CN113509558B - 四价抗体药物偶联物及其应用 - Google Patents

四价抗体药物偶联物及其应用 Download PDF

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CN113509558B
CN113509558B CN202110390226.7A CN202110390226A CN113509558B CN 113509558 B CN113509558 B CN 113509558B CN 202110390226 A CN202110390226 A CN 202110390226A CN 113509558 B CN113509558 B CN 113509558B
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CN113509558A (zh
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周宇虹
魏紫萍
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Bailisikang Biomedical Hangzhou Co ltd
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Abstract

本发明提供了一种抗体药物偶联物(ADC)或其药学上可接受的盐。所述ADC包括四价单克隆抗体，所述四价单克隆抗体通过化学接头与细胞毒性药物偶联。所述单克隆抗体包括两条长链和四条短链。单克隆抗体包括两个长链和四个短链。每条所述长链包括第一片段和第二片段，所述第一片段位于所述长链的N端附近，所述第二片段位于所述长链的C端附近。每个所述第一片段和每个所述第二片段与一条所述短链配对，从而形成抗原结合片段结构域，因此形成对同一抗原具有特异性的四个抗原结合片段结构域。本发明还提供了包括ADC的药物组合物以及使用所述组合物治疗疾病的方法。

Description

四价抗体药物偶联物及其应用
交叉引用
本申请要求2020年4月11日提交的美国临时申请63/008,726的优先权，其全文通过引用并入本文。
本申请要求2020年4月29日提交的美国专利申请16/862,042的优先权，其全文通过引用并入本文。
序列表引用
本申请包含以ASCII形式通过EFS-Web提交的序列表，其名称为“BLISS001US_ST25.txt”，大小为108KB，在2020年4月27日生成，序列表的全文通过引用并入本文。
背景技术
抗体是抵抗外来病原体的关键免疫分子。单克隆抗体(monoclonal antibody,mAb)技术的发展使单克隆抗体在疾病的研究、诊断和治疗中得到了广泛的应用。第一代mAb(主要是单特异性、二价mAb)的治疗用途在多种疾病(包括癌症、自身免疫性疾病和传染性疾病)的治疗中取得了成功。但是，许多疾病(例如实体瘤)已显示出对基于抗体的疗法较强的抗性。
为了提高效价、改善安全性并获得mAb的非天然特性，已开发出修饰的、具有多价特性的新形式的mAb。例如，已经开发了新的三价和四价抗体，以通过增强的生物分布和功能性亲和力来最大化肿瘤靶向能力。例如，已经产生了用于癌症免疫疗法的四价抗体，其中两个结合部分可以与癌细胞表面上的靶分子反应，而另外两个结合部分则与细胞毒性T细胞或自然杀伤(NK)细胞反应。
抗体药物偶联物(ADC)是与活性药物化学连接的mAb，因此，既具有mAb的特异性靶向作用，又具有细胞毒性药物的抗癌能力。选择特定mAb-药物组合的能力以及在mAb与药物连接方面的进展为靶向癌症提供了新的可能性，同时最大限度地减少了健康组织的暴露。到2019年，FDA总共批准了七个ADC，包括：ado-trastuzumab emtansine(KadcylaTM)、brentuximab vedotin(AdcetrisTM)、inotuzumab ozogamicin(BesponsaTM)、gemtuzumabozogamicin(MylotargTM)、polatuzinumab vegotin piiq(PolivyTM)、Enfortumab vedotin(PadcevTM)和Trastuzumab deruxtecan(EnhertuTM)。所有这些都涉及细胞毒性药物与二价mAb的偶联。除了已批准上市的七种ADC药物外，大量ADC也正在临床开发中。
HER2(Human Epidermal Growth Factor Receptor 2，人类表皮生长因子受体2)也称为Neu、ErbB-2、CD340或p185，是ERBB2基因编码的表皮生长因子受体(EGFR/ErbB)家族的成员。该基因的获得性体细胞改变导致在人类乳腺癌、膀胱癌、胃癌和肺癌中分别发生约20-25％、23-80％、10-30％和20％的扩增和过表达。扩增和过表达导致与HER2相关的增殖刺激增加。增殖刺激的增加导致肿瘤生长增强。因此，增强的或组成型的HER2活性被认为是表达HER2的人肿瘤细胞中恶性肿瘤的驱动力。罗氏(Roche)公司开发了靶向HER2的曲妥珠单抗(Trastuzumab)和帕妥珠单抗(Pertuzumab)，它们通过阻止HER2必要的二聚化或与HER家族其他成员(EGFR、HER3和HER4)的异源二聚化来抑制酪氨酸激酶信号通路，反过来减缓了HER2过表达(HER2阳性)癌细胞的生长。为了进一步提高靶向HER2的抗体疗法的治疗获益，罗氏推出了Trastuzumab emtansine(T-DM1)，该药物将曲妥珠单抗的抗肿瘤活性与抗微管剂DM1相结合。
表皮生长因子受体(Epidermal growth factor recepotr,EGFR，也称为HER1或c-erbB-1)是170kDa的跨膜糖蛋白，是细胞表面受体酪氨酸激酶家族的成员。EGFR在许多上皮肿瘤中被异常激活，包括在非小细胞肺癌、乳腺癌、大肠癌、头颈癌和前列腺癌中的那些。EGFR的异常激活可能是由于受体的过表达、基因扩增、激活突变、受体配体的过表达和/或EGFR活性调节剂的缺失引起的。
通过阻断受体胞外结构域上的EGFR结合位点或抑制细胞内酪氨酸激酶活性来中断EGFR信号传导，可以阻止表达EGFR的肿瘤的生长并改善患者的病情。抗EGFR抗体通过结合细胞表面的受体来干扰配体结合，从而发挥抗肿瘤作用，从而抑制了其下游信号传导途径。嵌合单克隆抗体C225(或cetuximab，西妥昔单抗)包含鼠mAb225的可变区和人IgG1的恒定区，可在世界各地用于治疗伊立替康难治性结肠癌。
批准用于EGFR的裸抗(即西妥昔单抗、尼莫妥珠单抗、帕尼单抗和尼西单抗)在恶性肿瘤中显示出治疗作用，但通常与化学疗法药物联合使用以达到显著的临床疗效。由于裸抗的活性欠佳，抗体药物偶联物(Antibody-drug conjugate,ADC)作为下一代疗法可能会增加抗体的抗肿瘤活性。在EGFR靶向治疗中，尚无商业批准的ADC，但数个ADC已进入临床试验。AVID-100是由美登木素生物碱与抗EGFR抗体连接而成，被开发用于治疗I/II期的上皮肿瘤患者。ABT-414由通过可裂解接头与抗EGFRvIII抗体连接的单甲基澳瑞他汀F组成，已在III期中显示出对表达扩增的EGFR和EGFRvIII的肿瘤的显著疗效(van den Bent etal.,2017)。所有临床阶段的靶向EGFR的ADC均使用常规的二价抗EGFR mAb作为靶向抗体。
发明简述
一方面，本公开提供了抗体药物偶联物(Antibody-drug conjugate,ADC)，其包括：四价单克隆抗体[或四聚体(tetrabody)]，所述四价单克隆抗体通过化学接头与细胞毒性药物偶联；其中，所述单克隆抗体包括：两条长链和四条短链；其中每条所述长链包括第一片段和第二片段，所述第一片段位于所述长链的N端附近，所述第二片段位于所述长链的C端附近，每个所述第一片段和每个所述第二片段与一条所述短链配对，从而形成抗原结合片段结构域，因此形成对同一抗原具有特异性的四个抗原结合片段结构域。
在所述ADC的一些实施方案中，所述两条长链彼此相同，并且所述四条短链彼此相同。在一些实施方案中，所述两条长链可以彼此不同。在一些实施方案中，所述四条短链可以彼此不完全相同。
在一些实施方案中，至少一条或每条所述长链的所述第一片段和所述第二片段具有相同的序列。在一些其他的实施方案中，至少一条或每条所述长链的所述第一片段和所述第二片段具有不同的序列。
在ADC的一些实施方案中，每条所述长链包括具有天然人IgG1、IgG2、IgG4抗体同种型之一的CH2-CH3结构域序列的子序列，所述子序列位于所述第一片段和所述第二片段之间。
在ADC的一些实施方案中，每条所述长链包含位于所述第一片段和所述第二片段之间的子序列，所述子序列包含人IgG1同种型的Fc(或CH2-CH3)结构域。在一些实施方案中，此类Fc结构域可包括一个或多个突变，以用于Fc结构域功能的期望的改善。
在ADC的一些实施方案中，至少一条或每条所述短链包括天然人IgG同种型的VL-CL(λ)或VL-CL(κ)的序列。
在ADC的一些实施方案中，至少一条或每条所述短链包括VH-CH1的序列，其中CH1是人IgG抗体同种型。在一些这样的实施方案中，所述VH可包含一个或多个突变。
在ADC的一些实施方案中，至少一条所述长链的至少一个所述第一片段或所述第二片段包括天然人IgG1、IgG2或IgG4抗体同种型的VL-CL(κ)序列。
在ADC的一些实施方案中，所述长链各自包含选自SEQ ID NO:3、5和9组成的组中的序列，而所述短链各自包含选自SEQ ID NO:4、6和10组成的组中的序列。
在一些实施方案中，每条所述长链的所述第一片段和所述第二片段各自包含选自SEQ ID NO:25、26、27、28、29、30、31、32、33和34组成的组中的序列。
在一些实施方案中，每条所述短链的所述第一片段和所述第二片段各自包含选自SEQ ID NO:25、26、27、28、29、30、31、32、33和34组成的组中的序列。
在一些实施方案中，每条所述长链包含如SEQ ID NO:25所示的序列，并且每条所述短链包含如SEQ ID NO:26所示的序列。在一些实施方案中，每条所述长链包含如SEQ IDNO:26所示的序列，并且每条所述短链包含如SEQ ID NO:25所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:27所示的序列，并且每条所述短链包含如SEQ ID NO:28所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:28所示的序列，并且每条所述短链包含如SEQ ID NO:27所示的序列。在一些实施方案中，每条所述长链包含如SEQID NO:29所示的序列，并且每条所述短链包含如SEQ ID NO:30所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:30所示的序列，并且每条所述短链包含如SEQ IDNO:29所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:31所示的序列，并且每条所述短链包含如SEQ ID NO:32所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:32所示的序列，并且每条所述短链包含如SEQ ID NO:31所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:33所示的序列，并且每条所述短链包含如SEQID NO:34所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:34所示的序列，并且每条所述短链包含如SEQ ID NO:33所示的序列。
在ADC的一些实施方案中，每条所述短链包含选自SEQ ID NO:2、SEQ ID NO:4、SEQID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQID NO:18、SEQ ID NO:20、SEQ ID NO:22和SEQ ID NO:24组成的组中的序列。
在ADC的一些实施方案中，每条所述长链包含选自SEQ ID NO:1、SEQ ID NO:3、SEQID NO:5、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ IDNO:17、SEQ ID NO:19、SEQ ID NO:21和SEQ ID NO:23组成的组中的序列。
在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:1所示的序列，并且每条所述短链包含如SEQ ID NO:2所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:3所示的序列，并且每条所述短链包含如SEQ ID NO:4所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:5所示的序列，并且每条所述短链包含如SEQ ID NO:6所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:7所示的序列，并且每条所述短链包含如SEQ ID NO:8所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:9所示的序列，并且每条所述短链包含如SEQ ID NO:10所示的序列。
在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:11所示的序列，并且每条所述短链包含如SEQ ID NO:12所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:13所示的序列，并且每条所述短链包含如SEQ ID NO:14所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:15所示的序列，并且每条所述短链包含如SEQ ID NO:16所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:17所示的序列，并且每条所述短链包含如SEQ ID NO:18所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:19所示的序列，并且每条所述短链包含如SEQ ID NO:20所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:21所示的序列，并且每条所述短链包含如SEQ ID NO:22所示的序列。在ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:23所示的序列，并且每条所述短链包含如SEQ ID NO:24所示的序列。
在一些实施方案中，本公开提供了一种ADC，其包含通过化学接头与细胞毒性药物偶联的单克隆抗体，其中所述单克隆抗体包含两条相同的长链和四条相同的短链，其中：
(a)每条所述长链包含如SEQ ID NO:1所示的序列，并且每条所述短链包含如SEQID NO:2所示的序列；或者
(b)每条所述长链包含如SEQ ID NO:3所示的序列，并且每条所述短链包含如SEQID NO:4所示的序列；或者
(c)每条所述长链包含如SEQ ID NO:5所示的序列，并且每条所述短链包含如SEQID NO:6所示的序列；或者
(d)每条所述长链包含如SEQ ID NO:7所示的序列，并且每条所述短链包含如SEQID NO:8所示的序列；或者
(e)每条所述长链包含如SEQ ID NO:9所示的序列，并且每条所述短链包含如SEQID NO:10所示的序列；或者
(f)每条所述长链包含如SEQ ID NO:11所示的序列，并且每条所述短链包含如SEQID NO:12所示的序列；或者
(g)每条所述长链包含如SEQ ID NO:13所示的序列，并且每条所述短链包含如SEQID NO:14所示的序列；或者
(h)每条所述长链包含如SEQ ID NO:15所示的序列，并且每条所述短链包含如SEQID NO:16所示的序列；或者
(i)每条所述长链包含如SEQ ID NO:17所示的序列，并且每条所述短链包含如SEQID NO:18所示的序列；或者
(j)每条所述长链包含如SEQ ID NO:19所示的序列，并且每条所述短链包含如SEQID NO:20所示的序列；或者
(k)每条所述长链包含如SEQ ID NO:21所示的序列，并且每条所述短链包含如SEQID NO:22所示的序列；或者
(1)每条所述长链包含如SEQ ID NO:23所示的序列，并且每条所述短链包含如SEQID NO:24所示的序列。
在ADC的一些实施方案中，所述第二片段通过柔性肽接头与所述长链的其余部分连接，所述柔性肽接头包括(GxS)y序列的一个或多个重复单元，其中x为1到6(包含)之间的整数，而y是0到8(包含)之间的整数。
在一些实施方案中，所述抗原是EGFR，并且所述ADC包含四个均与EGFR特异性结合的四个抗原结合片段结构域。在一些实施方案中，所述抗原是HER2，并且所述ADC包含四个均与HER2特异性结合的抗原结合片段结构域。在一些实施方案中，所述抗原是c-MET，并且所述ADC包含四个均与c-MET特异性结合的抗原结合片段结构域。
在ADC的一些实施方案中，所述细胞毒性药物选自单甲基澳瑞他汀E(MMAE)、单甲基澳瑞他汀F(MMAF)、澳瑞他汀E、澳瑞他汀F、美登素DM1和DM4、美登木醇、山卓霉素、吡咯并苯并二氮杂卓二聚体、蒽环类、加利车霉素、尾海兔素10、杜卡霉素、阿霉素、泰兰抑菌素A、uncialamycin、甘露糖苷、蓖麻毒蛋白、白喉毒素、艾瑞布林、131I、白细胞介素、肿瘤坏死因子、趋化因子和纳米颗粒组成的组。
在ADC的一些实施方案中，所述接头是可裂解的或不可裂解的，并可选自6-马来酰亚胺基己酰基(MC)、马来酰亚胺基丙酰基(MP)、缬氨酸-瓜氨酸(val-cit)、丙氨酸-苯丙氨酸(ala-phe)、对氨基苄氧羰基(PAB)、N-琥珀酰亚胺基4-(2-吡啶硫基)戊酸酯(SPP)、N-琥珀酰亚胺基4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(SMCC)、N-琥珀酰亚胺基(4-碘-乙酰基)氨基苯甲酸酯(SIAB)、6-马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苄氧基羰基(MC-vc-PAB)、Val-Cit-PABC，N-琥珀酰亚胺基-4-(2-吡啶基二硫代)丁酸酯(SPDB)、N-琥珀酰亚胺基3-(吡啶-2-基二硫代)-丙酸酯(SPDP)、Phe-Lys(Fmoc)-PAB、Aloc-D-Ala-Phe-Lys(Aloc)-PAB-PNP、Boc-Phe-(Alloc)Lys-PAB-PNP和全氟苯基3-(吡啶-2-基二硫烷基)丙酸酯组成的组。
在ADC的一些实施方案中，所述药物接头可以通过半胱氨酸偶联、胺偶联、末端偶联、酶偶联或碳水化合物偶联与四价抗体连接。
在ADC的一些实施方案中，所述药物抗体比在1与12(包含)之间。在一些实施方案中，所述药物抗体比为约3或4。
本公开还提供了如本文所述的ADC的各种实施方案的其药学上可接受的盐。
在另一方面，本公开提供了一种药物组合物，其包含ADC或其药学上可接受的盐和药学上可接受的载体。
在另一方面，本公开提供了一种方法，通过向受试者施用有效量的本文所述的药物组合物来治疗增生性疾病、紊乱或病症。所述增生性疾病可以是癌症，例如结肠癌、直肠癌、肺癌、乳腺癌、卵巢癌、子宫颈癌、膀胱癌、食道癌、肉瘤和头颈癌。
附图说明
图1为根据本公开的实施方案的四价ADC的结构的示意图。
图2为本公开的一些实施方案的特定四价ADC与对照ADC的HIC分布的比较图；
A图：Ctl-MMAE；B图：具有低DAR的BB01E-MMAE；C图：具有高DAR的BB01E-MMAE。
图3示出了本公开的一些实施方案的四价抗体和对照抗体的ELISA结合结果；
A图：EGFR结合结果；B图：HER2结合结果。
图4示出了本公开的一些实施方案的四价抗EGFR抗体和对照抗体的FACS分析；
A图：高表达EGFR的MDA-MB-468细胞；B图：低表达EGFR的NUGC3细胞。
图5示出了本公开的一些实施方案的四价抗EGFR抗体和对照抗体的内化分析；
A图：高表达EGFR的MDA-MB-468细胞；B图：低表达EGFR的NUGC3细胞。
图6A-6C示出了本公开的一些实施方案的四价ADC和对照ADC的内化分析；
6A图：在高表达EGFR的MDA-MB-468细胞上具有MMAE效应分子的ADC；6B图：在MDA-MB-468细胞上具有DM1效应分子的ADC；6C图：在低表达EGFR的NUGC3细胞上具有MMAE效应分子的ADC。
图7A-7C示出了本公开的实施方案的四价ADC和对照ADC的细胞毒性；
7A图：在高表达EGFR的MDA-MB-468细胞上具有MMAE效应分子的ADC；7B图：在MDA-MB-468细胞上具有DM1效应分子的ADC；7C图：在低表达EGFR的NUGC3细胞上具有MMAE效应分子的ADC。
发明详述
在一个方面，并且结合图1所示，本公开提供了一种抗体药物偶联物(Antibody-drug conjugate,ADC)1000，其包括：通过化学接头30与细胞毒性药物40偶联的四价单克隆抗体10；其中，所述单克隆抗体10包括：两条长链(110和120)和四条短链(210、220、230和240)；其中每条所述长链包括第一片段(111、121)和第二片段(112、122)，所述第一片段位于所述长链的N端附近，所述第二片段位于所述长链的C端附近，每个所述第一片段和每个所述第二片段与一条所述短链配对，从而形成抗原结合片段结构域，因此形成对同一抗原具有特异性的四个抗原结合片段结构域。
如本文所用，“特异性结合”靶标(或靶标抗原，例如HER2、HER3、EGFR、CLDN18.2、TROP2、BMCA、CD33、CD22、CD72或其他抗原)的抗体或其部分可以指与人靶标蛋白结合从而抑制其相关信号传导的抗体或其部分。优选地，所述抗体以“高亲和力”结合人靶标蛋白，所述高亲和力即KD为1×10-8M或更小，更优选地为5×10-9M或更小或进一步更优选地为1×10-9M或更小。
如本文所用的术语“细胞毒性药物”或“细胞毒性剂”，如本文所用，旨在指已知的抑制细胞生长和/或复制、和/或杀死细胞的任何试剂或药物。作为所述ADC的一个组分，它也称为“效应分子”(payload)。
在一些实施方案中，本公开的四价单特异性抗体的构建可以被认为是前体抗体的完整Fab结构域与相同前体抗体的Fc的C端连接，或者与具有同一抗原特异性的不同前体抗体的Fc的C端连接。
四价抗体的所述抗原结合区的正确排列和间隔可促进同一抗原的几个分子在细胞表面上的多价结合。设计不佳的抗体可能会导致某些结合表位的障碍。本发明的设计隔开了四个Fab结构域，Fc结构域每侧两个，在C端的Fab结构域与柔性GS接头连接。这种排列为每个臂(Fab)接触(结合)靶标抗原提供了合适的灵活性和范围，并且可以使不同Fab的空间位阻最小化。
本公开的所述四价抗体可以同时通过N端的Fab和C端的Fab与靶标结合，并且所述多价结合可以诱导所述靶标-抗体复合物更有效的内化。与传统ADC相比，这提供了四价ADC的明显优势。
已经报道了scFv与Fc的C端融合的多价抗体。这种设计的主要挑战是当Fab结构转换为scFv时亲和力降低。当转换为scFv时，大多数Mab序列变得不稳定或亲和力降低。相反，具有完整VH-CH1和VL-CL的Fab通常是稳定的，并保持其亲和力。
本公开的四价抗体药物偶联物在癌细胞上多价结合抗原的过程中利用了ADC-靶标复合物的增强的内化能力，这潜在地改善了细胞毒性药物向表达靶标的肿瘤细胞中的递送。
在所述ADC的一些实施方案中，所述两条长链彼此相同，并且所述四条短链彼此相同。在一些实施方案中，所述两条长链可以彼此不同。在一些实施方案中，所述四条短链可以彼此不完全相同。
在所述ADC的一些实施方案中，至少一条或每条所述长链的所述第一片段和所述第二片段具有相同的序列。在一些其他的实施方案中，至少一条或每条所述长链的所述第一片段和所述第二片段可具有不同的序列。
在所述ADC的一些实施方案中，每条所述长链包括具有天然人IgG1、IgG2、IgG4同种型之一的CH2-CH3结构域序列的子序列，所述子序列位于所述第一片段和所述第二片段之间。
在所述ADC的一些实施方案中，每条所述长链包含位于所述第一片段和所述第二片段之间的子序列，所述子序列包含人IgG1同种型的CH2-CH3(或Fc)结构域，其中该Fc结构域可包括一个或多个突变，以用于Fc结构域功能的期望的改善。
在所述ADC的一些实施方案中，至少一条或每条所述短链包括天然人IgG抗体同种型的VL-CL(λ)或VL-CL(κ)的序列。
在所述ADC的一些实施方案中，至少一条或每条所述短链包括VH-CH1的序列，其中CH1是人IgG抗体同种型。所述序列的所述VH部分可包含一个或多个突变。
在所述ADC的一些实施方案中，至少一条所述长链的至少一个所述第一片段或所述第二片段包括天然人IgG1、IgG2或IgG4抗体同种型的VL-CL(κ)序列。
在所述ADC的一些实施方案中，所述长链各自包含选自SEQ ID NO:3、5和9组成的组中的序列，而所述短链各自包含选自SEQ ID NO:4、6和10组成的组中的序列。
在所述ADC的一些实施方案中，每条所述长链的所述第一片段和所述第二片段各自包含选自SEQ ID NO:25、26、27、28、29、30、31、32、33和34组成的组中的序列。
在所述ADC的一些实施方案中，每条所述长链的所述第一片段和所述第二片段各自包含选自由：
(1)一种抗原结合序列，其包含(1a)包含序列如SEQ ID NO:35所示的CDR1，(1b)包含序列如SEQ ID NO:36所示的CDR2，和(1c)包含序列如SEQ ID NO:37所示的CDR3；
(2)一种抗原结合序列，其包含(2a)包含序列如SEQ ID NO:38所示的CDR1，(2b)包含序列如SEQ ID NO:39所示的CDR2和(2c)包含序列如SEQ ID NO:40所示的CDR3；
(3)一种抗原结合序列，其包含(3a)包含序列如SEQ ID NO:41所示的CDR1，(3b)包含序列如SEQ ID NO:42所示的CDR2，和(3c)包含序列如SEQ ID NO:43所示的CDR3；
(4)一种抗原结合序列，其包含(4a)包含序列如SEQ ID NO:44所示的CDR1，(4b)包含序列如SEQ ID NO:45所示的CDR2，和(4c)包含序列如SEQ ID NO:46所示的CDR3；
(5)一种抗原结合序列，其包含(5a)包含序列如SEQ ID NO:47所示的CDR1，(5b)包含序列如SEQ ID NO:48所示的CDR2，和(5c)包含序列如SEQ ID NO:49所示的CDR3；
(6)一种抗原结合序列，其包含(6a)包含序列如SEQ ID NO:50所示的CDR1，(6b)包含序列如SEQ ID NO:51所示的CDR2，和(6c)包含序列如SEQ ID NO:52所示的CDR3。
(7)一种抗原结合序列，其包含(7a)包含序列如SEQ ID NO:53所示的CDR1，(7b)包含序列如SEQ ID NO:54所示的CDR2，和(7c)包含序列如SEQ ID NO:55所示的CDR3；
(8)一种抗原结合序列，其包含(8a)包含序列如SEQ ID NO:56所示的CDR1，(8b)包含序列如SEQ ID NO:57所示的CDR2，和(8c)包含序列如SEQ ID NO:58所示的CDR3。
(9)一种抗原结合序列，其包含(9a)包含序列如SEQ ID NO:59所示的CDR1，(9b)包含序列如SEQ ID NO:60所示的CDR2，和(9c)包含序列如SEQ ID NO:61所示的CDR3；以及
(10)一种抗原结合序列，其包含(10a)包含序列如SEQ ID NO:62所示的CDR1，(10b)包含序列如SEQ ID NO:63所示的CDR2，和(10c)包含序列如SEQ ID NO:64所示的CDR3组成的组中的序列。
在所述ADC的一些实施方案中，每条所述短链的所述第一片段和所述第二片段各自包含选自SEQ ID NO:25、26、27、28、29、30、31、32、33和34组成的组中的序列。
在所述ADC的一些实施方案中，每条所述短链的所述第一片段和所述第二片段各自包含选自由：
(1)一种抗原结合序列，其包含(1a)包含序列如SEQ ID NO:35所示的CDR1，(1b)包含序列如SEQ ID NO:36所示的CDR2，和(1c)包含序列如SEQ ID NO:37所示的CDR3；
(2)一种抗原结合序列，其包含(2a)包含序列如SEQ ID NO:38所示的CDR1，(2b)包含序列如SEQ ID NO:39所示的CDR2和(2c)包含序列如SEQ ID NO:40所示的CDR3；
(3)一种抗原结合序列，其包含(3a)包含序列如SEQ ID NO:41所示的CDR1，(3b)包含序列如SEQ ID NO:42所示的CDR2，和(3c)包含序列如SEQ ID NO:43所示的CDR3；
(4)一种抗原结合序列，其包含(4a)包含序列如SEQ ID NO:44所示的CDR1，(4b)包含序列如SEQ ID NO:45所示的CDR2，和(4c)包含序列如SEQ ID NO:46所示的CDR3；
(5)一种抗原结合序列，其包含(5a)包含序列如SEQ ID NO:47所示的CDR1，(5b)包含序列如SEQ ID NO:48所示的CDR2，和(5c)包含序列如SEQ ID NO:49所示的CDR3；
(6)一种抗原结合序列，其包含(6a)包含序列如SEQ ID NO:50所示的CDR1，(6b)包含序列如SEQ ID NO:51所示的CDR2，和(6c)包含序列如SEQ ID NO:52所示的CDR3。
(7)一种抗原结合序列，其包含(7a)包含序列如SEQ ID NO:53所示的CDR1，(7b)包含序列如SEQ ID NO:54所示的CDR2，和(7c)包含序列如SEQ ID NO:55所示的CDR3；
(8)一种抗原结合序列，其包含(8a)包含序列如SEQ ID NO:56所示的CDR1，(8b)包含序列如SEQ ID NO:57所示的CDR2，和(8c)包含序列如SEQ ID NO:58所示的CDR3。
(9)一种抗原结合序列，其包含(9a)包含序列如SEQ ID NO:59所示的CDR1，(9b)包含序列如SEQ ID NO:60所示的CDR2，和(9c)包含序列如SEQ ID NO:61所示的CDR3；以及
(10)一种抗原结合序列，其包含(10a)包含序列如SEQ ID NO:62所示的CDR1，(10b)包含序列如SEQ ID NO:63所示的CDR2，和(10c)包含序列如SEQ ID NO:64所示的CDR3组成的组所示的序列。
在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:25所示的序列，并且每条所述短链包含如SEQ ID NO:26所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:26所示的序列，并且每条所述短链包含如SEQ ID NO:25所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:27所示的序列，并且每条所述短链包含如SEQID NO:28所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:28所示的序列，并且每条所述短链包含如SEQ ID NO:27所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:29所示的序列，并且每条所述短链包含如SEQ ID NO:30所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:30所示的序列，并且每条所述短链包含如SEQ ID NO:29所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:31所示的序列，并且每条所述短链包含如SEQ ID NO:32所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:32所示的序列，并且每条所述短链包含如SEQ ID NO:31所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:33所示的序列，并且每条所述短链包含如SEQ ID NO:34所示的序列。在一些实施方案中，每条所述长链包含如SEQ ID NO:34所示的序列，并且每条所述短链包含如SEQ ID NO:33所示的序列。
在所述ADC的一些实施方案中，每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:35、SEQ ID NO:36和SEQ ID NO:37所示的序列，并且每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ IDNO:38、SEQ ID NO:39和SEQ ID NO:40所示的序列。在所述ADC的一些实施方案中，每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:35、SEQID NO:36和SEQ ID NO:37所示的序列，并且每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:38、SEQ ID NO:39和SEQ ID NO:40所示的序列。
在所述ADC的一些实施方案中，每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:41、SEQ ID NO:42和SEQ ID NO:43所示的序列，并且每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ IDNO:44、SEQ ID NO:45和SEQ ID NO:46所示的序列。在所述ADC的一些实施方案中，每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:41、SEQID NO:42和SEQ ID NO:43所示的序列，并且每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:44、SEQ ID NO:45和SEQ ID NO:46所示的序列。
在所述ADC的一些实施方案中，每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:47、SEQ ID NO:48和SEQ ID NO:49所示的序列，并且每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ IDNO:50、SEQ ID NO:51和SEQ ID NO:52所示的序列。在所述ADC的一些实施方案中，每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:47、SEQID NO:48和SEQ ID NO:49所示的序列，并且每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:50、SEQ ID NO:51和SEQ ID NO:52所示的序列。
在所述ADC的一些实施方案中，每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:53、SEQ ID NO:54和SEQ ID NO:55所示的序列，并且每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ IDNO:56、SEQ ID NO:57和SEQ ID NO:58所示的序列。在所述ADC的一些实施方案中，每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:53、SEQID NO:54和SEQ ID NO:55所示的序列，并且每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:56、SEQ ID NO:57和SEQ ID NO:58所示的序列。
在所述ADC的一些实施方案中，每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:59、SEQ ID NO:60和SEQ ID NO:61所示的序列，并且每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ IDNO:62、SEQ ID NO:63和SEQ ID NO:64所示的序列。在所述ADC的一些实施方案中，每条所述短链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:59、SEQID NO:60和SEQ ID NO:61所示的序列，并且每条所述长链包括包含三个CDR区的抗原结合序列，所述三个CDR区分别包含如SEQ ID NO:62、SEQ ID NO:63和SEQ ID NO:64所示的序列。
在所述ADC的一些实施方案中，每条所述短链包含选自SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ ID NO:20、SEQ ID NO:22和SEQ ID NO:24组成的组中的序列。
在所述ADC的一些实施方案中，每条所述长链包含选自SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:17、SEQ ID NO:19、SEQ ID NO:21和SEQ ID NO:23组成的组中的序列。
在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:1所示的序列，并且每条所述短链包含如SEQ ID NO:2所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:3所示的序列，并且每条所述短链包含如SEQ ID NO:4所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:5所示的序列，并且每条所述短链包含如SEQ ID NO:6所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:7所示的序列，并且每条所述短链包含如SEQ ID NO:8所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:9所示的序列，并且每条所述短链包含如SEQ ID NO:10所示的序列。
在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:11所示的序列，并且每条所述短链包含如SEQ ID NO:12所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:13所示的序列，并且每条所述短链包含如SEQ ID NO:14所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:15所示的序列，并且每条所述短链包含如SEQ ID NO:16所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:17所示的序列，并且每条所述短链包含如SEQ ID NO:18所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:19所示的序列，并且每条所述短链包含如SEQ ID NO:20所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:21所示的序列，并且每条所述短链包含如SEQ ID NO:22所示的序列。在所述ADC的一些实施方案中，每条所述长链包含如SEQ ID NO:23所示的序列，并且每条所述短链包含如SEQ ID NO:24所示的序列。
在一些实施方案中，本公开提供了一种ADC，其包含通过化学接头与细胞毒性药物偶联的单克隆抗体，其中所述单克隆抗体包含两条相同的长链和四条相同的短链，其中：
(a)每条所述长链包含如SEQ ID NO:1所示的序列，并且每条所述短链包含如SEQID NO:2所示的序列；或者
(b)每条所述长链包含如SEQ ID NO:3所示的序列，并且每条所述短链包含如SEQID NO:4所示的序列；或者
(c)每条所述长链包含如SEQ ID NO:5所示的序列，并且每条所述短链包含如SEQID NO:6所示的序列；或者
(d)每条所述长链包含如SEQ ID NO:7所示的序列，并且每条所述短链包含如SEQID NO:8所示的序列；或者
(e)每条所述长链包含如SEQ ID NO:9所示的序列，并且每条所述短链包含如SEQID NO:10所示的序列；或者
(f)每条所述长链包含如SEQ ID NO:11所示的序列，并且每条所述短链包含如SEQID NO:12所示的序列；或者
(g)每条所述长链包含如SEQ ID NO:13所示的序列，并且每条所述短链包含如SEQID NO:14所示的序列；或者
(h)每条所述长链包含如SEQ ID NO:15所示的序列，并且每条所述短链包含如SEQID NO:16所示的序列；或者
(i)每条所述长链包含如SEQ ID NO:17所示的序列，并且每条所述短链包含如SEQID NO:18所示的序列；或者
(j)每条所述长链包含如SEQ ID NO:19所示的序列，并且每条所述短链包含如SEQID NO:20所示的序列；或者
(k)每条所述长链包含如SEQ ID NO:21所示的序列，并且每条所述短链包含如SEQID NO:22所示的序列；或者
(1)每条所述长链包含如SEQ ID NO:23所示的序列，并且每条所述短链包含如SEQID NO:24所示的序列。
在所述ADC的一些实施方案中，所述第二片段通过柔性肽接头与所述长链的其余部分连接，所述柔性肽接头包括(GxS)y序列的一个或多个重复单元，其中x为1到6(包含)之间的整数，而y是0到8(包含)之间的整数。
在一些实施方案中，所述抗原是HER2、EGFR、cMet或其他抗原，并且所述ADC包含四个均与EGFR特异性结合的抗原结合片段结构域。
在所述ADC的一些实施方案中，所述细胞毒性药物选自单甲基澳瑞他汀E(MMAE)、单甲基澳瑞他汀F(MMAF)、澳瑞他汀E、澳瑞他汀F、美登素DM1和DM4、美登木醇、山卓霉素、吡咯并苯并二氮杂卓二聚体、蒽环类、加利车霉素、尾海兔素10、杜卡霉素、阿霉素、泰兰抑菌素A、uncialamycin、甘露糖苷、蓖麻毒蛋白、白喉毒素、艾瑞布林、131I、白细胞介素、肿瘤坏死因子、趋化因子和纳米颗粒组成的组。在一个实施方案中，所述细胞毒性药物是MMAE。在一实施方案中，所述细胞毒性药物是MMAF。在一个实施方案中，所述细胞毒性药物是DM1。在一个实施方案中，所述细胞毒性药物是DM4。
连接抗体部分和细胞毒性药物的化学接头可以是可裂解的或不可裂解的。在一些实施方案中，所述接头包括PEGn，其中n在1至20之间(即，具有1-20个重复单元(CH2CH2O))。在一些实施方案中，所述化学接头还包括连接所述PEGn间隔子的肽接头。在一些实施方案中，所述化学接头包括肽接头，但不包括PEGn间隔子。所述肽接头可以选自6-马来酰亚胺基己酰基(MC)、马来酰亚胺基丙酰基(MP)、缬氨酸-瓜氨酸(val-cit)、丙氨酸-苯丙氨酸(ala-phe)、对氨基苄氧羰基(PAB)、N-琥珀酰亚胺基4-(2-吡啶硫基)戊酸酯(SPP)、N-琥珀酰亚胺基4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(SMCC)、N-琥珀酰亚胺基(4-碘-乙酰基)氨基苯甲酸酯(SIAB)、6-马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苄氧基羰基(MC-vc-PAB)、Val-Cit-PABC，N-琥珀酰亚胺基-4-(2-吡啶基二硫代)丁酸酯(SPDB)、N-琥珀酰亚胺基3-(吡啶-2-基二硫代)-丙酸酯(SPDP)、Phe-Lys(Fmoc)-PAB、Aloc-D-Ala-Phe-Lys(Aloc)-PAB-PNP、Boc-Phe-(Alloc)Lys-PAB-PNP和全氟苯基3-(吡啶-2-基二硫烷基)丙酸酯组成的组。
在所述ADC的一些实施方案中，所述药物-接头可通过半胱氨酸偶联、胺偶联、末端偶联、酶促偶联或碳水化合物偶联与四聚体连接。
在所述ADC的一些实施例中，所述药物抗体比在1与12(包含)之间。在一些实施方案中，所述药物抗体比为约3或4。
在如本文所述的ADC的各种实施方案中，本公开还提供了其药学上可接受的盐。
在另一方面，本公开提供了一种药物组合物，其包含ADC或其药学上可接受的盐和药学上可接受的载体。
在另一方面，本公开提供了一种方法，通过向受试者施用有效量的本文所述的药物组合物来治疗增生性疾病、紊乱或病症。所述增生性疾病可以是癌症，例如结肠癌、直肠癌、肺癌、乳腺癌、卵巢癌、子宫颈癌、膀胱癌、食道癌、肉瘤和头颈癌。本公开还提供了一种方法，所述方法治疗与EGRF、HER2或c-MET相关的疾病、紊乱或病症，比如增生性疾病、紊乱或病症例如癌症的方法。
在另一方面，本公开提供了编码本发明的抗体、或抗原结合部分的核酸分子。本发明还涵盖重组表达载体，所述重组表达载体包含编码本发明抗体的核酸；以及宿主细胞，所述宿主细胞被此类载体转染；以及通过培养此类宿主细胞制备本发明所述抗体的方法；例如，一种表达载体，所述表达载体包含编码抗体2F8的重链和轻链的可变区和恒定区的核苷酸序列，所述抗体2F8由杂交瘤产生。
本公开还提供了能够产生本发明所述单克隆抗体的哺乳动物细胞，所述单克隆抗体与目的靶标特异性结合。在一个实施方案中，所述杂交瘤包括与永生细胞融合的B细胞，所述B细胞获自转基因非人动物，例如转基因小鼠；所述转基因小鼠具有包括人重链转基因和人轻链转基因的基因组，所述人重链转基因和人轻链转基因编码本发明的抗体的全部或一部分。
如本文所用的术语“约”是指相对于特定的给定值或(大于或小于)所述给定值高达25％的范围。
如本文所用的术语“癌症”旨在涵盖非转移性癌症和转移性癌症。在本文中，治疗癌症涉及原发性肿瘤和肿瘤转移的治疗。
如本文所用的“治疗”是指试图改变被治疗个体的自然病程的临床干预，其可以包括预防疾病的复发、缓解症状、减弱疾病任何直接或间接的病理学后果、预防转移、疾病减缓疾病进展速度、改善或缓解疾病状况、以及消除或改善预后。
在本公开中，“受试者”是指哺乳动物，例如牛、猫、狗和马、灵长类、小鼠和大鼠。在某些实施方案中，所述哺乳动物是指人。
在本公开中，“有效量”是指在期望的剂量和时间内有效地实现期望的治疗或预防效果的量。物质的所述“治疗有效量”可以根据诸如个体的疾病状态、年龄、性别和体重以及所述物质/分子在个体中引起期望的应答的能力等因素而变化。对于癌症，ADC的所述治疗有效量可以减少癌细胞的数量、减小肿瘤体积、抑制所述癌细胞渗入周围器官、抑制肿瘤转移、抑制肿瘤生长、和/或在某种程度上缓解与癌症有关的一种或多种症状。为了预防或治疗疾病，本公开的ADC的合适剂量将取决于要治疗的疾病的类型、抗体药物偶联物的类型、所述疾病的严重性和进展、所述ADC的施用等。适当地，将所述抗体药物偶联物一次性或通过一系列治疗施用于所述患者。根据疾病的类型和严重程度，施用于所述患者的剂量可以是约1μg/kg-100mg/kg(例如0.1mg/kg-20mg/kg)的ADC，例如或通过一次或多次单独施用或通过连续输注。取决于上述因素，通常日剂量可以在约1μg/kg-100mg/kg或更大的范围内。对于几天或更久的重复给药，视情况而定，通常会继续所述治疗，直到症状出现所需的抑制为止。抗体药物偶联物的示例性剂量可以在约0.05mg/kg至约10mg/kg的范围内。这样，可以将约0.5mg/kg、2.0mg/kg、4.0mg/kg或10mg/kg(或其任何组合)的一种或多种剂量的抗体药物偶联物施用于所述患者。这样的剂量可以间歇地施用，例如每周或每三周施用(例如患者接受约2至约20剂，或，例如约6剂的抗体药物偶联物)。可以施用较高的初始负荷剂量，然后施用较低剂量的一剂或多剂。该疗法的过程很容易通过常规技术和分析进行监测。
当在本公开中使用时，“药学上可接受的载体”包括药学上可接受的载体、赋形剂或稳定剂，其对于暴露于其的细胞或哺乳动物在所采用的剂量和浓度下是无毒的。通常，生理上可接受的载体是pH缓冲水溶液。生理上可接受的载体的示例包括缓冲剂，例如磷酸盐、柠檬酸盐和其他有机酸；抗氧化剂，包括抗坏血酸；低分子量(少于约10个残基)的多肽；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，例如聚乙烯吡咯烷酮；氨基酸，例如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸；单糖、二糖和其他碳水化合物，包括葡萄糖、甘露糖、蔗糖、海藻糖或糊精；螯合剂，例如EDTA；糖醇，例如甘露醇或山梨糖醇；成盐的反离子，例如钠；和/或非离子表面活性剂。
在本公开中，所述载药量或药物抗体比(即ADC中每种抗体的细胞毒性药物模块的平均数目)可以在每抗体1-12个药物的范围内，例如，约1、约2、约3、约4、约5、约6、约7、约8、约9、约10、约11或约12个药物。可以使用不同的连接位点，例如通过重链和轻链之间的链间二硫键、通过铰链区中的重链之间的链间二硫键、在工程化的半胱氨酸、在选定的每条链上的Lys残基、在碳水化合物、末端残基。可以通过常规手段，例如质谱、ELISA分析、和HPLC来验证来自ADC制备的偶联反应的每个抗体的平均药物模块数目。在某些实施方案中，本公开的ADC可以具有从1到大约8、从约4到约12、从约2到约6、从约3到约5、从大约4到大约5、从约3.5到约4.5、约4的载药量。在某些实施方案中，为了产生用于接头与抗体连接的反应性硫醇基，可以在部分或完全还原条件下还原所述抗体以产生反应性的半胱氨酸硫醇基。
在本公开中，所述ADC的所述药学上可接受的盐包括无机酸、羧酸和磺酸的酸加成盐，例如以下酸的盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸。
本公开的所述抗体药物偶联物的所述药学上可接受的盐还包括常规碱的盐，例如碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如钙盐和镁盐)和衍生自氨或含1-16个碳原子的有机胺的铵盐，其中所述有机胺为例如乙胺、二乙胺、三乙胺、乙二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、二甲基氨基乙醇、普鲁卡因、二苯甲酰胺、N-甲基哌啶、N-甲基吗啉、精氨酸、赖氨酸和1,2-乙二胺。
可以用本发明的ADC治疗的与靶标蛋白相关的肿瘤包括具有靶标过度表达的肿瘤。例如，与EGFR有关的肿瘤，包括呼吸道肿瘤(例如小细胞癌和非小细胞癌、支气管癌)；消化道肿瘤(例如食道、胃、胆囊、小肠、大肠、直肠)；内分泌腺和外分泌腺肿瘤(例如甲状腺和甲状旁腺、胰腺和唾液腺)；头和颈部区域的肿瘤(例如喉、下咽、鼻咽、口咽、唇、口腔、舌头和食道)；和/或神经胶质瘤。HER2相关的肿瘤，包括膀胱癌、食道癌、乳腺癌、宫颈癌、胃腺癌等。
本公开的ADC可以与已知的化学治疗剂组合使用以治疗肿瘤。所述化学治疗剂可以是，例如，阿霉素、环磷酰胺和紫杉烷[Taxol和Taxotere]、Xeloda、Gemzar、Navelbine、Tamoxifen、芳香酶抑制剂(Arimidex、Femara、Aromasin)、5-FU加亚叶酸、camptosar、奥沙利铂、顺铂、卡铂、雌莫司汀、Novantrone、泼尼松、Oncovin等，或其组合。
实施例
制备的所述四价抗体总结列表如表1所示。
表1
ID 蛋白结构(长链/短链) SEQ ID No.(长链) SEQ ID No.(短链)
BB01H VHCH1Fc(g1)(G3S)4VHCH1/VLCL(κ) 1 2
BB01E VHCH1Fc(g2)(G3S)4VHCH1/VLCL(λ) 3 4
BB02E VHCH1Fc(g1)(G3S)4VHCH1/VLCL(κ) 5 6
BB03E VHCH1Fc(g1)(G3S)4VHCH1/VLCL(κ) 7 8
BB04E VHCH1Fc(g2)(G3S)1VHCH1/VLCL(κ) 9 10
BB05E VLCL(κ)Fc(g1)(G3S)4VLCL(κ)/VHCH1 11 12
BB02H VHCH1Fc(g1)(G3S)4VHCH1/VLCL(κ) 13 14
BB03H VLCL(κ)Fc(g1)(G3S)4VLCL(κ)/VHCH1 15 16
BB04H VLCL(κ)Fc(g1)(G3S)4VLCL(κ)/VHCH1 17 18
BB06E VLCL(κ)Fc(g1)(G3S)4VLCL(κ)/VHCH1 19 20
BB01M VHCH1Fc(g1)(G3S)4VHCH1/VLCL(κ) 21 22
BB02M VLCL(κ)Fc(g1)(G3S)4VLCL(κ)/VHCH1 23 24
1.四价抗体的制备
使用表1中的序列与选择的稳定同种型融合，以设计并合成示例性四价抗体。在一些实施例中，出于特定目的引入了某些点突变。制备了两种类型的四价抗体，常规形式和转换形式。每种四价抗体包含两条长链和四条短链。对于常规形式，长链的序列包含一条全长重链和同一抗体的完整VH-CH1片段，该片段通过柔性(GS)接头与Fc的C端融合。短链序列与同一抗体的轻链相同。
对于转换形式，长链的序列包含直接与Fc(CH2-CH3)的N端融合的全长轻链(VL-CL)和另一条通过柔性(GS)接头与Fc的C端融合的全长轻链(VL-CL)(同一抗体)。短链的序列包含同一抗体的全长VH-CH1。
为了表达工程化的四价抗体，进行了密码子优化和基因合成。将特定的全长长链和短链DNA分别克隆到单独的pcDNA3质粒中。配对的质粒对HEK293细胞瞬时转染并使用一步Protein A纯化来制备足量的蛋白进行测定。
示例性四价抗体：
(a)BB01H：BB01H以IgG1κ同种型的常规形式制备，其中，其长链包含：VH-CH1-CH2-CH3-(G3S)4-VH-CH1，而短链包含：VL-CL(κ)。如所描述的四价抗体的序列中所使用的，VH、VL、CH1、CH2、CH3指来自其构建四价抗体的前体抗体的结构域或片段。BB01H的长链的序列如SEQ ID NO:1所示。BB01H的短链的序列如SEQ ID NO:2所示。
(b)BB01E：BB01E以IgG2λ同种型的常规形式制备，其中，其长链包含：VH-CH1-CH2-CH3-(G3S)4-VH-CH1(IgG2的CH2-CH3也称为Fc(g2))，而短链包含：VL-CL(λ)。BB01E的长链的序列如SEQ ID NO:3所示。BB01E的短链的序列如SEQ ID NO:4所示。
(c)BB04E：BB04E以IgG2κ同种型的常规形式制备，其中，其长链包含：VH-CH1-CH2-CH3-(G3S)1-VH-CH1，而短链包含：VL-CL(κ)。BB04E的长链的序列如SEQ ID NO:9所示。BB04E的短链的序列如SEQ ID NO:10所示。
(d)BB05E：BB05E以IgG1κ同种型的转换形式制备，其中，其长链包含：VL-CL(κ)-CH2-CH3-(G3S)4-VL-CL(κ)，而短链包含：VH-CH1(IgG1)。BB05E的长链的序列如SEQ ID NO:11所示。BB05E的短链的序列如SEQ ID NO:12所示。
2.四价ADC的制备
四价抗体(BB01E、BB02E、BB03E、BB04E、BB05E)和对照二价抗体(Ctl)通过接头与细胞毒性剂(例如MMAE、DM1)偶联。向在中性pH的磷酸盐缓冲液中的抗体加入TCEP进行部分还原。加入在DMA中的药物-接头(MC-val-cit-PAB-MMAE或MC-DM1)，并使其与四聚体反应以获得期望的药物抗体比(drug-to-antibody ratio,DAR)。
将在磷酸盐缓冲液中的四价抗体加入到在DMA中的OSu-Glu-val-cit-PAB-MMAE中，使其反应以获得期望的DAR。
3.四价抗体和四价ADC的表征
(a)疏水相互作用色谱法(Hydrophobic Interaction Chromatography,HIC)：HIC用于评价ADC中的药物分布和药物与抗体的摩尔比。
通过HIC分析具有低DAR的Ctl-MMAE(二价ADC)、BB01E-MMAE(四价ADC)、以及具有高DAR的BB01E-MMAE，其代表性HIC色谱图如图2所示。对于具有低DAR的Ctl-MMAE(二价ADC)和BB01E-MMAE(四价ADC)，主峰是与2个和4个药物分子相连的抗体(分别为DAR2、DAR4)，次峰是抗体(DAR0)以及与6个和8个药物分子相连的抗体(DAR6、DAR8)。结果表明BB01E-MMAE和Ctl-MMAE具有相似的药物分布和DAR值。具有高DAR的BB01E-MMAE主要包含与8个和10个药物分子相连的抗体(DAR8、DAR10)。
(b)结合
(b1)结合重组表达的靶标蛋白
使用ELISA分析检验和比较四价抗体和对照二价抗体的靶标结合能力(与EGFR或HER2结合)。将四价抗体样品或对照抗体从20μg/mL开始以5倍梯度稀释，总共稀释8个梯度，将四价抗体样品或对照抗体包被在96孔板上，并将板在4℃孵育过夜。使用HRP标记的人靶标蛋白(5ng/mL的EGFR或HER2)作为检测剂，并使用TMB进行比色反应，在MicroplateReader(Molecular Devices，SpectraMax 190)上450/650nm读取板的吸光度，并采用剂量反应曲线形式的四参数逻辑模型进行数据分析。
如图3所示的结果表明，与对照二价抗体相比，所有四价抗体变体以增强的结合能力结合它们的特定靶标蛋白。
(b2)结合表达EGFR的癌细胞
对具有不同表面EGFR水平的几种癌细胞系(MDA-MB-468、NUGC3)进行FACS分析，以分析四价抗体与表达EGFR的细胞系的结合活性，并与二价对照进行比较。简而言之，首先将单细胞悬液用饱和浓度(10μg/mL)的四价抗体样品或对照抗体染色，然后用FITC标记的、作为二抗的抗人kappa抗体染色。
如图4所示的结果表明，四价抗EGFR抗体结合高表达EGFR的MDA-MB468细胞的平均荧光强度(Mean fluorescent intensity,MFI)比二价对照高3-4倍。在低表达EGFR的NUGC3细胞上，MFI差异更大(相差近10倍)。尽管四价抗体上多出的两个拷贝的kappa可能有助于产生更强的信号(两倍)，但四价抗体染色显著更高的MFI(3-10倍)表明，当结合靶标时，四价形式的四个靶向臂提供了比双价形式的两个臂显著更有效的协同效应。当结合低表达EGFR的细胞时，这种协同效应比结合高表达EGFR的细胞更为明显。
(c)内化
在具有不同表面EGFR水平的几种癌细胞系(MDA-MB-468、NUGC3)上分析了四价抗体诱导的抗体-靶标复合物的内化，并与二价对照进行了比较。为了进行分析，首先将单细胞悬液与抗体样品(10μg/mL)在冰上孵育1小时，然后洗涤以去除未结合的抗体。当一份等分试样留在冰上时，将其余等分试样在37℃下孵育不同的时间(0.5、1、2和4小时)。在每个规定的孵育时间结束时，将一份等分细胞从37℃的培养箱中取出并置于冰上。最长的孵育时间结束后，将所有等分试样均用FITC标记的二抗染色，并通过流式细胞仪分析染色的样品。在减去染色对照的MFI背景值后，根据相对于冰上，在37℃下的MFI损失计算受体-抗体复合物的内化。内化百分比计算如下：内化百分比(％)＝(MFI0小时-MFI其他时间)/MFI0小时。
如图5所示的结果表明，在高表达EGFR的MDA-MB-468细胞和低表达EGFR的NUGC3细胞上，内化的四价抗体的百分比均高于二价对照，表明在EGFR阳性的人癌细胞中四价抗体的内化潜力比二价对照抗体显著增强。
对四价ADC和作为对照的常规ADC进行了相似的内化分析。在所有情况下，具有MMAE效应分子或DM1效应分子的四价ADC的内化比常规二价ADC更为有效(图6A-6C)。
(d)细胞毒性
为了研究四价抗体和ADC增强的内化是否将转变为更强的细胞毒性，在基于比色的细胞毒性测定中，评估了具有不同EGFR表达水平的靶标表达癌细胞的体外细胞毒性，并与常规二价ADC进行比较。为了进行测定，将靶标细胞接种到96孔平底组织培养板中，每种细胞系以优化的细胞密度接种并在37℃，5％CO2下孵育过夜(16-20小时)。将ADC样品的梯度稀释液转移至细胞板，并将测定板孵育一段指定的时间(3-5天，取决于细胞系)，以产生更大的杀伤。
如图7A-7C所示结果表明，具有MMAE效应分子或DM1效应分子的各种四价ADC产物相比常规的二价ADC，在结合靶标表达的细胞时具有更强的细胞毒性。
尽管已经详细描述了本发明的特定实施方案，但是本领域技术人员应理解，根据已经公开的所有教导，可以对那些细节进行各种修改和替换，并且所有这些改变都落入本发明的范围内。本发明的全部范围由所附权利要求书及其任何等同形式给出。
序列表
BB01H
链1(长链，SEQ ID NO:1)：
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
链2(短链，SEQ ID NO:2)：
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
BB01E
链1(长链，SEQ ID NO:3)：
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTV
链2(短链，SEQ ID NO:4)：VL-CL(λ):
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
BB02E
链1(长链，SEQ ID NO:5)：
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSDDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSDDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
链2(短链，SEQ ID NO:6)：
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
BB03E
链1(长链，SEQ ID NO:7)：
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSQVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
链2(短链，SEQ ID NO:8)：
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
BB04E
链1(长链，SEQ ID NO:9)：
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSDDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSDDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTV
链2(短链，SEQ ID NO:10)：
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
BB05E
链1(长链，SEQ ID NO:11)：
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
链2(短链，SEQ ID NO:12)：
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSDDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
BB02H
链1(长链，SEQ ID NO:13)：
EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
链2(短链，SEQ ID NO:14)：
DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
BB03H
链1(长链，SEQ ID NO:15)：
DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
链2(短链，SEQ ID NO:16)：
EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
BB04H
链1(长链，SEQ ID NO:17)：
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
链2(短链，SEQ ID NO:18)：
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
BB06E
链1(长链，SEQ ID NO:19)：
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
链2(短链，SEQ ID NO:20)：
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
BB01M
链1(长链，SEQ ID NO:21)：
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
链2(短链，SEQ ID NO:22)：
DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
BB02M
链1(长链，SEQ ID NO:23)：
DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGSGGGSGGGSGGGSDIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
链2(短链，SEQ ID NO:24)：
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
抗体抗原结合位点部分序列
链1(SEQ ID NO:25)(下划线部分表示CDR1、CDR2、CDR3)：
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS
链2(SEQ ID NO:26)(下划线部分表示CDR1、CDR2、CDR3)：
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK
抗体抗原结合位点部分序列
链1(SEQ ID NO:27)(下划线部分表示CDR1、CDR2、CDR3)：
EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS
链2(SEQ ID NO:28)(下划线部分表示CDR1、CDR2、CDR3)：
DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK
抗体抗原结合位点部分序列
链1(SEQ ID NO:29)(下划线部分表示CDR1、CDR2、CDR3)：QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSDDTAIYYCARALTYYDYEFAYWGQGTLVTVSA
链2(SEQ ID NO:30)(下划线部分表示CDR1、CDR2、CDR3)：DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK
抗体抗原结合位点部分序列
链1(SEQ ID NO:31)(下划线部分表示CDR1、CDR2、CDR3)：
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS
链2(SEQ ID NO:32)(下划线部分表示CDR1、CDR2、CDR3)：
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK
抗体抗原结合位点部分序列
链1(SEQ ID NO:33)(下划线部分表示CDR1、CDR2、CDR3)：
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRFNPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTVSS
链2(SEQ ID NO:34)(下划线部分表示CDR1、CDR2、CDR3)：
DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIK
如SEQ ID No:25-34所示的CDR序列
GFNIKDT(SEQ ID NO:35)
YPTNGY(SEQ ID NO:36)
WGGDGFYAMDY(SEQ ID NO:37)
RASQDVNTAVA(SEQ ID NO:38)
SASFLYS((SEQ ID NO:39)
QQHYTTPPT(SEQ ID NO:40)
GFTFTDY(SEQ ID NO:41)
NPNSGG(SEQ ID NO:42)
NLGPSFYFDY(SEQ ID NO:43)
KASQDVSIGVA(SEQ ID NO:44)
SASYRYT(SEQ ID NO:45)
QQYYIYPYT(SEQ ID NO:46)
GFSLTNY(SEQ ID NO:47)
WSGGN(SEQ ID NO:48)
ALTYYDYEFAY(SEQ ID NO:49)
RASQSIGTNIH(SEQ ID NO:50)
YASESIS(SEQ ID NO:51)
QQNNNWPTT(SEQ ID NO:52)
GGSVSSGDY(SEQ ID NO:53)
YYSGN(SEQ ID NO:54)
DRVTGAFDI(SEQ ID NO:55)
QASQDISNYLN(SEQ ID NO:56)
DASNLET(SEQ ID NO:57)
QHFDHLPLA(SEQ ID NO:58)
GYTFTSY(SEQ ID NO:59)
DPSNSD(SEQ ID NO:60)
YRSYVTPLDY(SEQ ID NO:61)
KSSQSLLYTSSQKNYLA(SEQ ID NO:62)
WASTRES(SEQ ID NO:63)
QQYYAYPWT(SEQ ID NO:64)
SEQUENCE LISTING
<110> 百力司康生物医药（杭州）有限公司
<120> 四价抗体药物偶联物及其应用
<130> P21133100W
<150> 63/008,726
<151> 2020-04-11
<150> 16/862,042
<151> 2020-04-29
<160> 64
<170> PatentIn version 3.5
<210> 1
<211> 689
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 1
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly
450 455 460
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
465 470 475 480
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys
485 490 495
Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
500 505 510
Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp
515 520 525
Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr
530 535 540
Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
545 550 555 560
Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp
565 570 575
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
580 585 590
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
595 600 605
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
610 615 620
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
625 630 635 640
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
645 650 655
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
660 665 670
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
675 680 685
Cys
<210> 2
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 2
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 Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 3
<211> 678
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 3
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
210 215 220
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
290 295 300
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ser Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
435 440 445
Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln
450 455 460
Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser
465 470 475 480
Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His
485 490 495
Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile
500 505 510
Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu
515 520 525
Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn
530 535 540
Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu
545 550 555 560
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
565 570 575
Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
580 585 590
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
595 600 605
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
610 615 620
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
625 630 635 640
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe
645 650 655
Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
660 665 670
Lys Val Asp Lys Thr Val
675
<210> 4
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 4
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gln Pro Lys Ala
100 105 110
Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala
115 120 125
Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala
130 135 140
Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys Ala Gly Val
145 150 155 160
Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser
165 170 175
Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr
180 185 190
Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala
195 200 205
Pro Thr Glu Cys Ser
210
<210> 5
<211> 687
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 5
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
450 455 460
Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser
465 470 475 480
Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn
485 490 495
Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
500 505 510
Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe
515 520 525
Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe
530 535 540
Phe Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Ile Tyr Tyr Cys
545 550 555 560
Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln
565 570 575
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
580 585 590
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
595 600 605
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
610 615 620
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
625 630 635 640
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
645 650 655
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
660 665 670
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
675 680 685
<210> 6
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 6
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 7
<211> 687
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 7
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
450 455 460
Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser
465 470 475 480
Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser
485 490 495
Gly Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu
500 505 510
Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro
515 520 525
Ser Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln
530 535 540
Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr
545 550 555 560
Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln
565 570 575
Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
580 585 590
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
595 600 605
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
610 615 620
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
625 630 635 640
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
645 650 655
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
660 665 670
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
675 680 685
<210> 8
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 8
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 Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 9
<211> 666
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 9
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
210 215 220
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu
290 295 300
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ser Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
435 440 445
Ser Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser
450 455 460
Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn
465 470 475 480
Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
485 490 495
Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe
500 505 510
Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe
515 520 525
Phe Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Ile Tyr Tyr Cys
530 535 540
Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln
545 550 555 560
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
565 570 575
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
580 585 590
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
595 600 605
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
610 615 620
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
625 630 635 640
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
645 650 655
Pro Ser Asn Thr Lys Val Asp Lys Thr Val
660 665
<210> 10
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 10
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 11
<211> 671
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 11
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
210 215 220
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Ser Gly Gly Gly Ser Asp Ile Leu Leu Thr Gln Ser
450 455 460
Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
465 470 475 480
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg
485 490 495
Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile
500 505 510
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
515 520 525
Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr
530 535 540
Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys
545 550 555 560
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
565 570 575
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
580 585 590
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
595 600 605
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
610 615 620
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
625 630 635 640
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
645 650 655
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
660 665 670
<210> 12
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 12
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
<210> 13
<211> 688
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 13
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 Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
450 455 460
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
465 470 475 480
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp
485 490 495
Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
500 505 510
Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser
515 520 525
Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala
530 535 540
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
545 550 555 560
Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly
565 570 575
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
580 585 590
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
595 600 605
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
610 615 620
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
625 630 635 640
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
645 650 655
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
660 665 670
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
675 680 685
<210> 14
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 14
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 Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 15
<211> 671
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 15
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 Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
210 215 220
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Ser Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
450 455 460
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
465 470 475 480
Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr
500 505 510
Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
515 520 525
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
530 535 540
Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys
545 550 555 560
Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
565 570 575
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
580 585 590
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
595 600 605
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
610 615 620
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
625 630 635 640
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
645 650 655
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
660 665 670
<210> 16
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 16
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 Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
<210> 17
<211> 671
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 17
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 Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
210 215 220
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Ser Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
450 455 460
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
465 470 475 480
Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr
500 505 510
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe
515 520 525
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
530 535 540
Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys
545 550 555 560
Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
565 570 575
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
580 585 590
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
595 600 605
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
610 615 620
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
625 630 635 640
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
645 650 655
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
660 665 670
<210> 18
<211> 223
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 18
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
<210> 19
<211> 671
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 19
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 Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
210 215 220
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
260 265 270
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
275 280 285
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
290 295 300
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
305 310 315 320
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
325 330 335
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
340 345 350
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
370 375 380
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
385 390 395 400
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
405 410 415
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Ser Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
450 455 460
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
465 470 475 480
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu
500 505 510
Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
515 520 525
Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe
530 535 540
Cys Gln His Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys
545 550 555 560
Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
565 570 575
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
580 585 590
Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
595 600 605
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
610 615 620
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
625 630 635 640
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
645 650 655
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
660 665 670
<210> 20
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 20
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
<210> 21
<211> 687
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 21
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
450 455 460
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
465 470 475 480
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser
485 490 495
Tyr Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
500 505 510
Val Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn
515 520 525
Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala
530 535 540
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
545 550 555 560
Cys Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gln
565 570 575
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
580 585 590
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
595 600 605
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
610 615 620
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
625 630 635 640
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
645 650 655
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
660 665 670
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
675 680 685
<210> 22
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 22
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 Lys Ser Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 23
<211> 683
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 23
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 Lys Ser Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
435 440 445
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Asp
450 455 460
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
465 470 475 480
Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr Ser
485 490 495
Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
500 505 510
Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro
515 520 525
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
530 535 540
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
545 550 555 560
Tyr Ala Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
565 570 575
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
580 585 590
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
595 600 605
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
610 615 620
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
625 630 635 640
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
645 650 655
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
660 665 670
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
675 680
<210> 24
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 24
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
<210> 25
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 25
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 26
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 26
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 Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 27
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 27
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 Thr Asp Tyr
20 25 30
Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe
50 55 60
Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 28
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 28
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 Lys Ala Ser Gln Asp Val Ser Ile Gly
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 29
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 29
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 30
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 30
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 31
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 31
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 32
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 32
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 Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 33
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 33
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 Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 34
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 34
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 Lys Ser Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 35
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 35
Gly Phe Asn Ile Lys Asp Thr
1 5
<210> 36
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 36
Tyr Pro Thr Asn Gly Tyr
1 5
<210> 37
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 37
Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
1 5 10
<210> 38
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 38
Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala
1 5 10
<210> 39
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 39
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 40
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 40
Gln Gln His Tyr Thr Thr Pro Pro Thr
1 5
<210> 41
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 41
Gly Phe Thr Phe Thr Asp Tyr
1 5
<210> 42
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 42
Asn Pro Asn Ser Gly Gly
1 5
<210> 43
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 43
Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr
1 5 10
<210> 44
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 44
Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala
1 5 10
<210> 45
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 45
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 46
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 46
Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr
1 5
<210> 47
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 47
Gly Phe Ser Leu Thr Asn Tyr
1 5
<210> 48
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 48
Trp Ser Gly Gly Asn
1 5
<210> 49
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 49
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr
1 5 10
<210> 50
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 50
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
1 5 10
<210> 51
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 51
Tyr Ala Ser Glu Ser Ile Ser
1 5
<210> 52
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 52
Gln Gln Asn Asn Asn Trp Pro Thr Thr
1 5
<210> 53
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 53
Gly Gly Ser Val Ser Ser Gly Asp Tyr
1 5
<210> 54
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 54
Tyr Tyr Ser Gly Asn
1 5
<210> 55
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 55
Asp Arg Val Thr Gly Ala Phe Asp Ile
1 5
<210> 56
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 56
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 57
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 57
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 58
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 58
Gln His Phe Asp His Leu Pro Leu Ala
1 5
<210> 59
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 59
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 60
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 60
Asp Pro Ser Asn Ser Asp
1 5
<210> 61
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 61
Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr
1 5 10
<210> 62
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 62
Lys Ser Ser Gln Ser Leu Leu Tyr Thr Ser Ser Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 63
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 63
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 64
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 合成的
<400> 64
Gln Gln Tyr Tyr Ala Tyr Pro Trp Thr
1 5

Claims (4)

1.抗体药物偶联物(ADC)或其药学上可接受的盐，其包括：
四价单克隆抗体，所述四价单克隆抗体通过化学接头与细胞毒性药物偶联；
其中，所述单克隆抗体包括：
两条长链和四条短链；其中每条所述长链包括第一片段和第二片段，所述第一片段位于所述长链的N端附近，所述第二片段位于所述长链的C端附近，每个所述第一片段和每个所述第二片段与一条所述短链配对，从而形成抗原结合片段结构域，因此形成对同一抗原具有特异性的四个抗原结合片段结构域；其中：
每条所述长链为如SEQ ID NO:5所示的序列，并且每条所述短链为如SEQ ID NO:6所示的序列；
所述细胞毒性药物为单甲基澳瑞他汀E(MMAE)。
2.如权利要求1所述的ADC或其药学上可接受的盐，其中所述化学接头为6-马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苄氧基羰基(MC-vc-PAB)。
3.如权利要求1所述的ADC或其药学上可接受的盐，其中，所述化学接头包含PEGn间隔子，其中n为1至20之间的整数。
4.如权利要求1所述的ADC或其药学上可接受的盐，其中，所述药物抗体比在1与12(包含)之间。
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