CN106794266B - 双特异性cd33和cd3结合蛋白 - Google Patents
双特异性cd33和cd3结合蛋白 Download PDFInfo
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Abstract
本文描述了与人类CD33特异性结合的结合蛋白，特别是与人类CD33和人类CD3特异性结合的双特异性结合蛋白。本文还描述了与CD33和CD33结合的双特异性串联双抗体及其用于CD33+癌症、疾病和病况如急性髓性白血病(AML)的免疫疗法的用途。
Description
相关申请的交叉引用
本申请要求于2014年7月1日提交的美国临时申请号62/019,795、于2015年2月3日提交的美国临时申请号62/111,470的权益；并且是于2015年3月9日提交的美国非临时申请号14/642,497的继续申请，每个申请均通过引用以其全文并入本文。
序列表
本申请含有序列表，该序列表通过引用以其全文并入本文。该序列表文件创建于2015年6月30日，命名为45375-704.601_SL.txt，并且大小为147,965个字节。
发明背景
急性髓性白血病(AML)是成年人和儿童中的急性白血病。CD33在AML中的大多数原始粒细胞上表达。在一些报道中，CD33通常局限于早期多谱系骨髓祖细胞，并且在正常的多能造血干细胞中缺失。
发明内容
本文提供了与人类CD33特异性结合的结合蛋白，以及与人类CD33和人类CD3特异性结合的双特异性结合蛋白。本文还提供了用于生成多种双特异性CD33/CD3结合蛋白例如串联双抗体(diabody)的抗CD33可变结构域和抗CD3可变结构域。本文还进一步提供了与CD33和CD3结合的双特异性串联双抗体，及其用于急性髓性白血病(AML)和其他恶性血液疾病、病症或病况的免疫疗法的用途。
特别地，提供了显示与人类和食蟹猴CD33两者都结合的结合蛋白。在实施例中证明，这些CD33/CD3串联双抗体可重新指向来自健康供体的多克隆CD3+T细胞以及来自AML患者的自体T细胞，以便以低E：T细胞比有效溶解CD33+AML细胞。在依赖于CD33+靶细胞和T细胞两者的存在的该过程中，如由CD25和CD69的诱导所示的，重新指向的T细胞被激活并被刺激从而增殖。显示出这些串联双抗体的抗AML效果取决于所使用的抗体的浓度和E：T细胞比。所述串联双抗体是四价的，并具有两个针对CD33的结合位点和两个针对CD3的结合位点。本文所述的CD33/CD3串联双抗体的特定特征在于，由于二价结合赋予每种抗原即CD33和CD3亲合性(avidity)，因此其有利于强力且有效的凋亡。
总之，本文所述的提供的CD33/CD3结合蛋白，特别是串联双抗体，在体外诱导CD33+白血病细胞和原代AML细胞的强细胞溶解。呈串联双抗体的抗体形式的双特异性CD33/CD3结合蛋白的实例证明了在细胞系、原代AML细胞中和在具有AML细胞系和具有来源于患者的原代AML细胞的体内模型中的体内细胞溶解活性。这表明了在严格的AML PDX模型中尤其值得注意的高体内活性。此外，呈串联双抗体的抗体形式的双特异性CD33/CD3结合蛋白的实例证明了在来自处于AML所有阶段的患者的样品中的离体细胞溶解活性，所述患者包括新诊断的、复发性和难治性患者。
此外，本文所述的这些CD33/CD3结合蛋白能够在约4小时内实现CD33表达细胞的显著溶解。因此，CD33/CD3结合蛋白在细胞表面上的低CD33密度下表现出高细胞毒性，并且在低效应物：靶标(E：T)比下表现出高细胞毒性。另外，本文所述的CD33/CD3结合蛋白不但表现出与人类蛋白质的强CD33和CD3结合亲和力(affinity)，而且显示出与相应食蟹猴蛋白质的极好的交叉反应性，例如其人类：食蟹猴KD比在5与0.2之间。此外，本文所述的CD33/CD3结合蛋白在不存在CD33+靶细胞的情况下不显示细胞因子释放的显著诱导，而其为这些分子的安全性概况的必要组分。另外，本文所述的CD33/CD3串联双抗体属于半衰期在约8-24h范围内的分子类别，该范围应允许方便的给药。
在一个方面，本文提供了与人类CD33的表位特异性结合的CD33结合蛋白。在一些实施方案中，所述结合蛋白包含来源于人类的轻链可变结构域和重链可变结构域。
在一些实施方案中，CD33结合蛋白具有至少一个包含轻链可变结构域和重链可变结构域的结合位点，其中该轻链可变结构域包含由选自SEQ ID NO:21-27的序列组成的CDR1、由选自SEQ ID NO:28-34的序列组成的CDR2以及由选自SEQ ID NO:35-41的序列组成的CDR3。
在一些实施方案中，CD33结合蛋白具有至少一个包含轻链可变结构域和重链可变结构域的结合位点，其中该重链可变结构域包含由选自SEQ ID NO:42-48的序列组成的CDR1、由选自SEQ ID NO:49-55的序列组成的CDR2以及由选自SEQ ID NO:56-63的序列组成的CDR3。
在某些情况下，所述轻链可变结构域的CDR1、CDR2和CDR3选自：SEQ ID NO:21、28和35；SEQ ID NO:22、29和36；SEQ ID NO:23、30和37；SEQ ID NO:24、31和38；SEQ ID NO:25、32和39；SEQ ID NO:26、33和40；以及SEQ ID NO:27、34和41。
在某些情况下，所述重链可变结构域的CDR1、CDR2和CDR3选自：SEQ ID NO:42、49和56；SEQ ID NO:43、50和57；SEQ ID NO:43、50和58；SEQ ID NO:43、50和59；SEQ ID NO:43、50和60；SEQ ID NO:44、51和61；SEQ ID NO:45、52和62；SEQ ID NO:46、53和63；SEQ IDNO:47、54和63；以及SEQ ID NO:48、55和63。
在某些情况下，可变重链结构域和可变轻链结构域的人类CD33结合位点选自：SEQID NO:1和SEQ ID NO:11；SEQ ID NO:2和SEQ ID NO:12；SEQ ID NO:3和SEQ ID NO:13；SEQID NO:4和SEQ ID NO:14；SEQ ID NO:5和SEQ ID NO:15；SEQ ID NO:6和SEQ ID NO:16；SEQID NO:7和SEQ ID NO:17；SEQ ID NO:8和SEQ ID NO:18；SEQ ID NO:9和SEQ ID NO:19；以及SEQ ID NO:10和SEQ ID NO:20。
在一些实施方案中，所述CD33表位在人类CD33的62DQEVQEETQ70(SEQ ID NO:94)(SEQ ID NO:93的氨基酸残基62-70)内。
在上述实施方案的任一实施方案中，所述CD33结合蛋白包含至少一个其他的功能性结构域。在一些情况下，该功能性结构域为与效应细胞结合的效应物结构域。在某些情况下，该效应物结构域为CD3结合位点，其包含形成针对人类CD3的抗原结合位点的至少一个抗体可变重链结构域和至少一个可变轻链结构域。
在某些情况下，所述CD3结合位点包含重链可变结构域，该重链可变结构域包含STYAMN(SEQ ID NO:72)的CDR1序列、RIRSKYNNYATYYADSVKD(SEQ ID NO:73)的CDR2序列以及HGNFGNSYVSWFAY(SEQ ID NO:74)的CDR3序列。在其他情况下，所述CD3结合位点包含轻链可变结构域，该轻链可变结构域包含RSSTGAVTTSNYAN(SEQ ID NO:90)的CDR1序列、GTNKRAP(SEQ ID NO:91)的CDR2序列以及ALWYSNL(SEQ ID NO:92)的CDR3序列。
在某些情况下，所述CD3结合位点包含SEQ ID NO:64的重链可变结构域和SEQ IDNO:68的可变轻链结构域；SEQ ID NO:65的重链可变结构域和SEQ ID NO:69的可变轻链结构域；SEQ ID NO:66的重链可变结构域和SEQ ID NO:70的可变轻链结构域；或SEQ ID NO:67的重链可变结构域和SEQ ID NO:71的可变轻链结构域。
在上述实施方案的任一实施方案中，所述CD33结合蛋白为二聚体蛋白质。在上述实施方案的任一实施方案中，所述CD33结合蛋白是多功能的。
在某些情况下，所述多功能CD33结合蛋白具有针对CD33和CD3的双特异性，其中所述结合特异性由选自下组的针对CD33和CD3的重链可变结构域和轻链可变结构域提供：SEQID NO:2、12、65和69；SEQ ID NO:3、13、65和69；SEQ ID NO:4、14、65和69；SEQ ID NO:5、15、65和69；SEQ ID NO:1、11、64和68；SEQ ID NO:2、12、64和68；SEQ ID NO:2、12、66和70；SEQID NO:4、14、66和70；SEQ ID NO:5、15、66和70；SEQ ID NO:3、13、64和68；SEQ ID NO:3、13、67和71；SEQ ID NO:4、14、64和68；SEQ ID NO:5、15、64和68；SEQ ID NO:7、17、64和68；SEQID NO:6、16、64和68；SEQ ID NO:6、16、67和71；SEQ ID NO:8、18、64和68；SEQ ID NO:9、19、64和68；SEQ ID NO:9、19、67和71；以及SEQ ID NO:10、20、64和68。
在另一个方面，本文提供了对人类CD3和人类CD33具有特异性的双特异性抗原结合串联双抗体。在一些实施方案中，该串联双抗体包含第一多肽和第二多肽，每个多肽均具有至少四个相继连接的可变链结构域，其中每个多肽均包含对人类CD33具有特异性的可变重链结构域；对人类CD33具有特异性的可变轻链结构域；对人类CD3具有特异性的可变重链结构域，以及对人类CD3具有特异性的可变轻链结构域，并且其中在每个多肽中，所述四个可变链结构域通过肽连接体L1、L2和L3按以下顺序相继连接：VL(CD3)-L1-VH(CD33)-L2-VL(CD33)-L3-VH(CD3)；VH(CD3)-L1-VL(CD33)-L2-VH(CD33)-L3-VL(CD3)；VL(CD33)-L1-VH(CD3)-L2-VL(CD3)-L3-VH(CD33)；或VH(CD33)-L1-VL(CD3)-L2-VH(CD3)-L3-VL(CD33)。
在一些实施方案中，所述对人类CD33具有特异性的VL结构域包含由选自SEQ IDNO:21-27的序列组成的CDR1、由选自SEQ ID NO:28-34的序列组成的CDR2以及由选自SEQID NO:35-41的序列组成的CDR3。
在一些实施方案中，所述对人类CD33具有特异性的VH结构域包含由选自SEQ IDNO:42-48的序列组成的CDR1、由选自SEQ ID NO:49-55的序列组成的CDR2以及由选自SEQID NO:56-63的序列组成的CDR3。
在一些实施方案中，所述对人类CD33具有特异性的VL结构域的CDR1、CDR2和CDR3为选自下组的序列：SEQ ID NO:21、28和35；SEQ ID NO:22、29和36；SEQ ID NO:23、30和37；SEQ ID NO:24、31和38；SEQ ID NO:25、32和39；SEQ ID NO:26、33和40；以及SEQ ID NO:27、34和41。
在一些实施方案中，所述对人类CD33具有特异性的VH结构域的CDR1、CDR2和CDR3为选自下组的序列：SEQ ID NO:42、49和56；SEQ ID NO:43、50和57；SEQ ID NO:43、50和58；SEQ ID NO:43、50和59；SEQ ID NO:43、50和60；SEQ ID NO:44、51和61；SEQ ID NO:45、52和62；SEQ ID NO:46、53和63；SEQ ID NO:47、54和63；以及SEQ ID NO:48、55和63。
在一些实施方案中，对CD33具有特异性的VL和VH结构域为选自下组的序列：SEQID NO:1和SEQ ID NO:11；SEQ ID NO:2和SEQ ID NO:12；SEQ ID NO:3和SEQ ID NO:13；SEQID NO:4和SEQ ID NO:14；SEQ ID NO:5和SEQ ID NO:15；SEQ ID NO:6和SEQ ID NO:16；SEQID NO:7和SEQ ID NO:17；SEQ ID NO:8和SEQ ID NO:18；SEQ ID NO:9和SEQ ID NO:19；以及SEQ ID NO:10和SEQ ID NO:20。
在一些实施方案中，所述对人类CD3具有特异性的VH结构域包含STYAMN(SEQ IDNO:72)的CDR1序列、RIRSKYNNYATYYADSVKD(SEQ ID NO:73)的CDR2序列以及HGNFGNSYVSWFAY(SEQ ID NO:74)或HGNFGNSYVSYFAY(SEQ ID NO:75)的CDR3序列。
在一些实施方案中，所述对人类CD3具有特异性的VL结构域包含RSSTGAVTTSNYAN(SEQ ID NO:90)的CDR1序列、GTNKRAP(SEQ ID NO:91)的CDR2序列以及ALWYSNL(SEQ IDNO:92)的CDR3序列。
在一些实施方案中，所述对CD3具有特异性的VL和VH结构域为选自下组的序列：SEQ ID NO:64和SEQ ID NO:68；SEQ ID NO:65和SEQ ID NO:69；SEQ ID NO:66和SEQ IDNO:70；以及SEQ ID NO:67和SEQ ID NO:71。
在一些实施方案中，每个多肽均包含四个可变链结构域，该可变链结构域选自SEQID NO:2、12、65和69；SEQ ID NO:3、13、65和69；SEQ ID NO:4、14、65和69；SEQ ID NO:5、15、65和69；SEQ ID NO:1、11、64和68；SEQ ID NO:2、12、64和68；SEQ ID NO:2、12、66和70；SEQID NO:4、14、66和70；SEQ ID NO:5、15、66和70；SEQ ID NO:3、13、64和68；SEQ ID NO:3、13、67和71；SEQ ID NO:4、14、64和68；SEQ ID NO:5、15、64和68；SEQ ID NO:7、17、64和68；SEQID NO:6、16、64和68；SEQ ID NO:6、16、67和71；SEQ ID NO:8、18、64和68；SEQ ID NO:9、19、64和68；SEQ ID NO:9、19、67和71；以及SEQ ID NO:10、20、64和68。
在一些实施方案中，连接体L1、L2和L3由约12个或更少的氨基酸残基组成。在某些情况下，连接体L1、L2和L3各自独立地为GGSGGS(SEQ ID NO:95)、GGSG(SEQ ID NO:96)或GGSGG(SEQ ID NO:97)。在其他情况下，连接体L1和L3为GGSGGS(SEQ ID NO:95)，且连接体L2为GGSG(SEQ ID NO:96)或GGSGG(SEQ ID NO:97)。
在一些实施方案中，双特异性串联双抗体具有选自SEQ ID NO:98-121的序列。在其他实施方案中，双特异性串联双抗体为串联双抗体01(SEQ ID NO:98)、02(SEQ ID NO:99)、03(SEQ ID NO:100)、04(SEQ ID NO:101)、05(SEQ ID NO:102)、06(SEQ ID NO:103)、07(SEQ ID NO:104)、08(SEQ ID NO:105)、09(SEQ ID NO:106)、10(SEQ ID NO:107)、11(SEQ ID NO:108)、12(SEQ ID NO:109)、13(SEQ ID NO:110)、14(SEQ ID NO:111)、15(SEQID NO:112)、16(SEQ ID NO:113)、17(SEQ ID NO:114)、18(SEQ ID NO:115)、19(SEQ IDNO:116)、20(SEQ ID NO:117)、21(SEQ ID NO:118)、22(SEQ ID NO:119)、23(SEQ ID NO:120)或24(SEQ ID NO:121)。
在一些实施方案中，所述双特异性抗原结合串联双抗体对选自HL-60、KG-1和U-937的CD33+肿瘤细胞上的CD33具有10nM或更小的结合KD。
在一些实施方案中，所述双特异性抗原结合串联双抗体与人类CD33的表位特异性结合，该表位在人类CD33的62DQEVQEETQ70(SEQ ID NO:94)(SEQ ID NO:93的氨基酸残基62-70)内。
在另一个方面，本文提供了编码上述实施方案中的任一实施方案的CD33结合蛋白或双特异性串联双抗体的多核苷酸。在另一个方面，本文提供了包含所描述的多核苷酸的载体。在另一个方面，本文提供了用所描述的载体转化的宿主细胞。
在又一个方面，本文提供了药物组合物，其包含上述实施方案中的任一实施方案的CD33结合蛋白或双特异性串联双抗体以及药学上可接受的载体。
在又一个方面，本文提供了产生上述实施方案中的任一实施方案的CD33结合蛋白或双特异性串联双抗体的方法，该方法包括将编码上述实施方案中的任一实施方案的CD33结合蛋白或双特异性串联双抗体的多核苷酸或包含所描述的多核苷酸的载体引入至宿主细胞中，在使得该CD33结合蛋白或双特异性串联双抗体表达的条件下培养该宿主细胞，以及纯化所表达的CD33结合蛋白或双特异性串联双抗体。
本文还提供了用于治疗CD33+癌症的方法，该方法包括向患有CD33+癌症的个体施用上述实施方案中的任一实施方案的双特异性串联双抗体。在一些实施方案中，该CD33+癌症为急性髓性白血病(AML)、急性成淋巴细胞性白血病(ALL)、前体B细胞成淋巴细胞性白血病、髓样肉瘤、多发性骨髓瘤、急性淋巴瘤、急性淋巴母细胞性淋巴瘤或慢性粒单核细胞白血病(CMML)。在一些实施方案中，该CD33+癌症为急性髓性白血病(AML)。在一些实施方案中，该CD33+癌症为多发性骨髓瘤。在一些实施方案中，该CD33+癌症为急性成淋巴细胞性白血病(ALL)。
本文还提供了用于治疗急性髓性白血病(AML)的方法，该方法包括向患有AML的个体施用上述实施方案中的任一实施方案的双特异性串联双抗体。在一些实施方案中，该AML为伴有复发性遗传异常的AML、伴有脊髓发育不良相关变化的AML、与治疗相关的髓样肿瘤、髓样肉瘤、与唐氏综合征相关的骨髓增生、母细胞性浆细胞样树突状细胞肿瘤或尚未分类的AML。在一些实施方案中，该AML为AML-M0、AML-M1、AML-M2、AML-M3、AML-M4、AML-M5、AML-M6或AML-M7。在进一步的实施方案中，该AML是新诊断的、复发性的或难治性的。
本文还提供了用于治疗骨髓发育不良综合征(MDS)的方法，该方法包括向患有MDS的个体施用上述实施方案中的任一实施方案的双特异性串联双抗体。
本文还提供了用于治疗骨髓增生性疾病(MPD)的方法，该方法包括向患有MPD的个体施用上述实施方案中的任一实施方案的双特异性串联双抗体。
本文还提供了用于治疗慢性粒单核细胞白血病(CMML)的方法，该方法包括向患有CMML的个体施用上述实施方案中的任一实施方案的双特异性串联双抗体。
本文还提供了用于治疗骨髓衍生的抑制细胞(MDSC)所致的免疫抑制的方法，该方法包括向罹患免疫抑制的个体施用上述实施方案中的任一实施方案的双特异性串联双抗体。
在以上治疗方法中，在某些情况下，所述方法进一步包括施用阿糖胞苷(cytarabine)、阿扎胞苷(azacitidine)、地西他滨(decitabine)、蒽环类药物(anthracycline，例如，柔红霉素(daunorubicin)、伊达比星(idarubicin)、多柔比星(doxorubicin)等)、安吖啶(amsacrine)、氟达拉滨(fludarabine)、氯法拉滨(clofarabine)、克拉屈滨(cladribine)、奈拉滨(nelarabine)、甲氨蝶呤(methotrexate)、硼替佐米(bortezomib)、卡非佐米(carfilzomib)、美法仑(melphalan)、依鲁替尼(ibrutinib)、沙利度胺(thalidomide)、来那度胺(lenalidomide)、泊马度胺(pomalidomide)、阿普斯特(apremilast)、表鬼臼毒素(epipodophyllotoxin，例如，依托泊苷(etoposide)、替尼泊苷(teniposide)等)、蒽醌(anthracenedione，例如，米托蒽醌(mitoxantrone)、匹克生琼(pixantrone)、洛索蒽醌(losoxantrone)、吡罗蒽醌(piroxantrone)、阿美蒽醌等(ametantrone))、抗CD20剂(例如，利妥昔单抗(rituximab)、奥瑞珠单抗(ocrelizumab)、奥法木单抗(ofatumumab)等)或其组合。
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图1CD3/CD33串联双抗体
的基因组织和结构域顺序的示意图。串联双抗体被表示为由经由短肽连接体L1、L2和L3连接的四个可变结构域构成的单一多肽。表达后，两个单体多肽非共价地头尾缔合以形成功能性的同型二聚体串联双抗体分子。L1、L2、L3：连接体；VH：重链可变结构域；VL：轻链可变结构域。
图2与CD3接合的串联双抗体及其作用模式。串联双抗体为可经由与CD3结合而接合细胞毒性T细胞的四价双特异性蛋白质。该串联双抗体采用四个结合结构域中的两个与CD33+肿瘤细胞结合，并采用另外两个结合结构域与CD3结合。这一T细胞/靶细胞结合(交联)事件促进T细胞的激活并通过ADCC促进肿瘤细胞的后续破坏。
图3CD33/CD3串联双抗体的结构域顺序变体。在编码串联双抗体的基因序列内的可变重链(VH)和可变轻链(VL)的结构域顺序的变化允许产生具有位于分子内部或外部的CD33和CD3特异性的抗体。示出了结构域特异性、信号序列(ss)和连接体(L1、L2、L3)和亲和标记物(His)的位置以及5'-和3'-末端。
图4正富集(positively enriched)的健康供体T细胞与负选择的健康供体T细胞的比较。如图所示，将KG-1a细胞与10pM(大约1ng/mL)和25pM(大约2.5ng/mL)的10种所选串联双抗体之一和负选择的健康供体T细胞或正选择的健康供体T细胞以1：1或3：1的E：T细胞比一起温育。48小时后，确定细胞计数，并用DAPI染色评价细胞毒性。结果显示为来自在重复孔中进行的3个独立实验的死细胞百分比(上图)和特异性细胞毒性百分比(下图)的平均值±SEM。
图5分析策略。来自一个健康供体T细胞等份和1种代表性AML细胞系(HL-60)以及原代AML样本(AMP002)的散点图和直方图，每一幅图都示出了致力于确定串联双抗体诱导的细胞毒性的策略。FSC，前向散射；SSC，侧向散射。
图6CD33+AML细胞系中的筛选细胞毒性测定。如图所示，将亲代HL-60(A、B)和KG-1a(C、D)细胞与10pM(大约1ng/mL)和25pM(大约2.5ng/mL)的22种CD33/CD3串联双抗体分子之一或非结合对照串联双抗体(00)以及健康供体T细胞以1：1(A、C)或5：1(B、D)的E：T细胞比一起温育。48小时后，确定细胞计数，并用DAPI染色评价细胞毒性以量化药物特异性细胞毒性。结果显示为来自在重复孔中进行的3个独立实验的DAPI+细胞百分比的平均值±SEM。在将细胞毒性表示为特异性细胞毒性的百分比时，获得了在定性上相似的结果。
图7用于研究的原代AML样本的选择。获得来自全部原代人类AML样本的冷冻等份以用于分析。基于CD45/侧向散射性质，通过流式细胞术确定解冻时AML母细胞的百分比。使用DAPI作为活/死细胞标记物，经由流式细胞术在解冻时以及48小时后在含有细胞因子的液体培养物(不添加串联双抗体分子或健康供体T细胞)中确定样本的活力。示出了所有样本在解冻后以及48小时后的活力结果，该样本具有>58％的AML母细胞。正方形：在含有细胞因子的液体培养物中在解冻时显示出>50％的活力以及在48小时后显示出>50％的活力的原代AML样本，它们包含在最终分析中。
图8原代AML样本中串联双抗体诱导的细胞毒性。如图所示，在不添加健康供体T细胞的情况下(A)或在有健康供体T细胞的情况下以1：3(B)或1：1(C)的E：T细胞比将原代AML样本与2.5pM(大约250pg/mL)、10pM(大约1ng/mL)和25pM(大约2.5ng/mL)的9种串联双抗体分子之一一起温育。48小时后，确定细胞计数，并利用DAPI染色评价细胞毒性以量化药物特异性细胞毒性。结果显示为来自在重复孔中进行的实验的特异性细胞毒性百分比的平均值±SEM。
图9A为人类CD33的胞外域的序列(aa 18-259)(SEQ ID NO:93)；
图9B为串联双抗体1的全序列(SEQ ID NO:98)；
图9C为串联双抗体2的全序列(SEQ ID NO:99)；
图9D为串联双抗体3的全序列(SEQ ID NO:100)；
图9E为串联双抗体4的全序列(SEQ ID NO:101)；
图9F为串联双抗体5的全序列(SEQ ID NO:102)；
图9G为串联双抗体6的全序列(SEQ ID NO:103)；
图9H为串联双抗体7的全序列(SEQ ID NO:104)；
图9I为串联双抗体8的全序列(SEQ ID NO:105)；
图9J为串联双抗体9的全序列(SEQ ID NO:106)；
图9K为串联双抗体10的全序列(SEQ ID NO:107)；
图9L为串联双抗体11的全序列(SEQ ID NO:108)；
图9M为串联双抗体12的全序列(SEQ ID NO:109)；
图9N为串联双抗体13的全序列(SEQ ID NO:110)；
图9O为串联双抗体14的全序列(SEQ ID NO:111)；
图9P为串联双抗体15的全序列(SEQ ID NO:112)；
图9Q为串联双抗体16的全序列(SEQ ID NO:113)；
图9R为串联双抗体17的全序列(SEQ ID NO:114)；
图9S为串联双抗体18的全序列(SEQ ID NO:115)；
图9T为串联双抗体19的全序列(SEQ ID NO:116)；
图9U为串联双抗体20的全序列(SEQ ID NO:117)；
图9V为串联双抗体21的全序列(SEQ ID NO:118)；
图9W为串联双抗体22的全序列(SEQ ID NO:119)；
图9X为串联双抗体23的全序列(SEQ ID NO:120)；以及
图9Y为串联双抗体24的全序列(SEQ ID NO:121)。带下划线的序列代表连接体L1、L2和L3。
图10串联双抗体16和12对NOD/scid小鼠中HL-60细胞生长的影响。在第0天通过皮下注射4x106个HL-60细胞的悬浮液对免疫缺陷型NOD/scid小鼠的8个实验组进行异种移植。在注射之前，将HL-60细胞与来自健康供体的3x106个纯化T细胞混合。移植有肿瘤细胞和T细胞的实验组的所有动物均在第0天、第1天、第2天、第3天和第4天接受媒介物(对照)或所示3个不同剂量水平(0.1μg、1μg和10μg)的串联双抗体16或12的静脉内团注。未进行效应细胞和媒介物处理的一个组充当额外的阴性对照。
图11串联双抗体16在AML异种移植模型中的抗肿瘤活性。对NOD/scid小鼠进行亚致死辐照(2Gy)并皮下接种4x106个HL-60细胞。在第9天，动物接受抗去唾液酸基GM1兔Ab的单次团注。当在第10天肿瘤达到50-150mm3(平均73±11mm3)的体积时，将动物分配为3个处理组。向组2和组3(n＝8)腹膜内注射1.5x107个扩充并激活的人类T细胞。从第13天至第21天(qdxd9)，动物在侧尾静脉内接受串联双抗体16(组3)或媒介物(组1和组2)。
图12在用5μg(0.25mg/kg)或50μg(2.5mg/kg)CD33/CD3串联双抗体12和16处理后第38天，NSG小鼠的骨髓(BM)和脾中的人类AML母细胞的相对量(A)和绝对计数(B)。
图13CD33/CD3串联双抗体16介导的靶细胞溶解的动力学。在串联双抗体16的连续稀释液的存在下或在不存在抗体(w/o)的情况下，以25：1的E：T比将1x104个钙黄绿素标记的HL-60靶细胞与作为效应细胞的原代人类T细胞一起温育30min、1h、2h、3h、4h或5h。在每个时间点，使用从溶解的靶细胞释放的荧光钙黄绿素计算特异性溶解。将三次重复的平均值和SD作图。
图14CD33/CD3串联双抗体16的EC50和特异性溶解值的动力学。通过非线性回归/S形剂量-响应，在钙黄绿素释放的细胞毒性测定中确定在所示的温育时间的EC50值(黑色实心圆)和串联双抗体16介导的靶细胞溶解值(空心正方形)，并将其作图。
图15新诊断的、复发性和难治性AML患者样品中的细胞毒性活性。
具体实施方式
根据第一个方面，本文描述了对至少CD33、优选人类CD33具有特异性的结合蛋白。在一些实施方案中，该CD33结合蛋白对人类和食蟹猴CD33具有特异性，即，是交叉反应性的。在一些实施方案中，这些交叉反应性结合蛋白以相似的亲和力与人类和食蟹猴CD33结合。
CD33在骨髓细胞例如急性髓性白血病(AML)的母细胞上表达。为了分离对CD33如人类CD33具有特异性的抗体结构域，可筛查抗体文库。例如，可通过利用例如含有人类CD33的胞外域的氨基酸1-243(图9A，SEQ ID NO:93)的重组CD33-Fc融合蛋白来筛查IgM噬菌体展示文库。
在一些实施方案中，所述CD33结合蛋白具有至少一个包含轻链可变结构域和重链可变结构域的CD33结合位点。该轻链可变结构域包含轻链CDR1、CDR2和CDR3，并且该重链可变结构域包含重链CDR1、CDR2和CDR3。在一些实施方案中，这些轻链CDR(CDR1、CDR2和CDR3)选自表1中所示的人类CDR序列(SEQ ID NO:21-41)。在某些情况下，该轻链CDR1选自SEQ IDNO:21-27。在某些情况下，该轻链CDR2选自SEQ ID NO:28-34。在某些情况下，该轻链CDR3选自SEQ ID NO:35-41。
在一些实施方案中，这些重链CDR(重链CDR1、CDR2和CDR3)选自表2中所示的人类CDR序列(SEQ ID NO:42-63)。在某些情况下，该重链CDR1选自SEQ ID NO:42-48。在某些情况下，该重链CDR2选自SEQ ID NO:49-55。在某些情况下，该重链CDR3选自SEQ ID NO:56-63。
在一些实施方案中，选择没有相应可变结构域的周围框架序列的轻链和重链CDR，该框架序列包括来自其他免疫球蛋白或共有框架区的框架序列，任选地进一步突变并且/或者被其他合适的框架序列替代。因此，在一些实施方案中，本文提供了包含轻链可变结构域的CD33结合蛋白，其中轻链CDR1为SEQ ID NO:21；轻链CDR2为SEQ ID NO:28，并且轻链CDR3为SEQ ID NO:35。在一些实施方案中，CD33结合蛋白包含轻链可变结构域，其中轻链CDR1为SEQ ID NO:22；轻链CDR2为SEQ ID NO:29，并且轻链CDR3为SEQ ID NO:36。在一些实施方案中，CD33结合蛋白包含轻链可变结构域，其中轻链CDR1为SEQ ID NO:23；轻链CDR2为SEQ ID NO:30，并且轻链CDR3为SEQ ID NO:37。在一些实施方案中，CD33结合蛋白包含轻链可变结构域，其中轻链CDR1为SEQ ID NO:24；轻链CDR2为SEQ ID NO:31，并且轻链CDR3为SEQ ID NO:38。在一些实施方案中，CD33结合蛋白包含轻链可变结构域，其中轻链CDR1为SEQ ID NO:25；轻链CDR2为SEQ ID NO:32，并且轻链CDR3为SEQ ID NO:39。在一些实施方案中，CD33结合蛋白包含轻链可变结构域，其中轻链CDR1为SEQ ID NO:26；轻链CDR2为SEQ IDNO:33，并且轻链CDR3为SEQ ID NO:40。在一些实施方案中，CD33结合蛋白包含轻链可变结构域，其中轻链CDR1为SEQ ID NO:27；轻链CDR2为SEQ ID NO:34，并且轻链CDR3为SEQ IDNO:41。
在一些实施方案中，本文还提供了包含重链可变结构域的CD33结合蛋白，其中重链CDR1为SEQ ID NO:42；重链CDR2为SEQ ID NO:49，并且重链CDR3为SEQ ID NO:56。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:43；重链CDR2为SEQ ID NO:50，并且重链CDR3为SEQ ID NO:57。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:43；重链CDR2为SEQ ID NO:50，并且重链CDR3为SEQ ID NO:58。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:43；重链CDR2为SEQ ID NO:50，并且重链CDR3为SEQ ID NO:59。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:43；重链CDR2为SEQ IDNO:50，并且重链CDR3为SEQ ID NO:60。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:44；重链CDR2为SEQ ID NO:51，并且重链CDR3为SEQ IDNO:61。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ IDNO:45；重链CDR2为SEQ ID NO:52，并且重链CDR3为SEQ ID NO:62。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:46；重链CDR2为SEQ ID NO:53，并且重链CDR3为SEQ ID NO:63。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:47；重链CDR2为SEQ ID NO:54，并且重链CDR3为SEQ ID NO:63。在一些实施方案中，CD33结合蛋白包含重链可变结构域，其中重链CDR1为SEQ ID NO:48；重链CDR2为SEQ ID NO:55，并且重链CDR3为SEQ ID NO:63。
在进一步的实施方案中，CD33结合蛋白包含选自表3中所示的氨基酸序列SEQ IDNO:1-10的可变轻链结构域。在进一步的实施方案中，CD33结合蛋白包含选自表4中所示的氨基酸序列SEQ ID NO:11-20的可变重链结构域。在更进一步的实施方案中，CD33结合蛋白包含选自表3中所示的氨基酸序列SEQ ID NO:1-10的可变轻链结构域和选自表4中所示的氨基酸序列SEQ ID NO:11-20的可变重链结构域。
术语“结合蛋白”是指具有抗原结合性质的免疫球蛋白衍生物，即含有抗原结合位点的免疫球蛋白多肽或其片段。该结合蛋白包含抗体或其片段的可变结构域。每个抗原结合结构域由结合相同表位的抗体(即免疫球蛋白)可变重链结构域(VH)和抗体可变轻链结构域(VL)形成，而可变重链结构域(VH)包含三个重链互补决定区(CDR)：CDR1、CDR2和CDR3；并且可变轻链结构域(VL)包含三个轻链互补决定区(CDR)：CDR1、CDR2和CDR3。在一些情况下，根据本文的一些实施方案的结合蛋白缺乏免疫球蛋白恒定结构域。在一些情况下，形成抗原结合位点的可变轻链结构域和可变重链结构域例如通过肽连接体彼此共价连接，或在其他情况下，可变轻链结构域和可变重链结构域彼此非共价缔合以形成抗原结合位点。术语“结合蛋白”也指抗体片段或抗体衍生物，包括，例如，Fab、Fab'、F(ab′)2、Fv片段、单链Fv、串联单链Fv(scFv)2、双特异性T细胞接合物
双亲和性重靶向抗体(DARTTM)、双抗体和串联双抗体
此外，在某些情况下，该结合蛋白是多价的，即具有两个、三个或更多个针对CD33的结合位点。
表1：抗CD33可变轻链CDR1、CDR2和CDR3的氨基酸序列
表2：抗CD33可变重链CDR1、CDR2和CDR3的氨基酸序列
表3：所有抗CD33可变轻链结构域的氨基酸序列(可变轻链CDR1、CDR2和CDR3的氨基酸序列被加粗并加下划线)
表4：抗CD33可变重链结构域的氨基酸序列(可变重链CDR1、CDR2和CDR3的氨基酸序列被加粗并加下划线)
在一些实施方案中，赋予对CD33的特异性的结合蛋白选自表3和表4中所示的形成人类CD33结合位点的可变重链结构域和可变轻链结构域的以下组合之一。非限制性实例包括(i)SEQ ID NO:1和SEQ ID NO:11，(ii)SEQ ID NO:2和SEQ ID NO:12，(iii)SEQ ID NO:3和SEQ ID NO:13，(iv)SEQ ID NO:4和SEQ ID NO:14，(v)SEQ ID NO:5和SEQ ID NO:15，(vi)SEQ ID NO:6和SEQ ID NO:16，(vii)SEQ ID NO:7和SEQ ID NO:17，(viii)SEQ ID NO:8和SEQ ID NO:18，(ix)SEQ ID NO:9和SEQ ID NO:19，以及(x)SEQ ID NO:10和SEQ ID NO:20。
本文还描述了不但对CD33具有特异性而且还具有至少一个其他功能性结构域的结合蛋白。在进一步的实施方案中，至少一个其他功能性结构域为效应物结构域。“效应物结构域”包含对效应细胞具有特异性的抗体的结合位点，其可刺激或触发细胞毒性、吞噬作用、抗原呈递、细胞因子释放。这样的效应细胞例如是但不限于T细胞。特别地，效应物结构域包含形成针对T细胞上的抗原如人类CD3的抗原结合位点的至少一个抗体可变重链结构域和至少一个可变轻链结构域。
因此，在一些实施方案中，所述CD33结合蛋白是多功能性的。如本文所用的术语"多功能性的"意指结合蛋白表现出两种或更多种不同的生物功能。例如，所述不同的生物功能是针对不同抗原的不同特异性。在某些情况下，该多功能CD33结合蛋白是多特异性的，即具有对CD33和一种或多种其他抗原的结合特异性。在某些情况下，该结合蛋白是双特异性的，对CD33和CD3具有特异性。这样的双特异性结合蛋白包括，例如，IgA、IgD、IgE、IgG或IgM类别的双特异性单克隆抗体，双抗体，单链双抗体(scDb)，串联单链Fv(scFv)2，例如双特异性T细胞接合物
双亲和性重靶向抗体(DARTTM)，串联双抗体
和柔性抗体(flexibodies)。
在某些实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点对人类CD3具有特异性，且在一些情况下对食蟹猴CD3具有特异性。这样的结合位点的实例是包含来自表5所示序列(SEQ ID NO:64-67)的VH结构域CDR1、CDR2和CDR3以及来自表6所示序列(SEQ IDNO:68-71)的VL结构域CDR1、CDR2和CDR3的多肽。在某些情况下，CD3结合位点是SEQ ID NO:64的可变重链结构域与SEQ ID NO:68的可变轻链结构域的组合。在某些情况下，CD3结合位点是SEQ ID NO:65的可变重链结构域与SEQ ID NO:69的可变轻链结构域的组合。在某些情况下，CD3结合位点是SEQ ID NO:66的可变重链结构域与SEQ ID NO:70的可变轻链结构域的组合。在某些情况下，CD3结合位点是SEQ ID NO:67的可变重链结构域与SEQ ID NO:71的可变轻链结构域的组合。
表5：抗CD3可变重链结构域的氨基酸序列(可变重链CDR1、CDR2和CDR3的氨基酸序列被加粗并加下划线)
表6：抗CD3可变轻链结构域的氨基酸序列(可变轻链CDR1、CDR2和CDR3的氨基酸序列被加粗并加下划线)
在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含STYAMN(SEQ ID NO:72)的CDR1序列的可变重链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含RIRSKYNNYATYYADSVKD(SEQ ID NO:73)的CDR2序列的可变重链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含HGNFGNSYVSWFAY(SEQ ID NO:74)的CDR3序列的可变重链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含HGNFGNSYVSYFAY(SEQID NO:75)的CDR3序列的可变重链结构域。在更进一步的实施方案中，该CD3结合位点具有包含分别为SEQ ID NO:72-74的CDR1、CDR2和CDR3序列的可变重链结构域。在更进一步的实施方案中，该CD3结合位点具有包含分别为SEQ ID NO:72、73和75的CDR1、CDR2和CDR3序列的可变重链结构域。
在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含选自NTYAMN(SEQ ID NO:76)、NTYAMH(SEQ ID NO:77)和NKYAMN(SEQ ID NO:78)的CDR1序列的可变重链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含选自RIRNKYNNYATYYADSVKD(SEQ ID NO:79)、RIRNKYNNYATEYADSVKD(SEQ ID NO:80)、RIRSKYNNYATEYAASVKD(SEQ ID NO:81)、RIRNKYNNYATEYAASVKD(SEQ ID NO:82)、RIRSKYNNYATYYADSVKG(SEQ ID NO:83)和RIRSKYNNYATEYADSVKS(SEQ ID NO:84)的CDR2序列的可变重链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含选自HGNFGDSYVSWFAY(SEQ ID NO:85)、HGNFGNTYVSWFAY(SEQ ID NO:86)、HGNFGCSYVSWFAY(SEQ ID NO:87)、HGNFGNSYISYWAY(SEQ ID NO:88)和HGNFGNSYVSFFAY(SEQID NO:89)的CDR3序列的可变重链结构域。
在更进一步的实施方案中，所述CD3结合位点具有包含CDR1、CDR2和CDR3序列的可变重链结构域，该CDR1、CDR2和CDR3序列分别为SEQ ID NO:76、73和74，分别为SEQ ID NO:76、79和74，分别为SEQ ID NO:76、80和74，分别为SEQ ID NO:76、81和74，分别为SEQ IDNO:76、82和74，分别为SEQ ID NO:76、83和74，分别为SEQ ID NO:72、83和74，分别为SEQ IDNO:72、83和85，分别为SEQ ID NO:76、83和86，分别为SEQ ID NO:77、83和74，分别为SEQ IDNO:72、83和87，分别为SEQ ID NO:78、73和88，或分别为SEQ ID NO:78、84和89。
在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含RSSTGAVTTSNYAN(SEQ ID NO:90)的CDR1序列的可变轻链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含GTNKRAP(SEQ ID NO:91)的CDR2序列的可变轻链结构域。在进一步的实施方案中，双特异性CD33和CD3结合蛋白的CD3结合位点具有包含ALWYSNL(SEQ ID NO:92)的CDR3序列的可变轻链结构域。在更进一步的实施方案中，该CD3结合位点具有包含分别为SEQ ID NO:90-92的CDR1、CDR2和CDR3序列的可变轻链结构域。
在某些情况下，所述CD3结合位点对CD3具有高亲和力。或者，在其他情况下，来自重链结构域以及轻链结构域或任选地来自可变轻链结构域和可变重链结构域的CDR1、CDR2、CDR3来源于其他CD3抗体，例如，UCHT1、莫罗单抗-CD3(OKT3)、奥昔珠单抗(otelixizumab)(TRX4)、替利珠单抗(teplizumab)(MGA031)、维西珠单抗(visilizumab)(Nuvion)等。
在另一个方面，本文描述了人源化的或完全为人类的，即人类来源的CD33结合蛋白以及双特异性CD33和CD3结合蛋白。
在一些实施方案中，双特异性CD33和CD3结合蛋白具有通过针对CD33和CD3的可变轻链结构域和可变重链结构域提供CD33和CD3特异性的以下组合之一：包括但不限于(i)SEQ ID NO:2、12、65和69；(ii)SEQ ID NO:3、13、65和69；(iii)SEQ ID NO:4、14、65和69；(iv)SEQ ID NO:5、15、65和69；(v)SEQ ID NO:1、11、64和68；(vi)SEQ ID NO:2、12、64和68；(vii)SEQ ID NO:2、12、66和70；(viii)SEQ ID NO:4、14、66和70；(ix)SEQ ID NO:5、15、66和70；和(x)SEQ ID NO:3、13、64和68；(xi)SEQ ID NO:3、13、67和71；(xii)SEQ ID NO:4、14、64和68；(xiii)SEQ ID NO:5、15、64和68；(xiv)SEQ ID NO:7、17、64和68；(xv)SEQ IDNO:6、16、64和68；(xvi)SEQ ID NO:6、16、67和71；(xvii)SEQ ID NO:8、18、64和68；(xviii)SEQ ID NO:9、19、64和68；(xix)SEQ ID NO:9、19、67和71；以及(xx)SEQ ID NO:10、20、64和68。
CDR序列以及重链和轻链结构域的保守变体
在替代实施方案中，重链和轻链结构域包含本文所述的CDR序列的免疫活性同源物或变体。因此，在一些实施方案中，重链或轻链结构域中与CD33或CD3结合的CDR序列与SEQ ID NO:21-63或72-92中所示的氨基酸序列相似但不相同。在某些情况下，CDR变体序列与SEQ ID NO:21-63或72-90的序列相比具有99％、98％、97％、96％、95％、94％、93％、92％、91％、90％、89％、88％、87％、86％、85％、84％、83％、82％、81％或80％的序列同一性，并且是免疫活性的。
在其他情况下，CDR变体序列包含1、2、3、4或5个保守的氨基酸置换。保守置换包括用具有相似特征的另一种氨基酸置换给定氨基酸的氨基酸置换，并进一步包括脂肪族氨基酸丙氨酸、缬氨酸、亮氨酸和异亮氨酸的互换；羟基残基丝氨酸和苏氨酸的互换，酸性残基天冬氨酸和谷氨酸的交换，酰胺残基天冬酰胺和谷氨酰胺之间的置换，碱性残基赖氨酸和精氨酸的交换，以及芳香族残基苯丙氨酸和酪氨酸之间的替换。
在其他情况下，CDR变体序列包含使CDR的性质增强，诸如使稳定性、蛋白酶抗性和/或对CD33或CD3的结合亲和力增加的置换。
在其他情况下，对CDR变体序列进行修饰以改变非关键残基或非关键区域中的残基。非关键的氨基酸可通过诸如亲和力成熟、CDR步移(CDR walking)、定点诱变、结晶、核磁共振、光亲和标记或丙氨酸扫描诱变等己知方法来鉴别。
在进一步的替代实施方案中，所述CD33和CD3结合蛋白包含为本文提供的重链和轻链结构域序列的免疫活性同源物或变体的重链和轻链结构域。因此，在一些实施方案中，CD33和CD3结合蛋白包含与SEQ ID NO:1-20或64-71中所示的氨基酸序列相似但不相同的重链或轻链结构域序列。在某些情况下，变体重链或轻链结构域序列与SEQ ID NO:1-20或64-71的序列相比具有99％、98％、97％、96％、95％、94％、93％、92％、91％、90％、89％、88％、87％、86％、85％、84％、83％、82％、81％或80％的序列同一性，并且是免疫活性的。
在其他情况下，变体重链或轻链结构域序列包含1、2、3、4或5个保守的氨基酸置换。保守置换包括用具有相似特征的另一种氨基酸置换给定氨基酸的氨基酸置换，并进一步包括脂肪族氨基酸丙氨酸、缬氨酸、亮氨酸和异亮氨酸的互换；羟基残基丝氨酸和苏氨酸的互换，酸性残基天冬氨酸和谷氨酸的交换，酰胺残基天冬酰胺和谷氨酰胺之间的置换，碱性残基赖氨酸和精氨酸的交换，以及芳香族残基苯丙氨酸和酪氨酸之间的替换。
在其他情况下，变体重链或轻链结构域序列包含使CDR的性质增强，诸如使稳定性、蛋白酶抗性和/或对CD33或CD3的结合亲和力增加的置换。
在其他情况下，对变体重链或轻链结构域序列进行修饰以改变非关键残基或非关键区域中的残基。非关键的氨基酸可通过诸如亲和力成熟、CDR步移、定点诱变、结晶、核磁共振、光亲和标记或丙氨酸扫描诱变等己知方法来鉴别。
CD33和CD3双特异性串联双抗体
在另一个方面，CD33结合蛋白或双特异性CD33和CD3结合蛋白为二聚体，即包含具有针对CD33和CD3的抗原结合位点的两个多肽。
在另一个方面，本文还提供了为串联双抗体
形式的二聚体双特异性CD33和CD3结合蛋白。这样的串联双抗体是通过在单一基因构建体中连接四个抗体可变结合结构域(两个重链可变结构域(VH)和两个轻链可变结构域(VL))(图1)使其能够同源二聚化而构建的。在这样的串联双抗体中，连接体的长度使得其防止可变结构域的分子内配对，使得该分子不能回折到自身上以形成单链双抗体，而是被迫与另一条链的互补结构域配对。该结构域也进行排列，使得相应的VH和VL结构域在此二聚化期间配对。在从单一基因构建体表达之后，两条相同的多肽链头对尾折叠，形成大约105kDa的功能性非共价同型二聚体(图1)。尽管不存在分子间共价键，但该同型二聚体一旦形成就高度稳定，保持完整，并且不会回到单体形式。
串联双抗体具有提供优于传统单克隆抗体及其他更小的双特异性分子的优势的多种性质。串联双抗体仅含有抗体可变结构域，因此预期缺少可能与Fc部分相关的副作用或非特异性相互作用。例如，在许多细胞类型如白细胞(例如，嗜碱性粒细胞、B细胞、嗜酸性粒细胞、天然杀伤细胞、嗜中性粒细胞等)或枯否(Kuppfer)细胞上发现了可与Fc结构域结合的Fc受体。因为串联双抗体允许与CD33和CD3中的每一个二价结合，所以其亲合力与IgG的亲合力相同。串联双抗体的大小为大约105kDa，小于IgG的大小，这可允许增强的肿瘤渗透。然而，该大小远大于肾脏首过清除的阈值，从而与基于抗体结合结构域或非抗体支架的更小双特异性形式相比提供了药代动力学优势。此外，基于导致更长的固有半衰期和快速细胞毒性的这种药代动力学和亲合力性质，串联双抗体相对于其他双特异性结合蛋白如BiTE或DART分子具有优势。串联双抗体在宿主细胞如哺乳动物CHO细胞中良好表达。预期鲁棒(robust)的上游和下游制备工艺可用于串联双抗体。
本文所述的CD33和CD3双特异性串联双抗体被设计成允许通过募集细胞毒性T细胞而特异性靶向CD33+肿瘤细胞。与针对唯一抗原并且不能直接募集细胞毒性T细胞的全长抗体相比，这改善了ADCC(抗体依赖性细胞介导的细胞毒性)。相比之下，通过与在这些细胞上特异性表达的CD3分子接合，该串联双抗体可使细胞毒性T细胞与CD33+肿瘤细胞以高度特异性方式交联，从而显著提高这类分子的细胞毒性潜力。图2中概述了这种机制。该串联双抗体显示出强劲、特异性且有效的ADCC。据报道，T细胞可在控制肿瘤生长方面发挥作用。例如，显示来自NHL患者的结直肠肿瘤以及淋巴结中的细胞毒性T细胞的存在与更好的临床结果相关。此外，对于黑素瘤疫苗以及针对CTLA-4(T细胞激活的负调节物)的抗体，已经证明了被设计用于诱导T细胞应答的疗法的潜力。本文所述的串联双抗体通过与形成T细胞受体的一部分的表面表达的CD3结合来接合细胞毒性T细胞。该串联双抗体与在特定肿瘤细胞表面上表达的CD3和CD33的同时结合导致T细胞激活并介导该肿瘤细胞的随后溶解(图2)。
因此，在进一步的方面是多特异性串联双抗体。在一些实施方案中，多特异性串联双抗体对两个、三个或更多个不同的表位具有特异性，其中两个或更多个表位可具有相同的抗原靶标或不同的抗原靶标。在某些实施方案中，该多特异性串联双抗体是双特异性和四价的，即包含四个抗原结合位点。这样的双特异性串联双抗体采用至少一个抗原结合位点与人类CD3和人类CD33结合，其中在某些情况下，该串联双抗体采用两个抗原结合位点与人类CD3结合并采用另外两个抗原结合位点与人类CD33结合，即该串联双抗体与每个抗原二价结合。
在一些实施方案中，双特异性抗原结合串联双抗体对人类CD33和人类CD3是特异性的，其中所述串联双抗体包含第一多肽和第二多肽，每个多肽均具有至少四个相继连接的可变链结构域，其中每个多肽均包含：
(i)对人类CD33具有特异性的可变重链(VH)结构域；
(ii)对人类CD33具有特异性的可变轻链(VL)结构域；
(iii)对人类CD3具有特异性的VH结构域，以及
(iv)对人类CD3具有特异性的VL结构域。
在特定的实施方案中，双特异性串联双抗体与在人类CD33的62DQEVQEETQ70(SEQID NO:94)(SEQ ID NO:93的氨基酸残基62-70)内的人类CD33的表位特异性结合。在特定情况下，这样的串联双抗体包含第一多肽和第二多肽，每个多肽均具有至少四个相继连接的可变链结构域，其中每个多肽均包含：
(i)对在人类CD33的62DQEVQEETQ70(SEQ ID NO:94)(SEQ ID NO:93的氨基酸残基62-70)内的人类CD33的表位具有特异性的可变重链结构域；
(ii)对在人类CD33的62DQEVQEETQ70(SEQ ID NO:94)(SEQ ID NO:93的氨基酸残基62-70)内的人类CD33的表位具有特异性的可变轻链结构域；
(iii)对人类CD3具有特异性的可变重链结构域，以及
(iv)对人类CD3具有特异性的可变轻链结构域。
在其他实施方案中，本文描述了对CD33+细胞上的CD33具有亲和力的CD33/CD3串联双抗体，其KD为10nM或更小、5nM或更小、1nM或更小，或0.5nM或更小。该CD33+细胞可选自肿瘤细胞，例如，HL-60或KG-1。
在进一步的实施方案中，本文所述的CD33/CD3串联双抗体结合CD3，并且在某些情况下，结合CD3+细胞、特别是T细胞上的CD3的ε链，其KD为10nM或更小、5nM或更小或2nM或更小。
在一些实施方案中，双特异性串联双抗体的每个多肽均包含四个可变链结构域的以下组合之一：(i)SEQ ID NO:2、12、65和69；(ii)SEQ ID NO:3、13、65和69；(iii)SEQ IDNO:4、14、65和69；(iv)SEQ ID NO:5、15、65和69；(v)SEQ ID NO:1、11、64和68；(vi)SEQ IDNO:2、12、64和68；(vii)SEQ ID NO:2、12、66和70；(viii)SEQ ID NO:4、14、66和70；(ix)SEQID NO:5、15、66和70；和(x)SEQ ID NO:3、13、64和68；(xi)SEQ ID NO:3、13、67和71；(xii)SEQ ID NO:4、14、64和68；(xiii)SEQ ID NO:5、15、64和68；(xiv)SEQ ID NO:7、17、64和68；(xv)SEQ ID NO:6、16、64和68；(xvi)SEQ ID NO:6、16、67和71；(xvii)SEQ ID NO:8、18、64和68；(xviii)SEQ ID NO:9、19、64和68；(xix)SEQ ID NO:9、19、67和71；以及(xx)SEQ IDNO:10、20、64和68。
如本文所用的，“二聚体”是指两个多肽的复合物。在某些实施方案中，这两个多肽彼此非共价缔合，特别地，条件是在这两个多肽之间没有共价键。在某些情况下，这两个多肽具有共价缔合，如为了帮助二聚体稳定而形成的二硫键。在某些实施方案中，该二聚体为同型二聚体，即包含两个相同的多肽。术语“多肽”是指通过酰胺键连接的氨基酸残基的聚合物。在某些情况下，该多肽为没有分支的单链融合蛋白。在该多肽中，可变抗体结构域相继连接。在其他情况下，除了可变结构域N-末端和/或C-末端残基外，该多肽还可具有连续的氨基酸残基。例如，这样的连续氨基酸残基可包含标签(Tag)序列，在一些情况下，该标签序列在C-末端处，预期这对多肽的纯化和检测是有用的。
在一个方面，所述双特异性串联双抗体的每个多肽均包含四个可变结构域，即CD3结合蛋白的可变轻链(VL)和可变重链(VH)以及CD33结合蛋白的可变轻链(VL)和可变重链(VH)。在某些实施方案中，四个可变结构域通过肽连接体L1、L2和L3连接，并且在一些情况下，从N-末端至C-末端如下排列：
结构域顺序：
(1)VL(CD3)-L1-VH(CD33)-L2-VL(CD33)-L3-VH(CD3)；或
(2)VH(CD3)-L1-VL(CD33)-L2-VH(CD33)-L3-VL(CD3)；或
(3)VL(CD33)-L1-VH(CD3)-L2-VL(CD3)-L3-VH(CD33)；或
(4)VH(CD33)-L1-VL(CD3)-L2-VH(CD3)-L3-VL(CD33)。
根据所报道的研究，连接体的长度影响抗原结合串联双抗体的柔性。因此，在一些实施方案中，肽连接体L1、L2和L3的长度使得一个多肽的结构域可与另一个多肽的结构域发生分子间缔合，以形成二聚体抗原结合串联双抗体。在某些实施方案中，这样的连接体“较短”，即由0、1、2、3、4、5、6、7、8、9、10、11或12个氨基酸残基组成。因此，在某些情况下，该连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下，该连接体为肽键。这样的短连接体通过在不同多肽的抗体可变轻链结构域与抗体可变重链结构域之间结合并形成正确的抗原结合位点而有利于两个多肽的分子间二聚化。将连接体缩短至约12个或更少的氨基酸残基通常会防止同一多肽链的相邻结构域彼此发生分子内相互作用。在一些实施方案中，这些连接体由约3至约10个，例如4、5或6个连续氨基酸残基组成。
关于连接体的氨基酸组成，选择不干扰两个多肽的二聚化的肽。例如，包含甘氨酸和丝氨酸残基的连接体通常提供蛋白酶抗性。例如，可通过噬菌体展示法优化连接体的氨基酸序列，以改善抗原结合多肽二聚体的抗原结合和产率。在一些实施方案中，适用于串联双抗体的肽连接体的实例为GGSGGS(SEQ ID NO:95)、GGSG(SEQ ID NO:96)或GGSGG(SEQ IDNO:97)。
如本文所述的串联双抗体的非限制性实例为具有根据表7的抗CD33VL和VH结构域、抗CD3VL和VH结构域、结构域顺序以及连接体的串联双抗体。
表7：示例性CD33/CD3串联双抗体(TandAb)
在一些实施方案中，串联双抗体为如图9B至9Y中所示的串联双抗体01(SEQ IDNO:98)、02(SEQ ID NO:99)、03(SEQ ID NO:100)、04(SEQ ID NO:101)、05(SEQ ID NO:102)、06(SEQ ID NO:103)、07(SEQ ID NO:104)、08(SEQ ID NO:105)、09(SEQ ID NO:106)、10(SEQ ID NO:107)、11(SEQ ID NO:108)、12(SEQ ID NO:109)、13(SEQ ID NO:110)、14(SEQ ID NO:111)、15(SEQ ID NO:112)、16(SEQ ID NO:113)、17(SEQ ID NO:114)、18(SEQID NO:115)、19(SEQ ID NO:116)、20(SEQ ID NO:117)、21(SEQ ID NO:118)、22(SEQ IDNO:119)、23(SEQ ID NO:120)或24(SEQ ID NO:121)。
在一些实施方案中，通过表达编码串联双抗体的多肽的多核苷酸而产生本文所述的CD33结合蛋白和CD33/CD3双特异性结合蛋白(例如，CD33/CD3双特异性串联双抗体)，该多肽与另一个相同的多肽缔合而形成抗原结合串联双抗体。因此，另一个方面是编码如本文所述的抗原结合串联双抗体的多肽的多核苷酸，例如DNA或RNA。
通过己知方法，如通过以下方法构建多核苷酸：将编码通过肽连接体隔开或在其他实施方案中通过肽键直接连接的至少四个抗体可变结构域的基因组合成与合适的启动子并任选地与合适的转录终止子可操作地连接的单一遗传构建体，并使其在细菌或其他适当的表达系统如CHO细胞中表达。根据所用的载体系统和宿主，可使用任何数目的合适的转录和翻译元件，包括组成型和诱导型启动子。选择启动子使其驱动多核苷酸在相应宿主细胞中的表达。
在一些实施方案中，将多核苷酸插入至载体、优选表达载体中，这代表进一步的实施方案。该重组载体可根据已知方法进行构建。
可使用多种表达载体/宿主系统来包含并表达编码所述抗原结合串联双抗体的多肽的多核苷酸。用于在大肠杆菌(E.coli)中表达的表达载体的实例为pSKK(Le Gall等人,JImmunol Methods.(2004)285(1):111-27)或用于在哺乳动物细胞中表达的pcDNA5(Invitrogen)。
因此，在一些实施方案中，通过将编码如上文所述的多肽的载体引入宿主细胞中并在表达该多肽链的条件下培养所述宿主细胞而产生如本文所述的抗原结合串联双抗体，可将其分离并任选地进一步纯化。
在其他方面，本文所述的CD33结合蛋白或CD33/CD3双特异性结合蛋白(例如，CD33/CD3双特异性串联双抗体)具有修饰。典型的修饰包括但不限于乙酰化、酰化、ADP-核糖基化、酰胺化、黄素的共价附接、血红素部分的共价附接、核苷酸或核苷酸衍生物的共价附接、脂质或脂质衍生物的共价附接、磷脂酰肌醇的共价附接、药物缀合、交联、环化、二硫键形成、脱甲基化、共价交联的形成、胱氨酸的形成、焦谷氨酸的形成、甲酰化、γ羧化、糖基化、GPI锚形成、羟基化、碘化、甲基化、豆蔻酰化、氧化、蛋白水解加工、磷酸化、异戊烯化、外消旋化、硒化(selenoylation)、硫酸化、氨基酸至蛋白质的转移RNA介导的添加如精氨酰化(arginylation)以及泛素化。在进一步的实施方案中，用额外的氨基酸如前导序列或分泌序列或用于多肽纯化的序列修饰CD33结合蛋白或CD33/CD3双特异性结合蛋白。
在其他方面，本文提供了药物组合物，其包含CD33结合蛋白、抗原结合串联双抗体、包含编码该抗原结合串联双抗体的多肽的多核苷酸的载体(vector)或被该载体转化的宿主细胞，以及至少一种药学上可接受的载体(carrier)。术语“药学上可接受的载体”包括但不限于不干扰成分的生物活性的有效性且对所施用的患者无毒的任何载体。合适的药物载体的实例是本领域公知的，并包括磷酸盐缓冲盐水溶液、水、乳液如油/水乳液、各种类型的润湿剂、无菌溶液等。这样的载体可通过常规方法配制并可以以合适的剂量施用于受试者。优选地，该组合物是无菌的。这些组合物还可含有佐剂，诸如防腐剂、乳化剂和分散剂。可通过包含各种抗细菌剂和抗真菌剂来确保对微生物作用的预防。
与CD33和CD3高亲和力结合的双特异性CD33/CD3结合蛋白在大量原代AML样本中是高度活性的，表明这些分子可在整个细胞遗传学/分子病谱中具有对抗人类AML的活性，甚至在几乎无CD33表达的情况下也如此。值得注意的是，在残余自体T细胞的存在下也观察到药物特异性细胞毒性，并且该细胞毒性通过添加控制量的健康供体T细胞而显著增强(参见实施例6)。
所述CD33/CD3双特异性结合蛋白，特别是串联双抗体，可诱导CD33+白血病细胞在体外的强细胞溶解。数据表明，与CD33和CD3两者的高亲和力结合使双特异性蛋白诱导的T细胞激活和抗AML效力最大化。针对CD33/CD3的高亲和力双特异性结合蛋白，如本文所述的串联双抗体，在体外在原代AML中显示出细胞溶解活性。因此，这些双特异性结合蛋白和串联双抗体适用于治疗急性髓性白血病(AML)或其他恶性血液病，例如骨髓发育不良综合征(MDS)或骨髓增生性疾病(MPD)的治疗方法。
因此，本文提供了这样的方法，其中将如上文所述的抗原结合串联双抗体以有效剂量施用于受试者，例如患者，以用于治疗CD33+癌症(例如急性髓性白血病(AML))、疾病或病况。CD33+癌症包括但不限于，急性白血病如急性髓性白血病、急性成淋巴细胞性白血病(ALL)，包括前体B细胞成淋巴细胞性白血病、髓样肉瘤、多发性骨髓瘤、急性淋巴瘤如急性淋巴母细胞性淋巴瘤、慢性粒单核细胞白血病等。CD33+疾病和病况包括在某些癌症和慢性炎症中由骨髓衍生的抑制细胞(MDSC)引起的免疫抑制状态或环境。
在一些实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗急性髓性白血病(AML)。在某些实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗急性髓性白血病亚型。
French-American-British分类系统将AML分为八个亚型：AML-M0(最低分化型)、AML-M1(未成熟型)、AML-M2(伴有粒细胞成熟)、AML-M3(早幼粒细胞性或急性早幼粒细胞性白血病)、AML-4(急性粒单核细胞白血病)、AML-M5(急性单核母细胞性或单核细胞性白血病)、AML-M6(急性红白血病)和AML-M7(急性巨核母细胞白血病)。在某些情况下，施用如本文所述的抗原结合串联双抗体以用于治疗AML-M0、AML-M1、AML-M2、AML-M3、AML-M4、AML-M5、AML-M6或AML-M7。
WHO AML分类方案根据以下亚型将AML归类：伴有复发性遗传异常的AML、伴有脊髓发育不良相关变化的AML、与治疗相关的髓样肿瘤、髓样肉瘤、与唐氏综合征相关的骨髓增生、母细胞性浆细胞样树突状细胞肿瘤和尚未分类的AML。在某些其他的情况下，施用如本文所述的抗原结合串联双抗体以用于治疗伴有复发性遗传异常的AML、伴有脊髓发育不良相关变化的AML、与治疗相关的髓样肿瘤、髓样肉瘤、与唐氏综合征相关的骨髓增生、母细胞性浆细胞样树突状细胞肿瘤或尚未分类的AML。
在一些其他实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗新诊断的、复发性或难治性AML。
在进一步的实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗白血病前期血液疾病，如骨髓发育不良综合征(MDS)或骨髓增生性疾病(MPD)。在某些情况下，施用如本文所述的抗原结合串联双抗体以用于治疗MDS。在某些情况下，施用如本文所述的抗原结合串联双抗体以用于治疗MPD。
在其他实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗多发性骨髓瘤。在进一步的实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗慢性粒单核细胞白血病(CMML)。
在其他实施方案中，施用如本文所述的抗原结合串联双抗体以用于抑制或消除骨髓衍生的抑制细胞(MDSC)。MDSC在某些分离的病变组织中高度过表达CD33并具有强免疫抑制活性。在某些人类癌症(CD33+以及非CD33+)中，MDSC增殖并被激活以抑制肿瘤特异性CD4+T细胞应答并诱导Treg细胞，从而允许肿瘤或癌症在微环境中活跃。据报道，在慢性炎症中，MDSC扩充并被发现在炎症部位抑制T细胞免疫功能。在其他实施方案中，施用如本文所述的抗原结合串联双抗体以用于治疗与MDSC相关的病况。在其他实施方案中，施用如本文所述的抗原结合串联双抗体以治疗免疫抑制。在其他实施方案中，施用如本文所述的抗原结合串联双抗体以治疗被MDSC抑制的炎症。在其他实施方案中，施用如本文所述的抗原结合串联双抗体以治疗由MDSC引起的免疫应答降低。在其他实施方案中，施用如本文所述的抗原结合串联双抗体以治疗由MDSC促进的血管生成、肿瘤侵袭或癌症转移。在其他实施方案中，施用如本文所述的抗原结合串联双抗体以治疗被MDSC增强、加强、加重或增加的癌症或肿瘤。
预期本文所述的抗原结合串联双抗体用作药物。通过不同方式，例如通过静脉内、腹膜内、皮下、肌内、局部或皮内给药来实现给药。在一些实施方案中，给药途径取决于治疗的类型和药物组合物中所含化合物的类型。剂量方案将由主治医师和其他临床因素确定。用于任一患者的剂量取决于许多因素，包括患者的块头(size)、体表面积、年龄、性别、待施用的特定化合物、给药时间和途径、治疗类型、总体健康以及同时施用的其他药物。“有效剂量”是指足以影响疾病的过程和严重程度，从而导致这样的病理减轻或缓解的活性成分的量。可使用已知方法来确定对治疗和/或预防AML有用的“有效剂量”。
在进一步的实施方案中，本文所述的抗原结合串联双抗体与针对CD33+癌症、疾病或病况的标准疗法联合施用。标准疗法包括化疗、免疫疗法、激素疗法、放射疗法、手术、基因疗法等。在某些情况下，本文所述的抗原结合串联双抗体与标准AML疗法联合施用。在某些情况下，本文所述的抗原结合串联双抗体与以下药物联合施用：阿糖胞苷、阿扎胞苷、地西他滨、蒽环类药物(例如，柔红霉素、伊达比星、多柔比星等)、安吖啶、氟达拉滨、氯法拉滨、克拉屈滨、奈拉滨、甲氨蝶呤、硼替佐米、卡非佐米、美法仑、依鲁替尼、沙利度胺、来那度胺、泊马度胺、阿普斯特、表鬼臼毒素(例如，依托泊苷、替尼泊苷等)、蒽醌(例如，米托蒽醌、匹克生琼、洛索蒽醌、吡罗蒽醌、阿美蒽醌等)、抗CD20剂(例如，利妥昔单抗、奥瑞珠单抗、奥法木单抗)或其组合。在某些情况下，本文所述的抗原结合串联双抗体与阿糖胞苷(ara-C)联合施用。在某些情况下，本文所述的抗原结合串联双抗体与阿扎胞苷联合施用。在某些情况下，本文所述的抗原结合串联双抗体与地西他滨联合施用。在其他情况下，本文所述的抗原结合串联双抗体与蒽环类药物(例如，柔红霉素、伊达比星、多柔比星等)联合施用。在其他情况下，本文所述的抗原结合串联双抗体与检查点抑制剂(例如，PD-1抑制剂、CTLA-4抑制剂等)联合施用。在其他情况下，本文所述的抗原结合串联双抗体与表鬼臼毒素(例如，依托泊苷、替尼泊苷等)联合施用。在其他情况下，本文所述的抗原结合串联双抗体与蒽醌(例如，米托蒽醌、匹克生琼、洛索蒽醌、吡罗蒽醌、阿美蒽醌等)联合施用。
以下实施例进一步阐述了所描述的实施方案，而非限制本发明的范围。
实施例1
编码单链Fv抗体的DNA表达构建体的克隆
对于抗CD33单链Fv(scFv)抗体在大肠杆菌中的细菌表达，将所有分子的DNA编码序列克隆至细菌表达载体中。所有表达构建体均被设计成含有N-末端信号肽和C-末端六组氨酸(6xHis)-标签(SEQ ID NO:122)的编码序列，以分别促进抗体向周质中的分泌和纯化。来自所有抗CD33scFv克隆的VL和VH结构域的氨基酸序列示于表3和表4中。
重组抗CD33scFv抗体在大肠杆菌中的表达
重组scFv抗体在大肠杆菌周质中表达为可溶性分泌蛋白。在第一步中，在补充有氨苄青霉素的小量培养基中接种经转化的细菌并在28℃下温育16h。随后，通过添加补充有氨苄青霉素的第二培养基来调节光密度，并再次在28℃下温育，直到在600nm下的光密度达到0.6-0.8的范围。通过添加50μM IPTG并在21-28℃和200rpm下温育培养物最长16h来诱导蛋白质表达。温育后，使细胞沉淀(30min，4℃，7500rpm)并储存在-20℃下直到进一步处理。
抗CD33单链Fv抗体的纯化
在细菌细胞培养物离心后，通过将细胞沉淀重悬于缓冲液中并在温和搅拌下于室温下温育30min来从大肠杆菌周质中提取重组scFv。使细胞沉淀并保留含有重组蛋白的上清液。将该程序再重复一次，然后将上清液合并，通过超声处理均质化。将匀浆稀释，补充低浓度的咪唑，并加载至预充填的固定化金属亲和色谱(IMAC)柱(GE Healthcare)上。洗涤该柱直到达到基线，随后用咪唑缓冲液洗脱结合的蛋白质。合并含有抗体的级分，随后通过大小排阻色谱法(SEC)纯化。最后，通过超滤浓缩蛋白质洗出液并针对储存缓冲液进行透析。在低pH处理(在37℃、pH 3.0下温育20-24h)后，使用Tris中和样品。将纯化的蛋白质分份储存在-80℃下直到使用。
实施例2
编码串联双抗体
的DNA表达构建体的克隆
对于双特异性串联双抗体在CHO细胞中的表达，将所有分子的编码序列克隆至哺乳动物表达载体系统中。使用实施例1的抗CD33scFv结构域构建与抗CD3scFv结构域组合的CD33/CD3串联双抗体，结构域如表7和图3中所示进行组织。简言之，合成并亚克隆了编码由肽连接体隔开的抗CD33VH和VL结构域(VH-连接体-VL或VL-连接体-VH)的基因序列。将所得构建体消化以利用位于连接体序列内的Bam HI限制位点来生成单独的VH和VL编码序列。然后将这些VH和VL片段与编码抗CD3的VH和VL结构域的DNA片段连接(VH-连接体-VL或VL-连接体-VH)以产生最终的构建体。CD33/CD3串联双抗体的结构域顺序变体1至3示于图3中。所有表达构建体均被设计成含有N-末端信号肽和C-末端六组胺酸(6xHis)-标签(SEQ ID NO: 122)的编码序列，以分别促进抗体分泌和纯化。
串联双抗体在稳定转染的CHO细胞中的表达
使用CHO细胞表达系统(
Life Technologies)——CHO-K1中国仓鼠卵巢细胞(ATCC,CCL-61)的一种衍生物(Kao和Puck,Proc.Natl.Acad Sci USA1968；60(4):1275-81)。根据由Life Technologies提供的标准细胞培养方案来传代培养贴壁细胞。
为了适应悬浮生长，使细胞从组织培养瓶上脱离并置于无血清培养基中。将适应悬浮的细胞在含有10％DMSO的培养基中冷藏保存。
通过转染适应悬浮的细胞生成稳定表达分泌型串联双抗体的重组CHO细胞系。在用抗生素潮霉素B选择期间，每周测量活细胞密度两次，并将细胞离心并以0.1x106个活细胞/mL的最大密度重悬于新鲜的选择培养基中。在2-3周的选择后回收稳定表达串联双抗体的细胞合并物，此时将细胞转移至在摇瓶中的标准培养基中。通过进行蛋白质凝胶电泳或流式细胞术来确认重组分泌蛋白质的表达。将稳定的细胞合并物在含有DMSO的培养基中冷藏保存。
在稳定转染的CHO细胞系的10天补料分批培养中，通过向细胞培养上清液中分泌而产生串联双抗体。10天后在培养物活力通常>75％时收获细胞培养上清液。每隔一天从生产培养物中收集样品并评价细胞密度和活力。在收获当天，在进一步使用前通过离心和真空过滤使细胞培养上清液变澄清。
通过SDS-PAGE分析细胞培养上清液中的蛋白质表达效价和产物完整性。
串联双抗体的纯化
在两步程序中，从CHO细胞培养上清液中纯化串联双抗体。使His6标记(SEQ ID NO:122)的构建体在第一步中经受Ni-NTA Superflow色谱法，随后在第二步中在Superdex200上经受制备型大小排阻色谱法(SEC)。就同型二聚体(串联双抗体)含量对洗脱的串联双抗体进行表征，并且如果同型二聚体含量为90％或更高，则将其合并。最终，对合并的样品进行缓冲液交换，并通过超滤浓缩至>1mg/mL的典型浓度。通过在还原和非还原条件下的SDS PAGE，然后分别通过使用抗His-标签抗体的免疫印迹法以及分析型SEC，来评价最终样品的纯度和均匀性(通常>90％)。将纯化的蛋白质分份储存在-80℃下直到使用。
CD33/CD3串联双抗体的多肽示于表7和图3中。每个串联双抗体均由两个相同的多肽组成(图1)。外部连接体L1和L3均由六个氨基酸GGSGGS(SEQ ID NO:95)构成，而中心的肽连接体2的长度分别随序列GGSG(SEQ ID NO:96)、GGSGG(SEQ ID NO:97)或GGSGGS(SEQ IDNO:95)而变化(4-6个氨基酸)。
通过使用一系列抗CD33可变结构域和抗CD3可变结构域，生成了可在转染的细胞系中稳定产生并在体温下以及在反复冻/融循环后维持稳定性的大量串联双抗体分子。为了促进进一步的开发和临床前毒理学研究，将重点放在对显示出与人类和食蟹猴CD33两者都结合的串联双抗体分子的选择上。分别在图9M、9O和9Q中示出了串联双抗体12(SEQ IDNO:109)、14(SEQ ID NO:111)和16(SEQ ID NO:113)的单链的完整氨基酸序列的实例。在该实例中，该结构的可变结构域及其连接体的顺序为：VL(CD3)-L1-VH(CD33)-L2-VL(CD33)-L3-VH(CD3)。
实施例3
通过流式细胞术确定抗体亲和力
将细胞与100μL的CD33/CD3串联双抗体的连续稀释液一起温育。在用FACS缓冲液洗涤三次后，将细胞与在相同缓冲液中的0.1mL的10μg/mL小鼠单克隆抗His抗体一起在冰上温育45min。在第二次洗涤循环后，在与之前相同的条件下，将细胞与0.1mL的15μg/mLFITC偶联的山羊抗小鼠IgG抗体一起温育。作为对照，将细胞与抗His IgG一起温育，随后在没有抗CD33串联双抗体的情况下与FITC偶联的山羊抗小鼠IgG抗体一起温育。然后将细胞再次洗涤并重悬于含有2μg/mL碘化丙锭(PI)的0.2mL FACS缓冲液中以排除死细胞。通过使用Beckman-Coulter FC500MPL流式细胞仪采用MXP软件(Beckman-Coulter,Krefeld,Germany)，或通过使用Millipore Guava EasyCyte流式细胞仪采用Incyte软件(MerckMillipore,Schwalbach,Germany)测量1x104个活细胞的荧光。使用CXP软件(Beckman-Coulter,Krefeld,Germany)或Incyte软件(Merck Millipore,Schwalbach,Germany)计算细胞样品的平均荧光强度。在减去单独用二级和三级试剂染色的细胞的荧光强度值后，将该值用于通过GraphPad Prism(用于Windows的6.00版本，GraphPad软件，La JollaCalifornia USA)的单位点结合(双曲线)的方程式计算KD值。
检测串联双抗体与人类CD3+和CD33+细胞以及食蟹猴CD3+和CD33+细胞的结合亲和力。所选串联双抗体的示例性结合数据汇总于表8中：
表8：CD33/CD3串联双抗体的CD3和CD33结合特性：
#基于对分别表达食蟹猴CD33和人类CD33的CHO细胞测量的KD值计算cyno CD33/人类CD33的KD比。
基于对Jurkat细胞(hu CD3)测量的KD值和三种人类CD33+肿瘤细胞系(HL-60、KG-1、U937)的平均KD计算hu CD3/hu CD33的KD比。
在对CD3+Jurkat细胞(由Dr.Moldenhauer，DKFZ Heidelberg提供；人类急性T细胞白血病)和食蟹猴CD3+HSC-F细胞系(JCRB，目录号：JCRBI164)的滴定和流式细胞术实验中评估CD3结合亲和力和交叉反应性。在以下人类CD33+肿瘤细胞系上评价CD33结合和交叉反应性：HL-60(DSMZ，目录号：ACC3，人类B细胞前体白血病)、U-937(DSMZ，目录号：ACC5；人类组织细胞性淋巴瘤)和KG-1(DSMZ，目录号：ACC14；急性髓性白血病)。使用在表达重组人类抗原或重组食蟹猴抗原的CHO细胞系上确定的KD值计算交叉反应性的KD比。
串联双抗体对大部分测试的肿瘤细胞系上的人类CD33+表现出低于1nM的相对较高亲和力。对人类CD3的亲和力经确定等于或小于2nM。
实施例4
细胞毒性测定
对于细胞毒性测定，收获在标准条件下培养的靶细胞，将其洗涤并在提供于PKH67绿色荧光细胞连接体微型试剂盒(PKH67Green Fluorescent Cell Linker Mini Kit)中的稀释液C中重悬至2x107个细胞/mL的密度。然后将该细胞悬浮液与等体积的双倍浓缩的PKH67标记溶液混合并在室温下温育2-5min。如下进行染色反应：添加等体积的FCS并温育1min。在用完全RPMI培养基洗涤标记的靶细胞后，将细胞进行计数并在完全RPMI培养基中重悬至2x105个细胞/mL的密度。然后在递增浓度的指定串联双抗体的存在下，将2x104个靶细胞与作为效应细胞的富集的人类T细胞一起以5：1的E：T比、以200μL/孔的总体积接种到微量滴定板的单个孔中。对于每个板上的至少三个重复物，确定在不存在抗体的情况下的自发细胞死亡以及靶标被T细胞的杀伤。离心后，在37℃下，在5％CO2及潮湿气氛中将测定板温育指定的时间段。温育后，将培养物用FACS缓冲液洗涤一次，随后重悬于补充有2μg/mLPI的150μL FACS缓冲液中。通过采用PKH67的阳性绿色染色和PI的阴性染色，使用Beckman-Coulter FC500MPL流式细胞仪(Beckman-Coulter)或Millipore Guava EasyCyte流式细胞仪(Merck Millipore)测量活靶细胞的绝对量。基于所测量的剩余活靶细胞，根据以下公式计算特异性细胞溶解的百分比：[1-(活靶细胞数目(/活靶细胞数目()]x 100％。使用GraphPad软件，通过非线性回归/4参数逻辑拟合计算S形剂量-响应曲线和EC50值。将针对给定抗体浓度获得的溶解值用于通过使用Prism软件的4参数逻辑拟合分析计算S形剂量-响应曲线。
在针对CD33+U-937(DSMZ，目录号：ACC5；人类组织细胞性淋巴瘤)靶细胞、以富集的人类T细胞作为效应细胞、比例为5：1的20-24小时测定中确定EC50值。还在针对CD33+KG-1(DSMZ，目录号：ACC14；急性髓性白血病)和HL-60靶细胞的细胞毒性测定中测试了一些串联双抗体。具体地，选择HL-60细胞作为具有相对较高的CD33细胞表面表达的AML的模型(任意MFI[平均±SEM]：3,133±215；n＝3)，并选择KG-1a作为具有非常有限的CD33表达的AML的模型(任意MFI：277±11；n＝3)。所选串联双抗体的示例性细胞毒性数据汇总于表9中。HL-60细胞系的额外细胞毒性数据见表8的最后一列。
表9：CD33/CD3串联双抗体对不同CD33+肿瘤细胞系的体外效力：
在针对温育20-24小时的指定靶细胞系的、以原代人类T细胞作为效应细胞、E：T比为5：1的基于FACS的细胞毒性测定中确定EC50值。在至少两个独立实验中针对每个肿瘤细胞系测试每种串联双抗体。示出了平均值。
实施例5
在第48小时在人类CD33+AML细胞系中的进一步细胞毒性筛选实验
如上所述，早在第24小时就检测到显著的细胞毒性，然而在第48小时可检测到更高水平的毒性。对于后续测定，选择第48小时的时间点。测试了T细胞选择对串联双抗体诱导的细胞毒性的影响。为了实现该目的，获得了来自健康志愿者供体的未经刺激的PBMC，并通过经由使用CD3微珠的简单“正富集”以及通过经由针对CD14、CD15、CD16、CD19、CD34、CD36、CD56、CD123和CD235a的抗体的微珠混合物的更复杂“负选择”来分离CD3+细胞。如图4中所示，与使用正选择的T细胞时相比，使用负选择的健康供体T细胞时，串联双抗体诱导的细胞毒性更大。然而，单独串联双抗体的相对细胞毒性活性不受T细胞选择方法的影响。因此，用正富集的健康供体T细胞进行后续测定。
在由FHCRC机构审查委员会批准的研究方案下，由Fred Hutchinson癌症研究中心(FHCRC)造血细胞加工中心(Hematopoietic Cell Processing Core)(Core Center ofExcellence)通过白细胞去除术从健康成年志愿者中收集未经刺激的单个核细胞。经由CD3微珠(“正富集”)或经由泛T细胞分离试剂盒(“负选择”；二者均来自Miltenyi Biotec,Auburn,CA)通过磁性细胞分选来富集T细胞，随后将T细胞分份冷冻并储存于液氮中。根据制造商的说明，用3μM CellVue Burgundy(eBioscience,San Diego,CA)标记解冻的细胞等份。在不同浓度的串联双抗体分子的存在下培养纯化的PBMC。
对于药物诱导的细胞毒性的定量，如实施例4所述，在37℃下(在5％CO2和空气中)，以不同的E：T细胞比温育细胞。在24-72小时后，使用LSRII细胞计数器(BDBiosciences)确定细胞数目和药物诱导的细胞毒性(使用DAPI来检测非活细胞)并用FlowJo进行分析。通过前向/侧向散射性质以及在添加了健康供体T细胞的实验中对CellVue Burgundy染料的阴性来鉴别AML细胞(图5)。药物诱导的特异性细胞毒性表示为：％细胞毒性＝100x(1-活靶细胞/活靶细胞对照)。来自细胞毒性测定的结果表示为平均值±平均值的标准误差(SEM)。使用Spearman非参数相关来计算连续样品特征之间的相关性。所有P值都是双侧的。使用GraphPad Prism软件进行统计分析。
在不存在健康供体T细胞时，CD33/CD串联双抗体两者均没有在不存在T细胞时对AML细胞系产生任何明显的细胞毒性效应，从而证实了其细胞毒性效应对T细胞的绝对需要(数据未显示)。在T细胞的存在下，串联双抗体诱导的特异性细胞毒性的程度取决于串联双抗体的浓度以及E：T细胞比。针对CD33/CD3的串联双抗体分子与一种对照串联双抗体(00)之间的直接并排比较表明了HL-60细胞(图6A/B和表10)和KG-1a细胞(图6C/D和表10)两者中抗体诱导的细胞毒性的显著差异，其结果在重复实验中是高度可再现的。总之，串联双抗体诱导的细胞毒性的程度与对原代人类T细胞上CD3的结合亲和力相关(对于在25pM(大约2.5ng/mL)和E：T＝5：1下在KG-1a细胞中的细胞毒性：r＝-0.542，p＝0.009；对于在25pM和E：T＝5：1下在HL-60细胞中的细胞毒性：r＝-0.391，p＝0.07)。串联双抗体12、14、16对HL-60和KG-1a细胞两者是高细胞毒性的。
表10：CD33/CD3串联双抗体在48h时的CD25和CD69诱导以及细胞毒性
1串联双抗体(TandAb)以CD3亲和力递增的顺序列出。
224小时后在未分级分离的PBMC培养物中测量CD25和CD69诱导。
3在存在CD33+细胞的未分级PBMC中由CD33/CD3串联双抗体诱导的T细胞增殖。
4以25pM的串联双抗体浓度、在健康供体T细胞的存在下、在5：1的E：T细胞比下，DAPI+细胞在48小时后的细胞毒性(％)，其来自在重复孔中进行的3次独立实验。
ND：未检测到CD25激活
实施例6
串联双抗体在原代人类AML样本中的进一步表征
为了全面表征这些候选物的细胞毒性性质，从FHCRC样本贮藏库中获得了来自AML患者的样本以供研究。
从FHCRC的贮藏库中获得了来自成年AML患者的治疗前(“诊断”)外周血或骨髓样本的Ficoll分离的单个核细胞的冷冻等份。我们采用2008WHO标准来定义AML(Vardiman等人；Blood.2009；114(5):937-951)，并采用细化的英国医学研究委员会(MRC)标准来指示细胞遗传学风险(Grimwalde等人；Blood.2010；116(3):354-365)。向患者提供关于根据由FHCRC机构审查委员会批准的方案收集和使用其生物样本用于研究目的的书面知情同意书。按照健康保险可携带性和可归责性法案(Health Insurance Portability andAccountability Act)的规定将临床数据去标识(de-identified)。解冻后，用识别CD33(克隆P67.6；PE-Cy7偶联的)、CD3(克隆SK7；PerCP偶联的)、CD34(克隆8G12；APC偶联的；全部来自BD Biosciences,San Jose,CA)和CD45(克隆HI30；
780偶联的；eBioscience)的直接标记的抗体将细胞染色。为了鉴别非活细胞，用4',6-二脒基-2-苯基吲哚(DAPI)将样品染色。在Canto II流式细胞仪(BD Biosciences)上获得了至少10,000个事件，并使用FlowJo(Tree Star,Ashland,OR)分析DAPI-细胞。
解冻后，如基于CD45/侧向散射性质通过流式细胞术所确定的，样本具有>58％的AML母细胞。样本在刚解冻后具有>50％的活细胞，而在含有细胞因子的液体培养物中48小时后具有>50％的活细胞(图7)。患者的年龄中值为58.1(范围：23.9-76.2)岁；细胞遗传学疾病风险在2名患者中是有利的，在18名患者中是居中的，而在7名患者中是不利的。关于NPM1、FLT3和CEBPA的突变状态的信息是不完整的；然而，已知一个样品为CEBPA双突变体，而另一个样品为NPM1pos/FLT3-ITDneg。所研究的样本中骨髓母细胞和CD3+T细胞的中值百分比分别为86.1％(范围：58.4-97.0％)和2.0％(范围：0-11.9％)，并且在培养物中48小时后的中值样品活力为80.1％(范围：53.6-93.6％)。15名患者患有新诊断的AML，而在样本收集时12名患有复发性(n＝7)或难治性(n＝5)疾病。如表11中所总结的，就在骨髓母细胞上的CD33表达、自体T细胞的量、骨髓母细胞的比例和培养物活力而言，来自患有新诊断AML的患者的样本的基本特征与患有复发性/难治性疾病的那些患者是相似的。
向AML样本培养物中添加串联双抗体分子导致适度的、剂量依赖性的细胞毒性(图8A)，表明来自活动性AML患者的样本中包含的自体T细胞可用于溶解白血病细胞。在健康供体T细胞的存在下，单种串联双抗体的细胞毒性活性严格地依赖于药物剂量和E：T细胞比(图8B/C)。然而，甚至在一些在AML母细胞上具有极低CD33表达的样本中也观察到串联双抗体的高活性。在串联双抗体分子中，12似乎最具活性，因为在低浓度(2.5pM(大约250ng/mL)，以及10pM(大约1ng/mL)，此时显著程度较低)下，在E：T＝1：3和E：T＝1：1两种比例下，其具有最高的细胞毒性。
已经在代表性AML患者血液样品中筛选了CD33/CD3串联双抗体，其根据患者性别、年龄、疾病阶段(新诊断的、复发性的、难治性的)、CD33表达程度和细胞遗传学风险(表11)而变化。引人注目地，多种检查的串联双抗体(例如，02、08、09、11、12、14、16、19、22和23)在跨病谱的几乎所有患者样品中都具有高活性，如图15中所示。此外，活性的程度和范围在AML患者的所有阶段(包括新诊断的、复发性的和难治性的)是相似的。
表11：原代AML样本的特征
实施例7
CD33/CD3串联双抗体12和串联双抗体16在表达不同CD33水平的各种来源的不同
CD33+细胞系上的效力和功效
为了评价CD33/CD3串联双抗体的效力和功效是否取决于靶细胞上的CD33密度，使用QIFIKIT量化试剂盒和抗CD33mAb WM53检测了表达重组人类CD33的各种人类CD33+肿瘤细胞系和CHO细胞的CD33表达水平。表12中的结果显示，肿瘤细胞系上的CD33密度在约1300SABC(标准化抗体结合能力)至约46000SABC的范围内。CHO-CD33细胞上的表达为约197000SABC，显著高于在肿瘤细胞系上的表达。在CD33/CD3串联双抗体12和串联双抗体16的连续稀释液的存在下，在以人类T细胞作为效应细胞、效应物：靶标比例为5：1的至少3次独立的基于FACS的细胞毒性测定中，所有测试的CD33+细胞系均被用作靶细胞。在每个测定中，通过非线性回归计算EC50和串联双抗体介导的溶解值。结果表明，12和16的效力(EC50值)和功效(％溶解)均与靶细胞表面上的CD33密度无关。
值得注意的是，至少12和16针对具有低于1500SABC的极低CD33密度的细胞如SEM也表现出其细胞毒性活性。
表12：CD33靶细胞表面表达和CD33/CD3串联双抗体12和串联双抗体16的细胞毒性效力：
使用QIFIKIT和抗CD33mAb WM53确定对CD33+细胞系的标准化抗体结合能力(SABC)。在以人类原代T细胞作为效应细胞、E：T比为5：1并且温育20-24h的基于FACS的细胞毒性测定中确定串联双抗体12和串联双抗体16重新指向的靶细胞溶解的EC50值；将使用表达CD33的CHO细胞的测定温育40-48h。示出了至少3次独立测定的平均值和SD。
实施例8
T细胞的TandAb激活和AML细胞的体外杀伤
将TandAb与纯化的人类T细胞和VPD-450标记的人类CD33+白血病细胞系KG-1或CD33-人类ALL细胞系G2(E：T 5：1)一起温育。使用流式细胞术评估TandAb引起的靶细胞溶解(10-15至10-8M；24h，37℃)。
TandAb 12、16和19与人类T细胞的温育有效溶解了KG-1细胞(IC50分别为约0.01pM、0.5pM和5pM)。最多40％的T细胞被激活(CD25+)且随细胞毒性活性而增加。具有无关靶标的对照TandAb，即00(>10-7M)，未导致体外KG-1的显著杀伤。单独地，16诱导KG-1细胞的溶解(IC50＝5x 10-12M)，而1x 10-8M对CD33-G2细胞没有影响。结果表明，当被CD33/CD3TandAb靶向至CD33+白血病细胞(KG-1)和原代CD33+AML母细胞时，T细胞变得激活并强力溶解肿瘤细胞。
实施例9
表位作图
使用CLIPS技术(Pepscan)对含有不同CD33结合部分的串联双抗体进行表位作图以鉴别CD33结合表位。
CLIPS技术促使肽结构化为单环、双环、三环、片状折叠、螺旋状折叠及其组合，从而提供了定位靶分子的不连续表位的可能性。
合成了超过7000个独立肽的阵列，并在ELISA中测试每种抗体与肽的结合。
串联双抗体12、14、16和22与人类CD33的第一Ig样结构域中的区段62DQEVQEETQ70(SEQ ID NO:94)结合。相应的氨基酸区段在图9A中以加下划线并加粗显示。预期串联双抗体01、02、04、06、08、09、13和23也与该表位结合，因为这些串联双抗体与串联双抗体12、14、16和12共有相同的CD33结合结构域(SEQ ID NO:2和12、3和13、5和15、9和19)。
实施例10
在预防性体内肿瘤模型中的剂量-响应
在用人类T细胞重建的NOD/scid小鼠的预防性HL-60肿瘤异种移植模型中，在不同剂量水平下比较了串联双抗体12和16。为获得剂量-响应，选择10μg、1μg和0.1μg(0.5mg/kg、0.05mg/kg和0.005mg/kg)的三个剂量水平。
通过皮下注射4x106个HL-60细胞的悬浮液对免疫缺陷型NOD/scid小鼠的8个实验组进行异种移植。在注射前，将细胞与利用负选择从血沉棕黄层(健康供体)分离的3x106个T细胞混合。为了解释T细胞的潜在供体差异，将每个实验组再分为三个组群，每个组群仅接受一个单独供体的T细胞。移植有肿瘤细胞和T细胞的实验组的所有动物均在第0天、第1天、第2天、第3天和第4天(qdxd5)接受如所示的3个不同剂量水平(0.1μg、1μg和10μg)的媒介物(对照)或者16或12的静脉内团注。无效应细胞和媒介物处理的一组充当额外的对照。表13总结了组分配和给药时间表。
表13
在HL-60异种移植模型中用于体内剂量-响应研究的处理组。对照组中的所有动物均稳定地发展出肿瘤并表现出均匀的肿瘤生长。T细胞的存在对肿瘤发展没有影响。在媒介物处理的对照组中，在存在或不存在T细胞的情况下没有观察到HL-60生长的差异。
使用两个测试项的处理揭示了明显的剂量依赖性抗肿瘤效应(图10)。在两种串联双抗体之间未发现实质性差异。图10中的平均肿瘤体积的绘制局限于第29天，此时大部分处理组完成。该研究继续至第45天，并观察动物的无肿瘤存活。在用10μg或1μg 16处理的组中，9只动物中的6只在观察期结束时无肿瘤，而接受10μg 12的9只动物中的5只在第45天无肿瘤。当用1μg的12处理时，一只动物保持无肿瘤。
对照组中的所有动物均稳定地发展出肿瘤并表现出均匀的肿瘤生长。使用串联双抗体中的任一种的处理揭示了剂量依赖性抗肿瘤效应，并且直到第29天，未在两种串联双抗体之间发现实质性差异。
仅在延长观察后(第45天)观查到可检测的差异，此时低剂量组和对照组己经由于大肿瘤的生长而终止。用16处理的组具有更多无肿瘤的动物。
实施例11
已建立的肿瘤模型
开发采用16的、具有预建立的HL-60肿瘤的NOD/scid小鼠中的异种移植模型来证明概念验证。
简言之，对雌性免疫缺陷型NOD/scid小鼠进行亚致死辐照(2Gy)并皮下接种4x106个HL-60细胞。在第9天，动物接受抗去唾液酸基GM1兔抗体(Wako,Neuss,Germany)的单次团注以耗尽鼠自然杀伤(NK)细胞。在第10天，当肿瘤达到50-150mm3(平均73±11mm3)的体积时，将动物分配至3个处理组。向组2和组3(每组8只动物)腹膜内注射1.5x107个激活的人类T细胞。在注射之前，采用负选择从血沉棕黄层(健康供体)分离T细胞。根据制造商说明(Mi1tenyi Biotech)，用T细胞激活/扩充试剂盒扩充并激活T细胞。为了解决潜在的供体差异，将组2和组3再分为两个组群，每个组群均接受来自单独供体的扩充并激活的T细胞。每个组群仅接受来自一个单独T细胞供体的T细胞。
表14：用于建立的HL-60异种移植模型的处理组。
从第13天开始，组3中的动物显示出105mm3的平均肿瘤体积，并用总计9个50μg串联双抗体16的静脉内剂量(qdx9d)处理。表14示出了组分配和给药时间表。组1和组2仅用媒介物处理。测定体重和肿瘤体积直到第27天。
所有动物均稳定地发展出肿瘤，在第6天可触及。用媒介物处理的组1和组2(HL-60)动物的平均肿瘤体积不断增加，直到在第27天研究终止(图11)。在除了HL-60肿瘤细胞外还接受原代激活的人类T细胞的组2动物中，平均肿瘤体积与组1(仅HL-60)相比增加得更快。
相对于组1和组2，从第13天至第21天(qdxd9)在人类T细胞的存在下使用串联双抗体16(50μg/动物；2.5mg/kg)反复静脉内处理(组3)快速延缓了肿瘤的生长。与媒介物处理的对照组(组2)相比，串联双抗体16使组3中的肿瘤生长延迟了大约4-5天。在第22天(p<0.05)、第23天(p<0.01)和第27天(p<0.01)，在组2(HL-60、T细胞、媒介物)与组3(HL-60、T细胞、16)之间观察到从第6天至第27天的时间段中的统计学显著性差异(采用Bonferroni事后检验的双因素重复测量ANOVA)。由于组1中肿瘤的异常缓慢生长，组1与组3之间没有统计学显著性差异。
当比较组内接受来自不同供体的T细胞(参见表14)的组群1和组群2中的肿瘤发展时，没有观察到T细胞活性方面的供体差异。
实施例10显示，成功开发了在具有预建立的HL-60肿瘤(AML)和腹膜内植入的人类T细胞的NOD/scid小鼠中的异种移植模型。与对应的媒介物处理的对照组相比，用单剂量水平的串联双抗体16反复给药导致肿瘤生长的统计学显著的延缓。生成的数据与采用CD33/CD3BiTETM的相似研究(Aigner等人,2012；Leukemia,2013年4月；27(5):1107-15)发表的结果相当。
实施例12
CD33/CD3串联双抗体在NSG小鼠的AML PDX模型中的功效
使用来自CD33+白血病包含2-4％CD3+T细胞的AML患者的冷藏保存的细胞在NSG小鼠中建立AML PDX模型。在将肿瘤细胞注射入经辐照(250cGy)的NSG小鼠后1小时，以200μg团剂以两种静脉内剂量中的任一种(50μg或5μg；n＝8只小鼠/组)注射CD33/CD3串联双抗体16或12。在接下来的4天每天进行串联双抗体的额外注射。将小鼠每周称重一次，随后在第38天处死以允许收集外周血、骨髓和脾，以便通过流式细胞术进行分析(huCD33、huCD34、huCD45、muCD45、huCD14、huCD3、huCD4、huCD8和7AAD)。结果示于图12中。
图12显示，38天后，未处理的小鼠在骨髓和脾中具有大量人类母细胞。相比之下，用串联双抗体12或16每日静脉内注射处理的小鼠在骨髓和脾中显示出数目大幅减少的人类AML母细胞。在两个剂量水平(5μg/注射和50μg/注射)下均观察到CD33/CD3串联双抗体的强抗AML效果。
对于CD33/CD3串联双抗体12和16两者观察到的抗AML效果比靶向AML的CD123/CD3
抗体在相同小鼠模型中的效果要强得多(Hussaini等人:"Targeting CD123InLeukemic Stem Cells Using Dual Affinity Re-Targeting Molecules
2013年11月15日；Blood:122(21))。与消除了骨髓和脾中的几乎所有AML母细胞的CD33/CD3串联双抗体相比，Hussaini等人报道，CD123/CD3
在2.5mg/kg和0.25mg/kg下仅使PDX模型中的骨髓和脾中的AML母细胞数目减少50-1000倍，该作者进一步报道，CD123/CD3DARTTM在0.5mg/kg下仅使PDX模型中的骨髓和脾中的AML母细胞数目减少40-78％。
实施例13
CD33/CD3串联双抗体16介导的靶细胞溶解的快速发生
为了评价CD33/CD3串联双抗体介导的靶细胞溶解的动力学，进行了不同温育时间的钙黄绿素释放细胞毒性测定。将钙黄绿素标记的CD33+HL-60靶细胞与串联双抗体16的连续稀释液在作为效应细胞的原代人类T细胞的存在下以25：1的E：T比一起温育30min、1h、2h、3h、4h或5h。在每个时间点，将从溶解的靶细胞释放的钙黄绿素用于使用非线性回归/S形剂量-响应计算EC50值和串联双抗体16介导的靶细胞溶解。图13示出了串联双抗体介导的靶细胞溶解的意外快速的发生，其在饱和串联双抗体浓度下温育30min后有大于40％的溶解。在4小时温育后达到了大于90％的靶细胞溶解。表15和图14总结了在30min与5小时之间的温育时间测定的串联双抗体16的EC50和特异性溶解值。结果进一步表明，在所使用的测定条件下，在2小时温育后达到最大效力(最低的EC50值)，而在5小时温育后几乎所有的靶细胞都被溶解。总之，这些结果证明了由CD33/CD3串联双抗体介导的极其快速、强力且有效的靶细胞溶解。
表15：针对串联双抗体16确定的EC50和溶解值的动力学
实施例14
用于向AML患者施用CD33/CD3串联双抗体的概念验证性临床试验方案
这是用于研究CD33/CD3串联双抗体16作为针对急性髓性白血病(AML)的治疗的I/II期临床试验。
研究结果：
主要：CD33/CD3串联双抗体16的最大耐受剂量
次要：确定CD33/CD3串联双抗体16的体外反应是否与临床反应有关
I期
将在该试验的I期部分中确定最大耐受剂量(MTD)。
1.1将在该试验的I期部分中确定最大耐受剂量(MTD)。
1.2满足合格标准的患者将进入针对CD33/CD3串联双抗体16的试验。
1.3目标在于确定可安全施用、在参与者中无严重或难以控制的副作用的CD33/CD3串联双抗体16的最高剂量。给定剂量将取决于先前已入选该研究的参与者的数目和对该剂量的耐受性如何。并非所有参与者均将接受相同剂量。
II期
2.1后续的II期部分将以MTD治疗，目标为确定用CD33/CD3串联双抗体16的疗法治疗是否会导致至少20％的反应率。
II期的主要结果——确定CD33/CD3串联双抗体16治疗是否会导致至少20％的患者达到临床反应(爆发性反应(blast response)、轻微反应、部分反应或完全反应)
合格性：
通过外周血和骨髓分析证明满足WHO标准的AML，排除患有急性早幼粒细胞白血病(APL)的患者
患有主要诱导化疗难治性的AML、复发性疾病，或年龄≥60岁，且根据治疗医师判断由于年龄、体能状态和/或不利的风险因素而不适合标准细胞毒性疗法的患者
年龄≥18岁
Karnofsky体能状态≥50％或ECOG体能状态为0-2
预期寿命≥6周
尽管本文中已经示出并描述了某些实施方案，但对于本领域技术人员显而易见的是，这些实施方案仅以示例的方式提供。本领域技术人员在不脱离本发明的情况下现将想到多种变化、改变和替代。应当理解，本文中所述的实施方案的各种替代方案可用于实施这些实施方案。目的在于以下述权利要求限定本发明的范围，并由此涵盖这些权利要求范围内的方法和结构及其等同项。
序列表
<110> 克里斯蒂娜·埃尔万格
卢克·伊弗宁
朱迪斯·A·弗克斯
伊维卡·弗赛克
吉恩玛丽·盖诺
斯特凡·奈克马斯
洛里·孔克尔
梅尔文·利特尔
维拉·莫尔肯斯恩
埃里希·拉贾科维奇
乌维·罗伊施
克劳迪亚·沃尔
迈克尔·维切尔
尤金·朱可夫斯基
<120> 双特异性CD33和CD3结合蛋白
<130> 45375-704.601
<140> 14/642,497
<141> 2015-03-09
<150> 62/111,470
<151> 2015-02-03
<150> 62/019,795
<151> 2014-07-01
<160> 122
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Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 6
<211> 110
<212> PRT
<213> 智人
<400> 6
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asp Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Asn Gly Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 7
<211> 111
<212> PRT
<213> 智人
<400> 7
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Asp Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 8
<211> 110
<212> PRT
<213> 智人
<400> 8
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Ile Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Lys Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 9
<211> 110
<212> PRT
<213> 智人
<400> 9
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Asn Asn Gln Arg Ser Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 10
<211> 110
<212> PRT
<213> 智人
<400> 10
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asp Asn
20 25 30
Val Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Thr Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 11
<211> 119
<212> PRT
<213> 智人
<400> 11
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asn Tyr
20 25 30
Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Leu Ile Ser Tyr Asp Gly Asn Lys Lys Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ala Ile Ser Arg Asp Thr Ser Lys Asn Thr Val Asp
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Glu Ser Ala Ala Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 12
<211> 122
<212> PRT
<213> 智人
<400> 12
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ala Asn Thr Asp Phe Ser Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 13
<211> 122
<212> PRT
<213> 智人
<400> 13
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ala Val Thr Asp Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 14
<211> 122
<212> PRT
<213> 智人
<400> 14
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Phe Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 15
<211> 122
<212> PRT
<213> 智人
<400> 15
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Leu Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 16
<211> 123
<212> PRT
<213> 智人
<400> 16
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Val Pro Ala Ala Ile Asp Tyr Tyr Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 17
<211> 119
<212> PRT
<213> 智人
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg His Lys Arg Gly Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 18
<211> 122
<212> PRT
<213> 智人
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Tyr Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 19
<211> 122
<212> PRT
<213> 智人
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 20
<211> 122
<212> PRT
<213> 智人
<400> 20
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Asp Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 21
<211> 11
<212> PRT
<213> 智人
<400> 21
Gly Gly Asn Asn Ile Gly Ser Thr Thr Val His
1 5 10
<210> 22
<211> 13
<212> PRT
<213> 智人
<400> 22
Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn Thr Val Asn
1 5 10
<210> 23
<211> 13
<212> PRT
<213> 智人
<400> 23
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn
1 5 10
<210> 24
<211> 14
<212> PRT
<213> 智人
<400> 24
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 25
<211> 13
<212> PRT
<213> 智人
<400> 25
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Ile Val Asn
1 5 10
<210> 26
<211> 13
<212> PRT
<213> 智人
<400> 26
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Lys
1 5 10
<210> 27
<211> 13
<212> PRT
<213> 智人
<400> 27
Ser Gly Ser Ser Ser Asn Ile Gly Asp Asn Val Val Asn
1 5 10
<210> 28
<211> 7
<212> PRT
<213> 智人
<400> 28
Asp Asp Asn Glu Arg Pro Ser
1 5
<210> 29
<211> 7
<212> PRT
<213> 智人
<400> 29
Gly Asn Asn Gln Arg Pro Ser
1 5
<210> 30
<211> 7
<212> PRT
<213> 智人
<400> 30
Ser Asp Asn Gln Arg Pro Ser
1 5
<210> 31
<211> 7
<212> PRT
<213> 智人
<400> 31
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 32
<211> 7
<212> PRT
<213> 智人
<400> 32
Ser Asn Asn Gln Arg Pro Ser
1 5
<210> 33
<211> 7
<212> PRT
<213> 智人
<400> 33
Ser Asn Asn Gln Arg Ser Ser
1 5
<210> 34
<211> 7
<212> PRT
<213> 智人
<400> 34
Ser Thr Asn Lys Arg Pro Ser
1 5
<210> 35
<211> 9
<212> PRT
<213> 智人
<400> 35
Gln Val Trp Asp Ser Gly Ser Asp His
1 5
<210> 36
<211> 9
<212> PRT
<213> 智人
<400> 36
Ala Thr Trp Asp Asp Ser Leu Ile Gly
1 5
<210> 37
<211> 9
<212> PRT
<213> 智人
<400> 37
Ala Thr Trp Asp Asp Ser Leu Asn Gly
1 5
<210> 38
<211> 9
<212> PRT
<213> 智人
<400> 38
Gln Ser Tyr Asp Ser Ser Leu Ser Asp
1 5
<210> 39
<211> 9
<212> PRT
<213> 智人
<400> 39
Ala Ala Trp Asp Asp Ser Leu Lys Gly
1 5
<210> 40
<211> 9
<212> PRT
<213> 智人
<400> 40
Ala Ala Trp Asp Asp Ser Leu Asn Gly
1 5
<210> 41
<211> 9
<212> PRT
<213> 智人
<400> 41
Ala Ala Trp Asp Asp Ser Leu Ser Ala
1 5
<210> 42
<211> 6
<212> PRT
<213> 智人
<400> 42
Ser Asn Tyr Gly Ile His
1 5
<210> 43
<211> 6
<212> PRT
<213> 智人
<400> 43
Thr Ser Tyr Asp Ile Asn
1 5
<210> 44
<211> 6
<212> PRT
<213> 智人
<400> 44
Thr Ser Tyr Tyr Met His
1 5
<210> 45
<211> 6
<212> PRT
<213> 智人
<400> 45
Thr Ser Tyr Trp Ile Gly
1 5
<210> 46
<211> 6
<212> PRT
<213> 智人
<400> 46
Ser Ser Tyr Ala Ile Ser
1 5
<210> 47
<211> 6
<212> PRT
<213> 智人
<400> 47
Ser Ser Tyr Gly Ile Ser
1 5
<210> 48
<211> 6
<212> PRT
<213> 智人
<400> 48
Asp Ser Tyr Ala Ile Ser
1 5
<210> 49
<211> 17
<212> PRT
<213> 智人
<400> 49
Leu Ile Ser Tyr Asp Gly Asn Lys Lys Phe Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 50
<211> 17
<212> PRT
<213> 智人
<400> 50
Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 51
<211> 18
<212> PRT
<213> 智人
<400> 51
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
1 5 10 15
Gln Gly
<210> 52
<211> 17
<212> PRT
<213> 智人
<400> 52
Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
1 5 10 15
Gly
<210> 53
<211> 17
<212> PRT
<213> 智人
<400> 53
Gly Ile Tyr Pro Ile Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 54
<211> 17
<212> PRT
<213> 智人
<400> 54
Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 55
<211> 17
<212> PRT
<213> 智人
<400> 55
Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr Ser Gln Lys Phe Gln
1 5 10 15
Gly
<210> 56
<211> 10
<212> PRT
<213> 智人
<400> 56
Asp Arg Leu Glu Ser Ala Ala Phe Asp Tyr
1 5 10
<210> 57
<211> 13
<212> PRT
<213> 智人
<400> 57
Asp Arg Ala Asn Thr Asp Phe Ser Tyr Gly Met Asp Val
1 5 10
<210> 58
<211> 13
<212> PRT
<213> 智人
<400> 58
Asp Arg Ala Val Thr Asp Tyr Tyr Tyr Gly Met Asp Val
1 5 10
<210> 59
<211> 13
<212> PRT
<213> 智人
<400> 59
Asp Arg Ala Asn Thr Asp Tyr Ser Phe Gly Met Asp Val
1 5 10
<210> 60
<211> 13
<212> PRT
<213> 智人
<400> 60
Asp Arg Ala Asn Thr Asp Tyr Ser Leu Gly Met Asp Val
1 5 10
<210> 61
<211> 14
<212> PRT
<213> 智人
<400> 61
Asp Val Val Pro Ala Ala Ile Asp Tyr Tyr Gly Met Asp Val
1 5 10
<210> 62
<211> 10
<212> PRT
<213> 智人
<400> 62
His Lys Arg Gly Ser Asp Ala Phe Asp Ile
1 5 10
<210> 63
<211> 13
<212> PRT
<213> 智人
<400> 63
Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala Phe Asp Ile
1 5 10
<210> 64
<211> 125
<212> PRT
<213> 智人
<400> 64
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Tyr Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 65
<211> 125
<212> PRT
<213> 智人
<400> 65
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 66
<211> 125
<212> PRT
<213> 智人
<400> 66
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 67
<211> 125
<212> PRT
<213> 智人
<400> 67
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 68
<211> 110
<212> PRT
<213> 智人
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 69
<211> 110
<212> PRT
<213> 智人
<400> 69
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 70
<211> 110
<212> PRT
<213> 智人
<400> 70
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 71
<211> 110
<212> PRT
<213> 智人
<400> 71
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 72
<211> 6
<212> PRT
<213> 智人
<400> 72
Ser Thr Tyr Ala Met Asn
1 5
<210> 73
<211> 19
<212> PRT
<213> 智人
<400> 73
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 74
<211> 14
<212> PRT
<213> 智人
<400> 74
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 75
<211> 14
<212> PRT
<213> 智人
<400> 75
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Tyr Phe Ala Tyr
1 5 10
<210> 76
<211> 6
<212> PRT
<213> 智人
<400> 76
Asn Thr Tyr Ala Met Asn
1 5
<210> 77
<211> 6
<212> PRT
<213> 智人
<400> 77
Asn Thr Tyr Ala Met His
1 5
<210> 78
<211> 6
<212> PRT
<213> 智人
<400> 78
Asn Lys Tyr Ala Met Asn
1 5
<210> 79
<211> 19
<212> PRT
<213> 智人
<400> 79
Arg Ile Arg Asn Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 80
<211> 19
<212> PRT
<213> 智人
<400> 80
Arg Ile Arg Asn Lys Tyr Asn Asn Tyr Ala Thr Glu Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 81
<211> 19
<212> PRT
<213> 智人
<400> 81
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Glu Tyr Ala Ala Ser
1 5 10 15
Val Lys Asp
<210> 82
<211> 19
<212> PRT
<213> 智人
<400> 82
Arg Ile Arg Asn Lys Tyr Asn Asn Tyr Ala Thr Glu Tyr Ala Ala Ser
1 5 10 15
Val Lys Asp
<210> 83
<211> 19
<212> PRT
<213> 智人
<400> 83
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Gly
<210> 84
<211> 19
<212> PRT
<213> 智人
<400> 84
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Glu Tyr Ala Asp Ser
1 5 10 15
Val Lys Ser
<210> 85
<211> 14
<212> PRT
<213> 智人
<400> 85
His Gly Asn Phe Gly Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 86
<211> 14
<212> PRT
<213> 智人
<400> 86
His Gly Asn Phe Gly Asn Thr Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 87
<211> 14
<212> PRT
<213> 智人
<400> 87
His Gly Asn Phe Gly Cys Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 88
<211> 14
<212> PRT
<213> 智人
<400> 88
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 89
<211> 14
<212> PRT
<213> 智人
<400> 89
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Phe Phe Ala Tyr
1 5 10
<210> 90
<211> 14
<212> PRT
<213> 智人
<400> 90
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 91
<211> 7
<212> PRT
<213> 智人
<400> 91
Gly Thr Asn Lys Arg Ala Pro
1 5
<210> 92
<211> 7
<212> PRT
<213> 智人
<400> 92
Ala Leu Trp Tyr Ser Asn Leu
1 5
<210> 93
<211> 242
<212> PRT
<213> 智人
<400> 93
Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln Glu
1 5 10 15
Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro Tyr
20 25 30
Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly Ala
35 40 45
Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln Glu
50 55 60
Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro Ser
65 70 75 80
Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp Asn
85 90 95
Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser Tyr
100 105 110
Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg Pro
115 120 125
Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn Leu
130 135 140
Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile Phe
145 150 155 160
Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr His
165 170 175
Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr Asn
180 185 190
Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu Arg
195 200 205
Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr Gly
210 215 220
Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly Val
225 230 235 240
Val His
<210> 94
<211> 9
<212> PRT
<213> 智人
<400> 94
Asp Gln Glu Val Gln Glu Glu Thr Gln
1 5
<210> 95
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成肽
<400> 95
Gly Gly Ser Gly Gly Ser
1 5
<210> 96
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成肽
<400> 96
Gly Gly Ser Gly
1
<210> 97
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成肽
<400> 97
Gly Gly Ser Gly Gly
1 5
<210> 98
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 98
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Phe Ser Tyr Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 99
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 99
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Val Thr Asp Tyr Tyr Tyr Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 100
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 100
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Phe Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 101
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 101
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Leu Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 102
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 102
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Phe Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr
245 250 255
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile
260 265 270
Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
275 280 285
Lys Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp
290 295 300
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser
305 310 315 320
Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp
325 330 335
Asp Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
340 345 350
Leu Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
355 360 365
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
370 375 380
Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
385 390 395 400
Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn
405 410 415
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
420 425 430
Arg Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys
435 440 445
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly
450 455 460
Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
465 470 475 480
Thr Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490 495
<210> 103
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 103
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
50 55 60
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Leu Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr
245 250 255
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile
260 265 270
Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
275 280 285
Lys Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp
290 295 300
Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser
305 310 315 320
Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp
325 330 335
Asp Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
340 345 350
Leu Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
355 360 365
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
370 375 380
Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
385 390 395 400
Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn
405 410 415
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
420 425 430
Arg Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys
435 440 445
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly
450 455 460
Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
465 470 475 480
Thr Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490 495
<210> 104
<211> 491
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 104
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Val Val
115 120 125
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser
130 135 140
Phe Ser Asn Tyr Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly
145 150 155 160
Leu Glu Trp Val Ala Leu Ile Ser Tyr Asp Gly Asn Lys Lys Phe Tyr
165 170 175
Ala Asp Ser Val Lys Gly Arg Phe Ala Ile Ser Arg Asp Thr Ser Lys
180 185 190
Asn Thr Val Asp Leu Gln Met Thr Ser Leu Arg Pro Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Lys Asp Arg Leu Glu Ser Ala Ala Phe Asp Tyr
210 215 220
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Gly Gly
225 230 235 240
Ser Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly
245 250 255
Gln Thr Ala Met Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Thr Thr
260 265 270
Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val
275 280 285
Tyr Asp Asp Asn Glu Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly
290 295 300
Ser Asn Ser Gly Ser Thr Ala Thr Leu Thr Ile Asn Arg Val Glu Ala
305 310 315 320
Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Gly Ser Asp
325 330 335
His Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
340 345 350
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
355 360 365
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
370 375 380
Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
385 390 395 400
Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
405 410 415
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
420 425 430
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
435 440 445
Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr Val
450 455 460
Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
465 470 475 480
Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 105
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 105
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp Ser Leu
85 90 95
Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
100 105 110
Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
115 120 125
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
130 135 140
Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
145 150 155 160
Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
165 170 175
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
180 185 190
Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp
195 200 205
Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr
210 215 220
Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Gly Gly Ser Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
245 250 255
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser
260 265 270
Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Gln
275 280 285
Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Gly Gly Thr Asn Lys Arg
290 295 300
Ala Pro Gly Val Pro Ser Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys
305 310 315 320
Ala Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
325 330 335
Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gln Gly Thr
340 345 350
Lys Val Glu Ile Lys Gly Gly Ser Gly Gly Ser Gln Val Gln Leu Val
355 360 365
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
370 375 380
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asp Ile Asn Trp Val
385 390 395 400
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Met Asn Pro
405 410 415
Asn Ser Gly Asn Thr Gly Phe Ala Gln Lys Phe Gln Gly Arg Val Thr
420 425 430
Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser
435 440 445
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Ala
450 455 460
Asn Thr Asp Phe Ser Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Leu
465 470 475 480
Val Thr Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490 495
<210> 106
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 106
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Phe Ser Tyr Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 107
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 107
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Phe Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 108
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 108
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Leu Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 109
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 109
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Val Thr Asp Tyr Tyr Tyr Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 110
<211> 483
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 110
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Val Thr Asp Tyr Tyr Tyr Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser
<210> 111
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 111
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Phe Ser Tyr Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 112
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 112
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Phe Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 113
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 113
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Phe
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Arg Ala Asn Thr Asp Tyr Ser Leu Gly
210 215 220
Met Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Gly Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Asp
325 330 335
Ser Leu Ile Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 114
<211> 492
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 114
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser
130 135 140
Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly
145 150 155 160
Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr
165 170 175
Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile
180 185 190
Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala
195 200 205
Met Tyr Tyr Cys Ala Arg His Lys Arg Gly Ser Asp Ala Phe Asp Ile
210 215 220
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser Gly Gln
225 230 235 240
Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg
245 250 255
Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr
260 265 270
Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
275 280 285
Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
290 295 300
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln
305 310 315 320
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu
325 330 335
Ser Asp Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
340 345 350
Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
355 360 365
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
370 375 380
Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
385 390 395 400
Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
405 410 415
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
420 425 430
Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp
435 440 445
Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr
450 455 460
Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
465 470 475 480
Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 115
<211> 492
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 115
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Tyr Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser
115 120 125
Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala
130 135 140
Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile
145 150 155 160
Gly Ala Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala
165 170 175
Pro Lys Leu Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro
180 185 190
Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
195 200 205
Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
210 215 220
Asp Ser Ser Leu Ser Asp Val Val Phe Gly Gly Gly Thr Lys Leu Thr
225 230 235 240
Val Leu Gly Gly Ser Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu
245 250 255
Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly
260 265 270
Tyr Ser Phe Thr Ser Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly
275 280 285
Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr
290 295 300
Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys
305 310 315 320
Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp
325 330 335
Thr Ala Met Tyr Tyr Cys Ala Arg His Lys Arg Gly Ser Asp Ala Phe
340 345 350
Asp Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Ser
355 360 365
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
370 375 380
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala
385 390 395 400
Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys
405 410 415
Ala Pro Lys Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val
420 425 430
Pro Ser Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr
435 440 445
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu
450 455 460
Trp Tyr Ser Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile
465 470 475 480
Lys Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 116
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 116
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Val Val Pro Ala Ala Ile Asp Tyr Tyr
210 215 220
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
225 230 235 240
Gly Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr
245 250 255
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
260 265 270
Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
275 280 285
Lys Leu Leu Ile Tyr Ser Asp Asn Gln Arg Pro Ser Gly Val Pro Asp
290 295 300
Arg Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser
305 310 315 320
Gly Leu Gln Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp
325 330 335
Asp Ser Leu Asn Gly Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val
340 345 350
Leu Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
355 360 365
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
370 375 380
Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
385 390 395 400
Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn
405 410 415
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
420 425 430
Arg Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys
435 440 445
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly
450 455 460
Asn Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
465 470 475 480
Thr Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490 495
<210> 117
<211> 484
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 117
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
130 135 140
Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
180 185 190
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Asp Val Val Pro Ala Ala Ile Asp Tyr Tyr
210 215 220
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
225 230 235 240
Gly Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr
245 250 255
Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile
260 265 270
Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
275 280 285
Lys Leu Leu Ile Tyr Ser Asp Asn Gln Arg Pro Ser Gly Val Pro Asp
290 295 300
Arg Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser
305 310 315 320
Gly Leu Gln Ser Asp Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp
325 330 335
Asp Ser Leu Asn Gly Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val
340 345 350
Leu Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
355 360 365
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
370 375 380
Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
385 390 395 400
Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn
405 410 415
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
420 425 430
Arg Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys
435 440 445
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly
450 455 460
Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
465 470 475 480
Thr Val Ser Ser
<210> 118
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 118
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr
130 135 140
Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Gly Ile Tyr Pro Ile Phe Gly Ser Ala Asn Tyr
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala
210 215 220
Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly
260 265 270
Ser Asn Ile Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp
325 330 335
Ser Leu Lys Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 119
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 119
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr
130 135 140
Phe Ser Ser Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala
210 215 220
Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Ser Asn Asn Gln Arg Ser Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp
325 330 335
Ser Leu Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 120
<211> 483
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 120
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr
130 135 140
Phe Ser Ser Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr
165 170 175
Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala
210 215 220
Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly
260 265 270
Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Ser Asn Asn Gln Arg Ser Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp
325 330 335
Ser Leu Asn Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser
<210> 121
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成多肽
<400> 121
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr
20 25 30
Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ala Pro Lys
35 40 45
Ala Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ser Arg
50 55 60
Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Thr Leu Thr Ile Ser Ser
65 70 75 80
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Leu Trp Tyr Ser
85 90 95
Asn Leu Trp Val Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly Gly
100 105 110
Ser Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
115 120 125
Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr
130 135 140
Phe Asp Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
145 150 155 160
Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Ser Ala His Tyr
165 170 175
Ser Gln Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr
180 185 190
Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
195 200 205
Val Tyr Tyr Cys Ala Arg Glu Tyr Tyr Tyr Asp Ser Ser Glu Trp Ala
210 215 220
Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Ser Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro
245 250 255
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly
260 265 270
Asp Asn Val Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
275 280 285
Leu Leu Ile Tyr Ser Thr Asn Lys Arg Pro Ser Gly Val Pro Asp Arg
290 295 300
Phe Ser Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
305 310 315 320
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp
325 330 335
Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
340 345 350
Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
355 360 365
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
370 375 380
Phe Thr Phe Ser Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly
385 390 395 400
Lys Gly Leu Glu Trp Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr
405 410 415
Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg
420 425 430
Asp Asp Ser Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr
435 440 445
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg His Gly Asn Phe Gly Asn
450 455 460
Ser Tyr Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
465 470 475 480
Val Ser Ser Ala Ala Ala Gly Ser His His His His His His
485 490
<210> 122
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成6xHis标签
<400> 122
His His His His His His
1 5
Claims (28)
1.一种对人类CD33和人类CD3具有特异性的双特异性抗原结合串联双抗体，其中所述串联双抗体包含第一多肽和第二多肽，每个多肽均具有至少四个相继连接的可变链结构域，其中每个多肽均包含
(A)
(i)对人类CD33具有特异性的可变重链结构域，即VH(CD33)，其氨基酸序列为SEQ IDNO:13；
(ii)对人类CD33具有特异性的可变轻链结构域，即VL(CD33)，其氨基酸序列为SEQ IDNO:3；
(iii)对人类CD3具有特异性的可变重链结构域，即VH(CD3)，其氨基酸序列为SEQ IDNO:64，以及
(iv)对人类CD3具有特异性的可变轻链结构域，即VL(CD3)，其氨基酸序列为SEQ IDNO:68，
或(B)
(i)对人类CD33具有特异性的可变重链结构域，即VH(CD33)，其氨基酸序列为SEQ IDNO:15；
(ii)对人类CD33具有特异性的可变轻链结构域，即VL(CD33)，其氨基酸序列为SEQ IDNO:5；
(iii)对人类CD3具有特异性的可变重链结构域，即VH(CD3)，其氨基酸序列为SEQ IDNO:64，以及
(iv)对人类CD3具有特异性的可变轻链结构域，即VL(CD3)，其氨基酸序列为SEQ IDNO:68，
并且其中在每个多肽中，所述四个可变链结构域通过肽连接体L1、L2和L3按以下顺序相继连接：
VL(CD3)-L1-VH(CD33)-L2-VL(CD33)-L3-VH(CD3)。
2.根据权利要求1所述的双特异性抗原结合串联双抗体，其中连接体L1、L2和L3由12个或更少的氨基酸残基组成。
3.根据权利要求1所述的双特异性抗原结合串联双抗体，其中连接体L1、L2和L3各自独立地选自GGSGGS、GGSG或GGSGG。
4.根据权利要求1所述的双特异性抗原结合串联双抗体，其中连接体L1和L3为GGSGGS，且连接体L2为GGSG或GGSGG。
5.根据权利要求1所述的双特异性抗原结合串联双抗体，其中所述串联双抗体的氨基酸序列为SEQ ID NO:109或SEQ ID NO:113。
6.一种用于治疗CD33+癌症的组合物，所述组合物包含根据权利要求1所述的双特异性抗原结合串联双抗体。
7.根据权利要求6所述的组合物，其中所述CD33+癌症为急性髓性白血病(AML)、急性成淋巴细胞性白血病(ALL)、前体B细胞成淋巴细胞性白血病、髓样肉瘤、多发性骨髓瘤、急性淋巴瘤、急性淋巴母细胞性淋巴瘤或慢性粒单核细胞白血病(CMML)。
8.根据权利要求6所述的组合物，其中所述CD33+癌症是伴有复发性遗传异常的AML、伴有脊髓发育不良相关变化的AML、与治疗相关的髓样肿瘤、髓样肉瘤、与唐氏综合征相关的骨髓增生或母细胞性浆细胞样树突状细胞肿瘤。
9.根据权利要求6所述的组合物，其中所述CD33+癌症是新诊断的、复发性的或难治性的AML。
10.根据权利要求6所述的组合物，其中所述组合物还包含阿糖胞苷、阿扎胞苷、地西他滨、蒽环类药物、氟达拉滨、氯法拉滨、克拉屈滨、奈拉滨、甲氨蝶呤、硼替佐米、卡非佐米、美法仑、依鲁替尼、沙利度胺、来那度胺、泊马度胺、阿普斯特、表鬼臼毒素、蒽醌、抗CD20剂或其组合。
11.一种用于治疗骨髓发育不良综合征(MDS)的组合物，该组合物包含根据权利要求1所述的双特异性抗原结合串联双抗体。
12.根据权利要求11所述的组合物，其中所述组合物还包含阿糖胞苷、阿扎胞苷、地西他滨、蒽环类药物、安吖啶、氟达拉滨、氯法拉滨、克拉屈滨、奈拉滨、甲氨蝶呤、硼替佐米、卡非佐米、美法仑、依鲁替尼、沙利度胺、来那度胺、泊马度胺、阿普斯特、表鬼臼毒素、蒽醌、抗CD20剂或其组合。
13.一种用于治疗由骨髓衍生的抑制细胞(MDSC)引起的免疫抑制的组合物，所述组合物包含根据权利要求1的任一项所述的双特异性抗原结合串联双抗体。
14.一种对人类CD33和人类CD3具有特异性的双特异性抗原结合串联双抗体，其中所述串联双抗体包含第一多肽和第二多肽，每个多肽均具有至少四个相继连接的可变链结构域，其中每个多肽均包含：
(i)对人类CD33具有特异性的可变重链结构域，即VH(CD33)，其氨基酸序列为SEQ IDNO:15；
(ii)对人类CD33具有特异性的可变轻链结构域，即VL(CD33)，其氨基酸序列为SEQ IDNO:5；
(iii)对人类CD3具有特异性的可变重链结构域，即VH(CD3)，其氨基酸序列为SEQ IDNO:64，以及
(iv)对人类CD3具有特异性的可变轻链结构域，即VL(CD3)，其氨基酸序列为SEQ IDNO:68，
并且其中在每个多肽中，所述四个可变链结构域通过肽连接体L1、L2和L3按以下顺序相继连接：
VL(CD3)-L1-VH(CD33)-L2-VL(CD33)-L3-VH(CD3)。
15.根据权利要求14所述的双特异性抗原结合串联双抗体，其中连接体L1、L2和L3由12个或更少的氨基酸残基组成。
16.根据权利要求14所述的双特异性抗原结合串联双抗体，其中连接体L1和L3为GGSGGS，且连接体L2为GGSG或GGSGG。
17.一种用于治疗CD33+癌症的组合物，所述组合物包含根据权利要求14所述的双特异性抗原结合串联双抗体。
18.根据权利要求17所述的组合物，其中所述CD33+癌症为急性髓性白血病(AML)。
19.根据权利要求17所述的组合物，其中所述CD33+癌症为急性成淋巴细胞性白血病(ALL)。
20.根据权利要求17所述的组合物，其中所述CD33+癌症为前体B细胞成淋巴细胞性白血病。
21.根据权利要求17所述的组合物，其中所述CD33+癌症为髓样肉瘤。
22.根据权利要求17所述的组合物，其中所述CD33+癌症为多发性骨髓瘤。
23.根据权利要求17所述的组合物，其中所述CD33+癌症为急性淋巴瘤。
24.根据权利要求17所述的组合物，其中所述CD33+癌症为急性淋巴母细胞性淋巴瘤。
25.根据权利要求17所述的组合物，其中所述CD33+癌症为慢性粒单核细胞白血病(CMML)。
26.根据权利要求18所述的组合物，其中所述CD33+癌症为新诊断的、复发性的或难治性的AML。
27.一种用于治疗骨髓发育不良综合征(MDS)的组合物，该组合物包含根据权利要求14所述的双特异性抗原结合串联双抗体。
28.根据权利要求27所述的组合物，其中所述组合物还包含阿糖胞苷、阿扎胞苷、地西他滨、蒽环类药物、安吖啶、氟达拉滨、氯法拉滨、克拉屈滨、奈拉滨、甲氨蝶呤、硼替佐米、卡非佐米、美法仑、依鲁替尼、沙利度胺、来那度胺、泊马度胺、阿普斯特、表鬼臼毒素、蒽醌、抗CD20剂或其组合。
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