 2100
agagtgatga gctatctgaa tgcttcctag tgaaccggtc cgcagtctga cgtacgcgta 2160
atcaacctct ggattacaaa atttgtgaaa gattgactgg tattcttaac tatgttgctc 2220
cttttacgct atgtggatac gctgctttaa tgcctttgta tcatgctatt gcttcccgta 2280
tggctttcat tttctcctcc ttgtataaat cctggttgct gtctctttat gaggagttgt 2340
ggcccgttgt caggcaacgt ggcgtggtgt gcactgtgtt tgctgacgca acccccactg 2400
gttggggcat tgccaccacc tgtcagctcc tttccgggac tttcgctttc cccctcccta 2460
ttgccacggc ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctcggctgt 2520
tgggcactga caattccgtg gtgttgtcgg ggaagctgac gtcctttcca tggctgctcg 2580
cctgtgttgc cacctggatt ctgcgcggga cgtccttctg ctacgtccct tcggccctca 2640
atccagcgga ccttccttcc cgcggcctgc tgccggctct gcggcctctt ccgcgtcttc 2700
gccttcgccc tcagacgagt cggatctccc tttgggccgc ctccccgcc 2749
<210> 262
<211> 5048
<212> DNA
<213> Artificial Sequence
<220>
<223> CD69pro.IL12
<400> 262
tttatgatag catagtagcc cagaccccgg cctaccttaa aattctatat ggtacatttg 60
ctattttcac accattatct ttgagagtag tctccaaaaa tgttgtatat ggataagtct 120
ggaattaatt taggtaaagt actcagacat ggttaagcgt tatatctcat ctttaatata 180
gctcttcttt tattctctta tgtattttac tttcagaaac agtcaggttt ttcagagtcc 240
aagcttgtgt gtacacaagc actatctttt accttcactg tctcaagtca aaaagaagaa 300
aatgccagct cacactttcc aagctcattt tttgtgtttc agatgttcca ttgaagagga 360
aagttagaaa gttcaaagac ttgaagagga cagaaggttg gaaagtgttt aaaactggaa 420
atcccccgtt tactcatggt taccttcatt gaccctttac ggtaaacaat tcaaaaacac 480
aaaggcacct gcaggttaaa aataaatttt accaatttgt gtaatttgca ttaatttgag 540
agaggatgat gtattctaaa ttgaagtttt gattcacaag aagattaaaa gccattcaga 600
aacctaattc acccactgaa aggaaaaaaa aaaaaagaga gatgagcagt ttgtctccgg 660
aaattgtctt aggtcggaag tctgtggtcc ctgttcacat gtacccaaaa gcatcctgct 720
gctgcagctg tctgataagc acagagtacc ccaccttctc tgcacacttt gcatctagct 780
catattacct catctttact tcctttctga cgtctcaccc tggattctac atataaggtc 840
acacaggaag gaaagctgca ttgagttttg gtgtcctgaa agacttttgc caaccttgtc 900
cccgcactaa tttctctaag cctcggctat actattttct cagctacacg atgaaatgtg 960
aatgataatt tctgccctaa aaatatcact taatttttta acatatcatt tatgaaagaa 1020
gacacataaa atgtctccct gaagagtgag tcggttaaag ggagagcgag acatgcaggg 1080
agatggaaaa agaatctttt agagaaaaag taaaagccct gtagtggtag gatgcttggc 1140
atttttaagg aggaggtttc tgtcagagag gatactgaat aataggaaaa atgataagag 1200
aggtaaccag gggccatatt atgtataaag cattctcaac tattaggtct ttggatttta 1260
cggtacattt gataggaagc ctttcaaagt gcagtggggg gaggagttaa acacttcacc 1320
aaaatcatat gaattaatta taaaacaatg gttctagctg ctatgtggaa aagggactaa 1380
gaaattgact gaaaaatagg atggaagcaa agggagcttt tagggccaac atgtacctct 1440
ttgtgtctta ggtagacaaa tgcatctaat ggtccaacta acttctctag atgataactt 1500
ccaacccacc tatgcataaa atttaacgtc tttattctaa ataagtgata ttaataataa 1560
aatttggggc accaagatta ttaatcagag tggtattttg atttccctcc ttaaatcacc 1620
atacatagct ttctgcattc atcttgcgtt gactgtcatt acttgtctga gtgagactga 1680
taccacagcg atgttttaaa taataatcat acctcaaaag actgaagtct cagaggtatc 1740
tgaagagaat aacctagagc acagggggag aattgaagga gctgttactg aggtgacata 1800
aaagcagtct aaatgacagt aaaatgtgac aagaaaatta gcaggaaaca aatgaaacag 1860
ataatttaag ataaacaatt ttagagcata gcaaggaagt tccagaccac aagctttctg 1920
tttcctgcat tcttacttct tactacgtga tacatctagt caccagggaa gaagcgaatg 1980
acacacttcc aaaaaccaat tcgtagcttt ctaaataaaa ccctttcaag ctggagagag 2040
atccatgagc atagagatct taaaattcat gttcagcaat aaatcctggg gccccagaca 2100
gtgtcaggtg catagggggt gttcagtaaa tatcagttaa atgtatgcat aaatcgataa 2160
acgggattcc tggaaaatac tacactctcc ttctccaaat tatcttcatc tcaaagacag 2220
gaacctctaa cttttaattc tttacttaga ttatgctgtc tcctaaactg tttatgtttt 2280
ctagaaattt aaggcaggat gtctcagagt ctgggaaaat cccactttcc tcctgctaca 2340
ccttacagtt gtgagaaagc acatttcaga caacagggaa aacccatact tcaccacaac 2400
aacacactat acattgtctg gtccactgga gcataaatta aagagaaaca atgtagtcaa 2460
gcaagtaggc ggcaagagga agggggcgga gacatcatca gggagtataa actctgagat 2520
gcctcagagc ctcacagact caacaagagc tccagcaaag actttcactg tagcttgact 2580
tgacctgaga ttaactaggg aatcttgaca gcggccgccc cgggtcgacg ctaccaccat 2640
gtgtcaccag cagttggtca tctcttggtt ttccctggtt tttctggcat ctcccctcgt 2700
ggccatatgg gaactgaaga aagatgttta tgtcgtagaa ttggattggt atccggatgc 2760
ccctggagaa atggtggtcc tcacctgtga cacccctgaa gaagatggta tcacctggac 2820
cttggaccag agcagtgagg tcttaggctc tggcaaaacc ctgaccatcc aagtcaaaga 2880
gtttggagat gctggccagt acacctgtca caaaggaggc gaggttctaa gccattcgct 2940
cctgctgctt cacaaaaagg aagatggaat ttggtccact gatattttaa aggaccagaa 3000
agaacccaaa aataagacct ttctaagatg cgaggccaag aattattctg gacgtttcac 3060
ctgctggtgg ctgacgacaa tcagtactga tttgacattc agtgtcaaaa gcagcagagg 3120
ctcttctgac ccccaagggg tgacgtgcgg agctgctaca ctctctgcag agagagtcag 3180
aggggacaac aaggagtatg agtactcagt ggagtgccag gaggacagtg cctgcccagc 3240
tgctgaggag agtctgccca ttgaggtcat ggtggatgcc gttcacaagc tcaagtatga 3300
aaactacacc agcagcttct tcatcaggga catcatcaaa cctgacccac ccaagaactt 3360
gcagctgaag ccattaaaga attctcggca ggtggaggtc agctgggagt accctgacac 3420
ctggagtact ccacattcct acttctccct gacattctgc gttcaggtcc agggcaagag 3480
caagagagaa aagaaagata gagtcttcac ggacaagacc tcagccacgg tcatctgccg 3540
caaacaagcc agcattagcg tgcgggccca ggaccgctac tatagctcat cttggagcga 3600
gtgggcatct gtgccctgca gtggcggcgg cggcagcggc ggcggcggca gcggcggcgg 3660
cggcagcatg tggccccctg ggtcagcctc ccagccaccg ccctcacctg ccgcggccac 3720
aggtctgcat ccagcggctc gccctgtgtc cctgcagtgc cggctcagca tgtgtccagc 3780
gcgcagcctc ctccttgtgg ctaccctggt cctcctggac cacctcagtt tggccagaaa 3840
cctccccgtg gccactccag acccaggaat gttcccatgc cttcaccact cccaaaacct 3900
gctgagggcc gtcagcaaca tgctccagaa ggccagacaa actctagaat tttacccttg 3960
cacttctgaa gagattgatc atgaagatat cacaaaagat aaaaccagca cagtggaggc 4020
ctgtttacca ttggaattaa ccaagaatga gagttgccta aattccagag agacctcttt 4080
cataactaat gggagttgcc tggcctccag aaagacctct tttatgatgg ccctgtgcct 4140
tagtagtatt tatgaagact tgaagatgta ccaggtggag ttcaagacca tgaatgcaaa 4200
gcttctgatg gatcctaaga ggcagatctt tctagatcaa aacatgctgg cagttattga 4260
tgagctgatg caggccctga atttcaacag tgagactgtg ccacaaaaat cctcccttga 4320
agaaccggat ttttataaaa ctaaaatcaa gctctgcata cttcttcatg ctttcagaat 4380
tcgggcagtg actattgata gagtgatgag ctatctgaat gcttcctagt gaaccggtcc 4440
gcagtctgac gtacgcgtaa tcaacctctg gattacaaaa tttgtgaaag attgactggt 4500
attcttaact atgttgctcc ttttacgcta tgtggatacg ctgctttaat gcctttgtat 4560
catgctattg cttcccgtat ggctttcatt ttctcctcct tgtataaatc ctggttgctg 4620
tctctttatg aggagttgtg gcccgttgtc aggcaacgtg gcgtggtgtg cactgtgttt 4680
gctgacgcaa cccccactgg ttggggcatt gccaccacct gtcagctcct ttccgggact 4740
ttcgctttcc ccctccctat tgccacggcg gaactcatcg ccgcctgcct tgcccgctgc 4800
tggacagggg ctcggctgtt gggcactgac aattccgtgg tgttgtcggg gaagctgacg 4860
tcctttccat ggctgctcgc ctgtgttgcc acctggattc tgcgcgggac gtccttctgc 4920
tacgtccctt cggccctcaa tccagcggac cttccttccc gcggcctgct gccggctctg 4980
cggcctcttc cgcgtcttcg ccttcgccct cagacgagtc ggatctccct ttgggccgcc 5040
tccccgcc 5048
<210> 263
<211> 1540
<212> DNA
<213> Artificial Sequence
<220>
<223> NFAT.IL18.var1
<400> 263
gtcgaccgtg gaggaaaaac tgtttcatac agaaggcgtg gaggaaaaac tgtttcatac 60
agaaggcgtg gaggaaaaac tgtttcatac agaaggcgtg gaggaaaaac tgtttcatac 120
agaaggcgtg gaggaaaaac tgtttcatac agaaggcgtg gaggaaaaac tgtttcatac 180
agaaggcgca ttttgacacc cccataatat ttttccagaa ttaacagtat aaattgcatc 240
tcttgttcaa gagttcccta tcactctctt taatcactac tcacagtaac ctcaactcct 300
gcccaagctt ggcattccgg tactgttggt aaagccacca tggctgctga accagtagaa 360
gacaattgca tcaactttgt ggcaatgaaa tttattgaca atacgcttta ctttatagct 420
gaagatgatg aaaacctgga atcagattac tttggcaagc ttgaatctaa attatcagtc 480
ataagaaatt tgaatgacca agttctcttc attgaccaag gaaatcggcc tctatttgaa 540
gatatgactg attctgactg tagagataat gcaccccgga ccatatttat tataagtatg 600
tataaagata gccagcctag aggtatggct gtaactatct ctgtgaagtg tgagaaaatt 660
tcaactctct cctgtgagaa caaaattatt tcctttaagg aaatgaatcc tcctgataac 720
atcaaggata caaaaagtga catcatattc tttcagagaa gtgtcccagg acatgataat 780
aagatgcaat ttgaatcttc atcatacgaa ggatactttc tagcttgtga aaaagagaga 840
gaccttttta aactcatttt gaaaaaagag gatgaattgg gggatagatc tataatgttc 900
actgttcaaa acgaagacta gtgaaccggt ccgcagtctg acgtacgcgt aatcaacctc 960
tggattacaa aatttgtgaa agattgactg gtattcttaa ctatgttgct ccttttacgc 1020
tatgtggata cgctgcttta atgcctttgt atcatgctat tgcttcccgt atggctttca 1080
ttttctcctc cttgtataaa tcctggttgc tgtctcttta tgaggagttg tggcccgttg 1140
tcaggcaacg tggcgtggtg tgcactgtgt ttgctgacgc aacccccact ggttggggca 1200
ttgccaccac ctgtcagctc ctttccggga ctttcgcttt ccccctccct attgccacgg 1260
cggaactcat cgccgcctgc cttgcccgct gctggacagg ggctcggctg ttgggcactg 1320
acaattccgt ggtgttgtcg gggaagctga cgtcctttcc atggctgctc gcctgtgttg 1380
ccacctggat tctgcgcggg acgtccttct gctacgtccc ttcggccctc aatccagcgg 1440
accttccttc ccgcggcctg ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc 1500
ctcagacgag tcggatctcc ctttgggccg cctccccgcc 1540
<210> 264
<211> 3839
<212> DNA
<213> Artificial Sequence
<220>
<223> CD69pro.IL18.var1
<400> 264
tttatgatag catagtagcc cagaccccgg cctaccttaa aattctatat ggtacatttg 60
ctattttcac accattatct ttgagagtag tctccaaaaa tgttgtatat ggataagtct 120
ggaattaatt taggtaaagt actcagacat ggttaagcgt tatatctcat ctttaatata 180
gctcttcttt tattctctta tgtattttac tttcagaaac agtcaggttt ttcagagtcc 240
aagcttgtgt gtacacaagc actatctttt accttcactg tctcaagtca aaaagaagaa 300
aatgccagct cacactttcc aagctcattt tttgtgtttc agatgttcca ttgaagagga 360
aagttagaaa gttcaaagac ttgaagagga cagaaggttg gaaagtgttt aaaactggaa 420
atcccccgtt tactcatggt taccttcatt gaccctttac ggtaaacaat tcaaaaacac 480
aaaggcacct gcaggttaaa aataaatttt accaatttgt gtaatttgca ttaatttgag 540
agaggatgat gtattctaaa ttgaagtttt gattcacaag aagattaaaa gccattcaga 600
aacctaattc acccactgaa aggaaaaaaa aaaaaagaga gatgagcagt ttgtctccgg 660
aaattgtctt aggtcggaag tctgtggtcc ctgttcacat gtacccaaaa gcatcctgct 720
gctgcagctg tctgataagc acagagtacc ccaccttctc tgcacacttt gcatctagct 780
catattacct catctttact tcctttctga cgtctcaccc tggattctac atataaggtc 840
acacaggaag gaaagctgca ttgagttttg gtgtcctgaa agacttttgc caaccttgtc 900
cccgcactaa tttctctaag cctcggctat actattttct cagctacacg atgaaatgtg 960
aatgataatt tctgccctaa aaatatcact taatttttta acatatcatt tatgaaagaa 1020
gacacataaa atgtctccct gaagagtgag tcggttaaag ggagagcgag acatgcaggg 1080
agatggaaaa agaatctttt agagaaaaag taaaagccct gtagtggtag gatgcttggc 1140
atttttaagg aggaggtttc tgtcagagag gatactgaat aataggaaaa atgataagag 1200
aggtaaccag gggccatatt atgtataaag cattctcaac tattaggtct ttggatttta 1260
cggtacattt gataggaagc ctttcaaagt gcagtggggg gaggagttaa acacttcacc 1320
aaaatcatat gaattaatta taaaacaatg gttctagctg ctatgtggaa aagggactaa 1380
gaaattgact gaaaaatagg atggaagcaa agggagcttt tagggccaac atgtacctct 1440
ttgtgtctta ggtagacaaa tgcatctaat ggtccaacta acttctctag atgataactt 1500
ccaacccacc tatgcataaa atttaacgtc tttattctaa ataagtgata ttaataataa 1560
aatttggggc accaagatta ttaatcagag tggtattttg atttccctcc ttaaatcacc 1620
atacatagct ttctgcattc atcttgcgtt gactgtcatt acttgtctga gtgagactga 1680
taccacagcg atgttttaaa taataatcat acctcaaaag actgaagtct cagaggtatc 1740
tgaagagaat aacctagagc acagggggag aattgaagga gctgttactg aggtgacata 1800
aaagcagtct aaatgacagt aaaatgtgac aagaaaatta gcaggaaaca aatgaaacag 1860
ataatttaag ataaacaatt ttagagcata gcaaggaagt tccagaccac aagctttctg 1920
tttcctgcat tcttacttct tactacgtga tacatctagt caccagggaa gaagcgaatg 1980
acacacttcc aaaaaccaat tcgtagcttt ctaaataaaa ccctttcaag ctggagagag 2040
atccatgagc atagagatct taaaattcat gttcagcaat aaatcctggg gccccagaca 2100
gtgtcaggtg catagggggt gttcagtaaa tatcagttaa atgtatgcat aaatcgataa 2160
acgggattcc tggaaaatac tacactctcc ttctccaaat tatcttcatc tcaaagacag 2220
gaacctctaa cttttaattc tttacttaga ttatgctgtc tcctaaactg tttatgtttt 2280
ctagaaattt aaggcaggat gtctcagagt ctgggaaaat cccactttcc tcctgctaca 2340
ccttacagtt gtgagaaagc acatttcaga caacagggaa aacccatact tcaccacaac 2400
aacacactat acattgtctg gtccactgga gcataaatta aagagaaaca atgtagtcaa 2460
gcaagtaggc ggcaagagga agggggcgga gacatcatca gggagtataa actctgagat 2520
gcctcagagc ctcacagact caacaagagc tccagcaaag actttcactg tagcttgact 2580
tgacctgaga ttaactaggg aatcttgaca gcggccgccc cgggtcgacg ctaccaccat 2640
ggctgctgaa ccagtagaag acaattgcat caactttgtg gcaatgaaat ttattgacaa 2700
tacgctttac tttatagctg aagatgatga aaacctggaa tcagattact ttggcaagct 2760
tgaatctaaa ttatcagtca taagaaattt gaatgaccaa gttctcttca ttgaccaagg 2820
aaatcggcct ctatttgaag atatgactga ttctgactgt agagataatg caccccggac 2880
catatttatt ataagtatgt ataaagatag ccagcctaga ggtatggctg taactatctc 2940
tgtgaagtgt gagaaaattt caactctctc ctgtgagaac aaaattattt cctttaagga 3000
aatgaatcct cctgataaca tcaaggatac aaaaagtgac atcatattct ttcagagaag 3060
tgtcccagga catgataata agatgcaatt tgaatcttca tcatacgaag gatactttct 3120
agcttgtgaa aaagagagag acctttttaa actcattttg aaaaaagagg atgaattggg 3180
ggatagatct ataatgttca ctgttcaaaa cgaagactag tgaaccggtc cgcagtctga 3240
cgtacgcgta atcaacctct ggattacaaa atttgtgaaa gattgactgg tattcttaac 3300
tatgttgctc cttttacgct atgtggatac gctgctttaa tgcctttgta tcatgctatt 3360
gcttcccgta tggctttcat tttctcctcc ttgtataaat cctggttgct gtctctttat 3420
gaggagttgt ggcccgttgt caggcaacgt ggcgtggtgt gcactgtgtt tgctgacgca 3480
acccccactg gttggggcat tgccaccacc tgtcagctcc tttccgggac tttcgctttc 3540
cccctcccta ttgccacggc ggaactcatc gccgcctgcc ttgcccgctg ctggacaggg 3600
gctcggctgt tgggcactga caattccgtg gtgttgtcgg ggaagctgac gtcctttcca 3660
tggctgctcg cctgtgttgc cacctggatt ctgcgcggga cgtccttctg ctacgtccct 3720
tcggccctca atccagcgga ccttccttcc cgcggcctgc tgccggctct gcggcctctt 3780
ccgcgtcttc gccttcgccc tcagacgagt cggatctccc tttgggccgc ctccccgcc 3839
<210> 265
<211> 607
<212> DNA
<213> Artificial Sequence
<220>
<223> WPREmut1
<400> 265
cagtctgacg tacgcgtaat caacctctgg attacaaaat ttgtgaaaga ttgactggta 60
ttcttaacta tgttgctcct tttacgctat gtggatacgc tgctttaatg cctttgtatc 120
atgctattgc ttcccgtatg gctttcattt tctcctcctt gtataaatcc tggttgctgt 180
ctctttatga ggagttgtgg cccgttgtca ggcaacgtgg cgtggtgtgc actgtgtttg 240
ctgacgcaac ccccactggt tggggcattg ccaccacctg tcagctcctt tccgggactt 300
tcgctttccc cctccctatt gccacggcgg aactcatcgc cgcctgcctt gcccgctgct 360
ggacaggggc tcggctgttg ggcactgaca attccgtggt gttgtcgggg aaatcatcgt 420
cctttccttg gctgctcgcc tgtgttgcca cctggattct gcgcgggacg tccttctgct 480
acgtcccttc ggccctcaat ccagcggacc ttccttcccg cggcctgctg ccggctctgc 540
ggcctcttcc gcgtcttcgc cttcgccctc agacgagtcg gatctccctt tgggccgcct 600
ccccgcc 607
<210> 266
<211> 581
<212> DNA
<213> Artificial Sequence
<220>
<223> WPREmut2
<400> 266
gagcatctta ccgccattta tacccatatt tgttctgttt ttcttgattt gggtatacat 60
ttaaatgtta ataaaacaaa atggtggggc aatcatttac attttttggg atatgtaatt 120
actagttcag gtgtattgcc acaagacaaa cttgttaaga aactttcccg ttatttacgc 180
tctgttcctg ttaatcaacc tctggattac aaaatttgtg aaagattgac tgatattctt 240
aactttgttg ctccttttac gctgtgtgga tttgctgctt tattgcctct gtatcttgct 300
attgcttccc gtacggcttt cgttttctcc tccttgtata aatcctggtt gctgtctctt 360
tttgaggagt tgtggcccgt tgtccgtcaa cgtggcgtgg tgtgctctgt gtttgctgac 420
gcaaccccca ctggctgggg cattgccacc acctgtcaac tcctttctgg gactttcgct 480
ttccccctcc cgatcgccac ggcagaactc atcgccgcct gccttgcccg ctgctggaca 540
ggggctaggt tgctgggcac tgataattcc gtggtgttgt c 581
Claims (51)
1.权利要求内容为:
一种载体,其包含编码CD8α多肽的核苷酸序列S1、编码CD8β多肽的核苷酸序列S2、编码T细胞受体(TCR)α多肽的核苷酸序列S3和编码TCRβ多肽的核苷酸序列S4,其中所述核苷酸序列以选自S1-S2-S3-S4、S1-S2-S4-S3、S2-S1-S3-S4、S2-S1-S4-S3、S3-S4-S1-S2、S3-S4-S2-S1、S4-S3-S1-S2和S4-S3-S2-S1的5'至3'方向串联排列。
2.权利要求1所述的载体,其中所述核苷酸序列以选自S1-S2-S3-S4、S1-S2-S4-S3、S2-S1-S3-S4和S2-S1-S4-S3的5'至3'方向串联排列。
3.权利要求2所述的载体,其中所述核苷酸序列以S2-S1-S4-S3的5'至3'方向串联排列。
4.权利要求1-3中任一项所述的载体,其中所述CD8αβ多肽包含与SEQ ID NO:11至少90%相同且与SEQ ID NO:12至少90%相同的氨基酸序列。
5.权利要求1-4中任一项所述的载体,其中所述TCRαβ多肽包含与选自SEQ ID NO:13和14、15和16、17和18、19和20、21和22、23和24、25和26、27和28、29和30、31和32、33和34、35和36、37和38、39和40、41和42、43和44、45和46、47和48、49和50、51和52、53和54、55和56、57和58、59和60、61和62、63和64、65和66、67和68、69和70、71和72、73和74、75和76、77和78、79和80、81和82、83和84、85和86、87和88或89和90的氨基酸序列至少90%相同的氨基酸序列。
6.权利要求1-5中任一项所述的载体,其中所述TCRαβ多肽包含与SEQ ID NO:13至少90%相同且与SEQ ID NO:14至少90%相同的氨基酸序列。
7.权利要求1-6中任一项所述的载体,其进一步包括编码2A肽的核苷酸序列S5和编码连接子肽的核苷酸序列S6,其中S5和S6位于S1和S2、S1和S3、S1和S4、S2和S3、S2和S4和/或S3和S4之间。
8.权利要求7中所述的载体,其中2A肽选自P2A(SEQ ID NO:3)、T2A(SEQ ID NO:4)、E2A(SEQ ID NO:5)或F2A(SEQ ID NO:6)。
9.权利要求7或8所述的载体,其中所述连接子肽为GSG或SGSG(SEQ ID NO:8)。
10.权利要求1-9中任一项所述的载体,其进一步包括编码弗林蛋白酶肽(SEQ ID NO:2)的核苷酸序列S7,其中S7位于S1和S2、S1和S3、S1和S4、S2和S3、S2和S4和/或S3和S4之间。
11.一种载体,其包含编码蛋白质Z1的第一核苷酸序列S1、编码蛋白质Z2的第二核苷酸序列S2、编码蛋白质Y1的第三核苷酸序列S3和编码Y2蛋白质的第四核苷酸序列S4,其中Z1和Z2形成第一二聚体、Y1和Y2形成第二二聚体,其中第一二聚体Z1Z2在结构上与第二二聚体Y1Y2不同,其中载体在用于适应性细胞疗法的基因递送系统中。
12.权利要求11所述的载体,其中S1、S2、S3和S4以选自S1-S2-S3-S4、S1-S2-S4-S3、S1-S3-S2-S4、S1-S3-S4-S2、S1-S4-S3-S2、S1-S4-S2-S3、S2-S1-S3-S4、S2-S1-S4-S3、S2-S3-S1-S4、S2-S3-S4-S1、S2-S4-S3-S1、S2-S4-S1-S3、S3-S1-S2-S4、S3-S1-S4-S2、S3-S2-S1-S4、S3-S2-S4-S1、S3-S4-S1-S2、S3-S4-S2-S1、S4-S1-S2-S3、S4-S1-S3-S2、S4-S2-S1-S3、S4-S2-S3-S1、S4-S3-S1-S2或S4-S3-S2-S1的5'至3'方向串联排列。
13.权利要求11或12中所述的载体,其进一步包括编码2A肽的第五核苷酸序列S5和编码连接子肽的第六核苷酸序列S6,其中S5和S6位于S1和S2、S1和S3、S1和S4、S2和S3、S2和S4和/或S3和S4之间。
14.权利要求13中所述的载体,其中2A肽选自P2A(SEQ ID NO:3)、T2A(SEQ ID NO:4)、E2A(SEQ ID NO:5)或F2A(SEQ ID NO:6)。
15.权利要求13或14所述的载体,其中所述连接子肽为GSG或SGSG(SEQ ID NO:8)。
16.权利要求11-15中任一项所述的载体,其进一步包括编码弗林蛋白酶肽(SEQ IDNO:2)的第七核苷酸序列S7,其中S7位于S1和S2、S1和S3、S1和S4、S2和S3、S2和S4和/或S3和S4之间。
17.权利要求11-16中任一项所述的载体,其进一步包括选自土拨鼠PRE(WPRE)或乙型肝炎病毒(HBV)PRE(HPRE)的转录后调控元件(PRE)序列。
18.权利要求11-17中任一项所述的载体,其进一步包含控制S2-S7转录的启动子序列,其中所述启动子序列选自巨细胞病毒(CMV)启动子、磷酸甘油酸酯激酶(PGK)启动子、髓磷脂碱性蛋白(MBP)启动子、神经胶质纤维酸性蛋白(GFAP)启动子、包含骨髓增生性肉瘤病毒增强剂(MNDU3)的修饰MoMuLV LTR、泛素C启动子、EF-1α启动子或鼠干细胞病毒(MSCV)启动子。
19.权利要求11-18中任一项所述的载体,其中,第一二聚体ZlZ2选自SEQ ID NO:13和14、15和16、17和18、19和20、21和22、23和24、25和26、27和28、29和30、31和32、33和34、35和36、37和38、39和40、41和42、43和44、45和46、47和48、49和50、51和52、53和54、55和56、57和58、59和60、61和62、63和64、65和66、67和68、69和70、71和72、73和74、75和76、77和78、79和80、81和82、83和84、85和86、87和88或89和90。
20.权利要求11-19中任一项所述的载体,其中第二二聚体Y1和Y2为SEQ ID NO:11和12。
21.权利要求11-20中任一项所述的载体,其中方向为S2-S1-S4-S3。
22.权利要求21所述的载体,其包括选自PTE WPRE(SEQ ID NO:91)、TPE WPRE(SEQ IDNO:92)或PTE fn WPRE(SEQ ID NO:93)的序列。
23.权利要求11-20中任一项所述的载体,其中方向为S4-S3-S2-S1。
24.权利要求23所述的载体,其包括序列PTE CD8 TCR WPRE(SEQ ID NO:94)。
25.权利要求11-24中任一项所述的载体,其为选自腺病毒、痘病毒、α病毒、晕病毒、黄病毒、弹状病毒、逆转录病毒、慢病毒、疱疹病毒、副粘病毒或微小核糖核酸病毒的病毒载体。
26.权利要求25所述的载体,其中载体用病毒的包膜蛋白进行假型化处理,所述病毒选自天然猫内源性病毒(RD114)、RD114的嵌合版本(RD114TR)、长臂猿白血病病毒(GALV)、GALV的嵌合版本(GALV-TR)、两栖鼠白血病病毒(MLV 4070A)、杆状病毒(GP64)、水疱性口炎病毒(VSV-G)、猫瘟病毒(FPV)、埃博拉病毒(EboV)、狒狒逆转录病毒包膜糖蛋白(BaEV)或淋巴细胞性脉络膜脑膜炎病毒(LCMV)。
27.一种制备T细胞用于免疫治疗的方法,包括
从人体受试者的血液样本中分离T细胞,
在存在氨基双膦酸盐的情况下激活分离的T细胞,
用权利要求11-26中任一项所述的载体转导激活的T细胞,和
扩增转导的T细胞。
28.权利要求27所述的方法,其中T细胞从白细胞分离术人样本中分离。
29.权利要求27或28所述的方法,其中氨基二膦酸盐选自帕米膦酸、阿仑膦酸、唑来膦酸、利塞膦酸、伊班膦酸、恩加膦酸、前述任一项的盐和/或其水合物。
30.权利要求27-29中任一项所述的方法,其中,在存在人重组白细胞介素2(IL-2)和人重组白细胞介素15(IL-15)的情况下进一步进行所述的激活。
31.权利要求27-30中任一项所述的方法,其中,所述扩增在存在IL-2和IL-15的情况下进行。
32.权利要求27-31中任一项所述的方法,其中T细胞为γδT细胞。
33.权利要求27-32中任一项所述的方法,其中,第一二聚体ZlZ2和第二二聚体Y1Y2在扩增的T细胞表面上共表达。
34.扩增T细胞群,其透过权利要求27-32中任一项所述的方法制备。
35.一种治疗癌症患者的方法,其包括向所述患者施用包含权利要求34所述的扩增T细胞群的组合物,
其中,所述T细胞杀灭提呈与表面MHC分子复合的肽的癌细胞,其中所述肽选自SEQ IDNO:98-255,
其中所述癌症选自非小细胞肺癌、小细胞肺癌、黑色素瘤、肝癌、乳腺癌、子宫癌、梅克尔细胞癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、膀胱癌、肾癌、白血病、卵巢癌、食道癌、脑癌、胃癌和前列腺癌组成的组。
36.权利要求35所述的方法,其中所述组合物还包含佐剂。
37.权利要求36所述的方法,其中所述佐剂选自抗-CD40抗体、咪喹莫特、雷西喹莫特、GM-CSF、环磷酰胺、舒尼替尼、贝伐单抗、阿特珠单抗、干扰素-α、干扰素-β、CpG寡核苷酸和衍生物、聚(I:C)和衍生物、RNA、西地那非、含有聚(丙交酯-共-乙交酯)(PLG)的颗粒制剂、病毒体、白介素(IL)-1、IL-2、IL-4、IL-7、IL-12、IL-13、IL-15、IL-21和IL-23。
38.一种在癌症患者中引发免疫应答的方法,其包括向所述患者施用包含权利要求34所述的扩增T细胞群的组合物,
其中,所述T细胞杀灭提呈与表面MHC分子复合的肽的癌细胞,其中所述肽选自SEQ IDNO:98-255,
其中所述癌症选自非小细胞肺癌、小细胞肺癌、黑色素瘤、肝癌、乳腺癌、子宫癌、梅克尔细胞癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、膀胱癌、肾癌、白血病、卵巢癌、食道癌、脑癌、胃癌和前列腺癌组成的组。
39.权利要求38所述的方法,其中所述组合物还包含佐剂。
40.权利要求39所述的方法,其中所述佐剂选自抗-CD40抗体、咪喹莫特、雷西喹莫特、GM-CSF、环磷酰胺、舒尼替尼、贝伐单抗、阿特珠单抗、干扰素-α、干扰素-β、CpG寡核苷酸和衍生物、聚(I:C)和衍生物、RNA、西地那非、含聚聚(丙交酯-共-乙交酯)(PLG)的颗粒制剂、病毒体、白介素(IL)-1、IL-2、IL-4、IL-7、IL-12、IL-13、IL-15、IL-21和IL-23。
41.权利要求38-40中任一项所述的方法,其中所述免疫应答包括细胞毒性T细胞应答。
42.一种制备T细胞用于免疫治疗的方法,包括
在存在他汀类药物的情况下激活T细胞,
用权利要求11-26中任一项所述的载体转导激活的T细胞,
其中所述载体用VSV-G的包膜蛋白进行假型化处理,以及
扩增转导的T细胞。
43.权利要求42所述的方法,其中所述T细胞包括αβT细胞、γδT细胞和/或自然杀伤T细胞。
44.权利要求42或43所述的方法,其中,他汀类药物选自阿托伐他汀、西立伐他汀、达伐他汀、氟吲他汀、氟伐他汀、美伐他汀、普伐他汀、辛伐他汀、维洛他汀和瑞舒伐他汀。
45.一种制备T细胞用于免疫治疗的方法,包括
激活T细胞,
用权利要求11-26中任一项所述的载体转导激活的T细胞,和
扩增转导的T细胞。
46.权利要求45所述的方法,其中所述T细胞包括αβT细胞、γδT细胞和/或自然杀伤T细胞。
47.权利要求45或46所述的方法,其中所述T细胞包括αβT细胞。
48.权利要求47所述的方法,其中激活在存在抗CD3抗体和抗CD28抗体的情况下进行。
49.权利要求47或48所述的方法,其中,所述扩增在存在IL-7和IL-15的情况下进行。
50.扩增T细胞群,其透过权利要求42-49中任一项所述的方法制备。
51.一种治疗癌症患者的方法,其包括向所述患者施用包含权利要求50所述的扩增T细胞群的组合物,
其中,所述T细胞杀灭提呈与表面MHC分子复合的肽的癌细胞,其中所述肽选自SEQ IDNO:98-255,
其中所述癌症选自非小细胞肺癌、小细胞肺癌、黑色素瘤、肝癌、乳腺癌、子宫癌、梅克尔细胞癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、膀胱癌、肾癌、白血病、卵巢癌、食道癌、脑癌、胃癌和前列腺癌组成的组。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN117777314A (zh) * | 2024-02-26 | 2024-03-29 | 赛德特生物制药有限公司 | 慢病毒载体及其应用 |
CN117777314B (zh) * | 2024-02-26 | 2024-05-14 | 赛德特生物制药有限公司 | 慢病毒载体及其应用 |
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EP3976805A1 (en) | 2022-04-06 |
EA202193139A1 (ru) | 2022-03-01 |
KR20220029584A (ko) | 2022-03-08 |
CR20210669A (es) | 2022-05-05 |
US20200376031A1 (en) | 2020-12-03 |
CL2021003146A1 (es) | 2022-09-09 |
IL288403A (en) | 2022-01-01 |
MA56036A (fr) | 2022-04-06 |
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SG11202112860PA (en) | 2021-12-30 |
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TW202110875A (zh) | 2021-03-16 |
AU2020283500A1 (en) | 2022-01-27 |
CA3141505A1 (en) | 2020-12-03 |
WO2020243134A1 (en) | 2020-12-03 |
PE20220164A1 (es) | 2022-01-28 |
JP2022534716A (ja) | 2022-08-03 |
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