CN107096022A - 含特异性识别cd38的抗体和阿糖胞苷的抗肿瘤组合 - Google Patents

含特异性识别cd38的抗体和阿糖胞苷的抗肿瘤组合 Download PDF

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CN107096022A
CN107096022A CN201710103901.7A CN201710103901A CN107096022A CN 107096022 A CN107096022 A CN 107096022A CN 201710103901 A CN201710103901 A CN 201710103901A CN 107096022 A CN107096022 A CN 107096022A
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P·勒热纳
P·弗里尼奥
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Abstract

本发明涉及包含特异性识别CD38的抗体和阿糖胞苷的药物组合物。具体来说，本发明涉及含特异性识别CD38的抗体和阿糖胞苷的抗肿瘤组合。

Description

含特异性识别CD38的抗体和阿糖胞苷的抗肿瘤组合
本申请是申请日为2009年11月27日、中国申请号为200980148184.3、发明名称为“含特异性识别CD38的抗体和阿糖胞苷的抗肿瘤组合”的发明申请的分案申请。
本发明涉及针对CD38的单克隆抗体和阿糖胞苷的组合，其在肿瘤疾病的治疗中是治疗上有用的。
CD38是带有长C-端胞外域和短N-端胞质域的45kD II型跨膜糖蛋白。CD38蛋白是双功能胞外酶，其可催化NAD+转化成环ADP-核糖(cADPR)并且还将cADPR水解为ADP-核糖。CD38在许多造血恶性肿瘤中被上调，并已涉及其中。
特异性识别CD38的单克隆抗体38SB13、38SB18、38SB19、38SB30、38SB31和38SB39参见PCT申请WO2008/047242。所述抗CD38抗体能够通过三种不同细胞毒性机制即细胞凋亡的诱导、抗体依赖性细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)杀死CD38+细胞。此外，即便不存在基质细胞或基质衍生细胞因子，这些抗体也能够直接诱导CD38+细胞的凋亡。阿糖胞苷是化学治疗中所用的抗代谢药。仍然需要新型有效的用于治疗癌症的药物。
对于本发明，现在已发现：当将人源化抗CD38抗体与在抗癌治疗中是治疗上有用的并具有与人源化抗CD38抗体之一相同或不同的机制且在本发明中限定为阿糖胞苷的至少一种物质联合给药时，其功效可被显著提高。
术语“抗体”在本文中以最广含义使用，并特别涵盖任意同种型如IgG、IgM、IgA、IgD和IgE的单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体、嵌合抗体和抗体片段。典型的IgG抗体由通过二硫键连接的两条相同重链和两条相同轻链构成。每条重链和轻链包含恒定区和可变区。每个可变区包含三个称为“互补决定区”(“CDR”)或“高变区”的区段，它们主要负责结合抗原表位。它们通常被称为CDR1、CDR2和CDR3，从N-端按顺序编号。除CDR之外的较高度保守的可变区部分称作“构架区”。
本文所用"VH"或"VH"指抗体免疫球蛋白重链(包括Fv、scFv、dsFv、Fab、Fab'或F(ab')2片段的重链)的可变区。提及"VL"或"VL"是指抗体免疫球蛋白轻链(包括Fv、scFv、dsFv、Fab、Fab'或F(ab')2片段的轻链)的可变区。
38SB13抗体包括至少一个具有由SEQ ID NO:50组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:38组成的氨基酸序列的轻链，所述重链包括具有由SEQ ID NO:1、2和3组成的氨基酸序列的三个顺序CDR，且所述轻链包括具有由SEQ ID NO:4、5和6组成的氨基酸序列的三个顺序CDR。
38SB18抗体包括至少一个具有由SEQ ID NO:52组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:40组成的氨基酸序列的轻链，所述重链包括具有由SEQ ID NO:7、8和9组成的氨基酸序列的三个顺序CDR，且所述轻链包括具有由SEQ ID NO:10、11和12组成的氨基酸序列的三个顺序CDR。
38SB19抗体包括至少一个具有由SEQ ID NO:54组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:42组成的氨基酸序列的轻链，所述重链包括具有由SEQ ID NO:13、14和15组成的氨基酸序列的三个顺序CDR，且所述轻链包括具有由SEQ ID NO:16、17和18组成的氨基酸序列的三个顺序CDR。
38SB30抗体包括至少一个具有由SEQ ID NO:56组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:44组成的氨基酸序列的轻链，所述重链包括具有由SEQ ID NO:19、20和21组成的氨基酸序列的三个顺序CDR，且所述轻链包括具有由SEQ ID NO:22、23和24组成的氨基酸序列的三个顺序CDR。
38SB31抗体包括至少一个具有由SEQ ID NO:58组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:46组成的氨基酸序列的轻链，所述重链包括具有由SEQ ID NO:25、26和27组成的氨基酸序列的三个顺序CDR，且所述轻链包括具有由SEQ ID NO:28、29和30组成的氨基酸序列的三个顺序CDR。
38SB39抗体包括至少一个具有由SEQ ID NO:60组成的氨基酸序列的重链和至少一个具有由SEQ ID NO:48组成的氨基酸序列的轻链，所述重链包括具有由SEQ ID NO:31、32和33组成的氨基酸序列的三个顺序CDR，且所述轻链包括具有由SEQ ID NO:34、35和36组成的氨基酸序列的三个顺序CDR。
产生38SB13、38SB18、38SB19、38SB30、38SB31和38SB39鼠抗CD38抗体的杂交瘤细胞系已于2006年6月21日保藏于美国典型培养物保藏中心(10801University Bld,Manassas,VA,20110-2209,USA)，保藏编号分别为PTA-7667、PTA-7669、PTA-7670、PTA-7666、PTA-7668和PTA-7671(如WO2008/047242中所述)。
本文所用术语“人源化抗体”指含有源自非人免疫球蛋白最小序列的嵌合抗体。人源化目的是减少异种抗体如鼠抗体的免疫原性以引入人体内，同时保留抗体的全部抗原结合亲和性和特异性。人源化抗体或改造为不被其他哺乳动物排斥的抗体可利用数种技术如表面重塑(resurfacing)和CDR移植(CDR grafting)产生。本文所用表面重塑技术利用制作分子模型、统计分析和诱变的组合改变抗体可变区的非CDR表面，以模拟已知靶宿主抗体的表面。CDR移植技术涉及将例如小鼠抗体的互补决定区替换到人构架结构域中，例如参见WO92/22653。人源化嵌合抗体优选具有基本上或唯独地源自相应人抗体区域的恒定区和可变区(互补决定区(CDR)除外)，以及基本上或唯独地源自非人哺乳动物的CDR。
抗体表面重塑的策略和方法以及用于减少抗体在不同宿主中的免疫原性的其他方法公开于美国专利5,639,641，其整体通过引用结合到本文中。抗体可利用多种其他技术人源化，包括CDR移植(EP 0 239 400；WO 91/09967；美国专利号5,530,101和5,585,089)、镶饰(veneering)或表面重塑(EP 0 592 106；EP 0 519 596；Padlan E.A.,1991,Molecular Immunology 28(4/5):489-498；Studnicka G.M.等,1994,ProteinEngineering,7(6):805-814；Roguska M.A.等,1994,PNAS,91:969-973)、链改组(美国专利号5,565,332)和柔性残基鉴定(PCT/US2008/074381)。人抗体可通过包括噬菌体展示法在内的多种本领域已知方法产生。亦参见美国专利号4,444,887、4,716,111、5,545,806和5,814,318；以及国际专利申请公开号WO 98/46645、WO 98/50433、WO 98/24893、WO 98/16654、WO 96/34096、WO 96/33735和WO 91/10741(所述文献通过引用以其整体结合到本文中)。
本发明的药学组合中的抗CD38抗体是人源化抗体，其识别CD38并通过细胞凋亡、ADCC和CDC杀死CD38+细胞。在另一实施方案中，即便不存在基质细胞或基质衍生细胞因子，本发明的人源化抗体也能够通过细胞凋亡杀死所述CD38+细胞。
这样的人源化抗体的优选实施方案是人源化38SB13、38SB18、38SB19、38SB30、38SB31或38SB39抗体，或者其表位结合片段。
通过建模鉴定38SB13、38SB18、38SB19、38SB30、38SB31和38SB39抗体的CDR，并已预测它们的分子结构。因此，在一个实施方案中，本发明提供包括一个或多个具有选自SEQID NO:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35和36的氨基酸序列的CDR的人源化抗体或其表位结合片段。在优选实施方案中，提供一种人源化形式的38SB13，其包括至少一个重链和至少一个轻链，其中所述重链包括具有由SEQ ID NO:1、2和3表示的氨基酸序列的三个顺序互补决定区，且所述轻链包括具有由SEQ ID NO:4、5和6表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中，提供一种人源化形式的38SB18，其包括至少一个重链和至少一个轻链，其中所述重链包括具有由SEQ ID NO:7、8和9表示的氨基酸序列的三个顺序互补决定区，且所述轻链包括具有由SEQ ID NO:10、11和12表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中，提供一种人源化形式的38SB19，其包括至少一个重链和至少一个轻链，其中所述重链包括具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区，且所述轻链包括具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中，提供一种人源化形式的38SB30，其包括至少一个重链和至少一个轻链，其中所述重链包括具有由SEQ ID NO:19、20和21表示的氨基酸序列的三个顺序互补决定区，且所述轻链包括具有由SEQ ID NO:22、23和24表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中，提供一种人源化形式的38SB31，其包括至少一个重链和至少一个轻链，其中所述重链包括具有由SEQ ID NO:25、26和27表示的氨基酸序列的三个顺序互补决定区，且所述轻链包括具有由SEQ ID NO:28、29和30表示的氨基酸序列的三个顺序互补决定区。在另一优选实施方案中，提供一种人源化形式的38SB39，其包括至少一个重链和至少一个轻链，其中所述重链包括具有由SEQ ID NO:31、32和33表示的氨基酸序列的三个顺序互补决定区，且所述轻链包括具有由SEQ ID NO:34、35和36表示的氨基酸序列的三个顺序互补决定区。
在一个实施方案中，本发明提供包括具有选自SEQ ID NO:66和72的氨基酸序列的VH的人源化抗体或其片段。在优选实施方案中，提供包括具有由SEQ ID NO:66表示的氨基酸序列的VH的人源化38SB19抗体。在另一优选实施方案中，提供包括具有由SEQ ID NO:72表示的氨基酸序列的VH的人源化38SB31抗体。
在另一实施方案中，本发明提供包括具有选自SEQ ID NO:62、64、68和70的氨基酸序列的VL的人源化抗体或其片段。在优选实施方案中，提供包括具有选自SEQ ID NO:62和64的氨基酸序列的VL的人源化38SB19抗体。在另一优选实施方案中，提供包括具有选自SEQID NO:68和70的氨基酸序列的VL的人源化38SB31抗体。
已表明，每种人源化形式的38SB13、38SB18、38SB19、38SB30、38SB31和38SB39抗体作为抗癌剂是特别有利的。它们的制备、物理性质和有益药理学性质参见WO 2008/047242，通过引用以其整体结合到本文中。一般而言，用于治疗人的剂量为1-150mg/kg(口服给药)或1-150mg/kg(静脉内给药)，视因待治疗受试者而不同的因素而定。
阿糖胞苷(cytosine arabinoside或cytarabine或araC)(商品名AracytinTM)是抗代谢药(1β-阿拉伯呋喃糖基胞嘧啶)。当细胞周期处于S期(DNA合成)时，阿糖胞苷被迅速转化为破坏DNA的三磷酸阿糖胞苷。因此，需要DNA复制用于有丝分裂的快速分裂细胞最受影响。阿糖胞苷还抑制DNA合成所需的DNA和RNA聚合酶和核苷酸还原酶。阿糖胞苷在体内迅速脱氨基成为无活性的尿嘧啶衍生物，因此常常通过连续静脉输注给予。
本发明一个方面是包含与至少阿糖胞苷联合的抗CD38抗体的药物组合物。由于制品活性取决于所用剂量，所以可能的是使用较小剂量和提高活性，同时减少毒性现象。本发明组合的提高的功效可通过确定治疗协同作用来证明。如果在治疗上优于以其最大耐受剂量或其在动物物种中不能达到毒性时测试的最高剂量单独使用受试最佳药剂，则组合表现出治疗协同作用。
该功效可量化，例如通过log10细胞杀伤，其根据下式确定：
log10细胞杀伤＝T-C(天数)/3.32×Td
其中，T-C表示肿瘤生长延迟，是治疗组(T)肿瘤和对照组(C)肿瘤达到预定值(例如1g)以天数计的中位数时间，Td表示对照动物中肿瘤体积加倍所需的以天数计的时间[T.H.Corbett等,Cancer,40:2660-2680(1977)；F.M.Schabel等,Cancer DrugDevelopment,B部分,Methods in Cancer Research,17:3-51,New York,Academic PressInc.(1979)]。如果log10细胞杀伤大于等于0.7，那么制品被视为有活性。如果log10细胞杀伤大于2.8，那么制品被视为非常有活性。
当log10细胞杀伤大于最佳成分单独给药且以其最大耐受剂量或其最高受试剂量使用时的log10细胞杀伤值时，组合(其中每种成分存在的剂量通常不超出其最大耐受剂量)将表现治疗协同作用。
组合对实体瘤的功效可通过下述方法进行实验测定：
在第0天用30-60mg肿瘤碎片双侧皮下移植接受实验的动物(通常为小鼠)。在经历各种治疗和对照前，基于它们的肿瘤大小将荷瘤动物随机化。当移植后肿瘤已达到预定大小(取决于肿瘤类型)时，开始化学治疗，并每天观察动物。在治疗过程中，每天对不同动物组称重，直到达到最大体重减轻且已发生随后的完全体重恢复。之后每周称重组别一次或两次，直到试验结束。
根据肿瘤加倍时间，每周测量肿瘤1-5次，直到肿瘤达到约2g，或直到动物死亡(如果这发生在肿瘤达到2g之前)。在安乐死或死亡后，立即对动物进行尸体剖检。
依据记录的不同参数确定抗肿瘤活性。
利用hu38SB19和阿糖胞苷以它们的最佳剂量使用的组合所得结果在下文作为实施例表示。
因此，本发明还涉及包含本发明组合的药物组合物。
构成组合的成分可同时、半同时、单独或间隔一段时间给药，以便获得组合的最大功效；可能的是，每次给药在快速给药和连续灌注之间改变其持续时间。
因此，为本发明之目的，组合不唯独地限于通过成分的物理关联获得的那些组合，而且还为允许可同时或间隔一段时间的单独给药的那些组合。
本发明组合物优选为可胃肠外(parentally)给药的组合物。但是，在局限区域疗法(localized regional therapy)的情况下，这些组合物可口服、皮下或腹膜内给药。
用于胃肠外给药的组合物通常是药学上可接受的无菌溶液剂或混悬剂，其可任选地在使用时按需制备。为制备非水溶液剂或混悬剂，可使用天然植物油(例如橄榄油、芝麻油)或液化石蜡(liquid petroleum)或可注射有机酯(例如油酸乙酯)。无菌水溶液剂可由制品在水中的溶液构成。如果适当调节pH，且例如用足够量的氯化钠或葡萄糖使溶液等渗，则水溶液剂适合静脉内给药。灭菌可通过加热或通过不有害地影响组合物的任意其他方法进行。组合亦可采用脂质体形式或与载体如环糊精或聚乙二醇联合的形式。
用于口服、皮下或腹膜内给药的组合物优选为水混悬剂或溶液剂。
在本发明组合(其成分可同时、单独或间隔一段时间施用)中，尤其有利的是人源化抗CD38抗体的量表示为组合的10-90％重量，该含量可依据联合物质的性质、所寻求的功效和待治疗癌症的性质变化。
本发明组合尤其可用于包括(但不限于)下述的数种癌症类型的治疗：癌和腺癌，包括膀胱、乳腺、结肠、头颈、前列腺、肾、肝、肺、卵巢、胰腺、胃、子宫颈、甲状腺和皮肤的癌，以及包括鳞状细胞癌；淋巴系造血肿瘤，包括多发性骨髓瘤、白血病、急性和慢性淋巴细胞性(淋巴系)白血病、急性和慢性成淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、非Hodgkin淋巴瘤(例如Burkitt淋巴瘤)；骨髓系造血肿瘤，包括急性和慢性髓细胞性(骨髓或髓细胞的)白血病和前髓细胞性白血病；间质起源的肿瘤，包括纤维肉瘤、骨肉瘤和横纹肌肉瘤；中枢和外周神经系统肿瘤，包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤；和其他肿瘤，包括黑色素瘤、畸胎癌、着色性干皮病、角化棘皮瘤和精原细胞瘤，以及表达CD38的尚未被确定的其他癌症。它们主要可用于治疗白血病、淋巴瘤和对常用抗癌剂产生抗性的癌症，因为抗CD38抗体具有独特的作用机制。
因此，本发明还包括上述组合在制备用于治疗癌症的药物中的用途。
本发明还涉及下述各项：
1.一种包括特异性识别CD38的抗体和至少阿糖胞苷的药物组合，其中所述抗体能够通过细胞凋亡、抗体依赖性细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)杀死CD38+细胞。
2.项1的组合，其中所述抗体是人源化抗体。
3.项2的组合，其中所述抗体包含一个或多个具有选自SEQ ID NO:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35和36的氨基酸序列的互补决定区。
4.项3的组合，其中所述抗体包含至少一个重链和至少一个轻链，其中所述重链具有由SEQ ID NO:66表示的氨基酸序列，且所述重链包含具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区，所述轻链具有选自SEQ ID NO:62和64的氨基酸序列，且所述轻链包含具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。
5.项3的组合，其中所述抗体包含至少一个重链和至少一个轻链，其中所述重链具有由SEQ ID NO:72表示的氨基酸序列，且所述重链包含具有由SEQ ID NO:25、26和27表示的氨基酸序列的三个顺序互补决定区，所述轻链具有选自SEQ ID NO:68和70的氨基酸序列，且所述轻链包含具有由SEQ ID NO:28、29和30表示的氨基酸序列的三个顺序互补决定区。
6.特异性识别CD38的抗体在制备用于制备治疗癌症的药物的项1的药物组合中的用途。
7.项6的用途，其中所述抗体是人源化抗体。
8.项7的用途，其中所述抗体包含一个或多个具有选自SEQ ID NO:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35和36的氨基酸序列的互补决定区。
9.项8的用途，其中所述抗体包含至少一个重链和至少一个轻链，其中所述重链具有由SEQ ID NO:66表示的氨基酸序列，且所述重链包含具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区，所述轻链具有选自SEQ ID NO:62和64的氨基酸序列，且所述轻链包含具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。
10.项8的用途，其中所述抗体包含至少一个重链和至少一个轻链，其中所述重链具有由SEQ ID NO:72表示的氨基酸序列，且所述重链包含具有由SEQ ID NO:25、26和27表示的氨基酸序列的三个顺序互补决定区，所述轻链具有选自SEQ ID NO:68和70的氨基酸序列，且所述轻链包含具有由SEQ ID NO:28、29和30表示的氨基酸序列的三个顺序互补决定区。
实施例：
在该实施例中，体内证明了本发明的抗CD38抗体/阿糖胞苷组合对肿瘤生长抑制的有效性。
选择的肿瘤模型是植入SCID小鼠的可移植的人T细胞急性成淋巴细胞白血病(T-ALL)细胞系DND-41。
在不含Ca2+和Mg2+、pH 7.4的磷酸盐缓冲液中配制hu38SB19。在肿瘤植入后的第18、21、24、27天静脉内给予hu38SB19。
将Palmo Ara-C(适用于小鼠体内缓释给药的阿糖胞苷衍生物)配制到3％乙醇、1％聚山梨酯80、96％水中，并在肿瘤植入后的第18、21、24、27天皮下给药。
实验结果汇总于表1。
肿瘤加倍时间＝3.4天。
已利用下述终点：
●在诱导≥20％体重减轻或≥10％药物死亡的剂量下表明毒性，
●通过计算log10细胞杀伤＝(T-C)/[3.32x(以天数计的肿瘤加倍时间)]测定抗肿瘤功效
(T指受治疗小鼠达到750mg的中位数时间，C指对照小鼠达到相同大小的中位数时间(26.9天)；从这些计算中排除无肿瘤存活小鼠，并单独列表显示)。log细胞杀伤<0.7表明无抗肿瘤活性，log细胞杀伤≥2.8表明治疗非常有效
●无肿瘤存活小鼠(TFS)：对应于在整个研究持续期间(最后一次治疗后>100天)内低于触诊限(63mg)的完全消退。
●治疗协同作用：如果其比最佳单一受试药剂更具活性(大至少1log细胞杀伤)，则组合具有治疗协同作用。
在96.3mg/kg/注射的剂量下观察到Palmo Ara-C单独使用的毒性为6只治疗小鼠中6只药物相关死亡。Palmo Ara-C的最高无毒剂量(HNTD)是58.0mg/kg/注射(总注射剂量＝232.0mg/kg)。发现58.0mg/kg/注射的剂量具有5.4log10细胞杀伤和第160天3/6TFS的高度活性。还发现低于36.0mg/kg/注射(总注射剂量＝144.0mg/kg)具有4.3log10细胞杀伤的高度活性。22.3mg/kg/注射的最低剂量活性为2.0log10细胞杀伤。
至于hu38SB19，该制品在40mg/kg/注射的剂量下良好耐受。未观察到毒性，这可通过缺乏抗体与鼠CD38的交叉反应性解释。log10细胞杀伤为0.5，表明人38DB19在这些条件下无活性。
96.3mg/kg/注射的Palmo Ara-C和40mg/kg/注射的hu38SB19组合的毒性为6只治疗小鼠中5只药物相关死亡，即与Palmo Ara-C以相同剂量单独使用时的观察结果非常相似。58.0mg/kg/注射的Palmo Ara-C与40mg/kg/注射的hu38SB19的剂量被认为是HNTD。显著地，在该剂量下，6只小鼠中5只直到研究结束(第160天)一直是TFS。与等同毒性剂量的Palmo Ara-C单独使用时4.3的log10细胞杀伤和无TFS相比，36.0mg/kg/注射的Palmo Ara-C与40mg/kg/注射的hu38SB19的较低剂量表现出8.1的log10细胞杀伤和3/6TFS，因此认为其具有高度活性。与等同毒性剂量的Palmo Ara-C单独使用的2.0log10细胞杀伤相比，记录到最低剂量的组合的抗肿瘤活性为2.7log10细胞杀伤。我们得出结论：相比最佳单一受试药剂Palmo Ara-C，组合表现出治疗协同作用。
序列表
<110> 赛诺菲
<120> 含特异性识别CD38的抗体和阿糖胞苷的抗肿瘤组合
<130> FR2008-113
<160> 80
<170> PatentIn version 3.3
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<400> 15
Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr
1 5 10
<210> 16
<211> 11
<212> PRT
<213> 鼠
<400> 16
Lys Ala Ser Gln Asp Val Ser Thr Val Val Ala
1 5 10
<210> 17
<211> 7
<212> PRT
<213> 鼠
<400> 17
Ser Ala Ser Tyr Arg Tyr Ile
1 5
<210> 18
<211> 9
<212> PRT
<213> 鼠
<400> 18
Gln Gln His Tyr Ser Pro Pro Tyr Thr
1 5
<210> 19
<211> 5
<212> PRT
<213> 鼠
<400> 19
Gly Ser Trp Met Asn
1 5
<210> 20
<211> 17
<212> PRT
<213> 鼠
<400> 20
Arg Ile Tyr Pro Gly Asp Gly Asp Ile Ile Tyr Asn Gly Asn Phe Arg
1 5 10 15
Asp
<210> 21
<211> 10
<212> PRT
<213> 鼠
<400> 21
Trp Gly Thr Phe Thr Pro Ser Phe Asp Tyr
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 鼠
<400> 22
Lys Ala Ser Gln Asp Val Val Thr Ala Val Ala
1 5 10
<210> 23
<211> 7
<212> PRT
<213> 鼠
<400> 23
Ser Ala Ser His Arg Tyr Thr
1 5
<210> 24
<211> 9
<212> PRT
<213> 鼠
<400> 24
Gln Gln His Tyr Thr Thr Pro Thr Thr
1 5
<210> 25
<211> 5
<212> PRT
<213> 鼠
<400> 25
Ser Tyr Thr Leu Ser
1 5
<210> 26
<211> 17
<212> PRT
<213> 鼠
<400> 26
Thr Ile Ser Ile Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val Glu
1 5 10 15
Gly
<210> 27
<211> 8
<212> PRT
<213> 鼠
<400> 27
Asp Phe Asn Gly Tyr Ser Asp Phe
1 5
<210> 28
<211> 11
<212> PRT
<213> 鼠
<400> 28
Lys Ala Ser Gln Val Val Gly Ser Ala Val Ala
1 5 10
<210> 29
<211> 7
<212> PRT
<213> 鼠
<400> 29
Trp Ala Ser Thr Arg His Thr
1 5
<210> 30
<211> 9
<212> PRT
<213> 鼠
<400> 30
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 31
<211> 5
<212> PRT
<213> 鼠
<400> 31
Asn Phe Gly Met His
1 5
<210> 32
<211> 17
<212> PRT
<213> 鼠
<400> 32
Tyr Ile Arg Ser Gly Ser Gly Thr Ile Tyr Tyr Ser Asp Thr Val Lys
1 5 10 15
Gly
<210> 33
<211> 11
<212> PRT
<213> 鼠
<400> 33
Ser Tyr Tyr Asp Phe Gly Ala Trp Phe Ala Tyr
1 5 10
<210> 34
<211> 11
<212> PRT
<213> 鼠
<400> 34
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
1 5 10
<210> 35
<211> 7
<212> PRT
<213> 鼠
<400> 35
Ser Ala Ser Ser Arg Tyr Ser
1 5
<210> 36
<211> 9
<212> PRT
<213> 鼠
<400> 36
Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
1 5
<210> 37
<211> 336
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(336)
<400> 37
aac att gtg ctg acc caa tct cca gct tct ttg gct gtg tct ctt ggg 48
Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
cag agg gcc acc ata tcc tgc aga gcc agt gaa agt gtt gag att tat 96
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Glu Ile Tyr
20 25 30
ggc aat ggt ttt atg aac tgg ttc cag cag aaa cca gga cag cca ccc 144
Gly Asn Gly Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
aaa ctc ctc atc tat cgt gca tcc aac cta gaa tct ggg atc cct gcc 192
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
agg ttc agt ggc agt ggg tct agg aca gag ttc acc ctc acc att gat 240
Arg Phe Ser Gly Ser Gly Ser Arg Thr Glu Phe Thr Leu Thr Ile Asp
65 70 75 80
cct gtg gag gct gat gat gtt gca acc tat tac tgt caa caa att aat 288
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ile Asn
85 90 95
gag gat cca ttc acg ttc ggc tcg ggg aca aag ttg gaa ata aaa cgg 336
Glu Asp Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 38
<211> 112
<212> PRT
<213> 鼠
<400> 38
Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Glu Ile Tyr
20 25 30
Gly Asn Gly Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Glu Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ile Asn
85 90 95
Glu Asp Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 39
<211> 336
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(336)
<400> 39
gac att gta ctg acc caa tct cca gct tct ttg gct gtg tct cta ggg 48
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
cag agg gcc acc ata tcc tgc aga gcc agt gag agt gtt gct att tat 96
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Ala Ile Tyr
20 25 30
ggc aat agt ttt ctg aaa tgg ttc cag cag aaa ccg gga cag cca ccc 144
Gly Asn Ser Phe Leu Lys Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
aaa ctc ctc atc tat cgt gca tcc aac cta gaa tct ggg atc cct gcc 192
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
agg ttc agt ggc agt ggg tct ggg aca gac ttc acc ctc acc att aat 240
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
cct gtg gag gct gat gat gtt gca acc tat tac tgt cag caa att aat 288
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ile Asn
85 90 95
gag gat ccg tac acg ttc gga ggg ggg acc aag ctg gaa ata aaa cgg 336
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 40
<211> 112
<212> PRT
<213> 鼠
<400> 40
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Ala Ile Tyr
20 25 30
Gly Asn Ser Phe Leu Lys Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ile Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 41
<211> 324
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(324)
<400> 41
gac att gtg atg gcc cag tct cac aaa ttc atg tcc aca tca gtt gga 48
Asp Ile Val Met Ala Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
gac agg gtc agc atc acc tgc aag gcc agt cag gat gtg agt act gtt 96
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
gtg gcc tgg tat caa cag aaa cca gga caa tct cct aaa cga ctg att 144
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Arg Leu Ile
35 40 45
tac tcg gca tcc tat cgg tat att gga gtc cct gat cgc ttc act ggc 192
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
agt gga tct ggg acg gat ttc act ttc acc atc agc agt gtg cag gct 240
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
gaa gac ctg gca gtt tat tac tgt cag caa cat tat agt cct ccg tac 288
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
acg ttc gga ggg ggg acc aag ctg gaa ata aaa cgg 324
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 42
<211> 108
<212> PRT
<213> 鼠
<400> 42
Asp Ile Val Met Ala Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Arg Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 43
<211> 324
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(324)
<400> 43
gac att gtg atg acc cag tct cac aaa ttc ttg tcc aca tca gtt gga 48
Asp Ile Val Met Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
gac agg gtc agt atc acc tgc aag gcc agt cag gat gtg gtt act gct 96
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Val Thr Ala
20 25 30
gtt gcc tgg ttt caa cag aaa cca gga caa tct cca aaa cta ctg att 144
Val Ala Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
tat tcg gca tcc cac cgg tac act gga gtc cct gat cgc ttc act ggc 192
Tyr Ser Ala Ser His Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
agt gga tct ggg aca gat ttc act ttc acc atc atc agt gtg cag gct 240
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ile Ser Val Gln Ala
65 70 75 80
gaa gac ctg gca gtt tat tac tgt caa caa cat tat act act ccc acg 288
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Thr
85 90 95
acg ttc ggt gga ggc acc aag ctg gac ttc aga cgg 324
Thr Phe Gly Gly Gly Thr Lys Leu Asp Phe Arg Arg
100 105
<210> 44
<211> 108
<212> PRT
<213> 鼠
<400> 44
Asp Ile Val Met Thr Gln Ser His Lys Phe Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Val Thr Ala
20 25 30
Val Ala Trp Phe Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser His Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ile Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Thr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Asp Phe Arg Arg
100 105
<210> 45
<211> 324
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(324)
<400> 45
gac act gtg atg acc cag tct cac aaa ttc ata tcc aca tca gtt gga 48
Asp Thr Val Met Thr Gln Ser His Lys Phe Ile Ser Thr Ser Val Gly
1 5 10 15
gac agg gtc agc atc acc tgc aag gcc agt cag gtt gtg ggt agt gct 96
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Val Val Gly Ser Ala
20 25 30
gta gcc tgg tat caa cag aaa cca ggg caa tct cct aaa cta ctg att 144
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
tac tgg gca tcc acc cgg cac act gga gtc cct gat cgc ttc aca ggc 192
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
agt gga tct ggg aca gat ttc act ctc acc att agc aat gtg cag tct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
gaa gac ttg gca gat tat ttc tgt cag caa tat aac agc tat ccg tac 288
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
acg ttc gga ggg ggg acc aag ctg gaa ata aaa cgg 324
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 46
<211> 108
<212> PRT
<213> 鼠
<400> 46
Asp Thr Val Met Thr Gln Ser His Lys Phe Ile Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Val Val Gly Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 47
<211> 324
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(324)
<400> 47
gac att gtg atg acc cag tct caa aaa ttc atg tcc aca tca gta gga 48
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
gac agg gtc agc gtc acc tgc aag gcc agt cag aat gtg ggt act aat 96
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
gtt gcc tgg tat caa cac aaa cca gga caa tcc cct aaa ata atg att 144
Val Ala Trp Tyr Gln His Lys Pro Gly Gln Ser Pro Lys Ile Met Ile
35 40 45
tat tcg gcg tcc tcc cgg tac agt gga gtc cct gat cgc ttc aca ggc 192
Tyr Ser Ala Ser Ser Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
agt gga tct ggg aca ctt ttc act ctc acc atc aac aat gtg cag tct 240
Ser Gly Ser Gly Thr Leu Phe Thr Leu Thr Ile Asn Asn Val Gln Ser
65 70 75 80
gaa gac ttg gca gag tat ttc tgt cag caa tat aac agc tat cct ctc 288
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
acg ttc ggc tcg ggg aca aag ttg gaa ata aaa cgg 324
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 48
<211> 108
<212> PRT
<213> 鼠
<400> 48
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln His Lys Pro Gly Gln Ser Pro Lys Ile Met Ile
35 40 45
Tyr Ser Ala Ser Ser Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Leu Phe Thr Leu Thr Ile Asn Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 49
<211> 342
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(342)
<400> 49
cag atc cag ttg gtg cag tct gga cct gag ctg aag aag cct gga gag 48
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
aca gtc aag atc tcc tgc aag gct tct ggg tat acc ctc aca agc tac 96
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
gga atg aac tgg gtg aag cag gct cca gga aag ggt tta aag tgg atg 144
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
ggc tgg ata aac acc tac act gga gaa cca aca tat gct gat gac ttt 192
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
aag gga cgt ttt gcc ttc tct ttg gaa acc tct gcc agc act gcc ttt 240
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Phe
65 70 75 80
ttg cag atc aac aac ctc aaa aat gag gac acg gct aca tat ttc tgt 288
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
gta aga cgc ggg ttt gct tac tgg ggc caa ggg act ctg gtc act gtc 336
Val Arg Arg Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
tct gca 342
Ser Ala
<210> 50
<211> 114
<212> PRT
<213> 鼠
<400> 50
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Leu Thr Ser Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Phe
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Val Arg Arg Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ala
<210> 51
<211> 342
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(342)
<400> 51
cag atc cag ttg gtg cag tct gga cct gag ctg aag aag cct gga gag 48
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
aca gtc aag atc tcc tgc aag gct tct ggg tat acc ttc aca aac tct 96
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Ser
20 25 30
gga atg aac tgg gtg aag cag gct cca gga aag ggt tta aag tgg atg 144
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
ggc tgg ata aac acc tac act gga gag ccg aca tat gct gat gac ttc 192
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
aag gga cgg ttt gcc ttc tct ttg gaa acc tct gcc agc tct gcc tat 240
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Ser Ala Tyr
65 70 75 80
ttg cag atc agt aac ctc aaa aat gag gac acg gct aca tat ttc tgt 288
Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
gca aga agg ggt ttt gtt tac tgg ggc caa ggg act ctg gta act gtc 336
Ala Arg Arg Gly Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
tct gca 342
Ser Ala
<210> 52
<211> 114
<212> PRT
<213> 鼠
<400> 52
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Ser
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Ser Ala Tyr
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Arg Gly Phe Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ala
<210> 53
<211> 360
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(360)
<400> 53
cag gtt cag ctc cag cag tct ggg gct gag ctg gca aga cct ggg act 48
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Thr
1 5 10 15
tca gtg aag ttg tcc tgt aag gct tct ggc tac acc ttt act gac tac 96
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
tgg atg cag tgg gta aaa cag agg cct gga cag ggt ctg gag tgg att 144
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
ggg act att tat cct gga gat ggt gat act ggg tac gct cag aag ttc 192
Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe
50 55 60
aag ggc aag gcc aca ttg act gcg gat aaa tcc tcc aaa aca gtc tac 240
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Lys Thr Val Tyr
65 70 75 80
atg cac ctc agc agt ttg gct tct gag gac tct gcg gtc tat tac tgt 288
Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
gca aga ggg gat tac tac ggt agt aat tct ttg gac tat tgg ggt caa 336
Ala Arg Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr Trp Gly Gln
100 105 110
gga acc tca gtc acc gtc tcc tca 360
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 54
<211> 120
<212> PRT
<213> 鼠
<400> 54
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Lys Thr Val Tyr
65 70 75 80
Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 55
<211> 357
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(357)
<400> 55
cag gtc cag tta cag caa tct gga cct gaa ctg gtg agg cct ggg gcc 48
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
1 5 10 15
tca gtg aag att tcc tgc aaa act tct ggc tac gca ttc agt ggc tcc 96
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Ala Phe Ser Gly Ser
20 25 30
tgg atg aac tgg gtg aag cag agg cct gga cag ggt cta gag tgg att 144
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
gga cgg att tat ccg gga gat gga gat atc att tac aat ggg aat ttc 192
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Ile Ile Tyr Asn Gly Asn Phe
50 55 60
agg gac aag gtc aca ctg tct gca gac aaa tcc tcc aac aca gcc tac 240
Arg Asp Lys Val Thr Leu Ser Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
atg cag ctc agc agc ctg acc tct gtg gac tct gcg gtc tat ttt tgt 288
Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys
85 90 95
tcg aga tgg ggg aca ttt acg ccg agt ttt gac tat tgg ggc caa ggc 336
Ser Arg Trp Gly Thr Phe Thr Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
acc act ctc aca gtc tcc tca 357
Thr Thr Leu Thr Val Ser Ser
115
<210> 56
<211> 119
<212> PRT
<213> 鼠
<400> 56
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Ala Phe Ser Gly Ser
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Ile Ile Tyr Asn Gly Asn Phe
50 55 60
Arg Asp Lys Val Thr Leu Ser Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ser Arg Trp Gly Thr Phe Thr Pro Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 57
<211> 351
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(351)
<400> 57
gac gtg aag ctg gtg gag tct ggg gga ggc tta gtg aag cct gga ggg 48
Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
tcc ctg aaa ctc tcc tgt gaa gcc tct gga ttc act ttc agt agc tat 96
Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
acc ctg tct tgg gtt cgc cag act ccg gag acg agg ctg gag tgg gtc 144
Thr Leu Ser Trp Val Arg Gln Thr Pro Glu Thr Arg Leu Glu Trp Val
35 40 45
gca acc att agt att ggt ggt cgc tac acc tat tat cca gac agt gtg 192
Ala Thr Ile Ser Ile Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
gag ggc cga ttc acc atc tcc aga gac aat gcc aag aac acc ctg tac 240
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
ctg caa atg aac agt ctg aag tct gag gac aca gcc atg tat tac tgt 288
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
aca aga gat ttt aat ggt tac tct gac ttc tgg ggc caa ggc acc act 336
Thr Arg Asp Phe Asn Gly Tyr Ser Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
ctc aca gtc tcc tca 351
Leu Thr Val Ser Ser
115
<210> 58
<211> 117
<212> PRT
<213> 鼠
<400> 58
Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Leu Ser Trp Val Arg Gln Thr Pro Glu Thr Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ile Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Arg Asp Phe Asn Gly Tyr Ser Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 59
<211> 360
<212> DNA
<213> 鼠
<220>
<221> CDS
<222> (1)..(360)
<400> 59
aat gta cag ctg gta gag tct ggg gga ggc tta gtg cag cct gga ggg 48
Asn Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
tcc cgg aaa ctc tcc tgt gca gcc tct gga ttc act ttc agt aac ttt 96
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
gga atg cac tgg gtt cgt cag gct cca gag aag ggt ctg gag tgg gtc 144
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
gca tac att cgt agt ggc agt ggt acc atc tac tat tca gac aca gtg 192
Ala Tyr Ile Arg Ser Gly Ser Gly Thr Ile Tyr Tyr Ser Asp Thr Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aat ccc aag aac acc ctg ttc 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
ctg caa atg acc agt cta agg tct gag gac acg gcc atg tat tac tgt 288
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
gca aga tcc tac tat gat ttc ggg gcc tgg ttt gct tac tgg ggc caa 336
Ala Arg Ser Tyr Tyr Asp Phe Gly Ala Trp Phe Ala Tyr Trp Gly Gln
100 105 110
ggg act ctg gtc act gtc tct gca 360
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 60
<211> 120
<212> PRT
<213> 鼠
<400> 60
Asn Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Arg Ser Gly Ser Gly Thr Ile Tyr Tyr Ser Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Ser Tyr Tyr Asp Phe Gly Ala Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 61
<211> 324
<212> DNA
<213> 人(Homo sapiens)
<220>
<221> CDS
<222> (1)..(324)
<400> 61
gat atc gta atg acc cag tcc cac ctg agt atg agt acc tcc ctg gga 48
Asp Ile Val Met Thr Gln Ser His Leu Ser Met Ser Thr Ser Leu Gly
1 5 10 15
gat cct gtg tca atc act tgc aag gcc tca cag gat gtg agc acc gtc 96
Asp Pro Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
gtt gct tgg tat cag cag aag ccc ggg caa tca ccc aga cgt ctc atc 144
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Arg Leu Ile
35 40 45
tac tca gca tca tac cgt tac atc ggg gtg cct gac cga ttt act ggc 192
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
tct ggc gct ggc aca gat ttc acc ttt aca att agt tcc gtc cag gcc 240
Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
gaa gac ctg gcc gtg tac tac tgc cag cag cac tac agt ccc cca tac 288
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
act ttc ggg gga ggg act aag ctc gaa atc aaa cgt 324
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 62
<211> 108
<212> PRT
<213> 人
<400> 62
Asp Ile Val Met Thr Gln Ser His Leu Ser Met Ser Thr Ser Leu Gly
1 5 10 15
Asp Pro Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Arg Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 63
<211> 324
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(324)
<400> 63
gac att gtt atg gct caa agc cat ctg tct atg agc aca tct ctg gga 48
Asp Ile Val Met Ala Gln Ser His Leu Ser Met Ser Thr Ser Leu Gly
1 5 10 15
gat cct gtg tcc atc act tgc aaa gcc agt caa gac gtg tct aca gtt 96
Asp Pro Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
gtt gca tgg tat caa cag aag cca ggc cag tca ccc aga cgg ctc att 144
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Arg Leu Ile
35 40 45
tac tca gct tct tac cga tac atc ggg gtc cct gac aga ttt aca ggt 192
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
agt ggg gcc ggt act gac ttc act ttt act atc tca tcc gta caa gcc 240
Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
gaa gac ctg gca gta tat tac tgc cag caa cat tat tcc cca ccc tac 288
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
aca ttc ggc ggg ggt act aag ctg gaa att aaa cgt 324
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 64
<211> 108
<212> PRT
<213> 人
<400> 64
Asp Ile Val Met Ala Gln Ser His Leu Ser Met Ser Thr Ser Leu Gly
1 5 10 15
Asp Pro Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Arg Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ile Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 65
<211> 360
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(360)
<400> 65
cag gta cag ctc gtt cag tcc ggc gcc gag gta gct aag cct ggt act 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Ala Lys Pro Gly Thr
1 5 10 15
tcc gta aaa ttg tcc tgt aag gct tcc ggg tac aca ttt aca gac tac 96
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
tgg atg cag tgg gta aaa cag cgg cca ggt cag ggc ctg gag tgg att 144
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
gga aca ata tat ccc ggc gac ggc gac aca ggc tat gcc cag aag ttt 192
Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe
50 55 60
caa ggc aag gca acc ctt act gct gat aaa tct tcc aag act gtc tac 240
Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Lys Thr Val Tyr
65 70 75 80
atg cat ctg tct tcc ttg gca tct gag gat agc gct gtc tat tac tgt 288
Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
gct agg ggg gac tac tat ggg tca aat tcc ctg gat tac tgg ggc cag 336
Ala Arg Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr Trp Gly Gln
100 105 110
ggc acc agt gtc acc gtg agc agc 360
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 66
<211> 120
<212> PRT
<213> 人
<400> 66
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Ala Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Lys Thr Val Tyr
65 70 75 80
Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 67
<211> 324
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(324)
<400> 67
gac acc gtg atg acc cag tcc ccc tcc acc atc tcc acc tct gtg ggc 48
Asp Thr Val Met Thr Gln Ser Pro Ser Thr Ile Ser Thr Ser Val Gly
1 5 10 15
gac cgg gtg tcc atc acc tgt aag gcc tcc cag gtg gtg ggc tcc gcc 96
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Val Val Gly Ser Ala
20 25 30
gtg gcc tgg tat cag cag aag cct ggc cag tcc cct aag ctg ctg atc 144
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
tac tgg gcc tcc acc cgg cat acc ggc gtg cct gac cgg ttc acc ggc 192
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
tcc ggc agc ggc acc gac ttc acc ctg acc atc tcc aac gtg cag tcc 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
gac gac ctg gcc gac tac ttc tgc cag cag tac aac tcc tac cct tac 288
Asp Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
acc ttt ggc ggc gga aca aag ctg gag atc aag cgt 324
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 68
<211> 108
<212> PRT
<213> 人
<400> 68
Asp Thr Val Met Thr Gln Ser Pro Ser Thr Ile Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Val Val Gly Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Asp Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 69
<211> 324
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(324)
<400> 69
gac acc gtg atg acc cag tcc ccc tcc tcc atc tcc acc tcc atc ggc 48
Asp Thr Val Met Thr Gln Ser Pro Ser Ser Ile Ser Thr Ser Ile Gly
1 5 10 15
gac cgg gtg tcc atc acc tgt aag gcc tcc cag gtg gtg ggc tcc gcc 96
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Val Val Gly Ser Ala
20 25 30
gtg gcc tgg tat cag cag aag cct ggc cag tcc cct aag ctg ctg atc 144
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
tac tgg gcc tcc acc cgg cat acc ggc gtg cct gcc cgg ttc acc ggc 192
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ala Arg Phe Thr Gly
50 55 60
tcc ggc agc ggc acc gac ttc acc ctg acc atc tcc aac gtg cag tcc 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
gag gac ctg gcc gac tac ttc tgc cag cag tac aac tcc tac cct tac 288
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
acc ttt ggc ggc gga aca aag ctg gag atc aag cgt 324
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 70
<211> 108
<212> PRT
<213> 人
<400> 70
Asp Thr Val Met Thr Gln Ser Pro Ser Ser Ile Ser Thr Ser Ile Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Val Val Gly Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ala Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 71
<211> 351
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(351)
<400> 71
gag gtg cag ctg gtg gag tct ggc ggc gga ctg gtg aag cct ggc ggc 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
tcc ctg agg ctg tcc tgt gag gcc tcc ggc ttc acc ttc tcc tcc tac 96
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
acc ctg tcc tgg gtg agg cag acc cct ggc aag ggc ctg gag tgg gtg 144
Thr Leu Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
gcc acc atc tcc atc ggc ggc agg tac acc tac tac cct gac tcc gtg 192
Ala Thr Ile Ser Ile Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
aag ggc cgg ttc acc atc tcc cgg gac aac gcc aag aac acc ctg tac 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
ctg cag atg aac tcc ctg aag tcc gag gac acc gcc atg tac tac tgt 288
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
acc cgg gac ttc aac ggc tac tcc gac ttc tgg ggc cag ggc acc aca 336
Thr Arg Asp Phe Asn Gly Tyr Ser Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
ctg acc gtg tcc tcc 351
Leu Thr Val Ser Ser
115
<210> 72
<211> 117
<212> PRT
<213> 人
<400> 72
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Leu Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ile Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Arg Asp Phe Asn Gly Tyr Ser Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 73
<211> 36
<212> DNA
<213> 鼠
<400> 73
ggaggatcca tagacagatg ggggtgtcgt tttggc 36
<210> 74
<211> 32
<212> DNA
<213> 鼠
<400> 74
ggaggatccc ttgaccaggc atcctagagt ca 32
<210> 75
<211> 32
<212> DNA
<213> 鼠
<220>
<221> 其它特征
<222> (1)..(32)
<223> 混合碱基为如下定义：H=A+T+C, S=G+C, Y=C+T, K=
G+T, M=A+C, R=A+G, W=A+T, V = A+C+G, N = A+C+G+T
<400> 75
cttccggaat tcsargtnma gctgsagsag tc 32
<210> 76
<211> 35
<212> DNA
<213> 鼠
<220>
<221> 其它特征
<222> (1)..(35)
<223> 混合碱基为如下定义：H=A+T+C, S=G+C, Y=C+T, K=
G+T, M=A+C, R=A+G, W=A+T, V = A+C+G, N = A+C+G+T
<400> 76
cttccggaat tcsargtnma gctgsagsag tcwgg 35
<210> 77
<211> 31
<212> DNA
<213> 鼠
<220>
<221> 其它特征
<222> (1)..(31)
<223> 混合碱基为如下定义：H=A+T+C, S=G+C, Y=C+T, K=
G+T, M=A+C, R=A+G, W=A+T, V = A+C+G, N = A+C+G+T
<400> 77
ggagctcgay attgtgmtsa cmcarwctmc a 31
<210> 78
<211> 46
<212> DNA
<213> 鼠
<400> 78
tatagagctc aagcttggat ggtgggaaga tggatacagt tggtgc 46
<210> 79
<211> 21
<212> DNA
<213> 鼠
<400> 79
atggagtcac agattcaggt c 21
<210> 80
<211> 32
<212> DNA
<213> 鼠
<400> 80
ttttgaattc cagtaacttc aggtgtccac tc 32

Claims (13)

1.一种包括特异性识别CD38的抗体和至少阿糖胞苷的药物组合产品，其中所述抗体能够通过细胞凋亡、抗体依赖性细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)杀死CD38+细胞，
其中所述抗体是鼠38SB19抗体的人源化形式，其中所述鼠38SB19抗体的重链包含具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区，并且其中所述38SB19抗体的轻链包含具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。
2.权利要求1的组合产品，其中所述38SB19抗体是由以保藏编号PTA-7670保藏于美国典型培养物保藏中心的杂交瘤产生的抗体。
3.权利要求1或2的组合产品，其中所述抗体是通过表面重塑产生的人源化抗体。
4.权利要求1-3中任一项的组合产品，其中所述抗体包含至少一个重链和至少一个轻链，其中所述重链包含由SEQ ID NO:66表示的氨基酸序列，且其中所述轻链包含选自SEQID NO:62和64的氨基酸序列。
5.权利要求1-4中任一项的药物组合产品，其中所述药物组合是包含与阿糖胞苷组合的所述抗CD38抗体的药物组合物。
6.权利要求1-5中任一项的药物组合产品在制备用于治疗癌症的药物中的用途，其中所述癌症表达CD38。
7.权利要求6的用途，其中表达CD38的癌症是血液癌症。
8.权利要求7的用途，其中所述血液癌症选自下组：多发性骨髓瘤、白血病、急性和慢性淋巴细胞性白血病、急性和慢性淋巴系白血病、急性和慢性成淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、非Hodgkin淋巴瘤；急性和慢性髓细胞性白血病和前髓细胞性白血病。
9.权利要求6-8中任一项的用途，其中所述癌症是急性成淋巴细胞白血病。
10.权利要求1-9中任一项的组合，其中所述组合的组分用于单独施用。
11.权利要求1-9中任一项的组合，其中所述组合的组分用于同时施用。
12.一种用于制备用于治疗癌症的药物的药物组合，其中所述癌症表达CD38+，其中所述药物组合包含特异性识别CD38的抗体和至少阿糖胞苷，其中所述抗体能够通过细胞凋亡、抗体依赖性细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)杀死CD38+细胞，并且其中所述抗体是鼠38SB19抗体的人源化形式，其中所述鼠38SB19抗体的重链包含具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区，并且其中所述38SB19抗体的轻链包含具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。
13.与至少阿糖胞苷组合的特异性识别CD38的抗体用于治疗癌症的用途，其中所述癌症表达CD38+，其中所述抗体包含至少一个重链和至少一个轻链，其中所述抗体能够通过细胞凋亡、抗体依赖性细胞介导的细胞毒作用(ADCC)和补体依赖的细胞毒作用(CDC)杀死CD38+细胞，并且其中所述抗体是鼠38SB19抗体的人源化形式，其中所述鼠38SB19抗体的重链包含具有由SEQ ID NO:13、14和15表示的氨基酸序列的三个顺序互补决定区，并且其中所述38SB19抗体的轻链包含具有由SEQ ID NO:16、17和18表示的氨基酸序列的三个顺序互补决定区。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113278075A (zh) * 2021-06-18 2021-08-20 北京保图生物技术有限公司 一种炎症检测试剂盒

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2191842A1 (en) * 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and cytarabine
US8877899B2 (en) * 2010-09-27 2014-11-04 Morphosys Ag Anti-CD38 antibody and lenalidomide or bortezomib for the treatment of multipe myeloma and NHL
UA112170C2 (uk) * 2010-12-10 2016-08-10 Санофі Протипухлинна комбінація, що містить антитіло, яке специфічно розпізнає cd38, і бортезоміб
JOP20210044A1 (ar) 2010-12-30 2017-06-16 Takeda Pharmaceuticals Co الأجسام المضادة لـ cd38
PT2900232T (pt) 2012-09-25 2018-02-09 Morphosys Ag Combinações e suas utilizações
US20160022813A1 (en) * 2013-03-13 2016-01-28 Sanofi Compositions comprising anti-cd38 antibodies and carfilzomib
US9732154B2 (en) 2014-02-28 2017-08-15 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
US9603927B2 (en) 2014-02-28 2017-03-28 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
MA39070A1 (fr) 2014-07-31 2017-11-30 Sanofi Sa Anticorps anti-cd38 spécifiques pour le traitement de cancers humains
MY192918A (en) 2014-09-09 2022-09-15 Janssen Biotech Inc Combination therapies with anti-cd38 antibodies
US10793630B2 (en) 2014-12-04 2020-10-06 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute myeloid leukemia
JP6827426B2 (ja) 2015-05-20 2021-02-10 ヤンセン バイオテツク，インコーポレーテツド 軽鎖アミロイドーシス及びその他のｃｄ３８陽性血液悪性疾患の治療のための抗ｃｄ３８抗体
MX2018000265A (es) 2015-06-22 2018-05-23 Janssen Biotech Inc Terapias de combinacion para enfermedades malignas hematologicas con anticuerpos anti-cd38 e inhibidores de survivina.
US20170044265A1 (en) 2015-06-24 2017-02-16 Janssen Biotech, Inc. Immune Modulation and Treatment of Solid Tumors with Antibodies that Specifically Bind CD38
US10746739B2 (en) * 2015-09-14 2020-08-18 Leukemia Therapeutics, LLC Identification of novel diagnostics and therapeutics by modulating RhoH
US10781261B2 (en) 2015-11-03 2020-09-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
ES2862425T3 (es) 2015-11-03 2021-10-07 Janssen Biotech Inc Formulaciones subcutáneas de anticuerpos anti-CD38 y sus usos
WO2019035938A1 (en) 2017-08-16 2019-02-21 Elstar Therapeutics, Inc. MULTISPECIFIC MOLECULES BINDING TO BCMA AND USES THEREOF
CN111565751A (zh) 2017-10-31 2020-08-21 詹森生物科技公司 治疗高危多发性骨髓瘤的方法
CA3130132A1 (en) 2019-03-15 2020-09-24 Morphosys Ag Anti-cd38 antibodies and pharmaceutical compositions thereof for the treatment of autoantibody-mediated autoimmune disease
US11655302B2 (en) 2019-06-10 2023-05-23 Sanofi Anti-CD38 antibodies and formulations
CN112876563B (zh) * 2019-11-29 2022-08-16 康诺亚生物医药科技（成都）有限公司 药物组合物及其制备方法和应用
EP4069743A1 (en) 2019-12-05 2022-10-12 Sanofi-Aventis U.S. LLC Formulations of anti-cd38 antibodies for subcutaneous administration
MX2023008187A (es) 2021-01-14 2023-07-18 Morphosys Ag Anticuerpos anti-cd38 y sus usos.
TW202302642A (zh) 2021-03-01 2023-01-16 德商莫菲西斯公司 用於治療抗體介導移植物排斥用途之抗ｃｄ３８抗體
TW202321303A (zh) 2021-07-19 2023-06-01 德商莫菲西斯公司 抗pla2r自體抗體媒介膜性腎病變之治療

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062526A2 (en) * 1998-06-05 1999-12-09 Mayo Foundation For Medical Education And Research Use of genetically engineered antibodies to cd38 to treat multiple myeloma
WO2006099875A1 (en) * 2005-03-23 2006-09-28 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
EP1914242A1 (en) * 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
DK0463151T3 (da) 1990-01-12 1996-07-01 Cell Genesys Inc Frembringelse af xenogene antistoffer
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
DE69233482T2 (de) 1991-05-17 2006-01-12 Merck & Co., Inc. Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen
ATE255131T1 (de) 1991-06-14 2003-12-15 Genentech Inc Humanisierter heregulin antikörper
ES2136092T3 (es) 1991-09-23 1999-11-16 Medical Res Council Procedimientos para la produccion de anticuerpos humanizados.
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
EP1978033A3 (en) 1995-04-27 2008-12-24 Amgen Fremont Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
JP4215172B2 (ja) 1996-12-03 2009-01-28 アムジェン フレモント インク． 複数のＶ▲下Ｈ▼およびＶ▲下κ▼領域を含むヒトＩｇ遺伝子座を有するトランスジェニック哺乳動物、ならびにそれから産生される抗体
JP3876002B2 (ja) 1997-04-14 2007-01-31 ミクロメート・アクチエンゲゼルシャフト 抗ヒト抗原受容体を産生するための斬新な方法およびそれらの使用
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US20080057070A1 (en) * 2004-11-04 2008-03-06 Chiron Corporation Antagonist Anti-Cd40 Monoclonal Antibodies and Methods for Their Use
RS59005B1 (sr) * 2006-09-26 2019-08-30 Genmab As Anti-cd38 plus kortikosteroidi plus nekortikosteroidni hemoterapeutik za tretiranje tumora
WO2009094391A1 (en) * 2008-01-23 2009-07-30 Xencor, Inc. Optimized cd40 antibodies and methods of using the same
EP2191842A1 (en) * 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and cytarabine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062526A2 (en) * 1998-06-05 1999-12-09 Mayo Foundation For Medical Education And Research Use of genetically engineered antibodies to cd38 to treat multiple myeloma
WO2006099875A1 (en) * 2005-03-23 2006-09-28 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
EP1914242A1 (en) * 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113278075A (zh) * 2021-06-18 2021-08-20 北京保图生物技术有限公司 一种炎症检测试剂盒
CN113278075B (zh) * 2021-06-18 2021-12-14 芜湖森爱驰生物科技有限公司 一种炎症检测试剂盒

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