CN106559987A - 预防和/或治疗由于凝血因子viii和/或活化的凝血因子viii活性下降或丧失而发生或进展的疾病的药物组合物 - Google Patents
预防和/或治疗由于凝血因子viii和/或活化的凝血因子viii活性下降或丧失而发生或进展的疾病的药物组合物 Download PDFInfo
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Abstract
发明人发现，通过按照给定的给药方案施用包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性的抗原结合分子的药物组合物，可以更有效地预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病。
Description
技术领域
本发明涉及用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的药物组合物或给药方案。更具体地，本发明涉及包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子的剂量、方案或药物组合物，其用于预防和/或治疗血友病A(hemophiliaA)、获得性血友病A(acquired hemophilia A)、血管性血友病(von Willebrand disease)和其中出现抗凝血因子VIII和/或活化的凝血因子VIII的抑制剂的血友病A。此外，本发明涉及包括关于包含双特异性抗原结合分子的药物组合物的施用的说明的产品。
背景技术
血友病是一种由凝血因子VIII(FVIII)或凝血因子IX(FIX)的先天性缺乏或功能障碍引起的出血性疾病。前者称为血友病A，后者称为血友病B。关于这两种因子的基因位于X染色体上，并且由于遗传缺陷采取X-染色体连锁隐性遗传的形式，99％以上的发生该病的患者是男性。已知流行率大约为10,000例活男性出生中有一例，并且血友病A与血友病B之间的比例约为5∶1。
血友病A的严重性由血液中的FVIII活性定义。将具有少于1％的活性的患者分类为严重型，具有1％以上至小于5％的活性的患者分类为中度型，并且将具有5％以上且少于40％的活性的患者分类为轻度型。占血友病A患者大约一半的严重型患者每月表现数次出血症状，并且，与中度型和轻度型患者相比，这一频率明显是高的。
对于血友病A患者中的出血，通常施用FVIII制剂(按需疗法)。近年来，还预防性地施用FVIII制剂，以防止出血事件(定期的替代疗法；非专利文献1和2)。FVIII制剂在血液中的半衰期约为8-12小时。因此，对于连续的预防，患者每周施用FVIII制剂三次(非专利文献3和4)。在按需治疗中，还以预防出血所需要的定期的时间间隔另外施用FVIII制剂。另外，FVIII制剂主要在家施用，但是由于它们是静脉内施用的，找到血管的困难是一个问题。因此，对于与FVIII制剂相比关于它们的施用具有较小的负担的药剂存在强烈的需求。
偶然地，在血友病A患者中产生针对FVIII的抗体(抑制剂)。此类抑制剂抵消FVIII制剂的作用。对于已经产生了抑制剂的患者(抑制剂患者)中的出血，施用旁路药剂。它们的作用机制不依赖于FVIII功能，即，由活化的凝血因子IX(FIXa)催化凝血因子X(FX)的活化的功能。因此，在一些情形中，旁路药剂不能充分地停止出血。近来，已经获得了表明旁路药剂的定期施用疗法的有效性的结果，但是，与FVIII制剂相比，这还没有产生足以抑制出血的充分效果。因此，与抑制剂的存在无关，对于可以皮下施用的治疗剂，以及可以较不频繁施用的长效治疗剂存在强烈的需求。
近来，作为解决问题的方式，公开了功能上替代FVIII的抗体以及它们的应用(专利文献1，2，3和4，以及非专利文献5，6和7)。
现有技术文献
[专利文献]
[专利文献1]WO 2005/035754
[专利文献2]WO 2005/035756
[专利文献3]WO 2006/109592
[专利文献4]WO 2012/067176
[非专利文献]
[非专利文献1]Blood 58，1-13(1981)
[非专利文献2]Nature 312，330-337(1984)
[非专利文献3]Nature 312，337-342(1984)
[非专利文献4]Biochim.Biophys.Acta 871，268-278(1986)
[非专利文献5]Nature Medicine 18，1570-1574(2012)
[非专利文献6]PLOS ONE 8，1-13(2013)
[非专利文献7]J Thromb Haemost.12，206-213(2014)
发明概述
[发明要解决的问题]
本发明的一个目的是提供一种用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的更有效的药物组合物或给药方案。
[解决问题的方式]
作为专注的研究的结果，本发明人成功地发现了一种药物组合物的更有效的给药方案，所述药物组合物包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子，其用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病。
具体地，本发明涉及用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的药物组合物或给药方案，并且具体地涉及下述：
[1]用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的药物组合物，其中所述组合物包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性的抗原结合分子，其中酸化抗原结合分子以约0.001至100mg/kg的初始剂量施用，并且以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用数次，其中在各次施用之间的时间间隔为至少一天或更久；
[2][1]的药物组合物，其中所述继续剂量是选自由下述组成的组的剂量：与初始剂量相同的剂量，和约为初始剂量的一半、约为三分之一、约为0.3倍、约为四分之一、约为五分之一和约为十分之一的剂量；
[3][2]的药物组合物，其中所述初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg；
[4][2]的药物组合物，其中所述初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg；
[5][2]的药物组合物，其中所述初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg；
[6][1]-[5]中任一项的药物组合物，其中各次施用之间的时间间隔中的至少一个是一周；
[7][1]-[6]中任一项的药物组合物，其中所述疾病选自由下述组成的组：血友病A，获得性血友病A，血管性血友病，和出现抗凝血因子VIII和/或活化的凝血因子VIII的抑制剂的血友病A；
[8][1]-[7]中任一项的药物组合物，其中所述抗原结合分子是下述双特异性抗体，其中第一多肽和第三多肽连接，第二多肽和第四多肽连接：
双特异性抗体，其包含：第一多肽，所述第一多肽是包含SEQ ID NO：20的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：25的氨基酸序列的H链；第三多肽和第四多肽，它们是包含SEQ ID NO：32的氨基酸序列的共有的L链；
[9][1]-[8]中任一项的药物组合物，其中所述抗原结合分子皮下施用；
[10]一种产品，其包含：(i)容器；(ii)在所述容器中的药物组合物，其中所述组合物包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子；和(iii)指示以约0.001至100mg/kg的初始剂量施用所述抗原结合分子和以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用数次的文件，其中各次施用之间的时间间隔是至少一天或更久；
[11][10]的产品，其中所述初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg；
[12][10]或[11]的产品，其中各次施用之间的时间间隔中的至少一个是一周；
[13][10]-[12]中任一项的产品，其还包括附着在所述容器上指示所述药物组合物可以用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的标签；
[14][13]的产品，其中所述标签指示所述药物组合物可以用于治疗血友病A、获得性血友病A、血管性血友病和出现抗凝血因子VIII和/或活化的凝血因子VIII的抑制剂的血友病A；以及
[15][10]-[14]中任一项的产品，其中所述抗原结合分子是下述双特异性抗体，其中第一多肽和第三多肽连接，并且第二多肽和第四多肽连接：
双特异性抗体，其包含：第一多肽，所述第一多肽是包含SEQ ID NO：20的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：25的氨基酸序列的H链；第三多肽和第四多肽，它们是包含SEQ ID NO：32的氨基酸序列的共有的L链。
此外，本发明涉及：
[16]一种用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的方法，所述方法包括以约0.001至100mg/kg的初始剂量施用识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子，并且以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用所述抗原结合分子数次，其中各次施用之间的时间间隔是至少一天或更久；
[17]一种抗原结合分子，其用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病，其中所述双特异性抗原结合分子识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X，然后以约0.001至100mg/kg的初始剂量施用，并且以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用数次，其中各次施用之间的时间间隔是至少一天或更久；以及
[18]抗原结合分子在制备用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的药物组合物中的应用，其中所述双特异性抗原结合分子识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X，并且以约0.001至100mg/kg的初始剂量施用，然后以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用数次，其中各次施用之间的时间间隔是至少一天或更久。
附图简述
图1显示表示在检查1中接受ACE910施用12周的具有抑制剂的患者和不具有抑制剂的患者的出血频率的变化的图表。水平轴上的数字表示参与该检查的患者的编号。
图2显示表示在检查2中接受ACE910施用12周的具有抑制剂的患者和不具有抑制剂的患者的出血频率的变化的图表。水平轴上的数字表示参与该检查的患者的编号。
图3显示表示在检查3中接受ACE910施用12周的具有抑制剂的患者和不具有抑制剂的患者的出血频率的变化的图表。水平轴上的数字表示参与该检查的患者的编号。
实施发明的方式
识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子优选具有在功能上替代凝血因子VIII的活性。
在本发明中，短语“在功能上替代凝血因子VIII”意指凝血因子IX(FIX)或凝血因子IXa(FIXa)以及凝血因子X(FX)被识别，并且促使FIXa活化FX(促使通过FIXa的FXa产生)。例如，可以使用包含FXIa、FX、合成的底物S-2222(合成的FXa的底物)和磷脂的测量系统来评价促使FXa产生的活性。所述测量系统显示疾病的严重性与血友病A病例中的临床症状之间的相关性(Rosen S，Andersson M，Blomback M等人.Clinical applications of achromogenic substrate method for determination of FVIII activity.ThrombHaemost 1985；54：811-23)。
所述抗原结合分子可以按照例如WO2005/035756、WO2006/109592和WO2012/067176中所述的方法获得。具体地，基于抗凝血因子IX和/或活化的凝血因子IX的抗体和抗凝血因子X的抗体的序列，可以利用本领域技术人员已知的基因重组技术产生抗体。基于抗凝血因子IX和/或活化的凝血因子IX的抗体和抗凝血因子X的抗体的序列，可以构建编码抗体的多核苷酸，并且可以将其插入到表达载体中，然后在适当的宿主细胞中表达(例如，参见Co，M.S.等人.，J.Immunol.(1994)152，2968-2976；Better，M.and Horwitz，A.H.，Methods Enzymol.(1989)178，476-496；Pluckthun，A.and Skerra，A.，Methods Enzymol.(1989)178，497-515；Lamoyi，E.，Methods Enzymol.(1986)121，652-663；Rousseaux，J.等人.，Methods Enzymol.(1986)121，663-669；and Bird，R.E.and Walker，B.W，TrendsBiotechnol.(1991)9，132-137)。
所述双特异性抗原结合分子可以从宿主细胞内部或从细胞外部(如从培养基中)分离，并且纯化为基本上纯的和均质的抗体。抗体的分离和纯化可以使用通常用于分离和纯化抗体的方法进行，并且没有限制。例如，可以通过适当选择和组合柱层析柱、滤器、超滤、盐析、溶剂沉淀、溶剂提取、蒸馏、免疫沉淀、SDS-聚丙烯酰胺凝胶电泳、等电聚焦、透析、重结晶等分离和纯化抗体。
本发明的双特异性抗原结合分子包括例如在WO2005/035756、WO2006/109592和WO2012/067176中所述的抗体。
双特异性抗原结合分子包含第一抗原结合位点和第二抗原结合位点，它们可以特异性结合至少两种不同类型的抗原。尽管本发明的双特异性抗原结合分子的第一抗原结合位点和第二抗原结合位点没有特别限制，只要它们分别具有结合凝血因子IX和/或活化的凝血因子IX、和凝血因子X的活性即可，但是实例包括与抗原结合必需的位点，诸如抗体，构架分子(抗体样分子)和肽，以及包含所述位点的片段。构架分子是表现出与靶分子结合的功能的分子，并且可以使用任意多肽，只要其是能够结合至少一种靶抗原的构象稳定的多肽即可。所述多肽的实例包括抗体可变区、纤连蛋白(WO 2002/032925)、蛋白质A结构域(WO1995/001937)、LDL受体A结构域(WO 2004/044011，WO 2005/040229)、锚定蛋白(WO 2002/020565)以及在Nygren等人(Current Opinion in Structural Biology，7：463-469(1997)；和Journal of Immunol Methods，290：3-28(2004))、Binz等人.(Nature Biotech23：1257-1266(2005))和Hosse等人.(Protein Science 15：14-27(2006))中所述的分子。此外，如在Curr Opin Mol Ther.2010Aug；12(4)：487-95和Drugs.2008；68(7)：901-12在所述，也可以使用可以结合靶抗原的肽分子。
例如，可以使用基因重组技术产生双特异性抗原结合分子(例如，参见BorrebaeckCAK和Larrick JW，THERAPEUTIC MONOCLONAL ANTIBODIES，由MACMILLAN PUBLISHERS LTD在联合王国出版，1990)。重组的抗体可以通过从杂交瘤或产生抗体的细胞(如产生抗体的致敏的淋巴细胞)克隆编码抗体的DNAs，将其插入到适当的载体中，然后将其引入到宿主(宿主细胞)中以产生所述抗体而获得。
此外，双特异性抗原结合分子可以不仅包括完整的抗体，而且包括抗体片段和低分子量的抗体，以及修饰的抗体。
例如，抗体片段和低分子量抗体包括双抗体(Dbs)、线性抗体和单链抗体(以下，还表示为scFv)分子。此处，“Fv”片段是最小的抗体片段，并且包含完整抗体识别位点和结合位点。
双特异性抗体包括人抗体，小鼠抗体，大鼠抗体等，并且它们的来源没有限制。它们还可以是遗传改造的抗体，诸如嵌合抗体和人源化的抗体。
用于获得人抗体的方法是已经为人所知的。例如，感兴趣的人抗体或通过用目的抗原免疫携带完整的人抗体全部成员的转基因动物而获得(参见国际公布号WO 93/12227，WO 92/03918，WO 94/02602，WO 94/25585，WO 96/34096，和WO 96/33735)。
遗传修饰的抗体也可以使用已知的方法产生。具体地，例如，嵌合抗体是包含免疫的动物抗体的H链与L链可变区和人抗体的H链与L链恒定区的抗体。嵌合抗体可以通过将编码来源于免疫的动物的抗体的可变区的DNA与编码人抗体恒定区的DNA连接，将其插入到表达载体中，然后将其引入到宿主细胞中产生所述抗体而获得。
人源化的抗体是一种修饰的抗体，其通常也称为改变的人抗体。人源化的抗体通过将来源于免疫动物的抗体的CDR转移到人抗体的互补性决定区而构建。用于产生其的一般的遗传重组技术也是已知的(参见欧洲专利申请公布号EP 239400；国际公布号WO 96/02576；Sato K等人.，Cancer Research 1993，53：851-856；国际公布号WO 99/51743)。
更具体地，本发明的双特异性抗原结合分子是这样的双特异性抗原结合分子，其中第一多肽和第三多肽连接，并且第二多肽和第四多肽连接，并且优选是下述抗体中的任一种：
(a)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：1的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：4的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：9的氨基酸序列的共有L链(Q1-G4k/J268-G4h/L45-k)；
(b)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：1的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ IDNO：5的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：9的氨基酸序列的共有L链(Q1-G4k/J321-G4h/L45-k)；
(c)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：2的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：6的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：8的氨基酸序列的共有L链(Q31-z7/J326-z107/L2-k)；
(d)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：3的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：7的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：9的氨基酸序列的共有L链(Q64-z55/J344-z107/L45-k)；
(e)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：10的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：6的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：30的氨基酸序列的共有L链(Q64-z7/J326-z107/L334-k)；
(f)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：10的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：7的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：33的氨基酸序列的共有L链(Q64-z7/J344-z107/L406-k)；
(g)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：11的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：4的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：33的氨基酸序列的共有L链(Q85-G4k/J268-G4h/L406-k)；
(h)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：11的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：5的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：30的氨基酸序列的共有L链(Q85-G4k/J321-G4h/L334-k)；
(i)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：12的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：21的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：33的氨基酸序列的共有L链(Q153-G4k/J232-G4h/L406-k)；
(j)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：13的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：22的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：29的氨基酸序列的共有L链(Q354-z106/J259-z107/L324-k)；
(k)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：14的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：21的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：33的氨基酸序列的共有L链(Q360-G4k/J232-G4h/L406-k)；
(1)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：15的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：23的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：30的氨基酸序列的共有L链(Q360-z118/J300-z107/L334-k)；
(m)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：16的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：21的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：28的氨基酸序列的共有L链(Q405-G4k/J232-G4h/L248-k)；
(n)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：17的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：27的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：34的氨基酸序列的共有L链(Q458-z106/J346-z107/L408-k)；
(o)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：18的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：25的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：30的氨基酸序列的共有L链(Q460-z121/J327-z119/L334-k)；
(p)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：19的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：24的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：30的氨基酸序列的共有L链(Q499-z118/J327-z107/L334-k)；
(q)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：19的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：24的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：31的氨基酸序列的共有L链(Q499-z118/J327-z107/L377-k)；
(r)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：19的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：27的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：28的氨基酸序列的共有L链(Q499-z118/J346-z107/L248-k)；
(s)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：20的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：25的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：32的氨基酸序列的共有L链(Q499-z121/J327-z119/L404-k)；
(t)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：20的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：26的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：31的氨基酸序列的共有L链(Q499-z121/J339-zl19/L377-k)；以及
(u)包含下述的双特异性抗体：第一多肽，所述第一多肽是包含SEQ ID NO：12的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：35的氨基酸序列的H链；和第三和第四多肽，它们是包含SEQ ID NO：36的氨基酸序列的共有L链(Q153-G4k/J142-G4h/L180-k)。
特别优选(s)的双特异性抗体。
如果需要，本发明用于治疗或预防目的的药物组合物可以通过混合与适当的药用载体、赋形剂等混合而制备，并且制成冻干制剂或溶液制剂。适当的药用载体和赋形剂的实例包括无菌水、生理盐水、稳定剂、辅料、抗氧化剂(如抗坏血酸)、缓冲剂(如磷酸、柠檬酸、组氨酸、和其他有机酸)、杀菌剂、表面活性剂(如PEG和Tween)、螯合剂(如EDTA)和粘合剂。它们还可以包含其他低分子量多肽，蛋白(如血清白蛋白)，明胶，和免疫球蛋白，氨基酸(如甘氨酸、谷氨酰胺、天冬酰胺、谷氨酸、天冬氨酸、甲硫氨酸、精氨酸、和赖氨酸)、糖和碳水化合物(如多糖和单糖)、和糖醇(如甘露醇和山梨醇)。当制备用于注射的水溶液时，例如，可以使用包含葡萄糖和其他辅药(如D-山梨醇，D-甘露糖，D-甘露醇和氯化钠)的生理盐水和等渗溶液，并且可以组合使用适当的增溶剂，如醇(例如，乙醇)，多元醇(如丙二醇和PEG)，和非离子表面活性剂(如聚山梨醇酯80，聚山梨醇酯20，泊洛沙姆188，和HCO-50)。通过在制剂中混合透明质酸酶，可以皮下施用较大的流体体积(Expert Opin Drug Deliv.2007Jul；4(4)：427-40)。此外，本发明的药物组合物可以预先填装在注射器中。同时，可以按照WO 2011/090088所述的方法制备溶液制剂。
如果需要，本发明的抗原结合分子可以包封在微胶囊中(例如，由羟基甲基纤维素、明胶和聚(甲基丙烯酸甲酯)制成的那些)，或制备为胶体药物递送系统(例如，脂质体，白蛋白微球体，微乳液，纳米颗粒和纳米胶囊)(例如，参见“Remington′s PharmaceuticalScience 16th edition”(雷明顿药典第16版)，Oslo Ed.(1980))。制备作为控制释放的药物试剂的药物试剂的方法也是公知的，并且所述方法可以用于本发明的抗原结合分子(Langer等人.，J.Biomed.Mater.Res.15：267-277(1981)；Langer，Chemtech.12：98-105(1982)；U.S.Patent No.3，773，919；European Patent Application Publication No.EP58，481；Sidman等人.，Biopolymers 22：547-556(1983)；EP 133，988)。
本发明的药物组合物可以通过任意适当的途径施用给患者，例如，通过推注注射或在给定期间的连续的输注静脉内施用，肌肉内，腹膜内，脑脊髓内，经皮，皮下，关节内，舌下，滑膜内，口服，通过吸入，局部，或外部施用。优选静脉内施用或皮下施用。
在本发明中，“初始剂量”是指，例如，当第一次将本发明的双特异性抗原结合分子施用给患者时所用的剂量。初始剂量在约0.001mg/kg至约100mg/kg的范围内，并且例如，为约0.001mg/kg，约0.002mg/kg，约0.0025mg/kg，约0.003mg/kg，约0.004mg/kg，约0.005mg/kg，约0.006mg/kg，约0.007mg/kg，约0.0075mg/kg，约0.008mg/kg，约0.009mg/kg，约0.01mg/kg，约0.02mg/kg，约0.025mg/kg，约0.03mg/kg，约0.04mg/kg，约0.05mg/kg，约0.06mg/kg，约0.07mg/kg，约0.075mg/kg，约0.08mg/kg，约0.09mg/kg，约0.1mg/kg，约0.2mg/kg，约0.25mg/kg，约0.3mg/kg，约0.4mg/kg，约0.5mg/kg，约0.6mg/kg，约0.7mg/kg，约0.75mg/kg，约0.8mg/kg，约0.9mg/kg，约1mg/kg，约2mg/kg，约2.5mg/kg，约3mg/kg，约4mg/kg，约5mg/kg，约6mg/kg，约7mg/kg，约7.5mg/kg，约8mg/kg，约9mg/kg，约10mg/kg，约11mg/kg，约12mg/kg，约12.5mg/kg，约13mg/kg，约14mg/kg，约15mg/kg，约16mg/kg，约17mg/kg，约17.5mg/kg，约18mg/kg，约19mg/kg，约20mg/kg，约21mg/kg，约22mg/kg，约22.5mg/kg，约23mg/kg，约24mg/kg，约25mg/kg，约26mg/kg，约27mg/kg，约27.5mg/kg，约28mg/kg，约29mg/kg，约30mg/kg，约35mg/kg，约40mg/kg，约45mg/kg，约50mg/kg，约60mg/kg，约70mg/kg，约75mg/kg，约80mg/kg，约90mg/kg，或约100mg/kg。
“继续剂量”是指，例如，在初始剂量施用后继续施用的剂量。继续剂量几乎与初始剂量相同或少于初始剂量，并且，例如，其几乎与初始剂量相同，或为初始剂量的约1/2，约1/3，约1/4，约1/5，约1/6，约1/7，约1/8，约1/9，约1/10，约1/20，约1/25，约1/30，约1/40，约1/50，约1/60，约1/70，约1/80，约1/90，约1/100，初始剂量的约0.01倍，约0.02倍，约0.03倍，约0.04倍，约0.05倍，约0.06倍，约0.07倍，约0.08倍，约0.09倍，约0.1倍，约0.2倍，约0.25倍，约0.3倍，约0.4倍，约0.5倍，约0.6倍，约0.7倍，约0.8倍，约0.9倍，或约1倍。
只要所述继续剂量几乎与初始剂量相同或低于初始剂量，所述剂量可以在该范围内变化，并且在继续给药期间的多次剂量不必是相同的剂量。例如，剂量可以逐渐减小，或不同的剂量可以任意重复地施用。
优选地，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，或初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg。
更优选地，初始剂量为10mg/kg并且继续剂量为10mg/kg，初始剂量为10mg/kg并且继续剂量为3mg/kg，初始剂量为10mg/kg并且继续剂量为1mg/kg，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，初始剂量为3mg/kg并且继续剂量为3mg/kg，初始剂量为3mg/kg并且继续剂量为1mg/kg，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，初始剂量为1mg/kg并且继续剂量为1mg/kg，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，或初始剂量为1mg/kg并且继续剂量为0.1mg/kg。
除了mg/kg之外，剂量可以以固定的剂量(mg/体重)和/或与前述基于体重的剂量相对应的基于身体表面积的剂量(mg/m2)表示。
继续施用的继续剂量的次数没有特别限制，并且次数为，例如，一次，两次，三次，四次，五次，六次，七次，八次，九次，十次，15次，20次，25次，35次，40次，50次，60次，70次，80次，90次，100次，500次，1000次，和10000次。
“施用的时间间隔”(在各次施用之间的时间间隔)表示在初始剂量施用与第一次继续剂量施用之间的时间间隔，和在第n次继续剂量施用(n是1或更大的整数)与第(n+1)次继续剂量的施用之间的时间间隔。施用的时间间隔可以是一天以上，例如，2天，3天，4天，5天，6天，1周，2周，3周，4周，5周，6周，7周，8周，9周，10周，11周，12周，13周，14周，15周，16周，17周，18周，19周，20周，21周，22周，23周，24周，25周，1个月，2个月，3个月，4个月，5个月，6个月，7个月，8个月，9个月，10个月，11个月，或1年。施用的时间间隔可以以不同的术语表示，诸如一天一次，每2天一次，每3天一次，每4天一次，每5天一次，每6天一次，每周一次，每2周一次，每3周一次，每4周一次，每5周一次，每6周一次，每7周一次，每8周一次，每9周一次，每10周一次，每11周一次，每12周一次，每13周一次，每14周一次，每15周一次，每16周一次，每17周一次，每18周一次，每19周一次，每20周一次，每21周一次，每22周一次，每23周一次，每24周一次，每25周一次，每月一次，每2个月一次，每3个月一次，每4个月一次，每5个月一次，每6个月一次，每7个月一次，每8个月一次，每9个月一次，每10个月一次，每11个月一次，或一年一次。此外，施用的时间间隔可以以其他术语表示，诸如每天，每2天，每3天，每4天，每5天，每6天，每周，每2周，每3周，每4周，每5周，每6周，每7周，每8周，每9周，每10周，每11周，每12周，每13周，每14周，每15周，每16周，每17周，每18周，每19周，每20周，每21周，每22周，每23周，每24周，每25周，每月，每2个月，每3个月，每4个月，每5个月，每6个月，每7个月，每8个月，每9个月，每10个月，每11个月，或每年。
在初始剂量施用与第一次继续剂量施用之间的时间间隔和在第n次继续剂量施用(n是1或更大的整数)与第(n+1)次继续剂量施用之间的时间间隔可以都是相同的；然而，它们不必全部相同。例如，在初始剂量施用与第一次继续剂量施用之间的时间间隔可以长于在第n次继续剂量施用与第(n+1)次继续剂量施用之间的时间间隔；或在初始剂量施用与第一次继续剂量施用之间的时间间隔可以短于在第n次继续剂量施用与第(n+1)次继续剂量施用之间的时间间隔。此外，在第n次继续剂量施用与第(n+1)次继续剂量施用之间的时间间隔与在第m次继续剂量施用(m是1或更大的整数)与第(m+1)次继续剂量施用之间的时间间隔可以是相同的或不同的。例如，随着继续剂量施用的次数增加，施用的时间间隔可以变得更长或更短。
优选地，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是一周，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是一周，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是一周，初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是2周，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是2周，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是2周，初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是3周，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是3周，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是3周，初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是4周，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是4周，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是4周，初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是1个月，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是1个月，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是1个月，初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg，并且至少一个继续剂量为10mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是2个月，初始剂量为1mg/kg，并且至少一个继续剂量为1mg/kg，并且施用的时间间隔是2个月，初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg，并且施用的时间间隔是2个月，或初始剂量为1mg/kg，并且至少一个继续剂量为0.1mg/kg，并且施用的时间间隔是2个月。
更优选地，初始剂量为10mg/kg并且继续剂量为10mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是一周，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是一周，初始剂量为1mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是一周，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是一周，初始剂量为1mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是一周，初始剂量为10mg/kg并且继续剂量为10mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是2周，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是2周，初始剂量为1mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是2周，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是2周，初始剂量为1mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是2周，初始剂量为10mg/kg并且继续剂量为10mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是3周，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是3周，初始剂量为1mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是3周，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是3周，初始剂量为1mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是3周，初始剂量为10mg/kg并且继续剂量为10mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是4周，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是4周，初始剂量为1mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是4周，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是4周，初始剂量为1mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是4周，初始剂量为10mg/kg并且继续剂量为10mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是1个月，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是1个月，初始剂量为1mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是1个月，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是1个月，初始剂量为1mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是1个月，初始剂量为10mg/kg并且继续剂量为10mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是2个月，初始剂量为10mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg并且继续剂量为3mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是2个月，初始剂量为3mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是2个月，初始剂量为1mg/kg并且继续剂量为1mg/kg，并且施用的时间间隔是2个月，初始剂量为1mg/kg并且继续剂量为0.3mg/kg，并且施用的时间间隔是2个月，或初始剂量为1mg/kg并且继续剂量为0.1mg/kg，并且施用的时间间隔是2个月。
例如，通过考虑效应和安全性确定给药方案。此外，给药方案通过考虑患者的便利性在不损害功效和安全性的范围内确定。例如，用于血友病A患者的给药方案可以通过考虑防止患者出血的效应和临床可接受的安全性来确定。
在本发明中，“几乎相同”意指差异在约20％以下，优选差异在10％以下，或更优选地，差异在5％以下，4％以下，3％以下，2％以下，或1％以下。
例如，由于凝血因子VIII和/或活化的凝血因子VIII(FVIIIa)活性下降或缺乏而发生和/或进展的疾病是血友病A，出现抗FVIII/FVIIIa的抑制剂的血友病A，获得性血友病A，和血管性血友病，但是所述疾病并不特别限于此。
本发明提供一种产品，其至少包含：(i)容器；(ii)在所述容器中的药物组合物，所述组合物包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子；和(iii)指示以约0.001至100mg/kg的初始剂量和几乎与所述初始剂量相同或低于所述初始剂量的继续剂量、以至少一天或更久的施用时间间隔施用所述抗原结合分子的文件。另外，在所述产品中可以包装标签、注射器、注射器针头、药用介质、酒精浸泡的棉花、胶布绷带等。例如，容器是瓶子、玻璃瓶、或注射器，并且可以由多种材料如玻璃或塑料制成。药物组合物储存在容器中，并且容器嘴用橡胶塞等密封。例如，将指示所述药物组合物用于预防或治疗所选的病理状态的标签附着在容器上。
血友病的治疗是指，例如，通过向实际上表现出出血症状的血友病患者施用所述组合物阻止出血(治疗出血)和/或通过向已经表现出出血的患者施用所述组合物以预先防止出血症状显现而减少出血频率(预防出血)，但不限于此。在某些情形中，出血的治疗和预防可以理解为具有相同的意思。
此处，在患者中检查并作为出血事件次数计数的出血是，例如，需要通过凝血因子制剂止血治疗的出血。凝血因子制剂是指，例如，FVIII制剂和旁路药剂(活化的凝血酶原复合物制剂，重组FVIIa制剂等)。
每年出血的次数(年度出血率(ABR))计算为：(出血事件的次数x365.25)/观察的天数。
本文引用的所有现有技术参考文献通过引用结合在该说明书中。
实施例
本文以下，将参考实施例具体描述本发明，但是不应该解释为限于此。
实施例1：制备识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗体
按照前述非专利文献或专利文献中的说明，制备ACE910(Q499-z121/J327-z119/L404-k)，其是非专利文献(PLoS One.2013；8(2)：e57479)和专利文献(WO 2012/067176)中所述的双特异性抗体(这样的双特异性抗体，其中包含SEQ ID NO：20的氨基酸序列的H链与SEQ ID NO：32的L链连接，并且包含SEQ ID NO：25的氨基酸序列的H链与SEQ ID NO：32的L链连接)。如在所述专利文献中所述，ACE910具有替代凝血因子VIII功能的活性。
实施例2：在健康的成年日本和白人男性中的单次皮下施用研究
将表1所示体积的ACE910单次剂量(μL/kg)皮下施用到Part A(日本人)和Part B(白人)测试药物组中的腹部。ACE910施用溶液以下表所示的浓度(mg/mL)制备，并且以所示的体积(μL/kg)施用。对于0.1mg/kg以下的施用，使用稀释剂(通过用生理盐水溶液将辅助稀释剂稀释约100倍制备)；并且对于0.3mg/kg的施用，使用生理盐水溶液。
表1
在施用后，随访观察进行4周(A-1，A-2)，16周(A-3，B-1)，20周(A-4，B-2)，和24周(A-5，B-3)，并且没有特别观察到严重的副作用。
实施例3：在日本血友病A患者中的开放标签的、个体间、剂量增加的多次皮下施用研究(检查1和2)
选择满足下述标准的患者作为研究参与者：
(1)患有严重的先天性血友病A的患者；
(2)日本个体；
(3)体重为40kg以上的个体；
(4)在加入之前六个月有出血事件(出血时间、出血部位)和用凝血因子制剂治疗记录的个体；和
(5)在加入时满足下述标准之一的个体：
(a)对于具有抑制剂的患者，在加入前六个月过程中具有六次以上的出血事件的个体；和
(b)对于不具有抑制剂的患者，在加入之前已经接受150次以上的FVIII制剂施用并且在加入前已经使用FVIII制剂进行定期的替代疗法持续六个月的个体。
基于最近的体重测量，将表2所示的ACE910的剂量体积以每周一次的频率重复皮下施用到腹部，持续12周(共12次)。所用的测试药物是在单一小瓶中包含80mg ACE910的1.0mL溶液。
表2
ACE910的剂量、剂量溶液浓度和剂量体积
为了施用0.3mg/kg，用生理盐水溶液将包含80-mg/mL ACE910的溶液调整为具有表2所示的ACE910施用溶液浓度(mg/mL)，然后将其以表2所示的施用体积(μL/kg)施用。每个施用部位可以施用的最大体积设为1.5mL，并且当施用更大的体积时，在两个以上分开的部位进行皮下施用。在ACE910施用期间过程中，中断使用FVIII制剂的定期的替代疗法。
研究在ACE910施用前六个月的出血事件次数和在ACE910施用期间(12周)的出血事件次数。研究需要用FVIII制剂或旁路药剂止血治疗的出血事件。将在ACE910施用前和后的出血事件次数转化为年度出血频率。具体地，年度出血率(ABR)计算为：(出血事件的次数x 365.25)/观察的天数。
检查1的中间分析表明，与没有施用ACE910时相比，没有给与任意针对出血的预防性治疗的抑制剂患者通过ACE910施用表现出年度出血频率的显著降低。并且，在已经给予使用FVIII制剂的定期的替代疗法的非抑制剂患者中，与施用FVIII制剂时相比，通过ACE910施用降低了年度出血频率(图1)。
使用变化的ACE910剂量进行的检查2表明，在没有给予任意抗出血的预防性治疗的抑制剂患者中和在已经给予使用FVIII制剂的定期替代疗法的非抑制剂患者中，通过ACE910施用，年度出血频率都显著降低(图2)。
由于ACE910在血液中具有长半衰期，其施用频率低，其可以皮下施用，其也对抑制剂患者有效，其可以不诱导抑制剂，等等；因此，认为其是突出的药物试剂。
实施例4：在日本血友病A患者中的开放标签的、个体间、剂量增加的多次皮下施用研究(检查3)
按照与实施例3中相同的标准选择患者，进行表3所述的检查3，并且研究年度出血率。
基于最近的体重测量，将表3所示的ACE910剂量体积以每周一次的频率重复皮下施用到腹部，持续12周(共12次)。所用的测试药物是在单一小瓶中包含80mg ACE910的1.0mL溶液。
表3
ACE910的剂量、剂量溶液浓度和剂量体积
施用溶液的制备、出血率的研究等按照实施例3进行。关于检查3，在已经给予使用预防出血出现的旁路药剂的定期施用治疗的抑制剂患者(在ACE910施用前6个月)和已经给予使用FVIII制剂的定期替代疗法的非抑制剂患者(在ACE910施用前6个月)中，通过ACE910施用，年度出血频率都显著下降(图3)。
工业适用性
本发明提供包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子的药物组合物，其作为用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的更有效的药物组合物，或其给药方案。
序列表
<110> 中外制药株式会社
<120> 预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或丧失而发生或进展的疾病的药物组合物
<130> C1-X1404Y1P
<150> JP 2014-127240
<151> 2014-06-20
<150> JP 2014-226988
<151> 2014-11-07
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Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn Arg Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 7
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Lys Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys
85 90 95
Ala Arg Arg Gln Ser Tyr Gly Tyr His Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn Arg Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 8
<211> 213
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<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 Lys Ala Ser Gln Asn Ile Tyr Lys Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Gly Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 9
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 9
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 Asn Ile Tyr Lys Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Pro Pro Leu
85 90 95
Thr 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> 10
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 10
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Gly Gly Ser Thr Tyr Tyr Arg Arg Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser 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 Arg Ala Gly His Asn Phe Gly Ala Gly Trp Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu 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 Leu
435 440 445
<210> 11
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 11
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Gly Gly Ser Thr Tyr Tyr Arg Arg Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Ser 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 Arg Ala Gly His Asn Tyr Gly Ala Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp 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 Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu 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 Leu
435 440 445
<210> 12
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 12
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Pro Ser Gly Gly Ser Thr Tyr Tyr Arg Arg Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser 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 Thr Arg Ala Gly His Asn Tyr Gly Ala Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp 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 Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu 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 Leu
435 440 445
<210> 13
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 13
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Ser Gly His Asn Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Glu 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 Leu
435 440 445
<210> 14
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 14
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Ser Gly His Asn Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp 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 Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu 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 Leu
435 440 445
<210> 15
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 15
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Ser Gly His Asn Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Glu 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
<210> 16
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Ser Gly His Asn Phe Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Trp 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 Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu 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 Leu
435 440 445
<210> 17
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 17
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Ser Gly Lys Ser Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Glu 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 Leu
435 440 445
<210> 18
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Ser Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
<210> 19
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 19
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Glu 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
<210> 20
<211> 448
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 20
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 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 Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 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 Gln Glu
260 265 270
Asp Pro Glu Val Gln 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 Gly Leu Pro Ser Ser 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 Gln Lys 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 Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
<210> 21
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 21
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Gly Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr His Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Cys Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440
<210> 22
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 22
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Gly Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn Arg Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 23
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr His Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn Arg Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 24
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn Arg Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 25
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 25
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 26
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr His Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 27
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 27
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys
85 90 95
Ala Arg Arg Lys Ser Tyr Gly Tyr His Leu Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn Arg Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro
435 440
<210> 28
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<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 Lys Asn Ile Glu Arg Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Pro Pro Leu
85 90 95
Thr 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> 29
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 29
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 Arg Asn Ile Glu Arg Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Arg Ala Asp Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Pro Pro Leu
85 90 95
Thr 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> 30
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 30
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 Arg Asn Ile Glu Arg Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Pro Pro Leu
85 90 95
Thr 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> 31
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 31
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 Arg Asn Ile Glu Arg Gln
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Pro Pro Leu
85 90 95
Thr 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> 32
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<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 Lys Ala Ser Arg Asn Ile Glu Arg Gln
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu
85 90 95
Thr 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> 33
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 33
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 Arg Asn Ile Glu Arg Gln
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu
85 90 95
Thr 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> 34
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<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 Ala Ser Arg Asn Ile Glu Arg Gln
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Arg Ala Asp Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu
85 90 95
Thr 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> 35
<211> 444
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 35
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn
20 25 30
Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe
50 55 60
Gln Asp Arg Val Thr Met Thr Ile Asp Lys Ser Thr Gly Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ser Tyr Gly Tyr Tyr His Asp Glu Trp Gly Glu 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 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 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Cys Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440
<210> 36
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 人工序列
<400> 36
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 Arg Asn Ile Glu Arg Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Pro Pro Leu
85 90 95
Thr 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
Claims (15)
1.用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的药物组合物，其中所述组合物包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子，其中所述抗原结合分子以约0.001至100mg/kg的初始剂量施用，并且以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用数次，其中在各次施用之间的时间间隔为至少一天或更久。
2.权利要求1的药物组合物，其中所述继续剂量是选自由下述组成的组的剂量：与初始剂量相同的剂量，和约为初始剂量的一半、约为三分之一、约为0.3倍、约为四分之一、约为五分之一和约为十分之一的剂量。
3.权利要求2的药物组合物，其中所述初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg。
4.权利要求2的药物组合物，其中所述初始剂量为3mg/kg，并且至少一个继续剂量为1mg/kg。
5.权利要求2的药物组合物，其中所述初始剂量为3mg/kg，并且至少一个继续剂量为3mg/kg。
6.权利要求1-5中任一项的药物组合物，其中各次施用之间的时间间隔中的至少一个是一周。
7.权利要求1-6中任一项的药物组合物，其中所述疾病选自由下述组成的组：血友病A，获得性血友病A，血管性血友病，和出现抗凝血因子VIII和/或活化的凝血因子VIII的抑制剂的血友病A。
8.权利要求1-7中任一项的药物组合物，其中所述抗原结合分子是下述双特异性抗体，其中第一多肽和第三多肽连接，并且第二多肽和第四多肽连接：
双特异性抗体，其包含：第一多肽，所述第一多肽是包含SEQ ID NO：20的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：25的氨基酸序列的H链；第三多肽和第四多肽，它们是包含SEQ ID NO：32的氨基酸序列的共有的L链。
9.权利要求1-8中任一项的药物组合物，其中所述抗原结合分子皮下施用。
10.一种产品，其包含：(i)容器；(ii)在所述容器中的药物组合物，其中所述组合物包含识别凝血因子IX和/或活化的凝血因子IX与凝血因子X和/或活化的凝血因子X的双特异性抗原结合分子；和(iii)指示以约0.001至100mg/kg的初始剂量施用所述抗原结合分子和以几乎与所述初始剂量相同或低于所述初始剂量的继续剂量继续施用数次的文件，其中各次施用之间的时间间隔是至少一天或更久。
11.权利要求10的产品，其中所述初始剂量为1mg/kg，并且至少一个继续剂量为0.3mg/kg。
12.权利要求10或11的产品，其中各次施用之间的时间间隔中的至少一个是一周。
13.权利要求10-12中任一项的产品，其还包括附着在所述容器上指示所述药物组合物可以用于预防和/或治疗由于凝血因子VIII和/或活化的凝血因子VIII活性下降或缺乏而发生和/或进展的疾病的标签。
14.权利要求13的产品，其中所述标签指示所述药物组合物可以用于治疗血友病A、获得性血友病A、血管性血友病和出现抗凝血因子VIII和/或活化的凝血因子VIII的抑制剂的血友病A。
15.权利要求10-14中任一项的产品，其中所述抗原结合分子是下述双特异性抗体，其中第一多肽和第三多肽连接，并且第二多肽和第四多肽连接：
双特异性抗体，其包含：第一多肽，所述第一多肽是包含SEQ ID NO：20的氨基酸序列的H链；第二多肽，所述第二多肽是包含SEQ ID NO：25的氨基酸序列的H链；第三多肽和第四多肽，它们是包含SEQ ID NO：32的氨基酸序列的共有的L链。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014-127240 | 2014-06-20 | ||
| JP2014127240 | 2014-06-20 | ||
| JP2014226988 | 2014-11-07 | ||
| JP2014-226988 | 2014-11-07 | ||
| PCT/JP2015/060171 WO2015194233A1 (ja) | 2014-06-20 | 2015-03-31 | 血液凝固第ｖｉｉｉ因子および／または活性化血液凝固第ｖｉｉｉの活性の低下ないし欠損によって発症および／または進展する疾患の予防および／または治療に用いられる医薬組成物 |
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| Publication Number | Publication Date |
|---|---|
| CN106559987A true CN106559987A (zh) | 2017-04-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580039806.4A Pending CN106559987A (zh) | 2014-06-20 | 2015-03-31 | 预防和/或治疗由于凝血因子viii和/或活化的凝血因子viii活性下降或丧失而发生或进展的疾病的药物组合物 |
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| Country | Link |
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| US (9) | US20170253663A1 (zh) |
| EP (2) | EP3159006A4 (zh) |
| JP (2) | JP6663846B2 (zh) |
| KR (2) | KR20240063162A (zh) |
| CN (1) | CN106559987A (zh) |
| AU (1) | AU2015275440B2 (zh) |
| BR (1) | BR112016029316A2 (zh) |
| CA (1) | CA2951622C (zh) |
| IL (1) | IL249330B (zh) |
| MX (1) | MX2016016380A (zh) |
| MY (1) | MY189333A (zh) |
| RU (1) | RU2721910C2 (zh) |
| SG (2) | SG10201811185YA (zh) |
| TW (2) | TWI831106B (zh) |
| WO (1) | WO2015194233A1 (zh) |
| ZA (1) | ZA201700459B (zh) |
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| EP3689912A1 (en) | 2007-09-26 | 2020-08-05 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substitution in cdr |
| TWI609698B (zh) | 2010-01-20 | 2018-01-01 | Chugai Pharmaceutical Co Ltd | 穩定化的含抗體溶液製劑 |
| MX355060B (es) | 2010-11-17 | 2018-04-03 | Chugai Pharmaceutical Co Ltd | Molecula multiespecifica de union a antigeno que tiene funcion alternativa a la funcion del factor viii de coagulacion sanguinea. |
| DK3050896T3 (da) | 2013-09-27 | 2021-07-19 | Chugai Pharmaceutical Co Ltd | Fremgangsmåde til fremstilling af en polypeptid-heteromultimer |
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| JP7219005B2 (ja) | 2015-12-28 | 2023-02-07 | 中外製薬株式会社 | Ｆｃ領域含有ポリペプチドの精製を効率化するための方法 |
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| CN109661241A (zh) * | 2016-09-06 | 2019-04-19 | 中外制药株式会社 | 使用识别凝血因子ix和/或活化凝血因子ix以及凝血因子x和/或活化凝血因子x的双特异性抗体的方法 |
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| US20210107994A1 (en) * | 2017-03-31 | 2021-04-15 | Public University Corporation Nara Medical University | Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor viii |
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| BR112021012065A2 (pt) | 2018-12-21 | 2021-12-07 | Kymab Ltd | Anticorpo biespecífico que se liga a fixa e fx e catalisa a ativação de fx mediada por fixa; método; anticorpo anti-fixa; anticorpo anti-fx; ácido nucleico isolado; célula hospedeira in vitro; população de células hospedeiras in vitro; kit para produção de um anticorpo biespecífico; método de produção de um anticorpo biespecífico; composição; método para controlar o sangramento em um paciente com hemofilia a; uso de um anticorpo biespecífico; método, composição para uso ou uso; e método para reduzir o desenvolvimento de anticorpos antifármacos inibidores em um paciente com hemofilia a em tratamento com um polipeptídeo que substitui a atividade de fviiia |
| AU2020364698A1 (en) | 2019-10-11 | 2022-04-21 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical composition which can be used for prevention and/or treatment of acquired hemophilia A, and product comprising said pharmaceutical composition |
| WO2021070885A1 (ja) * | 2019-10-11 | 2021-04-15 | 中外製薬株式会社 | 後天性血友病ａの予防および／または治療に用いられる医薬組成物、および当該医薬組成物を含む製品 |
| KR20230130558A (ko) | 2022-03-02 | 2023-09-12 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | Fviii 모방 이중특이적 항체의 월 1회 투여 방법 |
| KR20230130560A (ko) | 2022-03-02 | 2023-09-12 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | Fviii 모방 이중특이적 항체의 주 1회 투여 방법 |
| KR20230130561A (ko) | 2022-03-02 | 2023-09-12 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | Fviii 모방 이중특이적 항체를 2주마다 1회 투여하는 방법 |
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