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CN107438618A - 赋予结合至cd123的嵌合抗原受体用于治疗复发性/难治性急性骨髓性淋巴瘤或母细胞性浆细胞样树突状细胞肿瘤的t细胞受体敲除的工程化免疫细胞 - Google Patents

赋予结合至cd123的嵌合抗原受体用于治疗复发性/难治性急性骨髓性淋巴瘤或母细胞性浆细胞样树突状细胞肿瘤的t细胞受体敲除的工程化免疫细胞 Download PDF

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Publication number
CN107438618A
CN107438618A CN201680006922.0A CN201680006922A CN107438618A CN 107438618 A CN107438618 A CN 107438618A CN 201680006922 A CN201680006922 A CN 201680006922A CN 107438618 A CN107438618 A CN 107438618A
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China
Prior art keywords
seq
cells
epitope
cell
tcr
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CN201680006922.0A
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Inventor
巴尔布拉·约翰逊·萨苏
阿尔温德·拉吉帕欧
菲利普·迪沙泰奥
亚历山大·朱耶拉特
朱利安·瓦尔顿
罗曼·加莱托
马蒂厄·西蒙
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Cellectis SA
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Cellectis SA
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Priority claimed from PCT/EP2015/055848 external-priority patent/WO2015140268A1/en
Application filed by Cellectis SA filed Critical Cellectis SA
Publication of CN107438618A publication Critical patent/CN107438618A/zh
Pending legal-status Critical Current

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Abstract

本发明涉及表达对于能够将免疫细胞特异性和反应性重定向于表达CD123的细胞的重组嵌合蛋白的CD123特异性的嵌合抗原受体(CAR)的TCRKO‑或TCR KO和dCK KO‑工程化的免疫细胞，并且更具体地，其中胞外配体结合是源自CD123单克隆抗体的scFV，其赋予抗CD123阳性细胞的特异性免疫。赋予这种CD123 CAR的工程化免疫细胞特别适用于治疗复发难治性AML和母细胞性浆细胞样树突细胞肿瘤，并用作骨髓移植前的治疗。

Description

赋予结合至CD123的嵌合抗原受体用于治疗复发性/难治性急 性骨髓性淋巴瘤或母细胞性浆细胞样树突状细胞肿瘤的T细 胞受体敲除的工程化免疫细胞
技术领域
本发明一般涉及工程化为表达对于白细胞介素3受体α链(IL-3Ra，分化群123CD123)特异性的嵌合抗原受体(CAR)的TCR基因敲除T细胞及其用途，例如，用于治疗与IL-3Ra，CD123的表达相关的疾病或病症，即急性髓细胞白血病(AML)和原发性浆细胞样树突状细胞肿瘤(BPDCN)。
本发明涉及T细胞受体(TCRα或β基因)和/或人脱氧胞苷激酶(dCK基因或dck基因)敲除(KO)免疫T细胞，其工程化为表达：
-包含至少一个来自可选地人源化的Klon43的胞外配体结合结构域、铰链、细胞内结构域和共刺激结构域的对于分化簇123(CD123)特异性的嵌合抗原受体(CAR)，
-可选地插入所述铰链中的自杀域(suicide domain)，
所述CD123 CAR对于人CD123特异性并赋予抗CD123阳性细胞的特异性免疫，
在一个实施方式中；提供了该目的用于治疗急性髓细胞白血病AML或AML并发症的用途，
在一个实施方式中；通过该目的用于治疗原发性浆细胞样树突状细胞肿瘤(BPDCN)。
在一个实施方式中；通过该目的作为骨髓移植前作为移植过渡的治疗。
与先前的CD123 CAR相比，根据本发明的赋予工程化免疫细胞的CD123 CAR在治疗淋巴瘤和白血病方面表现出高效能，并可以在嘌呤类似物的存在下使用，比以前在患者中的治疗副作用更少。
背景技术
淋巴增生性疾病如白血病，且特别是急性髓细胞白血病(AML)的诱导治疗在近50年内基本保持不变。这种标准诱导化疗可以诱导完全缓解，但许多患者最终会复发并罹难于疾病，需要开发用于AML，特别是复发性难治性AML的新疗法。
对于侵袭性淋巴增殖性疾病如BPDCN，也报道了相似的观察。这些疾病的预后仍然很差。这些癌细胞的免疫表型已经表明，白细胞介素3受体α链(IL-3Rα；CD123-NCBI参考号：NP_001254642)是潜在的免疫疗法靶标，因为它与正常细胞相比会过表达于这些肿瘤细胞上。另外，针对CD123特异性疗法的两个I期临床试验已经完成，其中两种药物都表现出良好的安全特性(ClinicalTrials.gov ID：NCT00401739和NCT00397579)。不幸的是，这些CD123靶向药物具有的功效有限，表明需要可替代的且更有效和特异性的靶向CD123的疗法以观察到抗白血病活性。
用于治疗白血病的可能更有效的替代疗法可以是使用表达以MHC独立的方式选择性地将免疫细胞特异性定向于细胞表面肿瘤相关的抗原(TAA)(Jena，Dotti et al。2010)并将其摧毁的嵌合抗原受体(CAR)的免疫细胞。
CAR是由与单个或多个融合分子中的一个或多个信令结构域相关的靶向部分组成的合成受体。通常，CAR的结合部分由单链抗体(scFv)的抗原结合结构域组成，其包含通过柔性接头连接的单克隆抗体的轻链和可变片段。基于受体或配体结构域的结合部分也已成功应用。第一代CAR的信令结构域源自CD3ζ或Fc受体γ链的细胞质区。已经表明第一代CAR成功地重定向T细胞的细胞毒性，然而，它们未能在体内提供延长的扩增和抗肿瘤活性。来自包括OX-40(CD134)和4-1BB(CD137)的共刺激分子的信令结构域已经单独或组合加入以增强CAR改造的T细胞在体外的存活并提高其增殖。然而，不是所有的结合域的组合都会导致体内可以将免疫细胞定向于靶向细胞的CAR。
在人类癌症的小鼠模型中，CAR可以重新定向抗在肿瘤细胞表面表达的抗原的CAR表达细胞，其中效率取决于每个结构域的性质和长度(Condomine M.et al.，2015 PlosOne 10(6)：e0130518)。迄今为止，单独的表达CAR的特异性T细胞的自体转移已证明在治疗特定形式的癌症方面是成功的，尽管存在多种副作用。如细胞因子风暴，细胞群的非特异性破坏，或不良特异性免疫反应的(Park，Rosenberg et al.，2011)。同种异体CD123 CAR工程化T细胞是否可以安全有效地用于治疗AML仍然未知(ClinicalTrials.gov ID：NCT02159495)。
因此，为了拓展可能受益于这种治疗的患者群体，已经制备所谓的表达CAR的同种异体T细胞，用于其在患癌症的人类中的使用。在这种情况下，从健康供体中分离免疫细胞，工程化，随后用作对其需要的几种不同的所选患者中的治疗。
为了这个目的并降低潜在的移植物抗宿主疾病的风险，将所选择的基因小心地敲除以提供工程化的表达CAR的免疫细胞，其中涉及免疫响应的分子，例如，MHC分子或TCR分子的亚单元的表达降低。这些工程化的细胞在任何宿主中仍然增殖和存活的程度仍然基本未知，特别是在已经用化疗药物治疗的患者中。
使用这种靶向CD123的表达CAR的免疫T细胞与细胞毒性化疗剂组合作为通常用作抗癌治疗的治疗仍然成问题，因为抗癌治疗也会影响T细胞的增殖和/或存活。
因此，还需要开发特异性效果并与使用药物，特别是抗癌化学疗药物，如影响细胞增殖的那些相容的靶向CD123的T细胞，其仍将可以增殖和存活而达到其靶标(癌细胞)。
为了使用“现成”的同种异体治疗细胞与化学疗法相结合，本发明人确定了提供同种异体工程化T细胞，其较不同种异体并是患癌症和/或已经用化疗药剂治疗的患者的免疫系统容许的。治疗益处由所要求保护的对象的化学疗法和免疫疗法之间的协同效应提供。
本发明还涉及抗-CD123嵌合抗原受体(抗-CD123 CAR)，其胞外结合结构域(scFv)以允许细胞分选和细胞消除二者的方式改造。允许其的结构是由单克隆抗体识别的表位(命名为mAb驱动的分选/消除系统或由特异性单克隆抗体或模拟表位识别的表位)，并包含插入到scFv和/或铰链内的胞外结构域中的所选表位。这种表位具有特异性而由特异性抗体(优选单克隆抗体(mAb)，可选地人源化的)识别。考虑到主要将CAR的外部配体结合结构域改造以包括表位的事实，可以设想不同的CAR结构：如PCTUS2013/058005中所公开的单链或多链。
由VH和VL多肽和特异性表位形成的本发明的嵌合scFv本身可以具有不同的结构，取决于表位的插入位置和接头的使用(图3)。本发明还涉及用于分选和/或消除赋予改性CAR的工程化免疫细胞的所获得的方法。
几种表位-mAb配偶体可以用于产生这种系统；特别是已经批准用于医疗用途的那些，如作为非限制性实例的CD20/利妥昔单抗。
最后，本发明涵盖治疗方法，其中赋予抗CD123 CAR的工程化免疫细胞的数目、活性和存活通过使用引导CAR的外部配体结合结构域的抗体消除细胞来调节。
发明内容
白细胞介素3受体α链(CD123)已经被确定为特别是在急性髓细胞白血病(AML)的情况下，与相同谱系的正常细胞相比在白血病肿瘤细胞上频繁过度表达。
本发明人已经产生了工程化为表达CD123特异性CAR的免疫细胞，其包含来自KLON43抗体的scFV，来自FcγRIIIα的铰链和赋予宿主细胞体内增殖、达到CD123靶细胞并改变其存活的能力的细胞内结构域，所述细胞包含一旦靶细胞被包含就允许它们特异性破坏的另外的标记或自杀结构域。这些CD123特异性CAR无差别地标识为CD123特异性CAR或抗CD123 CAR，或123 CAR，或“本发明的CAR”。
在本发明中，使用对这种IL-3受体亚单元特异性的一种抗体，即klon43或源自这种klon43抗体的人源化序列，制备表达特异性和选择性的耐受原TCR KO CD123 CAR的T细胞，用于治疗患有AML、B细胞淋巴增生性疾病(BC-LPD)或BPDCN的患者。
伴随的是，这些细胞允许破坏癌前期细胞，阻止难治性/复发性癌症的进展和出现。由于它们在体内增殖并达到组织或微环境(niche)的能力，这些细胞比癌细胞本身行动更快，并甚至可以根除侵袭性淋巴增殖性疾病。
在体外非特异性活化后(例如，用抗CD3/CD28涂覆的珠和重组IL2)，来自供体的T-细胞已经用本发明的表达CAR的多核苷酸使用病毒转导而转化。通过破坏T细胞受体TCR(αβ-T细胞受体)的组件而减少移植物抗宿主反应，将T细胞进一步工程化而产生较少同种异体反应性的T细胞。
在优选的实施方式中，通过删除表9中确定的基因的特定组合而进一步工程化T细胞，以产生对抗癌药物抗性的耐受原T细胞，以与所述经典抗癌药物，即嘌呤类似物组合使用。
得到的工程化T细胞表现出对CD123阳性细胞的反应性，表明本发明的CAR有助于T细胞的抗原依赖性活化以及增殖，使其对免疫疗法有用。
得到的工程化T细胞表现出体内抗CD123阳性细胞的反应性，并显著降低了体内癌细胞的数量。
在具体实施方式中，可以进行本发明的工程化T细胞的几次给予，使其作为第一治疗(诱导)，作为巩固治疗，作为与经典抗癌化疗相组合的治疗有用于免疫疗法。
编码本发明的CAR的多肽和多核苷酸序列在本说明书中进行详细描述。
本发明的工程化免疫细胞特别有用于治疗应用，如B细胞淋巴瘤或白血病治疗，并可以从生物体中选择性地消除。
附图说明
图1：根据本发明的工程化免疫细胞的示意图。图中所示的工程化免疫细胞是用编码CAR的逆转录病毒多肽转导的T细胞。这种T细胞进一步工程化以允许更好且更安全地植入患者体内，这是本发明框架的一部分。X基因是表达TCR的组件的基因(TCRα或TCRβ基因)，Y是涉及T细胞对嘌呤类似物敏感性的基因dCK。
图2：包含可选地人源化的CD123 scfv，来自FcRIII或CD8α的铰链，来自CD8α的跨膜结构域和两个来自4-1BB和CD3ζ的细胞内结构域的本发明两种CAR(123CAR)的示意图。
图3：显示根据本发明的CAR的实例。
L：(GGGGS)n的VH和VL之间的接头(SEQ ID NO：10)，其中n＝1至4，优选n＝3
Li：对应于GGGS或SGGGGS或GSGGGGS的接头序列，TM：跨膜结构域。
制备了本发明的包含来自可选地人源化的Klon 43的VH，接头L，来自可选地人源化的Klon 43的VL，自杀结构域(例如，序列CPYSNPSLCS(SEQ ID NO：161)的CD20模拟表位的两个拷贝和SEQ ID NO 169的拷贝)的CD123 CAR，所述模拟表位优选位于scfv，CD8铰链或其部分，来自CD8α的跨膜结构域(CD8 TM)，以及共刺激结构域(4-1BB)和刺激结构域(ITAMCD3ζ)。
在本发明的CD123 CAR中，将相互连接并通过接头Li连接至VL的序列CPYSNPSLCS的CD20模拟表位的两个拷贝插入到抗CD123 scFv和来自CD8α的铰链之间，可选的接头LI将模拟表位连接至铰链(SEQ ID NO160)。
设想了表位(例如scfv中)插入的其他可能性，并如图3中的圆圈所示。
图4：当将CAR+ T细胞与表达CD123的细胞(RPMI8226)，或与不表达CD123的细胞(K562)共培养6小时时，对于一种结构(v3：CD8-铰链/CD8-跨膜)根据本发明的不同scFv的脱粒活性。
图5：与表达不同水平的CD123的细胞(KG1a或RPMI8226)，或与不表达CD123的细胞(K562)共培养24小时时，通过T-细胞的IFNγ释放
图6：用PNA(20mg/kg)腹腔内处理的小鼠体内CAR-T细胞的特异性溶胞活性的剂量响应。
图7：用PNA(20mg/kg)腹腔内处理的小鼠体内CAR-T细胞的特异性溶胞活性的剂量响应。
表1
表2：对于本发明的CD123 CAR在本发明的抗CD123 scfv中使用的来自Klon 43的抗体片段的序列
表3：对于本发明的CD123 CAR在本发明的抗CD123 scfv中使用的来自Klon 43的人源化抗体片段的序列
表4：结构V-1的CAR
表5：结构V-3的CAR
表6：结构V-5的CAR
表7：可以用于本发明的CAR的胞外结构域中的也称为模拟表位的mAb特异性表位(及其相应的mAb)的实例，如例如模拟表位和具有其对应mAb的表位
本发明的抗CD123 CAR的序列(SEQ ID NO：31-160)，优选的序列是SEQ ID NO：31、32、160和34-117，在34-117中更优选的是76-117，更加优选的是SEQ ID NO：32、SEQ ID NO：89、SEQ ID NO：94、SEQ ID NO：95、SEQ ID NO：96、SEQ ID NO：97。
具体实施方式
本发明提供：
1.一种CD123特异性嵌合抗原受体(CD123 CAR)，包含
■胞外结构域，包含胞外配体结合结构域，其依次包含可选地人源化的VH，接头，优选序列(GGGGS)n的接头，其中n＝1至4，优选n＝3，和可选地人源化的VL，铰链，
■跨膜结构域和
■细胞质结构域。
■至少一个对于单克隆抗体特异性的表位(模拟表位)。
2.根据1的CD123 CAR，包含
■胞外结构域，包含胞外配体结合域，其依次包括选自SEQ ID NO 12、SEQ ID NO24、SEQ ID NO 25、SEQ ID NO 26、SEQ ID NO 27、SEQ ID NO 28、SEQ ID NO 29和SEQ IDNO 30的可选地人源化的VH，接头，优选序列(GGGGS)n的接头，其中n＝1-4，优选n＝3，选自SEQ ID NO 11、SEQ ID NO 18、SEQ ID NO 19、SEQ ID NO 20、SEQ ID NO 21、SEQ ID NO 22和SEQ ID NO 23的可选地人源化的VL，铰链，
■来自CD8α的跨膜结构域
■包含CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域。
3.根据1或2的CD123 CAR，其不包含与人CD28 NP_006130.1具有一致性的序列。
4.根据1至3中任一项的CD123 CAR，其包含选自SEQ ID NO 172、SEQ ID NO 173、SEQ ID NO 174、SEQ ID NO 175、SEQ ID NO 176、SEQ ID NO 177、SEQ ID NO 178、SEQ IDNO 179、SEQ ID NO 180、SEQ ID NO 181、SEQ ID NO 182、SEQ ID NO 183、SEQ ID NO 184、SEQ ID NO 185、SEQ ID NO 186和SEQ ID NO 187的序列，可选地进一步包含至少一个SEQID N°161。
5.根据1至4中任一项的CD123 CAR，其中所述胞外结构域包含至少一个对单克隆抗体特异性的表位(模拟表位)，选自由SEQ ID NO 161、SEQ ID NO 162、SEQ ID NO 163、SEQ ID NO 164、SEQ ID NO 165、SEQ ID NO 166、SEQ ID NO 167、SEQ ID NO 168、SEQ IDNO 169和SEQ ID NO 170组成的列表，优选SEQ ID NO 161和SEQ ID NO 169。
6.根据1至5中任一项的CD123 CAR，包含选自SEQ ID NO 160、SEQ ID NO 171、SEQID NO 188、SEQ ID NO 189、SEQ ID NO 190、SEQ ID NO 191、SEQ ID NO 192、SEQ ID NO193、SEQ ID NO 194、SEQ ID NO 195、SEQ ID NO 196和SEQ ID NO 197的序列。
7.一种编码根据权利要求1至6中任一项所述的CD123特异性嵌合抗原受体(CD123CAR)的多核苷酸。
8.一种包含根据权利要求7所述的多核苷酸的表达载体。
9.一种包含骨架和至少一个编码权利要求1至6中任一项中限定的任意一种CD123CAR的序列的表达载体。
10.一种表达载体，包含骨架、EF1启动子、RQR8开放阅读框(RQR8ORF)、编码1至6中任一项的CD123 CAR的序列。
11.一种在细胞表面膜表达根据1至6中任一项的CD123 CAR的T细胞受体(TCR)敲除(KO)或TCR和人脱氧胞苷激酶(dCK)KO工程化的免疫细胞。
12.一种包含编码根据1至6中任一项的CD123特异性嵌合抗原受体(CD123 CAR)的多核苷酸的TCR KO或TCR和dCK KO工程化的免疫细胞。
13.一种在细胞表面进一步表达自杀结构域的根据4的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化的免疫细胞。
14.根据11至13中任一项的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，其中至少一种MHC蛋白的表达受到抑制。
15.根据11至14中任一项的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化的免疫细胞，用于治疗。
16.根据15的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化的免疫细胞，其中病症是急性髓细胞白血病(AML)，优选难治/复发性AML，BPDNL，或在骨髓移植期间或之前使用。
17.根据15的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化的免疫细胞，用作治疗，优选用作淋巴增生性病症的治疗，更优选用作淋巴瘤的白血病或用于选自由急性髓细胞白血病，慢性髓细胞白血病，骨髓增生异常综合征，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征和BPDNL组成的组的治疗。
18.根据15的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，用作AML的治疗。
本发明还提供：
1a.编码对包含至少一个胞外结合结构域的CD123特异性的嵌合抗原受体(CAR)的多肽，所述胞外结构域包含至少一个scFv。
所述scfv包含与CD123特异性结合的至少一个VH链和VL链，其中所述细胞外结合结构域包含至少一个mAb特异性表位或模拟表位。
2a.根据1a的多肽，其中所述mAb特异性表位位于VH和VL链之间，或VH和VL之前。
在一个实施方式中，编码CD123特异性的嵌合抗原受体(CAR)的多肽包含跨膜结构域(TM)和铰链，并且mAb-特异性表位位于scfv和铰链之间。
本发明提供：
3a.根据1a或2a的多肽，其中所述VH和VL链和mAb特异性表位通过至少一个接头结合在一起并通过铰链结合至所述CAR的跨膜结构域。
4a.根据3a的多肽，其中mAb表位通过两个接头连接到VH和VL链上。
5a.根据1a至3a中任一项的多肽，其中mAb-特异性表位是由用于体外细胞分选和/或表达包含这种表位的CAR的T细胞的体内细胞消除的表位特异性mAb结合的表位。
6a.根据1a至5a中任一项的多肽，其中多肽包含一个胞外结合结构域，跨膜结构域和胞内结构域，其中所述胞外结合结构域包含至少一个mAb特异性表位。
7a.根据1a至6a中任一项的多肽，其中胞外结合结构域包括1、2、3、4、5、6、7、8、9或10个mAb-特异性表位。
8a.根据1a至7a中任一项的多肽，其中胞外结合结构域包含1、2、3或4个mAb特异性表位。
9a.根据1a至8a中任一项的多肽，其中胞外结合结构域包含2、3或4个mAb特异性表位。
10a.根据1a至9a中任一项的多肽，其中胞外结合结构域包含以下序列。
V1-L1-V2-(L)x-表位1-(L)x-；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2；
表位1-(L)x-表位2-(L)x-表位3-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x-；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-表位4-(L)x-；
V1-(L)x-表位1-(L)x-V2；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2；or，
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2-(L)x-表位3-(L)x；
其中，
V1是VL且V2是VH或V1是VH且V2是VL；
L1是适合于将VH链连接至VL链的接头；
L是包含甘氨酸和丝氨酸残基的接头，且胞外结合结构域中L的每次出现可以与相同的胞外结合结构域中L的其它出现是相同的或不同的，并且
x是0或1，并x的每次出现独立于其它；并且
表位1、表位2和表位3是mAb特异性表位，并可以是相同的或不同的。
11a.根据10a的多肽，其中胞外结合结构域包含以下序列
V1-L1-V2-L-表位1；V1-L1-V2-L-表位1-L；V1-L1-V2-L-表位1-L-表位2；V1-L1-V2-L-表位1-L-表位2-L；V1-L1-V2-L-表位1-L-表位2-L-表位3；V1-L1-V2-L-表位1-L-表位2-L-表位3-L；V1-L1-V2-表位1；V1-L1-V2-表位1-L；V1-L1-V2-表位1-L-表位2；V1-L1-V2-表位1-L-表位2-L；V1-L1-V2-表位1-L-表位2-L-表位3；V1-L1-V2-表位1-L-表位2-L-表位3-L；表位1-V1-L1-V2；表位1-L-V1-L1-V2；L-表位1-V1-L1-V2；L-表位1-L-V1-L1-V2；表位1-L-表位2-V1-L1-V2；表位1-L-表位2-L-V1-L1-V2；L-表位1-L-表位2-V1-L1-V2；L-表位1-L-表位2-L-V1-L1-V2；表位1-L-表位2-L-表位3-V1-L1-V2；表位1-L-表位2-L-表位3-L-V1-L1-V2；L-表位1-L-表位2-L-表位3-V1-L1-V2；L-表位1-L-表位2-L-表位3-L-V1-L1-V2；V1-L-表位1-L-V2；L-表位1-L-V1-L-表位2-L-V2；V1-L-表位1-L-V2-L-表位2-L；V1-L-表位1-L-V2-L-表位2-L-表位3；V1-L-表位1-L-V2-L-表位2-表位3；V1-L-表位1-L-V2-L-表位2-L-表位3-表位4；L-表位1-L-V1-L-表位2-L-V2-L-表位3-L；表位1-L-V1-L-表位2-L-V2-L-表位3-L；L-表位1-L-V1-L-表位2-L-V2-L-表位3；L-表位1-L-V1-L1-V2-L-表位2-L；L-表位1-L-V1-L1-V2-L-表位2-L-表位3；L-表位1-L-V1-L1-V2-L-表位2-表位3，或表位1-L-V1-L1-V2-L-表位2-L-表位3-表位4，其中
V1是VL且V2是VH或者V1是VH且V2是VL；
L1是适用于将VH链与VL链连接的任何接头；
L是包含甘氨酸和丝氨酸残基的接头，并且胞外结合结构域中L的每次出现与相同的胞外结合结构域中L的其它出现可以是相同的或不同的，
表位1、表位2和表位3是mAb特异性表位，并可以是相同的或不同的。
12a.根据10a的多肽，其中L1是包含甘氨酸和/或丝氨酸的接头。
13a.根据12a的多肽，其中L1是包含氨基酸序列(Gly-Gly-Gly-Ser)n或(Gly-Gly-Gly-Gly-Ser)n的接头，其中n是1，2，3，4或5或包含氨基酸序列(Gly4Ser)4或(Gly4Ser)3的接头。
14a.根据10a至13a中任一项的多肽，其中L是包含甘氨酸和/或丝氨酸的接头。
15a.根据14a的多肽，其中L是具有选自SGG、GGS、SGGS、SSGGS、GGGG、SGGGG、GGGGS、SGGGGS、GGGGGS、SGGGGGS、SGGGGG、GSGGGGS、GGGGGGGS、SGGGGGGG、SGGGGGGGS、或SGGGGSGGGGS的氨基酸序列的接头。
16a.根据14a的多肽，其中L是SGGGG，GGGGS或SGGGGS。
17a.根据10a至16a中任一项的多肽，其中表位1、表位2、表位3和表位4独立地选自替伊莫单抗(ibritumomab、tiuxetan)、莫罗单抗(muromonab)-CD3、托西莫单抗(tositumomab)、阿昔单抗(abciximab)、巴利昔单抗(basiliximab)、布伦昔单抗(brentuximab vedotin)、西妥昔单抗(cetuximab)、英夫利昔单抗(infliximab)、利妥昔单抗(rituximab)、阿伦单抗(alemtuzumab)、贝伐单抗(bevacizumab)、赛妥珠单抗(certolizumab pegol)、达利珠单抗(daclizumab)、艾库组单抗(eculizumab)、依法珠单抗(efalizumab)、吉妥珠单抗(gemtuzumab)、那他珠单抗(natalizumab)、奥马珠单抗(omalizumab)、帕利珠单抗、雷珠单抗(ranibizumab)、托美珠单抗(tocilizumab)、曲妥珠单抗(trastuzumab)、韦多珠单抗(vedolizumab)、阿达木单抗(adalimumab)、贝利木单抗(belimumab)、卡那单抗(canakinumab)、地诺单抗(denosumab)、戈利木单抗(golimumab)、伊匹单抗(ipilimumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、QBEND-10和优特克单抗(ustekinumab)特异性识别的mAb-特异性表位。
在优选的实施方式中，所述表位1、表位2由利妥抗单抗特异性识别，而表位3由QBEND-10特异性识别。
18a.根据10a至16a中任一项的多肽，其中表位1、表位2、表位3和表位4独立地选自具有SEQ ID NO 161至170的氨基酸序列的mAb特异性表位。
19a.根据10a至18a中任一项的多肽，其中表位1是具有SEQ ID NO 161的氨基酸序列的mAb特异性表位。
20a.根据权利要求10a至19a中任一项的多肽，其中表位2是具有SEQ ID NO 161的氨基酸序列的mAb特异性表位。
21a.根据权利要求10至20中任一项的多肽，其中表位3是具有SEQ ID NO 161或SEQ ID NO 169的氨基酸序列的mAb特异性表位。
22a.根据权利要求10a至21a中任一项的多肽，其中表位4是具有SEQ ID NO 161的氨基酸序列的mAb特异性表位。
23a.根据权利要求22a的多肽，其中表位1、表位2和表位4是具有SEQ ID NO 161的氨基酸序列的mAb特异性表位，并且表位3是具有SEQ ID NO 169的氨基酸序列的mAb-特异性表位。
24a.根据1a至9a中任一项的多肽，其中mAb-特异性表位来自选自表7中列出的那些中的一种多肽。
25a.根据1a至9a中任一项的多肽、其中mAb-特异性表位选自由替伊莫单抗、、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、QBEND-10和优特克单抗特异性识别的mAb特异性表位。
26a.根据1a至9a中任一项的多肽，其中mAb特异性表位选自具有SEQ ID NO 161、SEQ ID NO 162、SEQ ID NO 163、SEQ ID NO 164、SEQ ID NO 165、SEQ ID NO 166、SEQ IDNO 167、SEQ ID NO 168、SEQ ID NO 169或SEQ ID NO 170的氨基酸序列的mAb特异性表位。
27a.根据1a至9a中任一项的多肽，其中mAb特异性表位具有SEQ ID NO 160的氨基酸序列。
28a.根据1a至27a中任一项的多肽，其中所述VH和VL链具有与SEQ ID NO 11(CD123抗原VH)，SEQ ID NO 12(CD123抗原VL)超过80％，优选超过90％，更优选超过95％的一致性的抗原性靶序列。
29a.根据1a至27a中任一项的多肽，其中所述CD123抗原是细胞表面标记抗原。
30a.根据1a至27a中任一项的多肽，其中所述CD123抗原是肿瘤相关的表面抗原。
31a.根据1a至27a中任一项的多肽，其中所述抗原是CD123，
32a.根据1a至27a中任一项的多肽，其中VH和VL选自SEQ ID NO 11，SEQ ID NO 24至SEQ ID NO 30的VH和SEQ ID NO 12；-SEQ ID NO 18至SEQ ID NO 23的VL。
33a.根据2a至32a中任一项的多肽，其中铰链包含CD8α铰链或FcγRIIIα铰链。
34a.根据2a至3a3中任一项的多肽，其中跨膜结构域包含一个或多个跨膜区CD8，
35a.根据2a至33a中任一项的多肽，其中跨膜结构域包含CD8α的一个或多个跨膜区。
36a.根据2a至33a中任一项的多肽，其中跨膜结构域包含CD8α的一个或多个跨膜区和来自CD8α的铰链。
37a.根据2a至37a中任一项的多肽，其中胞内结构域包含CD3ζ信令结构域。
38a.根据2a至37a中任一项的多肽，其中胞内结构域包含4-1BB结构域。
39a.根据1a至38a中任一项的多肽，其中CAR是单链CAR。
40a.根据1a至38a中任一项的多肽，其中CAR是多链CAR。
40a根据1a至39a中任一项的多肽，其中CAR是选自SEQ ID NO 189至SEQ ID NO197的序列。
41a.一种编码根据1a至40a中任一项的多肽的多核苷酸。
42a.一种编码根据1a至40a中任一项的嵌合抗原受体的多核苷酸，其中所述CAR包含CD3ζ信令结构域和来自4-1BB的共刺激结构域。
43a.一种包含41a或42a的核酸的表达载体。
44a.一种在其细胞表面表达根据1a至40a中任一项的多肽的工程化免疫细胞。
45a.根据44a的工程化免疫细胞，其中所述细胞源自炎性T淋巴细胞，细胞毒性T淋巴细胞(CTL)，调节性T淋巴细胞或辅助性T淋巴细胞，优选CTL细胞。
46a.根据44a或45a的工程化免疫细胞，用作药物。
47a.一种用于工程化44a-46a中任一种的免疫细胞的方法，包括：
(a)提供免疫细胞；
(b)向所述细胞中引入至少一种编码根据1a至40a中任一项的嵌合抗原受体的多核苷酸。
(c)将所述多核苷酸表达于所述细胞中。
48a.用于工程化47a的免疫细胞的方法，其中免疫细胞是T细胞。
49a.一种用于体外分选在其细胞表面表达根据权利要求1a至40a中任一项的包含至少一个mAb特异性表位的多肽的工程化免疫细胞的方法，包括
-将包含所述工程化免疫细胞的免疫细胞群体与对mAb特异性表位特异性的单克隆抗体接触；
-选择结合至单克隆抗体的细胞以获得富含工程化免疫细胞的细胞群。
50a.根据49a的方法，其中对mAb特异性表位特异性的单克隆抗体与荧光团结合，并且通过荧光活化细胞分选(FACS)完成选择结合至单克隆抗体的细胞的步骤。
51a.根据49a的方法，其中对mAb特异性表位特异性的单克隆抗体与磁性颗粒结合，并且通过磁性活化细胞分选(MACS)完成结合至单克隆抗体的细胞的选择的步骤。
52a.根据49至51中任一项的方法，其中多肽包含具有SEQ ID NO 160的氨基酸序列的mAb特异性表位，而单克隆抗体是利妥昔单抗。
53a.根据49a至51a中任一项的方法，其中多肽包含具有SEQ ID NO 169的氨基酸序列的mAb特异性表位，且用于接触免疫细胞群体的抗体是QBEND-10。
54a.根据49a至53a中任一项的方法，其中富含工程化免疫细胞的细胞群体包含至少70％、75％、80％、85％、90％、95％的表达CAR的免疫细胞。
55a.一种用于在患者中体内消除在其细胞表面表达包含至少一种根据1a至40a中任一项的mAb特异性表位的多肽的工程化免疫细胞的方法，包括使所述工程化免疫细胞与至少一个表位特异性mAb接触。
56a.根据56a的方法，其中mAb特异性表位是CD20表位或模拟表位，且表位特异性mAb是利妥昔单抗。
57a.根据57a的方法，其中mAb特异性表位具有SEQ ID NO 160的氨基酸序列。
58a.根据56a至58a中任一项的方法，其中表位特异性mAb与可以活化补体系统的分子结合。
59a.根据56a至58a中任一项的方法，其中将细胞毒性药物与表位特异性mAb偶联。
60a.一种用于在患者中体内消除在其细胞表面表达包含至少一种根据1a至40a任一项的mAb特异性表位的多肽的工程化免疫细胞的方法，包括使所述工程化免疫细胞与能够与所述细胞上承载的mAb特异性表位以及效应(和细胞毒性)细胞上承载的表面抗原结合的双特异性mAb(BsAb)接触。
61a.根据47a至60a中任一项的方法，其中所述免疫细胞是T细胞。
具体地，本发明还提供了1b，CD123特异性嵌合抗原受体(CD123 CAR)，包含
■胞外结构域，含有胞外配体结合域，其依次包含可选地人源化的VH，选自SEQ IDNO 12、SEQ ID NO 24、SEQ ID NO 25、SEQ ID NO 26、SEQ ID NO 27、SEQ ID NO 28、SEQ IDNO 29和SEQ ID NO 30，，接头，优选序列(GGGGS)n的接头，其中n＝1-4，更优选n＝3，以及可选地人源化的VL，选自SEQ ID NO 11，SEQ ID NO 18，SEQ ID NO 19，SEQ ID NO 20，SEQ IDNO 21，SEQ ID NO 22和SEQ ID NO 23，铰链，
■来自CD8α的跨膜结构域，和
■包含CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域。
一种CD123特异性嵌合抗原受体(CD123 CAR)，包含
■细胞外结构域，含有胞外配体结合域，其依次包含选自SEQ ID NO 12、SEQ IDNO 24、SEQ ID NO 25、SEQ ID NO 26、SEQ ID NO 27、SEQ ID NO 28、SEQ ID NO 29和SEQID NO 30的VH，SEQ ID NO.10的接头和选自SEQ ID NO 11、SEQ ID NO 18、SEQ ID NO 19、SEQ ID NO 20、SEQ ID NO 21、SEQ ID NO 22和SEQ ID NO 23的VL，铰链，
■来自CD8α的跨膜结构域，和
■包含CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域。
2b本发明提供了根据1b的CD123 CAR，其不包含与人CD28 NP_006130.1具有一致性的序列。
3b本发明提供了根据1b或2b的CD123 CAR，其中所述胞外结构域包含至少一个对选自SEQ ID NO 161至SEQ ID NO 170的序列的单克隆抗体，或其组合特异性的表位，优选至少一个对SEQ ID NO 161的单克隆抗体特异性的表位。
本发明提供一种CD123 CAR，其中CD123 CAR包含选自SEQ ID NO 189至SEQ ID NO197的序列。
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 190的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 191的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 192的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 193的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 194的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 195的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 196的序列
本发明提供一种CD123 CAR，其中CD123 CAR包含SEQ ID NO 197的序列。
本发明提供了根据1b或2b的CD123 CAR，其中所述胞外结构域包含含有至少一个对选自SEQ ID NO161、SEQ ID NO 162、SEQ ID NO 163、SEQ ID NO 164、SEQ ID NO 165、SEQ ID NO 166、SEQ ID NO 167、SEQ ID NO 168和SEQ ID NO 169和SEQ ID NO 170的序列的单克隆抗体特异性的表位的scfv，
优选地，本发明提供根据1b或2b的CD123 CAR，其中所述胞外结构域包含含有对识别SEQ ID NO 161的单克隆抗体特异性的两个表位和另外两个对识别SEQ ID NO 169的单克隆抗体特异性的表位的scfv。
4b.本发明提供了包含SEQ ID NO 171的序列的根据3b的CD123 CAR。
5b.本发明提供了具有选自SEQ ID NO.31，SEQ ID NO.32，SEQ ID NO.33和SEQ IDN°34至SEQ ID N°160的序列的根据1b的CD123特异性嵌合抗原受体(CD123 CAR)。
6b.本发明提供了具有选自SEQ ID N°34至SEQ ID N°160的序列的根据1b至5b中任一项的CD123特异性嵌合抗原受体(CD123 CAR)。
7b.本发明提供了编码根据1b至6b中任一项的CD123特异性嵌合抗原受体(CD123CAR)的多核苷酸。
8b.本发明提供了包含根据7b的多核苷酸的表达载体。
9b)本发明提供了包含骨架和编码1b至6b中任一项中所限定的任一种CD123 CAR的序列的表达载体。
10b)本发明提供了包含骨架，优选包含EF1启动子的骨架，RQR8开放阅读框(RQR8ORF)，编码上述1至8实施方式的任一种CD123 CAR的序列的表达载体。
11b)本发明提供了在细胞表面膜上表达根据1b至9b中任一项的CD123 CAR的T-细胞受体(TCR)敲除(KO)或TCR和人脱氧胞苷激酶(dCK)KO的工程化免疫细胞。
12b)本发明提供了包含编码根据1b至6b中任一项的CD123特异性嵌合抗原受体(CD123 CAR)的多核苷酸的TCR KO或TCR和dCK KO工程化免疫细胞。
一种TCR KO或TCR和dCK KO工程化免疫细胞，其包含含有编码本发明的CD123特异性嵌合抗原受体(CD123 CAR)的多核苷酸的表达载体。
一种TCR KO或TCR和dCK KO工程化免疫细胞，其包含含有骨架和包含编码本发明的CD123特异性嵌合抗原受体(CD123 CAR)的多核苷酸的序列的表达载体。
一种TCR KO或TCR和dCK KO工程化免疫细胞，其包含含有骨架、EF1启动子、RQR8开放阅读框(RQR8 ORF)、编码本发明的任何一种CD123 CAR的序列的表达载体。
13b)本发明提供了根据11b或12b的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，其进一步在细胞表面表达自杀结构域。
(14b)本发明提供了根据10b至13b中任一项的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫T细胞，其中细胞表面的所述自杀结构域插入到CD123 CAR胞外结构域中。
根据11b至14b中任一项的TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，其中dCK基因缺失赋予对嘌呤核苷酸类似物(PNA)的抗性。
(15b)本发明提供了根据11b至14b中任一项的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，其中至少一种MHC蛋白的表达受到抑制。
16b)本发明提供了根据(11b)至(15b)中任一项的TCR KO或TCRKO和dCK KO表达CD123 CAR的工程化免疫细胞，用于治疗。
本发明提供了包含如1b)至6b)中的CD123 CAR的药物组合物。
本发明提供了包含根据11b至15b中任一项的TCR KO或TCR KO和dCK KO表达CD123CAR的工程化免疫细胞的药物组合物。
17b)本发明提供了根据16b的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，其中病症是急性髓细胞白血病(AML)，优选难治性/复发性AML，BPDNL，或用于骨髓移植期间使用。
18b)本发明提供了根据16b的TCR KO或TCR KO和dCK KO表达CD123 CAR的工程化免疫细胞，其用作治疗，优选用作淋巴增生性疾病的治疗，更优选用于淋巴瘤的白血病或用于选自急性髓细胞白血病、慢性髓细胞白血病、骨髓增生异常综合征、急性淋巴细胞白血病、慢性淋巴细胞白血病、以及骨髓增生异常综合征和BPDNL的治疗。
本发明提供了如上的药物组合物，用于治疗。
本发明提供了如上的药物组合物，用于治疗急性髓细胞白血病(AML)，优选难治性/复发性AML，BPDNL的治疗的疗法，或用于骨髓移植期间使用。
本发明提供了一种药物组合物，其用作治疗，优选用作淋巴组织增生性疾病的治疗，更优选用于淋巴瘤的白血病的治疗或用于选自由急性髓细胞白血病、慢性髓细胞性白血病、骨髓增生异常综合征、急性淋巴样白血病、慢性淋巴细胞白血病、以及骨髓增生异常综合征和BPDNL组成的组的治疗。
除非在本文中明确定义，所使用的所有技术和科学术语具有与本领域技术人员在基因疗法、药理学、免疫学、生物化学、遗传学和分子生物学领域通常理解的相同含义。
与本文的那些相似或相当的所有方法和材料可以用于本发明的实践或测试，而合适的方法和材料将在本文中进行描述。本文提及的所有出版物、专利申请、专利和其它参考文献以其全部内容结合于本文中作为参考。在发生冲突的情况下，以本说明书为主，包括定义。此外，除非另有说明，材料、方法和实施例仅仅是说明性的而非旨在是限制性的。
除非另有说明，本发明的实践将使用属于本领域技术范围内的细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学、重组DNA和免疫学的常规技术。这些技术在文献中充分解释。参见，例如，Current Protocols in Molecular Biology(FrederickM.AUSUBEL，2000，Wiley and son Inc，Library of Congress，USA)；Molecular Cloning：ALaboratory Manual，Third Edition，(Sambrook et al，2001，Cold Spring Harbor，NewYork：Cold Spring Harbor Laboratory Press)；Oligonucleotide Synthesis(M.J.Gaited.，1984)；Mullis et al.U.S.Pat.No.4，683，195；Nucleic Acid Hybridization(B.D.Harries&S.J.Higgins eds.1984)；Transcription And Translation(B.D.Hames&S.J.Higgins eds.1984)；Culture Of Animal Cells(R.I.Freshney，Alan R.Liss，Inc.，1987)；Immobilized Cells And Enzymes(IRL Press，1986)；B.Perbal，A PracticalGuide To Molecular Cloning(1984)；丛书，Methods In ENZYMOLOGY(J.Abelson andM.Simon，eds.-in-chief，Academic Press，Inc.，New York)，specifically，Vols.154 and155(Wu et al.eds.)and Vol.185，"Gene Expression Technology"(D.Goeddel，ed.)；Gene Transfer Vectors For Mammalian Cells(J.H.Miller and M.P.Calos eds.，1987，Cold Spring Harbor Laboratory)；Immunochemical Methods In Cell And MolecularBiology(Mayer and Walker，eds.，Academic Press，London，1987)；Handbook OfExperimental Immunology，Volumes I-IV(D.M.Weir and C.C.Blackwell，eds.，1986)；和Manipulating the Mouse Embryo，(Cold Spring Harbor Laboratory Press，ColdSpring Harbor，N.Y.，1986)。
本发明公开了表达包含含有来自单克隆抗-CD123抗体KLON43的VH和VL或其人源化VH和人源化VH和VL序列、来自FcγRIIIα的CD8α的铰链、来自CD8α的跨膜结构域、包括CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域的胞外配体结合域的CD123特异性嵌合抗原受体(“CD123 CAR”或“CAR”)的工程化免疫细胞(TCR KO和/或dck KO)，所述123CAR具有与SEQ ID NO.31，SEQ ID NO.32，或SEQ ID NO.33，或SEQ ID NO.34至SEQ IDNO.117、SEQ ID NO.160或优选，SEQ ID NO188至SEQ ID NO 197中任一种具有序列一致性。
优选地，本发明公开了表达SEQ ID N°31，32或160的CD123特异性CAR的遗传工程化免疫细胞(TCR KO和/或dck KO)，更优选地表达SEQ ID N°31的CD123特异性CAR的工程化免疫细胞(TCR KO)，而更加优选表达SEQ ID N°32的CD123特异性CAR的工程化免疫细胞(TCR KO和dck KO)。
有利地，本发明公开了表达SEQ ID N°31，32或160和自杀结构域的CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，更优选地表达SEQ ID N°31的CD123特异性CAR和自杀结构域的工程化免疫细胞(TCR KO)，更加优选表达SEQ ID N°32的CD123特异性CAR的工程化免疫细胞(TCR KO和dck KO)，而甚至更加优选地表达SEQ ID N°160或以下序列SEQ ID NO188至SEQ ID NO 197中的一种的CD123特异性CAR的工程化免疫细胞(TCR KO和dck KO)。
本发明公开了表达具有如图2所示的选自V1、V3的多肽结构中的一种的CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，所述结构包含含有来自单克隆抗-CD123抗体KLON 43的VH和VL、来自CD8α或FcγRIIIa的铰链、来自CD8α的跨膜结构域、包括CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域且无来自CD28的序列的胞外配体结合结构域，所述123 CAR具有与SEQ ID NO.31，SEQ ID NO.32，优选SEQ ID NO.32至少80％的序列一致性。
本发明公开了表达具有如图2中所示的选自V1、V3的多肽结构中的一种的CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，所述结构包含含有来自单克隆抗-CD123抗体KLON43的VH和VL、来自CD8α或FcγRIIIa的铰链、来自CD8α的跨膜结构域、包括CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域且无来自CD28的序列的胞外配体结合域，123 CAR具有与SEQ ID NO 34至SEQ ID NO 159，优选SEQ ID NO 34至SEQ ID NO117，优选SEQ ID NO 76至SEQ ID NO 117中任一种具有至少80％的序列一致性。
在一个实施方式中，本发明公开了一种表达具有选自SEQ ID NO.34、SEQ IDNO.76、SEQ ID NO.36、SEQ ID NO.78；SEQ ID NO.37、SEQ ID NO.79、SEQ ID NO.41、SEQ IDNO.83、SEQ ID NO.42、SEQ ID NO.8)、SEQ ID NO.43、SEQ ID NO.85、SEQ ID NO.46、SEQ IDNO.47、SEQ ID NO.48、SEQ ID NO.49、SEQ ID NO.88、SEQ ID NO.89、SEQ ID NO.90、SEQ IDNO.91.SEQ ID NO.52、SEQ ID NO.53、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.94、SEQ IDNO.95、SEQ ID NO.96、SEQ ID NO.97中的序列的CD123特异性CAR的工程化免疫细胞(TCRKO和/或dck KO)。
优选地，本发明公开了表达具有选自SEQ ID NO.34、SEQ ID NO.76、SEQ IDNO.36、SEQ ID NO.78；SEQ ID NO.43、SEQ ID NO.85、SEQ ID NO.46、SEQ ID NO.47、SEQ IDNO.48、SEQ ID NO.88、SEQ ID NO.89、SEQ ID NO.90、SEQ ID NO.52、SEQ ID NO.53、SEQ IDNO.54、SEQ ID NO.55、SEQ ID NO.94、SEQ ID NO.95、SEQ ID NO.96、SEQ ID NO.97的序列的CD123特异性CAR的工程化免疫细胞(TCR KO 和/或dck KO)。
更优选地，本发明公开了表达具有选自SEQ ID NO.47、SEQ ID NO.89、SEQ IDNO.52、SEQ ID NO.53、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.94、SEQ ID NO.95、SEQ IDNO.96、SEQ ID NO.97的序列的CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)。
并且更加优选地，发明公开了表达具有选自SEQ ID NO.32、SEQ ID NO.89、SEQ IDNO.94、SEQ ID NO.95、SEQ ID NO.96、SEQ ID NO.97的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)。
本发明最优选的实施方式公开了表达具有SEQ ID NO 172的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 173的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 174的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 175的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 176的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 177的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 178的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 179的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 180的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 181的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 182的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 183的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 184的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 185的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 186的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
另一最优选的实施方式公开了表达具有SEQ ID NO 187的序列的CD123特异性123CAR的工程化免疫细胞(TCR KO和/或dck KO)，包含由特异性单克隆抗体识别的至少一个选自SEQ ID NO 161至SEQ ID NO 170的表位，优选SEQ ID NO 161的两个和SEQ ID NO 169的一个。
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.188的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.189的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.190的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.191的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.192的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.193的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.194的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.195的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.196的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)
在另一最优选的实施方式中，本发明公开了表达具有SEQ ID NO.197的序列的CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
本发明公开了表达CD123特异性123 CAR的工程化免疫细胞(TCR KO和/或dckKO)，其胞外结合结构域以允许细胞分选和细胞消除两者的方式改造。这种结构，即“mAb-驱动的分选/消除系统”或“对单克隆抗体特异性的表位”或“模拟表位”，是插入到本发明的抗CD123 CAR的细胞外结构域内，具体地插入到抗CD123 scFv中；或TM和铰链之间的选择的表位；这种表位具有被特异性抗体(优选mAb)识别的特异性。考虑到主要是CAR的外部配体结合域改造而包括该表位，可以设想不同的CAR结构：单链或多链。由VH和VL多肽和特异性表位形成的本发明的嵌合scFv本身可以具有不同的结构，取决于表位的插入位置和接头的使用。本发明还涉及用于分选和/或消除赋予改造的CAR的工程化免疫细胞的所获得的方法。
在一些实施方式中，抗CD123 CAR的胞外结合结构域包括以下序列(包括模拟表位)(N端位于左手侧)：
V1-L1-V2-(L)x-表位1-(L)x；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x；
V1-L1-V2-(L)x-表位1-(L)x-表位2-(L)x-表位3-(L)x；
(L)x-表位1-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2；
表位1-(L)x-表位2-(L)x-表位3-(L)x-V1-L1-V2；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x；
(L)x-表位1-(L)x-V1-L1-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x；
(L)x-表位1-(L)x-表位2-(L)x-V1-L1-V2-(L)x-表位3-(L)x-表位4-(L)x；
V1-(L)x-表位1-(L)x-V2；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x；
V1-(L)x-表位1-(L)x-V2-(L)x-表位2-(L)x-表位3-(L)x-表位4-(L)x；
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2；
(L)x-表位1-(L)x-V1-(L)x-表位2-(L)x-V2-(L)x-表位3-(L)x；
V1-L1-V2-L-表位1；
V1-L1-V2-L-表位1-L；
V1-L1-V2-L-表位1-L-表位2；
V1-L1-V2-L-表位1-L-表位2-L；
V1-L1-V2-L-表位1-L-表位2-L-表位3；
V1-L1-V2-L-表位1-L-表位2-L-表位3-L；
V1-L1-V2-表位1；
V1-L1-V2-表位1-L；
V1-L1-V2-表位1-L-表位2；
V1-L1-V2-表位1-L-表位2-L；
V1-L1-V2-表位1-L-表位2-L-表位3；
V1-L1-V2-表位1-L-表位2-L-表位3-L；
表位1-V1-L1-V2；
表位1-L-V1-L1-V2；
L-表位1-V1-L1-V2；
L-表位1-L-V1-L1-V2；
表位1-L-表位2-V1-L1-V2；
表位1-L-表位2-L-V1-L1-V2；
L-表位1-L-表位2-V1-L1-V2；
L-表位1-L-表位2-L-V1-L1-V2；
表位1-L-表位2-L-表位3-V1-L1-V2；
表位1-L-表位2-L-表位3-L-V1-L1-V2；
L-表位1-L-表位2-L-表位3-V1-L1-V2；
L-表位1-L-表位2-L-表位3-L-V1-L1-V2；
V1-L-表位1-L-V2；
L-表位1-L-V1-L-表位2-L-V2；
V1-L-表位1-L-V2-L-表位2-L；
V1-L-表位1-L-V2-L-表位2-L-表位3；
V1-L-表位1-L-V2-L-表位2-表位3；
V1-L-表位1-L-V2-L-表位2-L-表位3-表位4；
L-表位1-L-V1-L-表位2-L-V2-L-表位3-L；
表位1-L-V1-L-表位2-L-V2-L-表位3-L；
L-表位1-L-V1-L-表位2-L-V2-L-表位3；
L-表位1-L-V1-L1-V2-L-表位2-L；
L-表位1-L-V1-L1-V2-L-表位2-L-表位3；
L-表位1-L-V1-L1-V2-L-表位2-表位3，或，
表位1-L-V1-L1-V2-L-表位2-L-表位3-表位4。
其中，
V1和V2是ScFv抗CD123的VH和VL(即，V1是VL且V2是VH或者V1是VH且V2是VL)；
L1是适用于在ScFv中将VH链连接至VL链的任何接头；
L是接头，优选包含甘氨酸和丝氨酸残基，且胞外结合结构域中L的每次出现可以与相同的胞外结合结构域中L的其它出现相同或不同，并且
x是0或1，且x的每次出现相互独立；并且，
表位1、表位2和表位3是mAb特异性表位(或模拟表位)并可以是相同的或不同的。
在一些实施方式中，胞外结合结构域包含以下序列(N端位于左侧)：
VH-L1-VL-L-表位1-L-表位2-L；
L-表位1-L-VH-L-表位2-L-VL-L-表位3-L；
VL-L1-VH-L-表位1-L-表位2-L；或，
L-表位1-L-VL-L-表位2-L-VH-L-表位3-L。
其中L，L1，表位1，表位2和表位3如以上定义。
L1是包含甘氨酸和/或丝氨酸的接头。在一些实施方式中，L1是包含氨基酸序列(Gly-Gly-Gly-Ser)n或(Gly-Gly-Gly-Gly-Ser)n的接头，其中n是1，2，3，4或5。在一些实施方式中，L1是(Gly4Ser)4或(Gly4Ser)3。
L是优选地包含甘氨酸和/或丝氨酸的柔性接头。在一些实施方式中，L具有选自SGG、GGS、SGGS、SSGGS、GGGG、SGGGG、GGGGS、SGGGGS、GGGGGS、SGGGGGS、SGGGGG、GSGGGGS、GGGGGGGS、SGGGGGGG、SGGGGGGGS、或SGGGGSGGGGS，优选SGG、SGGS、SSGGS、GGGG、SGGGGS、SGGGGGS、SGGGGG、GSGGGGS或SGGGGSGGGGS的氨基酸序列。在一些实施方式中，当胞外结合结构域包含L的多次出现时，所有的L都相同。在一些实施方式中，当胞外结合结构域包含L的多次出现时，L并不全部相同。在某些实施方式中，L是SGGGGS。在一些实施方式中，胞外结合结构域包括几次出现的L，且所有的L是SGGGGS。
在一些实施方式中，表位1、表位2和表位3是相同的或不同的，并且选自具有如表7所示的氨基酸序列的mAb特异性表位。
在优选的实施方式中、表位1、表位2是相同的或不同的、并且选自由替伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、QBEND-10、阿伦单抗或优特克单抗、优选已经批准医疗用途的那些，如作为非限制性实例的利妥昔单抗特异性识别的mAb特异性表位。
最后，本发明包括治疗方法，其中赋予CAR的工程化免疫细胞的数量、活化和/或存活通过使用在细胞表面直接结合至对CD123 CAR中单克隆抗体特异性的至少一个表位的抗体来控制。
本发明包括公开了各自表达本文中公开的任一种CD123特异性CAR，优选以下序列SEQ ID NO188至SEQ ID NO 197中的一种的工程化免疫细胞(TCR KO和/或dck KO)的实施方式。
本发明包括公开了编码允许制备各自表达上文公开的任何(每)一种CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)的载体的实施方式。具体地，本发明包括公开了编码以上公开的CD123特异性CAR中的一种(每种)，优选包含骨架的载体。
本发明包括公开了编码允许制备各自表达本文中公开的任(每)一种CD123特异性CAR，优选以下序列SEQ ID NO188至SEQ ID NO 197中的一种的工程化免疫细胞(TCR KO和/或dck KO)的载体的实施方式。本发明包括公开了包含各自表达上文中公开的任(每)一种CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)和药用载体的药物组合物的实施方式。
本发明包括公开了包含各自表达以上公开的何(每)一种CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)的药物组合物和药用载体药物组合物用作药物的实施方式。
本发明包括公开了包含104至1010/kg各自表达以上公开的任何(每)一种CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)和药用载体的药物组合物用作药物的实施方式。
本发明公开了表达具有如图2所示和如上所述的多肽结构V3的特异性CD123 CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中所述CD123 CAR与SEQ ID NO.31具有至少80％的序列一致性。
本发明公开了表达具有如图2所示和如上所述的多肽结构V3的特异性CD123 CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中所述CD123 CAR与SEQ ID NO.32具有至少80％的序列一致性。
本发明公开了表达具有如图2所示和如上所述的多肽结构V3的特异性CD123 CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中CD123 CAR与SEQ ID NO.33具有至少80％的序列一致性。
本发明公开了表达具有如图2所示和如上所述的多肽结构V3的特异性CD123 CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中CD123 CAR与SEQ ID NO.160具有至少80％的序列一致性。
本发明公开了表达具有以下序列SEQ ID NO188至SEQ ID NO 197之一的特异性CD123 CAR的工程化免疫细胞(TCR KO和/或dck KO)。
本发明公开了如上所述的表达CD123 CAR的工程化免疫细胞(TCR KO和/或dckKO)，其中来自单克隆抗-CD123抗体的所述胞外配体结合域VH和VL分别包含至少一种以下序列：
(变体VH1：SEQ ID NO.24)：
EVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，
(变体VH2：SEQ ID NO.25)：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，
(变体VH3：SEQ ID NO.26)：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，
(变体VH4：SEQ ID NO.27)：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，
(变体VH5：SEQ ID NO.28)：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，
(变体VH6：SEQ ID NO.29)：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，
(变体VH7：SEQ ID NO.30)：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSS，
变体VH8
EVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS
变体VH9：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS
变体VH10：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS
变体VH11：
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQPPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS
和以下序列中的一种：
变体VL1：SEQ ID NO.18)：
MADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，
变体VL2：SEQ ID NO.19)：
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，
变体VL3：SEQ ID NO.20)：
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，
变体VL4：SEQ ID NO.21)：
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，
变体VL5：SEQ ID NO.22)：
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，和
变体VL6：SEQ ID NO.23)：
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，
变体VL1a：
DIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR
变体VL2a：
DIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR
变体VL3a：
DIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR
变体VL4a：
DIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR
变体VL6a：
DIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR
变体VL7a：
DIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR
变体VL8a：
DIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKR
变体VL9a：
DIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKR
本发明公开了如上所述的表达CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中来自单克隆抗-CD123抗体的所述胞外配体结合结构域VH和VL分别包含以下序列中的至少一种：
EVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.24)，
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.25)，
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.26)，
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.27)，
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.28)，
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.29)，
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.30)，
MADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID NO.18)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID NO.19)，
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID NO.20)，
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID NO.21)，
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID NO.22)，和
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID NO.23)或它们的组合。
有利地，本发明公开了如上所述的表达CD123特异性CAR的工程化免疫细胞(TCRKO和/或dck KO)，其中来自单克隆抗CD123抗体的所述胞外配体结合结构域VH和VL分别包含以下序列至少一种：
EVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°24)
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°25)
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°26)
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°27)
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°28)
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°29)
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID N°30)
和以下序列中的至少一种：
MADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID N°18)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID N°19)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID N°20)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID N°21)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID N°22)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID N°23)
在更优选的实施方式中，本发明提供了具有各自来自(SEQ ID NO 172至SEQ IDNO 187)的序列的CAR：
huK43-VH10/VL1
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 172)
huK43-VH9/VL6
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO173)
huK43-VH10/VL3
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 174)
huK43-VH9/VL8
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 175)
huK43-VH2/VL3
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 176)
huK43-VH10/VL9
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 177)
huK43-VH9/VL3
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 178)
huK43-VH2/VL1
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 179)
在另一实施方式中，本发明提供了赋予以下CAR的工程化免疫细胞。
V5
huK43-VH10/VL1
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 180)
huK43-VH9/VL6
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 181)
huK43-VH10/VL3
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 182)
huK43-VH9/VL8
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 183)
huK43-VH2/VL3
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 184)
huK43-VH10/VL9
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 185)
huK43-VH9/VL3
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 186)
huK43-VH2/VL1
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 187)。
本发明公开了如上所述的表达CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中所述结构V3(参见图2)优选包含CD8α铰链和CD8α跨膜结构域，而无CD28序列。
本发明公开了如上所述的表达CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中所述结构V3包含CD8α铰链，4-1BB胞质结构域和CD8α跨膜结构域。
本发明公开了如上所述的表达CD123特异性CAR的工程免疫细胞(TCRKO和/或dckKO)，其中所述结构V3包含CD8α铰链和4-1BB跨膜结构域而无来自CD28的序列。
本发明公开了如上所述的表达CD123特异性CAR的工程化免疫细胞，并进一步包含对CD123不是特异性的另一胞外配体结合结构域。在优选的实施方式中，对CD123不是特异性的另一胞外配体结合结构域是自杀结构域，更优选如专利申请PA 2015 70044表2)中公开的任何一种的自杀结构域。
本发明公开了如上所述的表达CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)，其中所述CD123特异性CAR包含通过含有G和S的接头Li结合的含有至少一个SEQID NO：161，优选至少两个SEQ ID NO：161的自杀体结构域。
在一个实施方式中，所述自杀结构域整合到本发明的CD123 CAR的铰链结构域中。在一个更优选的实施方式中，本发明提供了SEQ ID NO:160的或与SEQ ID NO:160具有至少95％一致性的CD123 CAR。
如专利申请PA201570044的表2中所描述的那些的其它自杀结构域适用于本发明，将其以其全部内容通过引证结合于本文中。
本发明公开了如上所述的工程化免疫细胞，其中在所述工程化免疫细胞中抑制了至少一种MHC蛋白质，优选β2m或HLA的表达。β2m代表β2微球蛋白而HLA代表人白细胞抗原。MHC蛋白是I类或II类的MHC蛋白。
本发明公开了如上的工程化免疫细胞，其中所述工程化免疫细胞工程化为赋予对至少一种免疫抑制药物、化疗药物或抗癌药物，优选对嘌呤类似物的抗性。
本发明公开了包含药用载体和如上所述的表达CD123特异性CAR的工程化免疫细胞(TCR KO和/或dck KO)中的任一种的组合物。
本发明公开了一种包含药用载体和如上所述的表达CD123特异性CAR的上述工程化免疫细胞(TCR KO和/或dck KO)和另一种药物，优选嘌呤类似物而更优选FLAG治疗的组合物。
根据本发明的嘌呤类似物的实例可以是喷司他丁(pentostatin)，氟达拉滨2-脱氧腺苷(fludarabine 2-deoxyadenosine)，克拉屈滨(cladribine)，氯法拉滨(clofarabine)，奈拉滨(Nelarabine)，优选喷司他丁，氟达拉滨单磷酸酯和2-氯脱氧腺苷(2-CDA)。
可以与本发明的CD123 T细胞相关的FLAG治疗的实例如下：无添加的标准FLAG，FLAG-IDA，Mito-FLAG，FLAMSA。
根据本发明的FLAG治疗的实例可以是无添加的标准FLAG
FLAG-IDA
Mito-FLAG
FLAMSA
本文公开了以下组合治疗：
本发明公开了如上所述的任一种的工程化免疫细胞，包含如上文所公开的所述工程化免疫细胞的组合物，用于治疗。
本发明公开了本发明的工程化免疫细胞，包含如上的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中患者是人。
本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中病症是特征为表达CD123的细胞的恶性前或恶性癌症。
本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中病症是特征为过多的表达CD123的细胞的病症。
本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中恶性癌症病症是血液癌症病症。
本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中血液癌症病症是白血病或恶性淋巴增生性疾病。
本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中所述白血病选自由急性髓细胞白血病，慢性髓细胞白血病，骨髓增生异常综合征，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征组成的组。
本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中白血病是急性髓细胞白血病(AML)，优选难治性/复发性AML。
在一个实施方式中，本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中血液癌症是恶性淋巴组织增生性疾病。
本发明公开了工程化免疫细胞，用于如上所述的治疗，其中所述恶性淋巴组织增生性疾病是淋巴瘤。
本发明公开了工程免疫细胞，用于如上所述的治疗，其中所述淋巴瘤选自由多发性骨髓瘤，非霍奇金淋巴瘤，Burkitt淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)组成的组。
表达于本发明的TCR KO和dck KO T细胞，104至108细胞/kg中的SEQ ID N°31或SEQID N°32或SEQ ID N°160的CD123 CAR，与无添加FLAG治疗组合，用于AML，优选难治性复发性AML的治疗。
表达于本发明的TCR KO和dck KO T细胞，104至108细胞/kg中的SEQ ID NO°31或SEQ ID NO°32或SEQ ID NO°160的CD123 CAR，与无添加FLAG治疗组合，用于BPDCN的治疗。
表达于本发明的TCR KO和dck KO T细胞，104至108细胞/kg中的SEQ ID NO°31或SEQ ID NO°32或SEQ ID NO°160的CD123 CAR，与无添加FLAG治疗组合，用作骨髓移植前作为移植过渡的治疗。
表达于本发明的TCR KO和dck KO T细胞(104至108细胞/kg)中的SEQ ID NO°31或SEQ ID NO°32或SEQ ID NO°160的CD123 CAR，与氟达拉滨(20mg/kg至50mg/kg)组合，用于AML，优选难治性复发性AML的治疗。
表达于本发明的TCR KO和dck KO T细胞(104至108个细胞/kg)中的SEQ ID NO°31或SEQ ID NO°32或SEQ ID NO°160的CD123 CAR，与氟达拉滨(20mg/kg至50mg/kg)组合，用于BPDCN的治疗。
表达于本发明的TCR KO和dck KO T细胞(104至108个细胞/kg)中的SEQ ID NO°31或SEQ ID NO°32或SEQ ID NO°160的CD123 CAR，与氟达拉滨(20mg/kg至50mg/kg)组合，用作骨髓移植前作为移植过渡的治疗。
本发明公开了减少血液癌细胞的方法，包括以有效引起所述癌细胞减少的量(104至108细胞/kg)使所述血液癌细胞与本发明的工程化细胞接触。
本发明公开了工程化免疫细胞的方法，包括：
1.由供体提供免疫细胞，
2.敲除TCR基因，
3.在所述细胞的表面上表达如以上任何一种根据本发明的CD123特异性嵌合抗原受体。
供体可以是患癌症的患者本身(对于自体过继转移)或另一个人(对于过继转移同种异体T细胞)。本发明公开了工程化如上所述的免疫细胞的方法，包括：
1.由供体提供免疫细胞，
2.敲除TCR基因，以及dck基因
3.通过将至少一种编码所述CD123特异性嵌合抗原受体的多核苷酸引入所述细胞中而在所述细胞表面表达根据上述任一项的CD123特异性嵌合抗原受体，
在更优选的实施方式中，所述方法包括在细胞表面上表达自杀结构域。
本发明公开了工程化如上所述的免疫细胞的方法，包括：
1.提供免疫细胞，
2.使用SEQ ID NO:16和SEQ ID NO:17的半TALE-核酸酶TALEN敲除TCR基因，以及dck基因
3.通过向所述细胞中引入至少一种编码所述CD123特异性嵌合抗原受体的多核苷酸，在所述细胞表面上表达根据以上的任一种CD123特异性嵌合抗原受体。
在优选的实施方式中，所述方法包括在细胞表面上表达自杀结构域，优选地由以下抗体中的一种识别的自杀结构域：替伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、QBEND-10、阿伦单抗或优特克单抗。
在另一实施方式中，所述方法进一步包括将本发明的所述工程化免疫细胞结合至如本文公开的那些选自以下的特异性单克隆抗原：替伊莫单抗、莫罗单抗-CD3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、QBEND-10、阿伦单抗或优特克单抗。
本发明公开了治疗对其需要的受试者的方法，包括：
1.提供在表面表达根据上述任一种的CD123特异性嵌合抗原受体的免疫细胞或包含其的组合物
2.将所述免疫细胞给药于所述患者。在优选实施方式中，所述组合物进一步包含嘌呤类似物氟达拉滨
在另一实施方式中，所述组合物与FLAG治疗，无添加FLAG治疗相关。
在一个实施方式中，所述对其需要的受试者患有AML，优选难治性复发性AML，BPDNL，或必须进行骨髓移植。
本发明公开了如上的治疗对其需要的受试者的方法，其中免疫细胞由供体提供。
本发明公开了一种如上的治疗对其需要的受试者的方法，其中所述免疫细胞由患者本身提供。
CD123特异性嵌合抗原受体
本发明涉及新的抗CD123嵌合抗原受体(CAR)，其包含来自或源自KLON 43抗体的胞外配体结合结构域，来自CD8α的跨膜结构域，来自CD8α或FcγRIIIα的铰链，自杀域和信令转导域。在优选的实施方式中，所述自杀结构域整合到铰链结构域中。在更优选的实施方式中，所述自杀结构域包含整合到铰链结构域中的至少两个SEQ ID NO 161的序列。
在优选的实施方式中，本发明的所述抗CD123 CAR是SEQ ID NO:31，32或160的多肽，
在另一实施方式中，本发明的所述抗-CD123 CAR是SEQ ID NO:34至SEQ ID NO:15，SEQ ID NO:34至SEQ ID NO:117，SEQ ID NO:76至SEQ ID NO:117的多肽。
本文所用的术语“胞外配体结合结构域”定义为能够结合CD123的寡肽或多肽。优选地，胞外配体结合结构域可以选择为识别充当与特定疾病状态相关的靶细胞上的细胞表面标记的CD123。更优选地，胞外配体结合结构域可以选择为识别充当与AML，BPDCN或涉及癌症病症中的表达CD123的细胞相关的靶细胞上的细胞表面标记的CD123。
在优选的实施方式中，所述胞外配体结合结构域包含含有靶抗原特异性单克隆抗CD-123抗体KLON 43的通过柔性接头连接的轻(VL)和重(VH)可变片段的单链抗体片段(scFv)。所述VL和VH优选选自表1至2中公开的序列，更优选选自包含来自或源自Klon43的VH、接头和VL(如表2中的人源化VH和VL)的scfv。它们优选通过包含序列SEQ ID NO.10的序列(GGGGS)n，其中n＝1至4，更优选n＝3的柔性接头连接至一起。换句话说，所述CAR优选包含含有与选自由VH的SEQ ID NO:12和VL的SEQ ID NO:11以及人源化片段的SEQ ID NO:18至SEQ ID NO:30(见表2)组成的组中的氨基酸序列具有100％的一致性的多肽序列的胞外配体结合域。
本文使用的术语“重组抗体”是指使用重组DNA技术产生的抗体或抗体片段，如例如由噬菌体、酵母表达系统或哺乳动物细胞表达系统表达的抗体或抗体片段。该术语也应解释为是指通过合成编码抗体或抗体片段的DNA分子产生的抗体或抗体片段，并且该DNA分子表达抗体或抗体片段蛋白，或指定抗体或抗体片段的氨基酸序列，其中DNA或氨基酸序列已经使用本领域可用和熟知的重组或合成DNA或氨基酸序列技术获得。
正如本文所用的术语“保守序列改造”或“人源化”或“人源化抗体”或“人源化抗体片段”，“人源化VH或人源化VL”旨在是指不会显著影响或改变CAR的结合特性和/或不显著影响含有改造的氨基酸序列的CAR的活性和降低或消除人抗鼠抗体(HAMA)响应的氨基酸改造。
在优选的实施方式中，氨基酸改造显著改善CAR的结合特性和/或显著改善含有改造的氨基酸序列的CAR的活性，并降低或消除人抗鼠抗体(HAMA)响应。
这种保守改造包括在所述CAR和/或所述CAR分子的任何其它部分中的抗体片段内的氨基酸取代、添加和缺失。通过本领域已知的标准技术，如定向诱变，PCR介导诱变或通过使用优化的种系序列，可以将改造引入抗体，引入抗体片段或本发明的CAR分子的任何其它部分中。
保守氨基酸取代是其中氨基酸残基被具有相似侧链的氨基酸残基取代的一种。具有相似侧链的氨基酸残基家族已经在本领域中定义。这些家族包括以下的氨基酸：具有碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如、苏氨酸、缬氨酸、异亮氨酸)和芳族侧链(例如、酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此，本发明的CAR内的一个或多个氨基酸残基可以被来自相同侧链家族的其它氨基酸残基取代，并且改变的CAR可以使用本文描述的功能性试验对结合CD123的能力测试。
在一个实施方式中，所述scfv包含结合至单克隆抗体的至少一个，优选两个表位。这种表位的实例在表7中公开。
根据本发明的CAR的信号转导结构域或胞内信令结构域负责胞外配体结合结构域结合至靶标后的胞内信号传导，导致免疫细胞的活化和免疫响应。换言之，信号转导结构域负责活化其中表达CAR的免疫细胞的至少一种正常效应功能。例如，T细胞的效应功能可以是细胞溶解活性或辅助活性，包括细胞因子的分泌。因此，术语“信号转导结构域”是指转导效应信号功能信号并引导细胞执行专门功能的蛋白部分。
用于CAR的信号转导结构域的优选实例可以是T细胞受体和抗原受体衔接之后共同作用以引发信号转导的共受体的细胞质序列，以及这些序列的任何衍生物或变体和任何具有相同功能性能力的合成序列。信号转导结构域包含两种不同类型的细胞质信令序列，引发抗原依赖性初级活化的那些，以及以抗原非依赖性方式作用而提供次级或共刺激信号的那些。初级细胞质信令序列可以包含被称为ITAM的免疫受体酪氨酸类活化基序的信令基序。ITAM是在用作syk/zap70类酪氨酸激酶的结合位点的各种受体的胞质内尾区中发现的明确定义的信令基序。本发明中使用的ITAM的实例可以包括作为非限制性实例的源自TCRζ、FcRγ、FcRβ、FcRε、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD79b和CD66d的那些。在优选的实施方式中，CAR的信令转导结构域可以包含具有与选自由SEQ ID NO:9组成的组中的氨基酸序列至少70％、优选至少80％、更优选至少90％、95％、97％或99％的序列一致性的氨基酸序列的CD3ζ信令结构域。
在具体的实施方式中，本发明的CAR的信号转导结构域包含共刺激信号分子。共刺激分子是除抗原受体外的细胞表面分子或其有效免疫响应所需的配体。“共刺激配体”是指特异性结合T细胞上的同源共刺激分子的抗原呈递细胞上的分子，从而提供除了通过例如TCR/CD3复合物与加载有肽的MHC分子的结合提供的初级信号之外介导T细胞响应，包括但不限于增殖活化，分化等的信号。共刺激配体可以包括但不限于CD7、B7-1(CD80)、B7-2(CD86)、PD-L1、PD-L2、4-1BBL、OX40L、诱导型共刺激配体(ICOS-L)、胞间粘附分子(ICAM、CD30L、CD40、CD70、CD83、HLA-G、MICA、M1CB、HVEM、淋巴毒素β受体、3/TR6、ILT3、ILT4、结合Toll配体受体的激动剂或抗体、和特异性地结合B7-H3的配体。共刺激配体除此之外还涵盖与T细胞上存在的共刺激分子特异性结合的抗体，如但不限于CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LTGHT、NKG2C、B7-H3、与CD83特异性结合的配体。“共刺激分子”是指T细胞上与共刺激配体特异性结合的同源结合配偶体，从而由细胞介导共刺激响应，例如但不限于增殖。共刺激分子包括但不限于MHCI类分子，BTLA和Toll配体受体。共刺激分子的实例包括CD27、CD28、CD8、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3和与CD83特异性结合的配体。
在一个实施方式中，本发明的CAR的信号转导结构域，特别是共刺激分子，并不包括CD28(NP_006130.1)。
在一个优选的实施方式中，本发明的CAR不包括人CD28(NP_006130.1)的序列和/或来自任何其它CD28的序列。
在另一优选的实施方式中，本发明的CAR的信号转导结构域包含选自由4-1BB(GenBank：AAA53133)的片段组成的组中的共刺激信号分子的部分。具体地，本发明的CAR的信号转导结构域包含含有与选自由SEQ ID NO:8组成的组中的氨基酸序列具有至少70％、优选至少80％、更优选至少90％、95％、97％或99％的序列一致性的氨基酸序列。
根据本发明的CAR表达于细胞的表面膜上。因此，这样的CAR进一步包含跨膜结构域。合适的跨膜结构域的区别特征包括在细胞，在本发明中优选免疫细胞，特别是淋巴细胞或天然杀手(NK)细胞的表面上表达和一起相互作用用于引导免疫细胞对抗预定义的靶细胞的细胞响应的能力。跨膜结构域可以源自天然的或合成的来源。跨膜结构域可以源自任何膜结合蛋白或跨膜蛋白。作为非限制性实例，跨膜多肽可以是T细胞受体的亚单位，如α，β，γ或δ，构成CD3复合物的多肽，IL2受体p55(α链)，p75(β链)或γ链，Fc受体的亚单位链，特别是Fcγ受体III或CD蛋白。另外，跨膜结构域可以是合成的，并可以主要包含疏水性残基如亮氨酸和缬氨酸。
在优选的实施方式中，所述跨膜结构域(TM)源自人CD8α链(例如，NP_001139345.1)、IgG1、IgG4、FcγRIIIα。
在更优选的实施方式中，所述TM结构域包含SEQ ID NO 6的序列或部分。根据本发明的CD123 CAR通常进一步包含来自CD8α的跨膜结构域(TM)，显示出与SEQ ID NO.6的多肽至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的序列一致性。
在一个实施方式中，本发明的CD123 CAR不包含来自4-1BB，优选序列IISFFLALTSTLFLLFFLTLRFSVV(SEQ ID NO.7)的TM结构域。在更优选的实施方式中，所述铰链是SEQ ID NO.171。
根据本发明的CAR包括在所述胞外配体结合结构域和所述跨膜结构域之间的铰链区。本文使用的术语“铰链区”通常是指作用为将跨膜结构域连接到胞外配体结合结构域的任何寡肽或多肽。具体地，铰链区用于为胞外配体结合结构域提供更多的柔性和可接近性。铰链区可以包含多达300个氨基酸，优选10至100个氨基酸而最优选25至50个氨基酸。铰链区可以源自天然存在的分子的全部或部分，如来自CD8、CD4的胞外区的全部或部分，或来自抗体恒定区的全部或部分。
在一个实施方式中，所述铰链区域包含至少一个由单克隆抗体识别的表位，如表7所公开。
在一个实施方式中，所述铰链区包含SEQ ID N°161的，优选SEQ ID N°171的至少两个序列。
在一个实施方式中，本发明的所述CD123 CAR包括scfv中的SEQ ID N°161的至少一个序列。
在一个实施方式中，本发明的所述CD123 CAR包括scfv中，优选在scfv的N端的SEQID N°161的两个序列和SEQ ID NO 169的序列。
另外，铰链区可以是对应于天然存在的铰链序列的合成序列，或可以是完全合成的铰链序列。在优选的实施方式中，所述铰链结构域包含在本说明书中分别称为SEQ IDNO.3，SEQ ID NO.4和SEQ ID NO.5的人CD8α链、FcγRIIIα受体或IgG1的一部分，或优选显示出与这些多肽至少80％、更优选至少90％、95％、97％或99％的序列一致性的铰链多肽。
在更优选的实施方式中，所述铰链结构域包含人CD8α链或FcγRIIIα受体的一部分，更优选铰链结构域包含序列SEQ ID NO.3或SEQ ID NO.4的序列，或与SEQ ID NO.3或SEQ ID NO.4具有至少80％、更优选至少90％、95％、97％或99％的序列一致性。
其他另外的scfv
通常在癌细胞中观察到靶抗原的下调或突变，产生抗原缺失逃逸变体。因此，为了抵消肿瘤逃逸并使免疫细胞对靶标更具特异性，根据本发明的CD123特异性CAR可以包含另一胞外配体结合结构域，以同时结合靶中的不同元件，从而增强免疫细胞活化和功能。在一个实施方式中，胞外配体结合域可以串联置于同一跨膜多肽上，并可选地可以通过接头分开。在另一实施方式中，所述不同的胞外配体结合结构域可以置于构成CAR的不同跨膜多肽上。在另一实施方式中，本发明涉及各自包含不同胞外配体结合域的CAR群体。具体地，本发明涉及工程化免疫细胞的方法，包括提供免疫细胞，并在所述细胞的表面表达各自包含不同胞外配体结合结构域的CAR群体。在另一具体实施方式中，本发明涉及工程化免疫细胞的方法，包括提供免疫细胞，并将编码构成各自包含不同胞外配体结合结构域的CAR群体的多肽引入所述细胞中。对于CAR群体，其是指至少两个、三个、四个、五个、六个或更多个CAR，每个CAR包含不同的胞外配体结合域。根据本发明的不同胞外配体结合结构域可以优选同时结合靶中的不同元件，从而增加免疫细胞的活化和功能。
本发明还涉及包含各自含有不同胞外配体结合结构域的CAR群体的分离的免疫细胞。
在优选的实施方式中，根据本发明的CD123 CAR包含SEQ ID NO.31的多肽或SEQID NO.32的多肽，更优选根据本发明的CD123 CAR包含与SEQ ID NO.31具有至少80％一致性，优选80％至99％一致性的多肽或与SEQ ID NO.32具有80％至99％一致性的多肽。更加优选地，根据本发明的CAR包含与SEQ ID NO.31的多肽或与SEQ ID NO.32具有85％至99％一致性的多肽。
在优选的实施方式中，根据本发明的CD123 CAR包含具有以下序列SEQ ID NO.31的多肽。
在优选的实施方式中，根据本发明的CD123 CAR包含具有选自以下序列SEQ IDNO.32，SEQ ID NO.31和SEQ ID NO.160的多肽。
在一个优选的实施方式中，根据本发明的CAR包含至少一种选自以下序列的多肽：
EVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID NO.24)EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID NO.25)EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID NO.26)EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID NO.27)EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS，(SEQ ID NO.28)EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.29)和EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSS(SEQ ID NO.30)
和至少一种选自以下序列的序列
MADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID NO.18)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID NO.19)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID NO.20)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR，(SEQ ID NO.21)
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID NO.22)和
MADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKR(SEQ ID NO.23)。
在一个实施方式中，根据本发明的CD123 CAR包含一种选自以下序列的多肽：SEQID NO.24、SEQ ID NO.25、SEQ ID NO.26、SEQ ID NO.27、SEQ ID NO.28、SEQ ID NO.29和SEQ ID NO.30，和选自以下序列的肽：SEQ ID NO.18、SEQ ID NO.19、SEQ ID NO.20、SEQ IDNO.21、SEQ ID NO.22和SEQ ID NO.23。
在一个实施方式中，根据本发明的CD123 CAR包含与SEQ ID NO.11的多肽具有80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的一致性，或与SEQ ID NO.12的多肽具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的一致性的多肽。
在更优选的实施方式中，根据本发明的CD123 CAR包含含有与SEQ ID NO.11+SEQID NO.10+SEQ ID NO.12的80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、或99％一致性的多肽。
根据本发明，表达本发明的抗CD123 CAR的免疫细胞，即使在FLAG治疗的嘌呤类似物存在下，也会引发抗癌免疫响应，没有或降低GVHD和增殖。
在优选的实施方式中，表达赋予本发明的抗-CD123 CAR的本发明的CAR的免疫细胞确实触发了不包含人抗鼠抗体(HAMA)响应的免疫响应。
根据本发明，有效量的本发明的工程化免疫细胞可以单独或与其他治疗组合向对其需要的患者给予至少一次。
多核苷酸，载体
本发明还涉及多核苷酸，编码根据本发明的上述CAR的载体。
多核苷酸可以包括在表达组件或表达载体(例如，用于引入到细菌宿主细胞中的质粒，或用于转染昆虫宿主细胞的病毒载体如杆状病毒载体，或用于转染哺乳动物宿主细胞的质粒或病毒载体如慢病毒)中。
在具体的实施方式中，不同核酸序列可以包括于一个包含编码核糖体跳过序列，如编码2A肽的序列的核酸序列的多核苷酸或载体中。在小核糖核酸病毒的口蹄疫病毒亚型中识别的2A肽导致核糖体从一个密码子“跳过”至下一密码子，而不在密码子编码的两个氨基酸之间形成肽键(参见(Donnelly and Elliott 2001；Atkins，Wills et al.2007；Doronina，Wu et al.2008))。“密码子”是指由核糖体转译成一个氨基酸残基的mRNA(或DNA分子的有义链)上的三个核苷酸。因此，当多肽被框内的2A寡肽序列分离时，两个多肽可以由mRNA内的单个连续的开放阅读框合成。这种核糖体跳过机制是本领域公知的，并已知由几个载体用于表达由单个信使RNA编码的几种蛋白。
为了将跨膜多肽导入宿主细胞的分泌路径，在多核苷酸序列或载体序列中提供了分泌信号序列(也称为先导序列(leader sequence)，前导序列(prepro sequence)或前序列(pre sequence))。分泌信号序列可操作地连接到跨膜核酸序列，即两个序列在正确的阅读框内连接并定位为将新合成的多肽导入宿主细胞的分泌路径中。分泌信号序列通常位于编码所感兴趣的多肽的核酸序列的5'，尽管某些分泌信号序列可以位于所感兴趣的核酸序列的其他位置(参见例如，Welch等的美国专利No.5，037，743；Holland等的美国专利No.5，143，830)。在优选的实施方式中，信号肽包含氨基酸序列SEQ ID NO:1和2或与SEQ ID NO:1或2，优选SEQ ID NO:1至少90％，95％，97％或99％的序列一致性。
本领域技术人员将认识到，考虑到遗传密码的简并性，这些多核苷酸分子之中相当大的序列变化是可能的。优选地，本发明的核酸序列对于哺乳动物细胞中的表达，优选人细胞中的表达是密码子优化的。密码子优化是指在给定物种中高度表达的基因中通常罕见的密码子的感兴趣的序列由该物种中高度表达的基因中通常常见的密码子替换，这种密码子编码如被替换的密码子的氨基酸。
在一个实施方式中，编码本发明的CD123 CAR的不同核酸序列可以包括于一个多核苷酸或载体中。
在更优选的实施方式中，要求保护的本发明涉及允许本发明的CAR稳定表达的载体。此处稳定是指本发明的CAR在注射后至少1年内在工程化细胞的细胞表面上被检测到。
在另一实施方式中，要求保护的本发明涉及允许本发明的CD123 CAR，优选SEQ IDNO.31，SEQ ID NO 32或SEQ ID NO 160稳定表达的载体。
在优选的实施方式中，本发明提供了包含编码本发明的任一种CD123 CAR，优选SEQ ID NO31、SEQ ID NO 32或SEQ ID NO.160的CD123 CAR的序列的pCLS27333载体。
细胞
根据本发明的细胞是指功能上参与先天和/或适应性免疫响应的引发和/或执行的造血源的细胞。根据本发明的细胞优选是从供体获得的T细胞。根据本发明的所述T细胞可以源自干细胞。干细胞可以是成体干细胞，胚胎干细胞，更具体地非人类干细胞、脐带血干细胞、祖细胞、骨髓干细胞、全能干细胞或造血干细胞。在优选的实施方式中，细胞是人类细胞、具体地人类干细胞。在更优选的实施方式中，细胞是人类T细胞，具体地人类工程化T细胞。
代表性的人类干细胞是CD34 +细胞。所述分离的细胞也可以是树突细胞、杀手树突细胞、肥大细胞、NK细胞、B细胞或选自由炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞或辅助T淋巴细胞组成的组的T细胞。在另一实施方式中，所述细胞可以源自由CD4+T淋巴细胞和CD8+ T淋巴细胞组成的组。在优选的实施方式中，所述细胞可以源自由工程化CD4+ T淋巴细胞和工程化CD8+ T淋巴细胞组成的组。
在本发明的细胞的扩增和遗传改造之前，可以通过各种非限制性方法从受试者获得细胞源。细胞可以获得自许多非限制性来源，包括外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。在本发明的某些实施方式中，可以使用本领域技术人员可用的和已知的任何数量的T细胞系。在另一实施方式中，所述细胞优选源自健康供体。在另一实施方式中，所述细胞是具有不同表型特性的混合细胞群体的部分。
优选地，干细胞的分离和制备不需要破坏至少一个人类胚胎。考虑操作自体治疗法，免疫细胞可以源自患者，或考虑产生同种异体细胞，可以源自一个或多个供体，其可以用于同种异体治疗。
更优选地，本发明的工程化免疫细胞在细胞表面上表达对应于SEQ ID NO 31，SEQID NO 32或SEQ ID NO 33的抗CD123 CAR，更加优选地，本发明的工程化免疫细胞表达相应于人源化SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 32的人源化抗CD123 CAR。
在一个实施方式中，本发明的工程化免疫细胞表达对应于SEQ ID NO.34至SEQ IDNO.159，优选SEQ ID NO.34至SEQ ID NO.117，更优选SEQ ID NO.76至SEQ ID NO.117的抗CD123 CAR。
在这些抗CD123 CAR之中，包含
VH1/VL1，VH1/VL3；VH1/VL4；
VH2/VL2，VH2/VL3，VH2/VL4；
VH3/VL1，VH3/VL2，VH3/VL3，VH3/VL4
VH4/VL1，VH4/VL2，VH4/VL3，VH4/VL4
的那些是优选的；
包含VH1/VL1，VH1/VL3；
VH2/VL4；
VH3/VL1，VH3/VL2，VH3/VL3，
VH4/VL1，VH4/VL2，VH4/VL3，VH4/VL4的那些是更优选的，
并且包含VH3/VL2，VH4/VL1，VH4/VL2，VH4/VL3，VH4/VL4的那些是更加优选的。
最优选的是具有人源化Klone 43(huK43)和
VH10a/VL1a
VH9a/VL6a
VH10a/VL3a
VH9a/VL8a
VH2a/VL3a
VH10a/VL9 a
VH9a/VL3a
VH2a/VL1 a
的那些。
在一个实施方式中，本发明的工程化免疫细胞表达对应于SEQ ID NO.160和SEQID NO.172至SEQ ID NO.187的抗CD123 CAR。
工程化赋予CAR的免疫细胞的方法：
本发明包括制备用于免疫疗法的免疫细胞的方法，包括将编码先前描述于WO2014/130635，WO2013/176916，WO2013/176915(通过引证并入本文)中的CD123 CAR的多核苷酸或载体体外引入免疫细胞中。
在优选的实施方式中，考虑到在免疫细胞中稳定表达，所述多核苷酸包括于慢病毒载体中。
在更优选的实施方式中，考虑到在免疫细胞中稳定表达，所述多核苷酸包括在慢病毒载体中。
根据进一步的实施方式，所述方法进一步包括遗传改造所述细胞而使其更适合同种异体移植并降低GVHD响应的步骤。
通过灭活至少一种编码T细胞受体(TCR)组件的基因来改造T-细胞。
根据第一方面，例如，如WO2013/176915中所述，通过使至少一个表达T细胞受体(TCR)的一个或多个组件的基因失活，可以使免疫细胞较不同种异体，这可以与编码或调节HLA或β2m蛋白表达的基因的灭活组合。因此，移植物抗宿主综合征和移植排异的风险会显著降低。
因此，当免疫细胞是T-细胞时，本发明还提供了工程化较不同种异体的T细胞的方法。
使细胞较不同种异体的方法可以包括使至少一个编码T细胞受体(TCR)组件的基因，特别是TCRα，TCRβ基因失活的步骤。
WO2013/176915中公开的通过灭活T细胞受体(TCR)的一个或多个组件来制备适于同种异体移植的表达CAR的免疫细胞的方法通过引证结合于本文中。
本发明包括表达抗CD123 CAR的免疫细胞，其中表达一个或多个T细胞受体(TCR)的组件的至少一个基因已被灭活。因此，本发明提供了表达抗CD123 CAR的T细胞，其中CAR源自Klon 43，特别是与SEQ ID N°31具有至少80％的一致性，并且其中至少一个表达T细胞受体(TCR)的一个或多个组件的基因被灭活。
本发明包括表达抗CD123 CAR的免疫细胞，其中至少一个表达T细胞受体(TCR)的一个或多个组件的基因已被灭活。因此，本发明提供了表达抗CD123 CAR的T细胞，其中CAR源自Klon 43，特别是具有与SEQ ID N°32至少80％的一致性，并且其中至少一个表达T细胞受体(TCR)的一个或多个组件的基因已被灭活。
本发明包括表达抗CD123 CAR的免疫细胞，其中至少一个表达T细胞受体(TCR)的一个或多个组件的基因已被灭活。因此，本发明提供了表达抗CD123 CAR的T细胞，其中CAR源自Klon 43，特别是具有与SEQ ID N°160至少80％的一致性并且其中至少一个表达T细胞受体(TCR)的一个或多个组件的基因已被灭活。
根据本发明，其中T细胞受体(TCR)的一个或多个组件灭活的抗CD123 CAR免疫细胞旨在用作药物。
通过灭活TCR基因，旨在使所感兴趣的基因不以功能性蛋白形式表达。在具体的实施方式中，该方法的遗传改造依赖于所提供的待工程化的细胞中一种稀切内切核酸酶的表达，使得所述稀切内切核酸酶特异性催化一种靶基因中的切割，从而使所述靶基因失活。由稀切内切核酸酶引起的核酸链断裂通常通过同源重组或非同源末端连接(NHEJ)的独特机制修复。然而，NHEJ是不完美的修复过程，通常会导致在切割位点上DNA序列的变化。机制涉及通过直接再连接(Critchlow and Jackson 1998)或经由所谓的微生物学介导的末端连接(Betts，Brenchley et al.2003；Ma，Kim et al.2003)重新连接两个DNA端的剩余部分。经由非同源末端连接(NHEJ)的修复通常导致小的插入或缺失，并可以用于产生特异性基因敲除。所述改造可以是至少一个核苷酸的取代，缺失或添加。其中已经发生裂解诱导的诱变事件，即，与NHEJ事件连续的诱变事件的细胞，可以通过本领域公知的方法识别和/或选择。在具体实施方式中，灭活至少一个编码T细胞受体(TCR)的组件的基因到每个个体样品的细胞中的步骤包括向细胞中引入可以破坏至少一个编码T细胞受体(TCR)的组件的基因的稀切内切核酸酶。在更具体的实施方式中，每个个体样品的所述细胞用编码能够破坏编码T细胞受体(TCR)的组件的至少一个基因的稀切内切核酸酶的核酸转化，且将所述稀切内切核酸酶表达至所述细胞中。
所述稀切内切核酸酶可以是大范围核酸酶，锌指核酸酶，CRISPR/Cas9核酸酶，Argonaute核酸酶，TALE-核酸酶或MBBBD-核酸酶。在优选的实施方式中，所述稀切内切核酸酶是TALE-核酸酶。TALE核酸酶旨在是由源自转录激活子样效应因子(TALE)的DNA结合结构域和一个切割核酸靶序列的核酸酶催化性结构域组成的融合蛋白(Boch，Scholze etal.2009；Moscou and Bogdanove 2009；Christian，Cermak et al.2010；Cermak，Doyle etal.2011；Geissler，Scholze et al.2011；Huang，Xiao et al.2011；Li，Huang etal.2011；Mahfouz，Li et al.2011；Miller，Tan et al.2011；Morbitzer，Romer etal.2011；Mussolino，Morbitzer et al.2011；Sander，Cade et al.2011；Tesson，Usal etal.2011；Weber，Gruetzner et al.2011；Zhang，Cong et al.2011；Deng，Yan et al.2012；Li，Piatek et al.2012；Mahfouz，Li et al.2012；Mak，Bradley et al.2012)。在本发明中，新的TALE-核酸酶设计用于精确靶向过继性免疫治疗策略的相关基因。
识别和切割靶序列的优选TALE核酸酶描述于PCT/EP2014/075317中。具体地，可以将其它催化性结构域进一步引入到具有所述稀切内切核酸酶的细胞中以增加诱变，以增强其灭活靶向基因的能力。更具体地，所述其它催化性结构域是DNA末端加工酶。DNA末端加工酶的非限制性实例包括5-3'外切核酸酶，3-5'外切核酸酶，5-3'碱性外切核酸酶，5'侧翼内切核酸酶，解旋酶，磷酸酶，水解酶和非模板依赖性DNA聚合酶。这种催化性结构域的非限制性实例包括选自由hExoI(EXO1_HUMAN)、酵母ExoI(EXO1_YEAST)、大肠杆菌ExoI、人TREX2、小鼠TREX1、人TREX1、牛TREX1、大鼠TREX1、TdT(末端脱氧核苷酸基转移酶)、人DNA2、酵母DNA2(DNA2_YEAST)组成的组中的蛋白结构域或蛋白结构域的催化活性衍生物。在优选的实施方式中，所述其它催化性结构域具有3'-5'外切核酸酶活性，并且在更优选的实施方式中，所述其它催化性结构域是TREX，更优选TREX2催化性结构域(WO2012/058458)。在另一个优选的实施方式中，所述催化性结构域由单链TREX2多肽编码。所述其它催化性结构域可以可选地通过肽接头融合至根据本发明的核酸酶融合蛋白或嵌合蛋白中。
已知内切核酸断裂会促进同源重组的速率。因此，在另一实施方式中，该方法的遗传改造步骤进一步包括将包含至少与一部分靶核酸序列同源的序列的外源核酸导入细胞中，使得同源重组发生于靶核酸序列和外源核酸之间的步骤。在具体实施方式中，所述外源核酸包含分别与靶核酸序列的5'区域和3'区同源的第一和第二部分。这些实施方式中的所述外源核酸还包含位于第一和第二部分之间不含与靶核酸序列的5'区和3'区同源的第三部分。在靶核酸序列切割后，会在靶核酸序列和外源核酸之间刺激同源重组事件。优选地，在所述供体基质内使用至少50bp，优选大于100bp，而更优选大于200bp的同源序列。在具体的实施方式中，同源序列可以是200bp至6000bp，更优选1000bp至2000bp。实际上，共有的核酸同源性位于断裂位点的上游和下游侧接的区域内，并且要引入的核酸序列应位于两臂之间。
药物抗性T-细胞
本发明人寻求工程化用于免疫疗法的TCR KO T细胞，特别是工程化可以与治疗药物(抗癌药物)组合使用的表达SEQ ID NO°31，SEQ ID NO°32，或SEQ ID NO 160的TCR KO抗CD123 CAR的免疫细胞。
如本文所用的对药剂“抗性或耐受”的细胞是指已经遗传改造使得细胞增殖并在一定量的抑制或防止没有遗传改造的细胞增殖的药物存在下活性的细胞。
通过使基因失活，旨在使所感兴趣的基因不以功能性蛋白形式表达。在具体实施方式中，该方法的遗传改造依赖于提供待工程化的细胞中一种稀切内切核酸酶的表达，使得所述稀切内切核酸酶特异性催化一种靶向基因中的切割，从而使靶基因失活。在具体的实施方式中，灭活至少一个药物敏化基因的步骤包括向细胞中引入可以破坏至少一个药物敏化基因的稀切内切核酸酶。在更具体的实施方式中，所述细胞用编码能够破坏药物敏化基因的稀切内切核酸酶的核酸转化，且将所述稀释内切核酸酶被表达至细胞中。所述稀切内切核酸酶可以是大范围核酸酶，锌指核酸酶，CRISPR/Cas9核酸酶，A MBBBD核酸酶或TALE-核酸酶。在优选实施方式中，稀切内切核酸酶是TALE-核酸酶。
在优选的实施方式中，可以灭活以赋予T细胞药物抗性的药物敏化基因是人脱氧胞苷激酶(dCK)基因。该酶是脱氧核糖核苷脱氧胞苷(dC)，脱氧鸟苷(dG)和脱氧腺苷(dA)的磷酸化所必需的。嘌呤核苷酸类似物(PNAs)通过dCK代谢成单-、二-和三-磷酸PNA。它们的三磷酸酯形式，且特别是氯法拉滨三磷酸酯会与ATP竞争DNA合成，充当促凋亡剂，并是参与三核苷酸生产的核糖核苷酸还原酶(RNR)的强效抑制剂。
优选地，T细胞中dCK的失活由TALE核酸酶介导。为了实现这一目标，已经设计了几对dCK TALE核酸酶，在多核苷酸水平下组装并通过测序验证。根据本发明可以使用的TALE核酸酶对的实例描述于PCT/EP2014/075317中。
T细胞中的这种dCK失活赋予了对嘌呤核苷类似物(PNAs)，如氯法拉宾和氟达拉滨的抗性。
在更优选的实施方式中，T细胞中的dCK失活与TRAC基因的失活相结合，赋予这些双敲除(KO)T细胞对药物如氯法拉滨的耐药性，以及比具有完整TCR的相同细胞更低的同种异体性。这种双重特征尤其适用于治疗目的，允许用于免疫疗法的“现成”同种异体细胞结合化疗治疗患癌症，优选难治的复发性AML或BPDNL的患者。
在SEQ ID NO°31，SEQ ID NO°32，或SEQ ID NO 160的CD123 CAR表达之前或之后，可以同时或依次实施这种双重KO灭活dCK/TRAC。在PCT/EP2014/075317中描述了本发明中成功的TALE核酸酶dCK/TRAC对的一个实例，具体地，2个位点中的靶序列(dCK和TRAC)。
根据另一方面，本发明的表达CD123 CAR的T细胞(表达SEQ ID NO°31，SEQ ID NO°32，或SEQ ID NO 160的TCR KO抗CD123 CAR的免疫细胞)可以进一步进行遗传工程化而改进其对用作治疗癌症的标准护理的免疫抑制药物或化疗治疗的耐受性。
几种细胞毒性药剂(抗癌药物)如抗代谢物，烷化剂，蒽环霉素，DNA甲基转移酶抑制剂，铂化合物和纺锤体抑制剂已经开发用于杀死癌细胞。然而，这些药剂与新疗法，如免疫疗法一起引入，是有问题的，因为这些药物会影响免疫T细胞的功能/存活。例如，由于药剂的非特异性毒性特征，化疗剂可能会有损于建立强健的抗肿瘤免疫活性细胞。靶向细胞增殖途径的基于小分子的疗法也可能会阻碍抗肿瘤免疫的建立。如果短时有效的化疗方案可以与新型的免疫活性细胞疗法相结合，则可以实现抗肿瘤疗法的显著改进(Dasgupta，McCarty et al.2011)。
为了改进癌症治疗和选择性植入SEQ ID NO 31、SEQ ID NO 32或SEQ ID NO 160的同种异体的表达TCR KO CD123 CAR的T细胞，对所述同种异体T细胞赋予抗药性而保护其免受化疗剂的毒副作用。T细胞的药物抗性也允许其在体内或体外富集，因为表达药物抗性基因的T细胞将会相对于药敏性细胞而存活和增殖。
用于工程化对化疗剂抗性的T细胞的方法公开于PCT/EP2014/075317中，该专利通过引证完全引入本文中。
具体地，本发明公开了工程化适用于免疫疗法的同种异体TCR KO，表达SEQ ID NO31、SEQ ID NO 32或SEQ ID NO 160的CD123 CAR的T细胞的方法，其中将编码T细胞受体(TCR)的组件的至少一个基因灭活，并且将至少一个基因改造而赋予药物抗性，优选灭活dCK基因。
一种工程化适用于与采用嘌呤类似物的组合疗法的表达SEQ ID NO 31、SEQ IDNO 32或SEQ ID NO 160的同种异体CD123 CAR的T细胞的方法，包括：
○提供表达SEQ ID NO°31、SEQ ID NO°32、SEQ ID NO°160的抗CD123 CAR的T细胞，
○通过使至少一个编码T细胞受体(TCR)组件的基因失活来改造所述表达抗CD123CAR的T细胞；
○改造所述表达抗CD123 CAR的T细胞以赋予所述表达抗CD123 CAR的T细胞抗药性；优选赋予对嘌呤类似物的抗性；
○在所述药物存在下扩增所述工程化的表达-CD123 CAR的T细胞，所述药物是选自喷司他丁、氟达拉滨2-脱氧腺苷、克拉屈滨、氯法拉滨、奈拉滨、优选喷司他丁、氟达拉滨单磷酸和2-氯脱氧腺苷(2-CDA)的嘌呤类似物。
可替换地，本发明涉及一种方法，包括：
○提供表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的T细胞，
○通过缺失dck基因，改造所述表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO160的抗CD123 CAR的T细胞，赋予所述表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的T细胞抗药性；优选地，所述药物是嘌呤类似物；
○通过使至少一个编码T细胞受体(TCR)组件的基因失活而改造所述表达SEQ IDNO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的T细胞；
○在药物存在下，扩增所述表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的T细胞，所述药物是选自喷司他丁、氟达拉滨2-脱氧腺苷、克拉屈滨、氯法拉宾、奈拉滨、优选喷司他丁、氟达拉滨单磷酸酯和2-氯脱氧腺苷(2-CDA)的嘌呤类似物。
具体地，本发明涉及工程化适用于免疫疗法的同种异体细胞的方法，其中编码T细胞受体(TCRα)组件的基因被灭活，并且dCK基因改造为赋予对嘌呤类似物的抗性，包括：
○提供表达抗CD123 CAR的T细胞；具体地表达SEQ ID NO°31、SEQ ID NO°32或SEQID NO°160的抗CD123 CAR的T细胞，
○通过使编码T细胞受体(TCRα)组件的基因失活而表达改造SEQ ID NO°31、SEQID NO°32或SEQ ID NO 160的抗CD123 CAR的T细胞；
○灭活所述表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的T细胞中的dCK基因而赋予对嘌呤类似物的抗性；
○在所述药物存在下扩增所述工程化的表达SEQ ID NO°31、SEQ ID NO°32或SEQID NO°160的抗CD123 CAR的T细胞。
可替换地，本发明涉及一种方法，包括：
○提供表达抗CD123 CAR的T细胞；具体地表达SEQ ID NO°31、SEQ ID NO°32或SEQID NO°160的抗CD123 CAR的T细胞，
○灭活表达所述SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的T细胞中的dCK基因而赋予对嘌呤类似物的抗性；
○通过使至少一个编码T细胞受体(TCRα)组件的基因失活而改造所述表达SEQ IDNO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123CAR的T细胞；
○在嘌呤类似物存在下扩增所述工程化的表达抗CD123 CAR的T细胞。
在优选的实施方式中，所提供的表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO°160的抗CD123 CAR的dCK KO，TCR KO T细胞对选自喷司他丁、氟达拉滨2脱氧腺苷、克拉屈滨、氯法拉积或尼拉滨、优选对氟达拉滨单磷酸、或对2氯脱氧腺苷(2CDA)的药物抗性。
赋予表达抗CD123 CAR的免疫细胞抗药性的基因表达
在具体实施方式中，所述药物抗性可以通过表达至少一种药物抗性基因而赋予于本发明的T细胞。所述药物抗性基因是指编码对药剂，如化疗剂(例如，氨甲喋呤)的“抗性”的核酸序列。换言之，药物抗性基因在细胞中的表达允许细胞在药物存在下增殖的程度大于没有药物抗性基因的相应细胞的增殖或在所述药物存在下存活。药物抗性基因在细胞中的表达允许细胞在药物存在下的增殖并且不影响其活性。本发明的药物抗性基因可以编码对于抗代谢物、甲氨蝶呤、长春花碱、顺铂，烷化剂，蒽环霉素，细胞毒性抗生素，抗免疫亲和素，其类似物或衍生物的抗性。
在一个实施方式中，药物抗性基因赋予对药物(或药剂)，特别是选自阿糖胞苷(Aracytine)，胞嘧啶阿拉伯糖苷(Cytosine Arabinoside)、安吖啶(amsacrine)、柔红霉素(Daunorubicine)、伊达比星(Idarubicine)、诺安托(Novantrone)、米托蒽醌(Mitoxantrone)、足叶乙苷(Vepeside)、依托泊苷(Etoposide)(VP16)、三氧化二砷(arsenic trioxyde)、反式维甲酸(transretinoic acid)，三氧化三砷、全反式维甲酸的组合、氮芥(mechlorethamine)、甲基苄肼(procarbazine)、苯丁酸氮芥(chlorambucil)、阿糖胞苷(cytarabine)、蒽环霉素、6-硫鸟嘌呤(thioguanine)、羟基脲、泼尼松及其组合的抗性。
几种已经确定的药物抗性基因可以潜在地用于赋予本发明的表达CD123 CART细胞抗药性(Takebe，Zhao et al.2001；Sugimoto，Tsukaharaet al.2003；Zielske，Reese etal.2003；Nivens，Felder et al.2004；Bardenheuer，Lehmberg et al.2005；Kushman，Kabler et al.2007)。
抗药性基因的一个实例也可以是二氢叶酸还原酶(DHFR)编码基因的突变或改造形式。DHFR是参与调节细胞中四氢叶酸的量的酶，并是DNA合成所必需的。叶酸类似物如甲氨蝶呤(MTX)会抑制DHFR，并因此在临床上用作抗肿瘤剂。已经描述了具有对通过疗法中所用的抗叶酸盐的抑制增加的抗性的DHFR的不同突变体形式。在具体的实施方式中，根据本发明的抗药性基因可以是编码包含赋予对抗叶酸治疗如甲氨蝶呤的抗性的至少一个突变的人野生型DHFR(GenBank：AAH71996.1)的突变形式的核酸序列。在具体的实施方式中，DHFR的突变形式在位置G15，L22，F31或F34，优选在位置L22或F31上包含至少一个突变的氨基酸(Schweitzer，Dicker et al.1990；国际申请WO94/24277；美国专利US6,642,043)。在具体的实施方式中，所述DHFR突变体形式包含位置L22和F31处的两个突变的氨基酸。本文描述的氨基酸位置的对应关系通常关于GenBank：AAH71996.1中列出的野生型DHFR多肽形式的氨基酸的位置表示。在具体的实施方式中，位置15上的丝氨酸残基优选被色氨酸残基取代。在另一具体的实施方式中，位置22上的亮氨酸残基优选被将会破坏突变型DHFR与抗叶酸剂的结合的氨基酸，优选被不带电荷的氨基酸残基如苯丙氨酸或酪氨酸取代。在另一具体实施方式中，位置31或34上的苯丙氨酸残基优选被小的亲水性氨基酸如丙氨酸，丝氨酸或甘氨酸替代。
正如本文所用，“抗叶酸剂”或“叶酸类似物”是指以某种程度干扰叶酸代谢途径的分子。抗叶酸剂的实例包括，例如，甲氨蝶呤(MTX)；氨基蝶呤(aminopterin)；曲麦克特(trimetrexate)(NeutrexinTM)；依达曲沙(edatrexate)；N10-炔丙基-5,8-二脱氮叶酸(CB3717)；ZD1694(Tumodex)，5,8-二脱氮异叶酸(IAHQ)；5,10-二脱氮四氢叶酸(DDATHF)；5-脱氮叶酸；PT523(Nα-(4-氨基-4-脱氧蝶酰基)-Nδ-半邻苯二甲酰基-L-鸟氨酸)；10-乙基-10-脱氮氨基蝶呤(DDATHF，lomatrexol)；吡曲克辛(piritrexim)；10-EDAM；ZD1694；GW1843；培美曲塞(Pemetrexate)和PDX(10-炔丙基-10-脱氮氨基蝶呤)。
抗药性基因的另一个实例也可以是肌苷-5'-单磷酸脱氢酶II(IMPDH2)，鸟苷核苷酸从头合成中的限速酶的突变或改造形式。IMPDH2的突变体或改造形式是IMPDH抑制剂抗性基因。IMPDH抑制剂可以是霉酚酸(MPA)或其前药霉酚酸酯(MMF)。突变体IMPDH2可以在野生型人IMPDH2(NP_000875.2)的MAP结合位点上包含导致对IMPDH抑制剂的抗性显著增加的至少一个，优选两个突变。突变优选在位置T333和/或S351上(Yam，Jensen et al.2006；Sangiolo，Lesnikova et al.2007；Jonnalagadda，Brown et al.2013)。在具体的实施方式中，位置333上的苏氨酸残基被异亮氨酸残基取代，且位置351上的丝氨酸残基被酪氨酸残基取代。本文描述的氨基酸位置的对应关系通常以NP_000875.2中的野生型人IMPDH2多肽的形式的氨基酸的位置表示。
另一种药物抗性基因是钙调磷酸酶的突变形式。钙调磷酸酶(PP2B)，普遍表达的丝氨酸/苏氨酸蛋白磷酸酶，涉及许多生物过程，并是T细胞活化的核心。钙调磷酸酶是由催化性亚单元(CnA；三种同种型)和调节亚单元(CnB；两种同种型)组成的异源二聚体。在与T细胞受体结合后，钙调磷酸酶使转录因子NFAT去磷酸化，使其转运到细胞核和活性关键靶基因如IL2。与FKBP12复合的FK506，或与CyPA阻断NFAT复合的环胞菌素A(CsA)进入钙调磷酸酶的活性位点，阻止其脱磷酸化，从而抑制T细胞活化(Brewin，Mancao et al.2009)。本发明的抗药性基因可以是编码对钙调神经磷酸酶抑制剂如FK506和/或CsA抗性的钙调磷酸酶的突变形式的核酸序列。在具体的实施方式中，所述突变体形式可以包含以下位置上的野生型钙调磷酸异源二聚体a的至少一个突变的氨基酸：V314、Y341、M347、T351、W352、L354、K360、优选在位置T351和L354或V314和Y341上双重突变。在具体的实施方式中，对应于GenBank：ACX34092.1的序列的位置341上的缬氨酸残基可以被赖氨酸或精氨酸残基取代，位置341上的酪氨酸残基可以被苯丙氨酸残基取代；位置347上的甲硫氨酸可以被谷氨酸、精氨酸或色氨酸残基替代；位置351上的苏氨酸可以被谷氨酸残基取代；位置352上的色氨酸残基可以被半胱氨酸，谷氨酸或丙氨酸残基取代，位置353上的丝氨酸可以被组氨酸或天冬酰胺残基取代，位置354上的亮氨酸可以被丙氨酸残基取代；位置360上的赖氨酸可以被丙氨酸或苯丙氨酸残基取代。本文描述的氨基酸位置的对应关系通常关于(GenBank：ACX34092.1)中描述的野生型人钙调磷酸酶异源二聚体a多肽的形式的氨基酸的位置表示。
在另一具体实施方式中，所述突变体形式可以包含以下位置上的野生型钙调磷酸酶异源二聚体b的至少一个突变的氨基酸：V120，N123，L124或K125，优选在位置L124和K125上双重突变。在具体的实施方式中，对应于GenBank：ACX34095.1的氨基酸序列中，位置120上的缬氨酸可以被丝氨酸，天冬氨酸，苯丙氨酸或亮氨酸残基取代；位置123上的天冬酰胺可以被色氨酸，赖氨酸，苯丙氨酸，精氨酸，组氨酸或丝氨酸取代；位置124上的亮氨酸可以被苏氨酸残基取代；位置125上的赖氨酸可以被丙氨酸，谷氨酸，色氨酸取代，或两个残基如亮氨酸-精氨酸或异亮氨酸-谷氨酸可以在位置125上的赖氨酸之后加入。本文的氨基酸位置的对应关系通常关于(GenBank：ACX34095.1)中描述的野生型人钙调磷酸酶异源二聚体b多肽的形式的氨基酸的位置表示。
另一种抗药性基因是编码人烷基鸟嘌呤转移酶(hAGT)的0(6)-甲基鸟嘌呤甲基转移酶(MGMT)。AGT是赋予对烷基化剂如亚硝基脲和替莫唑胺(TMZ)的细胞毒性作用的抗性的DNA修复蛋白。6-苄基鸟嘌呤(6-BG)是增强亚硝基脲毒性的AGT抑制剂，并与TMZ共同给予而增强该药剂的细胞毒性作用。编码AGT变体的几种MGMT突变体形式对6-BG的灭活作用高度抗性，但保留了其修复DNA损伤的能力(Maze，Kurpad et al.1999)。在具体的实施方式中，AGT突变体形式可以包含氨基酸序列SEQ ID NO:18(UniProtKB：P16455)中的野生型AGT位置P140的突变氨基酸。在优选的实施方式中，位置140上的所述脯氨酸被赖氨酸残基取代。
另一种抗药性基因可以是多药物抗性蛋白1(MDR1)基因。这个基因编码膜糖蛋白，称为P-糖蛋白(P-GP)，涉及代谢副产物跨细胞膜的转运。P-Gp蛋白对几种结构不相关的化疗剂显示出广泛的特异性。
过表达多药物抗性蛋白质1已经描述为赋予对药物如米托蒽醌的抗性(CharlesS.Morrow，Christina Peklak-Scott，Bimjhana Bishwokarma，Timothy E.Kute，PamelaK.Smitherman，and Alan J.Townsend.Multidrug Resistance Protein 1(MRP1，ABCC1)Mediates Resistance to Mitoxantrone via Glutathione-Dependent Drug Efflux MolPharmacol April 2006 69:1499-1505)。
因此，通过编码MDR-1(NP_000918)的核酸序列的表达可以将药物抗性赋予细胞。
制备根据本发明的抗药性细胞的又一种方法是制备具有特异性突变，如人拓扑异构酶II基因中的Arg486和Glu571上的突变的细胞，以赋予对安吖啶的抗性(S.PATEL，B.A.KELLER，and L.M.FISHER.2000.MOLECULAR PHARMACOLOGY.Vol 57：p784–791(2000)。
制备根据本发明的抗药性细胞的另一种方法是制备过表达microRNA-21的细胞以赋予对柔红霉素的抗性(Involvement of miR-21 in resistance to daunorubicin byregulating PTEN expression in the leukaemia K562 cell line Bai，Haitao etal.FEBS Letters，Volume 585，Issue 2，402–408)。
在优选的实施方式中，本发明的细胞携带这种赋予抗药性的mRNA或蛋白质，并且还包含抑制性mRNA或基因，其表达由另一药物调节，允许在所述其他药物存在下，或在给予所述其他药物时选择性地破坏根据本发明的抗药性细胞。
抗药性基因也可以赋予对细胞毒性抗生素的抗性，并可以是ble基因或mcrA基因。当暴露于化疗剂，分别为博莱霉素或丝裂霉素C时，免疫细胞中ble基因或mcrA的异位表达具有选择性优势。
基因治疗最实用的方法是通过使用采用载体，优选病毒载体的有效基因递送来添加基因以工程化T细胞。因此，在具体的实施方式中，本发明提供了通过将优选由至少一种载体编码的转基因引入细胞中以赋予本发明的CD123免疫细胞抗药性的方法。
将基因随机插入基因组中可能会导致插入的基因或插入位点附近的基因不适当的表达。使用包含内源序列的外源核酸向基因组中特异性位点的靶基因的同源重组的特异性基因疗法，可以允许T细胞的安全工程化。如上所述，根据本发明的方法的遗传改造步骤可以包括将包含至少一个编码抗药性基因和内源性基因的部分的序列的外源性核酸导入细胞中，使得同源重组发生于内源性基因和外源性核酸之间的步骤。在具体的实施方式中，所述内源性基因可以是野生型“抗药性”基因，使得之在同源重组后，野生型基因被赋予对药物的抗性的基因的突变形式取代。
已知内切核酸水解裂解会刺激同源重组的速率。因此，在具体的实施方式中，本发明的方法进一步包括在细胞中表达能够切割内源性基因内的靶序列的稀切内切核酸酶的步骤。所述内源性基因可以编码例如DHFR、IMPDH2、钙调磷酸酶或AGT。所述稀切内切核酸酶可以是TALE核酸酶、锌指核酸酶、CRISPR/Cas9内切核酸酶、MBBBD-核酸酶或巨型核酸酶。
可以被灭活的酶的另一个实例是人类次黄嘌呤-鸟嘌呤磷酸核糖基转移酶(HPRT)基因(GenBank：M26434.1)。具体地，HPRT可以在工程化T细胞中被灭活以赋予对细胞生长抑制代谢物6-硫鸟嘌呤(6TG)的抗性，其通过HPT转化为细胞毒性硫鸟嘌呤核苷酸并在当前用于治疗患癌症，特别是白血病的患者(Hacke，Treger et al.2013)。鸟嘌呤类似物被HPRT转移酶代谢，HPRT转移酶催化磷酸核糖基部分的加成并使得可以形成TGMP鸟嘌呤类似物，包括6-巯基嘌呤(6MP)和6-硫鸟嘌呤(6TG)，其通常用作淋巴消除(lymphodepleting)药物治疗ALL。它们被HPRT(次黄嘌呤磷酸核糖基转移酶，其催化磷酸核糖基部分的加成并可以形成TGMP)代谢。它们随后的磷酸化导致其最终整合到DNA中的三磷酸化形式的形成。一旦引入DNA中，硫代GTP通过其硫醇盐分组作用损害DNA复制的保真度，并产生对细胞完整性高度有害的随机点突变。
在另一实施方式中，通常在T细胞表面表达的CD3的失活可以赋予抗CD3抗体如泰瑞珠单抗的抗性。
组合治疗
本文所用的术语“治疗剂”，“化疗剂”或“药物”或“抗癌药物”是指可以与癌细胞相互作用，从而降低细胞的增殖状态和/或杀死细胞的药物，优选化合物或其衍生物。化疗剂或“抗癌药物”的实例包括，但不限于，烷化剂(例如，白消安(Busulfan)、卡铂(Carboplatine)、苯丁酸氮芥(Chlorambucil)、顺铂(Cisplatine)、环磷酰胺(Cyclophosphamide)、异环磷酰胺(Ifosfamide)、美法仑(Melphalan)、氮芥(Méchloréthamine)、奥沙利铂(Oxaliplatine)、乌拉莫司汀(Uramustine)、·替莫唑胺(Temozolomide)、福莫司汀(Fotemustine))，代谢拮抗剂(例如，嘌呤核苷抗代谢物，如氯法拉滨，氟达拉滨或2'-脱氧腺苷，甲氨蝶呤(MTX)，5-氟尿嘧啶或其衍生物，硫唑嘌呤(Azathioprine)、卡培他滨(Capecitabine)、阿糖胞苷(Cytarabine)、·氟尿苷(Floxuridine)、·氟尿嘧啶、·吉昔单抗(Gemcitabine)、·甲氨蝶呤、培美曲塞)、抗肿瘤抗生素(例如、丝裂霉素、阿霉素、博莱霉素、·柔红霉素、·多柔比星、·表柔比星、·羟基脲、·伊达比星、·丝裂霉素C、·米托蒽醌)、植物源的抗肿瘤药物(例如长春新碱、长春地辛、紫杉酚(Taxol)、长春花碱、·(长春瑞滨(Vinorelbine))、·多西他赛(Docetaxel)、·紫杉醇)、拓扑异构酶抑制剂(伊立替康(Irinotecan)、·托泊替康(Topotecan)、·依托泊苷(Etoposide))。
在优选的实施方式中，本文所用的治疗剂，化疗剂是指可以用于治疗癌症，具体地治疗造血液癌症细胞且更具体地AML，更加具体地难治性复发性AML，从而降低癌细胞的增殖状态和/或杀死癌细胞的化合物或其衍生物。
化疗剂的其它实例包括，但不限于阿糖胞苷、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(VP16)、三氧化二砷、反式维甲酸、氮芥、甲基苄肼、苯丁酸氮芥、及它们的组合。
在本发明的其他实施方式中，本发明的细胞结合选自以下的药物(或药剂)给予患者：阿糖胞苷(Aracytine)、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(VP16)、三氧化二砷、反式维甲酸、阿糖胞苷(cytarabine)、蒽环霉素、6-硫鸟嘌呤、羟基脲、泼尼松、及它们的组合。
这种药剂可以进一步包括但不限于抗癌剂TRIMETHOTRIXATETM(TMTX)、TEMOZOLOMIDETM、RALTRITREXEDTM、S-(4-硝基苄基)-6-硫代肌苷(NBMPR)、6-苄基鸟嘌呤(6-BG)、双氯亚硝基脲(BCNU)和CAMPTOTHECINTM，或其任一种的治疗性衍生物。
在更优选的实施方式中，与选自阿糖胞苷、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(VP16)、三氧化二砷、反式维甲酸及它们的组合中的至少一种组合向患者给予表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO 160的具有TCR和dck KO基因的T细胞。
表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO 160的抗CD123 CAR的具有TCR和dck KO基因的T细胞，与至少一种选自阿糖胞苷、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(VP16)、三氧化二砷、反式维甲酸及它们的组合的治疗药物组合用作治疗剂。
优选地，表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO 160的抗CD123 CAR的具有TCR和dck KO基因的T细胞优选与嘌呤类似物(氟达拉滨)组合用作治疗药物。
优选地，表达SEQ ID NO°31、SEQ ID NO°32或SEQ ID NO 160的抗CD123 CAR的具有TCR和dck KO基因的T细胞优选与FLAG治疗组合用作治疗药物。
在一个实施方式中，所述CD123 CAR选自SEQ ID NO 76至SEQ ID NO.117且表达于双TCR dCK KO T细胞中，并结合至嘌呤类似物或FLAG作为治疗药物。
在本发明中，组合治疗包括输液用于分选和/或消除目的的mAb。在优选的实施方式中，mAb是利妥昔单抗。
优选通过静脉内途径给药的利妥昔单抗最大剂量为2,250mg/m2。其不作为静脉内推注或丸剂给药。
表达抗CD123 CAR的免疫细胞的多抗药性
在另一具体实施方式中，本发明人力图寻求开发使用同种异体T细胞，特别是用不同药物治疗患者时对多种药物抗性的表达同种异体抗CD123CAR的T细胞而介导工程化T细胞的选择的“现成”免疫治疗策略。通过遗传工程化多种抗药性的同种异体T细胞，可以显著提高治疗效果。这样的策略可以特别有效地治疗对表现出协同作用的药物组合响应的肿瘤。此外，多重耐药性工程化的T细胞可以使用药物试剂的最小剂量的药剂来扩增和选择。
因此，根据本发明的方法可以包括改造本发明的T细胞而赋予本发明的所述T细胞多重抗药性。所述多重抗药性可以通过表达多于一种抗药性基因或通过灭活多于一种药敏基因赋予。在另一具体实施方式中，通过表达至少一种抗药性基因并使至少一种药敏基因失活，可以赋予所述T细胞多重抗药性。具体地，通过表达至少一种抗药性基因，例如DHFR的突变形式，IMPDH2的突变形式，钙调磷酸酶的突变体形式，MGMT的突变体形式，ble基因和mcrA基因并使至少一种药敏基因如HPRT基因失活，可以赋予T细胞多重抗药性。在优选的实施方式中，通过使HPRT基因失活并表达DHFR的突变形式；或通过灭活HPRT基因并表达IMPDH2的突变形式；或通过使HPRT基因失活并表达钙调磷酸酶的突变形式；通过灭活HPRT基因并表达MGMT的突变形式；通过使HPRT基因失活并表达ble基因；通过使HPRT基因失活并表达mcrA基因，可以赋予多重抗药性。
在一个实施方式中，本发明提供了表达多于一种抗药性基因，或其中多于一种药敏基因失活的同种异体的表达抗CD123 CAR的T细胞。
本发明的表达抗CD123 CAR的免疫细胞中的自杀基因
在一些情况下，由于工程化T细胞可以在给予后扩增并持续多年，因此期望的是包括安全机制以允许选择性消除给予的T细胞。因此，在一些实施方式中，本发明的方法包括用重组自杀基因改造T细胞。所述重组自杀基因用于降低一旦给予受试者，所述T细胞的直接毒性和/或失控增殖的风险(Quintarelli C，Vera F，blood 2007；Tey SK，Dotti G.，Rooney CM，boil blood marrow transplant 2007)。自杀基因使得可以体内选择性消除转化的细胞。具体地，自杀基因具有将无毒前药转化为细胞毒性药物或表达毒性基因表达产物的能力。换句话说，“自杀基因”是编码产物的核酸，其中该产物本身或在其它化合物存在下导致细胞死亡。
这种自杀基因的代表性实例是编码单纯疱疹病毒的胸苷激酶的基因。另外的实例是可以将5-氟胞嘧啶转化为高毒性化合物5-氟尿嘧啶的水痘带状疱疹病毒胸苷激酶和细菌基因胞嘧啶脱氨酶。自杀基因还包括作为非限制性实例的半胱天冬酶-9或半胱天冬酶-8或胞嘧啶脱氨酶。可以使用特定的二聚作用的化学诱导剂(CID)活化半胱天冬酶-9。自杀基因还可以是在细胞表面上表达并可以使细胞对治疗性单克隆抗体敏感的多肽。本文所用的“前药”是指可以用于本发明的方法中的任何可转化为毒性产物的化合物。在本发明的方法中，前药被自杀基因的基因产物转化为毒性产物。这种前药的代表性实例是更昔洛韦，其通过HSV-胸苷激酶在体内转化为毒性化合物。更昔洛韦衍生物随后对肿瘤细胞是有毒的。前药的其他代表性实例包括，无环鸟苷，FIAU[1-(2-脱氧-2-氟-β-D-阿拉伯呋喃糖基)-5-碘尿嘧啶]，VZV-TK的6-甲氧基阿拉伯糖苷和胞嘧啶的5-氟胞嘧啶脱氨酶。
本发明的一个优选自杀基因系统使用了包含由抗CD20mAb利妥昔单抗，特别是如WO2013153391中的所谓RQR8多肽中的QBen10识别的抗原基序的重组抗原多肽。然后可以使用批准的抗体药物利妥昔单抗，在需要时用于细胞消除。
在一个实施方式中，本发明提供了表达SEQ ID NO.31或32的抗CD123 CAR的TCRKO-dCK KO T细胞，其表达允许细胞选择性破坏的RQR8自杀基因。
更优选地，本发明提供了表达抗CD123 CAR的TCR KO-dCK KO T细胞，其中所述CD123 CAR包含允许表达CD123 CAR的细胞选择性破坏的自杀结构域，优选地，所述自杀体结构域包含SEQ ID NO 161的至少两个结构域，更优选地，所述CD123 CAR包含SEQ ID NO171的序列。
用于测试抗药性同种异体CAR T细胞的细胞毒性的CD123+/luc+抗药性Daudi细胞
本发明还包括用于生产表达CD123且对嘌呤类似物抗性的靶细胞的方法。这些靶细胞特别适用于测试本发明的CD123 CAR T细胞的细胞毒性。这些细胞很容易抵抗临床相关剂量的氯法拉滨和港口荧光素酶(harbor luciferase)活性。该特性的组合使其可以在小鼠模型中体内跟踪或在需要时将其破坏。
更具体地，它们可以用于评价在氯法拉滨或其它PNA存在下小鼠中的抗药性T细胞的细胞毒性性质。氯法拉滨抗性Daudi细胞模拟了急性淋巴细胞白血病(ALL)患者复发形式诱导疗法的生理状态，其具有抗药性B细胞恶性肿瘤。因此，这些细胞对于评价抗药性CAR T细胞的可靠性和细胞毒性是非常感兴趣的。优选地，这些靶细胞是CD123+萤光素酶+Daudi细胞。
分离的细胞
本发明涉及表达与CD123结合的CD123 CAR的分离的细胞。因此，本发明涉及表达抗CD123 CAR的细胞。在具体的实施方式中，所述表达抗CD123 CAR的细胞对至少一种药物抗性，和/或包含至少一个破坏的编码T细胞受体成分的基因。
在优选的实施方式中，本发明涉及分离的T细胞，其表达结合CD123的CAR并且对至少一种嘌呤类似物抗性，并且包含破坏的编码T细胞受体α组件的基因。
在更优选的实施方式中，本发明涉及分离的T细胞，其表达结合至CD123的SEQ IDNO 31，32或160的CAR，并且破坏CD123表达细胞并且对至少一种嘌呤类似物抗性，并且包含被破坏的编码T细胞受体α组分的基因。
在更优选的实施方式中，本发明涉及分离的T细胞，其表达结合至CD123的SEQ IDNO 160的CAR，并且破坏CD123表达细胞，并且对至少一种嘌呤类似物抗性，并且包含被破坏的编码T细胞受体β组分的基因。
在另一具体实施方式中，所述表达抗CD123 CAR的T细胞包含至少一个被破坏的药物致敏基因，如dCK或HPRT基因。在更具体的实施方式中，所述分离的抗CD123 CAR T细胞包含破坏的HPRT基因并表达DHFR突变体；所述分离的抗CD123 CAR T细胞包含破坏的HPRT基因并表达IMPDH2突变体；所述分离的抗CD123 CAR T细胞包含破坏的HPRT基因并表达钙调磷酸酶突变体；所述分离的抗CD123 CAR T细胞包含破坏的HPRT基因并表达AGT突变体。
具体地，本发明涉及分离的T细胞，特别是分离的同种异体的表达抗CD123 CAR的T细胞，并且优选包含具有SEQ ID NO 31，32或160的序列的分离的同种异体的表达抗CD123CAR的T细胞，所述分离的同种异体的表达抗CD123 CAR的T细胞对嘌呤类似物更加特别抗性，且特别适用于嘌呤类似物存在下的免疫治疗。
在一方面中，本发明提供了用于工程化分离的免疫细胞而使其对嘌呤类似物(嘌呤核苷酸类似物或PNA)，如氯法拉滨或氟达拉滨抗性的方法，以使其可以用于用这些传统化疗法预治疗的患者中的癌症免疫疗法治疗。
通过灭活负责细胞对药物的敏感性的一个或多个基因(药敏基因)，例如dcK和/或HPRT基因，可以对本发明的分离的T-细胞赋予对药物的抗性。
免疫检查点
本发明提供了表达抗CD123 CAR的同种异体dCK KO T细胞，特别是SEQ ID NO°31或SEQ ID NO°32或SEQ ID NO°160的抗-CD123 CAR，其中至少一种表达一个或多个T细胞受体(TCR)组件的基因被灭活和/或一个选自基因CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、LAG3、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、LAIR1、SIGLEC7、SIGLEC9、CD244、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、CSK、PAG1、SIT1、FOXP3、PRDM1(orblimp1)、BATF、GUCY1A2、GUCY1A3、GUCY1B2、GUCY1B3的基因如WO2014/184741中提及的被灭活。
根据本发明进一步的方面，通过使编码作用为“免疫检查点”，作用为T细胞活化的调节剂的蛋白的基因，如选自以下基因的基因失活，可以进一步操作免疫细胞而使其更具有活性或限制耗尽：CTLA4、PPP2CA、PPP2CB、PTPN6、PTPN22、PDCD1、LAG3、HAVCR2、BTLA、CD160、TIGIT、CD96、CRTAM、LAIR1、SIGLEC7、SIGLEC9、CD244、TNFRSF10B、TNFRSF10A、CASP8、CASP10、CASP3、CASP6、CASP7、FADD、FAS、TGFBRII、TGFBRI、SMAD2、SMAD3、SMAD4、SMAD10、SKI、SKIL、TGIF1、IL10RA、IL10RB、HMOX2、IL6R、IL6ST、CSK、PAG1、SIT1、FOXP3、PRDM1(orblimp1)、BATF、GUCY1A2、GUCY1A3、GUCY1B2、GUCY1B3，优选地，所述基因是PDCD1或CTLA-4。在本发明的T细胞中表达可以减少或抑制的基因的实例如表9中所示。
在一个实施方式中，所述基因是编码β2微球蛋白的作用为T细胞活化的调节剂的基因。
根据本发明进一步的方面，本发明的抗CD123 CAR免疫细胞可以进一步操作而使其对药物，特别是对抗癌症，尤其是表达CD123的细胞介导的癌症，如AML的化疗法期间使用的药物是抗性的。这可以通过引入赋予对所述药物的抗性的基因而实现。通过使用如前所述的基因可诱导抑制/表达系统，可以打开和关闭该基因(Garcia EL，Mills AA(2002)Getting around lethality with inducible Cre-mediated excision.Semin Cell DevBiol 13:151–8，Lewandoski M(2001)Conditional control of gene expression in themouse.Nat Rev Genet 2:743–55；Scharfenberger L，Hennerici T，Kirly G et al.(2014)Transgenic mouse technology in skin biology：Generation of complete ortissue-specific knockout mice.J Invest Dermatol 134:e16；Schwenk F，Kuhn R，Angrand PO et al.(1998)Temporally and spatially regulated somatic mutagenesisin mice.Nucleic Acids Res 26:1427–32)。
因此，本发明的目的是对应于表达SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160的序列的抗CD123 CAR的PNA抗性的免疫T细胞，其中(i)至少一种表达一个或多个T细胞受体(TCR)组件的基因被灭活(ii)并入至少一种赋予对药物(PNA之外)的抗性的基因或使赋予对所述药物(PNA之外)的敏感性的基因缺失或突变而失活(iii)选自表9中公开的基因的另一个基因被灭活。
本发明包括通过本发明方法可获得的分离的抗CD123 CAR免疫细胞或细胞系，更具体地包含本文描述的任何蛋白、多肽、等位变体、改变或缺失的基因或载体的分离的细胞。
该目的提供用于癌症，特别是AML，难治性复发性AML，BPDNL的治疗。
本发明的免疫细胞或细胞系可以进一步包含外源性重组多核苷酸，具体地CAR或自杀基因(编码SEQ ID NO.161)，或它们可以包含编码有助于它们作为治疗产品，理想地作为“现成”产品的效果的检查点蛋白或其配体的修改或缺失的基因。
在另一方面中，本发明涉及用于通过给予至少一次通过上述方法可获得的工程化免疫细胞治疗或预防癌症的方法。
表5：编码在本发明的工程化T细胞中改造的免疫检查点蛋白的基因的列表
在本发明的工程化T细胞中改造的上述基因中的一个，优选两个等位基因，对于用于KO所述基因/等位基因的TALEN的每种制备验证了基因座。
在优选的实施方式中，进一步工程化免疫细胞的所述方法涉及向所述T细胞中引入编码特异性稀切内切核酸酶的多核苷酸，特别是mRNA，而通过DNA切割选择性地灭活上述基因。在更优选的实施方式中，所述稀切内切核酸酶是TALE核酸酶或Cas9内切核酸酶。迄今为止，TAL核酸酶已经证明比其他类型的稀切内切核酸酶具有更高的特异性和切割效率，使其成为以恒定转化数大规模生产工程化免疫细胞的内切核酸酶的选择。
递送方法
上述的不同方法涉及使所感兴趣的蛋白如抗药性基因，稀切内切核酸酶，嵌合抗原受体(CAR)，特别是抗CD123 CAR，且更具体地，包含SEQ ID NO.31，或32或160和/包括自杀性结构域的CAR表达到分离的细胞中。
作为非限制性实例，所述感兴趣的蛋白可以通过其作为优选由至少一个质粒载体编码的转基因的引入而表达于细胞中。由于将编码多肽的多核苷酸引入细胞中，所述多肽可以表达于细胞中。或者，在细胞外可以产生所述多肽，而随后将其引入其中。
用于将多核苷酸构建体引入细胞中的方法在本领域内是已知的，并作为非限制性实例，包括其中将多核苷酸构建体整合到细胞的基因组中的稳定转化方法，其中多核苷酸构建体未整合到细胞的基因组中的瞬时转化方法，和病毒介导的方法。
所述多核苷酸可以通过例如重组病毒载体(例如，逆转录病毒，腺病毒)，脂质体等引入细胞中。例如，瞬时转化方法包括，例如，显微注射法，电穿孔法或粒子轰击法，细胞融合法。考虑到细胞中表达，所述多核苷酸可以包括于载体中，更特别是质粒或病毒中。质粒载体可以包含提供识别和/或选择接收载体的细胞的选择标记。
不同的转基因可以包含于一个载体中。载体可以包含编码核糖体跳跃序列的核酸序列，如编码2A肽的序列。在小核糖核酸病毒的口蹄疫病毒亚型中识别的2A肽，导致从一个密码子“跳过”到下一个密码子的核糖体，而不在密码子编码的两个氨基酸之间形成肽键(参见Donnelly et al.，J.of General Virology 82：1013-1025(2001)；Donnelly etal.，J.of Gen.Virology 78：13-21(1997)；Doronina et al.，Mol.And.Cell.Biology 28(13)：4227-4239(2008)；Atkins et al.，RNA 13：803-810(2007))。
“密码子”是指由核糖体翻译成一个氨基酸残基的mRNA(或DNA分子的有义链)上的三个核苷酸。因此，当多肽被框内的2A寡肽序列分离时，两个多肽可以由mRNA内的单个连续的开放阅读框合成。这种核糖体跳过机制在本领域是公知的，并且已知由几个用于表达由单个信使RNA编码的几个蛋白质的载体使用。
在本发明的更优选的实施方式中，编码根据本发明的多肽的多核苷酸可以是，例如，通过电穿孔直接引入细胞中的mRNA。本发明人确定了T细胞中的mRNA电穿孔的最佳条件。本发明人使用cytoPulse技术，这种技术允许通过使用脉冲电场而瞬时渗透活细胞以将材料递送到细胞中。这种技术基于PulseAgile(BTX Havard Apparatus，Holliston，May01746，USA)的电穿孔波形的使用，容许精确控制脉冲持续时间，强度以及脉冲之间的间隔(美国专利US 6,010,613和国际PCT申请WO2004083379)。所有这些参数都可以修改，以达到最高转染效率的最佳条件，而死亡率最低。基本上，第一高电场脉冲使得孔隙形成，而随后的低电场脉冲使得多核苷酸移动到细胞中。
上述不同的方法涉及将SEQ ID NO.31、SEQ ID NO 32或SEQ ID NO160的CD123CAR引入到细胞中。作为非限制性实例，所述CAR可以作为由一个质粒载体编码的转基因而引入。所述质粒载体也可以含有提供接收所述载体的细胞的识别和/或选择的选择标记。
作为将编码所述多肽的多核苷酸引入细胞中的结果，在细胞中可以原位合成多肽。可替换地，可以在细胞外产生所述多肽，并随后将其引入其中。由于将多核苷酸构建体引入细胞中的方法在本领域是已知的，并作为非限制性实例，包括将多核苷酸构建体整合到细胞的基因组中的稳定转化方法，多核苷酸构建体未整合到细胞的基因组中的瞬时转化方法，和病毒介导的方法。多核苷酸可以通过，例如，重组病毒载体(例如，逆转录病毒，腺病毒)，脂质体等引入到细胞中。例如，瞬时转化方法包括，例如，显微注射法，电穿孔法或粒子轰击法。鉴于在细胞中表达，多核苷酸可以包括于载体中，更具体地质粒或病毒中。
工程化免疫细胞
本发明还涉及所述通过工程化细胞的方法易于获得的分离的细胞或细胞系。具体地，所述分离的细胞包含至少一种如上的CAR。在另一个实施方式中，所述分离的细胞包含各自含有不同胞外配体结合结构域的CAR群体。具体地，所述分离的细胞包含编码CAR的外源性多核苷酸序列。本发明的遗传改造的免疫细胞不依赖抗原结合机制活化和增殖。
本发明的范围内还包括分离的免疫细胞，优选根据先前描述的任何一种方法获得的T细胞。所述免疫细胞是指功能上参与引发和/或执行先天的和/或适应性的免疫响应的造血来源的细胞。所述根据本发明的免疫细胞可以源自干细胞。干细胞可以是成体干细胞，非人胚胎干细胞，更具体地非人类干细胞，脐带血干细胞，祖细胞，骨髓干细胞，诱导多能干细胞，全能干细胞或造血干细胞。代表性的人类细胞是CD34+细胞。所述分离的细胞也可以是树突细胞、杀手树突状细胞、巨细胞、NK-细胞、B-细胞、或选自由炎性T-淋巴细胞、细胞毒性T-淋巴细胞、调节性T淋巴细胞或辅助性T淋巴细胞组成的组中的T细胞。在另一实施方式中，细胞可以源自由CD4+ T淋巴细胞和CD8+ T淋巴细胞组成的组。在本发明的细胞扩增和遗传改造之前，可以通过各种非限制性方法从受试者获得细胞来源。细胞可以从许多非限制性来源获得，包括外周血单核细胞，骨髓，淋巴结组织，脐带血，胸腺组织，来自感染部位的组织，腹水，胸腔积液，脾组织和肿瘤。在本发明的某些实施方式中，可以使用本领域技术人员可用的和已知的任何数量的T细胞系。在另一实施方式中，所述细胞可以来自健康供体，来自诊断患有癌症的患者或诊断患有感染的患者。在另一实施方式中，所述细胞是表现不同表型特性的混合细胞群体的部分。在本发明的范围内还包括根据前述方法由改造的T细胞获得的细胞系。对免疫抑制治疗抗性且易于通过先前方法获得的改造细胞都包括于本发明的范围内。
作为优选的实施方式，本发明提供了如上所述的赋予具有对应于SEQ ID NO.31，SEQ ID NO.32或SEQ ID NO 160的序列的CD123 CAR的T细胞或T细胞群体，其不表达功能性TCR，对PNA具有抗性，并且对CD123阳性细胞是反应性的，用于其过继转移到患者，优选患AML、难治性复发AML、BPDNL或淋巴组织增生性疾病的患者中，或作为骨髓移植前的治疗。
作为更优选的实施方式，本发明提供了如上所述的赋予具有对应于SEQ IDNO.31，SEQ ID NO.32或SEQ ID NO 160的序列的CD123 CAR的T细胞或T细胞群体，并且对CD123阳性细胞是反应性的，不表达功能性TCR并且对选择的PNA抗性，用于其向用所述选择的PNA治疗的患者的同种异体移植。
在更加优选的实施方式中，本发明提供了与另一种治疗组合的赋予包含具有对应于SEQ ID NO.31，SEQ ID NO.32或SEQ ID NO 160的序列的CD123 CAR的多肽的抗CD123CAR的TRC KO dCK KO T细胞或T细胞群体。
T细胞的活化和扩增
无论是在T细胞的遗传改造之前或之后，即使本发明的遗传改造的免疫细胞不依赖抗原结合机制活化和增殖，免疫细胞，尤其是本发明的T细胞，可以通常使用例如描述于以下的方法进一步活化和扩增：美国专利6,352,694；6,534,055；6,905,680；6,692,964；5,858,358；6,887,466；6,905,681；7,144,575；7,067,318；7,172,869；7,232,566；7,175,843；5,883,223；6,905,874；6,797,514；6,867,041；和美国专利申请公开号No.20060121005。T细胞可以体外或体内扩增。
通常，本发明的T细胞通过与刺激CD3 TCR复合物和T细胞表面上的共刺激分子的试剂接触而产生T细胞的活化信号来扩增。例如，可以使用化学品如钙离子载体A23187，佛波醇(phorbol)12-肉豆蔻酸酯13-乙酸酯(PMA)或如植物血凝素(PHA)的有丝分裂凝集素的产生T细胞的活化信号。
作为非限制性实例，T细胞群体可以，例如，通过与抗CD3抗体，或其抗原结合片段，或固定于表面上的抗CD2抗体接触，或通过与蛋白激酶C活化剂(例如，苔藓虫素)接触，结合钙离子载体而体外刺激。为了T细胞表面上辅助分子的共刺激，使用了结合辅助分子的配体。例如，在适于刺激T细胞增殖的条件下，T细胞群体可以与抗CD3抗体和抗CD28抗体接触。适合于T细胞培养的条件包括可能含有增殖和活力所必需的因子的合适培养基(例如，最低必需培养基(Minimal Essential Media)或RPMI培养基1640或X-vivo 5，(Lonza))，包括血清(例如、胎牛或人血清)、白细胞介素-2(IL-2)、胰岛素、IFN-g、1L-4、1L-7、GM-CSF、-10、-2、1L-15、TGFp和TNF或本领域技术人员已知用于细胞生长的任何其它添加剂。用于细胞生长的其它添加剂包括，但不限于，表面活性剂，人血浆蛋白粉(plasmanate)和还原剂如N-乙酰基-半胱氨酸和2-巯基乙醇。培养基可以包括RPMI 1640、A1M-V、DMEM、MEM、a-MEM、F-12、X-Vivo 1和X-Vivo 20、Optimizer，具有添加的氨基酸，丙酮酸钠和维生素，不含血清或补充有适量的血清(或血浆)或一组确定的激素，和/或一定量的足以使T细胞生长和扩增的细胞因子。抗生素，例如，青霉素和链霉素，仅包括于实验培养物中，而不包括于要输注到受试者中的细胞的培养物中。靶细胞保持于支持生长所必需的条件下，例如，合适的温度(例如，37℃)和气氛(例如，空气+5％CO2)。暴露于不同刺激时间的T-细胞可能会表现出不同的特性。
在另一个具体实施方式中，所述细胞可以通过与组织或细胞共培养来扩增。细胞还可以体内扩增，例如，在将细胞给予受试者之后在受试者的血液中扩增。
药物组合物
本文提供了包含本发明的工程化免疫细胞的药物组合物，例如，具有对应于SEQID NO.31，SEQ ID NO.32或SEQ ID NO 160的序列的工程化TCR KO-dCK KO CD123 CAR T细胞。
本文提供了包含本发明的工程化免疫细胞，例如具有对应于选自SEQ ID NO 188至SEQ ID NO 197中的任一种序列的工程化TCR KO-dCK KO CD123 CAR T细胞的药物组合物。
在另一实施方式中，提供了包含本发明的遗传工程化的免疫T细胞，例如，具有选自SEQ ID NO.34至SEQ ID NO.159，优选选自SEQ ID NO.34、SEQ ID NO.76、SEQ ID NO.36、SEQ ID NO.78；SEQ ID NO.37、SEQ ID NO.79、SEQ ID NO.41、SEQ ID NO.83、SEQ IDNO.42、SEQ ID NO.8)、SEQ ID NO.43、SEQ ID NO.85、SEQ ID NO.46、SEQ ID NO.47、SEQ IDNO.48、SEQ ID NO.49、SEQ ID NO.88、SEQ ID NO.89、SEQ ID NO.90、SEQ ID NO.91、SEQ IDNO.52、SEQ ID NO.53、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.94、SEQ ID NO.95、SEQ IDNO.96、和SEQ ID NO.97中的任何一个序列的CD123 CAR的工程化TCR KO dCK KO T细胞的药物组合物。
根据本公开，术语“药物组合物”涉及用于向个体给予的组合物。在优选的实施方式中，药物组合物包含用于胃肠外，经皮，管腔内，动脉内，鞘内或静脉内给药(iv)或直接注射入癌的组合物。特别设想的是，所述药物组合物经由输液或注射iv给予个体。合适的组合物的给药可以通过不同的方式，例如通过静脉内(iv)，皮下，腹膜内，肌内，局部或皮内给药实施。
本公开的药物组合物可以进一步包含药用载体。合适的药物载体的实例在本领域内是公知的，并包括磷酸盐缓冲盐溶液，水，乳液，如油/水乳液，各种类型的润湿剂，无菌溶液等。包含这些载体的组合物可以通过公知的常规方法配制。这些药物组合物可以以合适的剂量给予受试者。
给药方案由主治医师和临床因素决定。如在医学领域中众所周知的，任何一个患者的剂量取决于许多因素，包括患者的体型，体表面积，年龄，要给药的具体化合物，性别，给药时间和途径，一般健康和其他同时给药的药物。给予剂量的实例可以处于0.24μg至48mg的根据本发明的细胞，优选0.24μg至24mg，更优选0.24μg至2.4mg，更加优选0.24μg至1.2mg，而最优选0.24μg至240mg单位/千克体重/天的范围内。特别优选的剂量如下所述。通过定期评价可以监测进度。
本公开的CAR细胞组合物可以局部或全身给予。给予通常是非肠道的，例如静脉内；DNA也可以直接给予于靶位点，例如，通过向内部或外部靶位点的基因枪(biolistic)递送或通过导管向动脉中的位点给予。在优选的实施方式中，药物组合物经皮下给予，而在更加优选的实施方式中静脉内给予。用于肠胃外给予的制剂包括无菌水或非水溶液，悬浮液和乳液。非水溶剂的实例是丙二醇，聚乙二醇，植物油如橄榄油和可注射有机酯如油酸乙酯。水性载体包括水，醇/水溶液，乳液或悬浮液，包括盐水和缓冲介质。非肠道载体包括氯化钠溶液，林格氏葡萄糖，葡萄糖和氯化钠，乳酸林格氏液或固定油。静脉内载体包括流体和营养补充剂，电解质补充剂(如基于林格氏葡萄糖的那些)等。还可以存在防腐剂和其它添加剂，如抗微生物剂，抗氧化剂，螯合剂和惰性气体等。此外，本公开的药物组合物可以包含蛋白质载体，比如，例如，血清白蛋白或免疫球蛋白，优选来源于人。可以设想的是，除了蛋白质双特异性单链抗体构建体或核酸分子或对其编码的载体(如本公开中描述的)之外，本发明的药物组合物可以包含进一步的生物活性剂，这取决于药物组合物的预期用途。
本文描述的任何组合物可以包含于试剂盒中。在非限制性实例中，在试剂盒中可以包含根据本发明的用于细胞疗法的一种或多种细胞和/或用于产生用于细胞疗法的一种或多种细胞的试剂，其含有重组表达载体。试剂盒以合适的容器装置提供。
试剂盒的一些组件可以在水性介质中或以冻干形式，且在冷冻包装下包装。试剂盒的容器装置通常将包括至少一个小瓶，试管，烧瓶，瓶子，注射器或其他容器装置，可以将组分，优选适当地等份置入其中。在试剂盒中有不只一种组分的情况下，试剂盒通常还将包含第二，第三或其他附加容器，可以将另外的组件单独放置于其中。然而，组分的各种组合可以包括于小瓶中。试剂盒通常还将包括用于商业销售的密封包含组分的装置。这种容器可以包括注塑或吹塑成形的塑料容器，将期望的小瓶保持于其中。
当试剂盒的组分提供于一种和/或多种液体溶液中时，液体溶液是水溶液，其中无菌水溶液是特别有用的。在一些情况下，容器装置本身可以是注射器，移液管和/或其它这样的类似装置，制剂可以从该装置施加到身体的感染区域，注射到动物中，和/或甚至施加和/或与试剂盒的其他组分混合。
在优选的实施方式中，一种和/或多种液体溶液是防冻的。
然而，试剂盒的组分或其部分可以作为干燥粉末或片剂提供。当试剂和/或组分作为干燥粉末提供时，通过加入合适的溶剂可以重构粉末。设想的是，溶剂也可以提供于另一个容器装置中。试剂盒还可以包含用于容纳无菌的药用缓冲液和/或其它稀释剂的第二容器装置。
在具体实施方式中，将待用于细胞疗法的细胞提供于试剂盒中，并在一些情况下，细胞基本上是试剂盒的唯一组分。试剂盒可以包括制备期望的细胞的试剂和材料。在具体的实施方式中，试剂和材料包括用于扩增期望的序列的引物，核苷酸，合适的缓冲液或缓冲试剂，盐等，并且在一些情况下，试剂包括编码如本文中描述的CAR分子的载体和/或DNA和/或其调节元件。
在具体的实施方式中，试剂盒中有一个或多个装置适用于从个体提取一个或多个样品。装置可以是注射器，解剖刀等。
在一些情况下，试剂盒，除了细胞疗法实施方式之外，还包括，例如，如化疗，激素疗法和/或免疫疗法的第二癌症疗法。试剂盒可以针对个体的具体癌症定制，并包括针对个体的各自的第二癌症疗法。优选地，其它癌症疗法是嘌呤类似物，FLAG治疗。
包含本发明的CD123 CAR的工程化T细胞的治疗用途。
在各个实施方式中，如本文中所设想的CAR构建体，核酸序列，载体，宿主细胞和/或包含其的药物组合物用于癌性疾病，如肿瘤疾病的预防、治疗或改善。在具体实施方式中，本公开的药物组合物尤其适用于，例如，预防，改善和/或治疗癌症，包括具有实体瘤的癌症。
在具体实施方式中，本文中提供了治疗个体的癌症的方法，包括向个体提供治疗有效量的多种本公开的任何细胞的步骤。
在某些方面中，癌症是实体肿瘤，并且肿瘤可以是任何尺寸，但在具体的实施方式中，实体肿瘤的直径约2mm或更大。在某些方面中，方法进一步包括向个体提供治疗有效量的其它癌症疗法的步骤。
本文中所用的“治疗(treatment)”或“治疗(treating)”包括对疾病或病理状况的症状或病理学的任何有益或期望的影响，并可以包括所治疗的疾病或病症，例如，癌症的一个或多个可测量标志物的即使最小的降低。治疗可以涉及可选地降低或改善疾病或病症的症状，或延缓疾病或病症的进展。“治疗”不一定表示完全根除或治愈疾病或病症，或其相关症状。
如本文所用，“预防(prevent)”和类似的词语如“预防(prevented)”，“预防(preventing)”等表示预防，抑制或降低疾病或病症例如癌症发生或复发的可能性的方法。其也指延迟疾病或病症的发作或复发或延迟疾病或病症症状的发生或复发。如本文所用，“预防”和类似词语还包括在疾病或病症发作或复发之前降低疾病或病症的强度，影响，症状和/或负担。
在具体实施方式中，本发明部分设想了可以使用标准载体和/或基因递送系统，并且在至少某些方面中，与药用载体或赋形剂一起，单独或以任何组合给予的细胞，CAR构建体，核酸分子和载体。在某些实施方式中，在给予之后，核酸分子或载体可以稳定地整合到受试者的基因组中。
在具体的实施方式中，可以使用对某些细胞或组织特异性，并保持于所述细胞中的病毒载体。合适的药物载体和赋形剂在本领域内是公知的。根据本公开制备的组合物可以用于预防或治疗或延缓以上指出的疾病。
此外，本公开涉及用于预防，治疗或改善肿瘤疾病的方法，其包括以下步骤：向对其需要的受试者或个体给予有效量的免疫细胞，例如，T细胞或细胞毒性T淋巴细胞，其携带SEQ ID NO.31的CD123 CAR或SEQ ID NO.32的CD123 CAR或SEQ ID NO.160的CD123 CAR；编码其的核酸序列；包含编码如本文所述和/或通过本文描述的方法产生的所述CD123CAR的核苷酸序列的载体。
给予示例性CD123 CAR细胞的组合物的可能的适应症是癌性疾病，包括肿瘤疾病，包括：
本公开的组合物的给予适用于淋巴增生性疾病的所有阶段和类型，包括用于微小残留疾病，早期癌症，晚期癌症和/或复发和/或难治性癌症。
本公开进一步包括与通过免疫细胞起作用的其它化合物，例如，双特异性抗体构建体，靶向毒素或其他化合物的共给予方案。
共给予本发明化合物的临床方案可以包括在给予其它组分的同时，之前或之后共给予。具体的组合疗法包括化疗，放疗，手术，激素疗法，或其他类型的免疫疗法。
疗法的具体剂量可以使用本领域中的常规方法确定。然而，在具体的实施方式中，本发明的工程化CD123 T细胞一次性递送至对其需要的个体，但在一些情况下是多次的，包括2，3，4，5，6次或更多次。当提供多次给药，给药之间的时间间隔可以是任何合适的时间，但在具体的实施方式中，其是给药之间数天或数周或数月。剂量和T细胞供体源选择为避免任何不良副作用。给药之间的时间可以在单一方案中变化，并且可以取决于接受者(对其需要的患者)。在具体的实施方式中，给药之间的时间是2，3，4，5，6，7，8，9，10，或更多天或数周。在具体情况下，例如，其为4-8或6-8周。
在具体的实施方式中，一种方案包括本发明的CD123 T细胞的以下给药方案中的一种：
11×104/m2，
11×105/m2，
11×106/m2，
23×106/m2，
31×107/m2，
43×07/m2，
51×108/m2，
或104至1010个细胞/kg。
在可替换的实施方式中，T细胞以以下给药方案提供至个体：
给药水平CD123 CTL剂量
11×106/m2，
21×107/m2，
31×108/m2，
6×104至5×108个细胞/kg，
有效量的本发明的CD123 CAR工程化免疫细胞对应于这种可以根据每个治疗的个体的状态而调整的剂量。
治疗应用
在另一实施方式中，通过不同方法获得的分离的细胞或源自所述本发明的分离的细胞(体外1至50传代之后)的细胞可以用作药物。可以用作药物的本发明的工程化TCR KOdCK KO CD123 CAR T细胞可以是具有对应于SEQ ID NO.31，SEQ ID NO.32，SEQ ID NO160，SEQ ID NO.34至SEQ ID NO.159中任一种的序列的CD123 CAR的那些。
在优选的实施方式中，具有对应于SEQ ID NO.31，SEQ ID NO.32，SEQ ID NO 160的序列的工程化TCR KO dCK KO CD123 CAR T细胞提供用作药物。
在另一个优选的实施方式中，提供具有选自以下序列中的任一种序列的遗传工程化TCR KO dCK KO CD123 CAR T细胞用作药物：SEQ ID NO.34、SEQ ID NO.76、SEQ IDNO.36、SEQ ID NO.78、SEQ ID NO.37、SEQ ID NO.79、SEQ ID NO.41、SEQ ID NO.83、SEQ IDNO.42、SEQ ID NO.8)、SEQ ID NO.43、SEQ ID NO.85、SEQ ID NO.46、SEQ ID NO.47、SEQ IDNO.48、SEQ ID NO.49、SEQ ID NO.88、SEQ ID NO.89、SEQ ID NO.90、SEQ ID NO.91、SEQ IDNO.52、SEQ ID NO.53、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.94、SEQ ID NO.95、SEQ IDNO.96、SEQ ID NO.97。
在另一优选实施方式中，提供具有选自SEQ ID NO.160、SEQ ID NO.188、SEQ IDNO.189、SEQ ID NO.190、SEQ ID NO.191；SEQ ID NO.192、SEQ ID NO.193、SEQ ID NO.194、SEQ ID NO.195、SEQ ID NO.196、SEQ ID NO.197中的任何一种序列的工程化TCR KO dCKKO CD 123CAR T细胞用作药物。
在另一实施方式中，所述药物可以用于治疗癌症，特别是用于治疗对其需要的患者中的B细胞淋巴瘤和白血病。
在另一实施方式中，根据本发明的所述分离的细胞或源自所述分离的细胞的细胞系可以用于生产治疗对其需要的患者中的癌症的药物。
在具体实施方式中，提供表达抗CD123 CAR的T细胞用作用于治疗AML，AML亚型，AML相关并发症，AML相关病症的药物。在优选的实施方式中，提供表达抗CD123 CAR的T细胞作为药物，其中所述抗CD123 CAR包含SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160。
在另一实施方式中，所述药物可以用于治疗表达CD123的细胞介导的病理状况或特征在于表达CD123的细胞的直接或间接活性的病症。换言之，本发明涉及包含80％至100％的SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160的表达抗CD123 CAR的T细胞，其用作治疗与表达CD123的细胞的有害活性相关的病症，特别是治疗选自AML，AML亚型，AML相关并发症和AML相关病症的病症的药物；
另一方面，本发明依赖于用于治疗对其需要的患者的方法，所述方法包括以下步骤中的至少一个步骤：
(a)提供通过任一种前述方法可获得的免疫细胞；
(b)将所述转化的免疫细胞给予于患者，
在一个实施方式中，本发明的所述T细胞可以经受强健的体内T细胞扩增并可以持续延长的时间。
在优选实施方式中，所述T细胞通过给予选择性破坏所述T细胞的药物或抗体而破坏。
在更优选的实施方式中，具有含有对应于SEQ ID NO.31，SEQ ID NO.32，SEQ IDNO 160，SEQ ID NO.34至SEQ ID NO.159中的任一种的序列的CD123 CAR的本发明的工程化TCR KO dCK KO CD123 CAR T细胞用作药物/治疗，而随后使用识别自杀结构域RQR8，或CD20结构域，或SEQ ID NO 161的抗体，优选使用利妥昔单抗，从患者中清除。
所述治疗可以是改善，治愈或预防性的。其可能是自体免疫疗法的一部分或同种异体免疫疗法的一部分。自体免疫疗法是指用于治疗患者的细胞、细胞系或细胞群源自患者或来自人白细胞抗原(HLA)相容性供体。同种异体免疫疗法是指用于治疗患者的细胞或细胞群不是源自所述患者，而是来自供体。
可以用于所公开的方法的本发明的细胞已经在前面的部分中描述。所述治疗可以用于治疗诊断为恶性前或恶性癌症病症，其特征在于表达CD123的细胞，特别是表达CD12的细胞过多的患者。这些病症存在于血液癌症中，如白血病或恶性淋巴增生性疾病。淋巴增生性疾病可以是淋巴瘤，特别是多发性骨髓瘤，非霍奇金淋巴瘤，伯基特淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)。
使用本发明的细胞或包含所述细胞的药物组合物可以治疗的癌症可以包括非实体肿瘤(如血液肿瘤，包括但不限于前B ALL(儿科适应症)、成人ALL、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、BPDNL、AML、难治的复发性AML、或骨髓移植前。
用本发明的表达CAR的CD123细胞治疗的癌症的类型包括，但不限于，白血病或淋巴恶性肿瘤。还包括成人肿瘤/癌症和儿科肿瘤/癌症。
在一个实施方式中，本发明提供了药物组合物，用于其治疗表达CD123的细胞介导的疾病，特别是表达CD123的细胞介导的血液癌症的用途，所述组合物包含本发明的所述表达抗CD123 CAR的T细胞，优选地，所述抗CD123 CAR是SEQ ID NO 31，SEQ ID NO 32或SEQID NO 160的抗CD123 CAR，更优选具有选自SEQ ID NO.160、SEQ ID NO.188、SEQ IDNO.189、SEQ ID NO.190、SEQ ID NO.191；SEQ ID NO.192、SEQ ID NO.193、SEQ ID NO.194、SEQ ID NO.195、SEQ ID NO.196、SEQ ID NO.197的序列。本文公开的任何其它CD123介导的或CD123涉及的恶性淋巴增殖性疾病可以用本发明的表达抗CD123 CAR的细胞改善。
在优选的实施方式中，使用本发明的表达抗CD123 CAR的细胞可以治疗的癌症是白血病(AML)，与白血病相关的疾病或其并发症。
使用本发明的表达抗CD123 CAR的细胞可以治疗的白血病可以是急性髓细胞白血病(AML)，慢性髓细胞白血病，骨髓增生异常综合症，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征。
使用本发明的表达抗CD123 CAR的细胞可以治疗的AML或AML亚型可以是，具体地，急性髓细胞白血病、微分化急性髓细胞白血病(minimally differentiated acutemyeloblastic leukemia)、未成熟急性髓细胞性白血病、粒细胞成熟急性髓细胞性白血病、早幼粒细胞或急性早幼粒细胞白血病(APL)、急性骨髓单核细胞白血病、骨髓单核细胞与骨髓嗜酸粒细胞增多、急性原单核细胞白血病(acute monoblastic leukemia)(M5a)或急性单核细胞白血病(acute monocytic leukemia)(M5b)、急性红细胞白血病、包括红白血病(M6a)和非常罕见的纯红细胞性白血病(M6b)、急性巨核细胞白血病、急性嗜碱粒细胞白血病、伴有骨髓纤维化的急性全骨髓增生(acute panmyelosis with myelofibrosis)，不论是否涉及CD123阳性细胞。
使用本发明的表达抗CD123 CAR的细胞可以治疗的AML亚型也包括，毛细胞白血病，费城染色体阳性急性淋巴细胞白血病。
AML可以分类为具有特异性遗传异常的AML。分类是基于核型预测对诱导疗法的反应的能力，复发风险，存活率。
因此，使用SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160的本发明的表达抗CD123 CAR的细胞可以治疗的AML可以是在染色体8和21之间具有易位的AML，染色体16中具有易位或反转的AML，染色体9和11之间具有易位的AML，染色体15和17之间具有易位的APL(M3)，染色体6和9之间具有易位的AML，染色体3中具有易位或反转的AML，染色体1和22之间具有易位的AML(巨核细胞)。
本发明特别适用于治疗与这些具体的细胞遗传学标记相关的AML。
本发明还提供了用于治疗患有AML的特定细胞遗传学亚型的患者，如具有使用全反式视黄酸(ATRA)16-19识别的t(15；17)(q22；q22)的患者或用于治疗具有使用高剂量阿糖胞苷的重复给药识别的t(8；21)(q22；q22)或inv(16)(p13q22)/t(16；16)(p13；q22)的患者的SEQ ID NO 31、SEQ ID NO 32或SEQ ID NO 160的表达抗CD123 CAR的T细胞。
优选地，本发明提供了结合FLAG用于治疗患有畸变，如-5/del(5q)、-7、3q的异常，或复杂核型(complex karyotype)，已经显示出具有较差的完全缓解率和存活率的患者的SEQ ID NO 31、SEQ ID NO 32或SEQ ID NO 160的表达抗CD123 CAR的T细胞。
患者分组
在优选的实施方式中，本发明提供了SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO160的表达抗CD123 CAR的T细胞作为60岁以上患者或小于20岁的患者的AML的治疗。
在更优选的实施方式中，本发明提供了SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO160的表达抗CD123 CAR的T细胞用作儿科治疗，特别是针对AML，或AML相关疾病或并发症的儿科治疗。
在又一优选实施方式中，本发明用作具有低，差或不利状态，即具有小于5年存活率的预测存活率的AML患者的治疗。在该组中，患有具有以下细胞遗传学特性AML：-5；5q；-7；7q-；11q23；non t(9；11)；inv(3)；t(3；3)；t(6；9)；t(9；22)的患者与不良风险状态有关(Byrd J.C.et al.，December 15，2002；Blood：100(13))，并且特别设想的是根据本发明或使用本发明的目的来治疗。
在一个实施方式中，本发明的表达抗CD123 CAR的T细胞可以用作诱导疗法，作为AML的缓解后治疗或作为患有AML的患者的巩固治疗。优选地，TRC KO细胞或或表达SEQ IDNO.31，SEQ ID NO.32或SEQ ID NO.160的抗CD123 CAR的TCR KO和dck KO T细胞用作AML的缓解后治疗或作为患有AML的患者的巩固治疗。
在一个实施方式中，在AML复发的情况下，或在难治性或耐药性AML的情况下，可以使用本发明的TCR KO、dck KO，表达SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160的抗CD123 CAR的T细胞。优选地，本发明的所述TCR KO T dck KO，表达SEQ ID NO 31，SEQ IDNO 32或SEQ ID NO 160的抗CD123 CAR的T细胞用于患有AML复发，或难治性或耐药性AML的患者，更优选与至少一种其它抗癌药物组合。
在另一优选的实施方式中，本发明的TCR KO，dck KO，表达SEQ ID NO 31，SEQ IDNO 32或SEQ ID NO 160的抗CD123 CAR的T细胞适用于防止特别是在抗癌治疗，骨髓去除期间或骨髓移植前，骨髓破坏之后发生的癌细胞发展。
AML并发症
在一个具体实施发生中，本发明提供了改善患者，特别是患有与AML相关的并发症的患者的健康状况的药物。更优选地，TCR KO，dck KO，表达SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160的抗CD123 CAR的T细胞，优选与FLAG一起，用作治疗与AML有关的并发症的药物。
与AML相关的并发症或疾病可以包括前期骨髓增生阶段(precedingmyelodysplasia phase)，继发性白血病，特别是继发性AML，高白细胞计数，以及奥氏小体(Auer rods)缺失。其中，白血病和中枢神经系统(CNS)介入，高白细胞增生症(Hyperleukocytosis)，残留疾病，也认为是与AML有关的并发症或疾病。
AML相关的疾病
在一个实施方式中，本发明还提供了TCR KO，dck KO，表达SEQ ID NO 31，SEQ IDNO 32或SEQ ID NO 160的抗CD123 CAR的T细胞用于治疗与AML相关的病理状况。优选地，本发明提供了TCR KO，dck KO，表达SEQ ID NO 31，SEQ ID NO 32或SEQ ID NO 160的抗CD123CAR的T细胞用于治疗与AML相关的病理状况。
本发明提供了一种用于AML相关的髓性肿瘤，用于急性髓细胞白血病和骨髓增生异常综合征，治疗复发或难治性急性髓细胞白血病，治疗成人的复发性或难治性急性早幼粒细胞白血病，治疗急性前随细胞白血病(acute promyeloid leukaemia)，治疗60岁以上成人急性髓细胞白血病的疗法(TCR KO，dck KO，表达SEQ ID NO 31，SEQ ID NO 32或SEQID NO 160的抗CD123 CAR的T细胞，优选具有选自SEQ ID NO.160、SEQ ID NO.188、SEQ IDNO.189、SEQ ID NO.190、SEQ ID NO.191；SEQ ID NO.192、SEQ ID NO.193、SEQ ID NO.194、SEQ ID NO.195、SEQ ID NO.196、SEQ ID NO.197的序列)。
根据另一方面，本发明提供了用于治疗AML相关的疾病，特别是与AML相关的血液恶性肿瘤的组合物。
与AML病症相关的血液恶性肿瘤包括骨髓增生异常综合征(MDS，以前称为“前白血病”)，其是通过骨髓血液细胞的无效生产(或发育异常)和转化为AM的风险联合的血液病的多样集合。
在另一实施方式中，本发明提供了改善患有多发性骨髓瘤的患者的健康状态的药物。
与AML风险相关的其它病理状况或遗传综合征可以充分利用本发明而改进，所述遗传综合征包括唐氏综合征，三染色体性(trisomy)，范康尼贫血症(Fanconi anemia)，布卢姆综合征(Bloom syndrome)，共济失调毛细血管扩张症(Ataxia-telangiectasia)，戴-布二氏贫血症(Diamond-Blackfan anemia)，舒-戴二氏综合征(Schwachman-Diamondsyndrome)，李弗劳明综合征(Li-Fraumeni syndrome)，1型神经纤维瘤(Neurofibromatosis type 1)，重型先天性中性粒细胞减少症(Severe congenitalneutropenia)(也称为Kostmann综合征)。
其他CD123介导的病理状况
根据另一方面，本发明提供了用于治疗CD123+细胞介导的疾病的组合物。这些CD123+细胞介导的疾病包括炎症，自身免疫性疾病。
具体地，本发明可以用于治疗CD123+细胞介导的疾病，如胃肠粘膜的炎症，而更具体而言，炎性肠病，鼻过敏，皮肤炎症，如青少年皮肌炎，血液病。
本发明可以用作治疗CD123+细胞介导的疾病如自身免疫疾病，特别是菊池病(Kikushi disease)的药物。
优选地，本发明提供了复发性感染的治疗，包括由病毒引起的感染，如爱泼斯坦-巴尔(Epstein-Barr)病毒，单纯疱疹(herpes simplex)病毒，特别是致癌病毒，HHV-8，HHV-6，HTLV或HIV，寄生虫感染如由于恶性疟原虫(plasmodium falciparum)，间日疟原虫(Plasmodium vivax)，卵形疟原虫(Plasmodium ovale)或三日疟原虫(Plasmodiummalariae)的感染。
具体地，本发明提供了用于爱泼斯坦-巴尔病毒淋巴结炎(Epstein-Barr viruslymphadenitis)，单纯疱疹病毒淋巴结炎(herpes simplex virus lymphadenitis)的治疗。
在另一方面中，本发明提供了用于治疗系统性红斑狼疮淋巴结炎，结核病，囊性纤维化，肝炎，胆道闭锁，特别是儿童中的病毒诱导肝炎或胆道闭锁，自身免疫性肝炎，原发胆汁性肝硬化的组合物。
包含根据本发明的工程化T细胞的组合物用作药物和方法
本发明也提供了包含具有对应于SEQ ID NO.31，SEQ ID NO.32或SEQ ID NO 160的序列，或赋予选自SEQ ID NO.160、SEQ ID NO.188、SEQ ID NO.189、SEQ ID NO.190、SEQID NO.191；SEQ ID NO.192、SEQ ID NO.193、SEQ ID NO.194、SEQ ID NO.195、SEQ IDNO.196、SEQ ID NO.197的序列的遗传工程化免疫TCR KO-dCK KO-CD123 CAR T细胞，或具有任何一种选自以下的的序列的遗传工程化免疫TCR KO-dCK KO CD123 CAR T细胞的组合物：SEQ ID NO.34至SEQ ID NO.159、优选选自SEQ ID NO.34、SEQ ID NO.76、SEQ IDNO.36、SEQ ID NO.78；SEQ ID NO.37、SEQ ID NO.79、SEQ ID NO.41、SEQ ID NO.83、SEQ IDNO.42、SEQ ID NO.8、SEQ ID NO.43、SEQ ID NO.85、SEQ ID NO.46、SEQ ID NO.47、SEQ IDNO.48、SEQ ID NO.49、SEQ ID NO.88、SEQ ID NO.89、SEQ ID NO.90、SEQ ID NO.91、SEQ IDNO.52、SEQ ID NO.53、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.94、SEQ ID NO.95、SEQ IDNO.96和SEQ ID NO.97。
优选地，本发明提供了包含具有对应于SEQ ID NO 31的序列的工程化免疫TCRKO-dCK KO-CD123 CAR的T细胞的组合物。
优选地，本发明提供了包含具有对应于SEQ ID NO 32的序列的工程化免疫TCRKO-dCK KO-CD123 CAR的T细胞的组合物。
优选地，本发明提供了工程化免疫TCR KO-dCK KO-CD123 CAR的T细胞的组合物，包含具有对应于SEQ ID NO 160的序列
或任一种选自SEQ ID NO.160、SEQ ID NO.188、SEQ ID NO.189、SEQ ID NO.190、SEQ ID NO.191；SEQ ID NO.192、SEQ ID NO.193、SEQ ID NO.194、SEQ ID NO.195、SEQ IDNO.196、SEQ ID NO.197的序列，
用于其治疗癌症如BPDNL或作为骨髓移植前的治疗的用途或方法。一方面，该疾病是血液学癌症，特别是干细胞癌，包括但不限于白血病(例如急性髓细胞白血病(AML)、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病和骨髓增生异常综合征)和恶性淋巴增生性病症、包括淋巴瘤(例如多发性骨髓瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、小细胞和大细胞滤泡淋巴瘤)或其并发症(复发难治性AML)。
本发明还提供了如上述组合物用于其抑制增殖或降低患者中表达CD12的细胞群体或活性的用途或方法。示例性方法包括使包含CD123表达细胞的细胞群体与本发明的结合至表达CD123的细胞的CD123CART细胞接触。
在更具体的方面中，本发明提供了组合物，用于其抑制增殖或降低患者中表达CD123的癌细胞群体的用途和方法，该方法包括使表达CD123的癌细胞群体与本发明的与表达CD123的细胞结合的CD 123 CART细胞接触，本发明的CD 123 CART细胞与表达CD123的癌细胞的结合会导致表达CD123的癌细胞破坏
在某些方面中，本发明的CD 123 CART细胞相对于阴性对照，在具有髓细胞白血病或与表达CD123的细胞相关的另一种癌症的受试者或动物模型中将细胞和/或癌细胞的数量，数目，量或百分比降低至少25％、至少30％、至少40％、至少50％、至少65％、至少75％、至少85％、至少95％、或至少99％(至不可检测的水平)。
本发明还提供了组合物，用于其预防，治疗和/或控制与表达CD123的细胞(例如，与血液学癌症相关)的疾病或病症的用途或方法，方法包括向对其需要的受试者给予本发明的结合至表达CD123的细胞的CD 123 CART细胞。在一方面中，受试者是人类。与表达CD123的细胞相关的疾病的非限制性实例包括自身免疫性疾病(如狼疮)，炎症性疾病(如过敏，IBD和哮喘)和癌症(如血液癌症，特别是AML或AML并发症)。
本发明还提供了组合物，用于其预防，治疗和/或控制与表达CD123的细胞相关的疾病的用途或方法，方法包括向对其需要的受试者给予本发明的结合至表达CD123的细胞的CD 123 CART细胞。在一方面中，受试者是人类。与表达CD123的细胞相关的疾病的非限制性实例包括急性髓细胞白血病(AML)、脊髓发育不良(myelodysplasia)、B细胞急性淋巴白血病、T细胞急性淋巴白血病、毛细胞白血病、母细胞性浆细胞样树突状细胞肿瘤(BPDCN)、慢性髓细胞白血病、霍奇金淋巴瘤。
本发明提供了组合物，用于其治疗或预防与表达CD123的细胞相关的癌症复发的用途或方法，方法包括向对其需要的受试者给予本发明的结合至表达CD123的细胞的CD123 CART细胞。在另一方面中，方法包括结合有效量的另一种治疗，向对其需要的受试者给予有效量的本发明的结合至表达CD123的细胞的CD 123 CART细胞。
在一个方面中，CD123被认为是AML中的“癌干细胞”标记物。因此，本发明的CD 123CART细胞可以预防AML的复发，或甚至治疗主要为CD123阴性但具有CD123+细胞(表达CD123的细胞)的“干”群体的AML。
在一方面中，本发明提供用于治疗经受与CD19表达水平升高相关的疾病或病症的治疗，并表现出与升高的CD123水平相关的疾病或病症的受试者的组合物和方法。
在一方面中，B细胞急性淋巴细胞白血病(ALL)是需要使用CART细胞进行系列治疗的疾病的实例。例如，用抗CD19 CAR T细胞治疗有时可能导致CD19阴性复发，其可以用本发明的抗CD123 CAR T细胞治疗。另外，本发明包括使用包含抗CD19 CAR和抗CD123 CAR的CART细胞的双重靶向。
使用根据本发明的工程化免疫细胞的治疗可以与一种或多种抗癌治疗组合，该治疗选自抗体疗法、化学疗法、细胞因子疗法、树突细胞疗法、基因疗法、激素疗法、激光疗法和辐射疗法。
优选地，根据本发明的工程化免疫细胞的治疗可以与一种或多种选自以下的抗癌疗法组合(例如，之前，同时或之后)给予：阿糖胞苷(Aracytine)，胞嘧啶阿拉伯糖苷(Cytosine Arabinoside)，安吖啶，柔红霉素，伊达比星，诺安托，米托蒽醌，足叶乙苷，依托泊苷(VP16)，三氧化二砷，反式维甲酸，三氧化三砷、反式维甲酸、氮芥、甲基苄肼、苯丁酰氮芥的组合，及它们的组合。
根据本发明的优选实施方式，所述治疗可以给予正经受免疫抑制治疗的患者。实际上，本发明优选地依赖于由于编码这种免疫抑制剂的受体的基因失活而使其对至少一种免疫抑制剂抗性的细胞或细胞群。在这方面中，免疫抑制治疗应该有助于根据本发明的T细胞在患者体内的选择和扩增。
根据本发明的细胞或细胞群体的给予可以以任何方便的方式进行，包括通过气溶胶吸入、注射、摄入、输液、植入或移植。本文的组合物可以通过皮下、皮内、肿瘤内、结节内、髓内、肌肉内，通过静脉内或淋巴管内注射，或腹膜内给予于患者。在一个实施方式中，本发明的细胞组合物优选地通过静脉内注射给予。
细胞或细胞群体的给予可以由给予104-109个细胞/kg体重，优选105-106个细胞/kg体重组成，包括在该范围内的所有细胞数的整数值。细胞或细胞群体可以以一此或多次给药给予。在另一实施方式中，所述有效量的细胞作为单次给药给予。在另一实施方式中，所述有效量的细胞在一段时间内以多于一次给药给予。给予的时机在主任医师的判断之内，取决于患者的临床状况。细胞或细胞群体可以获得自任何来源，例如血库或供者。尽管个体需求不同，但确定特定疾病的给定细胞类型的有效量的最佳范围或条件都在本领域的技术范围内。有效量是指提供治疗或预防益处的用量。给予的剂量将取决于接受者的年龄、健康和体重，并发治疗的种类，如果有的话，治疗频率和所需效果的性质。
在另一实施方式中，将所述有效量的细胞或包含这些细胞的组合物肠胃外给予。所述给予可以是静脉内给予。所述给予可以通过肿瘤内注射直接进行。
在本发明的某些实施方式中，细胞与任何数量的相关治疗方式，包括但不限于采用药物的治疗如抗病毒疗法，西多福韦和白细胞介素-2，阿糖胞苷(也称为ARA-C)或用于MS患者的那他珠单抗治疗或用于牛皮癣患者的依法利珠单抗治疗或用于PML患者的其他治疗结合(例如，之前，同时或之后)给予患者。在进一步的实施方式中，本发明的T细胞可以与化学疗法、放射、免疫抑制剂如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯和FK506、抗体或其他免疫消融剂(immunoablative)如CAMPATH、抗CD3抗体或其他抗体疗法、细胞毒素、氟达拉滨、环孢菌素、FK506、雷帕霉素(rapamycin)、霉酚酸(mycoplienolic acid)、类固醇、FR901228、细胞因子和辐照组合使用。这些药物抑制钙依赖性磷酸酶钙调磷酸酶(环孢菌素和FK506)或抑制对生长因子诱导的信号传导重要的p70S6激酶(雷帕霉素)(Henderson，Naya et al.1991；Liu，Albers et al.1992；Bierer，Hollander et al.1993)。在进一步的实施方式中，本发明的细胞组合物与骨髓移植，使用化疗药物如氟达拉滨的T细胞消融疗法，外照射治疗(XRT)，环磷酰胺，或抗体如OKT3或CAMPATH结合(例如，之前，同时或之后)给予于患者。在另一实施方式中，本发明的细胞组合物在B细胞消融疗法，如与CD20反应的药物，例如利妥昔单抗(Rituxan)之后给予。在这种情况下，在本发明的T细胞中表达的CD123CAR不包含SEQ ID 160，除非其在利妥昔单抗之前给予。
例如，在一个实施方式中，受试者可以接受高剂量化疗，随后外周血干细胞移植的标准治疗。在某些实施方式中，在移植之后，受试者接受本发明的扩增的免疫细胞的输液。在其它实施方式中，扩增的细胞在手术之前或之后给予。
在本发明的某些实施方式中，将粘度抗CD123 CAR的细胞与选自阿胞嘧啶、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(VP16)、三氧化二砷、反式维甲酸、氮芥、甲基苄肼、苯丁酰氮芥、及其组合的药物组合(例如，之前，同时或之后)向患者给予。在这些实施方式中，表达抗CD123 CAR的细胞可以具有对具体药物或与表达抗CD123 CAR的细胞联合给予的药物组合的抗性。
在本发明的其他实施方式中，表达抗CD123 CAR的细胞与选自阿糖胞苷，蒽环霉素，6-硫鸟嘌呤，羟基脲，泼尼松及其组合的药物联合给予患者。
其他定义
-除非另有说明，否则“一个”，“一种”，“该”和“至少一个”可以互换使用，并是指一个或多于一个。-多肽序列中的氨基酸残基在本文中根据单字母代码表示，其中，例如，Q表示Gln或谷氨酰胺残基，R表示Arg或精氨酸残基，而D表示Asp或天冬氨酸残基。
-氨基酸取代是指将一个氨基酸残基用另一个氨基酸残基取代，例如，用肽序列中的谷氨酰胺残基取代精氨酸残基就是氨基酸取代。
-核苷酸指定如下：单字母代码用于指定核苷的碱基：a是腺嘌呤，t是胸腺嘧啶，c是胞嘧啶，而g是鸟嘌呤。对于简并核苷酸，r表示g或a(嘌呤核苷酸)，k表示g或t，s表示g或c，w表示a或t，m表示a或c，y表示t或c(嘧啶核苷酸)，d表示g，a或t，v表示g，a或c，b表示g，t或c，h表示a，t或c，而n表示g，a，t或c。
-如本文所用，“核酸”或“多核苷酸”是指核苷酸和/或多核苷酸，如脱氧核糖核酸(DNA)或核糖核酸(RNA)，寡核苷酸，通过聚合酶链反应(PCR)产生的片段，以及通过连接，剪切，内切核酸酶作用和外切核酸酶作用而产生的片段。核酸分子可以由天然存在的核苷酸(如DNA和RNA)或天然存在的核苷酸的类似物(例如，天然存在的核苷酸的对映体形式)，或两者的组合的单体构成。改造的核苷酸可以在糖部分和/或嘧啶或嘌呤碱基部分中具有改变。糖的改造包括，例如，用卤素，烷基基团，胺和叠氮基团取代一个或多个羟基基团，或糖可以官能化为醚或酯。此外，整个糖部分可以用空间和电子上相似的结构取代，如氮杂糖和碳环类似物。碱基部分中改造的实例包括烷基化嘌呤和嘧啶，酰化嘌呤或嘧啶，或其它众所周知的杂环替代物。核酸单体可以通过磷酸二酯键或这种连接键的类似物连接。核酸可以是单链或双链。
-嵌合抗原受体(CAR)旨在是结合针对存在于靶细胞上的组件的结合结构域，例如，对期望的抗原(例如，肿瘤抗原)的基于抗体的特异性，与T细胞受体活化的胞内结构域而产生展现特异性抗靶细胞免疫活性的分子。通常，CAR由融合到T细胞抗原受体复合物ζ链(scFv Fc：ζ)的胞内信令结构域的胞外单链抗体(scFv Fc)组成，并当在T细胞中表达时具有基于单克隆抗体的特异性重定向抗原识别的能力。在本发明中使用的CAR的一个实例是针对CD123抗原的CAR，并可以包含作为非限制性实例的氨基酸序列：SEQ ID NO:23至48和160。
-术语“内切核酸酶”是指可以催化DNA或RNA分子，优选DNA分子内的核酸之间的键的水解(切割)的任何野生型或变体酶。内切核酸酶不会切割与其序列无关的DNA或RNA分子，而是识别和切割在特定多核苷酸序列上的DNA或RNA分子，进一步称为“靶序列”或“靶位点”。当通常具有多于12个碱基对(bp)长度，更优选14-55bp的多核苷酸识别位点时，内切核酸酶可以分类为稀切内切核酸酶。稀切内切核酸酶通过在定义的位点上诱导DNA双链断裂(DSB)而显著提高HR(Perrin，Buckle et al.1993；Rouet，Smih et al.1994；Choulika，Perrin et al.1995；Pingoud and Silva 2007)。稀切内切核酸酶可以，例如，是归巢内切核酸酶(homing endonuclease)(Paques and Duchateau 2007)，由工程化的锌指结构域与限制酶如FokI的催化结构域融合产生的嵌合锌指核酸酶(ZFN)(Porteus and Carroll2005)，来自CRISPR系统的Cas9内切核酸酶(Gasiunas，Barrangou et al.2012；Jinek，Chylinski et al.2012；Cong，Ran et al.2013；Mali，Yang et al.2013)或化学内切核酸酶(Eisenschmidt，Lanio et al.2005；Arimondo，Thomas et al.2006)。在化学内切核酸酶中，化学或肽切割物与核酸聚合物缀合或缀合于识别特异性靶序列的另一DNA，从而将切割活性靶向于特异性序列。化学内切核酸酶也包括合成的核酸酶，比如邻菲咯啉的复合物，DNA切割分子，已知结合特异性DNA序列的三链体形成寡核苷酸(TFO)(Kalish and Glazer2005)。这样的化学内切核酸酶包含于根据本发明的术语“内切核酸酶”中。
-“TALE核酸酶”(TALEN)旨在是由通常源自转录活化因子样效应子(TALE)的核酸结合结构域和一个核酸酶催化结构域组成以切割核酸靶序列的融合蛋白。催化结构域优选是核酸酶结构域，而更优选具有内切核酸酶活性的结构域，如例如I-TevI，ColE7，NucA和Fok-I。在具体的实施方式中，TALE结构域可以融合到大范围核酸酶中，如例如I-CreI和I-OnuI或其功能变体。在更优选的实施方式中，所述核酸酶是单体TALE核酸酶。单体TALE核酸酶是不需要二聚用于特异性识别和切割的TALE核酸酶，如WO2012138927中描述的工程化TAL重复序列与I-TevI催化结构域的融合。转录活化因子样效应子(TALE)是来自细菌种黄杆菌属(Xanthomonas)的蛋白质，包含多个重复序列，每个重复序列包含对于核酸靶向的序列的每个核苷酸碱基特异性的12和13位上的二残基(RVD)。具有相似的模块化逐碱基核酸结合特性(MBBBD)的结合结构域也可以源自由本申请人最近在不同细菌种中发现的新模块化蛋白质。新的模块化蛋白质具有比TAL重复序列显示更多序列变异性的优点。优选地，与识别不同核苷酸相关的RVD是用于识别C的HD、用于识别T的NG、用于识别A的NI、用于识别G或A的NN、用于识别A、C、G或T的NS、用于识别T的HG、用于识别T的IG、用于识别G的NK、用于识别C的HA、用于识别C的ND、用于识别C的HI、用于识别G的HN、用于识别G的NA、用于识别G或A的SN和用于识别T的YG、用于识别A的TL、用于识别A或G的VT和用于识别A的SW。在另一个实施方式中，关键氨基酸12和13可以朝着其他氨基酸残基突变，以调节其对核苷酸A，T，C和G的特异性，且特别是增强这种特异性。已经描述了TALE核酸酶并用于刺激基因靶向和基因改造(Boch，Scholze et al.2009；Moscou and Bogdanove 2009；Christian，Cermak etal.2010；Li，Huang et al.2011)。工程化TAL核酸酶是在商品名TALENTM下可商购的(Cellectis，8 rue de la Croix Jarry，75013 Paris，France)。
根据本发明的稀切内切核酸酶也可以是Cas9内切核酸酶。最近，基于RNA导向的Cas9核酸酶(Gasiunas，Barrangou et al.2012；Jinek，Chylinski et al.2012；Cong，Ranet al.2013；Mali，Yang et al.2013)，由II型原核CRISPR(成簇规律间隔短回文重复序列(Clustered RegularlyInterspaced Short palindromic Repeats))适应性免疫系统(参见综述(Sorek，Lawrence et al.2013))开发了新的基因组工程化工具。CRISPR相关(Cas)系统首先发现于细菌中，并起到防御外来DNA，或病毒或质粒的作用。CRISPR介导的基因组工程化首先通过选择通常侧接称为前间区序列邻近基序(PAM)的短序列基序的靶序列进行。在靶序列选择后，将与该靶序列互补的特异性crRNA工程化。CRISPR II型系统中所需要的反式活化crRNA(tracrRNA)与crRNA配对并结合至提供的Cas9蛋白。Cas9起到促进tracRNA与cRNA的碱基配对的分子锚的作用(Deltcheva，Chylinski et al.2011)。在这种三元复合体中，双重tracrRNA:crRNA结构起到将内切核酸酶Cas9引导至同源靶序列的引导RNA的作用。通过扫描靶序列的靶序列和crRNA之间的同源性而开始通过Cas9-tracrRNA:crRNA复合体的靶识别。除了靶序列-crRNA互补性之外，DNA靶向要求存在与前间区序列相邻的短基序(前间区序列邻近基序-PAM)。在双-RNA和靶序列之间配对后，Cas9随后引入PAM基序上游的钝双链断裂3碱基(Garneau，Dupuis et al.2010)。
稀切内切核酸酶可以是归巢内切核酸酶，也称为大范围核酸酶。这种归巢内切核酸酶在本领域内是熟知的(Stoddard 2005)。归巢核酸内切酶会识别DNA靶序列并产生单链或双链断裂。归巢内切核酸酶是高度特异性的，会识别长度为12至45碱基对(bp)范围，通常为14至40bp范围的DNA靶位点。根据本发明的归巢内切核酸酶可以，例如对应于LAGLIDADG内切核酸酶，对应于HNH内切核酸酶，或对应于GIY-YIG内切核酸酶。根据本发明的优选归巢内切核酸酶可以是I-CreI变体。
-“递送载体(delivery vector)”或“递送载体(delivery vectors)”旨在是可以用于本发明以使本发明中所需的试剂/化学物质和分子(蛋白质或核酸)与细胞接触(即“接触”)或递送到细胞内或亚细胞区室(即“引入”)的任何递送载体。其包括，但不限于，脂质体递送载体、病毒递送载体、药物递送载体、化学载体、聚合物载体、脂质复合体、复合载体、树枝状聚合物、微泡(超声造影剂)、纳米颗粒、乳液或其它合适的转移载体。这些递送载体允许递送分子、化学物质、大分子(基因，蛋白)或其它载体如质粒，由Diatos开发的肽。在这些情况下，递送载体是分子载体。“递送载体(delivery vector)”或“递送载体(deliveryvectors)”还旨在是用于进行转染的递送方法。
-术语“载体(vector)”或“载体(vectors)”是指能够转运与其连接的另一个核酸的核酸分子。本发明中的“载体”包括，但不限于，病毒载体，质粒，RNA载体或可以由染色体，非染色体，半合成或合成的核酸组成的线性或环状DNA或RNA分子。优选的载体是能够自主复制(附加型载体)和/或表达其连接的核酸(表达载体)的那些。大量合适的载体是本领域技术人员已知的并可商购。
病毒载体包括逆转录病毒，腺病毒，细小病毒(例如，腺相关病毒)，冠状病毒，负链RNA病毒如正粘病毒(例如，流感病毒)，弹状病毒(例如，狂犬病和水泡性口炎病毒)，副粘病毒(例如，麻疹和仙台病毒)，正链RNA病毒如小核糖核酸病毒和甲病毒，以及双链DNA病毒，包括腺病毒，疱疹病毒(例如，1型和2型单纯疱疹病毒，爱泼斯坦-巴尔病毒，巨细胞病毒)和痘病毒(例如，牛痘，禽痘和金丝雀痘)。其他病毒包括，例如，诺瓦克病毒，披膜病毒，黄病毒，呼肠弧病毒，乳多空病毒，嗜肝DNA病毒和肝炎病毒。逆转录病毒的实例包括：禽白血病肉瘤(avian leukosis-sarcoma)，哺乳动物C型，B型病毒，D型病毒，HTLV-BLV组，慢病毒，泡沫病毒(Coffin，J.M.，Retroviridae：The viruses and their replication，InFundamental Virology，Third Edition，B.N.Fields，et al.，Eds.，Lippincott-RavenPublishers，Philadelphia，1996)。
-“慢病毒载体”是指由于其相对较大的包装容量，降低的免疫原性以及高效率地稳定转导大范围不同细胞类型的能力，用于基因递送非常有希望的基于HIV的慢病毒载体。慢病毒载体通常在将三种(包装，包膜和转运)或更多的质粒瞬时转染到生产细胞中后产生。像HIV一样，慢病毒载体通过病毒表面糖蛋白与细胞表面受体的相互作用而进入靶细胞中。进入时，病毒RNA会经历逆转录，其由病毒逆转录酶复合体介导。逆转录的产物是双链线性病毒DNA，其是用于病毒整合于感染细胞DNA的底物。“整合慢病毒载体(或LV)”是指作为非限制性实例，能够整合靶细胞基因组的这种载体。相反，“非整合慢病毒载体(或NILV)”是指不通过病毒整合酶的作用整合靶细胞的基因组的有效基因递送载体。
-递送载体和载体可以关联或结合任何细胞透化技术，如声孔作用或电穿孔或这些技术的衍生。
-细胞(cell)或细胞(cells)旨在是来自这些生物体而用于体外培养的任何真核活细胞，原代细胞和细胞系。
-“原代细胞(primary cell)”或“原代细胞(primary cells)”，旨在是直接从活组织采集的细胞(即，活检材料)，并建立用于体外生长，其会经历非常少的群体倍增，而因此与连续致瘤性或人造永生化细胞系相比，更能代表其衍生自的组织的主要功能组分和特性。
作为非限制性实例，细胞系可以选自由以下组成的组：CHO-K1细胞；HEK293细胞；Caco2细胞；U2-OS细胞；NIH3T3细胞；NSO细胞；SP2细胞；CHO-S细胞；DG44细胞；K-562细胞，U-937细胞；MRC5细胞；IMR90细胞；Jurkat细胞；HepG2细胞；HeLa细胞；HT-1080细胞；HCT-116细胞；Hu-h7细胞；Huvec细胞；Molt4细胞。
所有这些细胞系可以通过本发明的方法改造而提供细胞系模型以产生、表达、定量、检测、研究所感兴趣的基因或蛋白质；这些模型也可以用于在研究和生产以及各种领域，作为非限制性实例，如化学、生物燃油、治疗和农学中筛选所感兴趣的生物活性分子。
-“突变”旨在是多核苷酸(cDNA，基因)或多肽序列中高达一、二、三、四、五、六、七、八、九、十、十一、十三、十四、十五、二十、二十五、三十、四十、五十个或更多个核苷酸/氨基酸的取代，缺失，插入。突变可以影响基因或其调控序列的编码序列。其也可能影响基因组序列的结构或编码的mRNA的结构/稳定性。
-“变体(一个或多个)”旨在是指重复变体，变体，DNA结合变体，TALE-核酸酶变体，通过突变或取代母体分子的氨基酸序列中的至少一个残基而获得的多肽变体。
-“功能性变体”旨在是蛋白或蛋白结构域的催化活性突变体；这种突变体与其母体蛋白或蛋白结构域相比，可以具有相同的活性或其它性质，或更高或更低的活性。
-“一致性”是指两个核酸分子或多肽之间的序列一致性。一致性可以通过比较每个序列中为了比较目的对齐的位置来确定。当比较的序列中的位置被相同碱基占据时，则分子在该位置是相同的。核酸或氨基酸序列之间的相似性或一致性的程度是在核酸序列共有的位置上相同或匹配的核苷酸数量的函数。可以使用各种比对算法和/或程序，包括可用作GCG序列分析包的一部分的FASTA或BLAST(University of Wisconsin，Madison，Wis.)计算两个序列之间的一致性，并可以以默认设置使用。例如，设想了与本文的特异性多肽具有至少70％，85％，90％，95％，98％或99％的一致性并优选显示出基本上相同功能的多肽，以及编码此类多肽的多核苷酸。
-“相似性”描述了两个或多个多肽的氨基酸序列之间的关系。也可以使用BLASTP，采用相似性矩阵，如BLOSUM45，BLOSUM62或BLOSUM80，确定具有与对照氨基酸序列至少70％、75％、80％、85％、87.5％、90％、92.5％、95％、97.5％、98％、99％的序列相似性的氨基酸序列。除非另外指出，相似性计分将基于BLOSUM62的使用。当使用BLASTP时，百分比相似性基于BLASTP正数计分，并且百分比序列一致性基于BLASTP相等计分。BLASTP“相等”表示高分数序列对中总残基的数量和分数是相同的；而BLASTP“整数”表示比对分数具有正值并且彼此相似的残基数量和分数。设想到具有这些程度的一致性或相似性或与本文中公开的氨基酸序列的相似性的任何中间程度的一致性的氨基酸序列并涵盖于本公开中。相似多肽的多核苷酸序列可以使用遗传密码推导，并可以通过常规方法而获得。例如，pTα的功能变体可以与SEQ ID NO:107的氨基酸序列具有70％、75％、80％、85％、87.5％、90％、92.5％、95％、97.5％、98％、99％的序列相似性。编码这种功能性变体的多核苷酸将通过使用遗传密码反向翻译其氨基酸序列而产生。
-“信号转导结构域”或“共刺激配体”是指抗原呈递细胞上特异性结合T细胞上的同源共刺激分子的分子，从而提供除了例如通过TCR/CD3复合体与负载有肽的MHC分子的结合而提供的主要信号之外的介导T细胞响应，包括但不限于增殖活化，分化等的信号。共刺激配体可以包括但不限于CD7、B7-1(CD80)、B7-2(CD86)、PD-L1、PD-L2、4-1BBL、OX40L、诱导型共刺激配体(ICOS-L)、细胞间粘附分子(ICAM、CD30L、CD40、CD70、CD83、HLA-G、MICA、M1CB、HVEM、淋巴毒素β受体、3/TR6、ILT3、ILT4、结合Toll配体受体的激动剂或抗体、和特异性地与B7-H3结合的配体。共刺激分子除此之外还涵盖特异性结合T细胞上存在的共刺激分子的抗体，例如，但不限于CD27、CD28、4-IBB、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关的抗原-1(LFA-1)、CD2、CD7、LTGHT、NKG2C、B7-H3、与CD83特异性结合的配体。
“共刺激分子”是指T细胞上与共刺激配体特异性结合从而介导通过细胞的共刺激响应，如但不限于增殖作用的同源结合配偶体。共刺激分子包括，但不限于MHC I类分子，BTLA和Toll配体受体。
本文所用的“共刺激信号”是指与如TCR/CD3连接的主要信号组合，导致T细胞增殖和/或关键分子的上调或下调的信号。
本文所用的术语“胞外配体结合结构域”定义为能够结合配体的寡肽或多肽。优选地，结构域能够与细胞表面分子相互作用。例如，胞外配体结合结构域可以选择为识别充当与特定疾病状态相关的靶细胞上的细胞表面标志物的配体。因此，细胞表面标志物可以充当配体的实例包括与病毒、细菌和寄生虫感染，自身免疫疾病和癌细胞相关的那些。
本文所用的术语“受试者”或“患者”包括动物界的所有成员，包括非人类灵长类和人类。
术语“复发性”是指具有在治疗后已经缓解的癌症的受试者或哺乳动物具有癌细胞回归的情况。
术语“难治性或耐受性”是指受试者或哺乳动物即使在强烈治疗后在其体内也具有残留癌细胞的情况。
术语“抗药性”是指当疾病对一种或多种药物的治疗没有响应的情况。抗药性可以是内在的(或原发性抗性)，这意味着疾病从未对一种或多种药物响应，或其可以是获得性的，这意味着疾病停止对疾病以前响应的一种或多种药物的响应(继发性抗性)。在某些实施方式中，抗药性是固有的。在某些实施方式中，抗药性是获得性的。
术语“血液恶性肿瘤”或“血液癌症”是指身体的血液、骨髓和/或淋巴组织的癌症。血液恶性肿瘤的实例包括，例如，骨髓增生异常、白血病、淋巴瘤、如皮肤淋巴瘤、非霍奇金淋巴瘤、霍奇金氏症(也称为霍奇金淋巴瘤)和骨髓瘤，如急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞性白血病(CLL)、慢性髓细胞白血病(CML)、慢性嗜中性白血病(CNL)、急性未分化白血病(AUL)、间变性大细胞淋巴瘤(ALCL)、前淋巴细胞白血病(PML)、青少年骨髓单核细胞白血病(JMML)、成人T细胞ALL、具有三系骨髓造血异常(trilineage myelodysplasia)的AML(AML/TMDS)、混合谱系白血病(MLL)、骨髓增生异常综合征(MDS)、骨髓增生性疾病(MPD)和多发性骨髓瘤(MM)。
术语“白血病”是指血液形成组织的恶性肿瘤，包括但不限于慢性淋巴细胞白血病或慢性淋巴白血病，慢性髓细胞白血病，或慢性髓性白血病，急性淋巴细胞白血病，急性髓细胞白血病或急性髓性白血病(AML)和急性成髓细胞白血病。
通常，原代细胞是从血液样品或活检中分离，而随后可选地在体外进一步培养的细胞。细胞系是改造的癌细胞的细胞培养物，优选改造的癌细胞的同源细胞培养物(其中标记物由高斯曲线表示)。
本发明的以上书面描述提供了制备和使用其的方式和方法，使得本领域技术人员可以制备和使用其，特别是针对所附权利要求的主题提供了该实现，其构成了原始描述的一部分。
在本文中列出了数字限制或范围的情况下，包括端点。此外，数值限制或范围内的所有值和子范围都将明确包含在内，如同明显写出一样。
呈现以上描述而使本领域技术人员可以制备和使用本发明，并在具体应用及其要求的上下文中提供。对优选的实施方式的各种修改对于本领域技术人员将是显而易见的，并且在不脱离本发明的精神和范围的情况下，本文中定义的通用原理可以应用于其他实施方式和应用。因此，本发明预想并不限于所示的实施方式，而应该符合与本文公开的原理和特征相一致的最宽范围。
一般性地描述本发明，通过参考某些具体实施例可以获得进一步的理解，这些具体实施例仅为了说明的目的而提供于本文中，除非另有说明，否则并不旨在是限制的。
一般方法
通常，本发明的CD123 CAR T细胞使用从来自不同供体的血沉棕黄层(Buffycoat)样品纯化的T细胞制备。方法和产品满足“良好生产规范(Good ManufacturingPractices)”(FDA 21 CFR和EU GMP)的要求。
临床试验根据“良好临床实践惯例(Good Clinical Practices)”(UK GCP或USAGCP)Blood 2014；124(21):4689进行。
临床前研究
-原代T-细胞培养
T细胞使用Ficoll梯度密度培养基由EFS(Etablissement du Sang，Paris，France)提供的血沉棕黄层样品纯化。回收PBMC层，并使用可商购的T细胞富集试剂盒纯化T细胞。纯化的T细胞在补充有20ng/mL人IL-2，5％人和Dynabeads人T活化剂CD3/CD28的X-VivoTM-15培养基(Lonza)中以珠:细胞比率＝1:1(Life Technologies)活化。
-CAR mRNA转染
在T细胞纯化和活化后第4天或第11天进行转染。用15μg编码不同CAR构建体的mRNA转染5百万个细胞。使用T7 mRNA聚合酶转染产生CAR mRNA，其使用细胞脉冲Cytopulse技术，通过在3000 V/cm下施加两个0.1 mS脉冲，然后在0.4 cm间隙比色杯中以325 V/cm施加四个0.2 mS脉冲，在最终体积为200μL的“细胞穿孔(Cytoporation)缓冲液T”(BTXHarvard Apparatus)中完成。将细胞立即在X-VivoTM-15培养基中稀释，并在37℃下用5％CO2培养。以20 ng/mL电穿孔后2h加入IL-2。
T-细胞转导
在T细胞纯化/活化后3天，进行用重组慢病毒载体表达CAR转导T细胞。慢病毒载体由Vectalys SA(Toulouse，France)通过在HEK-293细胞中转染基因组和辅助质粒而产生。以5的感染倍率进行转导，每次转导使用106个细胞。使用由人CD123蛋白的胞外结构域与鼠IgG1 Fc片段(由LakePharma生产)融合构成的重组蛋白，在T细胞表面上完成CAR检测。用靶向蛋白质的小鼠Fc部分的PE结合的第二抗体(Jackson Immunoresearch)检测这种蛋白与CAR分子的结合，并通过流式细胞术分析。
-脱粒试验(CD107a迁移)
将T细胞连同等量的表达各种水平的CD123蛋白的细胞一起细胞培养于96孔板(40,000个细胞/孔)中。在37℃下以5％CO2将共培养物在最终体积100μL的X-VivoTM-15培养基(Lonza)中维持6小时。在细胞刺激期间，通过在共培养开始时加入荧光抗CD107a抗体，连同1μg/mL抗-CD49d、1μg/mL抗-CD28和1×莫能菌素(Monensin)溶液一起，完成CD107a染色。在6h培养期后，用可固定活性染料(fixable viability dye)和荧光染料结合的抗CD8染色细胞，并通过流式细胞术分析。作为CD8+/CD107a+细胞的％，并通过测定CD8+细胞中CD107a染色的平均荧光强度信号(MFI)，测定脱粒活性。mRNA转染后24h进行脱粒试验。
-IFNγ释放试验
将T细胞与表达各种水平的CD123蛋白的细胞系一起培养于96孔板(40,000个细胞/孔)中。在37℃下用5％CO2将共培养物在最终体积100μL的X-VivoTM-15培养基(Lonza)中维持24小时。在此培养期后，将板以1500 rpm离心5分钟，并将上清液回收于新的板中。通过ELISA试验进行细胞培养物上清液中的IFNγ检测。通过在mRNA转染后24小时开始细胞的共培养进行IFNγ释放试验。
-细胞毒性试验
将T细胞与10,000个靶细胞(表达CD123)和10,000对照(CD123阴性)细胞一起在同一孔中培养于96孔板中(100,000个细胞/孔)。在将其与CAR+ T细胞共培养前，用荧光胞内染料(CFSE或细胞示踪紫(CellTrace Violet))标记靶细胞和对照细胞。将共培养物在37℃下用5％CO2培养4小时。在这个培养期后，用可固定活性染料标记细胞，并通过流式细胞术分析。测定每个细胞群体(靶细胞或CD123阴性对照细胞)的存活率，并计算特异性细胞溶解的％。细胞毒性分析测定在mRNA转染后48小时进行。
-T细胞转导
在T细胞纯化/活化后3天，进行用表达CAR的重组慢病毒载体转染转导T细胞。使用由人CD123蛋白的胞外结构域与鼠IgG1 Fc片段的融合构成的重组蛋白质，在T细胞表面进行CAR检测。用靶向蛋白质的鼠Fc部分的荧光染料结合的第二抗体检测该蛋白对CAR分子的结合，并通过流式细胞术分析。
-抗肿瘤小鼠模型
用表达CD123表达的MOLM13-萤光素酶细胞静脉内(iv)注射免疫缺陷型NOG小鼠作为AML异种移植小鼠模型。可选地，小鼠接受PNA或FLAG的抗癌治疗。然后小鼠iv注射(注射肿瘤细胞系后2或7天)不同剂量的待测试的CAR+ T细胞，或未用CAR慢病毒载体转导的T细胞。在T细胞注射当天(D0)，T细胞注射后D7，14，21，28和40时测定生物发光信号，以跟踪不同动物上的肿瘤进展。
临床研究
I期剂量递增试验设计为评价遗传改造为表达靶向CD123分子(CD123 CAR)的人造T细胞受体(CAR)的同种异体TCR KO特异性细胞毒性T淋巴细胞(CTL)在具有复发/难治性急性髓细胞白血病(AML)、原发性浆细胞样树突细胞肿瘤、移植过渡的患者中的安全性和生物学效力。
每个患者将接受至少一次给药的供体衍生的遗传改造的CTL，并将对毒性和转导的CTL的检测以及疾病特异性标记物进行监测。
以下任何一种在医疗指示时可能会各自变化。
研究类型： 介入
研究设计： 终点分类：安全/功效研究
介入模型：单组分配
掩蔽：开放标签
主要目的：治疗
官方标题： 移植过渡期间使用遗传靶向B细胞特异性抗原CD123阳性残留或复发性急性髓细胞白血病，母细胞性浆细胞样树突细胞肿瘤的体外扩增的同种异体细胞毒性T淋巴细胞(CTL)的I期剂量递增试验。
关键词 急性髓细胞白血病，母细胞性浆细胞样树突细胞瘤，移植过渡
主要测量指标：
评价提供用于AML的持续性或复发，用于母细胞性浆细胞样树突细胞肿瘤或在移植过渡中的改造为表达靶向CD123分子的同种异体特异性CTL的递增剂量的安全性/持续性。
次要测量指标：
·评价过继转移的CD123特异性T细胞对AML进展的影响。
·定量输液之后在定义的间隔下血液中CD123嵌合抗原受体(CD123 CAR)阳性的T细胞的数量以确定其在宿主中的存活和增殖
在输液利妥昔单抗(375mg/m2)之后在定义的间隔下定量测定血液中CD123嵌合抗原受体(CD123 CAR)阳性T-细胞的数量
合格性
适合研究的性别：两者
接受健康志愿者：不
标准
包括标准：
·CD123+白血病史，有骨髓复发或持续的证据。
·持续性微量残留病必须通过形态学，FISH，流式细胞术或RT-PCR以至少2次间隔至少1周的顺序测试证实。
·患者无年龄限制
·KPS或Lansky得分>或＝至40
·肾功能(在调理化疗前测定)
·肝功能(在调理化疗前测定)：
·继发于白血病介入的AST≤5×惯常ULN升高不是排除标准。白血病介入将由前一个月内升高的骨髓或外周血白血病急变以及不存在开始已知的肝毒性药物(例如，唑类)所定义的进行性复发的存在确定。
·总胆红素≤2.5×惯常ULN
·足够的心脏功能(例如，LVEF≥40％)，如由在注册的1个月内进行ECHO或MUGA，或的其他类似心脏影像评价的。
·肺功能(调理化疗前测定)：
·室内空气的氧饱和度≥90％
供体合格性：
·供体，包括第三方供体，必须同意以一次或多次放血获得的白细胞分离或全血献血，这总体上将是成人共计约250毫升，而对于儿科供体每次抽取不超过5mL/kg。
·<18岁的年龄的相关供体需要放置白细胞分离术导管，将捐献通过放血采集的外周血(如果体重允许，会包括血液单位)，并且白细胞分离术不得进行导管置换，因为认为其高出供体的最小风险。
·供体没有上限年龄。然而，相关供体的最低年龄是7岁，因为这是一个人被认为有能力同意参与研究的最年轻的年龄。
·供体的高分辨率HLA分型必须可用于审查
·捐献一周内的CBC。测试结果必须处于不阻止献血或进行白细胞分离术的范围内。
·传染性疾病的血清学测试将按照现有NMDP和FACT指南中所采用的惯常准则进行。基于这些准则，供体应该认为有资格捐献白细胞分离或血液(献血准则)
排除标准：
·具有活性HIV、B型肝炎或C型肝炎感染的患者。
·患有任何由需要除预期观察之外的任何治疗的恶性肿瘤定义的并发活性恶性肿瘤的患者。
·怀孕的女性
·如果他们患有ALL的隔离性髓外复发，患者将被排除。
·具有活动性(2至4级)急性移植抗宿主病(GVHD)、慢性GVHD或需要糖皮质激素治疗(>0.5 mg/kg/天泼尼松或其等效物)作为治疗的明显自身免疫性疾病(例如，溶血性贫血)的患者
·在28天治疗内的活动性中枢神经系统(CNS)白血病，由脑脊髓液(CSF)或症状性CNS白血病(即，颅神经麻痹或其他显著神经功能障碍)中的淋巴母细胞的明确形态学证据定义。预防性鞘内药物不是排除的原因。
·患有以下心脏病症的成年患者(≥18岁)将被排除：
·纽约心脏协会(NYHA)III期或IV期充血性心力衰竭
·心肌梗死，注册之前≤6个月
·临床上显著的室性心律失常或不明原因性晕厥的病史，不被认为是天性的或由于脱水所致的血管迷走神经性的。
·严重非缺血性心肌病病史，EF≤20％
第一数据表明，本发明的工程化T-细胞可以以107个细胞/kg的剂量iv输注于复发难治性AML患者，并选择性地清除CD123-表达癌细胞长达至少11个月。
实施例
实施例1：表达CD123-CAR的TCRα灭活细胞的增殖。
设计并制备了靶向以T细胞受体α恒定链区(TRAC)基因内的15 bp间隔子隔开的两个17 bp长的序列(称为半靶)的异源二聚TALE核酸酶。每个半靶通过表10中列出的半TALE核酸酶的复制体识别。
表10：靶向TCRα基因的TAL核酸酶
在T7启动子的控制下，使用哺乳动物表达载体中的限制酶消化来亚克隆每个TALE核酸酶构建体。从携带T7启动子下游的编码序列的质粒合成编码切割TRAC基因组序列的TALE核酸酶的mRNA。
用编码两半TRAC_T01TALE-核酸酶的两个mRNA的每个转染用抗CD3/CD28涂覆的珠在72小时内预活化的纯化的T细胞。转染后48小时，分别用编码前述的CD-123 CAR(SEQ IDNO：23至48)之一的慢病毒载体转导来自同一供体的不同组的T细胞。转导后2天，使用抗CD3磁珠纯化CD3NEG细胞，且转导后5天，用可溶性抗CD28(5μg/mL)再活化细胞。
在再活化之后通过每周2次计数细胞，细胞增殖最高达30天。与未转导细胞相比，特别是在用抗CD28再活化时，观察到表达CD-123 CAR的TCRα灭活细胞中的增殖增加。
为了研究表达CD123-CAR的人T细胞是否显示出活化状态，在转导后7天通过FACS分析活化标记物CD25的表达。用编码CD-123 CAR的慢病毒载体转导的纯化细胞分析其表面上的CD25表达，以与未转导细胞比较而评价其活化。在CD28再活化或无再活化条件下都会预期CD25表达增加。
实施例2：
使用源自Klon43的抗CD123 scFv抗体片段构建CD123 CAR，TCR KO和dCK KO TCRCD123表达细胞中的功能分析
使用VH(SEQ ID NO 12，L(SEQ ID NO 10)，VL SEQ ID NO 11的组合，或选自SEQID NO 24至SEQ ID NO.30的VH，接头L和选自SEQ ID NO.18至SEQ ID NO.23的VL的组合制备来自Klon 43的scFv或人源化scFv，分别用于产生CD123嵌合抗原受体(本发明的CD123CAR)并筛选它们以选择高性能(具有较少副作用的抗肿瘤活性)。
使用结构V1或V3，优选V3(图2和图3)，并且在人T细胞中表达时测定活性(图4，图5，图6和图7)。
图4中所示的结果显示了在CAR+ T细胞与表达CD123的细胞(RPMI8226)，或不表达CD123的细胞(K562)共培养6小时时的根据本发明的不同scFv对于一种结构(v3：CD8-铰链/CD8-跨膜)的脱粒活性。白色条对应于单独培养的T细胞中观察到的脱粒信号，黑色条表示当与RPMI8226细胞共培养T细胞时观察到的信号，而灰色条显示了与K562细胞共培养的T细胞的脱粒信号。
图5显示了用表达不同水平的CD123的细胞(KG1a或RPMI8226)，或用不表达CD123的细胞(K562)共培养24小时时由T细胞释放的IFNγ的量。也显示了在与共培养物相同的条件下单独培养的T细胞的IFNγ释放。对三个独立供体进行了实验，并且此处显示了代表性供体的结果。
图6和7显示了在用PNA(20mg/kg)ip处理的小鼠体内的CAR T细胞的特异性溶胞活性的剂量响应。
在注射未转导的人T细胞，或用不同剂量的抗CD123 CAR+ T细胞注射前2天，对免疫缺陷小鼠注射MOLM13-荧光素酶细胞。结果表示在T细胞注射后的不同时间点观察到的生物发光信号。
实施例3：临床研究
临床研究提供了证明本文描述的临床研究的可行性的数据。
至少有一名患有难治性/复发性AML的患者接受了根据本发明的治疗，这显著提高了其预期寿命超过16个月，并将癌细胞降低至检测水平之下长达至少6个月。
在输液后至少3个月检测到表达CD123的工程化免疫细胞。
利妥昔单抗(美罗华(Rituxan)(R))的给予。
在初始利妥昔单抗给药375mg/m2后4天内静脉注射给予的利妥昔单抗的总剂量为2,250mg/m2。
在每次输液之前用乙酰氨基酚和抗组胺药进行预治疗。
在另一个实施方式中，第一次输液以50mg/小时的速度开始。在没有输液毒性的情况下，每30分钟将输液速率提高50mg/小时，直至最大的400mg/小时。
对于随后的输液，以100mg/小时的速率进行。在没有输液毒性的情况下，增加到最大400mg/小时而达到2,250mg/m2。
结果表明，患者血液中CD123 CAR细胞水平在最后一次输液后24 h时处于低于检测之下。
Klo43-1(SEQ ID NO.31)
在一个实施方式中，Klon43-1是
Klo43-3(SEQ ID NO.32)
在一个实施方式中，Klon43-3是
Klo43-5(SEQ ID NO.33)
在一个实施方式中，Klon43-5是
本发明的人源化CD123包含以下序列之一：
版本1 VH1
VL1
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本1 VH2
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本1 VH3
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本1 VH4
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本1 VH5
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本1 VH6
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本1 VH7
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRGLAVSTISSFFPPGYQIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本3 VH1
VL1
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本3 VH2
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本3 VH3
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本3 VH4
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VH5
版本3 VH5
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本3 VH6
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VH7
版本3 VH7
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
版本5 VH1
VL1
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCVL2
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVKLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
版本5 VH2
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
版本5 VH3
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
版本5 VH4
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYSASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCVH5
版本5 VH5
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
版本5 VH6
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VH7
版本5 VH7
VL1
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL2
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL3
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL4
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL5
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYRQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
VL6
MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGFIRSKADGYTTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTRDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSMADYKDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKLLIYSASYGQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYC
以下序列设想为本发明的优选CAR
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 172).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 173).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 174).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 175).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 176).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 177).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 178).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKRTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 179).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 180).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 181).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 182).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 183).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 184).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYAASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPDRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 185).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSQSIAYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 186).
EVQLVESGGGLVQPGRSLRLSCTASGFTFTDYYMSWVRQAPGKGLEWVGLIRSKADGYTTEYSASVKGRFTISRDDSKSILYLQMNSLKTEDTAVYYCARDAAYYSYYSPEGAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSVSASVGDRVTITCRASQNVDSAVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGRGSGTDFTLTISSLQPEDFATYYCQQYYSTPWTFGQGTKVEIKREPKSPDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMIARTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO 187).
根据本发明，这些抗CD123 CAR可以包括知识一个模拟表位。
参考文献
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序列表
<110> 塞勒克提斯公司; 雷纳神经科学公司
<120> 赋予结合至CD123的嵌合抗原受体用于治疗复发性/难治性急性骨髓性淋巴瘤或母细胞性浆细胞样树突状细胞肿瘤的T细胞受体敲除的工程化免疫细胞
<130> P81504115PCT02
<150> PA201570044
<151> 2015-01-26
<150> PCT/EP2015/055848
<151> 2015-03-19
<160> 197
<170> PatentIn version 3.5
<210> 1
<211> 21
<212> PRT
<213> 人造序列
<220>
<223> 信号肽
<400> 1
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 2
<211> 20
<212> PRT
<213> 人造序列
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<223> 信号肽
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly
20
<210> 3
<211> 16
<212> PRT
<213> 智人
<220>
<223> FcgRIIIa铰链
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Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln
1 5 10 15
<210> 4
<211> 45
<212> PRT
<213> 智人
<220>
<223> 片段T-cell surface glycoprotein CD8 alpha chain isoform 1 precursor(残基138-206)
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Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
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Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
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<213> 智人
<220>
<223> IgG1铰链
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Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
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Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val
35 40 45
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
50 55 60
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65 70 75 80
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100 105 110
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115 120 125
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
130 135 140
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
145 150 155 160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165 170 175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
180 185 190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195 200 205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
Leu Ser Leu Ser Pro Gly Lys
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<213> 智人
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<223> CD8alpha跨膜结构域
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Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
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Ser Leu Val Ile Thr Leu Tyr Cys
20
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<213> 智人
<220>
<223> 41BB跨膜结构域
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Ile Ile Ser Phe Phe Leu Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu
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Leu Phe Phe Leu Thr Leu Arg Phe Ser Val Val
20 25
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<211> 42
<212> PRT
<213> 智人
<220>
<223> 片段4-1BB (残基214-255)
<400> 8
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
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<211> 112
<212> PRT
<213> 智人
<220>
<223> T细胞表面糖蛋白CD3 zeta链片段
<400> 9
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
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<212> PRT
<213> 人造序列
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<223> 接头
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 11
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> Klon43 light chain variable region
<400> 11
Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met
1 5 10 15
Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 12
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> Klon43重链可变区
<400> 12
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 13
<211> 49
<212> DNA
<213> 人造序列
<220>
<223> 靶TALEN TRAC_T01
<400> 13
ttgtcccaca gatatccaga accctgaccc tgccgtgtac cagctgaga 49
<210> 14
<211> 530
<212> PRT
<213> 人造序列
<220>
<223> TAL结合域TRAC_T01-L
<400> 14
Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys
1 5 10 15
Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala
20 25 30
His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly
35 40 45
Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys
50 55 60
Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn
65 70 75 80
Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val
85 90 95
Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala
100 105 110
Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu
115 120 125
Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala
130 135 140
Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg
145 150 155 160
Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val
165 170 175
Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val
180 185 190
Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu
195 200 205
Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu
210 215 220
Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr
225 230 235 240
Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala
245 250 255
Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly
260 265 270
Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn Ile Gly Gly Lys
275 280 285
Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val Leu Cys Gln Ala
290 295 300
His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly
305 310 315 320
Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys
325 330 335
Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn
340 345 350
Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val
355 360 365
Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala
370 375 380
Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu
385 390 395 400
Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala
405 410 415
Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala
420 425 430
Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val
435 440 445
Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu Thr Val
450 455 460
Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu
465 470 475 480
Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu
485 490 495
Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr
500 505 510
Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala
515 520 525
Leu Glu
530
<210> 15
<211> 530
<212> PRT
<213> 人造序列
<220>
<223> TAL结合域TRAC_T01-R
<400> 15
Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His Asp Gly Gly Lys
1 5 10 15
Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala
20 25 30
His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly
35 40 45
Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys
50 55 60
Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser His
65 70 75 80
Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val
85 90 95
Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala
100 105 110
Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu
115 120 125
Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln Gln Val Val Ala
130 135 140
Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg
145 150 155 160
Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val
165 170 175
Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val
180 185 190
Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln
195 200 205
Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Lys Gln Ala Leu Glu
210 215 220
Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr
225 230 235 240
Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala
245 250 255
Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly
260 265 270
Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys
275 280 285
Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala
290 295 300
His Gly Leu Thr Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly
305 310 315 320
Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu Pro Val Leu Cys
325 330 335
Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala Ser Asn
340 345 350
Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala Leu Leu Pro Val
355 360 365
Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala Ile Ala
370 375 380
Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Arg Leu Leu
385 390 395 400
Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val Val Ala
405 410 415
Ile Ala Ser Asn Ile Gly Gly Lys Gln Ala Leu Glu Thr Val Gln Ala
420 425 430
Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Glu Gln Val
435 440 445
Val Ala Ile Ala Ser His Asp Gly Gly Lys Gln Ala Leu Glu Thr Val
450 455 460
Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr Pro Gln
465 470 475 480
Gln Val Val Ala Ile Ala Ser Asn Asn Gly Gly Lys Gln Ala Leu Glu
485 490 495
Thr Val Gln Arg Leu Leu Pro Val Leu Cys Gln Ala His Gly Leu Thr
500 505 510
Pro Gln Gln Val Val Ala Ile Ala Ser Asn Gly Gly Gly Arg Pro Ala
515 520 525
Leu Glu
530
<210> 16
<211> 2814
<212> PRT
<213> 人造序列
<220>
<223> TRAC_T01-L TALEN
<400> 16
Ala Thr Gly Gly Gly Cys Gly Ala Thr Cys Cys Thr Ala Ala Ala Ala
1 5 10 15
Ala Gly Ala Ala Ala Cys Gly Thr Ala Ala Gly Gly Thr Cys Ala Thr
20 25 30
Cys Gly Ala Thr Thr Ala Cys Cys Cys Ala Thr Ala Cys Gly Ala Thr
35 40 45
Gly Thr Thr Cys Cys Ala Gly Ala Thr Thr Ala Cys Gly Cys Thr Ala
50 55 60
Thr Cys Gly Ala Thr Ala Thr Cys Gly Cys Cys Gly Ala Thr Cys Thr
65 70 75 80
Ala Cys Gly Cys Ala Cys Gly Cys Thr Cys Gly Gly Cys Thr Ala Cys
85 90 95
Ala Gly Cys Cys Ala Gly Cys Ala Gly Cys Ala Ala Cys Ala Gly Gly
100 105 110
Ala Gly Ala Ala Gly Ala Thr Cys Ala Ala Ala Cys Cys Gly Ala Ala
115 120 125
Gly Gly Thr Thr Cys Gly Thr Thr Cys Gly Ala Cys Ala Gly Thr Gly
130 135 140
Gly Cys Gly Cys Ala Gly Cys Ala Cys Cys Ala Cys Gly Ala Gly Gly
145 150 155 160
Cys Ala Cys Thr Gly Gly Thr Cys Gly Gly Cys Cys Ala Cys Gly Gly
165 170 175
Gly Thr Thr Thr Ala Cys Ala Cys Ala Cys Gly Cys Gly Cys Ala Cys
180 185 190
Ala Thr Cys Gly Thr Thr Gly Cys Gly Thr Thr Ala Ala Gly Cys Cys
195 200 205
Ala Ala Cys Ala Cys Cys Cys Gly Gly Cys Ala Gly Cys Gly Thr Thr
210 215 220
Ala Gly Gly Gly Ala Cys Cys Gly Thr Cys Gly Cys Thr Gly Thr Cys
225 230 235 240
Ala Ala Gly Thr Ala Thr Cys Ala Gly Gly Ala Cys Ala Thr Gly Ala
245 250 255
Thr Cys Gly Cys Ala Gly Cys Gly Thr Thr Gly Cys Cys Ala Gly Ala
260 265 270
Gly Gly Cys Gly Ala Cys Ala Cys Ala Cys Gly Ala Ala Gly Cys Gly
275 280 285
Ala Thr Cys Gly Thr Thr Gly Gly Cys Gly Thr Cys Gly Gly Cys Ala
290 295 300
Ala Ala Cys Ala Gly Thr Gly Gly Thr Cys Cys Gly Gly Cys Gly Cys
305 310 315 320
Ala Cys Gly Cys Gly Cys Thr Cys Thr Gly Gly Ala Gly Gly Cys Cys
325 330 335
Thr Thr Gly Cys Thr Cys Ala Cys Gly Gly Thr Gly Gly Cys Gly Gly
340 345 350
Gly Ala Gly Ala Gly Thr Thr Gly Ala Gly Ala Gly Gly Thr Cys Cys
355 360 365
Ala Cys Cys Gly Thr Thr Ala Cys Ala Gly Thr Thr Gly Gly Ala Cys
370 375 380
Ala Cys Ala Gly Gly Cys Cys Ala Ala Cys Thr Thr Cys Thr Cys Ala
385 390 395 400
Ala Gly Ala Thr Thr Gly Cys Ala Ala Ala Ala Cys Gly Thr Gly Gly
405 410 415
Cys Gly Gly Cys Gly Thr Gly Ala Cys Cys Gly Cys Ala Gly Thr Gly
420 425 430
Gly Ala Gly Gly Cys Ala Gly Thr Gly Cys Ala Thr Gly Cys Ala Thr
435 440 445
Gly Gly Cys Gly Cys Ala Ala Thr Gly Cys Ala Cys Thr Gly Ala Cys
450 455 460
Gly Gly Gly Thr Gly Cys Cys Cys Cys Gly Cys Thr Cys Ala Ala Cys
465 470 475 480
Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys Ala Gly Cys Ala Gly Gly
485 490 495
Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly
500 505 510
Cys Ala Ala Thr Gly Gly Cys Gly Gly Thr Gly Gly Cys Ala Ala Gly
515 520 525
Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly
530 535 540
Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys
545 550 555 560
Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys
565 570 575
Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys
580 585 590
Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr
595 600 605
Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Ala Ala Thr Gly Gly Thr
610 615 620
Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly
625 630 635 640
Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr
645 650 655
Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys
660 665 670
Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala
675 680 685
Cys Cys Cys Cys Cys Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr
690 695 700
Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr
705 710 715 720
Gly Gly Cys Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly
725 730 735
Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala
740 745 750
Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly
755 760 765
Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly
770 775 780
Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala
785 790 795 800
Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys
805 810 815
Ala Gly Cys Cys Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly Cys Ala
820 825 830
Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys
835 840 845
Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly
850 855 860
Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly
865 870 875 880
Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys
885 890 895
Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys
900 905 910
Ala Thr Cys Gly Cys Cys Ala Gly Cys Cys Ala Cys Gly Ala Thr Gly
915 920 925
Gly Cys Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr
930 935 940
Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly
945 950 955 960
Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr
965 970 975
Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr
980 985 990
Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly
995 1000 1005
Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Cys
1010 1015 1020
Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly Cys Ala Ala Gly Cys Ala
1025 1030 1035 1040
Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys
1045 1050 1055
Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly
1060 1065 1070
Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala
1075 1080 1085
Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly
1090 1095 1100
Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly
1105 1110 1115 1120
Cys Cys Ala Gly Cys Ala Ala Thr Ala Thr Thr Gly Gly Thr Gly Gly
1125 1130 1135
Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly
1140 1145 1150
Ala Cys Gly Gly Thr Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Thr
1155 1160 1165
Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala
1170 1175 1180
Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys
1185 1190 1195 1200
Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly
1205 1210 1215
Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Cys Ala Cys Gly Ala
1220 1225 1230
Thr Gly Gly Cys Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly
1235 1240 1245
Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys
1250 1255 1260
Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr
1265 1270 1275 1280
Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys
1285 1290 1295
Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly
1300 1305 1310
Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly
1315 1320 1325
Cys Ala Ala Thr Ala Thr Thr Gly Gly Thr Gly Gly Cys Ala Ala Gly
1330 1335 1340
Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly
1345 1350 1355 1360
Thr Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Thr Thr Gly Cys Cys
1365 1370 1375
Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys
1380 1385 1390
Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys
1395 1400 1405
Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr
1410 1415 1420
Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Ala Ala Thr Gly Gly Thr
1425 1430 1435 1440
Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly
1445 1450 1455
Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr
1460 1465 1470
Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys
1475 1480 1485
Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala
1490 1495 1500
Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr
1505 1510 1515 1520
Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr
1525 1530 1535
Ala Thr Thr Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly
1540 1545 1550
Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Gly Cys Ala
1555 1560 1565
Gly Gly Cys Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly
1570 1575 1580
Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly
1585 1590 1595 1600
Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys Ala Gly Cys Ala
1605 1610 1615
Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys
1620 1625 1630
Ala Gly Cys Ala Ala Thr Gly Gly Cys Gly Gly Thr Gly Gly Cys Ala
1635 1640 1645
Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys
1650 1655 1660
Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly
1665 1670 1675 1680
Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly
1685 1690 1695
Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys
1700 1705 1710
Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys
1715 1720 1725
Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Ala Thr Thr Gly
1730 1735 1740
Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr
1745 1750 1755 1760
Gly Gly Ala Gly Ala Cys Gly Gly Thr Gly Cys Ala Gly Gly Cys Gly
1765 1770 1775
Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr
1780 1785 1790
Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr
1795 1800 1805
Gly Ala Cys Cys Cys Cys Cys Cys Ala Gly Cys Ala Gly Gly Thr Gly
1810 1815 1820
Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala
1825 1830 1835 1840
Ala Thr Gly Gly Cys Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala
1845 1850 1855
Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys
1860 1865 1870
Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly
1875 1880 1885
Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala
1890 1895 1900
Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly
1905 1910 1915 1920
Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly
1925 1930 1935
Cys Cys Ala Gly Cys Cys Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly
1940 1945 1950
Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly
1955 1960 1965
Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr
1970 1975 1980
Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala
1985 1990 1995 2000
Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys
2005 2010 2015
Cys Cys Thr Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly
2020 2025 2030
Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Gly Gly
2035 2040 2045
Cys Gly Gly Cys Gly Gly Cys Ala Gly Gly Cys Cys Gly Gly Cys Gly
2050 2055 2060
Cys Thr Gly Gly Ala Gly Ala Gly Cys Ala Thr Thr Gly Thr Thr Gly
2065 2070 2075 2080
Cys Cys Cys Ala Gly Thr Thr Ala Thr Cys Thr Cys Gly Cys Cys Cys
2085 2090 2095
Thr Gly Ala Thr Cys Cys Gly Gly Cys Gly Thr Thr Gly Gly Cys Cys
2100 2105 2110
Gly Cys Gly Thr Thr Gly Ala Cys Cys Ala Ala Cys Gly Ala Cys Cys
2115 2120 2125
Ala Cys Cys Thr Cys Gly Thr Cys Gly Cys Cys Thr Thr Gly Gly Cys
2130 2135 2140
Cys Thr Gly Cys Cys Thr Cys Gly Gly Cys Gly Gly Gly Cys Gly Thr
2145 2150 2155 2160
Cys Cys Thr Gly Cys Gly Cys Thr Gly Gly Ala Thr Gly Cys Ala Gly
2165 2170 2175
Thr Gly Ala Ala Ala Ala Ala Gly Gly Gly Ala Thr Thr Gly Gly Gly
2180 2185 2190
Gly Gly Ala Thr Cys Cys Thr Ala Thr Cys Ala Gly Cys Cys Gly Thr
2195 2200 2205
Thr Cys Cys Cys Ala Gly Cys Thr Gly Gly Thr Gly Ala Ala Gly Thr
2210 2215 2220
Cys Cys Gly Ala Gly Cys Thr Gly Gly Ala Gly Gly Ala Gly Ala Ala
2225 2230 2235 2240
Gly Ala Ala Ala Thr Cys Cys Gly Ala Gly Thr Thr Gly Ala Gly Gly
2245 2250 2255
Cys Ala Cys Ala Ala Gly Cys Thr Gly Ala Ala Gly Thr Ala Cys Gly
2260 2265 2270
Thr Gly Cys Cys Cys Cys Ala Cys Gly Ala Gly Thr Ala Cys Ala Thr
2275 2280 2285
Cys Gly Ala Gly Cys Thr Gly Ala Thr Cys Gly Ala Gly Ala Thr Cys
2290 2295 2300
Gly Cys Cys Cys Gly Gly Ala Ala Cys Ala Gly Cys Ala Cys Cys Cys
2305 2310 2315 2320
Ala Gly Gly Ala Cys Cys Gly Thr Ala Thr Cys Cys Thr Gly Gly Ala
2325 2330 2335
Gly Ala Thr Gly Ala Ala Gly Gly Thr Gly Ala Thr Gly Gly Ala Gly
2340 2345 2350
Thr Thr Cys Thr Thr Cys Ala Thr Gly Ala Ala Gly Gly Thr Gly Thr
2355 2360 2365
Ala Cys Gly Gly Cys Thr Ala Cys Ala Gly Gly Gly Gly Cys Ala Ala
2370 2375 2380
Gly Cys Ala Cys Cys Thr Gly Gly Gly Cys Gly Gly Cys Thr Cys Cys
2385 2390 2395 2400
Ala Gly Gly Ala Ala Gly Cys Cys Cys Gly Ala Cys Gly Gly Cys Gly
2405 2410 2415
Cys Cys Ala Thr Cys Thr Ala Cys Ala Cys Cys Gly Thr Gly Gly Gly
2420 2425 2430
Cys Thr Cys Cys Cys Cys Cys Ala Thr Cys Gly Ala Cys Thr Ala Cys
2435 2440 2445
Gly Gly Cys Gly Thr Gly Ala Thr Cys Gly Thr Gly Gly Ala Cys Ala
2450 2455 2460
Cys Cys Ala Ala Gly Gly Cys Cys Thr Ala Cys Thr Cys Cys Gly Gly
2465 2470 2475 2480
Cys Gly Gly Cys Thr Ala Cys Ala Ala Cys Cys Thr Gly Cys Cys Cys
2485 2490 2495
Ala Thr Cys Gly Gly Cys Cys Ala Gly Gly Cys Cys Gly Ala Cys Gly
2500 2505 2510
Ala Ala Ala Thr Gly Cys Ala Gly Ala Gly Gly Thr Ala Cys Gly Thr
2515 2520 2525
Gly Gly Ala Gly Gly Ala Gly Ala Ala Cys Cys Ala Gly Ala Cys Cys
2530 2535 2540
Ala Gly Gly Ala Ala Cys Ala Ala Gly Cys Ala Cys Ala Thr Cys Ala
2545 2550 2555 2560
Ala Cys Cys Cys Cys Ala Ala Cys Gly Ala Gly Thr Gly Gly Thr Gly
2565 2570 2575
Gly Ala Ala Gly Gly Thr Gly Thr Ala Cys Cys Cys Cys Thr Cys Cys
2580 2585 2590
Ala Gly Cys Gly Thr Gly Ala Cys Cys Gly Ala Gly Thr Thr Cys Ala
2595 2600 2605
Ala Gly Thr Thr Cys Cys Thr Gly Thr Thr Cys Gly Thr Gly Thr Cys
2610 2615 2620
Cys Gly Gly Cys Cys Ala Cys Thr Thr Cys Ala Ala Gly Gly Gly Cys
2625 2630 2635 2640
Ala Ala Cys Thr Ala Cys Ala Ala Gly Gly Cys Cys Cys Ala Gly Cys
2645 2650 2655
Thr Gly Ala Cys Cys Ala Gly Gly Cys Thr Gly Ala Ala Cys Cys Ala
2660 2665 2670
Cys Ala Thr Cys Ala Cys Cys Ala Ala Cys Thr Gly Cys Ala Ala Cys
2675 2680 2685
Gly Gly Cys Gly Cys Cys Gly Thr Gly Cys Thr Gly Thr Cys Cys Gly
2690 2695 2700
Thr Gly Gly Ala Gly Gly Ala Gly Cys Thr Cys Cys Thr Gly Ala Thr
2705 2710 2715 2720
Cys Gly Gly Cys Gly Gly Cys Gly Ala Gly Ala Thr Gly Ala Thr Cys
2725 2730 2735
Ala Ala Gly Gly Cys Cys Gly Gly Cys Ala Cys Cys Cys Thr Gly Ala
2740 2745 2750
Cys Cys Cys Thr Gly Gly Ala Gly Gly Ala Gly Gly Thr Gly Ala Gly
2755 2760 2765
Gly Ala Gly Gly Ala Ala Gly Thr Thr Cys Ala Ala Cys Ala Ala Cys
2770 2775 2780
Gly Gly Cys Gly Ala Gly Ala Thr Cys Ala Ala Cys Thr Thr Cys Gly
2785 2790 2795 2800
Cys Gly Gly Cys Cys Gly Ala Cys Thr Gly Ala Thr Ala Ala
2805 2810
<210> 17
<211> 2832
<212> PRT
<213> 人造序列
<220>
<223> TRAC_T01-R TALEN
<400> 17
Ala Thr Gly Gly Gly Cys Gly Ala Thr Cys Cys Thr Ala Ala Ala Ala
1 5 10 15
Ala Gly Ala Ala Ala Cys Gly Thr Ala Ala Gly Gly Thr Cys Ala Thr
20 25 30
Cys Gly Ala Thr Ala Ala Gly Gly Ala Gly Ala Cys Cys Gly Cys Cys
35 40 45
Gly Cys Thr Gly Cys Cys Ala Ala Gly Thr Thr Cys Gly Ala Gly Ala
50 55 60
Gly Ala Cys Ala Gly Cys Ala Cys Ala Thr Gly Gly Ala Cys Ala Gly
65 70 75 80
Cys Ala Thr Cys Gly Ala Thr Ala Thr Cys Gly Cys Cys Gly Ala Thr
85 90 95
Cys Thr Ala Cys Gly Cys Ala Cys Gly Cys Thr Cys Gly Gly Cys Thr
100 105 110
Ala Cys Ala Gly Cys Cys Ala Gly Cys Ala Gly Cys Ala Ala Cys Ala
115 120 125
Gly Gly Ala Gly Ala Ala Gly Ala Thr Cys Ala Ala Ala Cys Cys Gly
130 135 140
Ala Ala Gly Gly Thr Thr Cys Gly Thr Thr Cys Gly Ala Cys Ala Gly
145 150 155 160
Thr Gly Gly Cys Gly Cys Ala Gly Cys Ala Cys Cys Ala Cys Gly Ala
165 170 175
Gly Gly Cys Ala Cys Thr Gly Gly Thr Cys Gly Gly Cys Cys Ala Cys
180 185 190
Gly Gly Gly Thr Thr Thr Ala Cys Ala Cys Ala Cys Gly Cys Gly Cys
195 200 205
Ala Cys Ala Thr Cys Gly Thr Thr Gly Cys Gly Thr Thr Ala Ala Gly
210 215 220
Cys Cys Ala Ala Cys Ala Cys Cys Cys Gly Gly Cys Ala Gly Cys Gly
225 230 235 240
Thr Thr Ala Gly Gly Gly Ala Cys Cys Gly Thr Cys Gly Cys Thr Gly
245 250 255
Thr Cys Ala Ala Gly Thr Ala Thr Cys Ala Gly Gly Ala Cys Ala Thr
260 265 270
Gly Ala Thr Cys Gly Cys Ala Gly Cys Gly Thr Thr Gly Cys Cys Ala
275 280 285
Gly Ala Gly Gly Cys Gly Ala Cys Ala Cys Ala Cys Gly Ala Ala Gly
290 295 300
Cys Gly Ala Thr Cys Gly Thr Thr Gly Gly Cys Gly Thr Cys Gly Gly
305 310 315 320
Cys Ala Ala Ala Cys Ala Gly Thr Gly Gly Thr Cys Cys Gly Gly Cys
325 330 335
Gly Cys Ala Cys Gly Cys Gly Cys Thr Cys Thr Gly Gly Ala Gly Gly
340 345 350
Cys Cys Thr Thr Gly Cys Thr Cys Ala Cys Gly Gly Thr Gly Gly Cys
355 360 365
Gly Gly Gly Ala Gly Ala Gly Thr Thr Gly Ala Gly Ala Gly Gly Thr
370 375 380
Cys Cys Ala Cys Cys Gly Thr Thr Ala Cys Ala Gly Thr Thr Gly Gly
385 390 395 400
Ala Cys Ala Cys Ala Gly Gly Cys Cys Ala Ala Cys Thr Thr Cys Thr
405 410 415
Cys Ala Ala Gly Ala Thr Thr Gly Cys Ala Ala Ala Ala Cys Gly Thr
420 425 430
Gly Gly Cys Gly Gly Cys Gly Thr Gly Ala Cys Cys Gly Cys Ala Gly
435 440 445
Thr Gly Gly Ala Gly Gly Cys Ala Gly Thr Gly Cys Ala Thr Gly Cys
450 455 460
Ala Thr Gly Gly Cys Gly Cys Ala Ala Thr Gly Cys Ala Cys Thr Gly
465 470 475 480
Ala Cys Gly Gly Gly Thr Gly Cys Cys Cys Cys Gly Cys Thr Cys Ala
485 490 495
Ala Cys Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala
500 505 510
Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys
515 520 525
Ala Gly Cys Cys Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly Cys Ala
530 535 540
Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys
545 550 555 560
Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly
565 570 575
Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly
580 585 590
Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys
595 600 605
Cys Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys
610 615 620
Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Gly Gly Cys Gly
625 630 635 640
Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr
645 650 655
Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly
660 665 670
Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr
675 680 685
Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr
690 695 700
Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly
705 710 715 720
Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Cys
725 730 735
Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly Cys Ala Ala Gly Cys Ala
740 745 750
Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys
755 760 765
Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly
770 775 780
Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala
785 790 795 800
Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly
805 810 815
Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly
820 825 830
Cys Cys Ala Gly Cys Ala Ala Thr Ala Thr Thr Gly Gly Thr Gly Gly
835 840 845
Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly
850 855 860
Ala Cys Gly Gly Thr Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Thr
865 870 875 880
Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala
885 890 895
Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys
900 905 910
Cys Cys Cys Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly
915 920 925
Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Ala Ala
930 935 940
Thr Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly
945 950 955 960
Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys
965 970 975
Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr
980 985 990
Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys
995 1000 1005
Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly
1010 1015 1020
Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly
1025 1030 1035 1040
Cys Cys Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly Cys Ala Ala Gly
1045 1050 1055
Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly
1060 1065 1070
Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys
1075 1080 1085
Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys
1090 1095 1100
Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys
1105 1110 1115 1120
Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr
1125 1130 1135
Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Gly Gly Cys Gly Gly Thr
1140 1145 1150
Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly
1155 1160 1165
Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr
1170 1175 1180
Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys
1185 1190 1195 1200
Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala
1205 1210 1215
Cys Cys Cys Cys Cys Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr
1220 1225 1230
Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr
1235 1240 1245
Ala Ala Thr Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly
1250 1255 1260
Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala
1265 1270 1275 1280
Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly
1285 1290 1295
Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly
1300 1305 1310
Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys Ala Gly Cys Ala
1315 1320 1325
Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys
1330 1335 1340
Ala Gly Cys Ala Ala Thr Ala Ala Thr Gly Gly Thr Gly Gly Cys Ala
1345 1350 1355 1360
Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys
1365 1370 1375
Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly
1380 1385 1390
Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly
1395 1400 1405
Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys
1410 1415 1420
Cys Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys
1425 1430 1435 1440
Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Gly Gly Cys Gly
1445 1450 1455
Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr
1460 1465 1470
Gly Gly Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly
1475 1480 1485
Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr
1490 1495 1500
Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr
1505 1510 1515 1520
Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly
1525 1530 1535
Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala
1540 1545 1550
Ala Thr Ala Thr Thr Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala
1555 1560 1565
Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Gly
1570 1575 1580
Cys Ala Gly Gly Cys Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly
1585 1590 1595 1600
Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala
1605 1610 1615
Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly
1620 1625 1630
Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly
1635 1640 1645
Cys Cys Ala Gly Cys Cys Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly
1650 1655 1660
Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly
1665 1670 1675 1680
Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr
1685 1690 1695
Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala
1700 1705 1710
Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys
1715 1720 1725
Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly
1730 1735 1740
Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Ala Thr
1745 1750 1755 1760
Thr Gly Gly Thr Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly
1765 1770 1775
Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly Thr Gly Cys Ala Gly Gly
1780 1785 1790
Cys Gly Cys Thr Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr
1795 1800 1805
Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys
1810 1815 1820
Thr Thr Gly Ala Cys Cys Cys Cys Gly Gly Ala Gly Cys Ala Gly Gly
1825 1830 1835 1840
Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly
1845 1850 1855
Cys Cys Ala Cys Gly Ala Thr Gly Gly Cys Gly Gly Cys Ala Ala Gly
1860 1865 1870
Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly Ala Gly Ala Cys Gly Gly
1875 1880 1885
Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr Gly Thr Thr Gly Cys Cys
1890 1895 1900
Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys Cys Ala Gly Gly Cys Cys
1905 1910 1915 1920
Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala Cys Cys Cys Cys Cys Cys
1925 1930 1935
Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr Gly Gly Cys Cys Ala Thr
1940 1945 1950
Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr Ala Ala Thr Gly Gly Thr
1955 1960 1965
Gly Gly Cys Ala Ala Gly Cys Ala Gly Gly Cys Gly Cys Thr Gly Gly
1970 1975 1980
Ala Gly Ala Cys Gly Gly Thr Cys Cys Ala Gly Cys Gly Gly Cys Thr
1985 1990 1995 2000
Gly Thr Thr Gly Cys Cys Gly Gly Thr Gly Cys Thr Gly Thr Gly Cys
2005 2010 2015
Cys Ala Gly Gly Cys Cys Cys Ala Cys Gly Gly Cys Thr Thr Gly Ala
2020 2025 2030
Cys Cys Cys Cys Thr Cys Ala Gly Cys Ala Gly Gly Thr Gly Gly Thr
2035 2040 2045
Gly Gly Cys Cys Ala Thr Cys Gly Cys Cys Ala Gly Cys Ala Ala Thr
2050 2055 2060
Gly Gly Cys Gly Gly Cys Gly Gly Cys Ala Gly Gly Cys Cys Gly Gly
2065 2070 2075 2080
Cys Gly Cys Thr Gly Gly Ala Gly Ala Gly Cys Ala Thr Thr Gly Thr
2085 2090 2095
Thr Gly Cys Cys Cys Ala Gly Thr Thr Ala Thr Cys Thr Cys Gly Cys
2100 2105 2110
Cys Cys Thr Gly Ala Thr Cys Cys Gly Gly Cys Gly Thr Thr Gly Gly
2115 2120 2125
Cys Cys Gly Cys Gly Thr Thr Gly Ala Cys Cys Ala Ala Cys Gly Ala
2130 2135 2140
Cys Cys Ala Cys Cys Thr Cys Gly Thr Cys Gly Cys Cys Thr Thr Gly
2145 2150 2155 2160
Gly Cys Cys Thr Gly Cys Cys Thr Cys Gly Gly Cys Gly Gly Gly Cys
2165 2170 2175
Gly Thr Cys Cys Thr Gly Cys Gly Cys Thr Gly Gly Ala Thr Gly Cys
2180 2185 2190
Ala Gly Thr Gly Ala Ala Ala Ala Ala Gly Gly Gly Ala Thr Thr Gly
2195 2200 2205
Gly Gly Gly Gly Ala Thr Cys Cys Thr Ala Thr Cys Ala Gly Cys Cys
2210 2215 2220
Gly Thr Thr Cys Cys Cys Ala Gly Cys Thr Gly Gly Thr Gly Ala Ala
2225 2230 2235 2240
Gly Thr Cys Cys Gly Ala Gly Cys Thr Gly Gly Ala Gly Gly Ala Gly
2245 2250 2255
Ala Ala Gly Ala Ala Ala Thr Cys Cys Gly Ala Gly Thr Thr Gly Ala
2260 2265 2270
Gly Gly Cys Ala Cys Ala Ala Gly Cys Thr Gly Ala Ala Gly Thr Ala
2275 2280 2285
Cys Gly Thr Gly Cys Cys Cys Cys Ala Cys Gly Ala Gly Thr Ala Cys
2290 2295 2300
Ala Thr Cys Gly Ala Gly Cys Thr Gly Ala Thr Cys Gly Ala Gly Ala
2305 2310 2315 2320
Thr Cys Gly Cys Cys Cys Gly Gly Ala Ala Cys Ala Gly Cys Ala Cys
2325 2330 2335
Cys Cys Ala Gly Gly Ala Cys Cys Gly Thr Ala Thr Cys Cys Thr Gly
2340 2345 2350
Gly Ala Gly Ala Thr Gly Ala Ala Gly Gly Thr Gly Ala Thr Gly Gly
2355 2360 2365
Ala Gly Thr Thr Cys Thr Thr Cys Ala Thr Gly Ala Ala Gly Gly Thr
2370 2375 2380
Gly Thr Ala Cys Gly Gly Cys Thr Ala Cys Ala Gly Gly Gly Gly Cys
2385 2390 2395 2400
Ala Ala Gly Cys Ala Cys Cys Thr Gly Gly Gly Cys Gly Gly Cys Thr
2405 2410 2415
Cys Cys Ala Gly Gly Ala Ala Gly Cys Cys Cys Gly Ala Cys Gly Gly
2420 2425 2430
Cys Gly Cys Cys Ala Thr Cys Thr Ala Cys Ala Cys Cys Gly Thr Gly
2435 2440 2445
Gly Gly Cys Thr Cys Cys Cys Cys Cys Ala Thr Cys Gly Ala Cys Thr
2450 2455 2460
Ala Cys Gly Gly Cys Gly Thr Gly Ala Thr Cys Gly Thr Gly Gly Ala
2465 2470 2475 2480
Cys Ala Cys Cys Ala Ala Gly Gly Cys Cys Thr Ala Cys Thr Cys Cys
2485 2490 2495
Gly Gly Cys Gly Gly Cys Thr Ala Cys Ala Ala Cys Cys Thr Gly Cys
2500 2505 2510
Cys Cys Ala Thr Cys Gly Gly Cys Cys Ala Gly Gly Cys Cys Gly Ala
2515 2520 2525
Cys Gly Ala Ala Ala Thr Gly Cys Ala Gly Ala Gly Gly Thr Ala Cys
2530 2535 2540
Gly Thr Gly Gly Ala Gly Gly Ala Gly Ala Ala Cys Cys Ala Gly Ala
2545 2550 2555 2560
Cys Cys Ala Gly Gly Ala Ala Cys Ala Ala Gly Cys Ala Cys Ala Thr
2565 2570 2575
Cys Ala Ala Cys Cys Cys Cys Ala Ala Cys Gly Ala Gly Thr Gly Gly
2580 2585 2590
Thr Gly Gly Ala Ala Gly Gly Thr Gly Thr Ala Cys Cys Cys Cys Thr
2595 2600 2605
Cys Cys Ala Gly Cys Gly Thr Gly Ala Cys Cys Gly Ala Gly Thr Thr
2610 2615 2620
Cys Ala Ala Gly Thr Thr Cys Cys Thr Gly Thr Thr Cys Gly Thr Gly
2625 2630 2635 2640
Thr Cys Cys Gly Gly Cys Cys Ala Cys Thr Thr Cys Ala Ala Gly Gly
2645 2650 2655
Gly Cys Ala Ala Cys Thr Ala Cys Ala Ala Gly Gly Cys Cys Cys Ala
2660 2665 2670
Gly Cys Thr Gly Ala Cys Cys Ala Gly Gly Cys Thr Gly Ala Ala Cys
2675 2680 2685
Cys Ala Cys Ala Thr Cys Ala Cys Cys Ala Ala Cys Thr Gly Cys Ala
2690 2695 2700
Ala Cys Gly Gly Cys Gly Cys Cys Gly Thr Gly Cys Thr Gly Thr Cys
2705 2710 2715 2720
Cys Gly Thr Gly Gly Ala Gly Gly Ala Gly Cys Thr Cys Cys Thr Gly
2725 2730 2735
Ala Thr Cys Gly Gly Cys Gly Gly Cys Gly Ala Gly Ala Thr Gly Ala
2740 2745 2750
Thr Cys Ala Ala Gly Gly Cys Cys Gly Gly Cys Ala Cys Cys Cys Thr
2755 2760 2765
Gly Ala Cys Cys Cys Thr Gly Gly Ala Gly Gly Ala Gly Gly Thr Gly
2770 2775 2780
Ala Gly Gly Ala Gly Gly Ala Ala Gly Thr Thr Cys Ala Ala Cys Ala
2785 2790 2795 2800
Ala Cys Gly Gly Cys Gly Ala Gly Ala Thr Cys Ala Ala Cys Thr Thr
2805 2810 2815
Cys Gly Cys Gly Gly Cys Cys Gly Ala Cys Thr Gly Ala Thr Ala Ala
2820 2825 2830
<210> 18
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VL1
<400> 18
Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro Ser Ser Val
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 19
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VL2
<400> 19
Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 20
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VL3
<400> 20
Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 21
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VL4
<400> 21
Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 22
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VL5
<400> 22
Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 23
<211> 113
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VL6
<400> 23
Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val
1 5 10 15
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
20 25 30
Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
85 90 95
Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 24
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH1
<400> 24
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 25
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH2
<400> 25
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 26
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH3
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH4
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 28
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH5
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 29
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH6
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 30
<211> 127
<212> PRT
<213> 人造序列
<220>
<223> 人源化scFv Klon43变体VH7
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 31
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> Klo43-1+SP
<400> 31
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp
85 90 95
Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu
100 105 110
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His
165 170 175
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Gln Ser Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 32
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> Klo43-3+SP
<400> 32
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp
85 90 95
Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu
100 105 110
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His
165 170 175
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Gln Ser Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 33
<211> 685
<212> PRT
<213> 人造序列
<220>
<223> Klo43-5+SP
<400> 33
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp
85 90 95
Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu
100 105 110
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His
165 170 175
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Gln Ser Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
530 535 540
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
545 550 555 560
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
565 570 575
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
580 585 590
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
595 600 605
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
610 615 620
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
625 630 635 640
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
645 650 655
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
660 665 670
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
675 680 685
<210> 34
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-1 VH1/VL1
<400> 34
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 35
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-1 VH1/VL2
<400> 35
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 36
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-1 VH1/VL3
<400> 36
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 37
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-1 VH1/VL4
<400> 37
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 38
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL5
<400> 38
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 39
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL6
<400> 39
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 40
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL1
<400> 40
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 41
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL2
<400> 41
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 42
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL3
<400> 42
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 43
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL4
<400> 43
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 44
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL5
<400> 44
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 45
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL7
<400> 45
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 46
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL1
<400> 46
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 47
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL2
<400> 47
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 48
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL3
<400> 48
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 49
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL4
<400> 49
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 50
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL5
<400> 50
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 51
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL6
<400> 51
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 52
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL1
<400> 52
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 53
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL2
<400> 53
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 54
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL3
<400> 54
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 55
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL4
<400> 55
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 56
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL5
<400> 56
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 57
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL6
<400> 57
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 58
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL1
<400> 58
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 59
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL2
<400> 59
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 60
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL3
<400> 60
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 61
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL4
<400> 61
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 62
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL5
<400> 62
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 63
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL6
<400> 63
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 64
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL1
<400> 64
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 65
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL2
<400> 65
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 66
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL3
<400> 66
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 67
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL4
<400> 67
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 68
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL5
<400> 68
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 69
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL6
<400> 69
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 70
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL1
<400> 70
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 71
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL2
<400> 71
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 72
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL3
<400> 72
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 73
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL4
<400> 73
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 74
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL5
<400> 74
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 75
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL6
<400> 75
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro
275 280 285
Pro Gly Tyr Gln Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 76
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-3 VH1/VL1
<400> 76
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 77
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL2
<400> 77
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 78
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL3
<400> 78
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 79
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL4
<400> 79
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 80
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL5
<400> 80
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 81
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL6
<400> 81
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 82
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL1
<400> 82
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 83
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL2
<400> 83
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 84
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL3
<400> 84
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 85
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL4
<400> 85
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 86
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL5
<400> 86
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 87
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL6
<400> 87
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 88
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL1
<400> 88
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 89
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL2
<400> 89
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 90
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL3
<400> 90
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 91
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL4
<400> 91
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 92
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL5
<400> 92
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 93
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL6
<400> 93
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 94
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL1
<400> 94
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 95
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL2
<400> 95
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 96
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL3
<400> 96
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 97
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL4
<400> 97
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 98
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL5
<400> 98
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 99
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL6
<400> 99
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 100
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL1
<400> 100
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 101
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL2
<400> 101
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 102
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL3
<400> 102
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 103
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL4
<400> 103
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 104
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL5
<400> 104
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 105
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL6
<400> 105
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 106
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL1
<400> 106
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 107
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL2
<400> 107
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 108
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL3
<400> 108
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 109
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL4
<400> 109
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 110
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL5
<400> 110
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 111
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL6
<400> 111
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 112
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL1
<400> 112
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 113
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL2
<400> 113
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 114
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL3
<400> 114
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 115
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL4
<400> 115
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 116
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL5
<400> 116
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 117
<211> 499
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL6
<400> 117
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
275 280 285
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
290 295 300
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
305 310 315 320
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
325 330 335
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
340 345 350
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
355 360 365
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
370 375 380
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
385 390 395 400
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
405 410 415
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
420 425 430
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
435 440 445
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
450 455 460
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
465 470 475 480
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
485 490 495
Pro Pro Arg
<210> 118
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-5 VH1/VL1
<400> 118
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 119
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL2
<400> 119
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 120
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL3
<400> 120
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 121
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL4
<400> 121
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 122
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL5
<400> 122
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 123
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH1/VL6
<400> 123
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 124
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL1
<400> 124
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 125
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL2
<400> 125
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 126
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL3
<400> 126
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 127
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL4
<400> 127
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 128
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL5
<400> 128
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 129
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH2/VL7
<400> 129
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 130
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL1
<400> 130
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 131
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL2
<400> 131
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 132
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL3
<400> 132
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 133
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL4
<400> 133
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 134
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL5
<400> 134
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 135
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH3/VL6
<400> 135
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 136
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL1
<400> 136
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 137
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL2
<400> 137
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 138
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL3
<400> 138
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 139
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL4
<400> 139
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 140
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL5
<400> 140
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 141
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH4/VL6
<400> 141
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 142
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL1
<400> 142
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 143
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL2
<400> 143
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 144
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL3
<400> 144
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 145
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL4
<400> 145
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 146
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL5
<400> 146
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 147
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH5/VL6
<400> 147
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 148
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL1
<400> 148
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 149
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL2
<400> 149
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 150
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL3
<400> 150
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 151
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL4
<400> 151
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 152
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL5
<400> 152
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 153
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH6/VL6
<400> 153
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 154
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL1
<400> 154
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 155
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL2
<400> 155
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 156
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL3
<400> 156
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 157
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL4
<400> 157
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 158
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL5
<400> 158
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 159
<211> 531
<212> PRT
<213> 人造序列
<220>
<223> VH7/VL6
<400> 159
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys
50 55 60
Gly Leu Glu Trp Val Gly Phe Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
85 90 95
Asp Ser Lys Ser Ile Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu
100 105 110
Asp Thr Ala Val Tyr Tyr Cys Thr Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Gln Met Thr Gln Ser Pro
165 170 175
Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Gly Gln Ser
210 215 220
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val
260 265 270
Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro
275 280 285
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
290 295 300
Pro Lys Pro Lys Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr
305 310 315 320
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
325 330 335
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
340 345 350
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
355 360 365
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
370 375 380
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
385 390 395 400
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
405 410 415
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
420 425 430
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
435 440 445
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
450 455 460
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
465 470 475 480
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
485 490 495
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Ile Tyr Ile Trp Ala
500 505 510
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
515 520 525
Leu Tyr Cys
530
<210> 160
<211> 526
<212> PRT
<213> 人造序列
<220>
<223> hKlo43-3 -2xCD20铰链 CD8
<400> 160
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
20 25 30
Val Gln Pro Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe
35 40 45
Thr Phe Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys
50 55 60
Ala Leu Glu Trp Leu Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr
65 70 75 80
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp
85 90 95
Asp Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu
100 105 110
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr
115 120 125
Tyr Ser Pro Glu Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
130 135 140
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His
165 170 175
Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys
180 185 190
Ala Ser Gln Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro
195 200 205
Gly Gln Ser Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
210 215 220
Gly Val Pro Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr
225 230 235 240
Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys
245 250 255
Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
260 265 270
Glu Ile Lys Arg Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn
275 280 285
Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
290 295 300
Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Ile Ala Ser Gln
305 310 315 320
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
325 330 335
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
340 345 350
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
355 360 365
Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
370 375 380
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
385 390 395 400
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
405 410 415
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
420 425 430
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
435 440 445
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
450 455 460
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
465 470 475 480
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
485 490 495
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
500 505 510
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
515 520 525
<210> 161
<211> 9
<212> PRT
<220>
<223> CD20 mimotope
<400> 161
Cys Pro Tyr Ser Asn Pro Ser Leu Cys
1 5
<210> 162
<211> 24
<212> PRT
<213> 人造序列
<220>
<223> Palivizumab
<400> 162
Asn Ser Glu Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp
1 5 10 15
Gln Lys Lys Leu Met Ser Asn Asn
20
<210> 163
<211> 12
<212> PRT
<213> 人造序列
<220>
<223> Cetuximab 1
<400> 163
Cys Gln Phe Asp Leu Ser Thr Arg Arg Leu Lys Cys
1 5 10
<210> 164
<211> 12
<212> PRT
<213> 人造序列
<220>
<223> Cetuximab 2
<400> 164
Cys Gln Tyr Asn Leu Ser Ser Arg Ala Leu Lys Cys
1 5 10
<210> 165
<211> 12
<212> PRT
<213> 人造序列
<220>
<223> Cetuximab 3
<400> 165
Cys Val Trp Gln Arg Trp Gln Lys Ser Tyr Val Cys
1 5 10
<210> 166
<211> 12
<212> PRT
<213> 人造序列
<220>
<223> Cetuximab 4
<400> 166
Cys Met Trp Asp Arg Phe Ser Arg Trp Tyr Lys Cys
1 5 10
<210> 167
<211> 25
<212> PRT
<213> 人造序列
<220>
<223> Nivolumab 1
<400> 167
Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp
1 5 10 15
Lys Leu Ala Ala Phe Pro Glu Asp Arg
20 25
<210> 168
<211> 19
<212> PRT
<213> 人造序列
<220>
<223> Nivolumab 2
<400> 168
Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln
1 5 10 15
Ile Lys Glu
<210> 169
<211> 24
<212> PRT
<213> 人造序列
<220>
<223> QBEND-10
<400> 169
Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser
1 5 10 15
Pro Ala Lys Pro Thr Thr Thr Ala
20
<210> 170
<211> 12
<212> PRT
<213> 人造序列
<220>
<223> Alemtuzumab
<400> 170
Gly Gln Asn Asp Thr Ser Gln Thr Ser Ser Pro Ser
1 5 10
<210> 171
<211> 37
<212> PRT
<213> 人造序列
<220>
<223> 铰链 CD20
<400> 163
Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys
1 5 10 15
Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser
20 25 30
Gly Gly Gly Gly Ser
35
<210> 172
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH10/VL1 V3
<400> 172
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Arg Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 173
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH9/VL6 V3
<400> 173
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 174
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH10/VL3 V3
<400> 174
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 175
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH9/VL8 V3
<400> 175
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 176
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH2/VL3 V3
<400> 176
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 177
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH10/VL9 V3
<400> 177
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 178
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH9/VL3 V3
<400> 178
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 179
<211> 473
<212> PRT
<213> 人造序列
<220>
<223> huKlon43 VH2/VL1 V3
<400> 179
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Arg Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Thr Thr Pro Ala Pro
245 250 255
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
260 265 270
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
275 280 285
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
290 295 300
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
305 310 315 320
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
325 330 335
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
340 345 350
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
355 360 365
Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu
370 375 380
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
385 390 395 400
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
405 410 415
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
420 425 430
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
435 440 445
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
450 455 460
Leu His Met Gln Ala Leu Pro Pro Arg
465 470
<210> 180
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH10/VL1 V5
<400> 180
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Arg Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 181
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH9/VL6 V5
<400> 181
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 182
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH10/VL3 V5
<400> 182
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 183
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH9/VL8 V5
<400> 183
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 184
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH2/VL3 V5
<400> 184
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 185
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH10/VL9 V5
<400> 185
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 186
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huK43-VH9/VL3 V5
<400> 186
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 187
<211> 659
<212> PRT
<213> 人造序列
<220>
<223> huKlon43 VH2/VL1 V5
<400> 187
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Val Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Asp Ser Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
180 185 190
Ala Ser Tyr Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Arg Gly
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Thr Pro Trp Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Glu Pro Lys Ser Pro Asp
245 250 255
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
260 265 270
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ala
275 280 285
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
290 295 300
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
305 310 315 320
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
325 330 335
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
340 345 350
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
355 360 365
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
370 375 380
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
385 390 395 400
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
405 410 415
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
420 425 430
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
435 440 445
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
450 455 460
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
465 470 475 480
Lys Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
485 490 495
Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu
500 505 510
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
515 520 525
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
530 535 540
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
545 550 555 560
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
565 570 575
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
580 585 590
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
595 600 605
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
610 615 620
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
625 630 635 640
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
645 650 655
Pro Pro Arg
<210> 188
<211> 511
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 1
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln
145 150 155 160
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser
165 170 175
Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg
195 200 205
Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp
225 230 235 240
Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe
245 250 255
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly
260 265 270
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr
275 280 285
Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
290 295 300
Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly
305 310 315 320
Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp
325 330 335
Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile
340 345 350
Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
355 360 365
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
370 375 380
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
385 390 395 400
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
405 410 415
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
420 425 430
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
435 440 445
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
450 455 460
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
465 470 475 480
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
485 490 495
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
500 505 510
<210> 189
<211> 517
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 2
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln
145 150 155 160
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser
165 170 175
Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg
195 200 205
Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp
225 230 235 240
Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe
245 250 255
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly
260 265 270
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly
275 280 285
Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
290 295 300
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
305 310 315 320
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
325 330 335
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
340 345 350
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys
355 360 365
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
370 375 380
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
385 390 395 400
Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
405 410 415
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
420 425 430
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
435 440 445
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
450 455 460
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
465 470 475 480
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
485 490 495
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
500 505 510
Leu Pro Pro Arg Glu
515
<210> 190
<211> 526
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 3
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln
145 150 155 160
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser
165 170 175
Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg
195 200 205
Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp
225 230 235 240
Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe
245 250 255
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly
260 265 270
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly
275 280 285
Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr
290 295 300
Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln
305 310 315 320
Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala
325 330 335
Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala
340 345 350
Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr
355 360 365
Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln
370 375 380
Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser
385 390 395 400
Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys
405 410 415
Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln
420 425 430
Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu
435 440 445
Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg
450 455 460
Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met
465 470 475 480
Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly
485 490 495
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
500 505 510
Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
515 520 525
<210> 191
<211> 532
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 4
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln
145 150 155 160
Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser
165 170 175
Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His
180 185 190
Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg
195 200 205
Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
210 215 220
Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp
225 230 235 240
Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe
245 250 255
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly
260 265 270
Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly
275 280 285
Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly
290 295 300
Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala
305 310 315 320
Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg
325 330 335
Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys
340 345 350
Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu
355 360 365
Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu
370 375 380
Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln
385 390 395 400
Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly
405 410 415
Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
420 425 430
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
435 440 445
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
450 455 460
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
465 470 475 480
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
485 490 495
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
500 505 510
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
515 520 525
Pro Pro Arg Glu
530
<210> 192
<211> 495
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 5
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro
130 135 140
Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu
145 150 155 160
Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr
165 170 175
Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe
180 185 190
Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
195 200 205
Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly
210 215 220
Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala
225 230 235 240
Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro
245 250 255
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr
260 265 270
Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser
275 280 285
Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly
290 295 300
Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp
305 310 315 320
Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile
325 330 335
Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys
340 345 350
Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
355 360 365
Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val
370 375 380
Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn
385 390 395 400
Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val
405 410 415
Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg
420 425 430
Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys
435 440 445
Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg
450 455 460
Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys
465 470 475 480
Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
485 490 495
<210> 193
<211> 501
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 6
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu
20 25 30
Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr
35 40 45
Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
50 55 60
Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
65 70 75 80
Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr
100 105 110
Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly
130 135 140
Gly Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly
145 150 155 160
Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser
165 170 175
Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp
180 185 190
Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln
195 200 205
Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile
210 215 220
Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr
225 230 235 240
Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln
245 250 255
Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
260 265 270
Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro
275 280 285
Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys
290 295 300
Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala
305 310 315 320
Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu
325 330 335
Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys
340 345 350
Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr
355 360 365
Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly
370 375 380
Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala
385 390 395 400
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
405 410 415
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
420 425 430
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
435 440 445
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
450 455 460
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
465 470 475 480
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
485 490 495
Leu Pro Pro Arg Glu
500
<210> 194
<211> 508
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 7
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys
35 40 45
Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile
50 55 60
Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser
65 70 75 80
Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr
85 90 95
Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala
100 105 110
Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala
115 120 125
Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp
130 135 140
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
145 150 155 160
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser
165 170 175
Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys
180 185 190
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp
195 200 205
Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala
210 215 220
Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser
225 230 235 240
Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val
245 250 255
Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly
260 265 270
Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro
275 280 285
Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
290 295 300
Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
305 310 315 320
Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
325 330 335
Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
340 345 350
Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
355 360 365
Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
370 375 380
Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
385 390 395 400
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
405 410 415
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
420 425 430
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
435 440 445
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
450 455 460
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
465 470 475 480
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
485 490 495
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
500 505
<210> 195
<211> 514
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 8
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln
35 40 45
Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys
50 55 60
Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys
65 70 75 80
Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr
85 90 95
Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe
100 105 110
Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu
115 120 125
Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr
130 135 140
Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
145 150 155 160
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
165 170 175
Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln
180 185 190
Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly
195 200 205
Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys
210 215 220
Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg
225 230 235 240
Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro
245 250 255
Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu
260 265 270
Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser
275 280 285
Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
290 295 300
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
305 310 315 320
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile
325 330 335
Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser
340 345 350
Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr
355 360 365
Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu
370 375 380
Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu
385 390 395 400
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
405 410 415
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
420 425 430
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
435 440 445
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
450 455 460
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
465 470 475 480
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
485 490 495
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
500 505 510
Arg Glu
<210> 196
<211> 523
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?
<400> 9
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
35 40 45
Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys
50 55 60
Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe
65 70 75 80
Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe
85 90 95
Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser
100 105 110
Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser
115 120 125
Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr
130 135 140
Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly
145 150 155 160
Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
165 170 175
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro
180 185 190
Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg
195 200 205
Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr
210 215 220
Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser
225 230 235 240
Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg
245 250 255
Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala
260 265 270
Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala
275 280 285
Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala
290 295 300
Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
305 310 315 320
Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
325 330 335
Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
340 345 350
Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
355 360 365
Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
370 375 380
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
385 390 395 400
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
405 410 415
Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn
420 425 430
Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
435 440 445
Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
450 455 460
Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
465 470 475 480
Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His
485 490 495
Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
500 505 510
Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu
515 520
<210> 197
<211> 529
<212> PRT
<213> 人造序列
<220>
<223> 抗CD123 CAR N?0
<400> 10
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro
20 25 30
Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser
35 40 45
Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser
50 55 60
Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys
65 70 75 80
Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln
85 90 95
Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr
100 105 110
Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser
115 120 125
Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys
130 135 140
Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp
145 150 155 160
Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
180 185 190
Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg
195 200 205
Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn
210 215 220
Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
225 230 235 240
Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe
245 250 255
Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val
260 265 270
Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp
275 280 285
Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp
290 295 300
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
305 310 315 320
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
325 330 335
Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr
340 345 350
Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu
355 360 365
Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile
370 375 380
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
385 390 395 400
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
405 410 415
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
420 425 430
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
435 440 445
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
450 455 460
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
465 470 475 480
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
485 490 495
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
500 505 510
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
515 520 525
Glu

Claims (17)

1.一种CD123特异性嵌合抗原受体(CD123 CAR)，包含
■胞外结构域，包含胞外配体结合域，所述胞外配体结合域依次包含VH、可选地人源化的接头，优选其中n＝1至4，优选n＝3的序列(GGGGS)n的接头和VL、可选地人源化的铰链，
■跨膜结构域，和
■细胞质结构域，
■至少一个对单克隆抗体特异性的表位(模拟表位)。
2.根据权利要求1所述的CD123 CAR，包含
■胞外结构域，包含胞外配体结合域，所述胞外配体结合域依次包含选自SEQ ID NO12、SEQ ID NO 24、SEQ ID NO 25、SEQ ID NO 26、SEQ ID NO 27、SEQ ID NO 28、SEQ ID NO29和SEQ ID NO 30的VH，可选地人源化的接头，优选地其中n＝1至4，优选n＝3的序列(GGGGS)n的接头，和选自SEQ ID NO 11、SEQ ID NO 18、SEQ ID NO 19、SEQ ID NO 20、SEQID NO 21、SEQ ID NO 22和SEQ ID NO 23的VL，可选地人源化的铰链，
■来自CD8α的跨膜结构域，和
■包含CD3ζ信令结构域和来自4-1BB的共刺激结构域的细胞质结构域。
3.根据权利要求1或2所述的CD123 CAR，不包含与人CD28 NP_006130.1具有一致性的序列。
4.根据权利要求1至3中任一项所述的CD123 CAR，包含选自SEQ ID NO 172、SEQ ID NO173、SEQ ID NO 174、SEQ ID NO 175、SEQ ID NO 176、SEQ ID NO 177、SEQ ID NO 178、SEQID NO 179、SEQ ID NO 180、SEQ ID NO 181、SEQ ID NO 182、SEQ ID NO 183、SEQ ID NO184、SEQ ID NO 185、SEQ ID NO 186和SEQ ID NO 187的序列，可选地进一步包含至少一个SEQ ID N°161。
5.根据权利要求1至4中任一项所述的CD123 CAR，其中，所述胞外结构域包含至少一个对于单克隆抗体特异性的表位(模拟表位)，选自由SEQ ID NO 161、SEQ ID NO 162、SEQ IDNO 163、SEQ ID NO 164、SEQ ID NO 165、SEQ ID NO 166、SEQ ID NO 167、SEQ ID NO 168、SEQ ID NO 169和SEQ ID NO 170组成的列表，优选地SEQ ID NO 161和SEQ ID NO 169。
6.根据权利要求1至5中任一项所述的CD123 CAR，包含选自SEQ ID NO 160、SEQ ID NO171、SEQ ID NO 188、SEQ ID NO 189、SEQ ID NO 190、SEQ ID NO 191、SEQ ID NO 192、SEQID NO 193、SEQ ID NO 194、SEQ ID NO 195、SEQ ID NO 196和SEQ ID NO 197的序列。
7.一种编码根据权利要求1至6中任一项所述的CD123特异性嵌合抗原受体(CD123CAR)的多核苷酸。
8.一种表达载体，包含根据权利要求7所述的多核苷酸。
9.一种表达载体，包含骨架和至少一个编码根据权利要求1至6中任一项中限定的所述CD123 CAR中的任一种的序列。
10.一种表达载体，包含骨架、EF1启动子、RQR8开放阅读框(RQR8 ORF)、编码权利要求1至6所述的CD123 CAR中的任一种的序列。
11.一种T细胞受体(TCR)敲除(KO)或TCR和人脱氧胞苷激酶(dCK)KO的工程化免疫细胞，在细胞表面膜上表达根据权利要求1至6中任一项所述的CD123 CAR。
12.一种TCR KO或TCR和dCK KO的工程化免疫细胞，包含编码根据权利要求1至6中任一项所述的CD123特异性嵌合抗原受体(CD123CAR)的多核苷酸。
13.根据权利要求4所述的TCR KO或TCR KO和dCK KO的表达CD123 CAR的工程化免疫细胞，进一步在细胞表面表达自杀结构域。
14.根据权利要求11至13中任一项所述的TCR KO或TCR KO和dCK KO的表达CD123 CAR的工程化免疫细胞，其中，至少一种MHC蛋白的表达被抑制。
15.根据权利要求11至14中任一项所述的TCR KO或TCR KO和dCK KO的表达CD123 CAR的工程化免疫细胞，用于治疗。
16.根据权利要求15所述的TCR KO或TCR KO和dCK KO的表达CD123 CAR的工程化免疫细胞，其中，病症是急性髓细胞白血病(AML)，优选难治/复发性AML，BPDNL，或在骨髓移植期间或之前使用。
17.根据权利要求15所述的TCR KO或TCR KO和dCK KO的表达CD123 CAR的工程化免疫细胞，用作治疗，优选用作淋巴增生性病症的治疗，更优选用作淋巴瘤白血病或用作选自由急性髓细胞白血病，慢性髓细胞白血病，骨髓增生异常综合征，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征以及BPDNL组成的组中的治疗。
CN201680006922.0A 2015-01-26 2016-01-25 赋予结合至cd123的嵌合抗原受体用于治疗复发性/难治性急性骨髓性淋巴瘤或母细胞性浆细胞样树突状细胞肿瘤的t细胞受体敲除的工程化免疫细胞 Pending CN107438618A (zh)

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PCT/EP2016/051471 WO2016120220A1 (en) 2015-01-26 2016-01-25 T cell receptor knock out engineered immune cells, endowed with chimeric antigen receptors binding to cd123 for the treatment of relapsed/refractory acute myeloid lymphoma or blastic plasmacytoid dendritic cell neoplasm

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