CN113015750A - 抗liv1免疫细胞癌症疗法 - Google Patents
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Abstract
本文在一些实施例中提供了用于治疗癌症如LIV1+恶性肿瘤的方法和组合物(例如细胞组合物)。
Description
相关申请
本申请要求于2018年11月7日提交的美国临时专利申请号62/756,723的权益,将其披露内容通过引用以其全文特此并入。
以电子方式提交的材料通过引用并入
作为本披露的一部分的序列表将作为文本文件与说明书同时提交。包含序列表的文本文件的名称是“CT113_Seqlisting.txt”,它于2019年11月7日创建,并且大小为191,166字节。序列表的主题通过引用整体并入本文。
背景技术
嵌合抗原受体(CAR)T细胞疗法使用经基因修饰的T细胞来更特异性和有效地靶向和杀伤癌细胞。从血液中收集T细胞后,对细胞进行工程化,使其表面上包含CAR。可以使用CRISPR/Cas9基因编辑技术将CAR引入T细胞。将这些同种异体CAR T细胞注射入患者体内时,受体使T细胞能够杀伤癌细胞。
发明内容
LIV1是高度保守的跨膜锌转运蛋白的ZIP家族的成员,在雌激素受体阳性乳腺癌和淋巴结肿瘤中以升高的水平表达。已知锌转运蛋白如LIV1的进一步的异常表达导致解除对Zn摄入或缺乏的调节,导致癌症中发生的那样的不受控制的生长。因此,LIV1是靶向癌症的理想跨膜蛋白。实际上,LIV-1蛋白质与乳腺癌、前列腺癌、鳞状肿瘤和神经元肿瘤相关。
本披露内容的一些方面提供了工程化T细胞,该工程化T细胞包含编码嵌合抗原受体(CAR)的核酸,其中该CAR包含特异性结合LIV1的胞外结构域。在一些实施例中,该工程化T细胞进一步包含被破坏的T细胞受体α链恒定区(TRAC)基因。例如,可以通过插入编码CAR的核酸来破坏TRAC基因。在一些实施例中,该工程化T细胞进一步包含被破坏的β-2-微球蛋白(β2M)基因。
在一些实施例中,该CAR的胞外结构域包含抗LIV1抗体。在一些实施例中,该抗LIV1抗体是抗LIV1单链可变片段(scFv)。在一些实施例中,该抗LIV1 scFv包含SEQ ID NO:54、70、83或86中任一项的氨基酸序列。在一些实施例中,该抗LIV1 scFv包含重链可变区(VH)和/或轻链可变区(VL),其中该含重链可变区包含SEQ ID NO:55或90中任一项的氨基酸序列,所述轻链可变区包含SEQ ID NO:56或88中任一项的氨基酸序列。在一些实施例中,该抗LIV1 scFv包含VH,所述VH包含SEQ ID NO:57、SEQ ID NO:58和/或SEQ ID NO:59的CDR氨基酸序列;和/或抗LIV1 scFv包含VL序列,该VL序列包含SEQ ID NO:60、SEQ ID NO:61和/或SEQ ID NO:62的CDR氨基酸序列。
在一些实施例中,该CAR包含CD3ζ细胞质信号传导结构域。在一些实施例中,该CAR包含CD28共刺激结构域或41BB共刺激结构域。
在一些实施例中,该TRAC基因包含SEQ ID NO:63、64、107或111中任一项的核苷酸序列,和/或其中该CAR包含SEQ ID NO:49、51、104或108中任一项的核苷酸序列。在一些实施例中,该被破坏的β2M基因包含至少一个选自SEQ ID NO:9-14中任一项的核苷酸序列。
在一些方面,本文还提供了工程化T细胞(例如,包含编码抗LIV1 CAR的核酸)群体,其中该群体的至少25%或至少50%的工程化T细胞表达该CAR。在一些方面,该群体的至少15%或至少50%的工程化T细胞表达该CAR。例如,该群体的至少70%的工程化T细胞表达该CAR。在另一个实例中,该群体的至少30%的工程化T细胞表达该CAR。
在一些实施例中,该群体的至少25%的工程化T细胞在至少7天或至少14天的体外增殖后表达该CAR。
在一些实施例中,该群体的至少50%的工程化T细胞不表达可检测水平的T细胞受体(TCR)蛋白。例如,该群体的至少90%的工程化T细胞可能不表达可检测水平的TCR蛋白。
在一些实施例中,该群体的至少50%的工程化T细胞不表达可检测水平的β2M蛋白。例如,该群体的至少70%的工程化T细胞可能不表达可检测水平的β2M蛋白。
在一些实施例中,当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该群体的至少50%的癌细胞的细胞裂解。例如,该群体的工程化T细胞可以诱导该群体的至少70%、至少80%或至少90%的癌细胞的细胞裂解。在一些实施例中,当与癌细胞群体在体外共培养时,该群体的工程化T细胞分泌IFNγ。在一些实施例中,工程化T细胞与癌细胞的比率为1:1至2:1。癌细胞可以是,例如肉瘤细胞或乳腺癌细胞。可靶向其他癌细胞。
在一些实施例中,该群体的工程化T细胞的增殖能力在对照细胞的增殖能力的10%以内。
本披露的其他方面提供了一种方法,该方法包括施用本文所述的工程化T细胞群体。在一些实施例中,在施用5-10天后,该受试者的体重百分比在该受试者的初始体重的10%以内,其中该受试者的初始体重是施用时该受试者的体重。在一些实施例中,该受试者是人类受试者。在一些实施例中,该受试者患有癌症。该癌症可以表达,例如,LIV1。
本披露的其他方面提供了一种用于产生工程化T细胞的方法,该方法包括(a)向T细胞递送RNA引导性核酸酶(RNA-guided nuclease)、靶向TRAC基因的gRNA和包含供体模板的载体,该供体模板包含编码CAR的核酸,所述CAR包含特异结合LIV1的胞外结构域,其中编码该CAR的核酸的侧翼为TRAC基因的左和右同源臂,以及(b)产生工程化T细胞。在一些实施例中,该靶向TRAC基因的gRNA包含SEQ ID NO:18或19的核苷酸序列,或靶向SEQ ID NO:40的核苷酸序列。
在一些实施例中,该方法进一步包括向该T细胞递送靶向该β2M基因的gRNA。在一些实施例中,该靶向β2M基因的gRNA包含SEQ ID NO:20或21的核苷酸序列,或靶向SEQ IDNO:41的核苷酸序列。
在一些实施例中,该RNA引导性核酸酶是Cas9核酸酶,任选地是酿脓链球菌(S.pyogenes)Cas9核酸酶。
在一些实施例中,该供体模板包含SEQ ID NO:63、64、107或111中任一项的核苷酸序列。
在一些实施例中,该CAR包含SEQ ID NO:49、51、104或108中任一项的核苷酸序列。
附图说明
图1显示了用以评估在经编辑的细胞群体的细胞表面的TRAC、β2M和抗Liv1a CAR表达水平的流式细胞术结果。
图2A-2B显示,抗Liv1a CAR T细胞,特别是表达CTX971、CTX975和CTX976构建体的那些,表现出针对A498细胞系(图2A)和ZR-75-1细胞系(图2B)的高效细胞毒性。
图3A-3D显示了与靶细胞系A498和ZR-75-1共培养时抗Liv1a CAR T细胞的细胞因子分泌。图3A和3B显示了A498(图3A)和ZR-75-1(图3B)细胞系中的效应子细胞因子干扰素-γ(IFN-γ)的分泌。图3C和3D显示了A498细胞系(图3C)和ZR-75-1细胞系(图3D)中的效应子细胞因子白细胞介素-2(IL-2)的分泌。
图4显示了scFV构建体(VL和VH)的比对-971(SEQ ID NO:54);973(SEQ ID NO:82);975(SEQ ID NO:83);977(SEQ ID NO:84)
图5显示了scFV构建体(VH和VL)的比对-979(SEQ ID:70);974(SEQ ID NO:85);976(SEQ ID NO:86);978(SEQ ID NO:87),972(SEQ ID NO:127)
具体实施方式
LIV1癌症抗原
在一些实施例中,本披露的T细胞用设计用于靶向LIV1的嵌合抗原受体(CAR)进行工程化。LIV1也称为溶质载体家族39成员6、SLC39A6、ZIP6,并且LIV-1是高度保守的跨膜锌转运蛋白的Zip家族的成员。LIV1在乳腺癌(例如雌激素受体阳性乳腺癌)、前列腺癌、鳞状肿瘤(例如皮肤、膀胱、肺、子宫颈、子宫内膜、头颈和胆道鳞状肿瘤)、和神经元肿瘤中以升高的水平表达。值得注意的是,LIV1在正常组织(例如非癌性乳腺、前列腺和睾丸)中的表达受限。因此,LIV1是靶向癌症的理想跨膜蛋白。实际上,LIV-1蛋白质与乳腺癌、前列腺癌、鳞状肿瘤和神经元肿瘤相关。
因此,在一些实施例中,本披露的T细胞经工程化以表达包含抗LIV1抗体(例如,抗LIV1 scFv)的CAR。在一些实施例中,该抗LIV1抗体是由SEQ ID NO:53、69、97、102、106、110、114或118中任一项的序列编码的抗LIV1 scFv。在一些实施例中,该抗LIV1抗体是包含SEQ ID NO:54、70、82、83、84、85、86或87中任一项的序列的抗LIV1 scFv。在一些实施例中,该抗LIV1抗体是包含VH的抗LIV1 scFv,所述VH包含SEQ ID NO:55、90或98中任一项的氨基酸序列。在一些实施例中,该抗LIV1抗体是包含VL的抗LIV1 scFv,所述VL包含SEQ ID NO:56、88或128中任一项的氨基酸序列。在一些实施例中,包含抗LIV1抗体的CAR由SEQ ID NO:49、51、65、67、95、100、104、108、112或116中任一项的序列编码。在一些实施例中,包含抗LIV7抗体的CAR由包含如下核酸的序列编码,所述核酸与SEQ ID NO:49、51、65、67、95、100、104、108、112或116至少90%相同。在一些实施例中,包含抗LIV1抗体的CAR包含SEQ ID NO:49、51、65、67、95、100、104、108、112或116中任一项的序列。在一些实施例中,包含抗LIV1抗体的CAR包含如US 9,228,026中所述的抗LIV1抗体。
多基因编辑
在一些实施例中,本披露的工程化T细胞包括超过一个基因编辑,例如,在超过一个基因中。例如,工程化T细胞可包含被破坏的CD70基因、被破坏的T细胞受体α链恒定区(TRAC)基因、被破坏的β-2-微球蛋白(β2M)基因、被破坏的程序性细胞死亡-1(PD-1或PDCD1)基因、或两个或更多个前述被破坏的基因的任何组合。在一些实施例中,工程化T细胞包含被破坏的TRAC基因、被破坏的β2M基因和被破坏的CD70基因。在一些实施例中,工程化T细胞包含被破坏的TRAC基因、被破坏的β2M基因和被破坏的PD-1基因。在一些实施例中,工程化T细胞包含被破坏的TRAC基因、被破坏的β2M基因、被破坏的CD70基因和被破坏的PD-1基因。
应当理解,基因破坏包括通过基因编辑带来的基因修饰(例如,使用CRISPR/Cas基因编辑来插入或缺失一个或多个核苷酸)。在一些实施例中,被破坏的基因是不编码功能蛋白的基因。在一些实施例中,包含被破坏的基因的细胞不表达(例如,不在细胞表面表达)所述基因编码的可检测水平(例如,通过抗体,例如,通过流式细胞术)的蛋白质。不表达可检测水平的蛋白质的细胞可以称为敲除细胞。例如,如果使用特异性结合β2M蛋白的抗体在细胞表面不能检测到β2M蛋白,则具有β2M基因编辑的细胞可以认为是β2M敲除细胞。
在一些实施例中,本文提供了细胞群体,其中一定百分比的细胞已经被编辑(例如,β2M基因被编辑),导致一定百分比的细胞不表达特定的基因和/或蛋白质。在一些实施例中,经基因编辑的细胞群体的至少50%(例如,50%、55%、60%、65%、70%、75%、80%、85%、90%或85%)的细胞是β2M敲除细胞。在一些实施例中,群体的至少50%的细胞(例如,T细胞)不表达可检测水平的β2M蛋白。在一些实施例中,经基因编辑的细胞群体的至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%的细胞可以是β2M敲除细胞。
使用CRISPR-Cas基因编辑技术在细胞中产生基因组缺失(例如,以敲除细胞中的基因)的方法是已知的(Bauer DE等人Vis.Exp.[可视化实验]2015;95;e52118)。
TRAC基因编辑
在一些实施例中,工程化T细胞包含被破坏的TRAC基因。这种破坏导致TCR功能的丧失,并使工程化T细胞无同种异体反应性并适合于同种异体移植,从而最小化移植物抗宿主疾病的风险。在一些实施例中,消除内源性TRAC基因的表达以防止移植物抗宿主应答。在一些实施例中,通过将嵌合抗原受体(CAR)敲入TRAC基因(例如,使用腺相关病毒(AAV)载体和供体模板)来产生TRAC基因表达的破坏。在一些实施例中,通过靶向TRAC基因组区域的gRNA产生TRAC基因表达的破坏。在一些实施例中,通过将嵌合抗原受体(CAR)敲入TRAC基因(例如,使用AAV载体和供体模板)来产生TRAC基因的基因组缺失。在一些实施例中,利用靶向TRAC基因组区域的gRNA,并将嵌合抗原受体(CAR)敲入TRAC基因,来产生TRAC基因表达的破坏。
可以如本文所提供用于在TRAC基因中产生基因组破坏的经修饰和未修饰的TRACgRNA序列的非限制性实例列在表4中(例如,SEQ ID NO:18和19)。还参见2018年5月11日提交的国际申请号PCT/US2018/032334,其通过引用并入本文。可以使用位于第14号染色体上的TRAC基因序列(GRCh38:第14号染色体:22,547,506-22,552,154;Ensembl;ENSG00000277734)设计其他gRNA序列。在一些实施例中,靶向TRAC基因组区域的gRNA在TRAC基因中产生插缺(indel),破坏mRNA或蛋白质的表达。
在一些实施例中,至少50%的工程化T细胞群体不表达可检测水平的T细胞受体(TCR)表面蛋白。例如,群体的至少55%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%可能不表达可检测水平的TCR表面蛋白。在一些实施例中,工程化T细胞群体的50%-100%、50%-90%、50%-80%、50%-70%、50%-60%、60%-100%、60%-90%、60%-80%、60%-70%、70%-100%、70%-90%、70%-80%、80%-100%、80%-90%或90%-100%不表达可检测水平的TCR表面蛋白。
在一些实施例中,靶向TRAC基因组区域的gRNA在TRAC基因中产生插缺,所述TRAC基因包含选自表1中的以下序列的至少一个核苷酸序列:
表1.
在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中15-30个碱基对的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含在TRAC中基因中15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个碱基对的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中超过30个碱基对的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中20个碱基对的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中SEQ ID NO:92(AGAGCAACAGTGCTGTGGCC)的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中包含SEQ IDNO:92(AGAGCAACAGTGCTGTGGCC)的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中SEQ ID NO:40的缺失。在一些实施例中,相对于未修饰的T细胞,工程化T细胞包含TRAC基因中包含SEQ ID NO:40的缺失。
β2M基因编辑
在一些实施例中,工程化T细胞包含被破坏的β2M基因。β2M是MHC I复合物的常见(不变)组分。通过基因编辑破坏其表达将阻止宿主抗治疗性同种异体T细胞应答,从而导致同种异体T细胞持久性增加。在一些实施例中,消除内源性β2M基因的表达以防止移植物抗宿主应答。
可以如本文所提供用于在β2M基因中产生基因组破坏的经修饰和未修饰的β2MgRNA序列的非限制性实例列经修饰和未修饰的β2M gRNA序列的非限制性实例在表4中列出(例如,SEQ ID NO:20和21)。还参见2018年5月11日提交的国际申请号PCT/US2018/032334,其通过引用并入本文。可以使用位于第15号染色体上的β2M基因序列(GRCh38坐标:染色体15:44,711,477-44,718,877;Ensembl:ENSG00000166710)设计其他gRNA序列。
在一些实施例中,靶向β2M基因组区域的gRNA在β2M基因中产生插缺,破坏mRNA或蛋白质的表达。
在一些实施例中,工程化T细胞群体的至少50%的工程化T细胞不表达可检测水平的β2M表面蛋白。例如,群体的至少55%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%的工程化T细胞可能不表达可检测水平的β2M表面蛋白。在一些实施例中,群体的50%-100%、50%-90%、50%-80%、50%-70%、50%-60%、60%-100%、60%-90%、60%-80%、60%-70%、70%-100%、70%-90%、70%-80%、80%-100%、80%-90%或90%-100%的工程化T细胞不表达可检测水平的β2M表面蛋白。
在一些实施例中,经编辑的β2M基因包含选自以下表2中序列的至少一个核苷酸序列。
表2.
PD-1基因编辑
PD-1是在激活的T细胞中上调并用来抑制或终止T细胞应答的免疫检查点分子。通过基因编辑破坏PD-1可以导致受试者更持久和/或高效的治疗性T细胞应答和/或减少免疫抑制。在一些实施例中,工程化T细胞包含被破坏的PD-1基因。在一些实施例中,消除内源性PD-1基因的表达以增强本披露的CAR T细胞的抗肿瘤功效。
可以如本文所提供用于在PD-1基因中产生基因组缺失的经修饰和未修饰的PD-1gRNA序列的非限制性实例列在表4中(例如,SEQ ID NO:22和23)。还参见2018年5月11日提交的国际申请号PCT/US2018/032334,其通过引用并入本文。可以使用位于第2号染色体上的PD-1基因序列(GRCh38坐标:染色体2:241,849,881-241,858,908;Ensembl:ENSG00000188389)设计其他gRNA序列。
在一些实施例中,靶向PD-1基因组区域的gRNA在PD-1基因中产生插缺,破坏PD-1mRNA或蛋白质的表达。
在一些实施例中,工程化T细胞包含被破坏的PD-1基因。在一些实施例中,工程化T细胞群体的至少50%的工程化T细胞不表达可检测水平的PD-1表面蛋白。例如,群体的至少55%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%的工程化T细胞可能不表达可检测水平的PD-1表面蛋白。在一些实施例中,群体的50%-100%、50%-90%、50%-80%、50%-70%、50%-60%、60%-100%、60%-90%、60%-80%、60%-70%、70%-100%、70%-90%、70%-80%、80%-100%、80%-90%或90%-100%的工程化T细胞不表达可检测水平的PD-1表面蛋白。
CD70基因编辑
分化簇70(CD70)是肿瘤坏死因子超家族的成员,并且其表达限于激活的T和B淋巴细胞以及成熟的树突状细胞。还已经在血液肿瘤和癌上检测到CD70。CD70通过与其配体CD27相互作用而参与肿瘤细胞和调节性T细胞的存活。通过基因编辑破坏CD70可增加细胞的扩增并减少细胞的衰竭。在一些实施例中,工程化T细胞包含被破坏的CD70基因。在一些实施例中,消除内源性CD70基因的表达以增强本披露的CAR T细胞的抗肿瘤功效。在一些实施例中,靶向CD70基因组区域的gRNA在CD70基因中或周围产生插缺,破坏CD70 mRNA和/或蛋白质的表达。
可以如本文所提供用于在CD70基因中产生基因组破坏的经修饰和未修饰的CD70gRNA序列的非限制性实例列在表4中(例如,SEQ ID NO:24-27)。可以使用位于第19号染色体上的CD70基因序列(GRCh38坐标:染色体19:6,583,183-6,604,103;Ensembl:ENSG00000125726)设计其他gRNA序列。
在一些实施例中,工程化T细胞包含被破坏的CD70基因。在一些实施例中,工程化T细胞群体的至少50%的工程化T细胞不表达可检测水平的CD70表面蛋白。例如,群体的至少55%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%的工程化T细胞可能不表达可检测水平的CD70表面蛋白。在一些实施例中,群体的50%-100%、50%-90%、50%-80%、50%-70%、50%-60%、60%-100%、60%-90%、60%-80%、60%-70%、70%-100%、70%-90%、70%-80%、80%-100%、80%-90%或90%-100%的工程化T细胞不表达可检测水平的CD70表面蛋白。
细胞表型
在一些实施例中,细胞群体内的一个或多个基因编辑导致如下表型,所述表型与细胞增殖能力、细胞耗尽、细胞生存力、细胞裂解能力(例如,增加细胞因子产生和/或释放)或它们的任何组合的改变关联。
在一些实施例中,相对于对照T细胞,本披露的工程化T细胞表现出至少20%更大的细胞增殖能力。例如,相对于对照细胞,工程化T细胞可以表现出至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%或至少90%更大的细胞增殖能力。在一些实施例中,相对于对照T细胞,本披露的工程化T细胞表现出20%-100%、20%-90%、20%-80%、20%-70%、20%-60%、20%-50%、30%-100%、30%-90%、30%-80%、30%-70%、30%-60%、30%-50%、40%-100%、40%-90%、40%-80%、40%-70%、40%-60%、40%-50%、50%-100%、50%-90%、50%-80%、50%-70%或50%-60%更大的细胞增殖能力。
在一些实施例中,相对于对照细胞,本披露的工程化T细胞表现出细胞生存力增加至少20%。例如,相对于对照细胞,本披露的工程化T细胞的细胞生存力可表现出增加至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%或至少90%。在一些实施例中,相对于对照细胞,本披露的工程化T细胞的细胞生存力表现出增加20%-100%、20%-90%、20%-80%、20%-70%、20%-60%、20%-50%、30%-100%、30%-90%、30%-80%、30%-70%、30%-60%、30%-50%、40%-100%、40%-90%、40%-80%、40%-70%、40%-60%、40%-50%、50%-100%、50%-90%、50%-80%、50%-70%或50%-60%。
在一些实施例中,相对于对照细胞,本披露的工程化T细胞表现出细胞裂解能力增加至少20%(多杀伤至少20%的靶细胞)。例如,相对于对照细胞,本披露的工程化T细胞的细胞裂解能力可表现出增加至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%或至少90%。在一些实施例中,相对于对照细胞,本披露的工程化T细胞的细胞裂解能力表现出增加20%-100%、20%-90%、20%-80%、20%-70%、20%-60%、20%-50%、30%-100%、30%-90%、30%-80%、30%-70%、30%-60%、30%-50%、40%-100%、40%-90%、40%-80%、40%-70%、40%-60%、40%-50%、50%-100%、50%-90%、50%-80%、50%-70%或50%-60%。例如,工程化T细胞分泌的细胞因子(例如,IL-2和/或IFN-γ)的水平是对照T细胞分泌的细胞因子水平的至少2倍(例如,至少3倍、至少4倍或至少5倍)。
在一些实施例中,对照T细胞是工程化T细胞(例如,经基因编辑的T细胞)。在一些实施例中,对照T细胞是工程化T细胞,其包含被破坏的TRAC基因,插入到TRAC基因中的编码CAR的核酸(例如抗LIV1 CAR)和/或被破坏的β2M基因。在一些实施例中,对照T细胞是未经编辑的T细胞。
基因编辑方法
基因编辑(包括基因组编辑)是基因工程的一种类型,其中在DNA序列中,例如在靶细胞的基因组中插入、缺失和/或取代一个或多个核苷酸/一个或多个核酸。靶向基因编辑使得能够在靶细胞的基因组中的预选位点(例如,在靶基因或靶DNA序列中)实现插入、缺失和/或取代。当例如通过一个或多个核苷酸/一个或多个核酸的缺失、插入或取代来编辑内源基因的序列时,包含受影响序列的内源基因可能由于序列修饰而被敲除或敲低。因此,靶向编辑可用于破坏内源基因表达。“靶向整合”是指涉及在插入位点缺失或不缺失内源序列情况下,一个或多个外源序列的插入的过程。当存在包含外源序列的供体模板时,靶向整合可以由靶向基因编辑产生。
靶向编辑可以通过不依赖核酸酶的方法或依赖于核酸酶的方法来实现。在不依赖核酸酶的靶向编辑方法中,同源重组是由在外源多核苷酸侧翼的同源序列进行指导,所述外源多核苷酸通过宿主细胞的酶促机制引入内源序列中。外源多核苷酸可以在内源序列中引入核苷酸的缺失、插入或替换。
可替代地,依赖于核酸酶的方法可以通过特异性稀有切割核酸酶(例如,内切核酸酶)特异性引入双链断裂(DSB)来实现更高频率的靶向编辑。这种依赖核酸酶的靶向编辑还利用DNA修复机制,例如非同源末端连接(NHEJ),它响应于DSB而发生。NHEJ修复DNA通常会导致少量内源核苷酸的随机插入或缺失(插缺)。与NHEJ介导的修复相比,修复也可以通过同源定向修复(HDR)进行。当存在包含侧翼是一对同源臂的外源遗传物质的供体模板时,可通过HDR将外源遗传物质引入基因组,这导致外源遗传物质的靶向整合。
能够引入特异性和靶向DSB的可用内切核酸酶包括但不限于锌指核酸酶(ZFN)、转录激活子样效应子核酸酶(TALEN)和RNA指导的CRISPR-Cas9核酸酶(CRISPR/Cas9;聚簇规则间隔短回文重复序列相关9)。另外,利用phiC31和Bxb1整合酶的DICE(双整合酶盒交换)系统也可以用于靶向整合。
ZFN是靶向核酸酶,包含与锌指DNA结合结构域(ZFBD)融合的核酸酶,ZFBD是通过一个或多个锌指以序列特异性方式结合DNA的多肽结构域。锌指是锌指结合结构域内约30个氨基酸的结构域,其结构通过锌离子的配位稳定。锌指的实例包括但不限于C2H2锌指、C3H锌指和C4锌指。设计的锌指结构域是自然界中不存在的结构域,其设计/组成主要来自于合理的标准,例如,取代规则和用于在存储现有ZFP设计信息和结合数据的数据库中处理信息的计算机算法的应用。参见例如美国专利号6,140,081;6,453,242;和6,534,261;另参见WO 98/53058;WO 98/53059;WO 98/53060;WO 02/016536和WO 03/016496。选择的锌指结构域是在自然界中找不到的结构域,其产生主要来自经验过程,例如噬菌体展示、相互作用陷阱或杂交选择。ZFNs在美国专利号7,888,121和美国专利号7,972,854中更详细描述。ZFN的最广为人知的实例是FokI核酸酶与锌指DNA结合结构域的融合物。
TALEN是靶向核酸酶,其包含与TAL效应子DNA结合结构域融合的核酸酶。“转录激活子样效应子DNA结合结构域”、“TAL效应子DNA结合结构域”或“TALE DNA结合结构域”是TAL效应子蛋白的多肽结构域,其负责TAL效应子蛋白与DNA的结合。TAL效应子蛋白由黄杆菌属(Xanthomonas)的植物病原体在感染期间分泌。这些蛋白质进入植物细胞的核,通过其DNA结合结构域结合效应子特异性DNA序列,并通过其反式激活结构域激活这些序列上的基因转录。TAL效应子DNA结合结构域特异性取决于不完全的34个氨基酸重复的效应子可变数目,其在选择的称为重复可变二残基(RVD)的重复位置处包含多态性。在美国专利申请号2011/0145940中更详细地描述了TALEN。在本领域中最公认的TALEN实例是FokI核酸酶与TAL效应DNA结合结构域的融合多肽。
适用于如本文提供的用途的靶向核酸酶的其他实例包括但不限于Bxb1、phiC31、R4、PhiBT1和Wβ/SPBc/TP901-1,无论是单独使用还是组合使用。
靶向核酸酶的其他非限制性实例包括天然存在的核酸酶和重组核酸酶,例如CRISPR/Cas9、限制性内切核酸酶、大范围核酸酶归巢内切核酸酶等。CRISPR-Cas9基因编辑
CRISPR-Cas9系统是原核生物中天然存在的防御机制,其已被重新用作用于基因编辑的RNA指导的DNA靶向平台。它依赖于DNA核酸酶Cas9和两个非编码RNA(crisprRNA(crRNA)和反式激活RNA(tracrRNA))来靶向DNA的切割。
crRNA通过典型地与靶DNA中的20个核苷酸(nt)序列的沃森-克里克碱基配对来驱动CRISPR-Cas9复合物的序列识别和特异性。改变crRNA中5’20nt的序列可将CRISPR-Cas9复合物靶向特定基因座。如果靶序列后面是特定的短DNA序列(序列为NGG)作为原型间隔子相邻基序(PAM),CRISPR-Cas9复合物仅结合包含与crRNA的前20nt序列匹配的DNA序列,即单指导RNA(sgRNA)。
TracrRNA与crRNA的3’末端杂交形成RNA双链体结构,所述双链体结构与Cas9内切核酸酶结合形成催化活性的CRISPR-Cas9复合物,其然后可以切割靶DNA。
一旦CRISPR-Cas9复合物在靶位点与DNA结合,Cas9酶内的两个独立的核酸酶结构域各自切割PAM位点上游的DNA链之一,从而留下双链断裂(DSB),在这里DNA的两条链以碱基对(平末端)终止。
CRISPR-Cas9复合物在特定靶位点处与DNA结合并形成位点特异性DSB之后,下一个关键步骤是修复DSB。细胞使用两种主要的DNA修复途径来修复DSB:非同源末端连接(NHEJ)和同源定向修复(HDR)。
NHEJ是一种稳健的修复机制,在包括非分裂细胞在内的大多数细胞类型中显现出高活性。NHEJ容易出错,并且通常会在DSB的位点导致在一个到几百个核苷酸之间的去除或添加,尽管此类修饰典型地<20nt。产生的插入和缺失(插缺)可以破坏基因的编码或非编码区域。可替代地,HDR使用内源性或外源性提供的长段同源供体DNA来以高保真度修复DSB。HDR仅在分裂的细胞中有效,并且在大多数细胞类型中以相对较低的频率发生。在本披露的许多实施例中,NHEJ被作为自发的修复来利用。
在一些实施例中,尽管可以使用其他Cas9同源物,但是Cas9(CRISPR相关蛋白9)内切核酸酶来自酿脓链球菌。应当理解,如本文所提供的,可以使用野生型Cas9或可以使用Cas9的修饰版本(例如,Cas9的进化版本,或Cas9直向同源物或变体)。在一些实施例中,Cas9可以被另一种RNA指导的内切核酸酶诸如(II类CRISPR/Cas系统的)Cpf1取代。
指导RNA
本披露提供了靶向基因组的核酸,该靶向基因组的核酸可以将相关多肽(例如,定点多肽)的活性引导至靶核酸内的特定靶序列。靶向基因组的核酸可以是RNA。靶向基因组的RNA在本文中称为“指导RNA”或“gRNA”。指导RNA包含与目的靶核酸序列杂交的至少一个间隔子序列、和CRISPR重复序列。在II型系统中,gRNA还包含称为tracrRNA序列的第二RNA。在II型指导RNA(gRNA)中,CRISPR重复序列和tracrRNA序列彼此杂交形成双链体。在V型指导RNA(gRNA)中,crRNA形成双链体。在这两个系统中,双链体都结合定点多肽,使得指导RNA和定点多肽形成复合物。在一些实施例中,靶向基因组的核酸由于其与定点多肽的缔合而为复合物提供了靶特异性。因此,靶向基因组的核酸指导定点多肽的活性。
如本领域普通技术人员所理解的,每个指导RNA设计为包括与其基因组靶序列互补的间隔子序列。参见Jinek等人,Science[科学],337,816-821(2012)和Deltcheva等人,Nature[自然],471,602-607(2011)。
在一些实施例中,靶向基因组的核酸是双分子指导RNA。在一些实施例中,靶向基因组的核酸是单分子指导RNA。
双分子指导RNA包含两条链的RNA。第一条链在5'至3'方向上包含任选的间隔子延伸序列、间隔子序列和最小CRISPR重复序列。第二条链包含最小tracrRNA序列(与最小CRISPR重复序列互补)、3’tracrRNA序列和任选的tracrRNA延伸序列。
II型系统中的单分子指导RNA(sgRNA)在5'至3'方向上包含任选的间隔子延伸序列、间隔子序列、最小CRISPR重复序列、单分子指导接头、最小tracrRNA序列、3’tracrRNA序列和任选的tracrRNA延伸序列。任选的tracrRNA延伸序列可以包含为指导RNA贡献另外的功能(例如,稳定性)的元件。单分子向导接头将最小CRISPR重复序列和最小tracrRNA序列连接起来以形成发夹结构。任选的tracrRNA延伸包括一个或多个发夹。
V型系统中的单分子指导RNA(称为“sgRNA”或“gRNA”)在5'至3'方向上包含最小CRISPR重复序列和间隔子序列。
sgRNA可以在sgRNA序列的5'端包含20个核苷酸的间隔子序列。sgRNA可以在sgRNA序列的5’端包含少于20个核苷酸的间隔子序列。sgRNA可以在sgRNA序列的5’端包含超过20个核苷酸的间隔子序列。sgRNA可以在sgRNA序列的5’端包含17-30个核苷酸的可变长度的间隔子序列(参见表3)。
sgRNA可以在sgRNA序列的3’端不包含尿嘧啶。sgRNA可以在sgRNA序列的3’端包含一个或多个尿嘧啶。例如,sgRNA可以在sgRNA序列的3’端包含1个尿嘧啶(U)。sgRNA可以在sgRNA序列的3’端包含2个尿嘧啶(UU)。sgRNA可以在sgRNA序列的3'端包含3个尿嘧啶(UUU)。sgRNA可以在sgRNA序列的3'端包含4个尿嘧啶(UUUU)。sgRNA可以在sgRNA序列的3’端包含5个尿嘧啶(UUUUU)。sgRNA可以在sgRNA序列的3’端包含6个尿嘧啶(UUUUUU)。sgRNA可以在sgRNA序列的3'端包含7个尿嘧啶(UUUUUUU)。sgRNA可以在sgRNA序列的3'端包含8个尿嘧啶(UUUUUUUU)。
sgRNA可以是未经修饰的或经修饰的。例如,经修饰的sgRNA可以包含一个或多个2'-O-甲基硫代磷酸酯核苷酸。
表3.
举例说明,用于CRISPR/Cas/Cpf1系统中的指导RNA或其他较小的RNA可以通过化学方法容易地合成,如下文所示和本领域所述。随着化学合成程序的不断发展,通过诸如高效液相色谱法(HPLC,其避免使用诸如PAGE等凝胶)等程序纯化此类RNA随着多核苷酸长度显著增加超过约一百个核苷酸而趋于更具挑战性。用于产生更大长度的RNA的一种方法是产生两个或更多个连接在一起的分子。更长的RNA(诸如编码Cas9或Cpf1内切核酸酶的那些)更容易酶促产生。如本领域所述,可以在RNA的化学合成和/或酶促生成期间或之后引入多种类型的RNA修饰,例如,增强稳定性、降低先天免疫应答的可能性或程度、和/或增强其他属性的修饰。
间隔子序列
gRNA包含间隔子序列。间隔子序列是定义目的靶核酸的靶序列(例如,DNA靶序列,如基因组靶序列)的序列(例如,20个核苷酸的序列)。在一些实施例中,间隔子序列是15至30个核苷酸。在一些实施例中,间隔子序列是15、16、17、18、19、29、21、22、23、24、25、26、27、28、29或30个核苷酸。在一些实施例中,间隔子序列是20个核苷酸。
“靶序列”与PAM序列相邻并且是通过RNA引导性核酸酶(例如,Cas9)修饰的序列。“靶核酸”是双链分子:一条链包含靶序列并且被称为“PAM链”,并且另一条互补链被称为“非PAM链”。本领域技术人员认识到,gRNA间隔子序列与位于目的靶核酸的非PAM链中的、靶序列的反向互补序列杂交。因此,gRNA间隔子序列是靶序列的RNA等同物。例如,如果靶序列是5’-AGAGCAACAGTGCTGTGGCC-3’(SEQ ID NO:92),则gRNA间隔子序列是5’-AGAGCAACAGUGCUGUGGCC-3’(SEQ ID NO:93)。gRNA的间隔子经由杂交(即,碱基配对)以序列特异性方式与目的靶核酸相互作用。因此,间隔子的核苷酸序列根据目的靶核酸的靶序列而变化。
在本文的CRISPR/Cas系统中,将间隔子序列设计成与靶核酸的区域杂交,该区域位于该系统中使用的Cas9酶的PAM的5'。间隔子可以与靶序列完全匹配或可以有错配。每个Cas9酶都有特定的PAM序列,使得该酶识别靶DNA。例如,酿脓链球菌识别靶核酸中的包含序列5'-NRG-3'的PAM,其中R包含A或G,其中N是任何核苷酸并且N紧邻由间隔子序列靶向的靶核酸序列的3'。
在一些实施例中,靶核酸序列包含20个核苷酸。在一些实施例中,靶核酸包含小于20个核苷酸。在一些实施例中,靶核酸包含超过20个核苷酸。在一些实施例中,靶核酸包含至少:5、10、15、16、17、18、19、20、21、22、23、24、25、30个或更多个核苷酸。在一些实施例中,靶核酸包含至多:5、10、15、16、17、18、19、20、21、22、23、24、25、30个或更多个核苷酸。在一些实施例中,靶核酸序列包含紧邻PAM的第一核苷酸的5'的20个碱基。例如,在包含5'-NNNNNNNNNNNNNNNNNNNNNRG-3'(SEQ ID NO:130)的序列中,靶核酸包含对应于多个N的序列,其中N是任何核苷酸,并且该加下划线的NRG序列是酿脓链球菌PAM。
表4和2018年5月11日提交的PCT/US2018/032334提供了可按本文所述使用的gRNA的非限制性实例。
表4.gRNA序列/靶序列
*:2'-O-甲基硫代磷酸酯残基
嵌合抗原受体(CAR)T细胞
嵌合抗原受体是指人工免疫细胞受体,所述受体经工程化以识别并结合由肿瘤细胞表达的抗原。通常,CAR是为T细胞设计的,并且是T细胞受体(TCR)复合物的信号传导结构域与抗原识别结构域(例如,抗体的单链片段(scFv)或其他抗体片段)的嵌合体(Enblad等人,Human Gene Therapy[人类基因疗法].2015;26(8):498-505)。表达CAR的T细胞被称为CAR T细胞。CAR具有以非MHC限制的方式将T细胞特异性和反应性重定向至所选靶标的能力。非MHC限制性抗原识别赋予表达CAR的T细胞识别独立于抗原加工的抗原的能力,从而绕开了肿瘤逃逸的主要机制。此外,当在T细胞中表达时,CAR不会有利地与内源性T细胞受体(TCR)α和β链二聚。
有四代CAR,每代CAR含有不同组分。第一代CAR通过铰链结构域和跨膜结构域将抗体衍生的scFv与T细胞受体的CD3ζ(ζ或z)细胞内信号传导结构域连接。第二代CAR掺入了另外的结构域(例如CD28、4-1BB(41BB)或ICOS)以提供共刺激信号。第三代CAR含有两个与TCRCD3ζ链融合的共刺激结构域(costim.)。第三代共刺激结构域可以包括例如CD3ζ、CD27、CD28、4-1BB、ICOS或OX40的组合。在一些实施例中,CAR含有通常衍生自单链可变片段(scFv)、铰链的胞外结构域,跨膜结构域,以及具有一个(第一代)、两个(第二代)或三个(第三代)衍生自CD3Z和/或共刺激分子的信号传导结构域的胞内结构域(例如,CD3ζ)(Maude等人,Blood.[血液]2015;125(26):4017-4023;Kakarla和Gottschalk,Cancer J.[癌症杂志]2014;20(2):151-155)。
CAR通常在功能特性上有所不同。T细胞受体的CD3ζ信号传导结构域(在参与时)会激活并诱导T细胞增殖,但可能导致无反应性(机体防御机制缺少反应,导致直接诱导外周淋巴细胞耐受性)。当淋巴细胞对特定抗原无反应时,它们被认为是无反应的。在第二代CAR中增加共刺激结构域改善了经修饰的T细胞的复制能力和持久性。用CD28或4-1BB CAR在体外观察到相似的抗肿瘤作用,但临床前体内研究表明4-1BB CAR可以产生优异的增殖和/或持久性。临床试验表明,这两种第二代CAR都能够在体内诱导大量T细胞增殖,但是含有4-1BB共刺激结构域的CAR显现可以持续更长的时间。第三代CAR组合了多个信号传导结构域(共刺激)以增强效能。
在一些实施例中,嵌合抗原受体是第一代CAR。在其他实施例中,嵌合抗原受体是第二代CAR。在还其他实施例中,嵌合抗原受体是第三代CAR。
在一些实施例中,CAR包含含有抗原结合结构域(例如抗体,如scFv)的细胞外(胞外)结构域、跨膜结构域、和细胞质(胞内)结构域。
胞外结构域.胞外结构域是CAR的暴露于细胞外液的区域,并且在一些实施例中,CAR包括抗原结合结构域,以及任选地信号肽、间隔子结构域、和/或铰链结构域。在一些实施例中,抗原结合结构域是单链可变片段(scFv),其包括与短接头肽连接的免疫球蛋白的轻链和重链。在一些实施例中,接头包括亲水性残基,即,多段甘氨酸和丝氨酸用于柔性,以及多段谷氨酸和赖氨酸用于增加溶解度。单链可变片段(scFv)实际上不是抗体的片段,而是免疫球蛋白的重链(VH)和轻链(VL)的可变区的融合蛋白,该融合蛋白与十到约25个氨基酸的短链接头肽连接。接头通常富含甘氨酸用于柔性、以及丝氨酸或苏氨酸用于溶解度,并且可以将VH的N-末端与VL的C-末端相连,反之亦然。尽管去除了恒定区并引入了接头,但此蛋白仍保留了原始免疫球蛋白的特异性。可用于产生抗LIV1 scFv的VH和VL蛋白序列的非限制性实例可包括SEQ ID NO:55、90或98(VH)和SEQ ID NO:56、88或128(VL)的氨基酸序列。在一些实施例中,本披露的scFv是人源化的。在其他实施例中,scFv是完全人类的。在还其他实施例中,scFv是嵌合体(例如,小鼠和人序列的嵌合体)。在一些实施例中,scFv是抗LIV1scFv(特异性结合LIV1)。可以如本文提供而使用的抗LIV1 scFv蛋白的非限制性实例可以包括SEQ ID NO:54、70、82、83、84、85、86或87中任一项的氨基酸序列。可以使用其他scFv蛋白。
信号肽可以增强CAR结合的抗原特异性。信号肽可衍生自抗体(如但不限于CD8)、以及表位标签(如但不限于GST或FLAG)。信号肽的实例包括MLLLVTSLLLCELPHPAFLLIP(SEQID NO:94)和MALPVTALLLPLALLLHAARP(SEQ ID NO:73)。可以使用其他信号肽。
在一些实施例中,间隔子结构域或铰链结构域位于CAR的胞外结构域(包含抗原结合结构域)与跨膜结构域之间或者CAR的胞质结构域与跨膜结构域之间。间隔子结构域是起到将跨膜结构域连接至多肽链中的胞外结构域和/或胞质结构域的功能的任何寡肽或多肽。铰链结构域是起到向CAR或其结构域提供柔性或防止CAR或其结构域的空间位阻的作用的任何寡肽或多肽。在一些实施例中,间隔子结构域或铰链结构域可以包含多达300个氨基酸(例如,10至100个氨基酸或5至20个氨基酸)。在一些实施例中,一个或多个间隔子结构域可以包括在CAR的其他区域中。在一些实施例中,铰链结构域是CD8铰链结构域。可以使用其他铰链结构域。
跨膜结构域.跨膜结构域是跨过膜的疏水性α螺旋。跨膜结构域提供了CAR的稳定性。在一些实施例中,如本文提供的CAR的跨膜结构域是CD8跨膜结构域。在其他实施例中,跨膜结构域是CD28跨膜结构域。在还其他实施例中,跨膜结构域是CD8和CD28跨膜结构域的嵌合体。如本文提供的,可以使用其他跨膜结构域。在一些实施例中,跨膜结构域是CD8a跨膜结构域:FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGG AVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNR(SEQ ID NO:129)。可以使用其他跨膜结构域。
胞内结构域.胞内结构域是受体的功能端。抗原识别后,受体聚簇,并且信号被传递到细胞。最常用的胞内结构域组分是CD3-ζ,该组件含有三(3)个基于免疫受体酪氨酸的激活基序(ITAM)。这会在抗原结合后向T细胞传递激活信号。在许多情况下,CD3-ζ可能无法提供完全有效的激活信号,因此,使用了共刺激信号传导。例如,CD28和/或4-1BB可以与CD3-ζ(CD3ζ)一起使用,以传递增殖/存活信号。因此,在一些实施例中,如本文提供的CAR的共刺激分子是CD28共刺激分子。在其他实施例中,共刺激分子是4-1BB共刺激分子。在一些实施例中,CAR包括CD3ζ和CD28。在其他实施例中,CAR包括CD3-ζ和4-1BB。在仍其他实施例中,CAR包括CD3ζ、CD28、和4-1BB。表5提供了可以如本文所述使用的信号传导分子的实例。
表5
抗体
抗体(以多种形式可互换使用)是一种免疫球蛋白分子,能够通过位于免疫球蛋白分子可变区中的至少一个抗原识别位点特异性结合至靶,例如碳水化合物、多核苷酸、脂质、多肽等。如本文所用,术语“抗体”不仅包括完整的(即,全长)单克隆抗体,还包括抗原结合片段(例如Fab、Fab'、F(ab')2、Fv)、单链可变片段(scFv)、其突变体,包含抗体部分的融合蛋白、人源化抗体、嵌合抗体、双抗体、线性抗体、单链抗体、单结构域抗体(例如,骆驼或美洲驼VHH抗体)、多特异性抗体(例如,双特异性抗体)和包含所需特异性抗原识别位点的免疫球蛋白分子的任何其他经修饰的构型(包括抗体的糖基化变体、抗体的氨基酸序列变体和共价修饰的抗体)。
典型的抗体分子包含通常与抗原结合有关的重链可变区(VH)和轻链可变区(VL)。这些负责抗原结合的区域/残基可以使用本领域已知方法,从参考抗体(例如本文所述的抗LIV1抗体)的VH/VL序列的氨基酸序列来鉴定。VH和VL区可以进一步细分为超变区(称为“互补决定区”(“CDR”)),穿插更保守区(称为“框架区”(“FR”))。每个VH和VL典型地由三个CDR和四个FR构成,以下列顺序从氨基末端到羧基末端排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。可以使用本领域已知的方法,例如通过Kabat定义、Chothia定义、AbM定义和/或接触定义(所有这些在本领域中是众所周知的)来精确地鉴定框架区和CDR的程度。如本文所用,CDR可指通过本领域已知的任何方法定义的CDR。两种具有相同CDR的抗体是指两种抗体具有通过相同方法测定的该CDR的相同氨基酸序列。参见,例如,Kabat,E.A.等人,(1991)Sequences of Proteins of Immunological Interest[具有免疫学意义的蛋白质序列],第五版,美国卫生与公众服务部,NIH公开号91-3242,Chothia等人,(1989)Nature[自然]342:877;Chothia,C.等人,(1987)J.Mol.Biol.[分子生物学杂志]196:901-917;Al-lazikani等人,(1997)J.Molec.Biol.[分子生物学杂志]273:927-948;以及Almagro,J.Mol.Recognit.[分子识别杂志]17:132-143(2004)。另请参见hgmp.mrc.ac.uk和bioinf.org.uk/abs。
在一些实施例中,抗体是scFv,如抗LIV1 scFv。抗体包括任何类别的抗体,例如IgD、IgE、IgG、IgA或IgM(或其亚类),并且抗体不必是任何特定类别。根据免疫球蛋白重链的恒定结构域的抗体氨基酸序列,免疫球蛋白可分为不同类别。免疫球蛋白有五个主要的类别:IgA、IgD、IgE、IgG和IgM,并且其中一些可以进一步分为亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别的免疫球蛋白的重链恒定结构域分别被称为α、δ、ε、γ和μ。不同类别的免疫球蛋白的亚单元结构和三维构型是熟知的。
本文所用的抗体可以是鼠、大鼠、人或任何其他来源的抗体(包括嵌合或人源化抗体)。在一些实例中,抗体包含经修饰的恒定区,例如免疫学上惰性的恒定区,例如,不触发补体介导的裂解或不刺激抗体依赖性细胞介导的细胞毒性(ADCC)。
在一些实施例中,本披露的抗体是人源化抗体。人源化抗体是指非人(例如,鼠)抗体的形式,其是特异性嵌合免疫球蛋白、免疫球蛋白链或其抗原结合片段(所述片段包含衍生自非人免疫球蛋白的最小序列)。在大多数情况下,人源化抗体是人免疫球蛋白(受体抗体),其中来自接受体互补决定区(CDR)的残基被来自非人物种(例如小鼠、大鼠、兔)(供体抗体)的具有希望的特异性、亲和力和能力的CDR残基替换。在一些情况下,人免疫球蛋白的Fv框架区(FR)残基被相应的非人残基替换。此外,人源化抗体可包含在接受体抗体或导入的CDR或框架序列中均未发现的残基,但被包含在内以进一步完善和优化抗体性能。总体上,人源化抗体将包括至少一个、并且典型地两个可变结构域中的基本上全部,其中全部或基本上全部的CDR区相应于非人免疫球蛋白的那些,并且全部或基本上全部的FR区是人免疫球蛋白共有序列的那些。人源化抗体还任选地包括免疫球蛋白恒定区或结构域(Fc)的至少一部分,典型地是人免疫球蛋白的至少一部分。其他形式的人源化抗体具有相对于原始抗体改变的一个或多个CDR(一个、两个、三个、四个、五个、六个),也称为一个或多个CDR“衍生自”来自原始抗体的一个或多个CDR。人源化抗体也可涉及亲和力成熟。
在一些实施例中,本披露的抗体是嵌合抗体,其可以包括来自人抗体的重恒定区和轻恒定区。嵌合抗体是指具有来自第一物种的可变区或可变区的一部分以及来自第二物种的恒定区的抗体。典型地,在这些嵌合抗体中,轻链和重链的可变区都模拟衍生自一个哺乳动物物种(例如,非人哺乳动物(例如小鼠、兔和大鼠))的抗体的可变区,而恒定部分与衍生自另一种哺乳动物(例如,人)的抗体中的序列同源。在一些实施例中,可以在可变区和/或恒定区中进行氨基酸修饰。
在一些实施例中,本披露的抗体特异性结合靶抗原,例如人LIV1。“特异性结合”(在本文可互换使用)靶或表位的抗体是本领域众所周知的术语,并且确定这种特异性结合的方法也是本领域众所周知的。如果分子与特定靶抗原的反应比与其他靶抗原的反应更频繁、更迅速、更持久和/或更具有亲和力,则所述分子表现出“特异性结合”。如果抗体比其结合其他物质具有更大的亲和力、亲合力、更容易和/或更持久地结合靶抗原,则所述抗体“特异性结合”所述靶抗原。例如,特异性地(或优选地)与LIV1表位结合的抗体是以下抗体,所述抗体相对于与其他LIV1表位或非LIV1表位结合,与该LIV1表位以更大亲和力、亲合力、更容易和/或更持久地结合。通过阅读该定义还应理解,例如,特异性结合第一靶抗原的抗体可以或可以不特异性结合或不优先结合第二靶抗原。这样,“特异性结合”或“优先结合”并不一定要求(尽管可以包括)排他性结合。通常,但并非必须,提及结合是指优先结合。
在一些实施例中,抗体和LIV1之间的平衡解离常数(KD)为100pM至1μM。在一些实施例中,抗体和LIV1之间的K D为1nM至100nM。
同样在本披露的范围内的是本文披露的任何示例性抗体的功能变体。相对于参考抗体,功能变体可以在VH和/或VL中或在一个或多个VH CDR和/或一个或多个VL CDR中包含一个或多个氨基酸残基变异,同时保持与参考抗体基本相似结合和生物学活性(例如,基本相似的结合亲和力、结合特异性、抑制活性,抗肿瘤活性或其组合)。
在一些实例中,与参考抗体(如VH:SEQ ID NO:55或90或98;VL:SEQ ID NO:56或88或128)的VH CDR1、VH CDR2和VH CDR3相比,本文披露的抗体包含总共包含不超过10个氨基酸变异(例如,不超过9、8、7、6、5、4、3、2或1个氨基酸变异)的VH CDR1、VH CDR2和VH CDR3。“总共”是指所有三个VH CDR中氨基酸变异的总数在限定的范围内。可替代地或另外地,与参考抗体的VL CDR1、VL CDR2和VL CDR3相比,抗体可包含总共包含不超过10个氨基酸变异(例如,不超过9、8、7、6、5、4、3、2或1个氨基酸变异)的VL CDR1、VL CDR2和VL CDR3。
在一些实例中,本文披露的抗体可以包含其中至少一个包含不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)的VH CDR1、VH CDR2和VH CDR3作为参考抗体(如VH:SEQ ID NO:55或90或98;VL:SEQ ID NO:56或88或128)的对应VH CDR。在特定实例中,抗体包含含有不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)的VH CDR3作为参考抗体(如VH:SEQ ID NO:55或90或98;VL:SEQ ID NO:56或88或128)的VH CDR3。可替代地或另外地,抗体可包含其中至少一个包含不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)的VL CDR1、VL CDR2和VL CDR3作为参考抗体的对应VL CDR。在特定实例中,抗体包含含有不超过5个氨基酸变异(例如,不超过4、3、2或1个氨基酸变异)的LC CDR3作为参考抗体的VL CDR3。
在一些情况下,氨基酸残基变异可以是保守的氨基酸残基取代。如本文所用,“保守氨基酸取代”是指不改变进行氨基酸取代的蛋白质的相对电荷或大小特征的氨基酸取代。可以根据本领域的普通技术人员已知的用于改变多肽序列的方法来制备变体,例如改变多肽序列的方法在编译此类方法的以下参考文献中可以找到:例如,MolecularCloning:A Laboratory Manual[分子克隆:实验室手册],J.Sambrook等人编辑,第二版,冷泉港实验室出版社,冷泉港,纽约,1989,或Current Protocols in Molecular Biology[分子生物学的当前方案],F.M.Ausubel等编辑,约翰威利父子出版社(John Wiley&Sons,Inc.),纽约。氨基酸的保守取代包括在以下组内的氨基酸之间进行的取代:(a)A→G,S;(b)R→K,H;(c)N→Q,H;(d)D→E,N;(e)C→S,A;(f)Q→N;(g)E→D,Q;(h)G→A;(i)H→N,Q;(j)I→L,V;(k)L→I,V;(l)K→R,H;(m)M→L,I,Y;(n)F→Y,M,L;(o)P→A;(p)S→T;(q)T→S;(r)W→Y,F;(s)Y→W,F;和(t)V→I,L。
在一些实施例中,本文披露的抗体可以包含与参考抗体(如抗体A(VH:SEQ ID NO:55;VL:SEQ ID NO:56)或抗体B(VH:SEQ ID NO:90;VL:SEQ ID NO:88))的VH CDR总共至少80%(例如,85%、90%、95%或98%)相同的VH CDR。可替代地或另外地,抗体可以包含与参考抗体的VL CDR总共至少有80%(例如,85%、90%、95%或98%)相同的VL CDR。在一些实施例中,抗体可包含与参考抗体(如VH:SEQ ID NO:55或90或98;VL:SEQ ID NO:56或88或128)的VH至少80%(例如,85%、90%、95%或98%)相同的VH和/或与参考抗体的VL可变区至少80%(例如,85%、90%、95%或98%)相同的VL可变区。
供体模板
可以将编码CAR的核酸递送至T细胞,所述T细胞包含在本文中所称的供体模板(也称为供体多核苷酸)。供体模板可以包含非同源序列,例如编码CAR的核酸,其侧翼是两个同源区域,以允许在目的基因组位置进行有效的HDR。可替代地,供体模板可以与DNA中的靶位置不具有同源区域,并且可以通过在靶位点切割后通过NHEJ依赖性末端连接而整合。
供体模板可以是单链和/或双链的DNA或RNA,并且可以线性或环状形式引入细胞中。如果以线性形式引入,则可以通过本领域技术人员已知的方法保护供体序列的末端(例如,以防止核酸外切降解)。例如,将一个或多个双脱氧核苷酸残基添加至线性分子的3'末端和/或将自身互补的寡核苷酸连接至一个或两个末端。参见,例如,Chang等人,(1987)Proc.Natl.Acad.Sci.USA[美国国家科学院院刊]84:4959-4963;Nehls等人(1996)Science[科学]272:886-889。保护外源多核苷酸免于降解的其他方法包括但不限于一个或多个末端氨基基团的添加和经修饰的核苷酸间键的使用,例如硫代磷酸酯、氨基磷酸酯和O-甲基核糖或脱氧核糖残基。
可以将供体模板作为载体分子的一部分引入细胞中,所述载体分子具有另外的序列,例如复制起点、启动子和编码抗生素抗性的基因。此外,供体模板可以作为裸露的核酸引入(作为与试剂(例如脂质体或泊洛沙姆)复合的核酸引入),或可以通过病毒递送(例如,腺病毒、AAV、疱疹病毒、逆转录病毒、慢病毒和整合酶缺陷型慢病毒(IDLV))。
在一些实施例中,插入供体模板,使得其表达由整合位点处的内源启动子驱动,即驱动供体插入其中的内源基因表达的启动子。然而,在一些实施例中,供体模板包含外源启动子和/或增强子,例如组成型启动子、诱导型启动子或组织特异性启动子。在一些实施例中,外源启动子是包含SEQ ID NO:79的序列的EF1α启动子。可以使用其他启动子。
此外,外源序列还可包括转录或翻译调控序列,例如启动子、增强子、绝缘子、内部核糖体进入位点、编码2A肽的序列和/或聚腺苷酸化信号。
递送方法和构建体
可以使用载体系统递送核酸酶和/或供体模板,所述载体系统包括但不限于质粒载体、DNA小环、逆转录病毒载体、慢病毒载体、腺病毒载体、痘病毒载体、疱疹病毒载体和腺相关病毒载体及其组合。
常规的基于病毒和非病毒的基因转移方法可用于将编码核酸酶和供体模板的核酸引入细胞(例如,T细胞)中。非病毒载体递送系统包括DNA质粒、DNA小环、裸核酸以及与递送媒介物诸如脂质体或泊洛沙姆复合的核酸。病毒载体递送系统包括DNA和RNA病毒,这些病毒在递送至细胞后具有附加型基因组或整合型基因组。
核酸的非病毒递送方法包括电穿孔、脂转染、显微注射、生物射弹、病毒体、脂质体、免疫脂质体、聚阳离子或脂质:核酸缀合物、裸DNA、裸RNA、带帽的RNA、人工病毒体和增强对DNA的吸收的试剂。使用例如Sonitron 2000系统(Rich-Mar公司)的超声操作也可用于递送核酸。
腺相关病毒递送
可以使用腺相关病毒(AAV)将编码CAR构建体的供体核酸递送至细胞。AAV是小病毒,其位点特异性整合到宿主基因组中,并且因此可以递送转基因,例如CAR。存在反向末端重复序列(ITR),位于AAV基因组和/或目的转基因的侧翼,并用作复制起点。AAV基因组中还存在rep和cap蛋白,它们在转录时形成衣壳,所述衣壳封装了AAV基因组以递送到靶细胞中。这些衣壳上的表面受体会赋予AAV血清型,其决定衣壳主要结合哪个靶器官,并且因此决定AAV将最有效地感染哪些细胞。目前已知十二种人AAV血清型。在一些实施例中,AAV是AAV血清型6(AAV6)。
出于多种原因,腺相关病毒是用于基因治疗的最常用病毒之一。首先,AAV在施用于包括人在内的哺乳动物后不会引起免疫应答。第二,将AAV有效地递送至靶细胞,尤其是在考虑选择合适的AAV血清型时。最后,因为基因组可以在宿主细胞中持续存在而不整合,AAV具有感染分裂和非分裂细胞的能力。这种特性使它们成为基因治疗的理想候选。
同源定向修复(HDR)
通过同源定向修复(HDR)将编码CAR的供体核酸插入靶基因座。CRISPR Cas9酶切割靶基因座处的两条DNA链。然后发生HDR,以修复双链断裂(DSB)并插入供体DNA。为了使此正确发生,设计供体序列的侧翼残基与靶基因中DSB位点周围的序列(以下简称“同源臂”)互补。这些同源臂用作DSB修复的模板,并使HDR成为基本无错误的机制。同源定向修复(HDR)的速率是突变与切割位点之间的距离的函数,因此选择重叠或附近的靶位点很重要。模板可以包括同源区侧翼的额外序列或者可以含有与基因组序列不同的序列,从而可以进行序列编辑。
靶基因可以与受试者的免疫应答相关,其中永久缺失靶基因的至少一部分将调节免疫应答。例如,为了产生CAR T细胞,靶基因可以是TCRα恒定区(TRAC)。TRAC的破坏导致内源性TCR的功能丧失。
在一些实施例中,靶基因在安全港基因座中。
工程化T细胞
本披露的经工程化的(经基因编辑的)CAR T细胞可以是自体的(“自身”)或非自体的(“非自身的”,例如,同种异体的、同基因的或异基因的)。“自体”是指来自相同受试者的细胞。“同种异体的”是指与受试者相同物种的细胞,但是在遗传上不同于受试者中的细胞。在一些实施例中,T细胞获自哺乳动物受试者。在一些实施例中,T细胞获自人类受试者。
T细胞可从多种来源获得,包括但不限于外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、感染部位的组织、腹水、胸腔积液、脾脏组织、和肿瘤。在某些实施例中,可以使用本领域技术人员已知的许多技术,例如沉淀(例如,FICOLLTM分离),由从受试者收集的单位血液中获得T细胞。
在一些实施例中,使用分离的T细胞群体。在一些实施例中,在分离外周血单核细胞(PBMC)之后,可以在激活、扩增和/或基因修饰之前或之后,将细胞毒性T细胞和辅助T淋巴细胞分类为幼稚、记忆和效应T细胞亚群。
T细胞的特定亚群(其表达以下一种或多种细胞表面标志物:TCRab、CD3、CD4、CD8、CD27 CD28、CD38 CD45RA、CD45RO、CD62L、CD127、CD122、CD95、CD197、CCR7、KLRG1、MCH-I蛋白和/或MCH-II蛋白)可以通过阳性或阴性选择技术进一步分离。在一些实施例中,通过阳性或阴性选择技术进一步分离T细胞的特定亚群,所述特定亚群表达选自由TCRab、CD4和/或CD8组成的组中的标志物中的一种或多种。在一些实施例中,工程化T细胞群体不表达或基本不表达一种或多种以下标志物:CD70、CD57、CD244、CD160、PD-1、CTLA4、HΜ3和LAG3。在一些实施例中,可以在基因工程化之前和/或基因工程化之后通过阳性或阴性选择来分离T细胞的亚群。
在一些实施例中,分离的T细胞群体表达一种或多种标志物,包括但不限于CD3+、CD4+、CD8+或其组合。在一些实施例中,从受试者分离T细胞,并在进行基因编辑之前首先激活和刺激其体外增殖。
为了获得足够的治疗剂量的T细胞组合物,通常对T细胞进行一轮或多轮刺激、激活和/或扩增。通常可以使用,例如以下美国专利中所述的方法来激活和扩增T细胞:美国专利6,352,694;6,534,055;6,905,680;6,692,964;5,858,358;6,887,466;6,905,681;7,144,575;7,067,318;7,172,869;7,232,566;7,175,843;5,883,223;6,905,874;6,797,514;和6,867,041。在一些实施例中,在将基因组编辑组合物引入T细胞之前,T细胞被激活并扩增约1天至约4天、约1天至约3天、约1天至约2天、约2天至约3天、约2天至约4天、约3天至约4天或约1天、约2天、约3天或约4天。
在一些实施例中,在将基因组编辑组合物引入T细胞之前,T细胞被激活并扩增约4小时、约6小时、约12小时、约18小时、约24小时、约36小时、约48小时、约60小时或约72小时。
在一些实施例中,在将基因组编辑组合物引入T细胞的同时激活T细胞。
治疗方法和组合物
在一些实施例中,本文提供了治疗癌症(例如:乳腺癌)的方法。如本文所提供的可治疗的癌症的非限制性实例包括:乳腺癌(例如雌激素受体阳性乳腺癌)、前列腺癌、鳞状肿瘤(例如皮肤、膀胱、肺、子宫颈、子宫内膜、头颈和胆道鳞状肿瘤)、和神经元肿瘤。在一些实施例中,这些方法包括将本披露的CAR T细胞(例如,抗LIV1型CAR T细胞)递送给患有癌症的受试者,所述癌症包括乳腺癌(例如雌激素受体阳性乳腺癌)、前列腺癌、鳞状肿瘤(例如皮肤、膀胱、肺、子宫颈、子宫内膜、头颈和胆道鳞状肿瘤)、和/或神经元肿瘤。
施用步骤可包括通过引入的细胞至少部分定位在所希望位点(例如,肿瘤)的方法或途径将细胞(例如,工程化T细胞)放置(例如,移植)到受试者体内,从而产生所希望的一种或多种效果。工程化T细胞可以通过任何适当的途径施用,所述途径导致递送至受试者中的所需位置,在该位置中至少一部分植入的细胞或细胞组分保持活力。在施用于受试者后,细胞的活力期可以短至数小时(例如二十四小时)、几天,长达数年,或甚至受试者的寿命(即长期植入)。例如,在本文所述的一些方面,有效量的工程化T细胞是经由全身性施用途径(如腹膜内或静脉内途径)施用的。
受试者可以是期望对其进行诊断,治疗或疗法的任何受试者。在一些实施例中,受试者是哺乳动物。在一些实施例中,受试者是人。
供体是非正在治疗的受试者的个体。供体是非患者个体。在一些实施例中,供体是不患有或不怀疑患有要治疗的癌症的个体。在一些实施例中,可以使用多个供体,例如两个或更多个供体。
在一些实施例中,根据本文所述方法施用的工程化T细胞群体包含获自一个或多个供体的同种异体T细胞。“同种异体”是指从相同物种的一个或多个不同供体获得的细胞、细胞群体或包含细胞的生物学样品,其中一个或多个基因座处的基因与接受体不同。例如,施用于受试者的工程化T细胞群体可以衍生自一个或多个不相关的供体,或衍生自一个或多个不同的同胞。在一些实施例中,可以使用同系细胞群体,例如从遗传上相同的供体(例如,相同的双胞胎)获得的那些。在一些实施例中,细胞是自体细胞;即,这些工程化T细胞是从受试者获得或分离并施用给相同受试者的,即,供体和接受体是相同的。
在一些实施例中,根据本文所述方法施用的工程化T细胞群体在受试者中不诱导毒性,例如,工程化T细胞不诱导非癌细胞的毒性。在一些实施例中,施用的工程化T细胞群体不触发补体介导的裂解,或不刺激抗体依赖性细胞介导的细胞毒性(ADCC)。
有效量是指预防或减轻医学病症(例如,癌症)的至少一种或多种体征或症状所需的工程化T细胞群体的量,并且涉及足以提供所希望的效果(例如,治疗患有医学病症的受试者)的组合物的量。有效量还包括足以预防或延迟疾病症状的发展、改变疾病症状的进程(例如但不限于减慢疾病症状的进展)或逆转疾病症状的量。应当理解,对于任何给定的情况,本领域的普通技术人员可以使用常规实验来测定适当的有效量。
为了用于本文所述的各个方面,有效量的细胞(例如,工程化T细胞)包括至少102个细胞、至少5X102个细胞、至少103个细胞、至少5X103个细胞、至少104个细胞、至少5X104个细胞、至少105个细胞、至少2X105个细胞、至少3X105个细胞、至少4X105个细胞、至少5X105个细胞、至少6X105个细胞、至少7X105个细胞、至少8X105个细胞、至少9X105个细胞、至少1X106个细胞、至少2X106个细胞、至少3X106个细胞、至少4X106个细胞、至少5X106个细胞、至少6X106个细胞、至少7X106个细胞、至少8X106个细胞、至少9X106个细胞或其倍数。细胞衍生自一个或多个供体或获自自体来源。在本文所述的一些实例中,将细胞在施用给有需要的受试者之前在培养中扩增。
施用模式包括注射、输注、滴注或摄取。注射包括但不限于静脉内、肌内、动脉内、鞘内、心室内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、被膜下、蛛网膜下、脊柱内、脊髓内和胸骨内注射和输注。在一些实施例中,该途径是静脉内。
在一些实施例中,全身性施用工程化T细胞,这是指将细胞群体以不同于直接施用至靶部位、组织或器官的方式施用,而是使其进入受试者的循环系统,从而经受代谢和其他类似过程。
可以由熟练的临床医生确定包含用于治疗医学病症的组合物的治疗的功效。如果疾病(例如,癌症)的任何一种或所有体征或症状(举一个例子,以有益的方式改变功能性靶标的水平(例如,增加至少10%))或其他临床上可接受的症状或标志物得到改善或减轻,则该治疗被认为是“有效治疗”。功效还可以通过如通过住院治疗或需要医疗干预所评估的受试者恶化的失败(例如,疾病进展停止或至少减慢)来测量。测量这些指标的方法是本领域技术人员已知的和/或本文所述的。治疗包括对受试者疾病的任何治疗,包括:(1)抑制疾病,例如阻止或减缓症状的进展;或(2)减轻疾病,例如引起症状消退;以及(3)预防或降低症状发展的可能性。
通过以下实施例举例说明本披露内容:
实施例1.一种工程化T细胞,该工程化T细胞包含编码嵌合抗原受体(CAR)的核酸,其中该CAR包含特异性结合LIV1的胞外结构域。
实施例2.如实施例1所述的工程化T细胞,该工程化T细胞进一步包含被破坏的T细胞受体α链恒定区(TRAC)基因。
实施例3.如实施例2所述的工程化T细胞,其中将编码该CAR的核酸插入该TRAC基因中。
实施例4.如实施例1-3中任一项所述的工程化T细胞,该工程化T细胞进一步包含被破坏的β-2-微球蛋白(β2M)基因。
实施例5.如实施例1-4中任一项所述的工程化T细胞,其中该CAR的胞外结构域包含抗LIV1抗体。
实施例6.如实施例5所述的工程化T细胞,其中该抗LIV1抗体是抗LIV1单链可变片段(scFv)。
实施例7.如实施例6所述的工程化T细胞,其中该抗LIV1 scFv包含与参考抗体相同的重链可变区(VH)互补决定区(CDR)和相同的轻链可变区(VL)CDR,其中该参考抗体包含(i)SEQ ID NO:55所示的VH和SEQ ID NO:56所示的VL,(ii)SEQ ID NO:69所示的VH和SEQID NO:70所示的VL,(iii)SEQ ID NO:76所示的VH和SEQ ID NO:77所示的VL,或(iv)SEQ IDNO:83所示的VH和SEQ ID NO:84所示的VL。
实施例8.如实施例7所述的工程化T细胞,其中该抗LIV1 scFv包含与该参考抗体相同的VH和VL链。
实施例8.1.如实施例7所述的工程化T细胞,其中该抗LIV1 scFv包含SEQ ID NO:54或70中任一项的氨基酸序列。
实施例9.如实施例1-8.1中任一项所述的工程化T细胞,其中该CAR包含CD28共刺激结构域或41BB共刺激结构域。
实施例10.如实施例9所述的工程化T细胞,其中该CAR进一步包含CD3z细胞质信号传导结构域。
实施例11.如实施例3-10中任一项所述的工程化T细胞,其中该TRAC基因包含SEQID NO:63、64、71或72中任一项的核苷酸序列,且/或其中该CAR由SEQ ID NO:49、51、65或67中任一项的核苷酸序列编码。
实施例12.如实施例4-11中任一项所述的工程化T细胞,其中该被破坏的β2M基因包含至少一个选自SEQ ID NO:9-14中任一项的核苷酸序列。
实施例13.一个如实施例1-12中任一项所述的工程化T细胞群体,其中该群体的至少25%或至少50%的工程化T细胞表达该CAR。
实施例14.如实施例14所述的群体,其中该群体的至少70%的工程化T细胞表达该CAR。
实施例15.如实施例13所述的群体,其中该群体的至少25%的工程化T细胞在至少7天或至少14天的体外增殖后表达CAR。
实施例16.如实施例13-15中任一项所述的群体,其中该群体的至少50%的工程化T细胞不表达可检测水平的T细胞受体(TCR)蛋白。
实施例17.如实施例16所述的群体,其中该群体的至少90%的工程化T细胞不表达可检测水平的TCR蛋白。
实施例18.如实施例13-17中任一项所述的群体,其中该群体的至少50%的工程化T细胞不表达可检测水平的β2M蛋白。
实施例19.如实施例18所述的群体,其中该群体的至少70%的工程化T细胞不表达可检测水平的β2M蛋白。
实施例20.如实施例13-19中任一项所述的群体,其中当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该群体的至少10%、至少25%或至少50%的癌细胞的细胞裂解。
实施例21.如实施例20所述的群体,其中当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该癌细胞群体的至少70%、至少80%或至少90%的细胞裂解。
实施例22.如实施例20或21所述的群体,其中当与癌细胞群体在体外共培养时,该群体的工程化T细胞分泌IFNγ。
实施例23.如实施例20-22中任一项所述的群体,其中工程化T细胞与癌细胞的比率为1:1至2:1。
实施例24.如实施例20-23中任一项所述的群体,其中这些癌细胞包含肉瘤细胞。
实施例25.如实施例20-23中任一项所述的群体,其中这些癌细胞包括乳腺癌细胞。
实施例27.如实施例13-26中任一项所述的群体,当在向受试者体内施用时,不会在该受试者中诱导毒性。
实施例26.一种方法,该方法包括向受试者施用如实施例13-27中任一项所述的工程化T细胞群体。
实施例27.如实施例26所述的方法,其中该受试者是人类受试者。
实施例28.如实施例27所述的方法,其中该受试者患有癌症。
实施例29.如实施例28所述的方法,其中该癌症是选自下组,该组由以下各项组成:乳腺癌(例如雌激素受体阳性乳腺癌)、前列腺癌、鳞状肿瘤(例如皮肤、膀胱、肺、子宫颈、子宫内膜、头颈和胆道鳞状肿瘤)、和/或神经元肿瘤。
实施例30.如实施例28或31所述的方法,其中该癌症包括表达LIV1的癌细胞。
实施例31.一种产生工程化T细胞的方法,该方法包括(a)向T细胞递送RNA引导性核酸酶、靶向TRAC基因的gRNA和包含供体模板的载体,该供体模板包含编码CAR的核酸,所述CAR包含特异结合LIV1的胞外结构域;以及(b)产生具有被破坏的TRAC基因并表达该CAR的工程化T细胞。
实施例32.如实施例31所述的方法,其中靶向该TRAC基因的gRNA包含SEQ ID NO:18或19的核苷酸序列,或靶向SEQ ID NO:40的核苷酸序列。
实施例33.如实施例31或32所述的方法,其中编码该CAR的核酸的侧翼为TRAC基因的左和右同源臂。
实施例34.如实施例31-33中任一项所述的方法,该方法进一步包括向该T细胞递送靶向该β2M基因的gRNA。
实施例35.如实施例34所述的方法,其中靶向该β2M基因的gRNA包含SEQ ID NO:20或21的核苷酸序列,或靶向SEQ ID NO:41的核苷酸序列。
实施例36.如实施例31-35中任一项所述的方法,其中该RNA引导性核酸酶是Cas9核酸酶,任选地是酿脓链球菌Cas9核酸酶。
实施例37.如实施例31-38中任一项所述的方法,其中该CAR的胞外结构域是抗LIV1抗体。
实施例38.如实施例37所述的方法,其中该抗LIV1抗体是抗LIV1单链可变片段(scFv)。
实施例39.如实施例38所述的方法,其中该抗LIV1 scFv包含与参考抗体相同的VH互补决定区(CDR)和相同的VL CDR,其中该参考抗体包含(i)SEQ ID NO:55所示的VH和SEQID NO:56所示的VL。
实施例40.如实施例39所述的方法,其中该抗LIV1 scFv包含与该参考抗体相同的VH和VL链。
实施例41.如实施例39所述的方法,其中该抗LIV1 scFv包含SEQ ID NO:54或70中任一项的氨基酸序列。
实施例42.如实施例31-41中任一项所述的方法,其中该CAR包含CD28共刺激结构域或41BB共刺激结构域。
实施例43.如实施例42所述的方法,其中该CAR进一步包含CD3z细胞质信号传导结构域。
实施例44.如实施例31-43中任一项所述的方法,其中该供体模板包含SEQ ID NO:63、64、71或72中任一项的核苷酸序列。
实施例45.如实施例31-44中任一项所述的方法,其中该CAR由SEQ ID NO:49、51、65或67中任一项的核苷酸序列编码。
通过以下实施例进一步举例说明本披露内容:
实施例A1.一种工程化T细胞,该工程化T细胞包含编码嵌合抗原受体(CAR)的核酸,其中该CAR包含特异性结合LIV1的胞外结构域。
实施例A2.如实施例A1所述的工程化T细胞,该工程化T细胞进一步包含被破坏的T细胞受体α链恒定区(TRAC)基因。
实施例A3.如实施例A1或A2所述的工程化T细胞,该工程化T细胞进一步包含被破坏的β-2-微球蛋白(β2M)基因。
实施例A4.如实施例A1-3中任一项所述的工程化T细胞,其中该CAR的胞外结构域包含抗LIV1抗体。
实施例A5.如实施例A4所述的工程化T细胞,其中该抗LIV1抗体是抗LIV1单链可变片段(scFv)。
实施例A6.如实施例A5所述的工程化T细胞,其中该抗LIV1 scFv包含与参考抗体相同的重链可变结构域(VH)互补决定区(CDR)和相同的轻链可变结构域(VL)CDR,其中该参考抗体包含(i)SEQ ID NO:55所示的VH和SEQ ID NO:56所示的VL,或(ii)SEQ ID NO:90所示的VH和SEQ ID NO:88所示的VL。
实施例A7.如实施例A6所述的工程化T细胞,其中该抗LIV1 scFv包含与该参考抗体相同的VH和VL链。
实施例A8.如实施例A6所述的工程化T细胞,其中该抗LIV1 scFv包含SEQ ID NO:54、70、83或86中任一项的氨基酸序列。
实施例A9.如实施例A1-A8中任一项所述的工程化T细胞,其中该CAR进一步包含CD28共刺激结构域或41BB共刺激结构域。
实施例A10.如实施例A9所述的工程化T细胞,其中该CAR进一步包含CD3ζ细胞质信号传导结构域。
实施例A11.如实施例A1-A10中任一项所述的工程T细胞,其中该CAR由SEQ ID NO:49、51、104或108中任一项的核苷酸序列或包含与SEQ ID NO:49、51、104或108至少90%相同的核酸序列的核苷酸序列编码。
实施例A12.如实施例A1-A11中任一项所述的工程化T细胞,其中将编码该CAR的核酸插入该被破坏的TRAC基因中。
实施例A13.如实施例A2-A12中任一项所述的工程化T细胞,其中该被破坏的TRAC基因包含SEQ ID NO:63、64、107或111中任一项的核苷酸序列和/或SEQ ID NO:49、51、104或108中任一项的核苷酸序列。
实施例A14.如实施例A4-A13中任一项所述的工程化T细胞,其中该被破坏的β2M基因包含至少一个选自SEQ ID NO:9-14中任一项的核苷酸序列。
实施例A15.一种工程化T细胞,该工程化T细胞包含:(i)被破坏的TRAC基因;(ii)被破坏的β2M基因;以及(iii)编码包含抗LIV1抗原结合片段的CAR的核酸。
实施例A16.如实施例A15所述的工程化T细胞,其中该CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域。
实施例A17.如实施例A15或A16所述的工程化T细胞,其中该被破坏的TRAC基因包含编码该CAR的核酸。
实施例A18.一种工程化T细胞,该工程化T细胞包含:(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,所述CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域;以及(ii)被破坏的β2M基因。
实施例A19.一种工程化T细胞,该工程化T细胞包含:(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,所述CAR包含SEQ ID NO:50、52、105、109、68或66中任一项的氨基酸序列;以及(ii)被破坏的β2M基因。
实施例A20.一种工程化T细胞,该工程化T细胞包含:(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,其中该核酸序列与SEQ ID NO:49、51、104或108至少90%相同和/或编码包含SEQ ID NO:50、52、105、109、68或66中任一项的氨基酸序列的CAR;以及(ii)被破坏的β2M基因。
实施例A21.如实施例A1-A20中任一项所述的工程化T细胞,其中该T细胞是人T细胞。
实施例A22.一个包含如实施例A1-A21中任一项所述的工程化T细胞的细胞群体,其中该群体的至少15%或至少50%的工程化T细胞表达该CAR。
实施例A23.如实施例A22所述的群体,其中该群体的至少30%的工程化T细胞表达该CAR。
实施例A24.如实施例A22所述的群体,其中该群体的至少70%的工程化T细胞表达该CAR。
实施例A25.如实施例A22所述的群体,其中该群体的至少25%的工程化T细胞在至少7天或至少14天的体外增殖后表达该CAR。
实施例A26.如实施例A22-A25中任一项所述的群体,其中该群体的至少50%的工程化T细胞不表达可检测水平的T细胞受体(TCR)蛋白。
实施例A27.如实施例A26所述的群体,其中该群体的至少90%的工程化T细胞不表达可检测水平的TCR蛋白。
实施例A28.如实施例A22-A27中任一项所述的群体,其中该群体的至少50%的工程化T细胞不表达可检测水平的β2M蛋白。
实施例A29.如实施例A28所述的群体,其中该群体的至少70%的工程化T细胞不表达可检测水平的β2M蛋白。
实施例A30.如实施例A22-A29中任一项所述的群体,其中当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该群体的至少10%、至少25%或至少50%的癌细胞的细胞裂解。
实施例A31.如实施例A30所述的群体,其中当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该癌细胞群体的至少70%、至少80%或至少90%的细胞裂解。
实施例A32.如实施例A30或A31所述的群体,其中当与癌细胞群体在体外共培养时,该群体的工程化T细胞分泌IFNγ。
实施例A33.如实施例A30-A32中任一项所述的群体,其中工程化T细胞与癌细胞的比率为1:1至2:1。
实施例A34.如实施例A30-A33中任一项所述的群体,其中这些癌细胞包括肉瘤细胞。
实施例A35.如实施例A30-A33中任一项所述的群体,其中这些癌细胞包括乳腺癌细胞。
实施例A36.如实施例A22-A35中任一项所述的群体,当在向受试者体内施用时,不会在该受试者中诱导毒性。
实施例A37.一种包含工程化T细胞的细胞群体,其中这些工程化T细胞包含:(i)被破坏的TRAC基因;(ii)被破坏的β2M基因;以及(iii)编码包含抗LIV1抗原结合片段的CAR的核酸。
实施例A38.如实施例A37所述的细胞群体,其中该CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域。
实施例A39.如实施例A37或A38所述的细胞群体,其中该被破坏的TRAC基因包含编码该CAR的核酸。
实施例A40.一种包含工程化T细胞的细胞群体,其中这些工程化T细胞包含:(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,所述CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域;以及(ii)被破坏的β2M基因。
实施例A41.一种包含工程化T细胞的细胞群体,其中这些工程化T细胞包含:(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,其中该核酸序列与SEQ IDNO:49、51、104或108至少90%相同和/或编码SEQ ID NO:50、52、105、109、68或66的CAR;以及(ii)被破坏的β2M基因。
实施例A42.一种方法,该方法包括向受试者施用如实施例A22-A41中任一项所述的工程化T细胞群体。
实施例A43.如实施例A42所述的方法,其中该受试者是人类受试者。
实施例A44.如实施例A43所述的方法,其中该受试者患有癌症。
实施例A45.如实施例A44所述的方法,其中该癌症是选自下组,该组由以下各项组成:乳腺癌(例如雌激素受体阳性乳腺癌)、前列腺癌、鳞状肿瘤(例如皮肤、膀胱、肺、子宫颈、子宫内膜、头颈和胆道鳞状肿瘤)、和/或神经元肿瘤。
实施例A46.如实施例A44或A45所述的方法,其中该癌症包括表达LIV1的癌细胞。
实施例A47.一种用于产生工程化T细胞的方法,该方法包括(a)向T细胞递送(i)RNA引导性核酸酶、(ii)靶向TRAC基因的gRNA、以及(iii)包含供体模板的载体,该供体模板包含编码CAR的核酸,所述CAR包含特异结合LIV1的胞外结构域;以及(b)产生具有被破坏的TRAC基因并表达该CAR的工程化T细胞。
实施例A48.如实施例A47所述的方法,其中靶向该TRAC基因的gRNA包含SEQ IDNO:18或19的核苷酸序列,或靶向SEQ ID NO:40的核苷酸序列。
实施例A49.如实施例A47或A48所述的方法,该方法进一步包括向该T细胞递送靶向该β2M基因的gRNA。
实施例A50.如实施例A49所述的方法,其中靶向该β2M基因的gRNA包含SEQ ID NO:20或21的核苷酸序列,或靶向SEQ ID NO:41的核苷酸序列。
实施例A51.如实施例A47-A50中任一项所述的方法,其中该CAR的胞外结构域包含抗LIV1抗体。
实施例A52.如实施例A51所述的方法,其中该抗LIV1抗体是抗LIV1单链可变片段(scFv)。
实施例A53.如实施例A52所述的方法,其中该抗LIV1 scFv包含与参考抗体相同的重链可变结构域(VH)互补决定区(CDR)和相同的轻链可变结构域(VL)CDR,其中该参考抗体包含(i)SEQ ID NO:55所示的VH和SEQ ID NO:56所示的VL,或(ii)SEQ ID NO:90所示的VH和SEQ ID NO:88所示的VL。
实施例A54.如实施例A53所述的方法,其中该抗LIV1 scFv包含与该参考抗体相同的VH和VL链。
实施例A55.如实施例A53所述的方法,其中该抗LIV1 scFv包含SEQ ID NO:54、83、86或70中任一项的氨基酸序列。
实施例A56.如实施例A47-A56中任一项所述的方法,其中该CAR进一步包含CD28共刺激结构域或41BB共刺激结构域。
实施例A57.如实施例A56所述的方法,其中该CAR进一步包含CD3ζ细胞质信号传导结构域。
实施例A58.如实施例A47-A57中任一项所述的方法,其中该CAR由SEQ ID NO:49、51、104或108中任一项的核苷酸序列或包含与SEQ ID NO:49、51、104或108至少90%相同的核酸序列的核苷酸序列编码。
实施例A59.如实施例A47-A58中任一项所述的方法,其中编码该CAR的核酸的侧翼为TRAC基因的左和右同源臂。
实施例A60.如实施例A47-A59中任一项所述的方法,其中该供体模板包含SEQ IDNO:63、64、107或111中任一项的核苷酸序列。
实施例A61.如实施例A47-A60中任一项所述的方法,其中该RNA引导性核酸酶是Cas9核酸酶,任选地是酿脓链球菌Cas9核酸酶。
实施例A62.一种工程化T细胞,该工程化T细胞通过如实施例A47-A61中任一项所述的方法产生。
实施例A63.一种细胞群体,该细胞群体包含如实施例A62所述的工程化T细胞。
实施例A64.一种在受试者中治疗癌症的方法,该方法包括向该受试者施用如实施例A22-A41或A63中任一项所述的细胞群体。
实施例A65.如实施例A64所述的方法,其中该癌症是选自下组,该组由以下各项组成:胰腺癌、胃癌、卵巢癌、子宫癌、乳腺癌、前列腺癌、睾丸癌、甲状腺癌、鼻咽癌、非小细胞肺癌(NSCLC)、胶质母细胞瘤、神经元肿瘤、软组织肉瘤、白血病、淋巴瘤、黑色素瘤、结肠癌、结肠腺癌、脑胶质母细胞瘤、肝细胞癌、肝胆管细胞癌(liverhepatocholangiocarcinoma)、骨肉瘤、胃癌、食管鳞状细胞癌、晚期胰腺癌、肺腺癌、肺鳞状细胞癌、小细胞肺癌、肾癌和肝内胆管癌。
实施例A66.如实施例A64或A65所述的方法,其中该癌症包括表达LIV1的癌细胞。
实例
实例1.CAR T细胞产生和CAR表达
用Cas9:gRNA-RNP复合物和腺相关腺病毒载体(AAV)电穿孔激活原代人T细胞,以产生TRAC-/β2M-/抗Liv1a CAR+T细胞。包含编码抗Liv1a CAR(971(SEQ ID NO:49)、972(SEQID NO:65)、972b(SEQ ID NO:67)、973(SEQ ID NO:95)、974(SEQ ID NO:100)、975(SEQ IDNO:104)、和976(SEQ ID NO:108))的核苷酸序列之一的重组AAV血清型6(AAV6)与Cas9:sgRNA RNP(1μM Cas9,5μM gRNA)一起递送至激活的同种异体人T细胞。使用了以下sgRNA:TRAC(SEQ ID NO:28)和β2M(SEQ ID NO:30)。也可以使用gRNA的未修饰版本(或其他经修饰的版本)(例如,SEQ ID NO:18或20)。
电穿孔后约一(1)周,将细胞进行处理用于流式细胞术,以评估经编辑的细胞群体细胞表面的TRAC、β2M、和抗Liv1a CAR表达水平(图1)。对于所有抗Liv1a CAR T细胞和TRAC-/β2M-对照细胞,>90%的活细胞缺乏TCR的表达且>60%缺乏β2M的表达。用编码975和976Liv1a CAR的构建体处理的细胞具有最高百分比的表达抗Liv1a CAR+的活细胞(>30%)。
实例2.细胞毒性
细胞杀伤测定。使用细胞杀伤测定来评估TRAC-/β2M-/抗Liv1a CAR+T细胞在粘附肾癌和乳腺癌细胞系(分别为A498和ZR-75-1)中引起细胞裂解的能力。粘附细胞以每孔50,000个细胞每孔接种在96孔板中,并在37℃下放置过夜。在第二天,将T细胞以8:1、4:1、2:1或1:1T细胞:靶细胞的比率添加到含有靶细胞的孔中。将TRAC-/β2M-T细胞用作阴性对照。大约24小时后,除去100μL上清液用于细胞因子定量(参见下文),并通过抽吸从培养物中除去T细胞,并将100μL(普洛麦格公司(Promega))添加到该板的每个孔中,以评估剩余活细胞的数量。然后使用酶标仪对每孔发射的光量进行定量。抗Liv1a CAR T细胞,特别是表达CTX971、CTX975和CTX976构建体的那些,表现出针对A498(图2A)和ZR-75-1(图2B)的高效细胞毒性。
实例3.效应子细胞因子分泌
分别使用MILLIPLEX MAP人细胞因子/趋化因子磁珠组-免疫学多重测定试剂盒(密理博公司(Millipore),目录号HCYTOMAG-60K,使用磁性微球)、抗人IFNγ珠(密理博公司,目录号HCYIFNG-MAG)和抗人IL-2珠(密理博公司,目录号HIL2-MAG)来量化来自细胞毒性测定的样品中的IFN-γ和IL-2分泌。该测定遵循制造商的方案进行。重构标准品和质量控制(QC)样品,并制备从10,000pg/mL至3.2pg/mL的工作标准品的连续稀释液。将标准品、QC和细胞上清液添加到每个板中,并使用测定培养基稀释上清液。将所有样品与抗人IFNγ和抗人IL-2珠一起孵育2小时。孵育后,使用自动磁性板洗涤器洗涤板。向每孔中添加人细胞因子/趋化因子检测抗体溶液,并孵育1小时,随后与链霉亲和素-藻红蛋白一起孵育30分钟。随后洗涤板,用150μL鞘液重悬样品,并在板振荡器上搅拌5分钟。使用带软件的100/200TM仪器读取样品,并使用分析师软件完成数据采集和分析。使用5-参数逻辑曲线拟合方法自动分析荧光强度中值(MFI)数据,用于计算在未知样品中测量的细胞因子浓度。
如图3A-3D所示,当与靶细胞系A498和ZR-75-1共同培养时,含有CTX971、975或976CAR的同种异体T细胞以显著高于背景(与靶细胞系共同培养的2KO/AAV neg T细胞)的水平分泌效应子细胞因子干扰素-γ(3A、3B)和白细胞介素-2(3C、3D)。
表6.
表7.CAR组分
CAR结构:
CD8[信号肽]-抗LIV1[scFV]-CD8[tm]-CD28[共刺激结构域]-CD3ζ或者
CD8[信号肽]-抗LIV1[scFV]-CD8[tm]-41BB[共刺激结构域]-CD3ζ
表8.供体组分
供体结构:TRAC[LHA]-EF1a[启动子]-CAR-聚A-TRAC[RHA]
表9.
表10.CAR组分
在此披露的所有参考文献、专利和专利申请都相对于每个被引用的主题通过引用而并入,这在一些情况下可以包括文件的全部内容。
除非清楚地作相反指示,否则在说明书中和在权利要求中,如在此使用的不定冠词“一个/种)”(a/an)应当理解为意思指“至少一个(种)”。
还应当理解,除非明确指出相反,在包括多于一个步骤或动作的在此所要求保护的任何方法中,方法的步骤或动作的顺序不一定限于其中方法的步骤或动作被列举的顺序。
在权利要求中,以及在以上说明书中,所有连接词,如“包含”、“包括”、“带有”、“具有”、“含有”、“涉及”、“持有”、“由……构成”等应理解为开放性的,即,是指包括但不限于此。只有过渡性短语“由……组成”和“主要由……组成”应当各自地为封闭或半封闭式过渡性短语,如美国专利局专利审查程序手册(United States Patent Office Manual ofPatent Examining Procedures),第2111.03节中所述。
数值之前的术语“约”和“基本上”是指所列举数值的平均值±10%。
在提供值的范围的情况下,范围的上端和下端之间的每个值在本文中被具体地考虑和描述。
序列表
<110> 克里斯珀医疗股份公司(Crispr Therapeutics AG)
<120> 抗LIV1免疫细胞癌症疗法
<130> 33165/CT113
<150> US 62/756,723
<151> 2018-11-07
<160> 130
<170> PatentIn 3.5版
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<400> 15
nnnnnnnnnn nnnnnnnnnn guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 16
<211> 96
<212> DNA
<213> 人工序列
<220>
<223> 合成
<220>
<221> 尚未归类的特征
<222> (1)..(20)
<223> n 是 a, c, g, t 或 u
<400> 16
nnnnnnnnnn nnnnnnnnnn guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugc 96
<210> 17
<211> 78
<212> DNA
<213> 人工序列
<220>
<223> 合成
<220>
<221> 重复区域
<222> (1)..(1)
<223> 重复 17-30 次
<220>
<221> 尚未归类的特征
<222> (1)..(1)
<223> n 是 a, c, g, t 或 u
<220>
<221> 重复区域
<222> (78)..(78)
<223> 重复 1-8 次
<400> 17
nguuuuagag cuagaaauag caaguuaaaa uaaggcuagu ccguuaucaa cuugaaaaag 60
uggcaccgag ucggugcu 78
<210> 18
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 18
agagcaacag ugcuguggcc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 19
agagcaacag ugcuguggcc 20
<210> 20
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 20
gcuacucucu cuuucuggcc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 21
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 21
gcuacucucu cuuucuggcc 20
<210> 22
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 22
cugcagcuuc uccaacacau guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 23
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 23
cugcagcuuc uccaacacau 20
<210> 24
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 24
gcuuuggucc cauuggucgc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 25
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 25
gcuuuggucc cauuggucgc 20
<210> 26
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 26
gcccgcagga cgcacccaua guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 27
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 27
gcccgcagga cgcacccaua 20
<210> 28
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 28
agagcaacag ugcuguggcc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 29
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 29
agagcaacag ugcuguggcc 20
<210> 30
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 30
gcuacucucu cuuucuggcc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 31
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 31
gcuacucucu cuuucuggcc 20
<210> 32
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 32
cugcagcuuc uccaacacau guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 33
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 33
cugcagcuuc uccaacacau 20
<210> 34
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 34
gcuuuggucc cauuggucgc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 35
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 35
gcuuuggucc cauuggucgc 20
<210> 36
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 36
gcccgcagga cgcacccaua guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 37
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 37
gcccgcagga cgcacccaua 20
<210> 38
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 38
gctttggtcc cattggtcgc ggg 23
<210> 39
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 39
gcccgcagga cgcacccata ggg 23
<210> 40
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 40
agagcaacag tgctgtggcc tgg 23
<210> 41
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 41
gctactctct ctttctggcc tgg 23
<210> 42
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 42
ctgcagcttc tccaacacat cgg 23
<210> 43
<211> 126
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 43
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 44
<211> 42
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 44
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 45
<211> 120
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 45
tcaaagcgga gtaggttgtt gcattccgat tacatgaata tgactcctcg ccggcctggg 60
ccgacaagaa aacattacca accctatgcc cccccacgag acttcgctgc gtacaggtcc 120
<210> 46
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 46
Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro
1 5 10 15
Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro
20 25 30
Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 47
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 47
cgagtgaagt tttcccgaag cgcagacgct ccggcatatc agcaaggaca gaatcagctg 60
tataacgaac tgaatttggg acgccgcgag gagtatgacg tgcttgataa acgccggggg 120
agagacccgg aaatgggggg taaaccccga agaaagaatc cccaagaagg actctacaat 180
gaactccaga aggataagat ggcggaggcc tactcagaaa taggtatgaa gggcgaacga 240
cgacggggaa aaggtcacga tggcctctac caagggttga gtacggcaac caaagatacg 300
tacgatgcac tgcatatgca ggccctgcct cccaga 336
<210> 48
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 48
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 49
<211> 1533
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 49
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgga cgtggtcatg actcaaagcc cactttcctt gcccgtgact ctcggacaac 120
cggcttcaat atcttgccgc tcatcacagt ccctgctgca tagcagtggt aacacttatc 180
ttgagtggta ccaacagcgg cccggccaat ctcctaggcc cctgatatat aagataagta 240
ctcgcttttc cggggtcccg gaccggttca gcgggtctgg gagtggtaca gacttcacat 300
tgaagatttc acgagtagaa gccgaagacg tgggtgttta ttactgcttc caaggatctc 360
acgtgccata tacgtttggt gggggcacaa aagtcgagat taagggaggc ggaggatcag 420
gaggtggggg aagtggaggt ggtgggtcac aagtacagct cgtgcaatca ggggcggagg 480
tgaagaaacc aggggcgtct gtgaaggtaa gctgtaaggc atccggattg acaatcgagg 540
attattacat gcattgggtc cgccaggcac cagggcaggg attggagtgg atggggtgga 600
tagatcctga aaatggggat acagagtatg gccctaagtt ccagggcaga gttacgatga 660
ctcgagatac tagcattaat acggcctaca tggagcttag ccgcctgcgg tccgatgaca 720
cggccgttta ttattgcgcc gtacacaatg cgcactacgg gacatggttc gcgtattggg 780
gtcaaggaac gctcgttact gtctcaagta gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgctcaaagc 1080
ggagtaggtt gttgcattcc gattacatga atatgactcc tcgccggcct gggccgacaa 1140
gaaaacatta ccaaccctat gcccccccac gagacttcgc tgcgtacagg tcccgagtga 1200
agttttcccg aagcgcagac gctccggcat atcagcaagg acagaatcag ctgtataacg 1260
aactgaattt gggacgccgc gaggagtatg acgtgcttga taaacgccgg gggagagacc 1320
cggaaatggg gggtaaaccc cgaagaaaga atccccaaga aggactctac aatgaactcc 1380
agaaggataa gatggcggag gcctactcag aaataggtat gaagggcgaa cgacgacggg 1440
gaaaaggtca cgatggcctc taccaagggt tgagtacggc aaccaaagat acgtacgatg 1500
cactgcatat gcaggccctg cctcccagat aat 1533
<210> 50
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 50
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 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu
20 25 30
Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
35 40 45
Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln
50 55 60
Arg Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg
65 70 75 80
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
100 105 110
Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
145 150 155 160
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr
165 170 175
Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
180 185 190
Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr
195 200 205
Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile
210 215 220
Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala
225 230 235 240
Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala
245 250 255
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
355 360 365
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
370 375 380
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe
385 390 395 400
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
405 410 415
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
420 425 430
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
435 440 445
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
450 455 460
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
465 470 475 480
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
485 490 495
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 51
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 51
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgga cgtggtcatg actcaaagcc cactttcctt gcccgtgact ctcggacaac 120
cggcttcaat atcttgccgc tcatcacagt ccctgctgca tagcagtggt aacacttatc 180
ttgagtggta ccaacagcgg cccggccaat ctcctaggcc cctgatatat aagataagta 240
ctcgcttttc cggggtcccg gaccggttca gcgggtctgg gagtggtaca gacttcacat 300
tgaagatttc acgagtagaa gccgaagacg tgggtgttta ttactgcttc caaggatctc 360
acgtgccata tacgtttggt gggggcacaa aagtcgagat taagggaggc ggaggatcag 420
gaggtggggg aagtggaggt ggtgggtcac aagtacagct cgtgcaatca ggggcggagg 480
tgaagaaacc aggggcgtct gtgaaggtaa gctgtaaggc atccggattg acaatcgagg 540
attattacat gcattgggtc cgccaggcac cagggcaggg attggagtgg atggggtgga 600
tagatcctga aaatggggat acagagtatg gccctaagtt ccagggcaga gttacgatga 660
ctcgagatac tagcattaat acggcctaca tggagcttag ccgcctgcgg tccgatgaca 720
cggccgttta ttattgcgcc gtacacaatg cgcactacgg gacatggttc gcgtattggg 780
gtcaaggaac gctcgttact gtctcaagta gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 52
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 52
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 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu
20 25 30
Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
35 40 45
Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln
50 55 60
Arg Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg
65 70 75 80
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
100 105 110
Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
145 150 155 160
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr
165 170 175
Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
180 185 190
Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr
195 200 205
Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile
210 215 220
Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala
225 230 235 240
Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala
245 250 255
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 53
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 53
gacgtggtca tgactcaaag cccactttcc ttgcccgtga ctctcggaca accggcttca 60
atatcttgcc gctcatcaca gtccctgctg catagcagtg gtaacactta tcttgagtgg 120
taccaacagc ggcccggcca atctcctagg cccctgatat ataagataag tactcgcttt 180
tccggggtcc cggaccggtt cagcgggtct gggagtggta cagacttcac attgaagatt 240
tcacgagtag aagccgaaga cgtgggtgtt tattactgct tccaaggatc tcacgtgcca 300
tatacgtttg gtgggggcac aaaagtcgag attaagggag gcggaggatc aggaggtggg 360
ggaagtggag gtggtgggtc acaagtacag ctcgtgcaat caggggcgga ggtgaagaaa 420
ccaggggcgt ctgtgaaggt aagctgtaag gcatccggat tgacaatcga ggattattac 480
atgcattggg tccgccaggc accagggcag ggattggagt ggatggggtg gatagatcct 540
gaaaatgggg atacagagta tggccctaag ttccagggca gagttacgat gactcgagat 600
actagcatta atacggccta catggagctt agccgcctgc ggtccgatga cacggccgtt 660
tattattgcg ccgtacacaa tgcgcactac gggacatggt tcgcgtattg gggtcaagga 720
acgctcgtta ctgtctcaag t 741
<210> 54
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 54
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser
130 135 140
Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr Tyr
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
165 170 175
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe Gln
180 185 190
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr Met
195 200 205
Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser
245
<210> 55
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 55
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 56
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 56
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 57
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 57
Asp Tyr Tyr Met His
1 5
<210> 58
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 58
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe Gln
1 5 10 15
Gly
<210> 59
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 59
His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr
1 5 10
<210> 60
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 60
Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 61
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 61
Lys Ile Ser Thr Arg Phe Ser
1 5
<210> 62
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 62
Phe Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 63
<211> 4364
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 63
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccggacg tggtcatgac tcaaagccca ctttccttgc ccgtgactct cggacaaccg 2100
gcttcaatat cttgccgctc atcacagtcc ctgctgcata gcagtggtaa cacttatctt 2160
gagtggtacc aacagcggcc cggccaatct cctaggcccc tgatatataa gataagtact 2220
cgcttttccg gggtcccgga ccggttcagc gggtctggga gtggtacaga cttcacattg 2280
aagatttcac gagtagaagc cgaagacgtg ggtgtttatt actgcttcca aggatctcac 2340
gtgccatata cgtttggtgg gggcacaaaa gtcgagatta agggaggcgg aggatcagga 2400
ggtgggggaa gtggaggtgg tgggtcacaa gtacagctcg tgcaatcagg ggcggaggtg 2460
aagaaaccag gggcgtctgt gaaggtaagc tgtaaggcat ccggattgac aatcgaggat 2520
tattacatgc attgggtccg ccaggcacca gggcagggat tggagtggat ggggtggata 2580
gatcctgaaa atggggatac agagtatggc cctaagttcc agggcagagt tacgatgact 2640
cgagatacta gcattaatac ggcctacatg gagcttagcc gcctgcggtc cgatgacacg 2700
gccgtttatt attgcgccgt acacaatgcg cactacggga catggttcgc gtattggggt 2760
caaggaacgc tcgttactgt ctcaagtagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg ctcaaagcgg 3060
agtaggttgt tgcattccga ttacatgaat atgactcctc gccggcctgg gccgacaaga 3120
aaacattacc aaccctatgc ccccccacga gacttcgctg cgtacaggtc ccgagtgaag 3180
ttttcccgaa gcgcagacgc tccggcatat cagcaaggac agaatcagct gtataacgaa 3240
ctgaatttgg gacgccgcga ggagtatgac gtgcttgata aacgccgggg gagagacccg 3300
gaaatggggg gtaaaccccg aagaaagaat ccccaagaag gactctacaa tgaactccag 3360
aaggataaga tggcggaggc ctactcagaa ataggtatga agggcgaacg acgacgggga 3420
aaaggtcacg atggcctcta ccaagggttg agtacggcaa ccaaagatac gtacgatgca 3480
ctgcatatgc aggccctgcc tcccagataa taataaaatc gctatccatc gaagatggat 3540
gtgtgttggt tttttgtgtg tggagcaaca aatctgactt tgcatgtgca aacgccttca 3600
acaacagcat tattccagaa gacaccttct tccccagccc aggtaagggc agctttggtg 3660
ccttcgcagg ctgtttcctt gcttcaggaa tggccaggtt ctgcccagag ctctggtcaa 3720
tgatgtctaa aactcctctg attggtggtc tcggccttat ccattgccac caaaaccctc 3780
tttttactaa gaaacagtga gccttgttct ggcagtccag agaatgacac gggaaaaaag 3840
cagatgaaga gaaggtggca ggagagggca cgtggcccag cctcagtctc tccaactgag 3900
ttcctgcctg cctgcctttg ctcagactgt ttgcccctta ctgctcttct aggcctcatt 3960
ctaagcccct tctccaagtt gcctctcctt atttctccct gtctgccaaa aaatctttcc 4020
cagctcacta agtcagtctc acgcagtcac tcattaaccc accaatcact gattgtgccg 4080
gcacatgaat gcaccaggtg ttgaagtgga ggaattaaaa agtcagatga ggggtgtgcc 4140
cagaggaagc accattctag ttgggggagc ccatctgtca gctgggaaaa gtccaaataa 4200
cttcagattg gaatgtgttt taactcaggg ttgagaaaac agctaccttc aggacaaaag 4260
tcagggaagg gctctctgaa gaaatgctac ttgaagatac cagccctacc aagggcaggg 4320
agaggaccct atagaggcct gggacaggag ctcaatgaga aagg 4364
<210> 64
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 64
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccggacg tggtcatgac tcaaagccca ctttccttgc ccgtgactct cggacaaccg 2100
gcttcaatat cttgccgctc atcacagtcc ctgctgcata gcagtggtaa cacttatctt 2160
gagtggtacc aacagcggcc cggccaatct cctaggcccc tgatatataa gataagtact 2220
cgcttttccg gggtcccgga ccggttcagc gggtctggga gtggtacaga cttcacattg 2280
aagatttcac gagtagaagc cgaagacgtg ggtgtttatt actgcttcca aggatctcac 2340
gtgccatata cgtttggtgg gggcacaaaa gtcgagatta agggaggcgg aggatcagga 2400
ggtgggggaa gtggaggtgg tgggtcacaa gtacagctcg tgcaatcagg ggcggaggtg 2460
aagaaaccag gggcgtctgt gaaggtaagc tgtaaggcat ccggattgac aatcgaggat 2520
tattacatgc attgggtccg ccaggcacca gggcagggat tggagtggat ggggtggata 2580
gatcctgaaa atggggatac agagtatggc cctaagttcc agggcagagt tacgatgact 2640
cgagatacta gcattaatac ggcctacatg gagcttagcc gcctgcggtc cgatgacacg 2700
gccgtttatt attgcgccgt acacaatgcg cactacggga catggttcgc gtattggggt 2760
caaggaacgc tcgttactgt ctcaagtagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 65
<211> 1529
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 65
caccatggcg cttccggtga cagcactgct cctccccttg gcgctgttgc tccacgcagc 60
aaggccgcaa gttcaactgg tccagtcagg cgctgaggtc aaaaagcccg gcgcgagcgt 120
aaaagtctcc tgcaaggcgt cagggttgac gatagaagat tattacatgc attgggtcag 180
acaggcaccc ggacagggat tggagtggat gggttggatc gacccggaaa acggtgacac 240
ggagtatggg ccgaagtttc aggggagggt cacaatgaca cgagatacgt ccataaatac 300
cgcttacatg gaactttctc ggcttcgctc tgatgataca gcagtttact actgcgctgt 360
tcataatgcc cattacggaa cctggttcgc gtactggggc caagggaccc tggttacggt 420
tagctctggt gggggtggaa gcgggggagg gggtagcgga ggtggcggaa gtgatgttgt 480
tatgacacag agtcccctgt cattgcccgt caccctcgga caaccagcta gcatttcatg 540
caggtctagt caaagcctcc ttcacagtag cggcaacacc tacctcgaat ggtatcaaca 600
acggccaggg caatctcctc gcccactcat atacaaaatc tctacacgct tctcaggtgt 660
tcccgaccgc ttcagcggtt ccggctctgg gacagacttt accttgaaaa taagcagggt 720
tgaagctgag gacgtagggg tatattattg ttttcagggc agtcacgtgc cgtacactgg 780
gggcggaacc aaagtcgaga taaagagtgc tgctgccttt gtcccggtat ttctcccagc 840
caaaccgacc acgactcccg ccccgcgccc tccgacaccc gctcccacca tcgcctctca 900
acctcttagt cttcgccccg aggcatgccg acccgccgcc gggggtgctg ttcatacgag 960
gggcttggac ttcgcttgtg atatttacat ttgggctccg ttggcgggta cgtgcggcgt 1020
ccttttgttg tcactcgtta ttactttgta ttgtaatcac aggaatcgct caaagcggag 1080
taggttgttg cattccgatt acatgaatat gactcctcgc cggcctgggc cgacaagaaa 1140
acattaccaa ccctatgccc ccccacgaga cttcgctgcg tacaggtccc gagtgaagtt 1200
ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt ataacgaact 1260
gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga gagacccgga 1320
aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg aactccagaa 1380
ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac gacggggaaa 1440
aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt acgatgcact 1500
gcatatgcag gccctgcctc ccagataat 1529
<210> 66
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 66
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met
355 360 365
Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro
370 375 380
Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe
385 390 395 400
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu
405 410 415
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
420 425 430
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
435 440 445
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
450 455 460
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
465 470 475 480
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
485 490 495
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 67
<211> 1536
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 67
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgca agttcaactg gtccagtcag gcgctgaggt caaaaagccc ggcgcgagcg 120
taaaagtctc ctgcaaggcg tcagggttga cgatagaaga ttattacatg cattgggtca 180
gacaggcacc cggacaggga ttggagtgga tgggttggat cgacccggaa aacggtgaca 240
cggagtatgg gccgaagttt caggggaggg tcacaatgac acgagatacg tccataaata 300
ccgcttacat ggaactttct cggcttcgct ctgatgatac agcagtttac tactgcgctg 360
ttcataatgc ccattacgga acctggttcg cgtactgggg ccaagggacc ctggttacgg 420
ttagctctgg tgggggtgga agcgggggag ggggtagcgg aggtggcgga agtgatgttg 480
ttatgacaca gagtcccctg tcattgcccg tcaccctcgg acaaccagct agcatttcat 540
gcaggtctag tcaaagcctc cttcacagta gcggcaacac ctacctcgaa tggtatcaac 600
aacggccagg gcaatctcct cgcccactca tatacaaaat ctctacacgc ttctcaggtg 660
ttcccgaccg cttcagcggt tccggctctg ggacagactt taccttgaaa ataagcaggg 720
ttgaagctga ggacgtaggg gtatattatt gttttcaggg cagtcacgtg ccgtacactg 780
ggggcggaac caaagtcgag ataaagagtg ctgctgcctt tgtcccggta tttctcccag 840
ccaaaccgac cacgactccc gccccgcgcc ctccgacacc cgctcccacc atcgcctctc 900
aacctcttag tcttcgcccc gaggcatgcc gacccgccgc cgggggtgct gttcatacga 960
ggggcttgga cttcgcttgt gatatttaca tttgggctcc gttggcgggt acgtgcggcg 1020
tccttttgtt gtcactcgtt attactttgt attgtaatca caggaatcgc aaacggggca 1080
gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa actactcaag 1140
aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt gaactgcgag 1200
tgaagttttc ccgaagcgca gacgctccgg catatcagca aggacagaat cagctgtata 1260
acgaactgaa tttgggacgc cgcgaggagt atgacgtgct tgataaacgc cgggggagag 1320
acccggaaat ggggggtaaa ccccgaagaa agaatcccca agaaggactc tacaatgaac 1380
tccagaagga taagatggcg gaggcctact cagaaatagg tatgaagggc gaacgacgac 1440
ggggaaaagg tcacgatggc ctctaccaag ggttgagtac ggcaaccaaa gatacgtacg 1500
atgcactgca tatgcaggcc ctgcctccca gataat 1536
<210> 68
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 68
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 69
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 69
caagttcaac tggtccagtc aggcgctgag gtcaaaaagc ccggcgcgag cgtaaaagtc 60
tcctgcaagg cgtcagggtt gacgatagaa gattattaca tgcattgggt cagacaggca 120
cccggacagg gattggagtg gatgggttgg atcgacccgg aaaacggtga cacggagtat 180
gggccgaagt ttcaggggag ggtcacaatg acacgagata cgtccataaa taccgcttac 240
atggaacttt ctcggcttcg ctctgatgat acagcagttt actactgcgc tgttcataat 300
gcccattacg gaacctggtt cgcgtactgg ggccaaggga ccctggttac ggttagctct 360
ggtgggggtg gaagcggggg agggggtagc ggaggtggcg gaagtgatgt tgttatgaca 420
cagagtcccc tgtcattgcc cgtcaccctc ggacaaccag ctagcatttc atgcaggtct 480
agtcaaagcc tccttcacag tagcggcaac acctacctcg aatggtatca acaacggcca 540
gggcaatctc ctcgcccact catatacaaa atctctacac gcttctcagg tgttcccgac 600
cgcttcagcg gttccggctc tgggacagac tttaccttga aaataagcag ggttgaagct 660
gaggacgtag gggtatatta ttgttttcag ggcagtcacg tgccgtacac tgggggcgga 720
accaaagtcg agataaag 738
<210> 70
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 70
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr Lys Ile Ser
180 185 190
Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 71
<211> 4361
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 71
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccgcaag ttcaactggt ccagtcaggc gctgaggtca aaaagcccgg cgcgagcgta 2100
aaagtctcct gcaaggcgtc agggttgacg atagaagatt attacatgca ttgggtcaga 2160
caggcacccg gacagggatt ggagtggatg ggttggatcg acccggaaaa cggtgacacg 2220
gagtatgggc cgaagtttca ggggagggtc acaatgacac gagatacgtc cataaatacc 2280
gcttacatgg aactttctcg gcttcgctct gatgatacag cagtttacta ctgcgctgtt 2340
cataatgccc attacggaac ctggttcgcg tactggggcc aagggaccct ggttacggtt 2400
agctctggtg ggggtggaag cgggggaggg ggtagcggag gtggcggaag tgatgttgtt 2460
atgacacaga gtcccctgtc attgcccgtc accctcggac aaccagctag catttcatgc 2520
aggtctagtc aaagcctcct tcacagtagc ggcaacacct acctcgaatg gtatcaacaa 2580
cggccagggc aatctcctcg cccactcata tacaaaatct ctacacgctt ctcaggtgtt 2640
cccgaccgct tcagcggttc cggctctggg acagacttta ccttgaaaat aagcagggtt 2700
gaagctgagg acgtaggggt atattattgt tttcagggca gtcacgtgcc gtacactggg 2760
ggcggaacca aagtcgagat aaagagtgct gctgcctttg tcccggtatt tctcccagcc 2820
aaaccgacca cgactcccgc cccgcgccct ccgacacccg ctcccaccat cgcctctcaa 2880
cctcttagtc ttcgccccga ggcatgccga cccgccgccg ggggtgctgt tcatacgagg 2940
ggcttggact tcgcttgtga tatttacatt tgggctccgt tggcgggtac gtgcggcgtc 3000
cttttgttgt cactcgttat tactttgtat tgtaatcaca ggaatcgctc aaagcggagt 3060
aggttgttgc attccgatta catgaatatg actcctcgcc ggcctgggcc gacaagaaaa 3120
cattaccaac cctatgcccc cccacgagac ttcgctgcgt acaggtcccg agtgaagttt 3180
tcccgaagcg cagacgctcc ggcatatcag caaggacaga atcagctgta taacgaactg 3240
aatttgggac gccgcgagga gtatgacgtg cttgataaac gccgggggag agacccggaa 3300
atggggggta aaccccgaag aaagaatccc caagaaggac tctacaatga actccagaag 3360
gataagatgg cggaggccta ctcagaaata ggtatgaagg gcgaacgacg acggggaaaa 3420
ggtcacgatg gcctctacca agggttgagt acggcaacca aagatacgta cgatgcactg 3480
catatgcagg ccctgcctcc cagataataa taaaatcgct atccatcgaa gatggatgtg 3540
tgttggtttt ttgtgtgtgg agcaacaaat ctgactttgc atgtgcaaac gccttcaaca 3600
acagcattat tccagaagac accttcttcc ccagcccagg taagggcagc tttggtgcct 3660
tcgcaggctg tttccttgct tcaggaatgg ccaggttctg cccagagctc tggtcaatga 3720
tgtctaaaac tcctctgatt ggtggtctcg gccttatcca ttgccaccaa aaccctcttt 3780
ttactaagaa acagtgagcc ttgttctggc agtccagaga atgacacggg aaaaaagcag 3840
atgaagagaa ggtggcagga gagggcacgt ggcccagcct cagtctctcc aactgagttc 3900
ctgcctgcct gcctttgctc agactgtttg ccccttactg ctcttctagg cctcattcta 3960
agccccttct ccaagttgcc tctccttatt tctccctgtc tgccaaaaaa tctttcccag 4020
ctcactaagt cagtctcacg cagtcactca ttaacccacc aatcactgat tgtgccggca 4080
catgaatgca ccaggtgttg aagtggagga attaaaaagt cagatgaggg gtgtgcccag 4140
aggaagcacc attctagttg ggggagccca tctgtcagct gggaaaagtc caaataactt 4200
cagattggaa tgtgttttaa ctcagggttg agaaaacagc taccttcagg acaaaagtca 4260
gggaagggct ctctgaagaa atgctacttg aagataccag ccctaccaag ggcagggaga 4320
ggaccctata gaggcctggg acaggagctc aatgagaaag g 4361
<210> 72
<211> 4367
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 72
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccgcaag ttcaactggt ccagtcaggc gctgaggtca aaaagcccgg cgcgagcgta 2100
aaagtctcct gcaaggcgtc agggttgacg atagaagatt attacatgca ttgggtcaga 2160
caggcacccg gacagggatt ggagtggatg ggttggatcg acccggaaaa cggtgacacg 2220
gagtatgggc cgaagtttca ggggagggtc acaatgacac gagatacgtc cataaatacc 2280
gcttacatgg aactttctcg gcttcgctct gatgatacag cagtttacta ctgcgctgtt 2340
cataatgccc attacggaac ctggttcgcg tactggggcc aagggaccct ggttacggtt 2400
agctctggtg ggggtggaag cgggggaggg ggtagcggag gtggcggaag tgatgttgtt 2460
atgacacaga gtcccctgtc attgcccgtc accctcggac aaccagctag catttcatgc 2520
aggtctagtc aaagcctcct tcacagtagc ggcaacacct acctcgaatg gtatcaacaa 2580
cggccagggc aatctcctcg cccactcata tacaaaatct ctacacgctt ctcaggtgtt 2640
cccgaccgct tcagcggttc cggctctggg acagacttta ccttgaaaat aagcagggtt 2700
gaagctgagg acgtaggggt atattattgt tttcagggca gtcacgtgcc gtacactggg 2760
ggcggaacca aagtcgagat aaagagtgct gctgcctttg tcccggtatt tctcccagcc 2820
aaaccgacca cgactcccgc cccgcgccct ccgacacccg ctcccaccat cgcctctcaa 2880
cctcttagtc ttcgccccga ggcatgccga cccgccgccg ggggtgctgt tcatacgagg 2940
ggcttggact tcgcttgtga tatttacatt tgggctccgt tggcgggtac gtgcggcgtc 3000
cttttgttgt cactcgttat tactttgtat tgtaatcaca ggaatcgcaa acggggcaga 3060
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 3120
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgcgagtg 3180
aagttttccc gaagcgcaga cgctccggca tatcagcaag gacagaatca gctgtataac 3240
gaactgaatt tgggacgccg cgaggagtat gacgtgcttg ataaacgccg ggggagagac 3300
ccggaaatgg ggggtaaacc ccgaagaaag aatccccaag aaggactcta caatgaactc 3360
cagaaggata agatggcgga ggcctactca gaaataggta tgaagggcga acgacgacgg 3420
ggaaaaggtc acgatggcct ctaccaaggg ttgagtacgg caaccaaaga tacgtacgat 3480
gcactgcata tgcaggccct gcctcccaga taataataaa atcgctatcc atcgaagatg 3540
gatgtgtgtt ggttttttgt gtgtggagca acaaatctga ctttgcatgt gcaaacgcct 3600
tcaacaacag cattattcca gaagacacct tcttccccag cccaggtaag ggcagctttg 3660
gtgccttcgc aggctgtttc cttgcttcag gaatggccag gttctgccca gagctctggt 3720
caatgatgtc taaaactcct ctgattggtg gtctcggcct tatccattgc caccaaaacc 3780
ctctttttac taagaaacag tgagccttgt tctggcagtc cagagaatga cacgggaaaa 3840
aagcagatga agagaaggtg gcaggagagg gcacgtggcc cagcctcagt ctctccaact 3900
gagttcctgc ctgcctgcct ttgctcagac tgtttgcccc ttactgctct tctaggcctc 3960
attctaagcc ccttctccaa gttgcctctc cttatttctc cctgtctgcc aaaaaatctt 4020
tcccagctca ctaagtcagt ctcacgcagt cactcattaa cccaccaatc actgattgtg 4080
ccggcacatg aatgcaccag gtgttgaagt ggaggaatta aaaagtcaga tgaggggtgt 4140
gcccagagga agcaccattc tagttggggg agcccatctg tcagctggga aaagtccaaa 4200
taacttcaga ttggaatgtg ttttaactca gggttgagaa aacagctacc ttcaggacaa 4260
aagtcaggga agggctctct gaagaaatgc tacttgaaga taccagccct accaagggca 4320
gggagaggac cctatagagg cctgggacag gagctcaatg agaaagg 4367
<210> 73
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 73
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
20
<210> 74
<211> 261
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 74
gctgctgcct ttgtcccggt atttctccca gccaaaccga ccacgactcc cgccccgcgc 60
cctccgacac ccgctcccac catcgcctct caacctctta gtcttcgccc cgaggcatgc 120
cgacccgccg ccgggggtgc tgttcatacg aggggcttgg acttcgcttg tgatatttac 180
atttgggctc cgttggcggg tacgtgcggc gtccttttgt tgtcactcgt tattactttg 240
tattgtaatc acaggaatcg c 261
<210> 75
<211> 88
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 75
Ser Ala Ala Ala Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr
1 5 10 15
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
20 25 30
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
35 40 45
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
50 55 60
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
65 70 75 80
Leu Tyr Cys Asn His Arg Asn Arg
85
<210> 76
<211> 252
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 76
tttgtcccgg tatttctccc agccaaaccg accacgactc ccgccccgcg ccctccgaca 60
cccgctccca ccatcgcctc tcaacctctt agtcttcgcc ccgaggcatg ccgacccgcc 120
gccgggggtg ctgttcatac gaggggcttg gacttcgctt gtgatattta catttgggct 180
ccgttggcgg gtacgtgcgg cgtccttttg ttgtcactcg ttattacttt gtattgtaat 240
cacaggaatc gc 252
<210> 77
<211> 84
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 77
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
1 5 10 15
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
20 25 30
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
35 40 45
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
50 55 60
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
65 70 75 80
His Arg Asn Arg
<210> 78
<211> 800
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 78
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca 800
<210> 79
<211> 1178
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 79
ggctccggtg cccgtcagtg ggcagagcgc acatcgccca cagtccccga gaagttgggg 60
ggaggggtcg gcaattgaac cggtgcctag agaaggtggc gcggggtaaa ctgggaaagt 120
gatgtcgtgt actggctccg cctttttccc gagggtgggg gagaaccgta tataagtgca 180
gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg ccagaacaca ggtaagtgcc 240
gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg gcccttgcgt gccttgaatt 300
acttccactg gctgcagtac gtgattcttg atcccgagct tcgggttgga agtgggtggg 360
agagttcgag gccttgcgct taaggagccc cttcgcctcg tgcttgagtt gaggcctggc 420
ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct tcgcgcctgt ctcgctgctt 480
tcgataagtc tctagccatt taaaattttt gatgacctgc tgcgacgctt tttttctggc 540
aagatagtct tgtaaatgcg ggccaagatc tgcacactgg tatttcggtt tttggggccg 600
cgggcggcga cggggcccgt gcgtcccagc gcacatgttc ggcgaggcgg ggcctgcgag 660
cgcggccacc gagaatcgga cgggggtagt ctcaagctgg ccggcctgct ctggtgcctg 720
gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag gctggcccgg tcggcaccag 780
ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc agggagctca aaatggagga 840
cgcggcgctc gggagagcgg gcgggtgagt cacccacaca aaggaaaagg gcctttccgt 900
cctcagccgt cgcttcatgt gactccacgg agtaccgggc gccgtccagg cacctcgatt 960
agttctcgag cttttggagt acgtcgtctt taggttgggg ggaggggttt tatgcgatgg 1020
agtttcccca cactgagtgg gtggagactg aagttaggcc agcttggcac ttgatgtaat 1080
tctccttgga atttgccctt tttgagtttg gatcttggtt cattctcaag cctcagacag 1140
tggttcaaag tttttttctt ccatttcagg tgtcgtga 1178
<210> 80
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 80
aataaaatcg ctatccatcg aagatggatg tgtgttggtt ttttgtgtg 49
<210> 81
<211> 804
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 81
tggagcaaca aatctgactt tgcatgtgca aacgccttca acaacagcat tattccagaa 60
gacaccttct tccccagccc aggtaagggc agctttggtg ccttcgcagg ctgtttcctt 120
gcttcaggaa tggccaggtt ctgcccagag ctctggtcaa tgatgtctaa aactcctctg 180
attggtggtc tcggccttat ccattgccac caaaaccctc tttttactaa gaaacagtga 240
gccttgttct ggcagtccag agaatgacac gggaaaaaag cagatgaaga gaaggtggca 300
ggagagggca cgtggcccag cctcagtctc tccaactgag ttcctgcctg cctgcctttg 360
ctcagactgt ttgcccctta ctgctcttct aggcctcatt ctaagcccct tctccaagtt 420
gcctctcctt atttctccct gtctgccaaa aaatctttcc cagctcacta agtcagtctc 480
acgcagtcac tcattaaccc accaatcact gattgtgccg gcacatgaat gcaccaggtg 540
ttgaagtgga ggaattaaaa agtcagatga ggggtgtgcc cagaggaagc accattctag 600
ttgggggagc ccatctgtca gctgggaaaa gtccaaataa cttcagattg gaatgtgttt 660
taactcaggg ttgagaaaac agctaccttc aggacaaaag tcagggaagg gctctctgaa 720
gaaatgctac ttgaagatac cagccctacc aagggcaggg agaggaccct atagaggcct 780
gggacaggag ctcaatgaga aagg 804
<210> 82
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 82
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser
130 135 140
Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr Tyr
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
165 170 175
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe Gln
180 185 190
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met
195 200 205
Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser
245
<210> 83
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 83
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser
130 135 140
Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr Tyr
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
165 170 175
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe Gln
180 185 190
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr Met
195 200 205
Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser
245
<210> 84
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 84
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser
130 135 140
Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr Tyr
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
165 170 175
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe Gln
180 185 190
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met
195 200 205
Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser
245
<210> 85
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 85
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr Lys Ile Ser
180 185 190
Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 86
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 86
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Leu Gln Arg Pro Gly Gln Ser Pro Lys Pro Leu Ile Tyr Lys Ile Ser
180 185 190
Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 87
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 87
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Leu Gln Arg Pro Gly Gln Ser Pro Lys Pro Leu Ile Tyr Lys Ile Ser
180 185 190
Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 88
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 88
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 89
<400> 89
000
<210> 90
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 90
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 91
<400> 91
000
<210> 92
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 92
agagcaacag tgctgtggcc 20
<210> 93
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 93
agagcaacag ugcuguggcc 20
<210> 94
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 94
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro
20
<210> 95
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 95
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgga tgtcgttatg acacaatctc ccttgagttt gccggttacc ttgggacaac 120
ctgctagtat ttcatgtagg agttctcaaa gtctcttgca ctcctcaggg aacacctacc 180
tcgaatggta ccaacaacgc cctggccaaa gcccgcggcc cttgatatac aaaatatcaa 240
caagatttag cggggtaccc gatagattca gcggctctgg cagcgggacg gattttaccc 300
tgaaaattag tcgcgtagaa gctgaagacg ttggtgtgta ttactgcttt caagggagcc 360
atgtgcctta cacatttgga ggaggcacca aggtcgagat taagggaggg ggtggatcag 420
gtgggggtgg gtccggaggc ggcggcagtc aagtgcagtt ggttcaatca ggagctgaag 480
ttaaaaagcc aggagcttca gtcaaggttt catgcaaggc gtccggtctc actatagagg 540
attactacat gcactgggtg cggcaagctc caggccaggg gctggagtgg atgggatgga 600
ttgatccgga aaacggggac acagagtatg ggcccaaatt ccaaggccgg gtgacaatga 660
ccagagatac tagtatttca acagcataca tggagctgtc acggctgagg tcagacgata 720
cggcagtcta ctattgtgca gtacataacg cacattatgg tacgtggttc gcttattggg 780
gtcaaggtac cctggtcacg gtaagttcaa gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 96
<211> 509
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 96
Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His
1 5 10 15
Ala Ala Arg Pro Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro
20 25 30
Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser
35 40 45
Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg
50 55 60
Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
85 90 95
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys
115 120 125
Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
145 150 155 160
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile
165 170 175
Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
180 185 190
Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly
195 200 205
Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
210 215 220
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr
245 250 255
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Ala Ala Ala Phe
260 265 270
Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg
275 280 285
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
290 295 300
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
305 310 315 320
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
325 330 335
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His
340 345 350
Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
355 360 365
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
370 375 380
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
385 390 395 400
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
405 410 415
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
420 425 430
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
435 440 445
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
450 455 460
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
465 470 475 480
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
485 490 495
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 97
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 97
gatgtcgtta tgacacaatc tcccttgagt ttgccggtta ccttgggaca acctgctagt 60
atttcatgta ggagttctca aagtctcttg cactcctcag ggaacaccta cctcgaatgg 120
taccaacaac gccctggcca aagcccgcgg cccttgatat acaaaatatc aacaagattt 180
agcggggtac ccgatagatt cagcggctct ggcagcggga cggattttac cctgaaaatt 240
agtcgcgtag aagctgaaga cgttggtgtg tattactgct ttcaagggag ccatgtgcct 300
tacacatttg gaggaggcac caaggtcgag attaagggag ggggtggatc aggtgggggt 360
gggtccggag gcggcggcag tcaagtgcag ttggttcaat caggagctga agttaaaaag 420
ccaggagctt cagtcaaggt ttcatgcaag gcgtccggtc tcactataga ggattactac 480
atgcactggg tgcggcaagc tccaggccag gggctggagt ggatgggatg gattgatccg 540
gaaaacgggg acacagagta tgggcccaaa ttccaaggcc gggtgacaat gaccagagat 600
actagtattt caacagcata catggagctg tcacggctga ggtcagacga tacggcagtc 660
tactattgtg cagtacataa cgcacattat ggtacgtggt tcgcttattg gggtcaaggt 720
accctggtca cggtaagttc a 741
<210> 98
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 98
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 99
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 99
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccggatg tcgttatgac acaatctccc ttgagtttgc cggttacctt gggacaacct 2100
gctagtattt catgtaggag ttctcaaagt ctcttgcact cctcagggaa cacctacctc 2160
gaatggtacc aacaacgccc tggccaaagc ccgcggccct tgatatacaa aatatcaaca 2220
agatttagcg gggtacccga tagattcagc ggctctggca gcgggacgga ttttaccctg 2280
aaaattagtc gcgtagaagc tgaagacgtt ggtgtgtatt actgctttca agggagccat 2340
gtgccttaca catttggagg aggcaccaag gtcgagatta agggaggggg tggatcaggt 2400
gggggtgggt ccggaggcgg cggcagtcaa gtgcagttgg ttcaatcagg agctgaagtt 2460
aaaaagccag gagcttcagt caaggtttca tgcaaggcgt ccggtctcac tatagaggat 2520
tactacatgc actgggtgcg gcaagctcca ggccaggggc tggagtggat gggatggatt 2580
gatccggaaa acggggacac agagtatggg cccaaattcc aaggccgggt gacaatgacc 2640
agagatacta gtatttcaac agcatacatg gagctgtcac ggctgaggtc agacgatacg 2700
gcagtctact attgtgcagt acataacgca cattatggta cgtggttcgc ttattggggt 2760
caaggtaccc tggtcacggt aagttcaagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 100
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 100
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgca ggtgcagctg gtccaaagcg gcgccgaggt taagaaacca ggcgcatccg 120
tcaaggtttc atgtaaagca agtggcttga ctatagaaga ctactacatg cattgggtac 180
ggcaagcccc tgggcagggg ctggaatgga tggggtggat cgacccggag aatggtgata 240
cagagtacgg acctaagttc cagggacgag ttaccatgac gcgagataca tccatctcca 300
cggcatacat ggagctgagt cgactgcgga gcgatgatac agctgtctat tattgtgctg 360
tccacaatgc gcactacggc acctggttcg cttattgggg acaaggtacc ctggtcacag 420
tcagctctgg gggtggcggc agtggagggg gtggttctgg tggcgggggt tccgatgttg 480
taatgactca aagccctctt tctttgccag tcactctcgg acaacccgcg agcatatctt 540
gcaggtcttc acaatcactc cttcacagta gcgggaatac ttacttggag tggtatcagc 600
agcggcctgg tcagtcccct agaccgctta tatataagat ctccactagg ttcagtggag 660
tgccggaccg cttttcaggc tcaggttccg ggacggactt tacattgaaa atatccaggg 720
tggaggcgga ggacgtcgga gtctactatt gcttccaagg ctcccacgtc ccatacactt 780
tcggtggcgg tacaaaagtg gaaataaaaa gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 101
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 101
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 102
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 102
caggtgcagc tggtccaaag cggcgccgag gttaagaaac caggcgcatc cgtcaaggtt 60
tcatgtaaag caagtggctt gactatagaa gactactaca tgcattgggt acggcaagcc 120
cctgggcagg ggctggaatg gatggggtgg atcgacccgg agaatggtga tacagagtac 180
ggacctaagt tccagggacg agttaccatg acgcgagata catccatctc cacggcatac 240
atggagctga gtcgactgcg gagcgatgat acagctgtct attattgtgc tgtccacaat 300
gcgcactacg gcacctggtt cgcttattgg ggacaaggta ccctggtcac agtcagctct 360
gggggtggcg gcagtggagg gggtggttct ggtggcgggg gttccgatgt tgtaatgact 420
caaagccctc tttctttgcc agtcactctc ggacaacccg cgagcatatc ttgcaggtct 480
tcacaatcac tccttcacag tagcgggaat acttacttgg agtggtatca gcagcggcct 540
ggtcagtccc ctagaccgct tatatataag atctccacta ggttcagtgg agtgccggac 600
cgcttttcag gctcaggttc cgggacggac tttacattga aaatatccag ggtggaggcg 660
gaggacgtcg gagtctacta ttgcttccaa ggctcccacg tcccatacac tttcggtggc 720
ggtacaaaag tggaaataaa a 741
<210> 103
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 103
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccgcagg tgcagctggt ccaaagcggc gccgaggtta agaaaccagg cgcatccgtc 2100
aaggtttcat gtaaagcaag tggcttgact atagaagact actacatgca ttgggtacgg 2160
caagcccctg ggcaggggct ggaatggatg gggtggatcg acccggagaa tggtgataca 2220
gagtacggac ctaagttcca gggacgagtt accatgacgc gagatacatc catctccacg 2280
gcatacatgg agctgagtcg actgcggagc gatgatacag ctgtctatta ttgtgctgtc 2340
cacaatgcgc actacggcac ctggttcgct tattggggac aaggtaccct ggtcacagtc 2400
agctctgggg gtggcggcag tggagggggt ggttctggtg gcgggggttc cgatgttgta 2460
atgactcaaa gccctctttc tttgccagtc actctcggac aacccgcgag catatcttgc 2520
aggtcttcac aatcactcct tcacagtagc gggaatactt acttggagtg gtatcagcag 2580
cggcctggtc agtcccctag accgcttata tataagatct ccactaggtt cagtggagtg 2640
ccggaccgct tttcaggctc aggttccggg acggacttta cattgaaaat atccagggtg 2700
gaggcggagg acgtcggagt ctactattgc ttccaaggct cccacgtccc atacactttc 2760
ggtggcggta caaaagtgga aataaaaagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 104
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 104
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgga tgtagttatg acccagagtc cgctctcttt gccggtgacg ctcggccaac 120
cggcgtctat ttcttgcaga agtagtcaat cacttctgca ctctagcggt aacacttatt 180
tggagtggta tctccaacga ccagggcaaa gccccaagcc gttgatttat aagatctcta 240
caagattcag cggagtgccc gacagatttt ccgggagtgg gtccggtact gatttcactt 300
tgaaaatttc ccgcgtcgag gctgaagatg ttggtgtcta ctactgcttt caggggagcc 360
atgttccata tacctttgga ggtgggacta aggtagaaat taaaggtggg ggtggatcag 420
ggggtggcgg cagcggggga gggggctcac aagtgcaact tgtgcaaagt ggggccgagg 480
tgaaaaaacc cggtgcaagt gtaaaggtct catgcaaagc gtctggtttg acaattgaag 540
actattatat gcattgggtg agacaggccc cgggccaagg cttggaatgg atgggatgga 600
tagaccccga aaacggtgac acggagtacg gacctaaatt tcaaggaaga gtgacaatga 660
cacgcgatac atctattaac acggcttata tggaactgag ccgacttcgg agtgatgaca 720
ctgctgtata ttattgcgcc gtccacaacg cacattatgg cacctggttt gcgtactggg 780
gacagggaac tttggttaca gtatcaagca gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 105
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 105
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 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu
20 25 30
Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
35 40 45
Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln
50 55 60
Arg Pro Gly Gln Ser Pro Lys Pro Leu Ile Tyr Lys Ile Ser Thr Arg
65 70 75 80
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
100 105 110
Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
145 150 155 160
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr
165 170 175
Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
180 185 190
Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr
195 200 205
Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile
210 215 220
Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala
225 230 235 240
Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala
245 250 255
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 106
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 106
gatgtagtta tgacccagag tccgctctct ttgccggtga cgctcggcca accggcgtct 60
atttcttgca gaagtagtca atcacttctg cactctagcg gtaacactta tttggagtgg 120
tatctccaac gaccagggca aagccccaag ccgttgattt ataagatctc tacaagattc 180
agcggagtgc ccgacagatt ttccgggagt gggtccggta ctgatttcac tttgaaaatt 240
tcccgcgtcg aggctgaaga tgttggtgtc tactactgct ttcaggggag ccatgttcca 300
tatacctttg gaggtgggac taaggtagaa attaaaggtg ggggtggatc agggggtggc 360
ggcagcgggg gagggggctc acaagtgcaa cttgtgcaaa gtggggccga ggtgaaaaaa 420
cccggtgcaa gtgtaaaggt ctcatgcaaa gcgtctggtt tgacaattga agactattat 480
atgcattggg tgagacaggc cccgggccaa ggcttggaat ggatgggatg gatagacccc 540
gaaaacggtg acacggagta cggacctaaa tttcaaggaa gagtgacaat gacacgcgat 600
acatctatta acacggctta tatggaactg agccgacttc ggagtgatga cactgctgta 660
tattattgcg ccgtccacaa cgcacattat ggcacctggt ttgcgtactg gggacaggga 720
actttggtta cagtatcaag c 741
<210> 107
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 107
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccggatg tagttatgac ccagagtccg ctctctttgc cggtgacgct cggccaaccg 2100
gcgtctattt cttgcagaag tagtcaatca cttctgcact ctagcggtaa cacttatttg 2160
gagtggtatc tccaacgacc agggcaaagc cccaagccgt tgatttataa gatctctaca 2220
agattcagcg gagtgcccga cagattttcc gggagtgggt ccggtactga tttcactttg 2280
aaaatttccc gcgtcgaggc tgaagatgtt ggtgtctact actgctttca ggggagccat 2340
gttccatata cctttggagg tgggactaag gtagaaatta aaggtggggg tggatcaggg 2400
ggtggcggca gcgggggagg gggctcacaa gtgcaacttg tgcaaagtgg ggccgaggtg 2460
aaaaaacccg gtgcaagtgt aaaggtctca tgcaaagcgt ctggtttgac aattgaagac 2520
tattatatgc attgggtgag acaggccccg ggccaaggct tggaatggat gggatggata 2580
gaccccgaaa acggtgacac ggagtacgga cctaaatttc aaggaagagt gacaatgaca 2640
cgcgatacat ctattaacac ggcttatatg gaactgagcc gacttcggag tgatgacact 2700
gctgtatatt attgcgccgt ccacaacgca cattatggca cctggtttgc gtactgggga 2760
cagggaactt tggttacagt atcaagcagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 108
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 108
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgca ggttcaactg gttcagagtg gagcagaggt aaaaaagccc ggagcgtccg 120
tcaaagtgtc atgtaaagcc tctggactta ctatcgaaga ctactacatg cactgggtga 180
ggcaggcgcc tggccaaggt ctcgagtgga tgggttggat tgaccctgaa aatggagata 240
cagaatacgg ccctaagttt caagggcgag taactatgac tcgagatacg tcaattaata 300
cggcatacat ggagttgtct cggctccgat ctgatgacac tgcagtttac tattgtgccg 360
tccacaatgc tcattacggg acatggttcg cttactgggg gcaagggaca ctcgtaacgg 420
ttagctctgg gggaggaggg tctggtggag ggggctcagg agggggtggt agcgacgtag 480
taatgaccca gtcacctctg tctttgccgg tcacgttggg ccagcctgca tccatatcct 540
gcagatccag ccagagcctc ctgcacagta gtggcaacac gtatttggaa tggtacctgc 600
agaggccggg tcaaagtcca aaaccgctga tctataagat atctacgcga ttttcagggg 660
tgccggaccg atttagcgga tcaggaagtg gaaccgactt tacgctcaag atcagccggg 720
ttgaagccga agatgtcggc gtttactact gtttccaagg aagccacgta ccctatacgt 780
ttggtggcgg cacgaaggtc gagataaaga gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 109
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 109
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 110
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 110
caggttcaac tggttcagag tggagcagag gtaaaaaagc ccggagcgtc cgtcaaagtg 60
tcatgtaaag cctctggact tactatcgaa gactactaca tgcactgggt gaggcaggcg 120
cctggccaag gtctcgagtg gatgggttgg attgaccctg aaaatggaga tacagaatac 180
ggccctaagt ttcaagggcg agtaactatg actcgagata cgtcaattaa tacggcatac 240
atggagttgt ctcggctccg atctgatgac actgcagttt actattgtgc cgtccacaat 300
gctcattacg ggacatggtt cgcttactgg gggcaaggga cactcgtaac ggttagctct 360
gggggaggag ggtctggtgg agggggctca ggagggggtg gtagcgacgt agtaatgacc 420
cagtcacctc tgtctttgcc ggtcacgttg ggccagcctg catccatatc ctgcagatcc 480
agccagagcc tcctgcacag tagtggcaac acgtatttgg aatggtacct gcagaggccg 540
ggtcaaagtc caaaaccgct gatctataag atatctacgc gattttcagg ggtgccggac 600
cgatttagcg gatcaggaag tggaaccgac tttacgctca agatcagccg ggttgaagcc 660
gaagatgtcg gcgtttacta ctgtttccaa ggaagccacg taccctatac gtttggtggc 720
ggcacgaagg tcgagataaa g 741
<210> 111
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 111
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccgcagg ttcaactggt tcagagtgga gcagaggtaa aaaagcccgg agcgtccgtc 2100
aaagtgtcat gtaaagcctc tggacttact atcgaagact actacatgca ctgggtgagg 2160
caggcgcctg gccaaggtct cgagtggatg ggttggattg accctgaaaa tggagataca 2220
gaatacggcc ctaagtttca agggcgagta actatgactc gagatacgtc aattaatacg 2280
gcatacatgg agttgtctcg gctccgatct gatgacactg cagtttacta ttgtgccgtc 2340
cacaatgctc attacgggac atggttcgct tactgggggc aagggacact cgtaacggtt 2400
agctctgggg gaggagggtc tggtggaggg ggctcaggag ggggtggtag cgacgtagta 2460
atgacccagt cacctctgtc tttgccggtc acgttgggcc agcctgcatc catatcctgc 2520
agatccagcc agagcctcct gcacagtagt ggcaacacgt atttggaatg gtacctgcag 2580
aggccgggtc aaagtccaaa accgctgatc tataagatat ctacgcgatt ttcaggggtg 2640
ccggaccgat ttagcggatc aggaagtgga accgacttta cgctcaagat cagccgggtt 2700
gaagccgaag atgtcggcgt ttactactgt ttccaaggaa gccacgtacc ctatacgttt 2760
ggtggcggca cgaaggtcga gataaagagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 112
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 112
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgga cgttgtgatg acgcagtctc ctctgagcct gccagttacg ttggggcaac 120
ccgcatcaat atcttgtagg tccagtcaga gcctgcttca cagctctggc aacacttact 180
tggaatggta cctccagaga cctggacaga gtcccaagcc attgatttac aagatttcaa 240
cgcgatttag tggagtgccc gatcgattct ctgggagtgg ctctgggact gatttcacac 300
ttaaaataag tagggtggag gctgaagatg tgggtgtata ttattgtttt caagggtccc 360
atgtccctta cactttcggc ggcggcacca aagttgagat caaaggtggt ggtgggtccg 420
gcggtggagg cagtgggggt ggcgggtcac aagttcaact tgtccagtca ggggctgaag 480
taaaaaagcc tggtgcatca gttaaagttt catgtaaggc ttccggcctt accattgaag 540
attactatat gcactgggtt agacaagctc ctggacaagg tctggagtgg atgggctgga 600
tagaccccga gaatggtgac acagaatacg ggcctaagtt ccagggtagg gtaacaatga 660
cgcgggatac atccatttcc acagcttaca tggaactgag tagactcaga tctgacgaca 720
ctgctgtcta ctattgtgcc gtccataacg cgcattatgg cacttggttc gcatattggg 780
ggcaaggcac tcttgttaca gtgtcctcaa gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 113
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 113
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 Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu
20 25 30
Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
35 40 45
Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln
50 55 60
Arg Pro Gly Gln Ser Pro Lys Pro Leu Ile Tyr Lys Ile Ser Thr Arg
65 70 75 80
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr
100 105 110
Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
145 150 155 160
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr
165 170 175
Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
180 185 190
Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr
195 200 205
Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile
210 215 220
Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala
225 230 235 240
Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala
245 250 255
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 114
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 114
gacgttgtga tgacgcagtc tcctctgagc ctgccagtta cgttggggca acccgcatca 60
atatcttgta ggtccagtca gagcctgctt cacagctctg gcaacactta cttggaatgg 120
tacctccaga gacctggaca gagtcccaag ccattgattt acaagatttc aacgcgattt 180
agtggagtgc ccgatcgatt ctctgggagt ggctctggga ctgatttcac acttaaaata 240
agtagggtgg aggctgaaga tgtgggtgta tattattgtt ttcaagggtc ccatgtccct 300
tacactttcg gcggcggcac caaagttgag atcaaaggtg gtggtgggtc cggcggtgga 360
ggcagtgggg gtggcgggtc acaagttcaa cttgtccagt caggggctga agtaaaaaag 420
cctggtgcat cagttaaagt ttcatgtaag gcttccggcc ttaccattga agattactat 480
atgcactggg ttagacaagc tcctggacaa ggtctggagt ggatgggctg gatagacccc 540
gagaatggtg acacagaata cgggcctaag ttccagggta gggtaacaat gacgcgggat 600
acatccattt ccacagctta catggaactg agtagactca gatctgacga cactgctgtc 660
tactattgtg ccgtccataa cgcgcattat ggcacttggt tcgcatattg ggggcaaggc 720
actcttgtta cagtgtcctc a 741
<210> 115
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 115
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccggacg ttgtgatgac gcagtctcct ctgagcctgc cagttacgtt ggggcaaccc 2100
gcatcaatat cttgtaggtc cagtcagagc ctgcttcaca gctctggcaa cacttacttg 2160
gaatggtacc tccagagacc tggacagagt cccaagccat tgatttacaa gatttcaacg 2220
cgatttagtg gagtgcccga tcgattctct gggagtggct ctgggactga tttcacactt 2280
aaaataagta gggtggaggc tgaagatgtg ggtgtatatt attgttttca agggtcccat 2340
gtcccttaca ctttcggcgg cggcaccaaa gttgagatca aaggtggtgg tgggtccggc 2400
ggtggaggca gtgggggtgg cgggtcacaa gttcaacttg tccagtcagg ggctgaagta 2460
aaaaagcctg gtgcatcagt taaagtttca tgtaaggctt ccggccttac cattgaagat 2520
tactatatgc actgggttag acaagctcct ggacaaggtc tggagtggat gggctggata 2580
gaccccgaga atggtgacac agaatacggg cctaagttcc agggtagggt aacaatgacg 2640
cgggatacat ccatttccac agcttacatg gaactgagta gactcagatc tgacgacact 2700
gctgtctact attgtgccgt ccataacgcg cattatggca cttggttcgc atattggggg 2760
caaggcactc ttgttacagt gtcctcaagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 116
<211> 1539
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 116
ccaccatggc gcttccggtg acagcactgc tcctcccctt ggcgctgttg ctccacgcag 60
caaggccgca ggtacaactc gttcagagcg gtgcagaggt taagaaaccg ggcgccagtg 120
tcaaagtatc atgcaaggcg agtggtctga ccatcgaaga ttattatatg cattgggtga 180
gacaagcacc ggggcagggg ctcgaatgga tgggttggat cgaccccgaa aatggtgata 240
cggagtatgg cccgaaattt cagggtcggg tcacgatgac ccgcgataca agcatcagta 300
ctgcatacat ggagctctct cgcttgcgga gtgatgatac cgccgtttat tattgcgcgg 360
ttcacaacgc tcattatggc acttggttcg cgtattgggg ccaaggaaca ctggttacag 420
tgagcagtgg agggggtggc tctggtggcg gcgggagcgg cggagggggc agtgatgttg 480
tgatgacaca gtcacccctg agtctcccgg tcactcttgg gcaaccagcc agcataagct 540
gtcgcagttc tcagagcttg ctccatagct ccgggaatac ctacctcgaa tggtatctcc 600
aaagacccgg tcaatctcca aagcctttga tttacaagat tagtacacga tttagtgggg 660
tcccagatag attttcaggt agtggatctg gtacagattt cacattgaaa atatcacgcg 720
tcgaggcgga ggatgtcggg gtctactatt gctttcaagg tagtcacgtg ccctacacgt 780
ttggtggcgg tacgaaggtc gaaatcaaga gtgctgctgc ctttgtcccg gtatttctcc 840
cagccaaacc gaccacgact cccgccccgc gccctccgac acccgctccc accatcgcct 900
ctcaacctct tagtcttcgc cccgaggcat gccgacccgc cgccgggggt gctgttcata 960
cgaggggctt ggacttcgct tgtgatattt acatttgggc tccgttggcg ggtacgtgcg 1020
gcgtcctttt gttgtcactc gttattactt tgtattgtaa tcacaggaat cgcaaacggg 1080
gcagaaagaa actcctgtat atattcaaac aaccatttat gagaccagta caaactactc 1140
aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga tgtgaactgc 1200
gagtgaagtt ttcccgaagc gcagacgctc cggcatatca gcaaggacag aatcagctgt 1260
ataacgaact gaatttggga cgccgcgagg agtatgacgt gcttgataaa cgccggggga 1320
gagacccgga aatggggggt aaaccccgaa gaaagaatcc ccaagaagga ctctacaatg 1380
aactccagaa ggataagatg gcggaggcct actcagaaat aggtatgaag ggcgaacgac 1440
gacggggaaa aggtcacgat ggcctctacc aagggttgag tacggcaacc aaagatacgt 1500
acgatgcact gcatatgcag gccctgcctc ccagataat 1539
<210> 117
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 117
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala
260 265 270
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
275 280 285
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
290 295 300
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
305 310 315 320
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
325 330 335
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
340 345 350
His Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 118
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 118
caggtacaac tcgttcagag cggtgcagag gttaagaaac cgggcgccag tgtcaaagta 60
tcatgcaagg cgagtggtct gaccatcgaa gattattata tgcattgggt gagacaagca 120
ccggggcagg ggctcgaatg gatgggttgg atcgaccccg aaaatggtga tacggagtat 180
ggcccgaaat ttcagggtcg ggtcacgatg acccgcgata caagcatcag tactgcatac 240
atggagctct ctcgcttgcg gagtgatgat accgccgttt attattgcgc ggttcacaac 300
gctcattatg gcacttggtt cgcgtattgg ggccaaggaa cactggttac agtgagcagt 360
ggagggggtg gctctggtgg cggcgggagc ggcggagggg gcagtgatgt tgtgatgaca 420
cagtcacccc tgagtctccc ggtcactctt gggcaaccag ccagcataag ctgtcgcagt 480
tctcagagct tgctccatag ctccgggaat acctacctcg aatggtatct ccaaagaccc 540
ggtcaatctc caaagccttt gatttacaag attagtacac gatttagtgg ggtcccagat 600
agattttcag gtagtggatc tggtacagat ttcacattga aaatatcacg cgtcgaggcg 660
gaggatgtcg gggtctacta ttgctttcaa ggtagtcacg tgccctacac gtttggtggc 720
ggtacgaagg tcgaaatcaa g 741
<210> 119
<211> 4370
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 119
gagatgtaag gagctgctgt gacttgctca aggccttata tcgagtaaac ggtagtgctg 60
gggcttagac gcaggtgttc tgatttatag ttcaaaacct ctatcaatga gagagcaatc 120
tcctggtaat gtgatagatt tcccaactta atgccaacat accataaacc tcccattctg 180
ctaatgccca gcctaagttg gggagaccac tccagattcc aagatgtaca gtttgctttg 240
ctgggccttt ttcccatgcc tgcctttact ctgccagagt tatattgctg gggttttgaa 300
gaagatccta ttaaataaaa gaataagcag tattattaag tagccctgca tttcaggttt 360
ccttgagtgg caggccaggc ctggccgtga acgttcactg aaatcatggc ctcttggcca 420
agattgatag cttgtgcctg tccctgagtc ccagtccatc acgagcagct ggtttctaag 480
atgctatttc ccgtataaag catgagaccg tgacttgcca gccccacaga gccccgccct 540
tgtccatcac tggcatctgg actccagcct gggttggggc aaagagggaa atgagatcat 600
gtcctaaccc tgatcctctt gtcccacaga tatccagaac cctgaccctg ccgtgtacca 660
gctgagagac tctaaatcca gtgacaagtc tgtctgccta ttcaccgatt ttgattctca 720
aacaaatgtg tcacaaagta aggattctga tgtgtatatc acagacaaaa ctgtgctaga 780
catgaggtct atggacttca ggctccggtg cccgtcagtg ggcagagcgc acatcgccca 840
cagtccccga gaagttgggg ggaggggtcg gcaattgaac cggtgcctag agaaggtggc 900
gcggggtaaa ctgggaaagt gatgtcgtgt actggctccg cctttttccc gagggtgggg 960
gagaaccgta tataagtgca gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg 1020
ccagaacaca ggtaagtgcc gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg 1080
gcccttgcgt gccttgaatt acttccactg gctgcagtac gtgattcttg atcccgagct 1140
tcgggttgga agtgggtggg agagttcgag gccttgcgct taaggagccc cttcgcctcg 1200
tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc gtgcgaatct ggtggcacct 1260
tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt taaaattttt gatgacctgc 1320
tgcgacgctt tttttctggc aagatagtct tgtaaatgcg ggccaagatc tgcacactgg 1380
tatttcggtt tttggggccg cgggcggcga cggggcccgt gcgtcccagc gcacatgttc 1440
ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga cgggggtagt ctcaagctgg 1500
ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc gccccgccct gggcggcaag 1560
gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg ccgcttcccg gccctgctgc 1620
agggagctca aaatggagga cgcggcgctc gggagagcgg gcgggtgagt cacccacaca 1680
aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt gactccacgg agtaccgggc 1740
gccgtccagg cacctcgatt agttctcgag cttttggagt acgtcgtctt taggttgggg 1800
ggaggggttt tatgcgatgg agtttcccca cactgagtgg gtggagactg aagttaggcc 1860
agcttggcac ttgatgtaat tctccttgga atttgccctt tttgagtttg gatcttggtt 1920
cattctcaag cctcagacag tggttcaaag tttttttctt ccatttcagg tgtcgtgacc 1980
accatggcgc ttccggtgac agcactgctc ctccccttgg cgctgttgct ccacgcagca 2040
aggccgcagg tacaactcgt tcagagcggt gcagaggtta agaaaccggg cgccagtgtc 2100
aaagtatcat gcaaggcgag tggtctgacc atcgaagatt attatatgca ttgggtgaga 2160
caagcaccgg ggcaggggct cgaatggatg ggttggatcg accccgaaaa tggtgatacg 2220
gagtatggcc cgaaatttca gggtcgggtc acgatgaccc gcgatacaag catcagtact 2280
gcatacatgg agctctctcg cttgcggagt gatgataccg ccgtttatta ttgcgcggtt 2340
cacaacgctc attatggcac ttggttcgcg tattggggcc aaggaacact ggttacagtg 2400
agcagtggag ggggtggctc tggtggcggc gggagcggcg gagggggcag tgatgttgtg 2460
atgacacagt cacccctgag tctcccggtc actcttgggc aaccagccag cataagctgt 2520
cgcagttctc agagcttgct ccatagctcc gggaatacct acctcgaatg gtatctccaa 2580
agacccggtc aatctccaaa gcctttgatt tacaagatta gtacacgatt tagtggggtc 2640
ccagatagat tttcaggtag tggatctggt acagatttca cattgaaaat atcacgcgtc 2700
gaggcggagg atgtcggggt ctactattgc tttcaaggta gtcacgtgcc ctacacgttt 2760
ggtggcggta cgaaggtcga aatcaagagt gctgctgcct ttgtcccggt atttctccca 2820
gccaaaccga ccacgactcc cgccccgcgc cctccgacac ccgctcccac catcgcctct 2880
caacctctta gtcttcgccc cgaggcatgc cgacccgccg ccgggggtgc tgttcatacg 2940
aggggcttgg acttcgcttg tgatatttac atttgggctc cgttggcggg tacgtgcggc 3000
gtccttttgt tgtcactcgt tattactttg tattgtaatc acaggaatcg caaacggggc 3060
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 3120
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgcga 3180
gtgaagtttt cccgaagcgc agacgctccg gcatatcagc aaggacagaa tcagctgtat 3240
aacgaactga atttgggacg ccgcgaggag tatgacgtgc ttgataaacg ccgggggaga 3300
gacccggaaa tggggggtaa accccgaaga aagaatcccc aagaaggact ctacaatgaa 3360
ctccagaagg ataagatggc ggaggcctac tcagaaatag gtatgaaggg cgaacgacga 3420
cggggaaaag gtcacgatgg cctctaccaa gggttgagta cggcaaccaa agatacgtac 3480
gatgcactgc atatgcaggc cctgcctccc agataataat aaaatcgcta tccatcgaag 3540
atggatgtgt gttggttttt tgtgtgtgga gcaacaaatc tgactttgca tgtgcaaacg 3600
ccttcaacaa cagcattatt ccagaagaca ccttcttccc cagcccaggt aagggcagct 3660
ttggtgcctt cgcaggctgt ttccttgctt caggaatggc caggttctgc ccagagctct 3720
ggtcaatgat gtctaaaact cctctgattg gtggtctcgg ccttatccat tgccaccaaa 3780
accctctttt tactaagaaa cagtgagcct tgttctggca gtccagagaa tgacacggga 3840
aaaaagcaga tgaagagaag gtggcaggag agggcacgtg gcccagcctc agtctctcca 3900
actgagttcc tgcctgcctg cctttgctca gactgtttgc cccttactgc tcttctaggc 3960
ctcattctaa gccccttctc caagttgcct ctccttattt ctccctgtct gccaaaaaat 4020
ctttcccagc tcactaagtc agtctcacgc agtcactcat taacccacca atcactgatt 4080
gtgccggcac atgaatgcac caggtgttga agtggaggaa ttaaaaagtc agatgagggg 4140
tgtgcccaga ggaagcacca ttctagttgg gggagcccat ctgtcagctg ggaaaagtcc 4200
aaataacttc agattggaat gtgttttaac tcagggttga gaaaacagct accttcagga 4260
caaaagtcag ggaagggctc tctgaagaaa tgctacttga agataccagc cctaccaagg 4320
gcagggagag gaccctatag aggcctggga caggagctca atgagaaagg 4370
<210> 120
<400> 120
000
<210> 121
<400> 121
000
<210> 122
<400> 122
000
<210> 123
<400> 123
000
<210> 124
<400> 124
000
<210> 125
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 125
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala Phe
260 265 270
Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg
275 280 285
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
290 295 300
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
305 310 315 320
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
325 330 335
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His
340 345 350
Arg Asn Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn
355 360 365
Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr
370 375 380
Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser
385 390 395 400
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
405 410 415
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
420 425 430
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
435 440 445
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
450 455 460
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
465 470 475 480
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
485 490 495
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 126
<211> 509
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 126
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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu
35 40 45
Thr Ile Glu Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu
65 70 75 80
Tyr Gly Pro Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser
85 90 95
Ile Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Val His Asn Ala His Tyr Gly Thr Trp Phe
115 120 125
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met
145 150 155 160
Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser
165 170 175
Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr
180 185 190
Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu
195 200 205
Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
210 215 220
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
225 230 235 240
Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro
245 250 255
Tyr Thr Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ala Ala Ala Phe
260 265 270
Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg
275 280 285
Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg
290 295 300
Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly
305 310 315 320
Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr
325 330 335
Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn His
340 345 350
Arg Asn Arg Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
355 360 365
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
370 375 380
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
385 390 395 400
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
405 410 415
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
420 425 430
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
435 440 445
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
450 455 460
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
465 470 475 480
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
485 490 495
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505
<210> 127
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 127
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Leu Thr Ile Glu Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Val His Asn Ala His Tyr Gly Thr Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Val Val Met Thr Gln Ser Pro Leu
130 135 140
Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Gln Gln Arg Pro Gly Gln Ser Pro Arg Pro Leu Ile Tyr Lys Ile Ser
180 185 190
Thr Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Gly Gly Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 128
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 128
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Pro Leu Ile Tyr Lys Ile Ser Thr Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 129
<211> 84
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 129
Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro
1 5 10 15
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
20 25 30
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
35 40 45
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
50 55 60
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Asn
65 70 75 80
His Arg Asn Arg
<210> 130
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成
<220>
<221> 尚未归类的特征
<222> (1)..(21)
<223> n 是 a, c, g, t 或 u
<400> 130
nnnnnnnnnn nnnnnnnnnn nrg 23
Claims (66)
1.一种工程化T细胞,该工程化T细胞包含编码嵌合抗原受体(CAR)的核酸,其中该CAR包含特异性结合LIV1的胞外结构域。
2.如权利要求1所述的工程化T细胞,该工程化T细胞进一步包含被破坏的T细胞受体α链恒定区(TRAC)基因。
3.如权利要求1或2所述的工程化T细胞,该工程化T细胞进一步包含被破坏的β-2-微球蛋白(β2M)基因。
4.如权利要求1-3中任一项所述的工程化T细胞,其中该CAR的胞外结构域包含抗LIV1抗体。
5.如权利要求4所述的工程化T细胞,其中该抗LIV1抗体是抗LIV1单链可变片段(scFv)。
6.如权利要求5所述的工程化T细胞,其中该抗LIV1 scFv包含与参考抗体相同的重链可变结构域(VH)互补决定区(CDR)和相同的轻链可变结构域(VL)CDR,其中该参考抗体包含(i)SEQ ID NO:55所示的VH和SEQ ID NO:56所示的VL,或(ii)SEQ ID NO:90所示的VH和SEQID NO:88所示的VL。
7.如权利要求6所述的工程化T细胞,其中该抗LIV1 scFv包含与该参考抗体相同的VH和VL链。
8.如权利要求6所述的工程化T细胞,其中该抗LIV1 scFv包含SEQ ID NO:54、70、83或86中任一项的氨基酸序列。
9.如权利要求1-8中任一项所述的工程化T细胞,其中该CAR进一步包含CD28共刺激结构域或41BB共刺激结构域。
10.如权利要求9所述的工程化T细胞,其中该CAR进一步包含CD3ζ细胞质信号传导结构域。
11.如权利要求1-10中任一项所述的工程化T细胞,其中该CAR由SEQ ID NO:49、51、104或108中任一项的核苷酸序列或包含与SEQ ID NO:49、51、104或108至少90%相同的核酸序列的核苷酸序列编码。
12.如权利要求1-11中任一项所述的工程化T细胞,其中将编码该CAR的核酸插入该被破坏的TRAC基因中。
13.如权利要求2-12中任一项所述的工程化T细胞,其中该被破坏的TRAC基因包含SEQID NO:63、64、107或111中任一项的核苷酸序列和/或SEQ ID NO:49、51、104或108中任一项的核苷酸序列。
14.如权利要求4-13中任一项所述的工程化T细胞,其中该被破坏的β2M基因包含至少一个选自SEQ ID NO:9-14中任一项的核苷酸序列。
15.一种工程化T细胞,该工程化T细胞包含:
(i)被破坏的TRAC基因;
(ii)被破坏的β2M基因;和
(iii)编码包含抗LIV1抗原结合片段的CAR的核酸。
16.如权利要求15所述的工程化T细胞,其中该CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域。
17.如权利要求15或16所述的工程化T细胞,其中该被破坏的TRAC基因包含编码该CAR的核酸。
18.一种工程化T细胞,该工程化T细胞包含:
(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,所述CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域;和
(ii)被破坏的β2M基因。
19.一种工程化T细胞,该工程化T细胞包含:
(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,所述CAR包含SEQ ID NO:50、52、105、109、68或66中任一项的氨基酸序列;和
(ii)被破坏的β2M基因。
20.一种工程化T细胞,该工程化T细胞包含:
(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,其中该核酸序列与SEQ ID NO:49、51、104或108至少90%相同和/或编码包含SEQ ID NO:50、52、105、109、68或66中任一项的氨基酸序列的CAR;和
(ii)被破坏的β2M基因。
21.如权利要求1-20中任一项所述的工程化T细胞,其中该T细胞是人T细胞。
22.一个包含如权利要求1-21中任一项所述的工程化T细胞的细胞群体,其中该群体的至少15%或至少50%的工程化T细胞表达该CAR。
23.如权利要求22所述的群体,其中该群体的至少30%的工程化T细胞表达该CAR。
24.如权利要求22所述的群体,其中该群体的至少70%的工程化T细胞表达该CAR。
25.如权利要求22所述的群体,其中该群体的至少25%的工程化T细胞在至少7天或至少14天的体外增殖后表达该CAR。
26.如权利要求22-25中任一项所述的群体,其中该群体的至少50%的工程化T细胞不表达可检测水平的T细胞受体(TCR)蛋白。
27.如权利要求26所述的群体,其中该群体的至少90%的工程化T细胞不表达可检测水平的TCR蛋白。
28.如权利要求22-27中任一项所述的群体,其中该群体的至少50%的工程化T细胞不表达可检测水平的β2M蛋白。
29.如权利要求28所述的群体,其中该群体的至少70%的工程化T细胞不表达可检测水平的β2M蛋白。
30.如权利要求22-29中任一项所述的群体,其中当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该群体的至少10%、至少25%或至少50%的癌细胞的细胞裂解。
31.如权利要求30所述的群体,其中当与表达LIV1的癌细胞群体在体外共培养时,该群体的工程化T细胞诱导该癌细胞群体的至少70%、至少80%或至少90%的细胞裂解。
32.如权利要求30或31所述的群体,其中当与癌细胞群体在体外共培养时,该群体的工程化T细胞分泌IFNγ。
33.如权利要求30-32中任一项所述的群体,其中工程化T细胞与癌细胞的比率为1:1至2:1。
34.如权利要求30-33中任一项所述的群体,其中这些癌细胞包括肉瘤细胞。
35.如权利要求30-33中任一项所述的群体,其中这些癌细胞包括乳腺癌细胞。
36.如权利要求22-35中任一项所述的群体,当在向受试者体内施用时,不会在该受试者中诱导毒性。
37.一种包含工程化T细胞的细胞群体,其中这些工程化T细胞包含:
(i)被破坏的TRAC基因;
(ii)被破坏的β2M基因;和
(iii)编码包含抗LIV1抗原结合片段的CAR的核酸。
38.如权利要求37所述的细胞群体,其中该CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域。
39.如权利要求37或38所述的细胞群体,其中该被破坏的TRAC基因包含编码该CAR的核酸。
40.一种包含工程化T细胞的细胞群体,其中这些工程化T细胞包含:
(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,所述CAR包含(a)包含抗LIV1抗原结合片段的胞外结构域,(b)CD8跨膜结构域,和(c)包含41BB共刺激结构域和CD3ζ细胞质信号传导结构域的胞内结构域;和
(ii)被破坏的β2M基因。
41.一种包含工程化T细胞的细胞群体,其中这些工程化T细胞包含:
(i)被破坏的TRAC基因,其中该被破坏的TRAC基因包含编码CAR的核酸,其中该核酸序列与SEQ ID NO:49、51、104或108至少90%相同和/或编码SEQ ID NO:50、52、105、109、68或66的CAR;和
(ii)被破坏的β2M基因。
42.一种方法,该方法包括向受试者施用如权利要求22-41中任一项所述的工程化T细胞群体。
43.如权利要求42所述的方法,其中该受试者是人类受试者。
44.如权利要求43所述的方法,其中该受试者患有癌症。
45.如权利要求44所述的方法,其中该癌症选自由以下组成的组:乳腺癌(例如雌激素受体阳性乳腺癌)、前列腺癌、鳞状肿瘤(例如皮肤、膀胱、肺、子宫颈、子宫内膜、头颈和胆道鳞状肿瘤)、和/或神经元肿瘤。
46.如权利要求44或45所述的方法,其中该癌症包括表达LIV1的癌细胞。
47.一种产生工程化T细胞的方法,该方法包括
(a)向T细胞递送
(i)RNA引导性核酸酶,
(ii)靶向TRAC基因的gRNA,和
(iii)包含供体模板的载体,该供体模板包含编码CAR的核酸,所述CAR包含特异性结合LIV1的胞外结构域;以及
(b)产生具有被破坏的TRAC基因并表达该CAR的工程化T细胞。
48.如权利要求47所述的方法,其中靶向该TRAC基因的gRNA包含SEQ ID NO:18或19的核苷酸序列,或靶向SEQ ID NO:40的核苷酸序列。
49.如权利要求47或48所述的方法,该方法进一步包括:向该T细胞递送靶向该β2M基因的gRNA。
50.如权利要求49所述的方法,其中靶向该β2M基因的gRNA包含SEQ ID NO:20或21的核苷酸序列,或靶向SEQ ID NO:41的核苷酸序列。
51.如权利要求47-50中任一项所述的方法,其中该CAR的胞外结构域包含抗LIV1抗体。
52.如权利要求51所述的方法,其中该抗LIV1抗体是抗LIV1单链可变片段(scFv)。
53.如权利要求52所述的方法,其中该抗LIV1 scFv包含与参考抗体相同的重链可变结构域(VH)互补决定区(CDR)和相同的轻链可变结构域(VL)CDR,其中该参考抗体包含(i)SEQID NO:55所示的VH和SEQ ID NO:56所示的VL,或(ii)SEQ ID NO:90所示的VH和SEQ ID NO:88所示的VL。
54.如权利要求53所述的方法,其中该抗LIV1 scFv包含与该参考抗体相同的VH和VL链。
55.如权利要求53所述的方法,其中该抗LIV1 scFv包含SEQ ID NO:54、83、86或70中任一项的氨基酸序列。
56.如权利要求47-56中任一项所述的方法,其中该CAR进一步包含CD28共刺激结构域或41BB共刺激结构域。
57.如权利要求56所述的方法,其中该CAR进一步包含CD3ζ细胞质信号传导结构域。
58.如权利要求47-57中任一项所述的方法,其中该CAR由SEQ ID NO:49、51、104或108中任一项的核苷酸序列或包含与SEQ ID NO:49、51、104或108至少90%相同的核酸序列的核苷酸序列编码。
59.如权利要求47-58中任一项所述的方法,其中编码该CAR的核酸的侧翼为TRAC基因的左和右同源臂。
60.如权利要求47-59中任一项所述的方法,其中该供体模板包含SEQ ID NO:63、64、107或111中任一项的核苷酸序列。
61.如权利要求47-60中任一项所述的方法,其中该RNA引导性核酸酶是Cas9核酸酶,任选地是酿脓链球菌Cas9核酸酶。
62.一种工程化T细胞,该工程化T细胞通过如权利要求47-61中任一项所述的方法产生。
63.一种细胞群体,该细胞群体包含如权利要求62所述的工程化T细胞。
64.一种在受试者中治疗癌症的方法,该方法包括向该受试者施用如权利要求22-41或63中任一项所述的细胞群体。
65.如权利要求64所述的方法,其中该癌症选自由以下组成的组:胰腺癌、胃癌、卵巢癌、子宫癌、乳腺癌、前列腺癌、睾丸癌、甲状腺癌、鼻咽癌、非小细胞肺癌(NSCLC)、胶质母细胞瘤、神经元肿瘤、软组织肉瘤、白血病、淋巴瘤、黑色素瘤、结肠癌、结肠腺癌、脑胶质母细胞瘤、肝细胞癌、肝胆管细胞癌、骨肉瘤、胃癌、食管鳞状细胞癌、晚期胰腺癌、肺腺癌、肺鳞状细胞癌、小细胞肺癌、肾癌和肝内胆管癌。
66.如权利要求64或65所述的方法,其中该癌症包括表达LIV1的癌细胞。
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EP4284918A1 (en) | 2021-01-29 | 2023-12-06 | Allogene Therapeutics, Inc. | Knockdown or knockout of one or more of tap2, nlrc5, beta2m, trac, rfx5, rfxap and rfxank to mitigate t cell recognition of allogeneic cell products |
WO2023111913A1 (en) | 2021-12-15 | 2023-06-22 | Crispr Therapeutics Ag | Engineered anti-liv1 cell with regnase-1 and/or tgfbrii disruption |
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