CN110582513A - 用于治疗癌症的抗tnf相关细胞凋亡诱导配体受体2和抗钙粘蛋白-17的双特异性结合分子 - Google Patents
用于治疗癌症的抗tnf相关细胞凋亡诱导配体受体2和抗钙粘蛋白-17的双特异性结合分子 Download PDFInfo
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Abstract
本发明涉及特异性结合至TNF相关细胞凋亡诱导配体受体2(TNF‑related apoptosis‑inducing ligand receptor 2；TRAILR2)及钙粘蛋白‑17(cadherin‑17；CDH17)的结合分子及其于药剂中的用途、包含所述结合分子的药物组合物及使用所述结合分子作为药剂来治疗及/或预防癌症的方法。
Description
技术领域
本发明涉及结合至TNF相关细胞凋亡诱导配体受体2(TNF-related apoptosis-inducing ligand receptor 2；TRAILR2)及钙粘蛋白-17(cadherin-17；CDH17)的结合分子及其于药剂中的用途、含有所述结合分子的药物组合物及使用所述结合分子作为药剂来治疗及/或预防癌症的方法。
背景技术
癌症为一类通常基于异常细胞增殖及癌细胞在全身侵入或扩散的潜能的疾病，其为一种严重疾病且为全球死亡的主要原因。
业内已使用多种治疗方法尝试管控或在一些情形下治疗癌症，包括手术、化学疗法、放射疗法及激素疗法。尽管近年来某些癌症的治疗已取得进展，但业内仍需要改良此疾病的治疗。
基于抗体的生物分子提供作为强治疗剂治疗癌症的潜能。抗体经设计以识别并结合至细胞表面上的特定蛋白质(其靶抗原)，且所述蛋白质可仅存在于特定癌细胞的表面上或免疫细胞上。此结合可引起多种不同的生物反应，此依据其靶抗原蛋白的功能亦及抗体自身的结构而定。
举例而言，一些抗体通过将免疫细胞吸引至癌细胞或通过直接影响免疫系统自身的活性来触发免疫系统以攻击并杀死癌细胞。另一类型的基于抗体的疗法结合至癌细胞以终止或减少细胞分裂，由此减缓或防止异常细胞增殖。其他类型的抗体具有与其附接的药物或放射性粒子且因此将所述治疗剂递送至癌细胞自身。
细胞凋亡为受控性的细胞机制，其中生物体会维持正常组织隔室中的细胞稳态且消除患病细胞。
在哺乳动物细胞中存在两条引起细胞凋亡的主要信号传导路径：内在路径及外在路径。内在路径为在线粒体层级上起始且在化学疗法或辐射诱导的细胞死亡中起实质作用。相反，外在死亡路径为经由细胞表面上的死亡受体介导的信号起始。
业内已广泛研究在由肿瘤坏死因子(TNF)受体超家族的多个成员介导的信号后经由外在路径诱导的细胞死亡。TNF超家族的特征在于2至5个富含半胱氨酸的细胞外重复的序列。属TNF超家族的死亡受体共享约80个氨基酸的同源细胞内死亡结构域，其为细胞凋亡信号转导所必需。
TNF相关细胞凋亡诱导配体(TRAIL)为天然蛋白配体，其与两种类型的受体相互作用：触发TRAIL诱导的细胞凋亡的死亡受体及抑制TRAIL诱导的细胞凋亡的诱饵受体。迄今为止，已鉴别出四种针对TRAIL具有特异性的人类受体：死亡受体DR4(DR4/TRAIL受体1/TRAILR1)及DR5(TRAIL受体2/TRAIL-R2/KILLER)及诱饵受体DcR1/TRAILR3/TRID及DcR2/TRAILR4。TRAIL亦可以低亲和力结合至骨保护素(OPG)，其为一种可溶性诱饵受体。
靶向TRAIL受体已视为可用于研发癌症疗法的方法，这是因为若基于抗体的分子可结合且活化TRAIL受体(即TRAIL受体激动剂分子)，则其可诱导癌细胞的细胞凋亡。如许多临床前研究中所显示，TRAIL信号传导有效地诱导多个肿瘤细胞系的细胞凋亡，而不诱导大部分正常细胞的细胞凋亡。然而，亦报导正常组织、尤其肝中的肝细胞对此细胞凋亡诱导机制较为敏感。因此，若使用过于有效地活化该路径的分子，则可因亦诱导非癌细胞的细胞凋亡而引起严重副作用。另一方面，若仅使用弱活化分子，则已显示所述分子具有较差抗癌活性，尽管其耐受良好。
因此，业内需要研发出可起TRAIL受体激动剂分子作用的治疗有效且安全的基于抗体的生物分子。因此，本发明的目标为生成具有经改良治疗概况的TRAIL受体激动剂分子。
发明内容
本发明为基于在单一结合分子内组合特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点与特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点的概念。如下文更详细论述，本发明分子的一个优点在于仅有助于表面上存在TRAILR2及CDH17的细胞的细胞凋亡。
因此，本发明的第一方面提供结合分子，其具有至少一个特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点(第一抗原结合位点)及至少一个特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点(第二抗原结合位点)。
在本发明结合分子的优选实施方案中，分子为双特异性及四价。
在本发明结合分子的优选实施方案中，特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点为免疫球蛋白(Ig)分子(具有两条轻链及两条重链的全长抗体的常规Y形结构)，且特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点包含一或多个scFv。
在本发明结合分子的优选实施方案中，一或多个scFv自N末端至C末端具有VL-VH定向。
在本发明结合分子的优选实施方案中，一或多个scFv融合至Ig分子的重链的C末端。例如，一个scFv融合至Ig分子的重链之一的C末端，且一个scFv融合至Ig分子的另一重链的C末端。由此，对TRAILR2具有特异性的scFv融合至Ig分子的各重链，因而形成对称的双特异性四价结构。
在本发明结合分子的优选实施方案中，Ig分子为IgG1KO。在本发明结合分子的另一优选实施方案中，Ig分子为IgG1FcRnmut。
在本发明结合分子的优选实施方案中，一或多个scFv通过肽连接体、优选长度为约4至20个氨基酸(例如6个、9个、12个、15个氨基酸中的任一者)的肽连接体融合至Ig分子。
在本发明结合分子的优选实施方案中，特异性结合至TRAILR2的抗原结合位点(第一抗原结合位点)选自由抗原结合位点(i)至(xiii)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQID NO.:3(CDR3)的氨基酸序列的重链互补决定区(CDR)及包括SEQ ID NO.:4(CDR1)、SEQID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR；
ii)抗原结合位点，其包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQID NO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR；
iii)抗原结合位点，其包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR；
iv)抗原结合位点，其包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ ID NO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR；
v)抗原结合位点，其包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQID NO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR；
vi)抗原结合位点，其包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ ID NO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR；
vii)抗原结合位点，其包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR；
viii)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的轻链CDR；
ix)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:55(CDR3)的氨基酸序列的轻链CDR；
x)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR；
xi)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR；
xii)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR；及
xiii)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR。
在本发明结合分子的优选实施方案中，特异性结合至TRAILR2的抗原结合位点(第一抗原结合位点)选自由抗原结合位点(i)至(xiv)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域；
ii)抗原结合位点，其包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域；
iii)抗原结合位点，其包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域；
iv)抗原结合位点，其包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域；
v)抗原结合位点，其包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域；
vi)抗原结合位点，其包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域；
vii)抗原结合位点，其包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域；
viii)抗原结合位点，其包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域；
ix)抗原结合位点，其包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域；
x)抗原结合位点，其包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域；
xi)抗原结合位点，其包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域；
xii)抗原结合位点，其包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域；
xiii)抗原结合位点，其包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域；及
xiv)抗原结合位点，其包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域。
在本发明结合分子的优选实施方案中，特异性结合至CDH17的抗原结合位点(第二抗原结合位点)选自由抗原结合位点(i)至(iv)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR；
ii)抗原结合位点，其包含包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR；
iii)抗原结合位点，其包含包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR；及
iv)抗原结合位点，其包含包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。
在本发明结合分子的优选实施方案中，特异性结合至CDH17的抗原结合位点(第二抗原结合位点)选自由抗原结合位点(i)至(v)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域；
ii)抗原结合位点，其包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域；
iii)抗原结合位点，其包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域；
iv)抗原结合位点，其包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域；及
v)抗原结合位点，其包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。
在一些实施方案中，在本发明结合分子的背景下使用SEQ ID NO.:272的重链CDR3序列替代SEQ ID NO.:78的重链CDR3序列。
在一些实施方案中，下文各种方面中提供的结合分子(其由这些分子的重链氨基酸序列和轻链氨基酸序列所定义，所述重链氨基酸序列例如是scFv融合至Ig重链C末端的经修饰的重链)包含两条重链和两条轻链，因而形成对称的四价双特异性结构。
本发明的另一方面提供具有以下序列的结合分子：(i)包含SEQ ID NO.:159的氨基酸序列的重链、或包含SEQ ID NO.:160的氨基酸序列的重链、或包含SEQ ID NO.:161的氨基酸序列的重链、或包含SEQ ID NO.:162的氨基酸序列的重链、或包含SEQ ID NO.:163的氨基酸序列的重链、或包含SEQ ID NO.:164的氨基酸序列的重链、或包含SEQ ID NO.:165的氨基酸序列的重链、或包含SEQ ID NO.:166的氨基酸序列的重链、或包含SEQ IDNO.:167的氨基酸序列的重链、或包含SEQ ID NO.:168的氨基酸序列的重链、或包含SEQ IDNO.:169的氨基酸序列的重链、或包含SEQ ID NO.:170的氨基酸序列的重链、或包含SEQ IDNO.:171的氨基酸序列的重链、或包含SEQ ID NO.:172的氨基酸序列的重链，及(ii)包含SEQ ID NO.:173的氨基酸序列的轻链。
本发明的另一方面提供具有以下序列的结合分子：(i)包含SEQ ID NO.:174的氨基酸序列的重链、或包含SEQ ID NO.:175的氨基酸序列的重链、或包含SEQ ID NO.:176的氨基酸序列的重链、或包含SEQ ID NO.:177的氨基酸序列的重链、或包含SEQ ID NO.:178的氨基酸序列的重链、或包含SEQ ID NO.:179的氨基酸序列的重链、或包含SEQ ID NO.:180的氨基酸序列的重链、或包含SEQ ID NO.:181的氨基酸序列的重链、或包含SEQ IDNO.:182的氨基酸序列的重链、或包含SEQ ID NO.:183的氨基酸序列的重链、或包含SEQ IDNO.:184的氨基酸序列的重链、或包含SEQ ID NO.:185的氨基酸序列的重链、或包含SEQ IDNO.:186的氨基酸序列的重链、或包含SEQ ID NO.:187的氨基酸序列的重链，及(ii)包含SEQ ID NO.:188的氨基酸序列的轻链。
在另一方面中，本文提供具有以下序列的结合分子：(i)包含SEQ ID NO.:189的氨基酸序列的重链、或包含SEQ ID NO.:190的氨基酸序列的重链、或包含SEQ ID NO.:191的氨基酸序列的重链、或包含SEQ ID NO.:192的氨基酸序列的重链、或包含SEQ ID NO.:193的氨基酸序列的重链、或包含SEQ ID NO.:194的氨基酸序列的重链、或包含SEQ ID NO.:195的氨基酸序列的重链、或包含SEQ ID NO.:196的氨基酸序列的重链、或包含SEQ IDNO.:197的氨基酸序列的重链、或包含SEQ ID NO.:198的氨基酸序列的重链、或包含SEQ IDNO.:199的氨基酸序列的重链、或包含SEQ ID NO.:200的氨基酸序列的重链、或包含SEQ IDNO.:201的氨基酸序列的重链、或包含SEQ ID NO.:202的氨基酸序列的重链，及(ii)包含SEQ ID NO.:203的氨基酸序列的轻链。
本发明的另一方面提供具有以下序列的结合分子：(i)包含SEQ ID NO.:204的氨基酸序列的重链、或包含SEQ ID NO.:205的氨基酸序列的重链、或包含SEQ ID NO.:206的氨基酸序列的重链、或包含SEQ ID NO.:207的氨基酸序列的重链、或包含SEQ ID NO.:208的氨基酸序列的重链、或包含SEQ ID NO.:209的氨基酸序列的重链、或包含SEQ ID NO.:210的氨基酸序列的重链、或包含SEQ ID NO.:211的氨基酸序列的重链、或包含SEQ IDNO.:212的氨基酸序列的重链、或包含SEQ ID NO.:213的氨基酸序列的重链、或包含SEQ IDNO.:214的氨基酸序列的重链、或包含SEQ ID NO.:215的氨基酸序列的重链、或包含SEQ IDNO.:216的氨基酸序列的重链、或包含SEQ ID NO.:217的氨基酸序列的重链；或包含SEQ IDNO.:271的氨基酸序列的重链，及(ii)包含SEQ ID NO.:218的氨基酸序列的轻链。
在另一方面中，本文提供具有以下序列的结合分子：(i)包含SEQ ID NO.:145的氨基酸序列的重链、或包含SEQ ID NO.:147的氨基酸序列的重链、或包含SEQ ID NO.:149的氨基酸序列的重链、或包含SEQ ID NO.:151的氨基酸序列的重链、或包含SEQ ID NO.:153的氨基酸序列的重链、或包含SEQ ID NO.:155的氨基酸序列的重链、或包含SEQ ID NO.:157的氨基酸序列的重链、或包含SEQ ID NO.:219的氨基酸序列的重链、或包含SEQ IDNO.:220的氨基酸序列的重链、或包含SEQ ID NO.:221的氨基酸序列的重链、或包含SEQ IDNO.:222的氨基酸序列的重链、或包含SEQ ID NO.:223的氨基酸序列的重链、或包含SEQ IDNO.:224的氨基酸序列的重链、或包含SEQ ID NO.:225的氨基酸序列的重链；或包含SEQ IDNO.:226的氨基酸序列的重链、或包含SEQ ID NO.:227的氨基酸序列的重链、或包含SEQ IDNO.:228的氨基酸序列的重链、或包含SEQ ID NO.:229的氨基酸序列的重链、或包含SEQ IDNO.:230的氨基酸序列的重链、或包含SEQ ID NO.:231的氨基酸序列的重链、或包含SEQ IDNO.:232的氨基酸序列的重链，及(ii)包含SEQ ID NO.:233的氨基酸序列的轻链。
本发明的另一方面提供编码本发明结合分子的核酸分子或含有这样的核酸分子的表达载体。
本发明的另一方面提供宿主细胞，其包含与表达控制序列功能相关的本发明核酸分子。本文进一步提供宿主细胞，其包含包括编码如本文所述结合分子的核酸分子的表达载体。
本发明的另一方面提供产生本发明结合分子的方法，其包括
(a)在容许分子表达的条件下培养本发明的宿主细胞；及
(b)回收该分子。
本发明的另一方面提供本发明的结合分子，其用于药剂中。
本发明的另一方面提供本发明的结合分子，其用于癌症、优选结肠直肠癌(CRC)、胃癌(GC)、胰脏癌(PAC)、食道癌或神经内分泌肿瘤的疗法中。
本发明的另一方面提供药物组合物，其包含本发明的结合分子以及药学上可接受的载剂及任选的一或多种其他活性成分。
本发明的另一方面提供治疗癌症的方法，其包括向有需要的患者给予有效量的本发明结合分子。
本文进一步提供特异性结合至CDH17的抗体，其包含(i)包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR，(ii)包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR，(iii)包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ IDNO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR，或(iv)包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。
附图说明
图1A及B：本发明结合分子的示意图。
描述了本发明的结合分子的一个实例，其包含(i)特异性结合至CDH17的Ig分子，其包含两个重链和两个轻链，和(ii)特异性结合至TRAILR2的两个scFv分子。scFv的N-末端融合至所述Ig分子各重链的C-末端，由此形成对称的双特异性四价抗体样分子。
图2：TRAILR2(TR2)及CDH17在Colo-205细胞中的蛋白质表面表达的分析。结果显示为相对于仅含细胞的对照样品的平均PE值。数据代表四个独立实验。
图3：抗体培育对细胞活力的效应。用不同浓度的以下抗体将Colo-205细胞处理24h：(i)单独的抗TRAILR2(抗TR2v1)，(ii)单独的抗CDH17v1，(iii)TRAILR2/CDH17双特异性分子(CDH17v1/TR2v1)，或(iv)各别TRAILR2(抗TR2v1)及CDH17v1抗体的等效组合。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施两个独立分析。
图4：抗体培育后细胞凋亡诱导(半胱天冬酶活化分析)的分析。用不同浓度的以下抗体将Colo-205细胞处理(A)2h或(B)6h：(i)单独的抗TRAILR2(抗TR2v1)，(ii)单独的抗CDH17v1，及(iii)CDH17v1/TR2v1双特异性分子。(A)测量半胱天冬酶-8或(B)半胱天冬酶-3活化。数据表示为与未经处理的对照相比的倍数变化的平均相对值加标准偏差。在每一条件下以一式两份实施三个独立分析。
图5：CDH17v1/TR2v1双特异性分子的特异性的分析。生成识别人类TR2及三硝基苯酚(TNP)替代CDH17的另一双特异性分子。用不同浓度的以下抗体将Colo-205细胞处理24h：(i)单独针对TNP的抗体，(ii)单独的抗CDH17v1，(iii)单独的抗TRAILR2(抗TR2v1)，(iv)TNP/TR2v1，或(v)CDH17v1/TR2v1双特异性分子，且测量细胞活力。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施两个独立分析。
图6：抗体培育对CDH17阴性细胞的效应。(A)TRAILR2(TR2)及CDH17在HepG2细胞中的蛋白质表面表达的分析。结果显示为相对于仅含细胞的对照样品的平均PE值。数据代表三个独立实验。(B)用不同浓度的以下抗体将HepG2细胞处理72h：(i)单独的抗TRAILR2(抗TR2v1)，(ii)TRAILR2/CDH17双特异性分子(CDH17v1/TR2v1)，或(iii)抗TRAILR2(在交联剂存在下)、山羊抗人类IgG(抗TR2v1(Fc交联))。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施五个独立分析。
图7：含有不同IgG支架的双特异性分子对细胞活力的效应。用不同浓度的以下抗体将Colo-205细胞处理24h：单独的抗TRAILR2(抗TR2v1或抗TR2v2)及含有不同IgG1(A及C)及IgG4Pro(B)支架的识别人类TRAILR2及人类CDH17的不同双特异性四价分子。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施两个独立分析。
图8：scFv变体对细胞活力的效应。用不同浓度的含有不同scFv变体的不同双特异性分子将Colo-205细胞处理24h。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施两个独立分析。
图9：识别人类TRAILR2(TR2)及人类CDH17的双特异性四价分子对细胞活力的效应。(A-C)用不同浓度的含有不同CDH17结合剂及scFv变体的不同双特异性分子将Colo-205细胞处理24h。(D)用不同浓度的含有不同CDH17结合剂及scFv变体的不同双特异性分子将HepG2细胞处理72h。使用单独的抗TR2v2(A-D)及抗CDH17H2(C-D)抗体作为对照。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施至少两个独立分析。
图10：识别人类TRAILR2(TR2)及人类CD44v6的双特异性分子对细胞活力的效应。(A)TRAILR2(TR2)及CD44v6在Colo-205细胞中的蛋白质表面表达的分析。结果显示为相对于仅含细胞的对照样品的平均PE值。两种蛋白质皆显示与各别IgG对照相比显著的表达。数据代表3个独立实验。(B)用不同浓度的以下抗体将Colo-205细胞处理72h：单独的抗TRAILR2(抗TR2v1)、单独的抗CD44v6抗体及CD44v6/TR2v1双特异性分子。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施两个独立分析。
图11：抗体培育对CRC细胞活力的效应。(A及B)TRAILR2(TR2)及CDH17在CL-34(A)及SK-CO-1(B)细胞中的蛋白质表面表达的分析。结果显示为相对于仅含细胞的对照样品的平均PE值加标准偏差。数据代表2个独立实验。用不同浓度的以下抗体将CL-34(C)及SK-CO-1(D)细胞分别处理120h及96h：(i)单独的抗TRAILR2(抗TR2v1)，(ii)单独的抗CDH17v1，或(iii)CDH17v1/TR2v1。数据表示为与未经处理的对照相比的平均相对值加标准偏差。在每一条件下以一式两份实施两个独立分析。
图12：识别人类TRAILR2(TR2)及人类CDH17的四价分子的效能：将TRAILR2/CDH17双特异性分子(黑色圆)[CDH17H2/TR2v2-(Ig G1 KO)(A及B)或CDH17H2/TR2v2-(Ig G1FcRnmut)(C及D)]或媒剂对照(白色圆)给予带有Colo205(A及C)或Gp2d(B及D)肿瘤细胞的小鼠。在所指示日给予后测量肿瘤体积(mm3)且数据表示为肿瘤体积的中值。每组包括8-10只动物。
图13：使用新的CDH17抗体分子分析CDH17在Colo-205细胞中的蛋白质表面表达。结果显示为相对于仅含细胞的对照样品的平均APC值。一式两份实验的代表性数据。
图14：原发性CRC及CRC肝转移中的CDH17及TRAILR2蛋白表达。使用相应一级抗体、然后通过检测试剂并在DAB溶液中培育的TRAILR2及CDH17的代表性影像。
具体实施方式
如上文所述，一种治疗癌症的方法已通过使用特异性结合且活化TNF相关细胞凋亡诱导配体(TRAIL)受体介导的细胞凋亡路径的分子来诱导癌细胞的细胞凋亡。如许多临床前研究中所显示，TRAIL信号传导有效地诱导多个肿瘤细胞系的细胞凋亡，而不诱导大部分正常细胞的细胞凋亡。然而，亦报导正常组织、尤其肝中的肝细胞对此细胞凋亡诱导机制较为敏感。
TRAIL以高亲和力结合至四种不同的细胞表面受体。其中的两者TRAILR1及TRAILR2能够经由其细胞内死亡结构域与不同转接蛋白及半胱天冬酶8酶原的相互作用触发TRAIL诱导的细胞凋亡。TRAIL配体对TRAILR1或TRAILR2分子的分群有助于半胱天冬酶8酶原的自催化裂解及活化，此进而诱导细胞凋亡。TRAILR3及TRAILR4为诱饵受体，且尽管其细胞外结构域能够结合TRAIL，但所述受体的细胞内部分不含能够在TRAIL结合时诱导细胞凋亡的结构域。
诱饵TRAIL受体的过表达可使癌细胞对TRAIL配体的存在不敏感。特异性靶向非诱饵死亡诱导TRAIL受体避免了此问题且其代表肿瘤的一种更有效治疗。本发明致力于研发出TRAILR2激动剂分子。TRAILR2广泛性地表达于广谱的癌症中。
已研发出若干TRAILR2特异性激动抗体(包括来沙木单抗(Lexatumumab)(HGS-ETR2))来治疗癌症。然而，所述激动抗体缺乏临床效能。此可能归因于缺乏TRAILR2受体的充分分群且因此无法有效地诱导癌细胞的细胞凋亡。
在促进TRAILR2介导的癌细胞的细胞凋亡的不同尝试中，已研发出新颖四聚体TRAILR2结合纳米抗体TAS266。在临床前实验中，其展示优于常规TRAILR2靶向抗体的抗肿瘤效能。然而，已报导，肝中的肝细胞可能对TRAILR2介导的细胞凋亡敏感且因此如TAS266所促进的TRAILR2分群的非靶向增加具有潜在毒性的风险。实际上，TAS266的I期临床试验已终止。
因此，若使用过于有效地激动路径的分子，则可因诱导非癌细胞的细胞凋亡而引起严重副作用。另一方面，若仅使用弱激动分子，则已显示所述分子具有较差抗癌活性，尽管其耐受良好。
在过去，已尝试设计由TRAIL受体结合位点及结合癌细胞特异性细胞表面分子(称为“锚靶”)的位点组成的双特异性分子。理论上，所述双特异性分子唯一地结合至表达锚靶的癌细胞且诱导通过其TRAIL受体结合位点的细胞凋亡。
已提出多种不同锚靶作为TRAIL受体结合分子的适宜组合伴侣。
举例而言，在WO2011039126A1中建议CEA(CEAM5_人类)及CRIPTO作为适宜锚靶。CEA及CRIPTO通过GPI锚连接至细胞膜。然而，CEA及CRIPTO皆容易自细胞表面裂解且自肿瘤脱落至血流中。实际上，使用CEA血清含量作为癌症筛选的生物标记物。如可了解，血清CEA及CRIPTO可结合至具有TRAIL受体及所述锚靶的双重结合的双特异性分子。因此，血清CEA及CRIPTO不仅将与膜结合锚蛋白竞争，且亦可增加TRAIL受体在不表达CEA或CRIPTO的细胞中活化的可能性并因此可引起不期望副作用。
亦已提出FAP(纤维母细胞活化蛋白)作为锚靶。然而，FAP仅在位于肿瘤间质内的活化纤维母细胞上表达。FAP并不在上皮癌细胞中表达。因此，FAP双特异性分子将仅起到促进那些与活化纤维母细胞紧密物理接触的癌细胞的细胞凋亡作用(Brünker等人，Molecular Cancer Therapeutics(2016),15(5):946-957)。不与活化纤维母细胞直接接触的肿瘤细胞将不受此治疗的影响且将继续增殖。因此，使用FAP作为锚靶来介导TRAIL受体诱导的癌细胞的细胞凋亡具有明显缺点。另外，由于在组织重塑(包括肝纤维化、肺纤维化、全身性动脉粥样硬化及关节炎)的位点中亦发现活化纤维母细胞，故靶向FAP及TRAIL受体的双特异性分子可潜在地锚定至活化纤维母细胞的表面上且诱导肝或其他器官中的邻近正常TRAIL敏感细胞的细胞凋亡。
类似地，已提出MCSP(黑色素瘤相关硫酸软骨素蛋白多糖)及ROBO4(回旋同系物4)作为锚靶(He Yuan等人，The Journal of Investigative Dermatology(2016),136(2):541-544；WO2011039126A1)。MCSP除在黑色素瘤的细胞表面上表达外，其主要在新血管系统上表达。ROBO4在内皮细胞中特异性表达。二者阐述于不同肿瘤类型的血管生成位点处。因此，与FAP一样且仅除MSCP表达黑色素瘤以外有效，靶向MCSP或ROBO4及TRAIL受体的双特异性分子将仅在癌细胞与内皮细胞紧密物理接触时起到促进癌细胞的细胞凋亡作用。并非总是如此，这是因为随着肿瘤生长，其快速增长超过其血液供应。因此，使用所述分子作为锚靶亦具有缺点。
此外，已报导在鼠类肿瘤异种移植物模型中，靶向TRAILR2及LTβR(淋巴毒素-β受体)的双特异性抗体在抑制肿瘤生长方面有活性，其程度等于或大于各别亲代抗体的组合(Michaelson等人，mAbs(2009),1(2):128-141)。已显示小鼠中的LTβR信号传导对肝再生至关重要，其中LTβR在成熟肝细胞上表达(Anders R.A.等人，J Immunol(2005),175(2):1295-1300)。与FAP相似，LTβR信号传导在病毒性及非病毒性肝炎、胆管炎及HCC患者的慢性肝发炎期间广泛活化。具体而言，已阐述其在肝细胞中的表达(Haybaeck J.等人，CancerCell(2009),16(4)：295-308)。靶向LTβR及TRAIL受体可潜在地锚定至对TRAILR2活化敏感的LTβR表达肝细胞的表面上，且因此可潜在地引起肝毒性。
最后，亦已建议生腱蛋白C作为有用的锚靶。生腱蛋白C为分泌性蛋白且因此不会锚定至细胞膜。此代表诱导癌细胞的细胞凋亡的间接机制的另一实例。与MCSP或ROBO4锚定策略一样，生腱蛋白C部分必须正确定向至癌细胞膜上的TRAILR2分子以实现细胞凋亡。另外，生腱蛋白C表达亦在慢性肝病中上调且预期使用包含TRAIL激动剂的双特异性分子治疗会加重病况。
因此，目前问题为在治疗上特异性调节癌细胞中TRAIL受体介导的细胞凋亡路径。
因此，本发明者决定鉴别出不大量存在于血清中且位于共表达TRAILR2的癌细胞中的锚蛋白。重要的是，本发明者选择因上文所述的潜在肝毒性而不在肝中表达的锚蛋白。
本发明者将钙粘蛋白-17鉴别为潜在适宜的锚靶，其可与TRAIL受体结合分子组合使用。
钙粘蛋白-17(CDH17)为钙粘蛋白超家族的成员，即编码钙依赖性膜相关糖蛋白的基因。经编码蛋白质为类钙粘蛋白，由含有7个钙粘蛋白结构域的细胞外区域及跨膜区组成，但缺少在钙粘蛋白超家族的其他成员中保守的细胞质结构域。
本发明者分析CDH17在非肿瘤组织中的表达。IHC研究揭露小肠及结肠的粘膜上皮中的CDH17的均匀上皮染色。在胆囊、胃及胰内管上皮中亦检测到均匀上皮染色。
迄今为止尚未公开代表性研究揭露肿瘤中TRAILR2及CDH17的共表达。在CRC中一致地显示CDH17表达(88％-100％)以及TRAILR2表达(87％-100％)的高盛行率。在GC中，CDH17亦展示于56％-90％的所有病例中，且与扩散型相比在肠型中具有显著较高的频率，而TRAILR2已显示在原发性及转移性胃癌中大量组成性表达。在PAC中，CDH17表达可显示于50％-82％的所有病例中且TRAILR2可显示于81％的所有病例中(Gallmeier等人，PLoSOne.2013；8(2):e56760；Ito等人，Virchows Arch.2005年10月；447(4):717-22；Koornstra等人，Eur J Cancer.2005年5月；41(8):1195-202；Koyama等人，J Cancer Res ClinOncol.2002年2月；128(2):73-9；Luque-Garcia等人，Proteomics.2010年3月；10(5):940-52；Panarelli等人，Am J Clin Pathol.2012年8月；138(2):211-22；Su等人，ModPathol.2008年11月；21(11):1379-86；Takamura等人，Cancer Sci.2003年5月；94(5):425-30；van Geelen等人，J Clin Oncol.2006年11月1日；24(31):4998-5004。)。
因此，本发明者实施此研究且显示TRAILR2及CDH17在多种肿瘤(即结肠直肠癌(CRC)、胃癌(GC)及胰脏癌(PAC))中共表达，且在非癌细胞中极少或无共表达。应注意，在具有所报导对TRAILR2活化的敏感性的正常肝组织或肝细胞中无法检测到CDH17。
重要的是指出在本发明之前尚未揭示或甚至从未设想制备靶向该两种抗原的结合分子。
因此，本发明者制备结合分子，其包括至少一个特异性结合至TRAILR2的抗原结合位点及至少一个特异性结合至CDH17的抗原结合位点。
在随附实验数据中，可见所述分子能够以本发明分子的治疗上可接受的量诱导表达CDH17及TRAILR2二者的细胞的活体外细胞凋亡。重要的是，如实施例中所显示，相同分子基本上不诱导表达TRAILR2而不表达CDH17的细胞的细胞凋亡。因此，本发明结合分子可有效地治疗其中癌细胞表达CDH17及TRAILR2二者的癌症。在一方面中，本发明结合分子并不侵袭CDH17阴性肝细胞，由此降低肝毒性的风险。此外，显示本发明结合分子(例如具有以下各链的结合分子：(i)包含针对CDH17具有特异性的重链可变区、恒定IgG结构域及异性针对TRAILR2具有特异性的scFv的两条重链，及(ii)包含针对CDH17具有特异性的轻链可变区的两条轻链)稳定且单体含量高于95％，此进一步支持其治疗适用性。
因此，本发明的CDH17/TRAILR2结合分子具有明显优于那些业内已知分子的优点且提供治疗癌症(包括结肠直肠癌(CRC)、胃癌(GC)及胰脏癌(PAC))的效用。
此外，CDH17加强TRAIL受体结合分子对TRAILR2的激动效应的能力并非所有细胞表面蛋白所共有。此为自本发明者研究CD44v6是否亦可为适宜锚靶时获知。CD44v6为普遍表达的表面糖蛋白CD44的剪接变体，且已知CD44v6为肿瘤相关抗原并具有在肿瘤中优先于正常组织的表达模式。然而，如随附实施例中所显示，CD44v6并不起锚蛋白作用，这是因为其并不加强TRAIL受体结合分子的激动效应。因此，CDH17作为锚靶的效用无法简单地基于该蛋白的表达概况来预测。
本发明的第一方面提供结合分子，其具有至少一个特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点(第一抗原结合位点)及至少一个特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点(第二抗原结合位点)。
如上文所述，在本发明之前尚未揭示或甚至从未设想制备可特异性结合至TRAILR2及CDH17的结合分子，尽管每一蛋白质及其相关基因个别地为业内已知且充分表示于生物数据库中。
为免生疑问，“TNF相关细胞凋亡诱导配体受体2(TRAILR2)”是指UniProt O14763http://www.uniprot.org/uniprot/O14763中所提供的人类蛋白及编码该蛋白的核酸序列。
为免生疑问，“钙粘蛋白-17(CDH17)”是指UniProt Q12864http://www.uniprot.org/uniprot/Q12864中所提供的人类蛋白及编码该蛋白的核酸序列。
本发明涉及对至少两个不同靶具有结合特异性的结合分子。关于本发明，结合分子衍生自抗体。制备结合分子的技术包括(但不限于)重组共表达两个具有不同特异性的免疫球蛋白重链-轻链对(参见Milstein及Cuello,Nature 305：537(1983))、WO 93/08829及Traunecker等人，EMBO J.10：3655(1991))及“隆凸于孔洞中(knob-in-hole)”改造(例如，参见美国专利第5,731,168号)。亦可通过以下方式来制备结合分子：改造用于制备抗体Fc-异源二聚分子的静电牵引效应(WO 2009/089004A1)；使两个或更多个抗体或片段交联(例如，参见美国专利第4,676,980号及Brennan等人，Science 229：81(1985))；使用亮氨酸拉链产生双特异性抗体(例如，参见Kostelny等人，Immunol.,148(5)：1547-1553(1992))；使用用于制备双特异性抗体片段的“双价抗体”技术(例如，参见Hollinger等人，Proc.Natl.Acad.Sci.USA,90:6444-6448(1993))；及使用单链Fv(sFv)二聚体(例如，参见Gruber等人，/.Immunol.152:5368(1994))；及制备三特异性抗体，如例如Tutt等人，Immunol.147：60(1991)中所述。
应给予本文未明确定义的术语本领域技术人员根据本发明及上下文将给予的含义。然而，如本说明书中所用，除非指定相反含义，否则以下术语具有所指示含义且以下惯例依附于此。
如本文所用的术语“抗原结合位点”包含衍生自抗体的重链可变结构域(VH)及轻链可变结构域(VL)。在该情形下，每一可变结构域包含3个CDR。在一方面中，本发明的抗原结合位点或该蛋白的某些部分通常衍生自抗体。抗体或免疫球蛋白分子的广义结构为本领域技术人员所熟知。
“抗体”或“免疫球蛋白分子”(亦称为免疫球蛋白，缩写为Ig)为可在脊椎动物的血液或其他体液中发现、且免疫系统用于鉴别及中和外来物(例如细菌及病毒)的γ球蛋白。其通常为由基础结构单元构成，所述基础结构单元各自具有两条大重链及两条小轻链，以形成例如具有一个单元的单体、具有两个单元的二聚体或具有五个单元的五聚体。抗体可通过非共价相互作用结合至称为抗原的其他分子或结构。此结合具有特异性是指抗体将仅结合至特定结构且具有高亲和力。由抗体识别的抗原的独特部分称为表位或抗原性决定子。抗体与表位结合的部分有时称为互补位且驻留于抗体的所谓的可变结构域或可变区(Fv)中。可变结构域包含三个由框架区(FR)间隔开的所谓的互补决定区(CDR)。
在本发明上下文中，提及CDR为基于CCG(亦称为IMGT)的定义(Lefranc MP、PommiéC、Ruiz M、Giudicelli V、Foulquier E、Truong L、Thouvenin-Contet V、Lefranc G.“IMGTunique numbering for immunoglobulin and T cell receptor variable domains andIg superfamily V-like domains.”Dev Comp Immunol.2003年1月；27(1):55-77；Giudicelli V、Brochet X、Lefranc MP.“IMGT/V-QUEST：IMGT standardized analysis ofthe immunoglobulin(IG)and T cell receptor(TR)nucleotide sequences”.ColdSpring Harb Protoc.2011；2011(6):695-715。CDR的另一定义为基于Chothia(Chothia及Lesk,J.Mol.Biol.1987,196：901-917)以及Kabat(E.A.Kabat、T.T.Wu、H.Bilofsky、M.Reid-Miller及H.Perry,Sequence of Proteins of Immunological Interest,National Institutes of Health,Bethesda(1983))。
如本文所用的表述“可变结构域”或“可变区”或Fv表示直接参与抗体与抗原结合的轻链及重链对中的每一者。轻链可变结构域缩写为“VL”且重链可变结构域缩写为“VH”。轻链及重链可变结构域具有相同的一般结构，且每一结构域包含通过三个HVR(或CDR)连接的序列高度保守的四个框架区(FR)。框架区采用β-折叠构型，且CDR可形成连接β-折叠结构的环。每一链中的CDR通过框架区保持其三维结构并与另一链的CDR一起形成抗原结合位点。抗体的重链及轻链CDR3区在本发明抗体的结合特异性/亲和力方面起尤其重要的作用，且因此提供本发明的另一目标。如当前申请案内所用的术语“恒定结构域”或“恒定区”表示抗体中除可变区以外的结构域的和。所述恒定结构域及区域为业内所熟知且由例如Kabat等人予以阐述(“Sequence of proteins of immunological interest”,US PublicHealth Services,NIH Bethesda,MD，公开案第91号)。
抗体的“Fc部分”并不直接参与抗体与抗原的结合，但展现多种效应物功能。“抗体的Fc部分”为本领域技术人员所熟知且基于抗体的木瓜蛋白酶裂解定义的术语。依据抗体或免疫球蛋白的重链恒定区的氨基酸序列，其分成以下类别：IgA、IgD、IgE、IgG及IgM。根据重链恒定区，不同类别的免疫球蛋白分别称为α、δ、ε、γ及μ。所述类别中的若干可进一步分成多个子类(同型)，例如IgG1、IgG2、IgG3及IgG4、IgA1及IgA2。抗体的Fc部分基于补体活化、C1q结合及Fc受体结合直接参与ADCC(抗体依赖性细胞介导的细胞毒性)及CDC(补体依赖性细胞毒性)。补体活化(CDC)为通过补体因子C1q与大多数IgG抗体子类的Fc部分结合来起始。尽管抗体对补体系统的影响取决于某些条件，但与C1q的结合为由Fc部分中的经定义结合位点来引起。所述结合位点为业内已知且阐述于例如Boakle等人，Nature 282(1975)742-743；Lukas等人，J.Immunol.127(1981)2555-2560；Brunhouse及Cebra,Mol.Immunol.16(1979)907-917；Burton等人，Nature 288(1980)338-344；Thommesen等人，Mol.Immunol.37(2000)995-1004；Idusogie等人，J.Immunol.164(2000)4178-4184；Hezareh等人，J.Virology 75(2001)12161-12168；Morgan等人，Immunology 86(1995)319-324；EP 0307434。所述结合位点为例如L234、L235、D270、N297、E318、K320、K322、P331及P329(根据Kabat的EU索引编号，参见下文)。所述残基中介导IgG1中的C1q及Fcγ受体结合的最关键残基为L234及L235(Hezareh等人，J.Virology 75(2001)12161-12168)。子类IgG1及IgG3的抗体通常显示补体活化以及C1q及C3结合，而IgG2及IgG4并不活化补体系统且不结合C1q及C3。
业内已进一步研发出多种抗体且使其成为医学及技术中的通用工具。因此，在本发明上下文中，术语“抗体分子”或“抗体”(在本文中以同义使用)不仅包括如可在自然界中发现的包含例如两条轻链及两条重链或仅两条重链(如在骆驼科物种中)的抗体，且另外涵盖包含至少一个对抗原具有结合特异性且结构类似于免疫球蛋白的可变结构域的互补位的所有分子。
因此，抗体可包含单克隆抗体、人类抗体、人类化抗体、嵌合抗体、抗体片段(具体而言Fv、Fab、Fab’或F(ab’)2片段)、单链抗体(具体而言单链可变片段(scFv))、小模组免疫医药(SMIP)、结构域抗体、纳米抗体、双价抗体。抗体可具有通常由抗体的Fc部分(抗体恒定区)介导的效应物功能，例如ADCC或CDC，或其可不具效应物功能，例如因缺少Fc部分或具有经阻断经遮蔽的Fc部分，本质上由免疫细胞或免疫系统组分(如补体系统)无法识别或不充分识别的Fc部分。单克隆抗体(mAb)为氨基酸序列一致的单特异性抗体。其可通过杂交瘤技术自杂合细胞系(称为杂交瘤)产生，该杂合细胞系代表产生特异性抗体的B细胞与骨髓瘤(B细胞癌)细胞的融合纯系(Kohler G、Milstein C.Continuous cultures of fusedcells secreting antibody of predefined specificity.Nature 1975；256:495-7。)。或者，单克隆抗体可通过宿主细胞中的重组表达来产生(Norderhaug L、Olafsen T、Michaelsen TE、Sandlie I.(1997年5月)，“Versatile vectors for transient andstable expression of recombinant antibody molecules in mammalian cells.”JImmunol Methods 204(1)：77-87；亦参见下文)。“重组抗体”或“重组结合分子”为由经重组改造的宿主细胞产生的抗体或结合分子。其任选经分离或纯化。
对于人类中的应用，通常期望减小最初衍生自其他物种(如小鼠)的抗体的免疫原性。此可通过构筑嵌合抗体或通过称为“人类化”的过程来进行。在此情况下，“嵌合抗体”应理解为包含衍生自一物种(例如小鼠)的序列部分(例如可变结构域)融合至衍生自不同物种(例如人类)的序列部分(例如恒定结构域)的抗体。“人类化抗体”为包含最初衍生自非人类物种的可变结构域的抗体，其中某些氨基酸已经突变以使该可变结构域的总体序列更密切类似于人类可变结构域的序列。抗体的嵌合及人类化方法为业内所熟知(Billetta R、Lobuglio AF.“Chimeric antibodies.”Int Rev Immunol.1993；10(2-3):165-76；Riechmann L、Clark M、Waldmann H、Winter G(1988).“Reshaping human antibodies fortherapy”.Nature：332:323)。
“人类化”抗体是指包含来自非人类超变区(HVR)的氨基酸残基及来自人类FR的氨基酸残基的抗体。在某些实施方案中，人类化抗体将包含实质上所有的至少一个、且通常两个可变结构域，其中所有或实质上所有的HVR(例如互补决定区(CDR))对应于非人类抗体的那些HVR，且所有或实质上整个框架区(FR)对应于人类抗体的那些FR。人类化抗体任选可包含衍生自人类抗体的抗体恒定区的至少一部分。抗体(例如非人类抗体)的“人类化形式”是指已经受人类化的抗体。
此外，已研发出多种技术以基于衍生自人类基因体的序列产生抗体，例如通过噬菌体展示或使用转基因动物(WO 90/05144；D.Marks、H.R.Hoogenboom、T.P.Bonnert、J.McCafferty、A.D.Griffiths及G.Winter(1991)“By-passing immunisation.Humanantibodies from V-gene libraries displayed on phage.”J.Mol.Biol.,222,581-597；Knappik等人，J.Mol.Biol.296：57-86,2000；S.Carmen及L.Jermutus,“Concepts inantibody phage display.”Briefings in Functional Genomics and Proteomics 20021(2):189-203；Lonberg N、Huszar D.“Human antibodies from transgenic mice”.IntRev Immunol.1995；13(1):65-93.；Brüggemann M、Taussig MJ.“Production of humanantibody repertoires in transgenic mice”.Curr Opin Biotechnol.1997年8月；8(4):455-8。)。所述抗体在本发明情况下为“人类抗体”。
抗体亦可包括免疫球蛋白的保留抗原结合性质的片段，如Fab、Fab’或F(ab’)2片段。所述片段可通过免疫球蛋白的片段化、例如通过蛋白水解消化或通过所述片段的重组表达来获得。举例而言，免疫球蛋白消化可借助常规技术、例如使用木瓜酶或胃蛋白酶(WO94/29348)来实现。抗体的木瓜酶消化通常产生两个一致的抗原结合片段，即所谓的Fab片段，其各自具有单一抗原结合位点及残余Fc片段。胃蛋白酶处理产生F(ab')2。在Fab分子中，可变结构域各自融合至免疫球蛋白恒定结构域、优选人类来源的免疫球蛋白恒定结构域。因此，重链可变结构域可融合至CH1结构域(所谓的Fd片段)，且轻链可变结构域可融合至CL结构域。Fab分子可通过在宿主细胞中重组表达各别核酸产生，参见下文。
已研发出多种技术用于在不同分子环境中放置免疫球蛋白的可变结构域或衍生自所述可变结构域的分子。那些亦应视为本发明的“抗体”。一般而言，所述抗体分子的大小小于免疫球蛋白，且可包含单一氨基酸链或若干氨基酸链。举例而言，单链可变片段(scFv)为免疫球蛋白的通过短连接体(通常为丝氨酸(S)或甘氨酸(G))连接在一起的重链及轻链可变区的融合物(WO88/01649；WO 91/17271；Huston等人，International Reviews ofImmunology，第10卷，1993,195-217)。“单结构域抗体”或“纳米抗体”在单一Ig样结构域中具有抗原结合位点(WO 94/04678；WO 03/050531；Ward等人，Nature.1989年10月12日；341(6242):544-6；Revets等人，Expert Opin Biol Ther.5(1):111-24,2005)。一或多个对相同或不同抗原具有结合特异性的单结构域抗体可连接在一起。双价抗体为由包含两个可变结构域的两条氨基酸链组成的二价抗体分子(WO 94/13804；Holliger等人，Proc NatlAcad Sci U S A.1993年7月15日；90(14):6444-8)。抗体样分子的其他实施例为免疫球蛋白超家族抗体(IgSF；Srinivasan及Roeske,Current Protein Pept.Sci.2005,6(2)：185-96)。不同概念产生所谓的小模组免疫医药(SMIP)，其包含连接至单链铰链及效应物结构域的Fv结构域且不含恒定结构域CH1(WO 02/056910)。
关于本发明，本发明的第一方面提供结合分子，其包含至少一个特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点及至少一个特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点。
如本文所用的术语“结合”或“特异性结合”是指在活体外分析中抗体或抗原结合位点(例如在本文所述的结合分子中)与抗原表位的结合。亲和力为抗体分子上的单一抗原结合位点与单一表位之间的相互作用。其为通过平衡缔合常数Ka＝k缔合/k解离或平衡解离常数Kd＝k解离/k缔合来表示。
表位为抗原中由抗体或抗原结合部分结合的区域。术语“表位”包括能够特异性结合至抗体或抗原结合部分的任一多肽决定子。在某些实施方案中，表位决定子包括分子的化学活性表面基团(例如氨基酸、多糖侧链、磷酰基或磺酰基)，且在某些实施方案中，可具有特定三维结构特征及/或特定电荷特征。构型及非构型表位的不同之处在于，在变性溶剂存在下不与前者但与后者结合。如本文所用的术语“结合”及“特异性结合”是指在使用经纯化野生型抗原的活体外分析中、优选在等离子共振分析(GE-HealthcareUppsala,Sweden)中抗体或抗原结合部分与抗原表位的结合。
在一方面中，本发明结合分子以一定亲和力结合至TRAILR2或CDH17靶抗原，如例如通过表面等离子共振分析所测定(Malmqvist M.,“Surface plasmon resonance fordetection and measurement of antibody-antigen affinity and kinetics.”,CurrOpin Immunol.1993年4月；5(2):282-6.)，且KD值介于1pM至100μM、优选1pM至1μM范围内。抗体亲和力亦可使用动力学排除分析(KinExA)技术来测量(Darling,R.J.及Brault P-A.,“Kinetic exclusion assay technology：Characterization of MolecularInteractions.”ASSAY and Drug Development Technologies.2004年12月，2(6)：647-657)。
抗体分子的结合亲和力可通过称为亲和力成熟的过程增强(Marks等人，1992,Biotechnology 10:779-783；Barbas等人，1994,Proc.Nat.Acad.Sci,USA91:3809-3813；Shier等人，1995,Gene 169:147-155)。因此，亲和力成熟抗体亦涵盖于本发明中。
如本文所用的术语“结合”或“特异性结合”是指在活体外分析中、优选在表面等离子共振分析(SPR,BIAcore,GE-Healthcare Uppsala,Sweden)中抗体与抗原表位的结合。结合亲和力定义为术语k缔合(来自抗体/抗原复合物的抗体缔合的速率常数)、k解离(解离常数)及KD(k解离/k缔合)。特异性结合通常是指在受体分子与其配体之间形成复合物。在抗体-抗原结合的情况下，高亲和力抗体通常以10-9M或低于10-9M的亲和力结合其靶抗原。
在一个实施方案中，本发明结合分子可诱导TRAILR2介导的一或多种癌细胞类型(例如结肠直肠癌细胞系Colo205)的细胞凋亡，且在1nM或更小、且甚至更优选小于0.01nM的浓度下抑制大于50％的细胞活力。
在另一实施方案中，本发明的结合分子无法诱导TRAILR2介导的CDH17阴性肝源细胞(例如细胞系HepG2)的细胞凋亡，且在高达1nM、或更优选高达10nM、且甚至更优选高达100nM的浓度下抑制小于50％的细胞活力。
在另一优选实施方案中，特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点为免疫球蛋白(Ig)分子(具有两条重链及两条轻链的全长抗体的常规Y形结构)，且特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点包含一或多个scFv、scFab、Fab或Fv结合元件。优选地，特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点包含一或多个scFv。
“单链Fv片段”(scFv)为包含抗体重链可变结构域(VH)、连接体及抗体轻链可变结构域(VL)的多肽，其中所述抗体结构域及该连接体在N末端至C末端方向上具有以下顺序中的一者：a)VH--连接体-VL，b)VL-连接体-VH；且其中该连接体为长度为15至25个氨基酸、优选20个氨基酸的多肽。
另外，所述单链Fv片段可经由纳入半胱氨酸残基从而在VH与VL结构域之间、在VH结构域内或在VL结构域内纳入二硫键来进一步稳定。术语N末端表示多肽链的第一个氨基酸，而术语C末端表示多肽链的C末端的最后一个氨基酸。因此，在本发明实施方案中，一或多个scFv包含其他半胱氨酸残基以形成二硫键。
在本发明实施方案中，scFv部分的稳定性可通过纳入两个紧密三维靠近的半胱氨酸残基以在scFv内形成二硫键(在本文中称为scFvss)来增加。若scFv衍生自TRv1的V区序列(如下文所论述)，则所述稳定二硫键可经改造的实施例潜在位点包括：(a)VL的99位与VH的45位之间，(b)VL的102位与VH的44位之间，(c)VL的4位与100位之间，及(d)VH的6位与112位之间。为借助经改造二硫键实现稳定，优选用半胱氨酸残基取代所述位置的残基。
如随附实施例中所展示，本发明者已显示，自N末端至C末端具有VL-VH定向的TRAILR2 scFv在本发明结合分子中可起诱导靶细胞的细胞凋亡作用。尽管自N末端至C末端具有VH-VL定向的TRAILR2 scFv亦可起作用，但活性在此定向中可能减小。因此，在本发明的优选实施方案中，自N末端至C末端的顺序为VL-VH。
在本发明的另一优选实施方案中，一或多个特异性结合至TRAILR2的scFv通过肽连接体、优选长度为约4至20个氨基酸(例如6个、9个、12个或15个中的任一者)的肽连接体融合至特异性结合至CDH17的Ig分子(例如人类IgG1、IgG1(KO)、IgG1FcRnmut、IgG4Pro)。优选地，scFv融合至Ig分子重链的C末端。优选地，Ig分子为IgG。
将scFv分子连接至IgG分子重链的C末端或连接scFv分子内的可变结构域的方法为业内所熟知。通常使用甘氨酸及丝氨酸的小连接体序列(称为GS微型连接体)。连接体中的氨基酸数可自4(GGGS)(SEQ ID NO.:144)、6(GGSGGS)(SEQ ID NO.:141)、10(GGGGSGGGGS)(SEQ ID NO.:142)或更大变化。在实践中，连接体通常为通过以下方式形成：组合编码所关注IgG的核酸分子(其在该情形下将包括编码CDH17结合位点的重链可变结构域及IgG型恒定结构域的核酸)与编码期望scFv的核酸(其在该情形下将包括编码TRAILR2结合位点的呈VL-VH或VH-V1定向的重链及轻链可变结构域的核酸)，该两种核酸分子由编码连接体序列(例如5个、10个、15个或20个氨基酸中的任一者的GS微型连接体，优选SEQ IDNO.:143的连接体)的核酸分子隔开。然后如下文进一步解释，将此完整HC-scFv编码核酸分子置于表达载体内且引入适宜宿主细胞中，使得形成完整IgG重链-scFv单一多肽。
优选地，scFV分子与IgG分子重链C末端之间的GS微型连接体为GGSGGS(SEQ IDNO.:141)。
在一个实施方案中，本发明提供结合分子，其为包含以下的多特异性结合蛋白：(i)Ig分子，其特异性结合CDH17且具有两条重链和两条轻链，和(ii)两个scFv分子(scFv(s))，其各自特异性结合至TRAILR2。优选地，Ig分子的各重链具有一个融合至其C-末端的scFv，因而形成双特异性四价结合蛋白。
在一个实施方案中，本发明提供结合分子，其具有：
(i)两条重链，其自N至C末端各自包含：
-针对CDH17具有特异性的重链可变结构域(例如鼠类、人类化或人类VH结构域)
-IgG(例如人类IgG1或IgG4)的恒定结构域
-肽连接体(例如GS微型连接体)，及
-针对TRAILR2具有特异性的scFv(例如自N至C末端包含VH结构域(例如鼠类、人类化或人类VH结构域)、连接体及VL结构域(例如鼠类、人类化或人类VL结构域)的scFv，或反之包含VL结构域、连接体及VH结构域的scFv)；及
(ii)两条轻链，其自N至C末端各自包含：
-针对CDH17具有特异性的轻链可变结构域(例如鼠类、人类化或人类VL结构域)，
-轻链恒定结构域(例如人类κ链)。
本文所述的抗体分子或结合分子可融合(为融合蛋白)或以其他方式连接(通过共价键或非共价键)至对抗体分子的性质具有期望影响的其他分子实体。举例而言，可期望改良本文所述的抗体或结合分子的药物动力学性质，例如体液(例如血液)中的稳定性，尤其在单链抗体或结构域抗体的情形下。就此而言已研发出多种技术，具体而言延长所述抗体分子的循环半衰期，例如聚乙二醇化(WO 98/25971；WO 98/48837；WO 2004081026)、融合或以其他方式使抗体分子共价附接至对血清蛋白(如白蛋白)具有亲和力的另一抗体分子(WO2004041865；WO 2004003019)或使抗体分子表达为与血清蛋白(如白蛋白或运铁蛋白)的全部或一部分的融合蛋白(WO 01/79258)。
由于抗体的Fc区与多种Fc受体相互作用产生多种重要的功能能力(其称为“效应物功能”)，故在某些实施方案中抗体为全长抗体或含有Fc区的一部分的抗体，只要后一抗体展现与抗原的相关部分以及与Fc受体及补体二者的特异性结合即可。恒定区的类型及长度的选择依据效应物功能(如补体结合或抗体依赖性细胞介导的细胞毒性)是否为期望特征及抗体蛋白的期望药理学性质而定。
在本发明实施方案中，通过利用IgG4恒定区或在234位及235位具有L至A定向诱变的IgG1恒定区可除去本发明中结合分子与补体产物C1q或Fcγ受体的结合。
在本发明实施方案中，本发明结合分子可具有Fc区或其相关部分，其已经改造以避免可溶性Fcγ受体或补体C1q的不期望交联。在一个实施方案中，该结合分子或抗体变体具有远低于亲代抗体的对Fcγ受体及补体C1q的亲和力。(在下文中，若非另外说明，否则术语“亲代”在抗体分子背景下或在IgG或Fc区背景下分别是指未经改造的抗体分子Fc区或IgG，突变(经改造)分子为自其衍生而来。)。因此，在本发明实施方案中，Ig分子包含与野生型Fc区相比具有减小的对Fcγ受体或补体受体或二者的亲和力的Fc变体。该Ig分子在本文中称为IgG1(KO)。
在本发明的另一实施方案中，本发明结合分子包含Fc区或其相关部分，其已经改造以通过最优化其与新生Fc受体(FcRn)的相互作用(例如通过CH2结构域中H310A位的点突变)来改变血清含量(半衰期)。该Ig分子在本文中称为IgG1FcRnmut。
在本发明的另一实施方案中，结合分子包含Ig分子，该Ig分子包含除去重链与其他IgG4分子的调换的IgG4铰链区变体。该Ig分子在本文中称为IgG4Pro。
本发明提供结合分子，其具有至少一个特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点及至少一个特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点。
制备结合至特定靶抗原的结合位点的方法为业内所熟知。本领域技术人员可容易地使用所述方法来设计具有所需对TRAILR2或CDH17靶抗原的特异性的抗原结合位点。
生成抗体及抗体片段的方法为业内所熟知。举例而言，抗体可经由若干方法中的任一者生成，所述方法采用诱导活体内抗体分子的产生、筛选免疫球蛋白文库(Orlandi等人，1989.Proc.Natl.Acad.Sci.U.S.A.86:3833-3837；Winter等人，1991,Nature 349:293-299)或通过培养细胞系生成单克隆抗体分子。所述方法包括(但不限于)杂交瘤技术、人类B细胞杂交瘤技术及艾司坦-巴尔病毒(Epstein-Barr virus，EBV)杂交瘤技术(Kohler等人，1975.Nature256:4950497；Kozbor等人，1985.J.Immunol.Methods 81:31-42；Cote等人，1983.Proc.Natl.Acad.Sci.USA 80:2026-2030；Cole等人，1984.Mol.Cell.Biol.62:109-120)。
使用业内已知及本文所述的方法，本领域技术人员将容易地制备具有所需对TRAILR2及/或CDH17靶抗原的特异性的结合位点的抗体以及本文所述的结合分子。自所述抗体分离结合结构域为常规实践且实际上关于可用于生成如本文所述抗体及结合分子的方法的其他信息提供于随附实施例中。
本发明者制备本发明的特异性TRAILR2/CDH17结合分子，其论述于随附实施例中。
本发明者制备多个针对TRAILR2具有特异性的抗原结合位点，且将所述位点称为TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7。本发明者亦制备多个针对CDH17具有特异性的抗原结合位点，且将所述位点称为CDH17A6、CDH17E2、CDH17H2、CDH17E9及CDH17v1。在以下任意实施方案中，结合分子包含至少一个特异性结合至CDH17的抗原结合位点(CDH17A6、CDH17E2、CDH17H2、CDH17E9和CDH17v1中任意一种)，以及至少一个特异性结合至TRAILR2的抗原结合位点(TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6和TR2v7中任意一种)。优选地，该至少一个特异性结合至CDH17的抗原结合位点是Ig分子(其包含两条重链与两条轻链)，以及该至少一个TRAILR2的特异性抗原结合位点包含两个scFv,其中一个scFv为与重链之一的C末端连接以及一个scFv与该Ig分子的另一条重链的C末端连接，该Ig分子形成了一个双特异性及四价结合的蛋白质。
在一些实施方案中，抗原结合位点(TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6、TR2v7、CDH17A6、CDH17E2、CDH17H2、CDH17E9及CDH17v1中的任一者)为包含来自非人类超变区(HVR；例如互补决定区(CDR))的氨基酸残基及来自人类框架序列的氨基酸残基的“人类化”抗原结合位点(例如人类化VH/VL结构域)。在一些实施方案中，抗原结合位点(TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6、TR2v7、CDH17A6、CDH17E2、CDH17H2、CDH17E9及CDH17v1中的任一者)为包含皆衍生自人类基因体序列的CDR及FR序列的人类抗原结合位点(例如人类VH/VL结构域)。
特异性抗原结合位点的氨基酸序列提供于本说明(表3)及序列表中。
下文提供包含TRAILR2及/或CDH17的特异性抗原结合位点的本发明优选实施方案的细节。
为免生疑问，下文针对本发明第一方面列示的每一具体实施方案各自亦可视为本发明的独立方面。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQ ID NO.:3(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:4(CDR1)、SEQ ID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:134(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQ ID NO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:135(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:136(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ ID NO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:137(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQ ID NO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:138(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ ID NO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:92的氨基酸序列的可变重链及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:139(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:140(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v1或TR2v2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v1。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:124(定向VL-VH)、SEQ ID NO.:131(定向VH-VL)、SEQ ID NO.:132(具有二硫键的定向VH-VL，scFvss)或SEQ ID NO.:133(具有二硫键的定向VL-VH，scFV)的氨基酸序列的scFv分子。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v2。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:125(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:55(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v3。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v3。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:126(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v4。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v4。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:127(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v5。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v5。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:128(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v6。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:129(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v7。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR2v7。举例而言，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:130(定向VL-VH)的氨基酸序列的scFv分子。
在本发明结合分子的优选实施方案中，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQ ID NO.:3(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:4(CDR1)、SEQ ID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1(例如SEQ ID NO.:134的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQ ID NO.:3(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:4(CDR1)、SEQ ID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1(例如SEQ ID NO.:134的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQ ID NO.:3(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:4(CDR1)、SEQ ID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1(例如SEQ ID NO.:134的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1(例如SEQ ID NO.:134的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQ ID NO.:3(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:4(CDR1)、SEQ ID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#1(例如SEQ ID NO.:134的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQ ID NO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2(例如SEQ ID NO.:135的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQ ID NO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2(例如SEQ ID NO.:135的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQ ID NO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2(例如SEQ ID NO.:135的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2(例如SEQ ID NO.:135的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQ ID NO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#2(例如SEQ ID NO.:135的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3(例如SEQ ID NO.:136的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3(例如SEQ ID NO.:136的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3(例如SEQ ID NO.:136的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3(例如SEQ ID NO.:136的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#3(例如SEQ ID NO.:136的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ ID NO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7(例如SEQ ID NO.:137的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ ID NO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7(例如SEQ ID NO.:137的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ ID NO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7(例如SEQ ID NO.:137的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7(例如SEQ ID NO.:137的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ ID NO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#7(例如SEQ ID NO.:137的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQ ID NO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8(例如SEQ ID NO.:138的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQ ID NO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8(例如SEQ ID NO.:138的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQ ID NO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8(例如SEQ ID NO.:138的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8(例如SEQ ID NO.:138的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQ ID NO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#8(例如SEQ ID NO.:138的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ ID NO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10(例如SEQ ID NO.:139的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ ID NO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10(例如SEQ ID NO.:139的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ ID NO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:70(CDR1)、SEQ IDNO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10(例如SEQ ID NO.:139的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10(例如SEQ ID NO.:139的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ ID NO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:76(CDR1)、SEQ IDNO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR且具有包含SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#10(例如SEQ ID NO.:139的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12(例如SEQ ID NO.:140的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12(例如SEQ ID NO.:140的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12(例如SEQ ID NO.:140的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12(例如SEQ ID NO.:140的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TR#12(例如SEQ ID NO.:140的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1或TRv2且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1(例如SEQ ID NO.:124、SEQ ID NO.:131、SEQ ID NO.:132、SEQ ID NO.:133的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv2(例如SEQ ID NO.:125的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1或TRv2且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1(例如SEQ ID NO.:124、SEQ ID NO.:131、SEQ ID NO.:132、SEQ ID NO.:133的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv2(例如SEQ ID NO.:125的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1或TRv2且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1(例如SEQ ID NO.:124、SEQ ID NO.:131、SEQ ID NO.:132、SEQ ID NO.:133的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv2(例如SEQ ID NO.:125的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1(例如SEQ ID NO.:124、SEQ ID NO.:131、SEQ ID NO.:132、SEQ ID NO.:133的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv2(例如SEQ ID NO.:125的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1或TRv2且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv1(例如SEQ ID NO.:124、SEQ ID NO.:131、SEQ ID NO.:132、SEQ ID NO.:133的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv2(例如SEQ ID NO.:125的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:55(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3(例如SEQ ID NO.:126的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:55(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3(例如SEQ ID NO.:126的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:55(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3(例如SEQ ID NO.:126的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3(例如SEQ ID NO.:126的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:55(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv3(例如SEQ ID NO.:126的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4(例如SEQ ID NO.:127的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4(例如SEQ ID NO.:127的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4(例如SEQ ID NO.:127的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4(例如SEQ ID NO.:127的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv4(例如SEQ ID NO.:127的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5(例如SEQ ID NO.:128的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5(例如SEQ ID NO.:128的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5(例如SEQ ID NO.:128的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5(例如SEQ ID NO.:128的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ ID NO.:56(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv5(例如SEQ ID NO.:128的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6(例如SEQ ID NO.:129的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6(例如SEQ ID NO.:129的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6(例如SEQ ID NO.:129的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6(例如SEQ ID NO.:129的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv6(例如SEQ ID NO.:129的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7且针对CDH17具有特异性的抗原结合位点为CDH17E9。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7(例如SEQ ID NO.:130的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E9。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7且针对CDH17具有特异性的抗原结合位点为CDH17A6。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7(例如SEQ ID NO.:130的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17A6。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7且针对CDH17具有特异性的抗原结合位点为CDH17E2或CDH17H2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7(例如SEQ ID NO.:130的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17E2。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7(例如SEQ ID NO.:130的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17H2。
在本发明结合分子的优选实施方案中，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQ ID NO.:48(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ ID NO.:57(CDR3)的氨基酸序列的轻链CDR，且针对CDH17具有特异性的抗原结合位点包含包括SEQ IDNO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7且针对CDH17具有特异性的抗原结合位点为CDH17v1。
优选地，针对TRAILR2具有特异性的抗原结合位点包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域，且针对CDH17具有特异性的抗原结合位点包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。在此实施方案中，针对TRAILR2具有特异性的抗原结合位点为TRv7(例如SEQ ID NO.:130的scFv)且针对CDH17具有特异性的抗原结合位点为CDH17v1。
上文阐释可用于本发明结合分子(例如双特异性及四价结合分子)中的针对TRAILR2具有特异性及CDH17的抗原结合位点的具体组合(例如TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7中任一者的TRAILR2结合位点，与CDH17E9、CDH17A6、CDH17E2、CDH17H2及CDH17v1中任一者的CDH17结合位点的组合)。
在上文所述组合的一些实施方案中，CDH17的抗原结合位点包含针对CDH17具有特异性的重链可变结构域(例如抗原结合位点CDH17E9、CDH17A6、CDH17E2、CDH17H2或CDH17v1的VH)且融合至人类重链恒定区，例如IgG、IgG1、IgG2、IgG3、IgG4、IgA、IgE或IgM。优选地，使用人类IgG1的重链恒定区。
在本发明的另一实施方案中，CDH17的抗原结合位点包含针对CDH17具有特异性的轻链可变结构域(例如抗原结合位点CDH17E9、CDH17A6、CDH17E2、CDH17H2或CDH17v1的VL)且融合至人类轻链恒定区κ或λ。优选地，使用人类κ轻链恒定区。
在一些实施方案中，结合分子包含具有任一CDH17特异性抗原结合位点(CDH17E9、CDH17A6、CDH17E2、CDH17H2或CDH17v1)的Ig分子(例如IgG1)及具有任一TRAILR2特异性抗原结合位点(TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7)的scFv，其中scFv融合至IgG分子的C末端(例如经由肽连接体)，由此形成双特异性四价结合分子。
人类IgG1野生型的重链恒定区的实施例序列提供于SEQ ID NO.:120中，IgG1 KO提供于SEQ ID NO.:121中，IgG4 Pro野生型提供于SEQ ID NO.:122中。IgG1 FcRnmut提供于SEQ ID NO.:270中。优选地，重链恒定区为如SEQ ID:121中所提供的IgG1KO或如SEQ IDNO.:270中所提供的IgG1FcRnmut。
人类κ轻链恒定区的实施例序列提供于SEQ ID NO.:123中。
下文提供本发明的结合分子(本文中也称为多特异性结合蛋白)。本发明的每一特定分子包含经修饰的免疫球蛋白分子，其中(i)免疫球蛋白重链具有特异性结合至CDH17的重链可变结构域(例如CDH17E9、CDH17A6、CDH17E2、CDH17H2或CDH17v1中任一者的VH)的氨基酸序列、免疫球蛋白恒定结构域以及scFv，该scFv特异性结合至具有轻链及重链可变结构域(例如TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7中任一者VL及VH)的氨基酸序列的TRAILR2且连接至Ig恒定结构域的C末端；以及(ii)免疫球蛋白轻链包含特异性结合至CDH17的轻链可变结构域(例如CDH17E9、CDH17A6、CDH17E2、CDH17H2或CDH17v1中任一者的VL)以及轻链恒定结构域的氨基酸序列。优选地，经修饰的免疫球蛋白分子包含两条免疫球蛋白重链(例如经修饰的重链)和两条免疫球蛋白轻链。
在一些实施方案中，下文各种方面中提供的结合分子(其由这些分子的重链氨基酸序列和轻链氨基酸序列所定义，所述重链氨基酸序列例如是scFv融合至Ig重链C末端的经修饰的重链)包含两条重链和两条轻链，因而形成对称的四价双特异性结构。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:159的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:160的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:161的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:162的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:163的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#8。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:164的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#10。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:165的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TR#12。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:166的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:167的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:168的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:169的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv4。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:170的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv5。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:171的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv6。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:172的氨基酸序列的重链及包括SEQ ID NO.:173的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E9且针对TRAILR2具有特异性的抗原结合位点为TRv7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:174的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:175的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:176的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:177的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:178的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#8。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:179的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#10。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:180的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TR#12。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:181的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:182的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:183的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:184的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv4。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:185的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv5。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:186的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv6。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:187的氨基酸序列的重链及包括SEQ ID NO.:188的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17A6且针对TRAILR2具有特异性的抗原结合位点为TRv7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:189的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:190的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:191的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:192的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:193的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#8。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:194的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#10。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:195的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TR#12。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:196的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:197的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:198的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:199的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv4。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:200的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv5。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:201的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv6。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:202的氨基酸序列的重链及包括SEQ ID NO.:203的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17E2且针对TRAILR2具有特异性的抗原结合位点为TRv7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:204的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:205的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:206的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:207的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:208的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#8。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:209的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#10。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:210的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TR#12。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:211的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:212的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:271的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:213的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:214的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv4。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:215的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv5。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:216的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv6。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:217的氨基酸序列的重链及包括SEQ ID NO.:218的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17H2且针对TRAILR2具有特异性的抗原结合位点为TRv7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:219的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:220的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:221的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:222的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#7。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:223的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#8。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:224的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#10。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:225的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TR#12。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:226的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv1。
本发明的另一方面提供结合分子，其包含(i)包括SEQ ID NO.:145的氨基酸序列的重链及包括SEQ ID NO.:146的氨基酸序列的轻链；(ii)包括SEQ ID NO.:147的氨基酸序列的重链及包括SEQ ID NO.:148的氨基酸序列的轻链；(iii)包括SEQ ID NO.:153的氨基酸序列的重链及包括SEQ ID NO.:154的氨基酸序列的轻链；(iv)包括SEQ ID NO.:155的氨基酸序列的重链及包括SEQ ID NO.:156的氨基酸序列的轻链；或(v)包括SEQ ID NO.:157的氨基酸序列的重链及包括SEQ ID NO.:158的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv1。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:227的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含(i)包括SEQ ID NO.:149的氨基酸序列的重链及包括SEQ ID NO.:150的氨基酸序列的轻链，或(ii)包括SEQ ID NO.:151的氨基酸序列的重链及包括SEQ ID NO.:152的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv2。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:228的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv3。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:229的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv4。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:230的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv5。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:231的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv6。
本发明的另一方面提供结合分子，其包含包括SEQ ID NO.:232的氨基酸序列的重链及包括SEQ ID NO.:233的氨基酸序列的轻链。在此方面中，针对CDH17具有特异性的抗原结合位点为CDH17v1且针对TRAILR2具有特异性的抗原结合位点为TRv7。
本文进一步提供特异性结合至CDH17的抗体分子(例如具有两条重链及两条轻链的Y形结构的全长抗体/免疫球蛋白分子或其片段，例如Fv、Fab、Fab’或F(ab’)2片段、单链抗体、单链可变片段(scFv))。在一些实施方案中，针对CDH17具有特异性的抗体分子为重组单克隆抗体、嵌合、人类化或人类抗体分子。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。
在一些实施方案中，针对CDH17具有特异性的抗体分子包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。
在一些实施方案中，如上文所定义的CDH17特异性抗体进一步包含人类重链恒定结构域(例如IgG恒定结构域)及人类轻链恒定结构域(例如κ或λ轻链恒定结构域)。在一些实施方案中，重链恒定结构域为人类IgG1野生型(例如如提供于SEQ ID NO.:120中)、IgG1KO(例如如提供于SEQ ID NO.:121中)、IgG4 Pro野生型(例如如提供于SEQ ID NO.:122中)或IgG1 FcRnmut(例如如提供于SEQ ID NO.:270中)。在一些实施方案中，人类轻链恒定结构域为人类κ(例如如提供于SEQ ID NO.:123中)。
在一些实施方案中，CDH17特异性抗体具有包含SEQ ID NO.:110、112、114、116或118中任一者的序列的重链，该序列融合至SEQ ID NO.:120、121、122或270中任一者的序列；及包含SEQ ID NO.:111、113、115、117或119中任一者的序列的轻链，该序列融合至SEQID NO.:123的序列(例如包含SEQ ID NO.:173、188、203、218或233中任一者的序列的轻链)。
本文所提供的CDH17特异性抗体可通过附接对不同抗原具有结合特异性的染料、药物或另一分子用于标记、定位、鉴别或靶向表达CDH17的细胞(例如在ELISA分析、FACS分析、免疫组织学等之中)。本文所述的单独CDH17特异性抗体对表达CDH17的细胞的细胞活力无效应。在一些实施方案中，CDH17特异性抗体特异性结合至CDH17表达细胞的表面且用于定位及/或鉴别所述细胞。在一些实施方案中，本文所提供的CDH17抗体用于鉴别表达CDH17的细胞(例如肿瘤细胞)。在一些实施方案中，本文所提供的CDH17抗体通过将药物或细胞毒性剂附接至该CDH17抗体用于将该药物或细胞毒性剂递送至靶细胞(例如表达CDH17的肿瘤细胞)，由此例如杀死该靶细胞。
本发明的另一方面提供编码本发明结合分子或本发明抗体分子的分离的核酸分子或包含该(等)核酸分子的表达载体。
在一些实施方案中，本发明结合分子或本发明抗体分子包含抗体重链及/或轻链多肽。如本领域技术人员可了解，可容易地制备编码重链多肽、轻链多肽或重链多肽及轻链多肽的核酸分子。
编码轻链及重链的核酸分子可以化学方式及酶方式通过聚合酶链式反应(PCR)使用标准方法合成。首先，可利用业内已知的方法(例如Gait,1984)合成适宜寡核苷酸，其可用于产生合成基因。自寡核苷酸生成合成基因的方法为业内已知(例如Stemmer等人，1995；Ye等人，1992；Hayden et Mandecki,1988；Frank等人，1987)。
本发明的核酸分子包括(但不限于)编码序列表中所显示的多肽序列的DNA分子。而且，本发明亦涉及在高严格度结合及洗涤条件下与编码序列表中所显示的多肽序列的DNA分子杂交的核酸分子，如WO 2007/042309中所定义。优选分子(自mRNA角度来看)为与本文所述DNA分子中的一者具有至少75％或80％(优选至少85％、更优选至少90％且最优选至少95％)同源性或序列一致性的那些。举例而言，就在真核细胞中表达抗体而言，序列表中所显示的DNA序列已经设计以匹配真核细胞中的密码子使用。若期望在大肠杆菌(E.coli)中表达抗体，则可改变所述序列以匹配大肠杆菌密码子使用。本发明DNA分子的变体可以若干不同方式构筑，如例如WO 2007/042309中所述。
如本文所用的术语“一致”或“一致性％”在两个或更多个核酸或多肽序列的情况下是指在比较并比对以获得最大对应性时，两个或更多个序列或子序列相同或具有指定百分比的相同核苷酸或氨基酸残基。为测定一致性％，比对各序列用于最优选比较目的(例如可将空位引入第一氨基酸的序列或核酸序列中以与第二氨基酸或核酸序列最优选比对)。然后比较相应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置被与第二序列中的相应位置相同的氨基酸残基或核苷酸占据时，则所述分子在该位置处一致。两个序列之间的一致性％为所述序列所共享的一致位置数的函数(即一致性％＝一致位置数/总位置数(例如重叠位置)×100)。在一些实施方案中，若适宜，所比较的两个序列在序列内引入空位后具有相同长度(例如不包括延伸超出所比较序列的其他序列)。举例而言，当比较可变区序列时，并不考虑前导序列及/或恒定结构域序列。对于两个序列之间的序列比较，“相应”CDR是指两个序列中的相同位置(例如每一序列的CDR-H1)的CDR。
可使用数学算法测定两个序列之间的一致性％或相似性％。用于比较两个序列的数学算法的优选非限制性实施例为Karlin及Altschul,1990,Proc.Natl.Acad.Sci.USA87:2264-2268的算法，其为根据Karlin及Altschul,1993,Proc.Natl.Acad.Sci.USA 90:5873-5877修改而来。将此一算法纳入Altschul等人，1990,J.Mol.Biol.215:403-410的NBLAST及XBLAST程式中。可利用NBLAST程式、得分＝100、字长＝12来实施BLAST核苷酸检索，以获得与编码所关注蛋白的核酸同源的核苷酸序列。可利用XBLAST程式、得分＝50、字长＝3来实施BLAST蛋白质检索，以获得与所关注蛋白同源的氨基酸序列。为获得加空位比对用于比较目的，可如Altschul等人1997,Nucleic Acids Res.25:3389-3402中所述使用加空位BLAST。或者，可使用PSI-Blast来实施叠代检索以检测分子之间的疏远关系(Id.)。在利用BLAST、加空位BLAST及PSI-Blast程式时，可使用各别程式(例如XBLAST及NBLAST)的预设参数。用于比较序列的数学算法的另一优选非限制性实施例为Myers及Miller,CABIOS(1989)的算法。将此一算法纳入ALIGN程式(2.0版)中，该程式为GCG序列比对软体包的一部分。在使用ALIGN程式比较氨基酸序列时，可使用PAM120权重残基表、空位长度罚分12及空位罚分4。用于序列分析的其他算法为业内已知且包括如Torellis及Robotti,1994,Comput.Appl.Biosci.10:3-5中所述的ADVANCE及ADAM；及Pearson及Lipman,1988,Proc.Natl.Acad.Sci.USA 85:2444-8中所述的FASTA。在FASTA内，ktup为设定检索的灵敏度及速度的控制选择。若ktup＝2，则通过观察比对刺激对寻找所比较两个序列中的相似区域；若ktup＝1，则检查单一比对氨基酸。ktup对于蛋白质序列可设定为2或1或对于DNA序列可设定为1至6。若未指定ktup，则预设对于蛋白质为2且对于DNA为6。或者，可使用CLUSTALW算法实施蛋白质序列比对，如Higgins等人，1996,Methods Enzymol.266:383-402所述。
本发明的另一方面提供产生本文所述的结合或抗体分子的方法，其包括：
(a)在容许分子表达的条件下培养本发明的宿主细胞；及
(b)回收分子；及任选的(c)进一步纯化及/或修饰及/或调配分子。
在本发明此方面的实施方案中，产生方法进一步包含步骤(c)进一步纯化及/或修饰及/或调配本发明结合分子。
为产生本发明的结合分子或抗体，将编码全长轻链及/或重链的DNA分子或其片段插入表达载体中，使得所述序列可操作连接至转录及转译控制序列。
为制造本发明的结合分子或抗体，本领域技术人员可自业内所熟知的众多种表达系统、例如Kipriyanov及Le Gall,Curr Opin Drug Discov Devel.2004年3月；7(2):233-42所综述的那些进行选择。
表达载体包括质粒、逆转录病毒、粘粒、EBV源游离基因体等。表达载体及表达控制序列经选择与宿主细胞相容。可将抗体轻链基因及抗体重链基因或本文所述结合分子的重链的基因(例如包含其C末端附接至scFv序列的免疫球蛋白重链序列的基因)插入各别载体中。在某些实施方案中，将两种DNA序列轻链及重链序列插入相同表达载体中。方便载体为编码功能完整的人类CH或CL免疫球蛋白序列的那些，其中适当限制位点经改造以使得可容易插入并表达任何VH或VL序列，如上文所述。关于抗体轻链恒定链通常为κ或λ，关于抗体重链，其可为(但不限于)任一IgG同型(IgG1、IgG2、IgG3、IgG4)或其他免疫球蛋白，包括等位基因变体。
重组表达载体亦可编码促进抗体链(例如本文所述结合分子或抗体的重链及轻链)自宿主细胞分泌的信号肽。可将编码抗体链的DNA选殖至载体中，使得信号肽框内连接至成熟抗体链DNA的氨基末端。信号肽可为免疫球蛋白信号肽或来自非免疫球蛋白的异源肽。或者，编码抗体链(例如本文所述结合分子或抗体的重链及轻链)的DNA序列可已含信号肽序列。
除编码抗体链(例如本文所述结合分子或抗体的重链及轻链)的DNA序列外，重组表达载体携载调控序列，包括启动子、增强子、终止及多聚腺苷酸化信号及控制抗体链在宿主细胞中表达的其他表达控制元件。启动子序列(针对哺乳动物细胞中的表达例示)的实例为衍生自CMV(例如CMV猿猴病毒40(SV40))的启动子及/或增强子(例如SV40启动子/增强子)、腺病毒启动子(例如腺病毒主要晚期启动子(AdMLP))、多瘤启动子及强哺乳动物启动子(例如天然免疫球蛋白及肌动蛋白启动子)。多聚腺苷酸化信号的实例为BGH聚A、SV40晚期或早期聚A；或者，可使用免疫球蛋白基因的3′UTR等。
重组表达载体亦可携载调控载体在宿主细胞中的复制的序列(例如复制起点)及可选标记物基因。可根据业内所熟知的转染方法(包括脂质体介导的转染、聚阳离子介导的转染、原生质体融合、显微注射、磷酸钙沉淀、电穿孔或通过病毒载体转移)，将编码本文所述结合分子或抗体的重链或其抗原结合部分及/或轻链或其抗原结合部分的核酸分子及包含所述DNA分子的载体引入宿主细胞(例如细菌细胞或较高级真核细胞，例如哺乳动物细胞)中。
优选地，编码本文所述结合分子或抗体的重链及轻链的核酸分子存在于共转染至宿主细胞、优选哺乳动物细胞中的两种载体上。
因此，另一方面提供宿主细胞，其包含包括编码本文所述结合分子或抗体的重链的核酸分子的表达载体及包括编码本文所述结合分子或抗体的轻链的核酸分子的表达载体。
可用作表达宿主的哺乳动物细胞系为业内所熟知且包括尤其中国仓鼠卵巢(CHO、CHO-DG44)细胞、NSO、SP2/0细胞、HeLa细胞、幼小仓鼠肾(BHK)细胞、猴肾细胞(COS)、人类癌细胞(例如Hep G2)、A549细胞、3T3细胞或任一该细胞系的衍生物/子代。可使用其他哺乳动物细胞(包括但不限于人类、小鼠、大鼠、猴及啮齿类动物细胞系)或其他真核细胞(包括但不限于酵母、昆虫及植物细胞)或原核细胞(例如细菌)。本发明结合分子为通过将宿主细胞培养足以容许结合分子在宿主细胞中表达的时间段来产生。
如本文所述的结合分子及抗体分子优选为自培养基以分泌多肽形式回收或例如在无分泌信号下表达时其可自宿主细胞溶解物回收。需要使用用于重组蛋白及宿主细胞蛋白的标准蛋白质纯化方法以获得如本文所述结合分子或抗体的实质上均质的制剂的方式纯化本文所述的结合分子或抗体分子。举例而言，可用于获得本发明结合分子及抗体的最新纯化方法包括自培养基或溶解物去除细胞及/或颗粒细胞沉淀物作为第一步骤。然后例如通过免疫亲和或离子交换管柱上的分级分离、乙醇沉淀、反相HPLC、Sephadex色谱、二氧化硅或阳离子交换树脂上的色谱自污染物可溶性蛋白、多肽及核酸纯化结合分子或抗体。作为获得如本文所述TRAILR2及CDH17结合分子或CDH17抗体的过程中的最后步骤，可将经纯化结合分子或抗体干燥(例如冻干)，如下文所述用于治疗应用。
本发明的另一方面提供本发明的结合分子或抗体，其用于药剂中。
本发明的另一方面提供本发明结合分子(具有TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7中任一者的TRAILR2结合位点及CDH17E9、CDH17A6、CDH17E2、CDH17H2及CDH17v1中任一者的CDH17结合位点的结合分子)或针对CDH17具有特异性的抗体(例如融合至细胞毒性药物)，其用于癌症的疗法中。优选地，癌症为结肠直肠癌(CRC)、胃癌(GC)、胰脏癌(PAC)、肝癌(包括胆道系统癌症)或神经内分泌肿瘤。
如上文所述，本发明者已鉴别出，本文所述的结合分子在诱导癌细胞的细胞凋亡方面具有较大效用且因此可用于表达TRAILR2及CDH17二者的癌症的疗法中。鉴别特定肿瘤是否表达TRAILR2及CDH17的方法为业内所熟知。举例而言，可使用免疫组织化学来确定肿瘤组织是否表达TRAILR2及CDH17(例如使用如本文所述的CDH17抗体)且因此将适于用本发明结合分子治疗。
具体而言，本发明结合分子可用于治疗结肠直肠癌(CRC)。
CRC为ICD-10中所列示的典型恶性疾病且为世界范围内癌症发病率及死亡率的主要原因之一。约25％的CRC患者呈现明显转移且40％-50％的新近诊断患者罹患转移性疾病。尽管化学疗法的最新改良已延长转移性CRC的存活持续时间，但大部分患者将死于其疾病。因此，业内极大地需要其他治疗剂来治疗此疾病。
已知约30％-50％的结肠直肠癌具有突变(异常)KRAS基因。频繁发现于肿瘤中的KRAS突变包括外显子2(密码子12及13)及外显子3(密码子61)处的那些且可根据肿瘤生检来分析。所述突变包括活化突变，其引起连续信号转导，从而刺激参与细胞生长、增殖、侵入及转移的下游信号传导路径。已表明，致癌K-Ras可抵抗由TRAIL诱导的细胞凋亡(Hoogwater等人，Gastroenterology.2010年6月；138(7):2357-67)。在一些实施方案中，本文所述的结合分子(具有TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7中任一者的TRAILR2结合位点及CDH17E9、CDH17A6、CDH17E2、CDH17H2及CDH17v1中任一者的CDH17结合位点的结合分子)用于治疗KRAS野生型结肠直肠癌(即KRAS野生型肿瘤患者)。在一些实施方案中，本文所述的结合分子(具有TR#1、TR#2、TR#3、TR#7、TR#8、TR#10、TR#12、TR2v1、TR2v2、TR2v3、TR2v4、TR2v5、TR2v6及TR2v7中任一者的TRAILR2结合位点及CDH17E9、CDH17A6、CDH17E2、CDH17H2及CDH17v1中任一者的CDH17结合位点的结合分子)用于治疗KRAS突变体结肠直肠癌(即KRAS突变体肿瘤患者)。
在另一方面中，本发明涉及治疗或预防癌症的方法，该方法包括向人类(例如患有癌症或具有罹患癌症风险的个体)给予有效量的本发明结合分子。
优选施用模式为非经肠、通过输注或注射(静脉内、肌内、皮下、腹膜内、真皮内)，但亦可使用其他施用模式，例如通过吸入、经皮、鼻内、经颊、经口。
在另一方面中，本发明的结合分子为与可用于给予结合分子的装置组合使用，该装置为例如注射器、注射笔、微型泵或其他装置。在另一方面中，本发明的结合分子包含在部件的试剂盒中，例如亦包括包装插页及结合分子的使用说明书。
欲给予分子的“治疗有效量”为预防、改善或治疗癌症的临床症状所需的最小量，具体而言对所述病症有效的最小量。
本发明结合分子的每日施用的剂量范围通常为1μg/kg至100mg/kg，优选0.1mg/kg至20mg/kg。
通常，为治疗及/或缓和本文所提及的疾病、病症及病况且依据欲治疗的具体疾病、病症或病况、欲使用的本发明具体结合分子的功效、具体给予途径及所用具体医药调配物或组合物，本发明抗体分子通常将以下列量给予：0.005与20.0mg/公斤体重及剂量之间，优选0.05与10.0mg/kg/剂量之间，且更优选0.5与10mg/kg/剂量之间，呈连续(例如通过输注)或更优选单一剂量形式。给予间隔可为例如每周两次、每周一次或每月一次剂量，但可尤其依据之前所提及的参数显著变化。因此，在一些情形下，使用小于上文所给出的最小剂量可能足够，而在其他情形下可能必须超过该上限。在大量给予时，可适当地将其分成多个较小剂量并分散于全天。
依据本发明的具体结合分子及其具体药物动力学及其他性质，可每天一次、每隔一天、每隔两天、每隔三天、每隔四天或每隔五天、每周一次、每月一次等给予。给予方案可包括长期每周一次治疗。“长期”是指至少两周且优选持续数月或数年。
本发明结合分子及包含其的组合物的效能可使用任一适宜活体外分析、基于细胞的分析、活体内分析及/或本身已知的动物模型或其任一组合测试，此依据所涉及的具体疾病而定。适宜分析及动物模型对本领域技术人员而言将是明显的，且例如包括下文实施例中所用的分析及动物模型。
当然，实际医药有效量或治疗剂量将取决于本领域技术人员已知的要素，例如患者的年龄及体重、给予途径及疾病的严重程度。在任一情形下，本发明结合分子将以多个剂量及容许基于患者的独特病况递送医药有效量的方式给予。
本发明结合分子可单独或与其他药理学活性成分组合使用，所述活性成分为例如最新或标准护理化合物，例如细胞生长抑制或细胞毒性物质、细胞增殖抑制剂、抗血管生成物质、类固醇、免疫调节剂/检查点抑制剂等。
因此，本发明的另一方面提供药物组合物，其包含本发明的结合分子以及药学上可接受的载剂及任选的一或多种其他活性成分。
本发明的另一方面提供本发明的结合分子，其用于癌症的疗法(例如患有癌症或具有罹患癌症风险的个体)中，其中该疗法包含一或多种药理学活性物质。
本发明的另一方面提供一或多种活性成分的用途，其用于制造用于癌症及/或肿瘤疗法(例如患有癌症或具有罹患癌症风险的个体)的药剂，其中该药剂包含本发明的结合分子。
可与本发明的结合分子组合给予的细胞生长抑制及/或细胞毒性活性物质包括(但不限于)激素、激素类似物及抗激素、芳香酶抑制剂、LHRH激动剂及拮抗剂、生长因子(生长因子，例如血小板源生长因子(PDGF)、纤维母细胞生长因子(FGF)、血管内皮生长因子(VEGF)、表皮生长因子(EGF)、胰岛素样生长因子(IGF)、人类表皮生长因子(HER，例如HER2、HER3、HER4)及肝细胞生长因子(HGF))抑制剂，抑制剂为例如(抗)生长因子抗体、(抗)生长因子受体抗体及酪氨酸激酶抑制剂，例如西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、阿法替尼(afatinib)、尼达尼布(nintedanib)、伊马替尼(imatinib)、拉帕替尼(lapatinib)、伯舒替尼(bosutinib)及曲妥珠单抗(trastuzumab)；抗代谢物(例如抗叶酸剂，例如胺甲喋呤(methotrexate)、雷替曲塞(raltitrexed)、嘧啶类似物(例如5-氟尿嘧啶(5-FU)、吉西他滨(gemcitabine)、伊立替康(irinotecan)、多柔比星(doxorubicin)、TAS-102、卡培他滨(capecitabine)及吉西他滨(gemcitabine))、嘌呤及腺苷类似物(例如巯嘌呤、硫鸟嘌呤、克拉屈滨(cladribine)及喷司他汀(pentostatin))、阿糖胞苷(cytarabine)(ara C)、氟达拉滨(fludarabine))；抗肿瘤抗生素(例如蒽环)；铂衍生物(例如顺铂(cisplatin)、奥沙利铂(oxaliplatin)、卡铂(carboplatin))；烷基化剂(例如雌莫司汀(estramustin)、氮芥(meclorethamine)、美法仑(melphalan)、氮芥苯丁酸(chlorambucil)、白消安(busulphan)、达卡巴嗪(dacarbazin)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、替莫唑胺(temozolomide)、亚硝基脲(例如卡莫司汀(carmustin)及洛莫司汀(lomustin))、噻替派(thiotepa))；抗有丝分裂剂(例如长春花生物碱(Vinca alkaloid)，例如长春碱(vinblastine)、长春地辛(vindesin)、长春瑞滨(vinorelbin)及长春新碱(vincristine)；及紫杉烷(taxane)，例如太平洋紫杉醇(paclitaxel)、多西他赛(docetaxel))；血管生成抑制剂，包括贝伐珠单抗(bevacizumab)、雷莫芦单抗(ramucirumab)及阿柏西普(aflibercept)、微管蛋白抑制剂；DNA合成抑制剂、PARP抑制剂、拓朴异构酶抑制剂(例如表鬼臼毒素(epipodophyllotoxin)(例如依托泊苷(etoposide)及凡毕复(etopophos))、替尼泊苷(teniposide)、安吖啶(amsacrin)、托泊替康(topotecan)、伊立替康(irinotecan)、米托蒽醌(mitoxantrone))、丝氨酸/苏氨酸激酶抑制剂(例如PDK1抑制剂、Raf抑制剂、A-Raf抑制剂、B-Raf抑制剂、C-Raf抑制剂、mTOR抑制剂、mTORC1/2抑制剂、PI3K抑制剂、PI3Kα抑制剂、双重mTOR/PI3K抑制剂、STK33抑制剂、AKT抑制剂、PLK1抑制剂(例如伏拉塞替(volasertib))、CDK抑制剂(包括CDK9抑制剂)、极光激酶抑制剂)、酪氨酸激酶抑制剂(例如PTK2/FAK抑制剂)、蛋白蛋白相互作用抑制剂、MEK抑制剂、ERK抑制剂、FLT3抑制剂、BRD4抑制剂、IGF-1R抑制剂、Bcl-xL抑制剂、Bcl-2抑制剂、Bcl-2/Bcl-xL抑制剂、ErbB受体抑制剂、BCR-ABL抑制剂、ABL抑制剂、Src抑制剂、雷帕霉素(rapamycin)类似物(例如依维莫司(everolimus)、替西罗莫司(temsirolimus)、瑞达福罗莫司(ridaforolimus)、西罗莫司(sirolimus))、雄激素合成抑制剂、雄激素受体抑制剂、DNMT抑制剂、HDAC抑制剂、ANG1/2抑制剂、CYP17抑制剂、放射性医药、免疫治疗剂(例如免疫检查点抑制剂，例如CTLA4、PD1、PD-L1、LAG3及TIM3结合分子/免疫球蛋白，例如伊匹单抗(ipilimumab)、纳武单抗(nivolumab)、派姆单抗(pembrolizumab))及各种化学治疗剂(例如阿米福汀(amifostin)、阿那格雷(anagrelid)、氯膦酸盐(clodronat)、非尔司亭(filgrastin)、干扰素、干扰素α、甲酰四氢叶酸(leucovorin)、利妥昔单抗(rituximab)、丙卡巴肼(procarbazine)、左旋咪唑(levamisole)、美司钠(mesna)、米托坦(mitotane)、帕米膦酸(pamidronate)及卟吩姆钠(porfimer))；蛋白酶体抑制剂(例如硼替佐米(Bortezomib))；Smac及BH3模拟物；恢复p53功能性的药剂，包括mdm2-p53拮抗剂；Wnt/β-连环蛋白信号传导路径抑制剂；及/或周期蛋白依赖性激酶9抑制剂。
尤其优选地用本发明结合分子与选自以下的药物组合治疗：
(i)在乳癌患者中，抗VEGF抗体(贝伐珠单抗及其他抗血管生成物质)与或不与化学疗法组合(包括在新辅助环境中多柔比星/环磷酰胺组合及/或卡培他滨/多西他赛组合；紫杉烷/铂方案用于第一线及后续线治疗)；
(ii)用于治疗CRC的化学治疗剂(包括5-氟尿嘧啶、伊立替康、多柔比星及TAS-102)；
(iii)抗EGFR抗体(在KRAS野生型肿瘤中西妥昔单抗及帕尼单抗)与或不与化学疗法组合(包括伊立替康)、抗VEGF抗体组合(贝伐珠单抗及其他抗血管生成物质)或瑞格菲尼组合，例如用于治疗CRC患者；
(iv)免疫治疗剂，包括抗PD-1及抗PD-L1药剂，例如派姆单抗及纳武单抗，例如用于治疗CRC患者。
为用于疗法中，将本发明的结合分子或抗体调配成适于帮助给予动物或人类的药物组合物。本文所述结合分子或抗体分子的典型调配物可通过混合结合分子或抗体分子与生理上可接受的载剂、赋形剂或稳定剂、以冻干或其他干燥调配物或水溶液或水性或非水性悬浮液形式制备。载剂、赋形剂、改质剂或稳定剂在所用剂量及浓度下无毒。其包括缓冲液系统，例如磷酸盐、柠檬酸盐、乙酸盐及其他无机或有机酸及其盐；抗氧化剂，包括抗坏血酸及甲硫氨酸；防腐剂，例如十八烷基二甲基苄基氯化铵；氯化六羟季铵；氯化苄烷铵、氯化本索宁(benzethonium chloride)；酚、丁醇或苄醇；对羟苯甲酸烷基酯，例如对羟苯甲酸甲酯或对羟苯甲酸丙酯；儿茶酚；间苯二酚；环己醇；3-戊醇；及间甲酚；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水聚合物，例如聚乙烯基吡咯啶酮或聚乙二醇(PEG)；氨基酸，例如甘氨酸、麸酰氨酸、天冬酰胺、组氨酸、精氨酸或离氨酸；单糖、二糖、寡糖或多糖及其他碳水化合物，包括葡萄糖、甘露糖、蔗糖、海藻糖、糊精或聚葡萄糖；螯合剂，例如EDTA；糖醇，例如甘露醇或山梨醇；成盐相对离子，例如钠；金属错合物(例如Zn-蛋白质错合物)；及/或离子型或非离子型表面活性剂，例如TWEENTM(聚山梨醇酯)/PLURONICSTM或脂肪酸酯、脂肪酸醚或糖酯。在抗体调配物中亦可含有有机溶剂，例如乙醇或异丙醇。赋形剂亦可具有释放改质或吸收改质功能。
通常，水溶液或悬浮液将优选。通常，适用于治疗蛋白(例如本发明结合分子)的调配物为缓冲蛋白质溶液，例如包括适宜浓度(例如0.001至400mg/ml，优选0.005至200mg/ml，更优选0.01至200mg/ml，更优选1.0-100mg/ml，例如1.0至10.0mg/ml(静脉内给予)或100mg/ml(皮下给予)的蛋白质及诸如以下等水性缓冲液的溶液：
-磷酸盐缓冲盐水，pH 7.4，
-其他磷酸盐缓冲液，pH 6.2至8.2，
-乙酸盐缓冲液，pH 3.2至7.5、优选pH 4.8至5.5
-组氨酸缓冲液，pH 5.5至7.0，
-琥珀酸盐缓冲液，pH 3.2至6.6及
-柠檬酸盐缓冲液，pH 2.1至6.2，
及任选的盐(例如NaCl)及/或稳定剂(例如蔗糖、海藻糖、离氨酸)及/或其他多元醇(例如甘露醇及甘油)，用于提供溶液及任选的清洁剂(例如0.02％Tween-20或Tween-80)的等渗性以例如防止聚集。
用于静脉内给予的优选缓冲蛋白质溶液为包括约10mg/ml的溶解于10mM柠檬酸盐缓冲液(pH 5.5)中的本发明结合分子、207mM蔗糖、25mM离氨酸HCl及0.02％聚山梨醇酯20的溶液。用于皮下施用的调配物可包括显著较高浓度的本发明抗体，例如高达100mg/ml或甚至高于100mg/ml。然而，本领域技术人员将明了，如上文所给出的成分及其量仅代表一种优选选择。本领域技术人员即可明了其替代形式及变化形式或可容易地自上述揭示内容开始设想。
现将借助以下非限制性实施例来阐述本发明。
实施例1A：CDH17及TRAILR2二者在原发性及转移性结肠直肠癌(CRC)以及在原发性胃癌(GC)及胰脏癌(PAC)中的盛行率.
实施评估TRAILR2及CDH17在不同肿瘤类型中的蛋白质表达的研究。
对新鲜冷冻及OCT包埋样品实施原发性CRC上的TRAILR2及CDH17的IHC。在低温切片机(cryotome)上制备5μm厚切片且将其置于载玻片上，然后在室温下在4％PFA及封阻溶液(PBS/2％BSA)中固定。将切片与一级抗体(抗TRAILR2纯系TR2.21，来自Adipogen编号AG-20B-0028,C＝10μg/ml；抗CDH17(muIgG1)纯系141713，来自R&D Systems编号MAB1032,C＝1μg/ml)一起培育，然后与检测试剂(TRAILR2及CDH17：EnVision+,HRP,小鼠,DAKO编号4000)一起培育并在DAB溶液中培育。使用苏木素实施复染。若适宜，在PBS中实施洗涤步骤。
对福尔马林固定及石蜡包埋的样品实施CRC转移上的TRAILR2及CDH17的IHC。在切片机上制备2μm厚切片，将其置于载玻片上且脱蜡。以121℃/1巴施加未经遮蔽的溶液(TRAILR2：pH9,Vector Laboratories编号H3301；CDH17：pH6,Vector Laboratories编号H3300)，然后使用3％H2O2及随后PBS/2％BSA中的正常山羊血清(Vector Laboratories编号S-1000)进行封阻步骤。在室温下将切片与一级抗体(抗TRAILR2(D4E9)兔单抗，来自Cell Signaling编号8074，以1:20稀释；抗CDH17(muIgG1)纯系141713，来自R&D Systems编号MAB1032,C＝1μg/ml)一起培育1h，然后与检测试剂(TRAILR2：EnVision+,HRP,兔,DAKO编号K4003；CDH17：EnVision+,HRP,小鼠,DAKO编号4000)尤其培育并在DAB溶液中培育。使用苏木素实施复染。若适宜，在PBS中实施洗涤步骤。
在图14中，显示在原发性CRC及CRC肝转移中TRAILR2及CDH17二者的代表性IHC影像。在原发性CRC(n＝26)中，在100％的所有病例中观察到CDH17表达且在88％中观察到与TRAILR2共表达；在转移性CRC(n＝39；肝及肺)中，在100％的所有病例中观察到CDH17表达且在100％中观察到与TRAILR2共表达；在原发性GC(n＝49)中，在95％的所有病例中观察到CDH17表达，且在60％中观察到与TRAILR2共表达；在原发性PaC(n＝32)中，在80％的所有病例中观察到CDH17表达且在20％中观察到与TRAILR2共表达。
此研究支持CDH17及TRAILR2在很大的CRC、GC及PAC的群体中共表达。
实施例1B：识别人类TRAIL受体2(TRAILR2)及人类钙粘蛋白17(CDH17)的结合分子的设计
本发明者已研发出结合CDH17及TRAILR2且诱导表达CDH17及TRAILR2二者的癌细胞的细胞凋亡的结合分子。所用分子设计具有IgG抗体(称为“主控抗体”)，其对一种靶抗原具有特异性，且不同特异性的scFv偶合至重链的C末端。设计的示意图显示于图1中。
优选地，结合分子为双特异性及四价。
双特异性分子在scFv的可变重链(VH)与可变轻链(VL)结构域之间含有柔性肽序列，且scFv结构域经由另一为列连接体连接至主控IgG抗体。在一构型中，scFv经定向使得VL结构域形成scFv的“N末端”且因此融合至主控抗体重链的C末端，同时VH形成scFv的C末端且实际上形成整个重链多肽。然而，可了解此“N-VL-VH-C”结构可颠倒，即“N-VH-VL-C”。
为测试此概念的可行性，基于图1中所绘示的格式制备多个不同双特异性分子。
以下实施例解释用于生成结合CDH17及TRAILR2的双特异性分子的方法以及所述分子的格式及生物活性的变化。
实施例2：使用自杂交瘤高通量V基因回收及培养单B细胞制备识别CDH17及TRAILR2的结合结构域
如可了解，为制备结合至人类CDH17及TRAILR2的双特异性分子，需要获得结合至个别靶抗原的可变结构域。
为达成此目的，在活体外培养衍生自CDH17或TRAILR2免疫小鼠的纯系杂交瘤或单B细胞。针对人类CDH17或TRAILR2的反应性筛选上清液。然后自所鉴别的阳性纯系扩增免疫球蛋白(Ig)VH及VL基因。
为自杂交瘤分离RNA，使单一纯系的约2×106个细胞沉淀且用作源材料。对于单B细胞，使用100至500个自异常分离的B细胞扩增的细胞作为源材料。使用RNeasy Plus(Qiagen,Hilden,Germany)分离RNA。然后使用Smarter cDNA合成试剂盒(Clontech,MountView,CA)根据制造商说明书合成cDNA。
使用表1中所列示的引物扩增Ig VH及VL基因。每一50μl PCR反应物为由20μM正向及反向引物混合物、25μl Pfu预混合物(Agilent Technologies)、2μl未纯化cDNA及21μl双蒸H2O组成。PCR反应以94℃步骤保持3min开始，然后为15个PCR循环(92℃保持1min，55℃保持1min，68℃保持1min)，然后25个PCR循环(94℃保持1min，50℃保持1min，72℃保持1min)，且以72℃步骤保持7min结束。
然后用经条码化用于454下一代测序的引物组实施第二轮PCR。反应开始于在94℃下保持3min，然后在92℃下保持1min、53℃保持1min及68℃保持1min循环35轮。将VL及VHPCR产物汇集在一起，凝胶纯化，然后提交用于454DNA测序(Roche GS-FLX,SeqWright,U.S.A.)。
使用此方法，制备大量编码针对CDH17具有特异性或TRAILR2的结合结构域的IgVH及VL基因对。使用业内已知的方法进一步人类化一些VH及VL序列。
表1：引物序列
实施例3：结合CDH17及TRAILR2的双特异性分子的高通量构筑
为构筑编码TRAILR2 scFv的基因区段，通过编码柔性肽序列连接体GGGGSGGGGSGGGGSGGGGS(SEQ ID NO.:143)的基因区段连结编码实施例2中所制备或业内已知的TRAILR2结合可变结构域的VL及VH基因对。进而将所得scFv编码基因区段框内选殖至编码人类IgG抗体重链的基因的3’末端。通过重叠PCR方法合成所述编码区段且将其选殖至表达载体pTT5中。
然后将编码实施例2中所制备的CDH17结合可变结构域的VL及VH基因对格式化至实施例1中所概述的双特异性格式中。将VH基因选殖至pTT5表达载体中作为编码人类Igγ的基因的5’末端的框内融合物。将编码TRAILR2结合scFv的基因框内选殖至同一Igγ编码区段的3’末端。类似地，将VL基因选殖至pTT5表达载体中作为与编码人类IgGκ轻链的基因的框内融合物。
使用业内已知的方法将编码实施例2中所制备或业内已知的TRAILR2结合可变结构域的VL及VH基因对进一步用于制备特异性结合至TRAILR2(例如包含抗原结合位点TR2v1或TRv2)的抗体分子(包含两条轻链及两条重链的全长抗体分子)且用于检测/标记细胞或用作下文所述实施例中的对照抗体。所述抗体包括人类IgG1 WT或IgG1(KO)恒定结构域。
类似地，使用业内已知的方法将编码实施例2中所制备或业内已知的CDH17结合可变结构域的VL及VH基因对进一步用于制备特异性结合至CDH17(例如包含抗原结合位点CDH17v1或CDH17H2)的抗体分子(包含两条轻链及两条重链的全长抗体分子)且用于检测/标记细胞或用作下文所述实施例中的对照抗体。所述抗体包括人类IgG1 WT或IgG1(KO)恒定结构域。
上文所述且在下文实施例中用作对照抗体的针对TRAILR2具有特异性或CDH17的抗体为具有两条重链及轻链的常规全长抗体。所述对照抗体的结合位点为由与其比较的双特异性结合蛋白相同的可变结构域定义。举例而言，在图3中，具有CDH17特异性结合位点CDH17v1及TRAILR2特异性结合位点TR2v1的结合分子(称为结合分子CDH17v1/TR2v1)包含SEQ ID NO.:118的针对CDH17具有特异性的VH序列及SEQ ID NO.:119的针对CDH17具有特异性的VL序列以及SEQ ID NO.:96的针对TRAILR2具有特异性的VH序列及SEQ ID NO.:97的针对TRAILR2具有特异性的VL序列(参见表2)。因此，此实施例中所用的对照抗体抗CDH17v1包含SEQ ID NO.:118的针对CDH17具有特异性的VH序列及SEQ ID NO.:119的针对CDH17具有特异性的VL序列，且对照抗体抗TRv1包含SEQ ID NO.:96的针对TRAILR2具有特异性的VH序列及SEQ ID NO.:97的针对TRAILR2具有特异性的VL序列(参见图3)。
在上述程序中使用HD选殖试剂盒(Clonetech,U.S.A.)来定向选殖VH及VL基因。合成与线性化载体的末端互补的延长15bp的VL/VH的PCR引物。使用制造商的标准方案实施PCR且纯化扩增子或用选殖增强子处理，然后选殖至适当载体中。然后根据制造商说明书(Clonetech,U.S.A.)转变大肠杆菌。对DNA微小制剂进行测序。
每一表达载体含有链编码基因的真核启动子元件、编码信号序列及重链或轻链的基因、原核选择标记物基因(例如氨苄西林(ampicillin))的表达盒及复制起点。使所述DNA质粒在氨苄西林抗性大肠杆菌群落中繁殖并纯化。
实施例4：识别人类TRAILR2及人类CDH17的双特异性四价分子的表达及纯化
将实施例3中所制备的表达载体转染至CHO-E细胞中。
将以悬浮液形式生长于无血清培养基中的经转染CHO-E细胞在摇瓶中在140rpm、37℃及5％CO2搅动下培养且保持在指数生长条件下。在转染当天，用1mg轻链质粒及0.5mg重链质粒以化学方式转染细胞。然后将所述细胞以1至2×106个细胞/ml接种于1LFreeStyleTM CHO表达培养基(LifeTechnologies,NY,US)中。然后将细胞在回转式振荡下培育10至12天，且一次性进给150ml市售进料溶液以容许蛋白质表达。使用仪器(PallForteBio,CA,US)及protA生物传感器尖端根据制造商说明书测定细胞培养上清液中的抗体/结合分子效价。
通过蛋白质A亲和色谱使用MabSelectTM(Amersham Biosciences)自培养物上清液纯化重组结合分子或抗体且储存在60mM NaOAc缓冲液(pH 5.0)中。通过质谱及分析型超速离心评价样品的纯度及异质度。在功能测试之前，所有样品经确认具有≥90％的单体含量且含有<10％杂质。
实施例5：所制备识别人类TRAILR2及人类CDH17分子的双特异性分子的细节
在下文实施例中，制备多个本发明的不同双特异性TRAILR2/CDH17抗体分子。为避免混淆，所述分子的特征及序列提供于下文中。
表2：本发明双特异性TRAILR2/CDH17分子的细节
表3：本发明结合分子及抗体的CDR、VH、VL、scFv、轻链及重链的氨基酸
序列及SEQ ID NO：
实施例6：识别人类TRAILR2及人类CDH17的双特异性分子的增加的细胞凋亡效应
导论
上文所述的实施例显示识别TRAILR2及人类CDH17的双特异性分子的制备。为确定所述分子在细胞凋亡诱导中的作用，本发明者决定检查所述分子是否可降低细胞活力，任何该降低是否为由细胞凋亡引起及任何细胞凋亡效应是否由双特异性TRAILR2/CDH17结合分子特异性介导。
研发基于细胞的分析.
首先，需要鉴别出在细胞表面上具有TRAILR2及CDH17的癌细胞系。Colo-205细胞系衍生自人类高加索人结肠腺癌(Caucasian colon adenocarcinoma)。其为熟知的实验室细胞培养工具。本发明者选择此作为候选细胞系来评价双特异性TRAILR2/CDH17结合分子的功能。
如下分析Colo-205细胞上的TRAILR2及CDH17蛋白质表面表达。使用Accutase(Sigma A6964)将细胞剥离且用FACS缓冲液(PBS,Gibco 14190；3％FCS,Gibco 26140；及0.09％NaN3,Sigma Aldrich S2002)洗涤两次。使用ViCell(Beckman Coulter LifeSciences)对细胞进行计数且将细胞数调节至2-5×106个细胞/ml。将100μl/孔细胞悬浮液接种于96孔圆底板中。
接种细胞后，将板在1200rpm下离心5分钟且丢弃上清液。然后在4℃下将细胞与100μl/孔一级抗体适当稀释物一起培育60min。用FACS缓冲液将细胞洗涤两次且添加100μl/孔的二级/偶联抗体的适当稀释物。在4℃下在黑暗中将细胞与二级抗体一起培育45min。用FACS缓冲液洗涤两次后，将细胞重悬浮于100μl FACS缓冲液/孔中且在FACS Canto(BDBiosciences)中分析。
对于TRAILR2检测，使用偶联抗人类CD262(DR5)PE(eBioscience,12-9908-42)。对于CDH17，使用抗CDH17抗体(R&D Systems,MAB1032)，然后使用二级抗体兔抗小鼠IgG PE(Dako,R0439)。作为对照，分别使用小鼠IgG1同型对照PE(eBioscience,12-4714-42)及小鼠IgG1同型对照(AbDserotec,MCA928EL)。
在图2中，显示TRAILR2及CDH17在Colo-205细胞中的蛋白质表面表达，其中两种蛋白质证实大量表达。
双特异性TRAILR2/CDH17分子对Colo-205细胞的效应
已鉴别出Colo-205细胞作为适宜癌细胞系来评价双特异性TRAILR2/CDH17结合分子的功能，本发明者设计以下分析。
将Colo-205细胞平铺于培养基(RPMI1640/Glutamax,Gibco 61870-010；加10％FCS,Gibco 26140)中。在37℃及5％CO2下静置过夜后，将细胞与50μl期望浓度的不同抗体或结合分子稀释物一起培育24h。然后通过使用CellTiter-Glo发光细胞活力分析(PromegaG7571)根据制造商所提供的说明书评价细胞活力。最后，使用来自Perkin Elmer的VICTORX4 2030多标记读板仪记录发光。
双特异性TRAILR2/CDH17结合分子对细胞活力的效应显示于图3中。将Colo-205细胞与以下抗体一起培育24小时：(i)双特异性分子，(ii)单独的抗TRAILR2抗体，(iii)单独的抗CDH17抗体，或(iv)TRAILR2及CDH17抗体的等效自由组合。
如图3中所显示，抗CDH17抗体在7×10-4nM至70nM的浓度范围下使用时对Colo-205细胞的活力无效应。TRAILR2抗体在7nM与70nM之间使用时能够显著降低细胞活力，且添加自由组合的抗CDH17不会改变使用单独的抗TRAILR2抗体所观察到的效应。最后，与单独的抗TRAIL-R2抗体(包含VH及VL序列分别为SEQ ID NO.:96及SEQ ID NO.:97的抗原结合位点TRv1)及抗TRAIL-R2抗体与抗CDH17抗体(包含VH及VL序列分别为SEQ ID NO.:118及SEQ IDNO.:119的抗原结合位点CDH17v1)的组合相比，一起培育Colo-205细胞与如本文所述的双特异性TRAIL-R2/CDH17结合分子(包含SEQ ID NO.:145的重链序列及SEQ ID NO.:146的轻链序列的CDH17v1/TR2v1)产生1000倍以上改良的功效。
TRAILR2/CDH17分子诱导Colo-205细胞的细胞凋亡
随后研究如图3中所显示细胞活力的降低是否为由诱导细胞凋亡引起。TRAIL诱导的细胞凋亡为通过招募及活化半胱天冬酶-8进而活化效应物半胱天冬酶-3、从而引起细胞凋亡来介导。因此，为确定本文所制备的抗体及结合分子是否能够特异性活化细胞凋亡路径，本发明者测量半胱天冬酶-8及半胱天冬酶-3在靶细胞系中的活性二者。
半胱天冬酶-3及半胱天冬酶-8活性为分别使用Promega Apo-ONE均质半胱天冬酶-3/7分析(目录号G7790)及Promega半胱天冬酶-Glo 8分析(目录号G8201)来测量。在37℃及5％CO2下静置过夜后，将细胞沿不同时间点与50μl不同抗体或结合分子稀释物一起培育以达成期望浓度。然后根据制造商所提供的说明书评价半胱天冬酶-3及半胱天冬酶-8活性。然后使用来自Perkin Elmer的VICTOR X4 2030多标记读板仪测量每一样品的发光。
此分析的结果显示于图4中。在此处可见，单独的抗TRAILR2抗体(包含VH及VL序列分别为SEQ ID NO.:96及SEQ ID NO.:97的抗原结合位点TRv1)及双特异性TRAILR2/CDH17结合分子(包含SEQ ID NO.:145的重链序列及SEQ ID NO.:146的轻链序列的CDH17v1/TR2v1)皆能够有效地活化半胱天冬酶8(A)及半胱天冬酶3(B)二者。与未经处理的对照相比，在抗CDH17抗体(包含VH及VL序列分别为SEQ ID NO.:118及SEQ ID NO.:119的抗原结合位点CDH17v1)培育后未观察到效应。此数据展示，在图3中观察到的细胞活力的降低并不归因于任何非特异性机制，且两种分子能够有效且特异性诱导靶细胞的细胞凋亡。与细胞活力数据一致，本发明者观察到，与单独的抗TRAILR2抗体相比，一起培育Colo-205细胞与双特异性TRAILR2/CDH17结合分子明确产生优异的半胱天冬酶-8及半胱天冬酶-3活化(功效偏移3log以上)。
Colo-205细胞的细胞凋亡为由双特异性TRAILR2/CDH17分子特异性诱导
本发明者亦欲确认，由本发明的双特异性TRAILR2/CDH17结合分子调节的细胞凋亡的增加为由存在于Colo-205细胞表面上的CDH17特异性介导。为证实此推测，本发明者生成识别人类TRAILR2及三硝基苯酚(TNP)的另一双特异性四价分子，其中用IgG主控抗CDH17抗体取代识别TNP者。与TNP的结合区域充当该分子的非特异性对照，这是因为TNP抗原无法容易地在细胞表面上发现。
用不同浓度的以下抗体将Colo-205细胞处理24h：(i)单独针对TNP的抗体，(ii)单独的抗CDH17抗体，(iii)单独的抗TRAILR2抗体，(iv)双特异性TRAILR2/TNP结合分子，(v)双特异性TRAILR2/CDH17分子，且测量细胞活力。所获得数据显示于图5中。
如图5中所显示，与抗TRAILR2抗体(包含VH及VL序列分别为SEQ ID NO.:96及SEQID NO.:97的抗原结合位点TRv1)相比，双特异性TRAILR2/CDH17结合分子(包含SEQ IDNO.:145的重链序列及SEQ ID NO.:146的轻链序列的CDH17v1/TR2v1)能够诱导明显优异的降低细胞活力的效应。使用双特异性TRAILR2/TNP结合分子无法观察到此效应。因此，用CDH17取代TNP消除双特异性TRAILR2/CDH17结合分子的优异细胞凋亡效应，且双特异性TRAILR2/TNP结合分子具有与单独的抗TRAILR2抗体相当的效应。
双特异性TRAILR2/CDH17分子对HepG2细胞的效应
为研究双特异性TRAILR2/CDH17结合分子在肝源CDH17阴性及TRAILR2敏感性细胞中的效应，使用HepG2细胞实施与上文所述类似的实验。此细胞系最初衍生自15岁高加索人男性的肝细胞癌。
将HepG2细胞培养于在37℃及5％CO2下DMEM(Lonza,BE12-604F)加10％FCS(Gibco26140)中。
如针对Colo-205所述，如实施例3中所述分析蛋白质表面表达及细胞活力。在图6A中，显示TRAILR2及CDH17在HepG2细胞中的蛋白质表面表达，且仅TRAILR2证实大量表达。
将HepG2细胞与以下抗体一起培育：(i)单独的抗TRAILR2(包含VH及VL序列分别为SEQ ID NO.:96及SEQ ID NO.:97的抗原结合位点TRv1的抗TR2v1)，(ii)TRAILR2/CDH17双特异性结合分子(包含SEQ ID NO.:145的重链序列及SEQ ID NO.:146的轻链序列的CDH17v1/TR2v1))。另外，作为如多种激动性人类TRAILR1及TRAILR2抗体的文献(Ichikawa等人，2001.Nat Med.8月；7(8):954-60；Li等人，2008BMC Cancer.11月7日；8:325；Natoni等人，2007Br J Haematol.2007年11月；139(4):568-77；Pukac等人，2005Br JCancer.2005年4月25日；92(8):1430-41；Yada等人，2008Ann Oncol.2008年6月；19(6):1060-70；Zhang等人，2007a Cancer Lett.2007年6月18日；251(1):146-57)中所述的抗TRAILR2抗体的最大促细胞凋亡信号传导的对照，亦将HepG2细胞与(iii)抗TRAILR2(包含VH及VL序列分别为SEQ ID NO.:96及SEQ ID NO.:97的抗原结合位点TRv1)在交联剂山羊抗人类IgG(抗TR2v1(Fc交联))存在下一起培育。如图6B中所显示，单独的抗TRAILR2抗体及TRAILR2/CDH17双特异性分子对活力皆无效应。仅TRAILR2抗体的人工Fc交联能够显著降低细胞活力。
双特异性TRAILR2/CDH17分子对其他CRC细胞的效应.
为研究Colo-205的所观察到的效应是否可应用于其他CRC细胞系，使用两种其他CRC细胞系CL-34(KRAS野生型)及SK-CO-1(KRAS p.G12V)细胞实施与上文所述类似的实验。
将CL-34及SK-CO-1细胞分别培养于37℃及5％CO2下DMEM/F-12(ATCC 30-2006)加20％FCS(Gibco 26140)及EMEM(Lonza BE12-662F)加10％FCS(Gibco 26140)中。
如实施例6中所述，分析蛋白质表面表达及细胞活力。在图11A及11B中，显示TRAILR2及CDH17在CL-34(A)及SK-CO-1(B)细胞中的蛋白质表面表达，且两种蛋白质证实大量表达。
将CL-34及SK-CO-1细胞与以下抗体一起培育：(i)双特异性TRAILR2/CDH17结合分子(包含SEQ ID NO.:145的重链及SEQ ID NO.:146的轻链的CDH17v1/TR2v1))，(ii)单独的抗TRAILR2抗体(包含VH及VL序列分别为SEQ ID NO.:96及SEQ ID NO.:97的抗原结合位点TRv1)，或(iii)单独的抗CDH17抗体(包含VH及VL序列分别为SEQ ID NO.:118及SEQ IDNO.:119的抗原结合位点CDH17v1)。如图11中所显示，抗CDH17抗体对活力无效应，而TRAILR2抗体在7nM与70nM之间使用时能够显著降低细胞活力。如针对Colo-205细胞所述，与单独的抗TRAILR2抗体相比，一起培育CL-34及SK-CO-1细胞二者与双特异性TRAILR2/CDH17结合分子产生细胞活力的3log以上的明显功效偏移。
与在CL-34及SK-CO-1细胞中所观察到的类似反应一致，在19个CRC细胞系的扩大面板中未检测到KRASmut与KRASwt细胞系之间的显著敏感性差异(威尔卡森等级和测试(Wilcoxon-Rank-Sum-Test)，数据未显示)。
讨论
本发明者在上文已展示，双特异性TRAILR2/CDH17结合分子诱导CRC细胞系的细胞凋亡。此细胞凋亡效应为使用比单独TRAILR2抗体小3个以上数量级且为治疗上有用的剂量值的浓度来达成。亦展示此效应为由双特异性分子的CDH17部分特异性触发，且在最大效应的浓度下，无法检测到对肝源CDH17阴性及TRAILR2敏感性HepG2细胞的细胞活力的效应。
实施例7：不同IgG支架在双特异性TRAILR2/CDH17分子中的用途
本发明者亦研究改变双特异性TRAILR2/CDH17分子的主控抗体元件中所用的IgG支架是否会改变细胞凋亡的诱导。
用不同浓度的单独的抗TRAILR2抗体及包含IgG1(A及C)或IgG4Pro(B)恒定区的双特异性TRAILR2/CDH17结合分子将Colo-205细胞处理24h。在抗体培育后，测量细胞活力(图7)。
如图7中所显示，用先前所用的IgG1支架取代具有2个额外突变(L234A及L235A)的第二形式(IgG1 KO；SEQ ID NO.:121)或具有1个额外突变(H310A)的第三形式(FcRnmut,SEQ ID NO.:270)不会改变对降低Colo-205细胞活力的效应。
与野生型形式相似，新生成的双特异性结合分子(包含SEQ ID NO.:147的重链及SEQ ID NO.:148的轻链的TRv1/CDH17v1 IgG1(KO))在以低至10-2nM的浓度使用时能够显著降低细胞活力，而亲代TRAILR2抗体(包含VH及VL序列分别为SEQ ID NO.:96及SEQ ID NO.:97的抗原结合位点TRv1)未显示效应。此对于第二双特异性结合分子亦如此，其中用TRAILR2结合结构域取代稍经修饰的序列(与VH及VL序列分别为SEQ ID NO.:98及SEQ IDNO.:99的抗TR2v2相比，包含SEQ ID NO.:149的重链及SEQ ID NO.:150的轻链的TRAILR2v2))。此外，制备其中用双特异性支架的主控抗体元件中所用的IgG支架完全取代IgG4 Pro同种型(包含SEQ ID NO.:151的重链序列及SEQ ID NO.:152的轻链序列)或IgG1FcRnmut(CDH17H2/TR2v2)(包含SEQ ID NO.:271的重链序列及SEQ ID NO.:218的轻链序列)的不同双特异性分子。如图7中所显示，此分子变化不会改变其在降低Colo-205细胞活力方面的功效。
实施例8：scFv变体在降低细胞活力方面的效应.
然后研究改变scFv第二抗体组分是否影响本发明分子对细胞凋亡的诱导。
在实施例6中所用的分子中，scFv经定向使得VL形成结合部分的N末端，且因此经由连接体融合至主控抗体重链的C末端，同时scFv的VH形成整个重链分子的C末端。
因此，生成多种包含由可变结构域的一致序列定义但所述结构域的定向及/或其他修饰不同的结合位点的不同双特异性TRAILR2/CDH17结合分子(scFv形式1至4)。
1.双特异性TRAILR2/CDH17 scFv1分子具有VH-VL定向，即scFv的VH经由连接体融合至抗体的C末端，且scFv的VL形成整个重链分子的C末端(scFv序列为SEQ ID NO.:131的CDH17v1/TRv1)。
2.双特异性TRAILR2/CDH17 scFv2分子亦具有VH-VL定向，即scFv的VH经由连接体融合至抗体的C末端，且scFv的VL形成整个重链分子的C末端，并具有额外二硫键以稳定scFv结合结构域(scFv序列为SEQ ID NO.:132的CDH17v1/TRv1)。
3.双特异性TRAILR2/CDH17 scFv3分子为图7中所用且因此其具有VL-VH定向，即scFv的VL经由连接体融合至抗体的C末端，且scFv的VH形成整个重链分子的C末端(scFv序列为SEQ ID NO.:124的CDH17v1/TRv1)。
4.双特异性TRAILR2/CDH17 scFv4分子亦具有VL-VH定向，即scFv的VL经由连接体融合至抗体的C末端，且scFv的VH形成整个重链分子的C末端，并具有额外二硫键以稳定scFv结合结构域(scFv序列为SEQ ID NO.:133的CDH17v1/TRv1)。
然后研究双特异性TRAILR2/CDH17结合分子的所述变体在实施例6中所述的Colo-205细胞凋亡分析中的功能。在与结合分子一起培育后，测量细胞活力。
图8中所呈现的数据显示，双特异性TRAILR2/CDH17结合分子可诱导Colo-205细胞凋亡，而与VH及VL结构域在scFv抗体结构域内的定向无关，然而，VL-VH具有大于VH-VL定向的细胞凋亡效应。携载额外二硫键的分子与不具所述额外键的相应亲代分子相比无显著效应。
因此，改变实施例1中所概述的双特异性抗体格式的结构可耐受，但VL-VH确实具有显著较大的细胞凋亡效应。
实施例9：使用替代性结合序列的双特异性分子TRAILR2及CDH17bi-scFv在降低Colo-205细胞活力方面的效应.
制备具有不同结合结构域的双特异性TRAILR2/CDH17结合分子的变化形式。所用特异性结合分子的细节显示于实施例5中的表中。然后研究改变如实施例6中所述的Colo-205细胞凋亡分析中所用的结合结构域的效应。
用不同浓度的含有不同新鉴别出的CDH17(A)及TRAILR2(B及C)结合序列的不同双特异性分子将Colo-205细胞处理24h。在抗体培育后，测量细胞活力。
图9(A-C)中所呈现的数据展示，具有不同TRAILR2及CDH17结合序列的双特异性结合分子(包含SEQ ID NO.:182的HC及SEQ ID NO.:188的LC的CDH17A6/TR2v2；包含SEQ ODNO.:197的HC及SEQ ID NO.:203的LC的CDH17E2/TR2v2；包含SEQ ID NO.:167的HC及SEQ IDNO.:173的LC的CDH17E9/TR2v2；包含SEQ ID NO.:219的HC及SEQ ID NO.:233的LC的CDH17v1/TR2#1；包含SEQ ID NO.:220的HC及SEQ ID NO.:233的LC的CDH17v1/TR2#2；包含SEQ ID NO.:221的HC及SEQ ID NO.:233的LC的CDH17v1/TR2#3；包含SEQ ID NO.:223的HC及SEQ ID NO.:233的LC的CDH17v1/TR2#8；包含SEQ ID NO.:224的HC及SEQ ID NO.:233的LC的CDH17v1/TR2#10；包含SEQ ID NO.:212的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v2；包含SEQ ID NO.:213的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v3；包含SEQ ID NO.:214的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v4；包含SEQ ID NO.:215的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v5；包含SEQ ID NO.:216的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v6；包含SEQ ID NO.:217的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v7)在以低至10-2nM的浓度使用时能够显著降低细胞活力，而亲代TRAILR2抗体(包含SEQ ID NO.:98的VH及SEQID NO.:99的VL的TR2v2)在相同浓度下未显示效应。在图9D中，在上文所提及肝源CDH17阴性及TRAILR2敏感性HepG2细胞中测试所述分子中的一些(包含SEQ ID NO.:212的HC及SEQID NO.:218的LC的CDH17H2/TR2v2；包含SEQ ID NO.:213的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v3；包含SEQ ID NO.:214的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v4；包含SEQ ID NO.:215的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v5；包含SEQ ID NO.:216的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v6；包含SEQ ID NO.:217的HC及SEQ ID NO.:218的LC的CDH17H2/TR2v7)。如图中所显示，对于任一所测试分子，高达1nM的浓度无可检测到的HepG2细胞活力的效应。在图9C-D中亦显示，亲代CDH17抗体(包含SEQ ID NO.:116的VH及SEQ ID NO.:117的VL的CDH17H2)未显示在所测试浓度范围内降低Colo-205及HepG2的细胞活力的效应。
因此，不同TRAILR2及CDH17结合序列可用于本发明的双特异性TRAILR2/CDH17结合分子中。
实施例10：识别TRAILR2及CD44v6的双特异性分子无降低Colo-205细胞活力的额外效应
亦研究另一锚靶是否可用于替代CDH17。因此，制备识别TRAILR2及CD44v6的双特异性分子。
如在实施例6中，首先通过FACS测量TRAILR2及CD44v6蛋白质表面表达。对于CD44v6检测，使用BIWA1抗体，然后使用二级抗体山羊抗小鼠IgG PE(Dako,R0480)。作为对照，使用小鼠IgG1同型对照(AbDserotec,MCA928EL)。
在图10A中，显示TRAILR2及CD44v6在Colo-205细胞中的蛋白质表面表达，且两种蛋白质证实大量表达。
然后使用CellTiter-Glo发光细胞活力分析测量细胞活力。将Colo-205细胞与TRAILR2/CD44v6双特异性结合分子、单独的抗TRAILR2抗体或单独的抗CD44v6抗体一起培育。数据呈现于图10B中。
培育10-2ng/ml至10mg/ml的浓度范围内的抗CD44v6抗体无Colo-205细胞的活力的效应。在0.1μg/ml与10μg/ml之间使用时，与抗TRAILR2抗体(包含SEQ ID NO.:96的VH及SEQID NO.:97的VL的TR2v1)一起培育能够显著降低细胞活力，且将Colo-205细胞与等效量的识别人类TRAILR2及人类CD44v6的双特异性四价分子一起培育不同于使用单独的抗TRAILR2抗体所观察到的效应。
因此，CD44v6无法用作调节TRAILR2诱导的Colo-205细胞的细胞凋亡的锚靶。
实施例11：在CRC异种移植物模型中双特异性分子的活体内效能.
亦研究识别TRAILR2及CDH17的结合分子的活体内效能。出于此目的，将表达TRAILR2及CDH17二者的人类CRC癌细胞系Colo205(KRAS野生型)及Gp2d(KRAS p.G12D)植入免疫缺陷小鼠中且测量给予本发明分子对肿瘤体积的效应。
向雌性BomTac:NMRI-Foxn1nu同型接合小鼠皮下植入5.0×106个Colo205细胞(0.1mL PBS+5％FCS)或5.0×106个Gp2d细胞(0.1mL且细胞:基质胶比率为1:1(v/v))且监测肿瘤生长直至其达到180-200mm3。将小鼠随机化于两组中且给予媒剂对照或本发明结合分子的单一注射，对于Colo205为5mg/Kg且对于Gp2d为1.67mg/Kg[包含SEQ ID NO.:212的重链序列及SEQ ID NO.:218的轻链序列的CDH17H2/TR2v2-(Ig G1 KO)]；对于Colo205及Gp2d为5mg/Kg[包含SEQ ID NO.:271的重链序列及SEQ ID NO.:218的轻链序列的CDH17H2/TR2v2-(Ig G1 FcRnmut)]。
图12中所呈现的数据展示与对照组相比，本发明的结合分子能够诱导显著且延长的肿瘤体积减小。
实施例12：使用新生成的CDH17抗体检测CDH17表面表达。在图13中显示新生成的抗CDH17H2抗体(包含SEQ ID NO.:116的VH及SEQ ID NO.:117的VL及SEQ ID NO.:121的IgG1序列)能够检测CDH17蛋白质表面表达。如实施例6中所述实施FACS分析。使用新生成的抗CDH17H2抗体作为一级抗体用于检测，然后使用二级抗体兔抗小鼠IgG PE(Dako,R0439)。作为对照，使用人类IgG1同型对照APC(Biolegend,409306)。
实施例13：用于静脉内给予的医药调配物
可选择本发明的任一上述结合分子来制造用于静脉内施用的医药调配物。适用于本发明抗体的医药调配物的实施例如下。
10mL小瓶含有10mg/mL的于由10mM柠檬酸盐(pH 5.5)、207mM蔗糖、25mM离氨酸HCl及0.02％聚山梨醇酯20及注射用水(WFI)组成的缓冲液中的本发明结合分子。
实施例14：ProtA亲和色谱及通过分析型粒径筛析色谱(aSEC)测定单体含量：
通过重组蛋白A亲和色谱使用MabSelect SuRe树脂(GE Healthcare)自所收获细胞培养液捕获本文所述各种结合分子的样品。使用30mM乙酸钠(pH3.5)以等梯度模式洗脱样品且使用3M乙酸钠的1％溶液(pH 9.0)将所洗脱样品中和至pH 5.0。
使用Waters UHPLC系统上的Waters BEH200管柱实施aSEC。流动相缓冲液为50mM磷酸钠(pH 6.8)、200mM精氨酸、0.05％叠氮化钠。对于每一运行，以0.5ml/min的运行流速注射5-10μg样品。
测定单体含量的百分比且各种结合分子的结果显示于表4中。
序列表
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Gly
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<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 48
Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu
1 5 10
<210> 49
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 49
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210> 50
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 50
Gly Lys Asn Asn Arg Pro Ser
1 5
<210> 51
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 51
Gly Lys Thr Asn Arg Pro Ser
1 5
<210> 52
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 52
Gly Lys Ala Asn Arg Pro Ser
1 5
<210> 53
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 53
Gly Lys Asp Asn Arg Pro Ser
1 5
<210> 54
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 54
Asn Ser Arg Asp Ser Ser Gly Asn His Val Val
1 5 10
<210> 55
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 55
Asn Ser Arg Asp Ser Ser Gly Thr His Val Val
1 5 10
<210> 56
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 56
Asn Ser Arg Asp Ser Ser Gly Ala His Val Val
1 5 10
<210> 57
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 57
Asn Ser Arg Asp Ser Ser Gly Asp His Val Val
1 5 10
<210> 58
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 58
Gly Tyr Thr Leu Thr Asp His Thr Ile His
1 5 10
<210> 59
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 59
Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe Lys
1 5 10 15
Ala
<210> 60
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 60
Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
1 5 10
<210> 61
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 61
Lys Ala Ser Gln Asn Val Gly Thr Ala Leu Ala
1 5 10
<210> 62
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 62
Ser Ala Ser Asn Arg Phe Thr
1 5
<210> 63
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 63
Gln Gln Tyr Ser Thr Tyr Pro Leu Thr
1 5
<210> 64
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 64
Gly Tyr Thr Phe Thr Asp His Thr Ile His
1 5 10
<210> 65
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 65
Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 66
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 66
Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
1 5 10
<210> 67
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 67
Lys Ala Ser Gln Asn Val Gly Thr Gly Val Val
1 5 10
<210> 68
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 68
Ser Pro Ser Asn Arg Tyr Thr
1 5
<210> 69
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 69
Gln Gln Tyr Ser Thr Tyr Pro Trp Thr
1 5
<210> 70
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 70
Gly Tyr Thr Phe Thr Asp His Thr Ile His
1 5 10
<210> 71
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 71
Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 72
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 72
Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
1 5 10
<210> 73
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 73
Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala
1 5 10
<210> 74
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 74
Ser Ala Ser Asn Arg Tyr Thr
1 5
<210> 75
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 75
Gln Gln Tyr Ser Ser Tyr Pro Trp Thr
1 5
<210> 76
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 76
Gly Tyr Thr Leu Thr Asp His Thr Ile His
1 5 10
<210> 77
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 77
Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 78
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 78
Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
1 5 10
<210> 79
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 79
Lys Ser Ser Gln Ser Leu Leu His Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 80
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 80
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 81
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 81
Gln Gln Tyr Tyr Ser Tyr Pro Trp Thr
1 5
<210> 82
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 82
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Phe Asp Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Lys Asn Tyr Gly Gly Ser Tyr Ala Phe Thr Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 83
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 83
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Thr Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 84
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 84
Lys Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Thr Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Ile Ile His Trp Val Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Phe Tyr Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg His Glu Glu Gly Gly Tyr Ser Ala Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 85
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 85
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 86
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 86
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Tyr Leu Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys
50 55 60
Phe Lys Gly Lys Thr Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala
65 70 75 80
Tyr Met Glu Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
85 90 95
Cys Thr Arg Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val Trp Gly Thr
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 87
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 87
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asp Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Val Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly
85 90 95
Ser His Ile Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 88
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 88
Gln Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
Tyr Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Gly Pro Gly Ser Gly Asn Thr Tyr Tyr Asn Glu Lys Phe
50 55 60
Glu Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Ser Thr Gly Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Trp Ser Ala
115
<210> 89
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 89
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Pro Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Ser Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Val
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln His Tyr Ser Ser Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 90
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 90
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Arg Arg Leu Gly Pro Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 91
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 91
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 92
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 92
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys
50 55 60
Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala
65 70 75 80
Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp Val Trp Gly Thr
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 93
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 93
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 94
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 94
Lys Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Ile Ile His Trp Val Lys Gln Lys Ser Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Phe Tyr Pro Gly Ser Gly Asn Ile Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Thr Arg His Glu Gly Gly Ser Asn Phe Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 95
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 95
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Asn Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Asn Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 96
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 96
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 97
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 97
Asp Ile Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 98
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 98
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 99
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 99
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 100
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 100
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 101
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 101
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Thr Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Thr His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 102
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 102
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 103
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 103
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Ala Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Ala His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 104
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 104
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 105
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 105
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 106
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 106
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Ala Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 107
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 107
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Thr Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asp His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 108
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 108
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Thr Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 109
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 109
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asp Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asp His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 110
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 110
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 111
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 111
Asp Ile Val Met Thr Gln Ser Gln Thr Phe Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Arg Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Arg Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Val Cys Gln Gln Tyr Ser Thr Tyr Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Arg
100 105
<210> 112
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 112
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 113
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 113
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Gly
20 25 30
Val Val Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Pro Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Ile Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 114
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 114
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 115
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 115
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Met Gln Ser
65 70 75 80
Lys Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 116
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 116
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 117
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 117
Asp Ile Gln Met Thr Gln Ser Gln Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Gly Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Lys Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 118
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 118
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 119
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 可变结构域
<400> 119
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys
<210> 120
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 恒定结构域
<400> 120
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 121
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 恒定结构域
<400> 121
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 122
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> 恒定结构域
<400> 122
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 123
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 恒定结构域
<400> 123
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 124
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 124
Asp Ile Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp
145 150 155 160
Asp Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
165 170 175
Trp Val Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp
180 185 190
Ser Val Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
195 200 205
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
210 215 220
Tyr Cys Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu
225 230 235 240
Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 125
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 125
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
225 230 235 240
Lys Gly Thr Thr Val Thr Val Ser Ser
245
<210> 126
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 126
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Thr Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Thr His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
225 230 235 240
Lys Gly Thr Thr Val Thr Val Ser Ser
245
<210> 127
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 127
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Ala Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Ala His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
225 230 235 240
Lys Gly Thr Thr Val Thr Val Ser Ser
245
<210> 128
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 128
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Gly Ile Asn Trp Ser Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
225 230 235 240
Lys Gly Thr Thr Val Thr Val Ser Ser
245
<210> 129
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 129
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Thr Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asp His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Gly Ile Asn Trp Ala Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
225 230 235 240
Lys Gly Thr Thr Val Thr Val Ser Ser
245
<210> 130
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 130
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asp Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asp His
85 90 95
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Gly Ile Asn Trp Thr Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
225 230 235 240
Lys Gly Thr Thr Val Thr Val Ser Ser
245
<210> 131
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 131
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu
130 135 140
Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg
145 150 155 160
Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn
180 185 190
Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly
195 200 205
Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala
210 215 220
Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
245 250
<210> 132
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 132
Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly
100 105 110
Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu
130 135 140
Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg
145 150 155 160
Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn
180 185 190
Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly
195 200 205
Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala
210 215 220
Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe
225 230 235 240
Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gln
245 250
<210> 133
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 133
Asp Ile Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Val Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gln Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp
145 150 155 160
Asp Tyr Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu
165 170 175
Trp Val Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp
180 185 190
Ser Val Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
195 200 205
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
210 215 220
Tyr Cys Ala Lys Ile Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu
225 230 235 240
Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 134
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 134
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Thr Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser
130 135 140
Val Lys Leu Ser Cys Lys Ala Phe Asp Tyr Thr Phe Thr Ser Tyr Asp
145 150 155 160
Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Trp Ile Asp Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys
180 185 190
Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met
195 200 205
His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala
210 215 220
Arg Lys Asn Tyr Gly Gly Ser Tyr Ala Phe Thr Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ala
245
<210> 135
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 135
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys
115 120 125
Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Thr Gly Thr Ser
130 135 140
Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile
145 150 155 160
Ile His Trp Val Lys Gln Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Trp Phe Tyr Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys
180 185 190
Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr Met
195 200 205
Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala
210 215 220
Arg His Glu Glu Gly Gly Tyr Ser Ala Trp Phe Pro Tyr Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ala
245
<210> 136
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 136
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asp Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Val Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly
85 90 95
Ser His Ile Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
130 135 140
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
145 150 155 160
Thr Asp Tyr Tyr Tyr Leu Asn Trp Val Lys Gln Ser His Gly Lys Ser
165 170 175
Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Lys Thr Thr Leu Thr Val Asp Lys Ser Ser
195 200 205
Ser Thr Ala Tyr Met Glu Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val
225 230 235 240
Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 137
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 137
Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Pro Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Met Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Ser Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Phe Thr Ile Ser Ser Val Gln Val Glu
65 70 75 80
Asp Leu Ala Val Tyr Phe Cys Gln Gln His Tyr Ser Ser Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Lys Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val
130 135 140
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr Tyr Ile
145 150 155 160
Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys
165 170 175
Ile Gly Pro Gly Ser Gly Asn Thr Tyr Tyr Asn Glu Lys Phe Glu Gly
180 185 190
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
195 200 205
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Ser
210 215 220
Thr Gly Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Trp Ser
225 230 235 240
Ala
<210> 138
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 138
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr
130 135 140
Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly
145 150 155 160
Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp
165 170 175
Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu
180 185 190
Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val Phe
195 200 205
Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys
210 215 220
Ala Arg Arg Arg Leu Gly Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu
225 230 235 240
Val Thr Val Ser Ala
245
<210> 139
<211> 252
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 139
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val
130 135 140
Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Asp Tyr Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys
165 170 175
Ser Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg
180 185 190
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser
195 200 205
Ser Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser
210 215 220
Ala Val Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp
225 230 235 240
Val Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 140
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> scFv
<400> 140
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Asn Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Asn Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys
115 120 125
Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser
130 135 140
Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile
145 150 155 160
Ile His Trp Val Lys Gln Lys Ser Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Trp Phe Tyr Pro Gly Ser Gly Asn Ile Lys Tyr Asn Glu Lys Phe Lys
180 185 190
Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr Met
195 200 205
Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Thr
210 215 220
Arg His Glu Gly Gly Ser Asn Phe Phe Pro Tyr Trp Gly Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ala
245
<210> 141
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 连接体
<400> 141
Gly Gly Ser Gly Gly Ser
1 5
<210> 142
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 连接体
<400> 142
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 143
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 连接体
<400> 143
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 144
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 连接体
<400> 144
Gly Gly Gly Ser
1
<210> 145
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 145
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr
450 455 460
Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr
465 470 475 480
Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg
500 505 510
Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr
515 520 525
Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr
530 535 540
Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly
545 550 555 560
Gly Thr Lys Leu Thr Val Leu Gly Gln Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
580 585 590
Leu Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg
595 600 605
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser
610 615 620
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile
625 630 635 640
Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg
645 650 655
Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met
660 665 670
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile
675 680 685
Leu Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr
690 695 700
Thr Val Thr Val Ser Ser
705 710
<210> 146
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 146
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 147
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 147
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gln Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
580 585 590
Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu
595 600 605
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp
610 615 620
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn
625 630 635 640
Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val
645 650 655
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
660 665 670
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu
675 680 685
Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 148
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 148
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 149
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 149
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 150
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 150
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 151
<211> 705
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 151
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440 445
Gly Lys Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln Asp Pro
450 455 460
Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly
465 470 475 480
Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly
485 490 495
Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly
500 505 510
Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu
515 520 525
Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn
530 535 540
Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr Lys
545 550 555 560
Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly
580 585 590
Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
595 600 605
Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg Gln Ala
610 615 620
Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn Gly Gly
625 630 635 640
Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile Ser Arg
645 650 655
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
660 665 670
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala Gly Arg
675 680 685
Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr Val Ser
690 695 700
Ser
705
<210> 152
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 152
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 153
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 153
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Gln
450 455 460
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
465 470 475 480
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
485 490 495
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
500 505 510
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
545 550 555 560
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr Gln Asp Pro Ala
595 600 605
Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp
610 615 620
Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
625 630 635 640
Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile
645 650 655
Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr
660 665 670
Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser
675 680 685
Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly Thr Lys Leu
690 695 700
Thr Val Leu Gly Gln
705
<210> 154
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 154
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 155
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 155
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Glu Val Gln Leu Val Gln
450 455 460
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
465 470 475 480
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
485 490 495
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
500 505 510
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
545 550 555 560
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr Gln Asp Pro Ala
595 600 605
Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys Gln Gly Asp
610 615 620
Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
625 630 635 640
Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile
645 650 655
Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr
660 665 670
Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser
675 680 685
Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly Thr Lys Leu
690 695 700
Thr Val Leu Gly Gln
705
<210> 156
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 156
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 157
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 157
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gln Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
580 585 590
Val Gln Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu
595 600 605
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp
610 615 620
Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn
625 630 635 640
Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val
645 650 655
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
660 665 670
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu
675 680 685
Gly Ala Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 158
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 158
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 159
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 159
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ile Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Thr Gly Ser Gly Thr Asp
515 520 525
Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Phe Asp Tyr Thr Phe Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln
610 615 620
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Asp Pro Gly Ser
625 630 635 640
Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Lys Asn Tyr Gly Gly
675 680 685
Ser Tyr Ala Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ala
690 695 700
<210> 160
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 160
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Thr Gly Thr Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg His Glu Glu Gly Gly
675 680 685
Tyr Ser Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ala
705
<210> 161
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 161
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Val Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly Ser His Ile Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
580 585 590
Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys
595 600 605
Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr Leu
610 615 620
Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Tyr
625 630 635 640
Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
645 650 655
Lys Thr Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
660 665 670
Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Arg
675 680 685
Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 162
<211> 699
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 162
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ile Val Met Thr Gln
450 455 460
Thr Pro Lys Phe Leu Pro Val Ser Ala Gly Asp Arg Val Thr Met Thr
465 470 475 480
Cys Lys Ala Ser Gln Asn Val Gly Asn Asn Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Ser Tyr Ala Ser Asn Arg
500 505 510
Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Phe Thr Ile Ser Ser Val Gln Val Glu Asp Leu Ala Val Tyr Phe
530 535 540
Cys Gln Gln His Tyr Ser Ser Pro Leu Thr Phe Gly Ala Gly Thr Lys
545 550 555 560
Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly
580 585 590
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala
595 600 605
Ser Gly Tyr Ser Phe Thr Asp Tyr Tyr Ile Asn Trp Val Lys Gln Arg
610 615 620
Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys Ile Gly Pro Gly Ser Gly
625 630 635 640
Asn Thr Tyr Tyr Asn Glu Lys Phe Glu Gly Lys Ala Thr Leu Thr Ala
645 650 655
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
660 665 670
Glu Asp Ser Ala Val Tyr Phe Cys Ala Ser Thr Gly Pro Phe Ala Tyr
675 680 685
Trp Gly Gln Gly Thr Leu Val Thr Trp Ser Ala
690 695
<210> 163
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 163
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr
530 535 540
Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
580 585 590
Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser
595 600 605
Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Ser Trp Ile
610 615 620
Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala His Ile Tyr Trp
625 630 635 640
Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile
645 650 655
Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys Ile Thr Ser Val
660 665 670
Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Arg Arg Leu Gly
675 680 685
Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 164
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 164
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
580 585 590
Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val
595 600 605
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr
610 615 620
Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly
625 630 635 640
Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys
645 650 655
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met
660 665 670
Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala
675 680 685
Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr
690 695 700
Thr Val Thr Val Ser Ser
705 710
<210> 165
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 165
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Asn Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Asn Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Lys Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Asn Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Thr Arg His Glu Gly Gly Ser
675 680 685
Asn Phe Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 166
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 166
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 167
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 167
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 168
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 168
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Thr His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 169
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 169
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Ala Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Ala His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 170
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 170
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 171
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 171
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ala
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 172
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 172
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Asp Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Asp Ile Thr Gln Tyr Asn Glu Asn Phe
50 55 60
Lys Ala Lys Ser Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Ser Trp His Phe Gly Ser Asn Tyr Tyr Gly Leu Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asp Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Thr
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 173
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 173
Asp Ile Val Met Thr Gln Ser Gln Thr Phe Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Arg Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Arg Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Val Cys Gln Gln Tyr Ser Thr Tyr Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Arg Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 174
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 174
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ile Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Thr Gly Ser Gly Thr Asp
515 520 525
Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Phe Asp Tyr Thr Phe Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln
610 615 620
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Asp Pro Gly Ser
625 630 635 640
Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Lys Asn Tyr Gly Gly
675 680 685
Ser Tyr Ala Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ala
690 695 700
<210> 175
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 175
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Thr Gly Thr Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg His Glu Glu Gly Gly
675 680 685
Tyr Ser Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ala
705
<210> 176
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 176
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Val Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly Ser His Ile Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
580 585 590
Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys
595 600 605
Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr Leu
610 615 620
Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Tyr
625 630 635 640
Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
645 650 655
Lys Thr Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
660 665 670
Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Arg
675 680 685
Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 177
<211> 699
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 177
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ile Val Met Thr Gln
450 455 460
Thr Pro Lys Phe Leu Pro Val Ser Ala Gly Asp Arg Val Thr Met Thr
465 470 475 480
Cys Lys Ala Ser Gln Asn Val Gly Asn Asn Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Ser Tyr Ala Ser Asn Arg
500 505 510
Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Phe Thr Ile Ser Ser Val Gln Val Glu Asp Leu Ala Val Tyr Phe
530 535 540
Cys Gln Gln His Tyr Ser Ser Pro Leu Thr Phe Gly Ala Gly Thr Lys
545 550 555 560
Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly
580 585 590
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala
595 600 605
Ser Gly Tyr Ser Phe Thr Asp Tyr Tyr Ile Asn Trp Val Lys Gln Arg
610 615 620
Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys Ile Gly Pro Gly Ser Gly
625 630 635 640
Asn Thr Tyr Tyr Asn Glu Lys Phe Glu Gly Lys Ala Thr Leu Thr Ala
645 650 655
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
660 665 670
Glu Asp Ser Ala Val Tyr Phe Cys Ala Ser Thr Gly Pro Phe Ala Tyr
675 680 685
Trp Gly Gln Gly Thr Leu Val Thr Trp Ser Ala
690 695
<210> 178
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 178
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr
530 535 540
Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
580 585 590
Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser
595 600 605
Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Ser Trp Ile
610 615 620
Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala His Ile Tyr Trp
625 630 635 640
Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile
645 650 655
Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys Ile Thr Ser Val
660 665 670
Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Arg Arg Leu Gly
675 680 685
Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 179
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 179
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
580 585 590
Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val
595 600 605
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr
610 615 620
Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly
625 630 635 640
Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys
645 650 655
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met
660 665 670
Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala
675 680 685
Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr
690 695 700
Thr Val Thr Val Ser Ser
705 710
<210> 180
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 180
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Asn Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Asn Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Lys Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Asn Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Thr Arg His Glu Gly Gly Ser
675 680 685
Asn Phe Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 181
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 181
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 182
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 182
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 183
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 183
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Thr His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 184
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 184
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Ala Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Ala His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 185
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 185
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 186
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 186
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ala
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 187
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 187
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Ala Ile Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Phe Gly Ser Thr Ser Tyr Tyr Phe Asp Phe
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asp Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Thr
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 188
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 188
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Gly
20 25 30
Val Val Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Pro Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Ile Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 189
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 189
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ile Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Thr Gly Ser Gly Thr Asp
515 520 525
Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Phe Asp Tyr Thr Phe Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln
610 615 620
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Asp Pro Gly Ser
625 630 635 640
Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Lys Asn Tyr Gly Gly
675 680 685
Ser Tyr Ala Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ala
690 695 700
<210> 190
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 190
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Thr Gly Thr Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg His Glu Glu Gly Gly
675 680 685
Tyr Ser Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ala
705
<210> 191
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 191
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Val Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly Ser His Ile Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
580 585 590
Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys
595 600 605
Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr Leu
610 615 620
Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Tyr
625 630 635 640
Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
645 650 655
Lys Thr Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
660 665 670
Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Arg
675 680 685
Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 192
<211> 699
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 192
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ile Val Met Thr Gln
450 455 460
Thr Pro Lys Phe Leu Pro Val Ser Ala Gly Asp Arg Val Thr Met Thr
465 470 475 480
Cys Lys Ala Ser Gln Asn Val Gly Asn Asn Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Ser Tyr Ala Ser Asn Arg
500 505 510
Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Phe Thr Ile Ser Ser Val Gln Val Glu Asp Leu Ala Val Tyr Phe
530 535 540
Cys Gln Gln His Tyr Ser Ser Pro Leu Thr Phe Gly Ala Gly Thr Lys
545 550 555 560
Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly
580 585 590
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala
595 600 605
Ser Gly Tyr Ser Phe Thr Asp Tyr Tyr Ile Asn Trp Val Lys Gln Arg
610 615 620
Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys Ile Gly Pro Gly Ser Gly
625 630 635 640
Asn Thr Tyr Tyr Asn Glu Lys Phe Glu Gly Lys Ala Thr Leu Thr Ala
645 650 655
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
660 665 670
Glu Asp Ser Ala Val Tyr Phe Cys Ala Ser Thr Gly Pro Phe Ala Tyr
675 680 685
Trp Gly Gln Gly Thr Leu Val Thr Trp Ser Ala
690 695
<210> 193
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 193
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr
530 535 540
Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
580 585 590
Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser
595 600 605
Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Ser Trp Ile
610 615 620
Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala His Ile Tyr Trp
625 630 635 640
Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile
645 650 655
Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys Ile Thr Ser Val
660 665 670
Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Arg Arg Leu Gly
675 680 685
Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 194
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 194
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
580 585 590
Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val
595 600 605
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr
610 615 620
Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly
625 630 635 640
Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys
645 650 655
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met
660 665 670
Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala
675 680 685
Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr
690 695 700
Thr Val Thr Val Ser Ser
705 710
<210> 195
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 195
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Asn Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Asn Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Lys Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Asn Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Thr Arg His Glu Gly Gly Ser
675 680 685
Asn Phe Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 196
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 196
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 197
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 197
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 198
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 198
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Thr His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 199
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 199
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Ala Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Ala His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 200
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 200
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 201
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 201
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ala
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 202
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 202
Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asp Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Thr
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 203
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 203
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Thr Val Gly
1 5 10 15
Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Met Gln Ser
65 70 75 80
Lys Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 204
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 204
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ile Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Thr Gly Ser Gly Thr Asp
515 520 525
Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Phe Asp Tyr Thr Phe Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln
610 615 620
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Asp Pro Gly Ser
625 630 635 640
Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Lys Asn Tyr Gly Gly
675 680 685
Ser Tyr Ala Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ala
690 695 700
<210> 205
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 205
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Thr Gly Thr Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg His Glu Glu Gly Gly
675 680 685
Tyr Ser Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ala
705
<210> 206
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 206
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Val Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly Ser His Ile Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
580 585 590
Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys
595 600 605
Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr Leu
610 615 620
Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Tyr
625 630 635 640
Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
645 650 655
Lys Thr Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
660 665 670
Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Arg
675 680 685
Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 207
<211> 699
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 207
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ile Val Met Thr Gln
450 455 460
Thr Pro Lys Phe Leu Pro Val Ser Ala Gly Asp Arg Val Thr Met Thr
465 470 475 480
Cys Lys Ala Ser Gln Asn Val Gly Asn Asn Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Ser Tyr Ala Ser Asn Arg
500 505 510
Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Phe Thr Ile Ser Ser Val Gln Val Glu Asp Leu Ala Val Tyr Phe
530 535 540
Cys Gln Gln His Tyr Ser Ser Pro Leu Thr Phe Gly Ala Gly Thr Lys
545 550 555 560
Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly
580 585 590
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala
595 600 605
Ser Gly Tyr Ser Phe Thr Asp Tyr Tyr Ile Asn Trp Val Lys Gln Arg
610 615 620
Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys Ile Gly Pro Gly Ser Gly
625 630 635 640
Asn Thr Tyr Tyr Asn Glu Lys Phe Glu Gly Lys Ala Thr Leu Thr Ala
645 650 655
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
660 665 670
Glu Asp Ser Ala Val Tyr Phe Cys Ala Ser Thr Gly Pro Phe Ala Tyr
675 680 685
Trp Gly Gln Gly Thr Leu Val Thr Trp Ser Ala
690 695
<210> 208
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 208
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr
530 535 540
Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
580 585 590
Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser
595 600 605
Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Ser Trp Ile
610 615 620
Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala His Ile Tyr Trp
625 630 635 640
Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile
645 650 655
Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys Ile Thr Ser Val
660 665 670
Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Arg Arg Leu Gly
675 680 685
Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 209
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 209
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
580 585 590
Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val
595 600 605
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr
610 615 620
Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly
625 630 635 640
Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys
645 650 655
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met
660 665 670
Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala
675 680 685
Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr
690 695 700
Thr Val Thr Val Ser Ser
705 710
<210> 210
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 210
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Asn Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Asn Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Lys Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Asn Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Thr Arg His Glu Gly Gly Ser
675 680 685
Asn Phe Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 211
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 211
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 212
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 212
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 213
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 213
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Thr His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 214
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 214
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Ala Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Ala His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 215
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 215
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 216
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 216
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ala
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 217
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 217
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asp Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Thr
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 218
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 218
Asp Ile Gln Met Thr Gln Ser Gln Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Gly Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Lys Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 219
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 219
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ile Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Thr Gly Ser Gly Thr Asp
515 520 525
Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Phe Asp Tyr Thr Phe Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln
610 615 620
Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Asp Pro Gly Ser
625 630 635 640
Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Lys Asn Tyr Gly Gly
675 680 685
Ser Tyr Ala Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ala
690 695 700
<210> 220
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 220
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Thr Gly Thr Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Arg Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg His Glu Glu Gly Gly
675 680 685
Tyr Ser Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ala
705
<210> 221
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 221
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Val Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Arg Gly Ser His Ile Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
580 585 590
Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys
595 600 605
Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr Leu
610 615 620
Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Tyr
625 630 635 640
Ile Tyr Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly
645 650 655
Lys Thr Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu
660 665 670
Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Arg
675 680 685
Gly Ser Asn Trp Ile Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 222
<211> 699
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 222
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ile Val Met Thr Gln
450 455 460
Thr Pro Lys Phe Leu Pro Val Ser Ala Gly Asp Arg Val Thr Met Thr
465 470 475 480
Cys Lys Ala Ser Gln Asn Val Gly Asn Asn Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Ser Tyr Ala Ser Asn Arg
500 505 510
Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Phe Thr Ile Ser Ser Val Gln Val Glu Asp Leu Ala Val Tyr Phe
530 535 540
Cys Gln Gln His Tyr Ser Ser Pro Leu Thr Phe Gly Ala Gly Thr Lys
545 550 555 560
Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln Ser Gly
580 585 590
Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala
595 600 605
Ser Gly Tyr Ser Phe Thr Asp Tyr Tyr Ile Asn Trp Val Lys Gln Arg
610 615 620
Pro Gly Gln Gly Leu Glu Trp Ile Gly Lys Ile Gly Pro Gly Ser Gly
625 630 635 640
Asn Thr Tyr Tyr Asn Glu Lys Phe Glu Gly Lys Ala Thr Leu Thr Ala
645 650 655
Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser
660 665 670
Glu Asp Ser Ala Val Tyr Phe Cys Ala Ser Thr Gly Pro Phe Ala Tyr
675 680 685
Trp Gly Gln Gly Thr Leu Val Thr Trp Ser Ala
690 695
<210> 223
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 223
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr
530 535 540
Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Thr Leu Lys Glu Ser
580 585 590
Gly Pro Gly Ile Leu Gln Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser
595 600 605
Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Ser Trp Ile
610 615 620
Arg Gln Pro Ser Gly Lys Gly Leu Glu Trp Leu Ala His Ile Tyr Trp
625 630 635 640
Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile
645 650 655
Ser Lys Asp Thr Ser Arg Asn Gln Val Phe Leu Lys Ile Thr Ser Val
660 665 670
Asp Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Arg Arg Leu Gly
675 680 685
Pro Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 224
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 224
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Val Leu Met Thr Gln
450 455 460
Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser
465 470 475 480
Cys Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu
485 490 495
Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
500 505 510
Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
515 520 525
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu
530 535 540
Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Pro Thr
545 550 555 560
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
580 585 590
Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val
595 600 605
Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Tyr
610 615 620
Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly
625 630 635 640
Tyr Ile Tyr Pro Asn Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe Lys
645 650 655
Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met
660 665 670
Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala
675 680 685
Arg Gly Gly Asn Trp Asn Trp Tyr Phe Asp Val Trp Gly Thr Gly Thr
690 695 700
Thr Val Thr Val Ser Ser
705 710
<210> 225
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 225
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Val Met Thr Gln
450 455 460
Ser His Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr
465 470 475 480
Cys Lys Ala Ser Gln Asp Val Ser Asn Ala Val Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg
500 505 510
His Asn Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
515 520 525
Tyr Ile Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr
530 535 540
Tyr Cys Gln Gln His Tyr Arg Thr Pro Tyr Thr Phe Gly Gly Gly Thr
545 550 555 560
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Val Gln Leu Gln Gln Ser
580 585 590
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys
595 600 605
Ala Ser Gly Tyr Thr Phe Thr Glu Tyr Ile Ile His Trp Val Lys Gln
610 615 620
Lys Ser Gly Gln Gly Leu Glu Trp Ile Gly Trp Phe Tyr Pro Gly Ser
625 630 635 640
Gly Asn Ile Lys Tyr Asn Glu Lys Phe Lys Asp Lys Ala Thr Leu Thr
645 650 655
Ala Asp Lys Ser Ser Ser Thr Val Tyr Met Glu Leu Ser Arg Leu Thr
660 665 670
Ser Glu Asp Ser Ala Val Tyr Phe Cys Thr Arg His Glu Gly Gly Ser
675 680 685
Asn Phe Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
690 695 700
<210> 226
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 226
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Asp Ile Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Cys Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 227
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 227
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 228
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 228
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Thr His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 229
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 229
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Ala Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Ala His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 230
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 230
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ser
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 231
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 231
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Thr Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Ala
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 232
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 重链
<400> 232
Glu Val Gln Leu Gln Gln Ser Val Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Gly Ile Thr Gly Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asp Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asp His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Thr
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 233
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 轻链
<400> 233
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Val Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Thr Ser Val Lys Ser Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 234
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 234
ctaatacgac tcactatagg gcaagcagtg gtatcaacgc agagt 45
<210> 235
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 235
ctaatacgac tcactatagg gc 22
<210> 236
<211> 26
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 236
ctgctcactg gatggtggga agatgg 26
<210> 237
<211> 26
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 237
ggggccagtg gatagacaga tggggg 26
<210> 238
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 238
cgtatcgcct ccctcgcgcc atcagacgag tgcgtctaat acgactcact atagggc 57
<210> 239
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 239
cgtatcgcct ccctcgcgcc atcagacgct cgacactaat acgactcact atagggc 57
<210> 240
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 240
cgtatcgcct ccctcgcgcc atcagagacg cactcctaat acgactcact atagggc 57
<210> 241
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 241
cgtatcgcct ccctcgcgcc atcagagcac tgtagctaat acgactcact atagggc 57
<210> 242
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 242
cgtatcgcct ccctcgcgcc atcagatcag acacgctaat acgactcact atagggc 57
<210> 243
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 243
cgtatcgcct ccctcgcgcc atcagatatc gcgagctaat acgactcact atagggc 57
<210> 244
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 244
cgtatcgcct ccctcgcgcc atcagcgtgt ctctactaat acgactcact atagggc 57
<210> 245
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 245
cgtatcgcct ccctcgcgcc atcagctcgc gtgtcctaat acgactcact atagggc 57
<210> 246
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 246
ctatgcgcct tgccagcccg ctcagacgag tgcgtctgct cactggatgg tgggaagatg 60
g 61
<210> 247
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 247
ctatgcgcct tgccagcccg ctcagacgct cgacactgct cactggatgg tgggaagatg 60
g 61
<210> 248
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 248
ctatgcgcct tgccagcccg ctcagagacg cactcctgct cactggatgg tgggaagatg 60
g 61
<210> 249
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 249
ctatgcgcct tgccagcccg ctcagagcac tgtagctgct cactggatgg tgggaagatg 60
g 61
<210> 250
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 250
ctatgcgcct tgccagcccg ctcagatcag acacgctgct cactggatgg tgggaagatg 60
g 61
<210> 251
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 251
ctatgcgcct tgccagcccg ctcagatatc gcgagctgct cactggatgg tgggaagatg 60
g 61
<210> 252
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 252
ctatgcgcct tgccagcccg ctcagcgtgt ctctactgct cactggatgg tgggaagatg 60
g 61
<210> 253
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 253
ctatgcgcct tgccagcccg ctcagctcgc gtgtcctgct cactggatgg tgggaagatg 60
g 61
<210> 254
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 254
cgtatcgcct ccctcgcgcc atcagacgag tgcgtctaat acgactcact atagggc 57
<210> 255
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 255
cgtatcgcct ccctcgcgcc atcagacgct cgacactaat acgactcact atagggc 57
<210> 256
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 256
cgtatcgcct ccctcgcgcc atcagagacg cactcctaat acgactcact atagggc 57
<210> 257
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 257
cgtatcgcct ccctcgcgcc atcagagcac tgtagctaat acgactcact atagggc 57
<210> 258
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 258
cgtatcgcct ccctcgcgcc atcagatcag acacgctaat acgactcact atagggc 57
<210> 259
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 259
cgtatcgcct ccctcgcgcc atcagatatc gcgagctaat acgactcact atagggc 57
<210> 260
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 260
cgtatcgcct ccctcgcgcc atcagcgtgt ctctactaat acgactcact atagggc 57
<210> 261
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 261
cgtatcgcct ccctcgcgcc atcagctcgc gtgtcctaat acgactcact atagggc 57
<210> 262
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 262
ctatgcgcct tgccagcccg ctcagacgag tgcgtggggc cagtggatag acagatgggg 60
g 61
<210> 263
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 263
ctatgcgcct tgccagcccg ctcagacgct cgacaggggc cagtggatag acagatgggg 60
g 61
<210> 264
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 264
ctatgcgcct tgccagcccg ctcagagacg cactcggggc cagtggatag acagatgggg 60
g 61
<210> 265
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 265
ctatgcgcct tgccagcccg ctcagagcac tgtagggggc cagtggatag acagatgggg 60
g 61
<210> 266
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 266
ctatgcgcct tgccagcccg ctcagatcag acacgggggc cagtggatag acagatgggg 60
g 61
<210> 267
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 267
ctatgcgcct tgccagcccg ctcagatatc gcgagggggc cagtggatag acagatgggg 60
g 61
<210> 268
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 268
ctatgcgcct tgccagcccg ctcagcgtgt ctctaggggc cagtggatag acagatgggg 60
g 61
<210> 269
<211> 61
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 269
ctatgcgcct tgccagcccg ctcagctcgc gtgtcggggc cagtggatag acagatgggg 60
g 61
<210> 270
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> 引物
<400> 270
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
Ala Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 271
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> 引物
<400> 271
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Thr Ile His Trp Met Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Arg Asp Val Ile Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys
85 90 95
Ala Arg Trp Gly Tyr Phe Tyr Gly Ser Arg Ser Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu Ala Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Gly Gly Ser Gly Gly Ser Ser Ser Glu Leu Thr Gln
450 455 460
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
465 470 475 480
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
485 490 495
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
500 505 510
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
515 520 525
Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
530 535 540
Cys Asn Ser Arg Asp Ser Ser Gly Asn His Val Val Phe Gly Gly Gly
545 550 555 560
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
580 585 590
Ser Gly Gly Gly Val Glu Arg Pro Gly Gly Ser Leu Arg Leu Ser Cys
595 600 605
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Gly Met Ser Trp Val Arg
610 615 620
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Asn Trp Asn
625 630 635 640
Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys Gly Arg Val Thr Ile
645 650 655
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
660 665 670
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Ile Leu Gly Ala
675 680 685
Gly Arg Gly Trp Tyr Phe Asp Leu Trp Gly Lys Gly Thr Thr Val Thr
690 695 700
Val Ser Ser
705
<210> 272
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 272
Gly Tyr Ser Tyr Arg Asn Tyr Ala Tyr Tyr Tyr Asp Tyr
1 5 10
Claims (29)
1.一种结合分子，其包含至少一个特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点及至少一个特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点。
2.如权利要求1的结合分子，其中该分子为双特异性及四价。
3.如权利要求1或2的结合分子，其中该至少一个特异性结合至钙粘蛋白-17(CDH17)的抗原结合位点为免疫球蛋白(Ig)分子且该至少一个特异性结合至TNF相关细胞凋亡诱导配体受体2(TRAILR2)的抗原结合位点包含一或多个scFv。
4.如权利要求3的结合分子，其中该一或多个scFv具有自N末端至C末端的VL-VH定向。
5.如权利要求3或4的结合分子，其中该一或多个scFv融合至该Ig分子的重链的C末端。
6.如权利要求3至5中任一项的结合分子，其中该Ig分子为IgG。
7.如权利要求3至6中任一项的结合分子，其中该一或多个scFv通过肽连接体融合至该Ig分子，优选地肽连接体具有约4至20个氨基酸的长度。
8.如权利要求1至7中任一项的结合分子，其中该特异性结合至TRAILR2的抗原结合位点选自由抗原结合位点i)至xiii)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQ IDNO.:3(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:4(CDR1)、SEQ ID NO.:5(CDR2)及SEQ ID NO.:6(CDR3)的氨基酸序列的轻链CDR；
ii)抗原结合位点，其包含包括SEQ ID NO.:7(CDR1)、SEQ ID NO.:8(CDR2)及SEQ IDNO.:9(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:10(CDR1)、SEQ ID NO.:11(CDR2)及SEQ ID NO.:12(CDR3)的氨基酸序列的轻链CDR；
iii)抗原结合位点，其包含包括SEQ ID NO.:13(CDR1)、SEQ ID NO.:14(CDR2)及SEQID NO.:15(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR；
iv)抗原结合位点，其包含包括SEQ ID NO.:19(CDR1)、SEQ ID NO.:20(CDR2)及SEQ IDNO.:21(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:22(CDR1)、SEQ ID NO.:23(CDR2)及SEQ ID NO.:24(CDR3)的氨基酸序列的轻链CDR；
v)抗原结合位点，其包含包括SEQ ID NO.:25(CDR1)、SEQ ID NO.:26(CDR2)及SEQ IDNO.:27(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:28(CDR1)、SEQ ID NO.:29(CDR2)及SEQ ID NO.:30(CDR3)的氨基酸序列的轻链CDR；
vi)抗原结合位点，其包含包括SEQ ID NO.:31(CDR1)、SEQ ID NO.:32(CDR2)及SEQ IDNO.:33(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:34(CDR1)、SEQ ID NO.:35(CDR2)及SEQ ID NO.:36(CDR3)的氨基酸序列的轻链CDR；
vii)抗原结合位点，其包含包括SEQ ID NO.:37(CDR1)、SEQ ID NO.:38(CDR2)及SEQID NO.:39(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:40(CDR1)、SEQ ID NO.:41(CDR2)及SEQ ID NO.:42(CDR3)的氨基酸序列的轻链CDR；
viii)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:44(CDR2)及SEQID NO.:48(CDR3)的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ IDNO.:54(CDR3)的氨基酸序列的轻链CDR；
ix)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ IDNO.:48(CDR3)的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ IDNO.:55(CDR3)的氨基酸序列的轻链CDR；
x)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ IDNO.:48(CDR3)的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:52(CDR2)及SEQ IDNO.:56(CDR3)的氨基酸序列的轻链CDR；
xi)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:45(CDR2)及SEQ IDNO.:48(CDR3)的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:50(CDR2)及SEQ IDNO.:56(CDR3)的氨基酸序列的轻链CDR；
xii)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:46(CDR2)及SEQID NO.:48(CDR3)的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:51(CDR2)及SEQ IDNO.:57(CDR3)的氨基酸序列的轻链CDR；及
xiii)抗原结合位点，其包含包括SEQ ID NO.:43(CDR1)、SEQ ID NO.:47(CDR2)及SEQID NO.:48(CDR3)的重链CDR及包括SEQ ID NO.:49(CDR1)、SEQ ID NO.:53(CDR2)及SEQ IDNO.:57(CDR3)的氨基酸序列的轻链CDR。
9.如权利要求1至8中任一项的结合分子，其中该特异性结合至TRAILR2的抗原结合位点选自由抗原结合位点i)至xiv)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:82的氨基酸序列的重链可变结构域及包括SEQ ID NO.:83的氨基酸序列的轻链可变结构域；
ii)抗原结合位点，其包含包括SEQ ID NO.:84的氨基酸序列的重链可变结构域及包括SEQ ID NO.:85的氨基酸序列的轻链可变结构域；
iii)抗原结合位点，其包含包括SEQ ID NO.:86的氨基酸序列的重链可变结构域及包括SEQ ID NO.:87的氨基酸序列的轻链可变结构域；
iv)抗原结合位点，其包含包括SEQ ID NO.:88的氨基酸序列的重链可变结构域及包括SEQ ID NO.:89的氨基酸序列的轻链可变结构域；
v)抗原结合位点，其包含包括SEQ ID NO.:90的氨基酸序列的重链可变结构域及包括SEQ ID NO.:91的氨基酸序列的轻链可变结构域；
vi)抗原结合位点，其包含包括SEQ ID NO.:92的氨基酸序列的重链可变结构域及包括SEQ ID NO.:93的氨基酸序列的轻链可变结构域；
vii)抗原结合位点，其包含包括SEQ ID NO.:94的氨基酸序列的重链可变结构域及包括SEQ ID NO.:95的氨基酸序列的轻链可变结构域；
viii)抗原结合位点，其包含包括SEQ ID NO.:96的氨基酸序列的重链可变结构域及包括SEQ ID NO.:97的氨基酸序列的轻链可变结构域；
ix)抗原结合位点，其包含包括SEQ ID NO.:98的氨基酸序列的重链可变结构域及包括SEQ ID NO.:99的氨基酸序列的轻链可变结构域；
x)抗原结合位点，其包含包括SEQ ID NO.:100的氨基酸序列的重链可变结构域及包括SEQ ID NO.:101的氨基酸序列的轻链可变结构域；
xi)抗原结合位点，其包含包括SEQ ID NO.:102的氨基酸序列的重链可变结构域及包括SEQ ID NO.:103的氨基酸序列的轻链可变结构域；
xii)抗原结合位点，其包含包括SEQ ID NO.:104的氨基酸序列的重链可变结构域及包括SEQ ID NO.:105的氨基酸序列的轻链可变结构域；
xiii)抗原结合位点，其包含包括SEQ ID NO.:106的氨基酸序列的重链可变结构域及包括SEQ ID NO.:107的氨基酸序列的轻链可变结构域；及
xiv)抗原结合位点，其包含包括SEQ ID NO.:108的氨基酸序列的重链可变结构域及包括SEQ ID NO.:109的氨基酸序列的轻链可变结构域。
10.如权利要求1至9中任一项的结合分子，其中该特异性结合至CDH17的抗原结合位点选自由抗原结合位点i)至iv)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:58(CDR1)、SEQ ID NO.:59(CDR2)及SEQ IDNO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR；
ii)抗原结合位点，其包含包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ IDNO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR；
iii)抗原结合位点，其包含包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR；及
iv)抗原结合位点，其包含包括SEQ ID NO.:76(CDR1)、SEQ ID NO.:77(CDR2)及SEQ IDNO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。
11.如权利要求1至10中任一项的结合分子，其中该特异性结合至CDH17的抗原结合位点选自由抗原结合位点i)至v)组成的群：
i)抗原结合位点，其包含包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域；
ii)抗原结合位点，其包含包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域；
iii)抗原结合位点，其包含包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域；
iv)抗原结合位点，其包含包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域；及
v)抗原结合位点，其包含包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。
12.一种结合分子，其包含(i)包括SEQ ID NO.:159的氨基酸序列的重链、或包括SEQID NO.:160的氨基酸序列的重链、或包括SEQ ID NO.:161的氨基酸序列的重链、或包括SEQID NO.:162的氨基酸序列的重链、或包括SEQ ID NO.:163的氨基酸序列的重链、或包括SEQID NO.:164的氨基酸序列的重链、或包括SEQ ID NO.:165的氨基酸序列的重链、或包括SEQID NO.:166的氨基酸序列的重链、或包括SEQ ID NO.:167的氨基酸序列的重链、或包括SEQID NO.:168的氨基酸序列的重链、或包括SEQ ID NO.:169的氨基酸序列的重链、或包括SEQID NO.:170的氨基酸序列的重链、或包括SEQ ID NO.:171的氨基酸序列的重链、或包括SEQID NO.:172的氨基酸序列的重链，及(ii)包括SEQ ID NO.:173的氨基酸序列的轻链。
13.一种结合分子，其包含(i)包括SEQ ID NO.:174的氨基酸序列的重链、或包括SEQID NO.:175的氨基酸序列的重链、或包括SEQ ID NO.:176的氨基酸序列的重链、或包括SEQID NO.:177的氨基酸序列的重链、或包括SEQ ID NO.:178的氨基酸序列的重链、或包括SEQID NO.:179的氨基酸序列的重链、或包括SEQ ID NO.:180的氨基酸序列的重链、或包括SEQID NO.:181的氨基酸序列的重链、或包括SEQ ID NO.:182的氨基酸序列的重链、或包括SEQID NO.:183的氨基酸序列的重链、或包括SEQ ID NO.:184的氨基酸序列的重链、或包括SEQID NO.:185的氨基酸序列的重链、或包括SEQ ID NO.:186的氨基酸序列的重链、或包括SEQID NO.:187的氨基酸序列的重链，及(ii)包括SEQ ID NO.:188的氨基酸序列的轻链。
14.一种结合分子，其包含(i)包括SEQ ID NO.:189的氨基酸序列的重链、或包括SEQID NO.:190的氨基酸序列的重链、或包括SEQ ID NO.:191的氨基酸序列的重链、或包括SEQID NO.:192的氨基酸序列的重链、或包括SEQ ID NO.:193的氨基酸序列的重链、或包括SEQID NO.:194的氨基酸序列的重链、或包括SEQ ID NO.:195的氨基酸序列的重链、或包括SEQID NO.:196的氨基酸序列的重链、或包括SEQ ID NO.:197的氨基酸序列的重链、或包括SEQID NO.:198的氨基酸序列的重链、或包括SEQ ID NO.:199的氨基酸序列的重链、或包括SEQID NO.:200的氨基酸序列的重链、或包括SEQ ID NO.:201的氨基酸序列的重链、或包括SEQID NO.:202的氨基酸序列的重链，及(ii)包括SEQ ID NO.:203的氨基酸序列的轻链。
15.一种结合分子，其包含(i)包括SEQ ID NO.:204的氨基酸序列的重链、或包括SEQID NO.:205的氨基酸序列的重链、或包括SEQ ID NO.:206的氨基酸序列的重链、或包括SEQID NO.:207的氨基酸序列的重链、或包括SEQ ID NO.:208的氨基酸序列的重链、或包括SEQID NO.:209的氨基酸序列的重链、或包括SEQ ID NO.:210的氨基酸序列的重链、或包括SEQID NO.:211的氨基酸序列的重链、或包括SEQ ID NO.:212的氨基酸序列的重链、或包括SEQID NO.:213的氨基酸序列的重链、或包括SEQ ID NO.:214的氨基酸序列的重链、或包括SEQID NO.:215的氨基酸序列的重链、或包括SEQ ID NO.:216的氨基酸序列的重链、或包括SEQID NO.:217的氨基酸序列的重链；及(ii)包括SEQ ID NO.:218的氨基酸序列的轻链。
16.一种结合分子，其包含(i)包括SEQ ID NO.:145的氨基酸序列的重链、或包括SEQID NO.:147的氨基酸序列的重链、或包括SEQ ID NO.:149的氨基酸序列的重链、或包括SEQID NO.:151的氨基酸序列的重链、或包括SEQ ID NO.:153的氨基酸序列的重链、或包括SEQID NO.:155的氨基酸序列的重链、或包括SEQ ID NO.:157的氨基酸序列的重链、或包括SEQID NO.:219的氨基酸序列的重链、或包括SEQ ID NO.:220的氨基酸序列的重链、或包括SEQID NO.:221的氨基酸序列的重链、或包括SEQ ID NO.:222的氨基酸序列的重链、或包括SEQID NO.:223的氨基酸序列的重链、或包括SEQ ID NO.:224的氨基酸序列的重链、或包括SEQID NO.:225的氨基酸序列的重链、或包括SEQ ID NO.:226的氨基酸序列的重链、或包括SEQID NO.:227的氨基酸序列的重链、或包括SEQ ID NO.:228的氨基酸序列的重链、或包括SEQID NO.:229的氨基酸序列的重链、或包括SEQ ID NO.:230的氨基酸序列的重链、或包括SEQID NO.:231的氨基酸序列的重链、或包括SEQ ID NO.:232的氨基酸序列的重链；及(ii)包括SEQ ID NO.:233的氨基酸序列的轻链。
17.一种特异性结合至CDH17的抗体分子，其包含(i)包括SEQ ID NO.:58(CDR1)、SEQID NO.:59(CDR2)及SEQ ID NO.:60(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:61(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:63(CDR3)的氨基酸序列的轻链CDR，(ii)包括SEQ ID NO.:64(CDR1)、SEQ ID NO.:65(CDR2)及SEQ ID NO.:66(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:67(CDR1)、SEQ ID NO.:68(CDR2)及SEQ ID NO.:69(CDR3)的氨基酸序列的轻链CDR，(iii)包括SEQ ID NO.:70(CDR1)、SEQ ID NO.:71(CDR2)及SEQ ID NO.:72(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:73(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:75(CDR3)的氨基酸序列的轻链CDR，或(iv)包括SEQ ID NO.:76(CDR1)、SEQ IDNO.:77(CDR2)及SEQ ID NO.:78(CDR3)的氨基酸序列的重链CDR及包括SEQ ID NO.:79(CDR1)、SEQ ID NO.:80(CDR2)及SEQ ID NO.:81(CDR3)的氨基酸序列的轻链CDR。
18.如权利要求17的抗体分子，其包含(i)包括SEQ ID NO.:110的氨基酸序列的重链可变结构域及包括SEQ ID NO.:111的氨基酸序列的轻链可变结构域，(ii)包括SEQ ID NO.:112的氨基酸序列的重链可变结构域及包括SEQ ID NO.:113的氨基酸序列的轻链可变结构域，(iii)包括SEQ ID NO.:114的氨基酸序列的重链可变结构域及包括SEQ ID NO.:115的氨基酸序列的轻链可变结构域，(iv)包括SEQ ID NO.:116的氨基酸序列的重链可变结构域及包括SEQ ID NO.:117的氨基酸序列的轻链可变结构域，或(v)包括SEQ ID NO.:118的氨基酸序列的重链可变结构域及包括SEQ ID NO.:119的氨基酸序列的轻链可变结构域。
19.一种分离的核酸分子，其编码如权利要求8至11中任一项的结合分子或如权利要求17或18中任一项的抗体分子的重链可变结构域及/或轻链可变结构域。
20.一种分离的核酸分子，其编码如权利要求12至16中任一项的结合分子的重链及/或轻链。
21.一种表达载体，其包含如权利要求19或20的核酸分子。
22.一种宿主细胞，其经如权利要求21的表达载体转染。
23.一种制造如权利要求8至16中任一项的结合分子或如权利要求17或18的抗体分子的方法，其包括
(a)在容许该分子表达的条件下培养如权利要求22的宿主细胞；及
(b)回收该分子；及任选地
(c)进一步纯化及/或修饰及/或调配该分子。
24.如权利要求1至16中任一项的结合分子，其用于药剂中。
25.一种药物组合物，其包含如权利要求1至16中任一项的结合分子及药学上可接受的载剂。
26.一种治疗癌症的方法，其包括向有需要的患者施用治疗有效量的如权利要求1至16中任一项的结合分子。
27.如权利要求1至16中任一项的结合分子在制备用于治疗癌症的药物组合物中的用途。
28.如权利要求1至16中任一项的结合分子，其用于治疗癌症的方法中。
29.如权利要求26的方法、如权利要求27的用途、或如权利要求28使用的结合分子，其中该癌症为结肠直肠癌(CRC)、胃癌(GC)、胰脏癌(PAC)、食道癌或神经内分泌肿瘤。
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Also Published As
| Publication number | Publication date |
|---|---|
| EA201991480A1 (ru) | 2020-01-15 |
| JP7196076B2 (ja) | 2022-12-26 |
| US10858438B2 (en) | 2020-12-08 |
| WO2018115231A3 (en) | 2018-08-02 |
| AU2017384687A1 (en) | 2019-06-13 |
| MA47121A (fr) | 2019-10-30 |
| EP3360898A1 (en) | 2018-08-15 |
| MX2019007511A (es) | 2019-09-04 |
| WO2018115231A2 (en) | 2018-06-28 |
| PE20191251A1 (es) | 2019-09-18 |
| EP3559040A2 (en) | 2019-10-30 |
| CO2019006320A2 (es) | 2019-06-28 |
| TW201835102A (zh) | 2018-10-01 |
| CA3046591A1 (en) | 2018-06-28 |
| BR112019011750A2 (pt) | 2019-10-29 |
| TWI790219B (zh) | 2023-01-21 |
| KR102651761B1 (ko) | 2024-03-26 |
| JP2020501586A (ja) | 2020-01-23 |
| US11851495B2 (en) | 2023-12-26 |
| KR20190099223A (ko) | 2019-08-26 |
| US20210095038A1 (en) | 2021-04-01 |
| CN110582513B (zh) | 2023-11-14 |
| US20180179287A1 (en) | 2018-06-28 |
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