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CN117957256A - 新颖三特异性结合分子 - Google Patents

新颖三特异性结合分子 Download PDF

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CN117957256A
CN117957256A CN202280043054.9A CN202280043054A CN117957256A CN 117957256 A CN117957256 A CN 117957256A CN 202280043054 A CN202280043054 A CN 202280043054A CN 117957256 A CN117957256 A CN 117957256A
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amino acid
acid sequence
cdr
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P·亚当
S·R·科莫
P·N·戈尔曼
潘卡·古普塔
普里扬卡·古普塔
K-H·海德尔
S·卡斯特里兰甘
R·科诺皮茨基
K-P·昆克乐
S·库马尔
T·A-T·马克
E·K·奥斯特曼
A·沙班
D·魏斯曼
A·韦尼茨尼格
D·S·杨
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Boehringer Ingelheim International GmbH
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Abstract

本发明涉及新颖三特异性结合分子。本发明还涉及编码此类结合分子的核酸；用于制备此类结合分子的方法；表达或能够表达此类结合分子的宿主细胞；包含此类结合分子的组合物；及此类结合分子或此类组合物尤其用于在癌症疾病领域中达成治疗目的的用途。

Description

新颖三特异性结合分子
技术领域
本发明涉及新颖三特异性结合分子。本发明还涉及编码此类结合分子的核酸；用于制备此类结合分子的方法；表达或能够表达此类结合分子的宿主细胞；包含此类结合分子的组合物；及此类结合分子或此类组合物尤其用于在癌症疾病领域中达成治疗目的的用途。
背景技术
癌症为一组通常基于异常细胞增殖及癌细胞可能侵入或扩散在整个身体中的疾病。其为严重疾病及全球死亡的主要原因。
已尝试使用多种治疗方法管理或在一些情况下治疗癌症，包括手术、化学疗法、放射疗法及激素疗法。另外，抗体提供作为用于治疗癌症的强力治疗剂的可能性。抗体经设计以识别及结合于细胞表面上的特定蛋白质，即其目标抗原。此结合可激起多个不同生物反应，视例如表达目标抗原的细胞类型、目标抗原蛋白质的功能或抗体本身的结构而定。
举例而言，一些抗体直接结合于癌细胞，且可例如通过干扰细胞路径来中止或减少这些细胞的细胞分裂，由此减缓或防止异常细胞增殖。或者，此类靶向癌细胞的抗体亦可附接有药物或放射性粒子，由此将这些治疗剂递送至癌细胞，从而独立于细胞内源路径起作用。与这些靶向癌细胞的方法不同的方法为基于能够诱导免疫系统进攻及杀灭癌细胞的抗体。此可通过将免疫细胞、诸如细胞毒性T细胞重新引导至癌细胞或通过直接影响免疫系统本身的活性来达成。
虽然靶向癌细胞的方法以及重新引导免疫细胞的方法提供治疗癌症的有效作用模式(MoA)，但其通常依赖于癌细胞特异性标记物，即非癌细胞几乎不表达的目标蛋白的表达。此类肿瘤特异性目标蛋白为罕见的，且此稀缺仍然是在研发癌症特异性治疗剂中通常面临的主要缺点。
虽然已尝试将免疫细胞重新引导至更广泛表达的谱系抗原，但这些疗法的价值受到这些抗原在某些正常组织中的表达，例如Epcam在胃肠道中的表达所引起的毒性限制(Kebenko等人,Oncoimmunology 2018,第7卷,第8期)。尽管当前实行减少与位点外(off-site)抗原表达相关的毒性的各种方法，但对于许多化合物，毒性仍然为剂量限制性的。
因此，虽然近年来某些癌症的治疗已取得进展，且尽管当前实行大量不同方法，但仍需要提供新颖的治疗学上适合用于治疗癌症的化合物。因此，本发明的目标在于提供可用于各种癌症疾病的治疗中的此类药理学活性剂。
详言之，本发明的目标在于提供相较于当前所用和/或本领域已知的药剂、组合物和/或方法，提供特定优点的此类药理学活性剂、组合物和/或治疗方法。这些优点包括尤其相较于本领域已知的候选药物的体内功效、改良的治疗特性及药理学特性、较少副作用及其他有利特性，诸如改良的易于制备性或降低的商品成本。
此需求由本文中所提供的实施方案解决。
发明内容
本发明为基于将三个抗原结合位点组合在单一结合分子内的概念，即特异性结合于滋养层细胞表面抗原2(TROP2)的第一抗原结合位点、特异性结合于钙黏素-17(CDH17)的第二抗原结合位点及特异性结合于分化簇3(CD3)的第三抗原结合位点。如下文更详细地论述，本发明的分子的一个优点为其低亲和力、高亲和力设计，此提供优良的对靶细胞的特异性。
因此，本发明的第一方面提供一种结合分子，其包含：(a)至少一个以Kd≥1nM特异性结合于滋养层细胞表面抗原2(TROP2)的抗原结合位点；(b)至少一个特异性结合于钙黏素-17(CDH17)的抗原结合位点，其中该至少一个特异性结合于CDH17的抗原结合位点为选自由抗原结合位点(i)至(ii)组成的组：(i)抗原结合位点，其包括包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:33(CDR2)及SEQ ID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQID NO.:35(CDR1)、SEQ ID NO.:36(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR；及(ii)抗原结合位点，其包括包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:38(CDR2)及SEQID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:39(CDR1)、SEQ ID NO.:40(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR；及(c)至少一个特异性结合于分化簇3(CD3)的抗原结合位点。
在本发明的结合分子之一优选实施方案中，至少一个特异性结合于TROP2的抗原结合位点为选自由抗原结合位点(i)至(vi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQID NO.:3(CDR3)的氨基酸序列的重链CDR及包含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，其包括包含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及包含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，其包括包含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及包含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，其包括包含SEQ ID NO.:13(CDR1)、SEQ ID NO.:19(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:20(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR；
(v)抗原结合位点，其包括包含SEQ ID NO.:21(CDR1)、SEQ ID NO.:22(CDR2)及SEQ ID NO.:23(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:24(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:26(CDR3)的氨基酸序列的轻链CDR；
及
(vi)抗原结合位点，其包括包含SEQ ID NO.:27(CDR1)、SEQ ID NO.:28(CDR2)及SEQ ID NO.:29(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:30(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:31(CDR3)的氨基酸序列的轻链CDR。
在本发明的结合分子之一优选实施方案中，至少一个特异性结合于TROP2的抗原结合位点为选自由抗原结合位点(i)至(xii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:83的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:84的氨基酸序列的免疫球蛋白轻链可变域；
(ii)抗原结合位点，其包括包含SEQ ID NO:85的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:86的氨基酸序列的免疫球蛋白轻链可变域；
(iii)抗原结合位点，其包括包含SEQ ID NO:87的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:88的氨基酸序列的免疫球蛋白轻链可变域；
(iv)抗原结合位点，其包括包含SEQ ID NO:89的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:90的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含SEQ ID NO:91的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:92的氨基酸序列的免疫球蛋白轻链可变域；
(vi)抗原结合位点，其包括包含SEQ ID NO:93的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:94的氨基酸序列的免疫球蛋白轻链可变域；
(vii)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:94的氨基酸序列的免疫球蛋白轻链可变域；
(viii)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:96的氨基酸序列的免疫球蛋白轻链可变域；
(ix)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(x)抗原结合位点，其包括包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(xi)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:99的氨基酸序列的免疫球蛋白轻链可变域；
或
(xii)抗原结合位点，其包括包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:96的氨基酸序列的免疫球蛋白轻链可变域。
在本发明的结合分子之一优选实施方案中，至少一个特异性结合于CDH17的抗原结合位点为选自由抗原结合位点(i)至(ii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:100的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:101的氨基酸序列的免疫球蛋白轻链可变域；
及
(ii)抗原结合位点，其包括包含SEQ ID NO:102的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:103的氨基酸序列的免疫球蛋白轻链可变域。
在本发明的结合分子之一优选实施方案中，至少一个特异性结合于CD3的抗原结合位点为选自由抗原结合位点(i)至(xxxi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(ii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:46(CDR3)的氨基酸序列的轻链CDR；
(iii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(iv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:49(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:50(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(v)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(vi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:49(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(vii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:53(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(viii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:55(CDR1)、SEQ IDNO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(ix)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:56(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(x)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:58(CDR2)及SEQ ID NO.:59(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:60(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xiii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ IDNO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xiv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:63(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:56(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xvi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xvii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:64(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xviii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:69(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xix)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:72(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xx)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:73(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:73(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxiii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:75(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxiv)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:69(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxv)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:76(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxvi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxvii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:78(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxviii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:79(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:80(CDR1)、SEQID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxix)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:81(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxx)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:79(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:80(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
及
(xxxi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:81(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR。
在本发明的结合分子之一优选实施方案中，至少一个特异性结合于CD3的抗原结合位点为选自由抗原结合位点(i)至(xvi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:104的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:105、SEQ ID NO:106、SEQ ID NO:107、SEQ ID NO:109、SEQID NO:114、SEQ ID NO:115、SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:123及SEQ ID NO:129组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(ii)抗原结合位点，其包括包含SEQ ID NO:110的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:111的氨基酸序列的免疫球蛋白轻链可变域；
(iii)抗原结合位点，其包括包含SEQ ID NO:112的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:113的氨基酸序列的免疫球蛋白轻链可变域；
(iv)抗原结合位点，其包括包含SEQ ID NO:118的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:119及SEQ ID NO:122组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含SEQ ID NO:124的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:125、SEQ ID NO:126及SEQ ID NO:127组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含选自由SEQ ID NO:128及SEQ ID NO:130组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:127的氨基酸序列的免疫球蛋白轻链可变域；
(vi)抗原结合位点，其包括包含SEQ ID NO:131的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:132的氨基酸序列的免疫球蛋白轻链可变域；
(vii)抗原结合位点，其包括包含SEQ ID NO:133的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:134及SEQ ID NO:135组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(viii)抗原结合位点，其包括包含SEQ ID NO:136的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:137的氨基酸序列的免疫球蛋白轻链可变域；
(ix)抗原结合位点，其包括包含选自由SEQ ID NO:138及SEQ ID NO：156组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:139的氨基酸序列的免疫球蛋白轻链可变域；
(x)抗原结合位点，其包括包含选自由SEQ ID NO:140、SEQ ID NO:142、SEQ IDNO:143及SEQ ID NO:161组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:141的氨基酸序列的免疫球蛋白轻链可变域；
(xi)抗原结合位点，其包括包含选自由SEQ ID NO:144及SEQ ID NO:146组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:145的氨基酸序列的免疫球蛋白轻链可变域；
(xii)抗原结合位点，其包括包含选自由SEQ ID NO:147、SEQ ID NO:151、SEQ IDNO:153及SEQ ID NO:162组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:148的氨基酸序列的免疫球蛋白轻链可变域；
(xiii)抗原结合位点，其包括包含选自由SEQ ID NO:149及SEQ ID NO:152组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:150的氨基酸序列的免疫球蛋白轻链可变域；
(xiv)抗原结合位点，其包括包含SEQ ID NO:154的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:155的氨基酸序列的免疫球蛋白轻链可变域；
(xv)抗原结合位点，其包括包含SEQ ID NO:157的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:158的氨基酸序列的免疫球蛋白轻链可变域；及
(xvi)抗原结合位点，其包括包含SEQ ID NO:159的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:160的氨基酸序列的免疫球蛋白轻链可变域。
在本发明的结合分子的一个优选实施方案中，结合分子为经修饰的免疫球蛋白(Ig)分子，优选经修饰的IgG分子，其中该至少一个特异性结合于TROP2的抗原结合位点及该至少一个特异性结合于CDH17的抗原结合位点存在于该Ig分子的可变区，且其中该至少一个特异性结合于CD3的抗原结合位点为与该TROP2-CDH17特异性Ig分子融合的scFv。
在本发明的结合分子的一个优选实施方案中，scFv与Ig分子的重链的C端融合，优选与包含至少一个特异性结合于CDH17的抗原结合位点的Ig分子的部分的重链融合。
在本发明的结合分子之一优选实施方案中，结合分子包含：(a)选自(a-i)至(a-xii)的第一免疫球蛋白轻链及免疫球蛋白重链组合，优选通过肽接头连接在一起：
(a-i)包含SEQ ID NO:169的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:170的氨基酸序列的免疫球蛋白重链；
(a-ii)包含SEQ ID NO:171的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:172的氨基酸序列的免疫球蛋白重链；
(a-iii)包含SEQ ID NO:173的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:174的氨基酸序列的免疫球蛋白重链；
(a-iv)包含SEQ ID NO:175的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:176的氨基酸序列的免疫球蛋白重链；
(a-v)包含SEQ ID NO:177的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:178的氨基酸序列的免疫球蛋白重链；
(a-vi)包含SEQ ID NO:179的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:180的氨基酸序列的免疫球蛋白重链；
(a-vii)包含SEQ ID NO:181的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:182的氨基酸序列的免疫球蛋白重链；
(a-viii)包含SEQ ID NO:183的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:184的氨基酸序列的免疫球蛋白重链；
(a-ix)包含SEQ ID NO:185的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:186的氨基酸序列的免疫球蛋白重链；
(a-x)包含SEQ ID NO:187的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:188的氨基酸序列的免疫球蛋白重链；
(a-xi)包含SEQ ID NO:189的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:190的氨基酸序列的免疫球蛋白重链；或
(a-xii)包含SEQ ID NO:191的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:192的氨基酸序列的免疫球蛋白重链；
及(b)选自(b-i)至(b-ii)的第二免疫球蛋白重链及免疫球蛋白轻链组合，优选通过肽接头连接在一起：
(b-i)包含SEQ ID NO:196的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:197的氨基酸序列的免疫球蛋白重链；或
(b-ii)包含SEQ ID NO:198的氨基酸序列的免疫球蛋白重链及包含SEQ ID NO:199的氨基酸序列的免疫球蛋白轻链；
及(c)包含选自由SEQ ID NO:222至264组成的组的氨基酸序列的单链可变片段(scFv)，优选连接于该第二免疫球蛋白重链及免疫球蛋白轻链组合的该免疫球蛋白重链的C端。
在本发明的结合分子之一优选实施方案中，结合分子包含以下或由以下组成：
(a-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(b-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(c-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(d-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(e-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(f-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(g-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(h-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(i-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(j-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:427的氨基酸序列；(j-xi)SEQID NO.:216的氨基酸序列及SEQ ID NO.:427的氨基酸序列；(j-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:427的氨基酸序列；或(k)SEQ ID NO.:436的氨基酸序列及SEQ IDNO.:437的氨基酸序列。
本发明的另一方面提供一种结合分子，其包含以下或由以下组成：
(a-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-ii)SEQID NO.:207的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-iv)SEQ ID NO.:209的氨基酸序列及SEQ IDNO.:267的氨基酸序列；(a-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-vii)SEQ IDNO.:212的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-ix)SEQ ID NO.:214的氨基酸序列及SEQ IDNO.:267的氨基酸序列；(a-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(a-xii)SEQ IDNO.:217的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(b-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-v)SEQ IDNO.:210的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-vii)SEQ ID NO.:212的氨基酸序列及SEQ IDNO.:268的氨基酸序列；(b-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-x)SEQID NO.:215的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-xii)SEQ ID NO.:217的氨基酸序列及SEQ IDNO.:268的氨基酸序列；(c-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-iii)SEQ IDNO.:208的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-viii)SEQ IDNO.:213的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(d-i)SEQ IDNO.:200的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-iii)SEQ ID NO.:208的氨基酸序列及SEQ IDNO.:270的氨基酸序列；(d-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-vi)SEQ IDNO.:211的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(e-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(f-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(g-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(h-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(i-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(j-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:427的氨基酸序列；或
(k)SEQ ID NO.:436的氨基酸序列及SEQ ID NO.:437的氨基酸序列。
本发明进一步关于一种核酸分子，其编码本发明的结合分子或其一部分。本发明进一步关于一种表达载体，其包含一种或多种本发明的核酸分子。本发明进一步关于一种宿主细胞，其经本发明的表达载体转染。
本发明进一步关于一种产生本发明的结合分子的方法，该方法包含以下步骤：
(a)在允许根据技术方案1至11中任一项的结合分子表达的条件下培养技术方案12的宿主细胞；
(b)任选回收该分子；及任选地
(c)进一步纯化和/或修饰和/或调配该结合分子。
本发明进一步关于一种药物组合物，其包含一种或多种本发明的结合分子及任选选用的药学上可接受的载剂或由其组成。
本发明进一步关于用于药物中的本发明的结合分子或本发明的药物组合物。本发明进一步关于本发明的结合分子或本发明的药物组合物，其用于治疗、改善或预防癌症的方法中。
本发明进一步关于一种治疗、预防或改善癌症的方法，其包含向有需要的患者施用治疗有效量的本发明的结合分子或本发明的药物组合物。
本发明进一步关于本发明的结合分子用于制备供治疗、预防或改善癌症的药物组合物的用途。
在本发明的结合分子或本发明的药物组合物或本发明的方法或本发明的用途的一个优选实施方案中，癌症为大肠直肠癌(CRC)、胃癌(GC)或胰腺癌(PAC)。
在本发明的结合分子或本发明的药物组合物或本发明的方法或本发明的用途的一个优选实施方案中，结合分子将与免疫检查点抑制剂、优选抗PD-1或抗PD-1-L1抗体组合使用。
附图简要说明
图1：CDH17及Trop2在GI癌组织上共表达，但不在正常组织上共表达。肿瘤及关键正常组织中的基因表达。标度为MAS5正规化的表达值的经log2转换的任意单位。轴标记为基因符号(TACSTD2.202286_s_at＝Trop2，CDH17.209847_at＝CDH17)及Affymetrix探针组。
图2：证实GI肿瘤中的目标表达。在选定人类癌症组织上使用结合于Trop2(ENZ-ABS380，Enzo)及CDH17(760-4865，Roche Ventana)的抗体的免疫组织化学。
图3：本发明的示例性三特异性结合分子的示意图。
图4：选择具有亲和力潜能的CDH17结合剂。通过流动式细胞测量术测试，所示四种不同CDH17结合蛋白(二价与单价形式)结合于重组表达人类CDH17的HEK293细胞株。抗TNP结合臂为针对四硝基酚的不相关(非结合)对照。
图5：证实具有三特异性形式的CDH17结合剂的亲和力潜能。在仅表达CDH17(左图)或共表达Trop2/CDH17(右图)的HEK293细胞存在下具有不同CDH17抗原结合位点的Trop2/CDH17/CD3分子介导的CD8+T细胞上的T细胞活化标记物CD69的上调。
图6：选择具有亲和力潜能的Trop2结合剂。通过流动式细胞测量术测试，所示七种不同Trop2结合剂(二价与单价形式)结合于重组表达人类Trop2的HEK293细胞株。抗TNP结合臂为针对四硝基酚的不相关(非结合)对照。
图7：证实具有三特异性形式的Trop2结合剂的亲和力潜能。在仅表达CDH17(C)、仅表达Trop2(B)或共表达Trop2/CDH17(A)的HEK293细胞存在下具有不同CDH17抗原结合位点的Trop2/CDH17/CD3分子介导的CD8+T细胞上的T细胞活化标记物CD69的上调。
图8：在细胞结合分析中分析各种三特异性Trop2/CDH17/CD3结合剂组合的亲和力潜能。通过流动式细胞测量术测试，具有三特异性形式的Trop2与CDH17结合剂的不同组合结合于重组表达人类Trop2(A)或共表达人类Trop2及CDH17(B)的HEK293细胞株。抗TNP结合臂为针对四硝基酚的不相关(非结合)对照。
图9：表达CDH17、Trop2或共表达两者的细胞中介导T细胞诱导的溶解的效力。使用各种Trop2/CDH17/CD3结合剂(A中展示一种示例性Trop2/CDH17/CD3结合剂)以及单价或二价结合于仅一个目标的各种对照分子评估重组表达CDH17(左)、Trop2(中)或两者(右)的HEK293细胞的重新引导的T细胞介导的溶解(A)。使用不同Trop2/CDH17/CD3结合剂组合以及单价Trop2结合对照评估仅表达Trop2(左)或表达CDH17与Trop2两者(右)的DLD-1来源细胞株的重新引导的T细胞介导的溶解(B)。
图10：证实CDH17结合对亲和力诱导的效力增加的影响。使用不同Trop2/CDH17/CD3分子以及Trop2/TNP/CD3对照分子评估SK-CO1细胞的重新引导的T细胞介导的溶解。
图11：杵-臼形式比较。使用具有两种不同杵-臼形式的三特异性分子评估SK-CO1细胞的重新引导的T细胞介导的溶解。图例中的括号中的参考“臼”或“杵”指示CDH17/CD3臂的定位，即“臼”指示CDH17/CD3在臼臂上(参见SEQ ID No:271、272及424至427)，而“杵”指示CDH17/CD3在杵臂(参见SEQ ID No:428至433)上。
图12：证实体内的肿瘤生长抑制。不同Trop2/CDH17/CD3结合剂以及单价对照结合剂对人源化小鼠模型中HPAF-II来源的异种移植物肿瘤的生长的作用。
具体实施方式
在本说明书中，引用多个文献，包括专利申请案及制造商手册。尽管认为与本发明专利性不相关，但这些文献的公开内容在此以全文引用的方式并入本文中。更特定而言，所有参考文献均以引用的方式并入，其并入程度如同各个别文献经特定且个别指示以引用的方式并入一般。
定义
本发明的上文概述的方面以及本发明的其他方面及实施方案将自本文中的进一步描述变得清楚，其中：
a)本领域技术人员将清楚，除非另外指示或定义，否则所用全部术语均具有其在本领域的常用含义。倘若有冲突，将以专利说明书(包括定义)为准。
例如参考标准手册，诸如Sambrook等人,“Molecular Cloning:A LaboratoryManual”(第2版),第1-3卷,Cold Spring Harbor Laboratory Press(1989)；Lewin,“GenesIV”,Oxford University Press,New York,(1990)及Roitt等人,“Immunology”(第2版),Gower Medical Publishing,London,New York(1989)，以及本文中所引用的一般背景技术。此外，本领域技术人员将清楚，除非另外指示，否则所有未特定详细描述的方法、步骤、技术及操作可以本身已知的方式进行且已以本身已知的方式进行。例如再次提及标准手册及上文提及的一般背景技术及其中所引用的其他参考文献。
b)除非另外指示或定义，否则术语“抗体”根据本领域的定义使用。抗体通常为免疫球蛋白(缩写为Ig)，优选为γ球蛋白(IgG；亦进一步参见下文)。可在脊椎动物的血液或其他体液中发现天然存在的抗体，其中免疫系统使用所述抗体来鉴别及中和异物，诸如细菌及病毒，该功能由其与称为抗原的其他分子或结构通过非共价相互作用进行的结合所介导。此结合为特异性的，意为抗体将仅以高亲和力结合于特异性结构。由抗体识别的抗原的独特部分称为抗原决定基或抗原决定子。
天然存在的抗体(包括例如经典Y形免疫球蛋白分子)通常由基础结构单元制成：各具有两条大的重链及两条小的轻链，或如骆驼科物种或软骨鱼中，仅具有两条重链(即，分别为VHH及VNAR片段)，且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。各条重链在N端处具有可变域(VH)，之后为三个或四个(就IgE而言)恒定域(CH1、CH2、CH3及CH4)，以及在CH1与CH2之间的铰链区。各条轻链具有两个域：N端可变域(VL)及C端恒定域(CL)。介导与抗原决定基的结合的抗体部分有时称为互补位且存在于抗体的可变域或可变区(Fv)中。可变域包含三个所谓互补决定区(CDR)，所述CDR由构架区(FR)隔开。构架区采用β-折叠构象，且CDR可形成连接β-折叠结构的环。各条链中的CDR通过构架区保持其三维结构且通常与来自其他链(若存在/当存在时)的CDR一起介导与抗原的结合。如本申请案中使用的术语“恒定域”或“恒定区”表示抗体除可变区以外的域的总和。此类恒定域及恒定区为目前先进技术所熟知且例如由Kabat等人(“Sequence of proteinsof immunological interest”,US Public Health Services,NIH Bethesda,MD,公开案第91号)描述。
抗体的“Fc部分”不直接参与抗体与抗原的结合，但展现各种效应功能。“抗体的Fc部分”为本领域技术人员熟知的术语且基于抗体的木瓜蛋白酶裂解而定义。视重链的恒定区的氨基酸序列而定，抗体或免疫球蛋白分成以下类别：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。这些中的若干者可进一步分成子类(同型)，例如IgG1、IgG2、IgG3及IgG4、IgA1及IgA2。基于补体活化、C1q结合及Fc受体结合，抗体的Fc部分直接参与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(complement activation；CDC)通过补体因子C1q与大多数IgG抗体子类的Fc部分的结合来启动。虽然抗体对补体系统的影响视某些条件而定，但C1q结合为由Fc部分内的界定结合位点引起。此类结合位点为目前先进技术所已知且例如描述于Kellner等人Transfus Med Hemother.44(5)(2017)327-336。此类结合位点的非限制性实施例为例如L234、L235、D270、N297、E318、K320、K322、P331及P329(根据Kabat的EU索引编号)。在IgG1中这些残基中介导C1q及Fcγ受体结合最关键的残基为L234及L235(Hezareh等人,J.Virology 75(2001)12161-12168)。子类别抗体IgG1及IgG3通常显示补体活化及C1q及C3结合，而IgG2及IgG4不活化补体系统且不结合C1q及C3。
如本文所用，术语“抗体”亦包括保留抗原结合特性的免疫球蛋白片段，如Fab、Fab'或F(ab')2片段。此类片段可通过免疫球蛋白的片段化，例如通过蛋白水解消化，或通过此类片段的重组表达来获得。举例而言，免疫球蛋白消化可借助于常规技术，例如使用木瓜蛋白酶或胃蛋白酶(WO 94/29348)实现。抗体的木瓜蛋白酶消化通常产生两个一致抗原结合片段，所谓Fab片段，各自具有单个抗原结合位点；及残余Fc片段。胃蛋白酶处理产生F(ab')2。在Fab分子中，可变域各自与优选地人类来源的免疫球蛋白恒定域融合。因此，重链可变域可与CH1域(所谓Fd片段)融合，且轻链可变域可与CL域融合。此类分子可通过使用本领域已知的方法在宿主细胞中重组表达各别核酸来产生。
本领域已描述大量用于修饰天然存在的抗体以及用于在不同分子背景下置放免疫球蛋白的可变域或源自此类可变域的分子的方法，参见例如Holliger,P.,Hudson,P.NatBiotechnol 23,1126-1136(2005)或Nilvebrant,J.等人Current pharmaceutical design第22卷,43(2016):6527-6537。通常，这些修饰旨在使抗体成为在药物及技术中更通用的工具。这些方法产生结构上经修饰的分子，在本文中也称为“抗体衍生物”或“经修饰的免疫球蛋白”，所述分子通常不同于天然存在的抗体的基础组成(即，由两条大的重链及两条小的轻链组成或如骆驼科物种或软骨鱼中仅由两条重链组成的抗体)。通常，与天然存在的抗体相比，这些分子的尺寸较小，且可包含单一氨基酸链或若干氨基酸链。例如，单链可变片段(scFv)为免疫球蛋白的重链及轻链的可变区的融合，用短接头，通常丝氨酸(S)或甘氨酸(G)连接在一起(参见例如WO 88/01649；WO 91/17271)。“单域抗体”或在单一Ig域中具有抗原结合位点(参见例如WO 94/04678；WO 03/050531)。对相同或不同抗原具有结合特异性的单域抗体可连接在一起。双功能抗体为由包含两个可变域的两条氨基酸链组成的二价抗体分子(WO 94/13804)。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)。不同概念产生所谓小模块免疫药物(SMIP)，其包含Fv域连接于单链铰链及效应域，缺乏恒定域CH1(WO 02/056910)。然而，在一些情况下，修饰亦可产生大于天然存在的抗体的分子，例如当经典Ig形式与额外抗原结合位点组合时，例如具有scFv形式等。如本文所使用，更通用的术语“抗体”亦涵盖所有此类抗体衍生物或经修饰的免疫球蛋白。
因为对于在人中的应用，常常需要降低最初源自其他物种、如小鼠的抗体的免疫原性，所以已开发出改良方法，如构筑嵌合抗体或所谓抗体“人源化”。在此背景下，“嵌合抗体”应理解为包含来源于一种物种(例如小鼠)的序列部分(例如可变域)与来源于不同物种(例如人类)的序列部分(例如恒定域)融合的抗体。“人源化抗体”为包含最初来源于非人类物种的可变域的抗体，其中已使某些氨基酸突变，使得可变域的总序列更近似于人类可变域的序列。抗体嵌合及人源化的方法为本领域所熟知(Billetta R,Lobuglio AF.“Chimeric antibodies”.Int Rev Immunol.1993；10(2-3):165-76；Riechmann L,ClarkM,Waldmann H,Winter G(1988).“Reshaping human antibodies for therapy”.Nature:332:323.)。如本文所用，术语“人类抗体”是指基于来源于人类基因组的序列，例如通过噬菌体呈现或使用转殖基因动物建立的抗体(参见例如WO 90/05144)。如本文所用，术语“抗体”明确包括此类人源化抗体、嵌合抗体以及人类抗体。
抗体可进一步经融合(为融合蛋白)或者连接(通过共价键或非共价键)至对抗体特性具有期望影响的其他分子实体。例如，可能需要改善抗体分子的药物动力学特性，例如在诸如血液的体液中的稳定性，尤其在单链抗体或域抗体的情况下。关于此，特别是为延长此类抗体的循环半衰期，已研发出大量技术，诸如聚乙二醇化(WO 98/25971；WO 98/48837；WO 2004081026)，抗体与对如白蛋白的血清蛋白具有亲和力的另一抗体融合或共价附接(WO 2004041865；WO 2004003019)，或抗体表达为与如白蛋白或运铁蛋白的血清蛋白的全部或部分的融合蛋白(WO 01/79258)。用于抗体设计中的主要鉴别及主要优化的手段及方法为本领域所熟知且已例如评述于Goulet,D.R.及Atkins,W.M.J Pharm Sci2020；109(1):74-103或Tiller,K.E.及Tessier,P.M.(2015).Annual review of biomedicalengineering,17,191-216。
c)亦已开发“抗体模拟物”，其通常仅与免疫球蛋白可变域具有遥远的结构关系，或毫无此类关系，但显示与免疫球蛋白可变域相当之一定结合特异性及亲和力。此类非免疫球蛋白“抗体模拟物”有时称为“支架蛋白”，可例如基于蛋白A、脂质运载蛋白、纤维结合蛋白域、锚蛋白共同重复域及硫化还原蛋白的基因(Skerra,Current Opinion inBiotechnology 2007,18(4):295-304)。
d)如本文所用，术语“免疫球蛋白可变域”意为基本上由四个“构架区”组成的免疫球蛋白域，所述“构架区”在本领域且在下文中分别称为“构架区1”或“FR1”；“构架区2”或“FR2”；“构架区3”或“FR3”；及“构架区4”或“FR4”；所述构架区间杂有三个“互补决定区”或“CDR”，所述“互补决定区”在本领域且在下文中分别称为“互补决定区1”或“CDR1”；“互补决定区2”或“CDR2”；及“互补决定区3”或“CDR3”。因此，免疫球蛋白可变域的通用结构或序列可如下表示：FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。免疫球蛋白可变域通过携载抗原结合位点而赋予抗体对抗原的特异性。
e)可“结合”、“结合于”、“特异性结合”或“特异性结合于”一定抗原决定基、抗原或蛋白质(或其至少一个部分、片段或抗原决定基)、“对其具有亲和力”和/或“对其具有特异性”的分子(诸如本发明的结合分子或其片段)称为“抗”或“针对”该抗原决定基、抗原或蛋白质，或涉及此类抗原决定基、抗原或蛋白质的“结合”分子。
f)如本文所用，术语“抗原结合位点”是指赋予与特定抗原的结合的结合分子的域。抗原结合位点最初来源于抗体，不过此领域中的发展已使得在不需要产生针对所关注的目标的天然存在的抗体下亦可设计和/或获得抗原结合位点。无论来源如何，根据本发明的“抗原结合位点”至少包含允许与其特定目标抗原结合的最小结构组件，即必需及足够结构组件。因此，根据本发明的“抗原结合位点”包含至少三个重链CDR序列(在单域抗体的情况下)，更优选至少三个轻链及三个重链CDR序列。如上文所论述，这些CDR通常存在于抗体的所谓可变域或可变区(Fv)中。应了解，尽管抗原结合位点至少包含最小结构组件，但其通常涵盖额外组件(诸如例如构架区)。因此，如根据本发明所用，抗原结合位点亦可经由重链可变域与轻链可变域的各别组合的序列界定。根据本发明，尤其优选地，“抗原结合位点”包含于多肽中和/或所述CDR或所述可变域中的各者为多肽或肽。
g)术语结合分子或抗原结合位点的“特异性结合”可描述根据其交叉反应性来描述。优选地，本发明的结合分子的抗原结合位点不与或基本上不与不同于目标抗原但结构类似于目标抗原的抗原决定基交叉反应。优选地，“特异性结合于”是指抗原结合位点不结合于与特定叙述的目标，即分别抗原TROP2、CDH17及CD3具有小于65％、优选小于70％、小于75％、小于80％、小于85％、小于90％、小于95％且最佳小于98％一致性(使用本领域已知的方法计算)的目标。所研究之一组分子的交叉反应性可例如通过评估该组分子在常规条件下与所关注的抗原决定基以及与多个大体上(结构上和/或功能上)紧密相关的抗原决定基的结合来测试。仅认为那些与相关背景下所关注的抗原决定基(例如蛋白质结构中的特定模体)结合但不结合于或基本上不结合于任何其他抗原决定基的分子特异性结合。对应方法描述于教科书文献以及例如Brooks BD.Curr Drug Discov Technol.2014年6月；11(2):109-12或Abdiche YN等人,PLoS One.2014年3月20日；9(3):e92451。
然而，“特异性”亦可根据其亲和力和/或亲和力来描述或说明。
由抗原与结合分子的解离平衡常数(Kd)表示的亲和力为抗原决定基与结合分子上的抗原结合位点之间的结合强度的量度：Kd值愈小，抗原决定基与结合分子之间的结合强度愈强(或者，亲和力亦可表示为亲和力常数(Ka)，其为1/Kd)。
尤其优选地，特异性结合于其目标的抗原结合位点对各别目标，即抗原TROP2、CDH17或CD3的结合亲和力显著高于结构上不相关的分子。因此，TROP2的抗原结合位点对TROP2的结合亲和力显著高于任何其他结构上不相关的分子；CDH17的抗原结合位点对CDH17的结合亲和力显著高于任何其他结构上不相关的分子；且CD3的抗原结合位点对CD3的结合亲和力显著高于任何其他结构上不相关的分子。根据本发明，若在一致条件下抗原结合位点与其目标抗原的结合亲和力比对不相关抗原的亲和力大至少两倍、优选大至少十倍、更优选大至少20倍且最佳大至少100倍，则认为该抗原结合位点对该目标抗原具有显著较高结合亲和力。
优选结合亲和力视结合分子而变化，但包括解离常数(Kd)为至少10E-4摩尔/升或更低的结合分子，例如经由本领域已知的任何标准方法，优选经由下文及随附实施例中所述的Biacore分析量测。一般认为大于10E-4M的任何Kd值指示非特异性结合。优选地，抗原结合位点将以小于500nM、优选小于200nM、更优选小于100nM且最佳小于20nM的Kd特异性结合于期望抗原。对于某些结合剂，诸如本文所述的CD3的抗原结合位点，且除非本文中另外定义，否则优选地，解离常数(Kd)小于10nM，更优选小于5nM且甚至更优选小于2nM。
亲和力为结合分子(诸如本发明的结合分子或其片段)与相关抗原之间的结合强度的量度。亲和力与抗原决定基与结合分子上的其抗原结合位点之间的亲和力及结合分子上存在的相关结合位点数目两者有关。
如本领域技术人员清楚的(例如基于本文中的进一步公开内容)，可使用本领域本身已知的手段及方法测定特异性结合，视所关注的特定相关抗原而定。此类手段及方法包括不限于史卡查分析(Scatchard analysis)和/或竞争结合分析，诸如放射免疫分析(RIA)、酶免疫分析(EIA)及夹心竞争分析，及等离子共振分析(Malmqvist M.,Curr OpinImmunol.1993年4月；5(2):282-6.)，利用例如经纯化的野生型抗原。亦可使用动力学排除分析(KinExA)技术(Darling,R.J.及Brault P-A.,ASSAY and Drug DevelopmentTechnologies.2004年12月2(6):647-657)来量测抗体亲和力。优选地，特异性结合通过等离子共振分析，利用经纯化的野生型抗原来测定。更优选地，用于测定Kd值的方法为基于Biacore分析，如例如以下实施例3.2中所描述。因此，优选地，本文所提及的任何Kd值为在Biacore 4000上经由表面等离子共振(SPR)获得的Kd值，其中所关注的结合分子经由蛋白A/G捕捉至传感器表面上，在10μl/min下持续60秒，接着各别目标分子(例如人类Trop2、CDH17或CD3)优选以100nM的浓度施加，在30μl/min下缔合180秒，接着在HBS-EP缓冲液中解离120秒。
h)如本领域通常已知且同意的，将根据标准三字母或单字母氨基酸代码指示氨基酸残基。当比较两个氨基酸序列时，术语“氨基酸差异”是指相较于第二序列，在参考序列的某一位置处插入、缺失或取代指定数目个氨基酸残基。在取代的情况下，该取代将优选为保守氨基酸取代，此意为氨基酸残基经具有相似化学结构的另一氨基酸残基取代，且几乎不会或基本上不会对多肽的功能、活性或其他生物特性造成影响。此类保守氨基酸取代为本领域所熟知，例如WO 98/49185，其中保守氨基酸取代优选为以下组(i)-(v)内的一个氨基酸经同一组内的另一个氨基酸残基取代的取代：(i)小型脂族、非极性或略微极性残基：Ala、Ser、Thr、Pro及GIy；(ii)极性、带负电荷的残基及其(不带电荷)的酰胺：Asp、Asn、GIu及GIn；(iii)极性、带正电荷的残基：His、Arg及Lys；(iv)大型脂族、非极性残基：Met、Leu、Ile、VaI及Cys；及(v)芳族残基：Phe、Tyr及Trp。尤其优选的保守氨基酸取代如下：
Ala取代成GIy或取代成Ser；
Arg取代成Lys；
Asn取代成GIn或取代成His；
Asp取代成GIu；
Cys取代成Ser；
GIn取代成Asn；
GIu取代成Asp；
GIy取代成Ala或取代成Pro；
His取代成Asn或取代成GIn；
Ile取代成Leu或取代成VaI；
Leu取代成Ile或取代成VaI；
Lys取代成Arg、取代成GIn或取代成GIu；
Met取代成Leu、取代成Tyr或取代成Ile；
Phe取代成Met、取代成Leu或取代成Tyr；
Ser取代成Thr；
Thr取代成Ser；
Trp取代成Tyr；
Tyr取代成Trp或取代成Phe；
VaI取代成Ile或取代成Leu。
i)如本文所用，术语“分离”是指物质脱离其原始或原生环境(例如天然环境(若其为天然存在的))。例如，活动物中存在的天然存在的核酸分子或多肽未经分离，但通过人为干预与天然系统中的共同存在的材料中的一些或全部分离的相同核酸分子或多肽为经分离的。此类核酸分子可为载体的一部分和/或此类核酸分子或多肽可为组合物的一部分，且仍为经分离的，这是因为此类载体或组合物不为核酸分子或多肽天然存在的环境的一部分。举例而言，当与核酸分子或多肽所获自的天然生物来源和/或反应介质或培养介质相比，该核酸分子或多肽已与在该来源或培养基中通常相关联的至少一种其他组分，诸如另一核酸分子、另一多肽、另一生物组分或大分子或至少一种污染物、杂质或次要组分分离时，该核酸分子或多肽视为“(具有)基本上分离(形式)”。详言之，当以至少2倍，尤其至少10倍、更尤其至少100倍且高达1000倍或更大程度纯化核酸分子或多肽时，其视为“基本上分离”的。使用合适技术，诸如合适色谱技术，诸如聚丙烯酰胺-凝胶电泳测定，“具有基本上分离形式”的核酸分子或多肽优选为基本上均质的。本发明的结合分子及核酸优选经分离。
j)除非另外指示，否则如本文所用，术语“序列”(例如，在如“免疫球蛋白序列”、“结合分子序列”或“多肽序列”的术语中)通常应理解为包括相关氨基酸序列，以及编码其的核酸序列或核苷酸序列，除非上下文需要更具限制性的解释。
k)在两种或更多种核酸或多肽序列的情况下，如本文所用，术语“一致”或“一致性百分比”是指当出于最大对应性进行比较及比对时相同或具有指定百分比的相同核苷酸或氨基酸残基的两种或更多种序列或子序列。为确定一致性百分比，出于最佳比较目的而比对序列(例如，可在第一氨基酸或核酸序列的序列中引入间隙以与第二氨基酸或核酸序列最佳比对)。接着比较对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与第二序列中的相应位置由相同氨基酸残基或核苷酸残基占据，则分子在该位置处一致。两个序列之间的一致性百分比为所述序列共有的一致位置数的函数(即，一致性％＝一致位置数/位置总数(例如重叠位置)×100)。在一些实施方案中，适当时，在序列内引入间隙之后，进行比较的两个序列长度相同(例如不包括延伸超过比较序列的额外序列)。举例而言，当比较可变区序列时，不考虑前导和/或恒定域序列。对于两个序列之间的序列比较，“对应”CDR是指两个序列中相同位置的CDR(例如各序列的CDR-H1)。
可使用数学算法测定两个序列之间的一致性百分比或相似性百分比。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.USA 87:2264-2268的算法，修改为Karlin及Altschul,1993,Proc.Natl.Acad.Sci.USA90:5873-5877。将此类算法并入Altschul等人,1990,J.Mol.Biol.215:403-410的NBLAST及XBLAST程序中。BLAST核苷酸检索可用NBLAST程序(得分＝100，字长＝12)进行以获得与编码所关注蛋白质的核酸同源的核苷酸序列。BLAST蛋白质检索可用XBLAST程序(得分＝50，字长＝3)进行以获得与所关注蛋白质同源的氨基酸序列。为实现间隙比对以达成比较目的，可如Altschul等人,1997,Nucleic Acids Res.25:3389-3402中所述使用间隙BLAST。替代地，PSI-Blast可用于进行检测分子间的远缘关系的叠代检索(同上)。利用BLAST、间隙BLAST及PSI-Blast程序时，可使用各别程序(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。将此类算法并入ALIGN程序(版本2.0)中，该程序为GCG序列比对软件包的部分。当利用ALIGN程序来比较氨基酸序列时，可使用PAM120权重残基表、间隙长度罚分12及间隙罚分4。用于序列分析的额外算法为本领域所已知且包括如Torellis及Robotti,1994,Comput.Appl.Biosci.10:3-5中所描述的ADVANCE及ADAM；及Pearson及Lipman,1988,Proc.Natl.Acad.Sci.USA 85:2444-8中描述的FASTA。在FASTA内，ktup为设定检索的敏感性及速度的控制选项。若ktup＝2，则通过观察比对残基对发现两个比较序列中的相似区域；若ktup＝1，则检查单一比对氨基酸。对于蛋白质序列，ktup可设定为2或1，或对于DNA序列设定为1至6。若ktup未规定，则对于蛋白质默认值为2，且对于DNA为6。或者，可使用CLUSTAL W算法进行蛋白质序列比对，如Higgins等人,1996,Methods Enzymol.266:383-402所描述。优选地，使用上述CLUSTAL W算法。
l)如本文所用，术语“包含”表示除特定叙述的组分和/或步骤外可包括的进一步组分和/或步骤。然而，此术语亦涵盖所主张的主题完全由所叙述组分和/或步骤组成。
m)如本文所用，术语“至少”是指包括特定叙述的数目及高于其的任何数目的任何数目。举例而言，“至少一个”涵盖确切一个，以及超过一个，包括不限于两个，诸如(例如)三个或四个。进一步包括例如五个、六个、七个、八个、九个、10个、15个，诸如20个、30个、40个、50个、75个、100个、150个、200个、300个、400个或500个，以及这些特定叙述的数目之间或高于这些数目的任何整数。关于术语“至少一个抗原结合位点”，尤其优选地，该术语涵盖一、二、三或四个抗原结合位点。最佳地，该术语是指确切一个抗原结合位点。在选择超过一个针对目标的抗原结合位点的那些情况下，这些多个抗原结合位点可独立地加以选择，即其可一致或其可彼此不同。
n)如本文所用，术语“多肽”描述含有超过30个氨基酸的线性氨基酸分子链，包括单链多肽或其片段。另一方面，如本发明中所用，术语“肽”描述含有至多30个氨基酸的线性氨基酸链。如根据本发明使用的术语“(多)肽”是指包含由至多30个氨基酸组成的肽的群以及由超过30个氨基酸组成的多肽的群之一组分子。
o)如本文所用，术语“接头”涵盖肽接头，即氨基酸序列，以及非肽接头，其共价或非共价连接分子的个别部分。如本文所用，术语“非肽接头”是指具有两个或更多个反应性基团但排除如下所定义的肽接头的连接基团。举例而言，非肽接头可为在两端具有反应性基团的聚合物，所述反应性基团个别结合于本发明的分子的结合部分的反应性基团，例如氨基端、赖氨酸残基、组氨酸残基或半胱氨酸残基。聚合物的反应性基团包括醛基、丙醛基、丁醛基、顺丁烯二酰亚氨基、酮基、乙烯基砜基、硫醇基、酰肼基、羰基咪唑(CDI)基团、硝苯基碳酸酯(NPC)基团、三氟乙基磺酸酯基(trysylate)、异氰酸酯基及丁二酰亚胺衍生物。丁二酰亚胺衍生物的实施例包括丁二酰亚氨基丙酸酯(SPA)、丁二酰亚氨基丁酸(SBA)、丁二酰亚氨基羧甲基酯(SCM)、丁二酰亚氨基丁二酰胺(SSA)、丁二酰亚氨基丁二酸酯(SS)、丁二酰亚氨基碳酸酯及N-羟基丁二酰亚胺(NHS)。非肽聚合物的两个末端处的反应性基团可相同或不同。举例而言，非肽聚合物可在一个末端具有顺丁烯二酰亚氨基且在另一末端具有醛基。
如本文所设想，肽接头为长度为至少1个氨基酸的(多)肽接头。优选地，接头为1至100个氨基酸长。更优选地，接头为5至50个氨基酸长，更优选10至40个氨基酸长，且甚至更优选地，接头为15至30个氨基酸长。通常使用的小接头的非限制性实施例包括甘氨酸及丝氨酸氨基酸的序列，称为GS微型接头。这些接头中的氨基酸的数目可变化，例如，其可为4个(GGGS)(SEQ ID NO:273)或6个(GGSGGS)(SEQ ID NO:274)，或其倍数，诸如此四个/六个氨基酸的两个或三个或更多个重复序列。最佳地，此类GS微型接头具有20个氨基酸及序列GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:275)。
本领域技术人员应了解，当所关注分子为单一多肽链时，接头为肽接头。
本领域已知，接头的性质，即长度和/或组合物，诸如氨基酸序列，可调节或增加含有接头的分子的稳定性和/或溶解性。通常，接头的长度及序列视各别所关注分子的组成而选择。本领域技术人员十分了解设计及测试不同接头的适合性的方法，参见例如T.等人Protein Engineering,Design and Selection,第14卷,第10期,2001,第815-823页。举例而言，容易通过比较本发明的分子的结合部分的结合亲和力来测试分子的特性。在本发明的三特异性分子的情况下，可分别进行各结合部分的各别量测。可使用基于ELISA的方法测定在人类血清中在37℃下培育若干时段之后分子的残余结合力来量测所得分子的稳定性。其他适合的测试可见于例如Brian R.Miller,B.R.等人Protein Engineering,Design and Selection,第23卷,第7期,2010,第549-557页或Kügler,M.等人ProteinEngineering,Design and Selection,第22卷,第3期,2009,第135-147页。
(p)根据本发明，术语“核酸分子”可在本文中与术语“聚核苷酸”互换使用，包括DNA，诸如(例如)cDNA或基因组DNA，及RNA，例如mRNA。进一步包括本领域已知的核酸模拟分子，诸如(例如)DNA或RNA的合成或半合成衍生物及混合聚合物。根据本发明的此类核酸模拟分子或核酸衍生物包括硫代磷酸酯核酸、氨基磷酸酯核酸、2'-O-甲氧基乙基核糖核酸、N-吗啉基核酸、己糖醇核酸(HNA)及锁核酸(LNA)。LNA为一种RNA衍生物，其中核糖环受2'-氧与4'-碳之间的亚甲基键约束。如本领域技术人员将容易了解，其可含有额外非天然或衍生核苷酸碱基。
本发明的三特异性结合分子
本发明涉及一种结合分子，其包含：(a)至少一个以Kd≥1nM特异性结合于滋养层细胞表面抗原2(TROP2)，优选人类TROP2的抗原结合位点；(b)至少一个以Kd≥10nM，优选以Kd≥100nM特异性结合于钙黏素-17(CDH17)，优选人类CDH17的抗原结合位点；及(c)至少一个特异性结合于分化簇3(CD3)，优选人类CD3的抗原结合位点。
因此，本发明的结合分子(在本文中也称为“本发明的蛋白质”或“本发明的结合剂”)至少包含特定叙述的三个不同抗原结合位点，即至少一个TROP2结合位点、至少一个CDH17结合位点及至少一个CD3结合位点。由于此三种特异性，本发明的结合分子在本文中也称为本发明的“三特异性结合分子”。
如本文所用，术语TROP2是指“滋养层细胞表面抗原2”。TROP2属于肿瘤相关的钙信号转导子(TACSTD)家族且为紧密连接蛋白-7及紧密连接蛋白-1的稳定性所需。人类TROP2由SEQ ID NO:419以及数据库寄存编号UniProt P09758表示。
如本文所用，术语CDH17是指“钙黏素-17”。CDH17为钙依赖性膜相关糖蛋白的钙黏素超家族的一员。编码蛋白质类似于钙黏素，由含有7个钙黏素域的细胞外区及跨膜区组成，但缺乏保守细胞质域。已报导该蛋白质在胃肠道及胰管中表达。人类CDH17由SEQ IDNO:420以及数据库寄存编号UniProt Q12864表示。
如本文所用，术语CD3是指“分化簇3”。CD3为参与活化细胞毒性T细胞(即CD8+未处理T细胞)与T辅助细胞(即CD4+未处理T细胞)的蛋白质复合物及T细胞共受体。CD3由四个独特链构成，其中在哺乳动物中该复合物含有一条CD3γ链、一条CD3δ链及两条CD3ε链。与T细胞受体(TCR)及ζ-链(ζ链)一起，CD3在T淋巴球中产生活化信号。人类CD3中CD3δ链由SEQ IDNo:421以及数据库寄存编号UniProtKB-P04234表示，CD3ε链由SEQ ID No:422以及数据库寄存编号UniProtKB-P07766表示，CD3γ链由SEQ ID No:423以及数据库寄存编号UniProtKB-P09693表示，且CD3ζ链由SEQ ID No:424以及数据库寄存编号UniProtKB-P20963表示。
抗原结合位点的通用结构为本领域所熟知且可为例如单域，诸如抗原决定基结合域、单链Fv(ScFv)域或成对VH/VL域，如上文所论述。在一优选实施方案中，抗原结合位点至少包含轻链可变域及重链可变域。
如关于一般定义所论述，需要抗原结合位点与其各别目标抗原特异性结合。另外，本发明的结合分子的进一步特征在于特异性结合于TROP2及CDH17的抗原结合位点在TROP2情况下及在CDH17情况下分别以不低于1nM的Kd及不低于10nM(优选不低于100nM)的Kd结合。换言之，虽然需要所述抗原结合位点对其目标抗原具有特异性，但并不针对强结合亲和力来选择其，而实际上需要以较低亲和力结合，从而允许仅在两个目标存在下强结合本发明的结合分子。如下文更详细地论述且如实施例(尤其实施例6至8)中所示，发现此两个抗原结合位点对其各别抗原具有降低的亲和力的要求导致单价结合低，但在两个目标存在下由亲和力引起本发明的所得三特异性结合分子的结合增强。尤其优选地，TROP2的抗原结合位点具有1nM与20nM之间、更优选1nM与10nM之间、甚至更优选1nM与4nM之间的Kd。最佳地，特异性结合于TROP2的抗原结合位点具有2nM与5nM之间的Kd。此外，CDH17的抗原结合位点尤其优选具有10nM与200nM之间、更优选50nM与150nM之间、甚至更优选75nM与125nM之间的Kd。最佳地，特异性结合于CDH17的抗原结合位点具有100nM与120nM之间的Kd。优选地，该Kd如上文关于Biacore4000上的SPR所述测定。
根据本发明，对亲和力降低的结合剂的此类要求对于结合于CD3的抗原结合位点而言并非必需的。因此，且如上文中所陈述，对于靶向CD3的抗原结合位点，尤其优选地，结合剂以小于500nM、优选小于200nM、更优选小于10nm的Kd且最佳以小于2nM的Kd结合。特异性结合于CD3的许多抗原结合位点已描述于本领域，例如WO2004106383中，其中描述衍生自选自由以下组成的组的抗体的熟知抗原结合位点：X35-3、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、WT31及F101.01.e，以及SP34。详言之，WO2004106383描述VH及VL区来源于能够在其他TCR次单元的背景下，例如在针对人类CD3-ε链进行转殖基因的小鼠细胞中，特异性识别人类CD3-ε链的抗体/抗体衍生物及其类似物。合适CD3特异性抗原结合位点的进一步非限制性实施例提供于US20180118848、W02011090762(例如CRIS-7、OKT3、HU291、G19-4)、US9782478、US20180118827(SP34修饰)、US20160145340(SP34修饰)、US9212225(例如SP34 CDR的修饰)、US10174124(CD3杂交瘤克隆，包括克隆40G5C及38E4.V1)、US9914776及WO2020127619(SP34修饰)、US7,728,114、US5929212、WO2014047231(基于OKT3或CRIS-7)、WO2004108158(基于OKT3)、WO200703320(CD3克隆28F11、27H5、23F10、15C3)、US10066015(SP34修饰)、WO2018201051(SP34修饰)、WO201911871、US99759662、US20180326058、WO2019131988(包括SP34(mu、hu)、OKT3、UCHT1.v9、UCHT1、v1、UCHT1.vM1、HU40G5C、38E4.V1、抗CD3克隆AN104、AN119、AN121、AN395)、US20180161428、WO2019075378(SP34 CDR变体)、WO2016187594(例如与莫罗单抗(muromonab)-CD3相关的CDRS(OKT3)、奥昔珠单抗(otelixizumab)(TRX4)、替利珠单抗(teplizumab)(MGA031)、维西珠单抗(visilizumab)(Nuvion)、SP34、X35、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、F101.01、UCHT-1及WT-31)、US10066016(SP34CDR变体)、WO20180209298(tritac)或US10544221(SP34 CDR变体)。
本领域技术人员可自本文所述的抗原结合位点，自本领域描述的抗原结合位点(诸如本领域已知的CD3的抗原结合位点，如上文所详述)或自新开发的抗原结合位点选择所叙述目标的抗原结合位点，在各种情况下限制条件为满足上述关于特异性(即，特异性结合各别目标，但对于TROP2及CDH17，限制条件为Kd不过低，如上所定义)的先决条件。上文已提供测试这些要求的手段及方法且可通过本领域技术人员立即应用。
尽管本发明的结合分子的抗原结合位点作为(a)、(b)及(c)列出，但此清单并不意欲规定特定次序或排列。因此，抗原结合位点可以任何次序排列在本发明的结合分子内，诸如(例如)(a)-(b)-(c)、(b)-(c)-(a)、(c)-(a)-(b)、(b)-(a)-(c)等。下文将进一步详述本发明的结合分子内抗原结合位点的优选排列。
重要地，本发明的结合分子能够(实质上)同时结合所有三个目标(TROP2、CDH17及CD3)。因此，假定所有三个目标均存在，本发明的结合分子将结合于其中所有三者，由此充当T细胞接合分子(TcE)：其将结合于T细胞上的CD3，因此，将使T细胞接近表达TROP2与CDH17两者的肿瘤细胞。所关注的结合分子是否能够结合于靶细胞表面上的Trop2及CDH17两者且可诱导T细胞活性可如随附实施例中所描述，例如使用重组HEK293细胞或内源性表达抗原的癌细胞株，诸如大肠直肠癌DLD-1细胞株(已在实施例9中描述两者)来确定。
在一优选实施方案中，本发明的结合分子除特定叙述的TROP2、CDH17及CD3的三个抗原结合位点外不含进一步抗原结合位点。甚至更优选地，本发明的结合分子为三特异性及三价的，即其含有三个抗原目标中的各者的一个结合位点。
本发明的结合分子的形式不受特定限制，限制条件为其至少包含特定叙述的三个不同抗原结合位点(TROP2、CDH17及CD3)且如本文所定义，能够同时(实质上)结合此三个目标。因此，形式可基于天然存在的抗体或抗体衍生物或此类抗体的片段以及抗体模拟物的形式。此类形式可根据需要经修饰以容纳所有三个抗原结合位点，例如通过额外包含另一抗体片段(详言之，Fv、Fab、Fab'或F(ab')2片段)、单链抗体(详言之，单链可变片段(scFv))、小模块免疫药物(SMIP)、域抗体或纳米抗体。可采用的个别或所有抗原结合位点的合适形式的进一步非限制性实施例包括上文所定义的抗体模拟物。
优选地，本发明的结合分子为经修饰的免疫球蛋白(在本文中也称为经修饰的免疫球蛋白分子)。举例而言，在一优选实施方案中，TROP2及CDH17的抗原结合位点存在于具有(经典Y形)免疫球蛋白形式的结合分子的可变区中。在此类形式中，第一组免疫球蛋白轻链及重链在其可变区中含有TROP2的抗原结合位点且第二组免疫球蛋白轻链及重链在其可变区中含有CDH17的抗原结合位点，且两组链彼此例如经由二硫桥连接，形成免疫球蛋白分子。
用于制造此类免疫球蛋白分子的技术为本领域所熟知且包括不限于具有不同特异性的两个免疫球蛋白重链-轻链对的重组共表达(例如Milstein及Cuello,Nature 305:537(1983))、WO 93/08829及Traunecker等人,EMBO J.10:3655(1991))；“杵-臼”工程改造(例如美国专利第5,731,168号)；用于制造抗体Fc-杂二聚体分子的工程静电导向作用(WO2009/089004A1)；两个或更多个免疫球蛋白或片段的交联(例如美国专利第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(参见例如Kostelny等人,Immunol.,148(5):1547-1553(1992))等。本领域技术人员十分了解此类方法，所述方法亦评述于本领域，例如Liu H.等人(2017)Front.Immunol.8:38.doi:10.3389/fimmu.2017.00038或Moore,G.L.,Methods,第154卷,2019,第38-50页。
该免疫球蛋白分子通过包含CD3的抗原结合位点的额外组分的融合而进一步修饰，由此产生经修饰的免疫球蛋白。优选地，CD3的该抗原结合位点为与免疫球蛋白分子的重链中之一或两者的C端融合的scFv。各个组分彼此的融合为本领域所熟知。该融合可例如经由肽接头，或经由非肽接头进行。优选地，该融合经由肽接头进行。
更优选地，该免疫球蛋白分子和/或该经修饰的免疫球蛋白分子为单克隆、嵌合、人源化或人类免疫球蛋白(例如抗体)分子。更优选地，该免疫球蛋白分子的重链恒定区为选自由以下组成的组：IgG1、IgG2、IgG3、IgG4、IgM、IgA及IgE恒定区。在另一优选实施方案中，该免疫球蛋白分子的轻链恒定区为κ或λ。
根据本发明，构成本发明的结合分子的个别组件彼此可经由一种或多种接头连接。优选地，这些接头为肽接头且更优选地，其经由共价连接个别组件。本文中尤其优选地，各别轻链经由接头连接于其各别重链。
在本发明的结合分子含有超过一种接头的那些实施方案中，设想所述接头可具有相同或不同长度且可由相同或不同结构构成，例如包含相同或不同氨基酸序列或相同或不同非肽聚合物。在一优选实施方案中，本发明的结合分子中存在的接头彼此的长度和/或结构不同(例如氨基酸序列或非肽聚合物的性质)。
优选地，接头为肽接头。更优选地，接头为使用例如氨基酸丙氨酸及丝氨酸或甘氨酸及丝氨酸的可挠性接头，诸如SEQ ID NO:275中所示的接头，或为SEQ ID No:265及266中所示的接头中之一者。因此，尤其优选地，本发明的结合分子完全由氨基酸构成，即其为多肽。
据本发明人所了解，迄今为止未报导过连接癌细胞上的Trop2及CDH17及免疫细胞上的CD3的三特异性抗体与重组三特异性抗体衍生物，其中Trop2及CDH17特异性结合剂分别以高于1nM及10nM的Kd结合其目标。WO21113748为描述各种形式多特异性抗体的专利申请案，所述形式包括称为“TriAx-E”的结合于Trop2、CDH17和/或CD3的分子，然而，本发明人再现该分子的任何尝试均因稳定性不够而失败。经典抗体选择活动通常适合产生高亲和力结合剂。此亦为WO21113748中遵循的方法。然而，本发明人意外地发现对此两个目标具有高亲和力的抗原结合位点的并入引起治疗窗狭窄。如实施例、尤其实施例6至8中所示，较高亲和力的使用产生对仅表达一个或另一目标的细胞的单价结合及活性，因此增加不希望副作用的风险。另外，多价形式的使用亦减小治疗窗。这些发现显示对两个目标中的任一者的亲和力增加导致特异性丧失，这是在价数增加的情况下进一步增强的作用。因此，选择专注于获得低亲和力结合剂的不同选择策略。如自以下实施例显而易见，本发明的三特异性结合分子提供对靶细胞的优良特异性。如下文实施例中所示，获得低亲和力及单价结合剂组合的结合分子的最佳结果。
在本发明的结合分子的另一优选实施方案中，至少一个特异性结合于TROP2的抗原结合位点为选自由抗原结合位点(i)至(vi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:1(CDR1)、SEQ ID NO.:2(CDR2)及SEQID NO.:3(CDR3)的氨基酸序列的重链CDR及包含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，其包括包含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及包含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，其包括包含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及包含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，其包括包含SEQ ID NO.:13(CDR1)、SEQ ID NO.:19(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:20(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR；
(v)抗原结合位点，其包括包含SEQ ID NO.:21(CDR1)、SEQ ID NO.:22(CDR2)及SEQ ID NO.:23(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:24(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:26(CDR3)的氨基酸序列的轻链CDR；
及
(vi)抗原结合位点，其包括包含SEQ ID NO.:27(CDR1)、SEQ ID NO.:28(CDR2)及SEQ ID NO.:29(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:30(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:31(CDR3)的氨基酸序列的轻链CDR。
本文公开及SEQ ID NO:1至31中描绘的CDR根据Kabat命名法呈现，且展示于下表1中。如本文所用，HCDR表示重链CDR且LCDR表示轻链CDR。
由于本领域已知额外命名法，因此基于这些命名法中最常用者的CDR序列亦展示于下表1中，但仅针对这些替代命名法的应用产生不同氨基酸序列的那些情况。这些编号系统为基于(i)CCG(Almagro等人,Proteins 2011；79:3050-3066及Maier等人,Proteins2014；82:1599-1610所说明的Chemical Computing Group)；(ii)Chothia(Chothia andLesk,1987,J.Mol.Biol.196:901-917)、(iii)IMGT(Lefranc MP,Dev Comp Immunol.2003年1月；27(1):55-77)及(iv)North(North B,J Mol Biol.(2011)406:228-56)。
本文中(参见表1)根据Kabat、CCG、Chothia、IMGT及North位置指示CDR的氨基酸位置为线性的，即各别全长分子链的氨基酸在N端自编号1开始连续编号，且以与该分子中氨基酸的总数目相对应的编号结束。举例而言，由长度为118个氨基酸组成的重链将在N端以编号1开始，且将在最C端氨基酸以编号118结束。因此，自所提及的此分子的N端计数，对例如位置25的任何提及意为氨基酸编号25。
在本发明的结合分子之一更优选实施方案中，至少一个特异性结合于TROP2的抗原结合位点为选自由抗原结合位点(i)至(xii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:83的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:84的氨基酸序列的免疫球蛋白轻链可变域；
(ii)抗原结合位点，其包括包含SEQ ID NO:85的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:86的氨基酸序列的免疫球蛋白轻链可变域；
(iii)抗原结合位点，其包括包含SEQ ID NO:87的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:88的氨基酸序列的免疫球蛋白轻链可变域；
(iv)抗原结合位点，其包括包含SEQ ID NO:89的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:90的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含SEQ ID NO:91的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:92的氨基酸序列的免疫球蛋白轻链可变域；
(vi)抗原结合位点，其包括包含SEQ ID NO:93的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:94的氨基酸序列的免疫球蛋白轻链可变域；
(vii)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:94的氨基酸序列的免疫球蛋白轻链可变域；
(viii)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:96的氨基酸序列的免疫球蛋白轻链可变域；
(ix)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(x)抗原结合位点，其包括包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(xi)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:99的氨基酸序列的免疫球蛋白轻链可变域；
或
(xii)抗原结合位点，其包括包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:96的氨基酸序列的免疫球蛋白轻链可变域。
根据本发明，术语“免疫球蛋白重链可变域”及“免疫球蛋白轻链可变域”为根据本领域的定义使用。
在本发明的结合分子的另一优选实施方案中，至少一个特异性结合于CDH17的抗原结合位点为选自由抗原结合位点(i)至(ii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:33(CDR2)及SEQ ID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:35(CDR1)、SEQ ID NO.:36(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR；
及
(ii)抗原结合位点，其包括包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:39(CDR1)、SEQ ID NO.:40(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR。
本文公开及SEQ ID NO:32至40中描绘的CDR亦根据Kabat命名法呈现，且展示于下表1中。同样，由于本领域已知额外命名法，因此基于这些命名法中最常用者的CDR序列亦展示于下表1中，但仅针对这些替代命名法的应用产生不同氨基酸序列的那些情况。
在本发明的结合分子之一更优选实施方案中，至少一个特异性结合于CDH17的抗原结合位点为选自由抗原结合位点(i)至(ii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:100的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:101的氨基酸序列的免疫球蛋白轻链可变域；
及
(ii)抗原结合位点，其包括包含SEQ ID NO:102的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:103的氨基酸序列的免疫球蛋白轻链可变域。
在本发明的结合分子之一优选实施方案中，
(a)该至少一个特异性结合于TROP2的抗原结合位点包含于包含第一免疫球蛋白重链恒定CH1域、第一免疫球蛋白重链可变域、任选存在的第一接头、第一免疫球蛋白轻链恒定域及第一免疫球蛋白轻链可变域的第一多肽中，和/或
(b)该至少一个特异性结合于CDH17的抗原结合位点包含于包含第二免疫球蛋白重链恒定CH1域、第二免疫球蛋白重链可变域、任选存在的第二接头、第二免疫球蛋白轻链恒定域及第二免疫球蛋白轻链可变域的第二多肽中。
根据本发明，术语“免疫球蛋白重链恒定CH1域”及“免疫球蛋白轻链恒定域”亦为根据本领域的定义使用。优选地，上文所述的次序为自N端至C端。
如本文在某些多肽及免疫球蛋白链的情况下所用，术语“第一”及“第二”以及下文进一步的术语“第三”仅意欲指示这些分子为不同分子(因为其结合于不同目标抗原)。因此，这些术语不应理解为是指多肽或免疫球蛋白链在本发明的结合蛋白内的准确次序或序列。实际上，当提及与结合于TROP2相关的方面时，使用术语“第一”，当提及与结合于CDH17相关的方面时，使用术语“第二”，且当提及与结合于CD3相关的方面时，使用术语“第三”。
术语接头已在上文进行定义，且合适接头已描述于本领域。在本发明的结合分子之一优选实施方案中，第一和/或第二接头包含SEQ ID NO:265、SEQ ID NO:266、SEQ IDNO:273、SEQ ID NO:274或SEQ ID NO:275中的任一者的氨基酸序列。更优选地，第一和/或第二接头包含SEQ ID NO:266的氨基酸序列。
根据本发明的结合分子的此实施方案，TROP2和/或CDH17的抗原结合位点为选自上文所描述的抗原结合位点，而CD3的抗原结合位点为由本领域技术人员自本领域可获得的那些CD3特异性抗原结合位点或自本文公开的那些抗原结合位点选择。更优选地，CD3特异性抗原结合位点为选自下文所定义的scFv序列(SEQ ID No:222至264，优选SEQ IDNo:222至245，更优选SEQ ID No:222至224)中之一者。
本发明的结合分子可含有且优选含有Fc部分。术语Fc部分为本领域所已知且已在上文定义。天然存在的免疫球蛋白分子的Fc区通常与多种Fc受体相互作用，此产生多种重要的功能能力(称为“效应功能”)。根据本发明，优选地，本发明的结合分子含有Fc区或Fc区的一部分，其不干扰本发明的结合分子与目标抗原的相关部分的特异性结合。此外，本领域技术人员十分了解恒定区的类型及长度的选择视如补体结合或抗体依赖性细胞介导的细胞毒性的效应功能是否为期望特征以及抗体蛋白质的期望药理学特性而定。
因此，在本发明的结合分子的一个优选实施方案中，结合分子具有经工程改造以避免与可溶性Fcγ受体和/或补体C1q发生不希望的交联的Fc区或其相关部分。优选地，此类结合分子对Fcγ受体和/或补体C1q的亲和力比未经工程改造的结合分子(即，突变(经工程改造)分子来源于的Fc未经工程改造的结合分子)低得多。此类免疫球蛋白分子通常也称为Ig(KO)。
在本发明的结合分子之一尤其优选实施方案中，通过利用引导位置234及235的L至A突变诱发(所谓“LA-LA突变”；Hezareh等人,J.Virology 75(2001)12161-12168)的IgG4恒定区或IgG1恒定区，去除本发明中的结合分子与补体产物C1q或Fcγ受体的结合。优选地，本发明的结合分子含有该L至A突变诱发。
在本发明的结合分子的另一个优选实施方案中，结合分子包含经工程改造以通过例如使CH2域中位置H310A(根据EU编号方案)处发生点突变而优化与新生儿Fc受体(FcRn)的相互作用来调节血清含量(半衰期)的Fc区或其相关部分。此类Ig分子在本文中称为IgFcRnmut。
多聚体结合分子设计的一个挑战为在无随机链配对及其他错配下在工业规模上生产其。本领域技术人员了解大量尝试阻止尤其重链均二聚体形成的方法，包括例如所谓杵-臼(KiH)策略，使用相反电荷建立静电导向作用，或促进重链杂二聚化的疏水性突变，CH3股交换工程改造域(SEED技术)及CH3域C端中诸如可裂解亮氨酸拉链的杂二聚体模块的融合(LUZ-Y技术))，Amaral等人(J Appl Bioanal 6(1),26-51(2020))中近来概述。
因此，尤其优选地，本发明的结合分子至少含有促使杵-臼形成的突变。优选地，本发明的结合分子为基于经修饰的免疫球蛋白分子，其中Ig分子部分的重链包含以下突变：
(i)第一重链包含在位置366处的色氨酸(W)[T366W]，且第二重链包含在位置366处的丝氨酸(S)[T366S]、在位置368处的丙氨酸(A)[L368A]及在位置407处的缬氨酸(V)[Y407V]；
(ii)第一重链包含在位置366处的酪氨酸(Y)[T366Y]，且第二重链包含在位置407处的苏氨酸(T)[Y407T]；
(iii)第二重链包含在位置366处的色氨酸(W)[T366W]，且第一重链包含在位置366处的丝氨酸(S)[T366S]、在位置368处的丙氨酸(A)[L368A]及在位置407处的缬氨酸(V)[Y407V]；或
(iv)第二重链包含在位置366处的酪氨酸(Y)[T366Y]，且第一重链包含在位置407处的苏氨酸(T)[Y407T]，
且更优选地，其中免疫球蛋白分子的含有第一重链的部分为亦含有特异性结合于TROP2的抗原结合位点的部分(本文中也称为Ig分子的TROP2结合部分)且免疫球蛋白分子的含有第二重链的部分为亦含有特异性结合于CDH17的抗原结合位点的部分(本文中也称为Ig分子的CDH17结合部分)。
根据此优选实施方案，编号为基于各别重链，其中在重链的该恒定区N端的第一氨基酸为根据EU编号方案的位置118。换言之，位置366处的色氨酸为重链恒定区内的第366个氨基酸，自位置118的N端开始。此编号为本领域技术人员所熟知，且亦描述于文献中，关于CH1的EU编号系统，参见例如IMGT Scientific图，其中根据Edelman,G.M.等人,Proc.Natl.Acad.USA,63,78-85(1969)，对于IgG1，恒定区在氨基酸118处的“A”开始。
优选地，本发明的结合分子包含上文(i)中列举的突变，即Ig分子的一个结合部分含有杵突变(T366W)，而Ig分子的其他结合部分含有臼突变(T366S、L368A及Y407V)。更优选地，Ig分子的TROP2结合部分含有杵突变(T366W)，而Ig分子的CDH17结合部分含有臼突变(T366S、L368A及Y407V)。本领域技术人员知道如何将本文所述的目标特异性抗原结合位点(优选地，包含单链Fab或由其组成的目标特异性结合位点)与包含此类杵或臼突变的Fc域组合；例如，SEQ ID No:434及435中所示的Fc域可用于将所关注的任何抗原结合位点，优选Fab置放至期望杵或臼背景中。
在本发明的结合分子之一甚至更优选实施方案中，含有臼突变的重链另外进一步包含以下突变：
v)在位置435处的精氨酸[H435R]及在位置436处的苯丙氨酸[Y436F](移除蛋白A结合位点)；和/或
vi)在位置234处的丙氨酸[L234A]及在位置235处的丙氨酸[L235A]，如上文所论述。
关于如上所定义的编号的相同考虑因素在细节上作必要修改后适用。本领域技术人员可应用的进一步突变为本领域所熟知且已描述于例如Saunders KO(2019).Front.Immunol.10:1296。
在本发明的结合分子之一甚至更优选实施方案中，结合分子包含
(a-i)包含SEQ ID NO:169的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:170的氨基酸序列的免疫球蛋白重链；
(a-ii)包含SEQ ID NO:171的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:172的氨基酸序列的免疫球蛋白重链；
(a-iii)包含SEQ ID NO:173的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:174的氨基酸序列的免疫球蛋白重链；
(a-iv)包含SEQ ID NO:175的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:176的氨基酸序列的免疫球蛋白重链；
(a-v)包含SEQ ID NO:177的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:178的氨基酸序列的免疫球蛋白重链；
(a-vi)包含SEQ ID NO:179的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:180的氨基酸序列的免疫球蛋白重链；
(a-vii)包含SEQ ID NO:181的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:182的氨基酸序列的免疫球蛋白重链；
(a-viii)包含SEQ ID NO:183的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:184的氨基酸序列的免疫球蛋白重链；
(a-ix)包含SEQ ID NO:185的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:186的氨基酸序列的免疫球蛋白重链；
(a-x)包含SEQ ID NO:187的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:188的氨基酸序列的免疫球蛋白重链；
(a-xi)包含SEQ ID NO:189的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:190的氨基酸序列的免疫球蛋白重链；或
(a-xii)包含SEQ ID NO:191的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:192的氨基酸序列的免疫球蛋白重链；
和/或
(b-i)包含SEQ ID NO:196的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:197的氨基酸序列的免疫球蛋白重链；或
(b-ii)包含SEQ ID NO:198的氨基酸序列的免疫球蛋白重链及包含SEQ ID NO:199的氨基酸序列的免疫球蛋白轻链。
根据本发明，术语“免疫球蛋白重链”及“免疫球蛋白轻链”为根据本领域的定义使用。因此，这些术语是指IgG，例如IgG1、IgG2或IgG4的各别链或域。
详言之，免疫球蛋白重链通常包含具有所述次序的重链可变域VH、第一重链恒定CH1域及Fc域，包含铰链区及两个恒定域(CH2及CH3)，而免疫球蛋白轻链通常包含具有所述次序的轻链可变域VL及第一轻链恒定CL1域。
根据本发明的结合分子的此实施方案，TROP2和/或CDH17的抗原结合位点包含于上文所叙述的特定序列中，而CD3的抗原结合位点为由本领域技术人员自本领域可获得的那些CD3特异性抗原结合位点或自本文公开的那些抗原结合位点选择。更优选地，CD3特异性抗原结合位点为选自下文所定义的scFv序列(SEQ ID No:222至264，优选SEQ IDNo:222至245，更优选SEQ ID No:222至224)中之一者。
在本发明的结合分子的又一更优选实施方案中，结合分子包括包含至少第一及第二多肽的免疫球蛋白分子，其中
(a)该第一多肽特异性结合于TROP2且包含如上文在(a-i)至(a-xii)中定义的免疫球蛋白重链及免疫球蛋白轻链组合，任选通过第一接头连接，及
(b)该第二多肽特异性结合于CDH17且包含如上文在(b-i)至(b-ii)中定义的免疫球蛋白重链及免疫球蛋白轻链组合，任选通过第二接头连接。
术语接头已在上文进行定义，且合适接头已描述于本领域。在本发明的结合分子之一优选实施方案中，包含SEQ ID NO:265、SEQ ID NO:266、SEQ ID NO:273、SEQ ID NO:274或SEQ ID NO:275中的任一者的氨基酸序列。更优选地，第一和/或第二接头包含SEQ IDNO:266的氨基酸序列。
亦根据本发明的结合分子的此实施方案，TROP2及CDH17的抗原结合位点包含于上文所叙述的特定序列中，而CD3的抗原结合位点为由本领域技术人员自本领域可获得的那些CD3特异性抗原结合位点或自本文公开的那些抗原结合位点选择。更优选地，CD3特异性抗原结合位点为选自下文所定义的scFv序列(SEQ ID No:222至264，优选SEQ IDNo:222至245，更优选SEQ ID No:222至224)中之一者。
在本发明的结合分子的又一更优选实施方案中，结合分子包含
(a-i)SEQ ID NO:200的氨基酸序列；
(a-ii)SEQ ID NO:207的氨基酸序列；
(a-iii)SEQ ID NO:208的氨基酸序列；
(a-iv)SEQ ID NO:209的氨基酸序列；
(a-v)SEQ ID NO:210的氨基酸序列；
(a-vi)SEQ ID NO:211的氨基酸序列；
(a-vii)SEQ ID NO:212的氨基酸序列；
(a-viii)SEQ ID NO:213的氨基酸序列；
(a-ix)SEQ ID NO:214的氨基酸序列；
(a-x)SEQ ID NO:215的氨基酸序列；
(a-xi)SEQ ID NO:216的氨基酸序列；或
(a-xii)SEQ ID NO:217的氨基酸序列；
和/或
(b-i)SEQ ID NO:220的氨基酸序列；或
(b-ii)SEQ ID NO:221的氨基酸序列。
亦根据本发明的结合分子的此实施方案，TROP2及CDH17的抗原结合位点包含于上文所叙述的特定序列中，而CD3的抗原结合位点为由本领域技术人员自本领域可获得的那些CD3特异性抗原结合位点或自本文公开的那些抗原结合位点选择。更优选地，CD3特异性抗原结合位点为选自下文所定义的scFv序列(SEQ ID No:222至264)中之一者。甚至更优选地，CD3特异性抗原结合位点为选自SEQ ID No:222至245的scFV序列中之一者。甚至更优选地，CD3特异性抗原结合位点为选自SEQ ID No:222至224的scFV序列中之一者。
在本发明的结合分子的另一优选实施方案中，至少一个特异性结合于CD3的抗原结合位点为选自由抗原结合位点(i)至(xxxi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(ii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:46(CDR3)的氨基酸序列的轻链CDR；
(iii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(iv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:49(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:50(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(v)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(vi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:49(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(vii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:53(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(viii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:55(CDR1)、SEQ IDNO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(ix)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:56(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(x)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:58(CDR2)及SEQ ID NO.:59(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:60(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xiii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:62(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ IDNO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xiv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:63(CDR2)及SEQ ID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:56(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xvi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ ID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xvii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:64(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xviii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:69(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xix)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:72(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xx)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:73(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:74(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:73(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxiii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:75(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxiv)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:69(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxv)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:76(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxvi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:77(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxvii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:78(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxviii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:79(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:80(CDR1)、SEQID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxix)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:81(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxx)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:79(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:80(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
及
(xxxi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:81(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ IDNO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR。
除非另外明确说明，否则上文在TROP2和/或CDH17的抗原结合位点的背景下叙述的定义及优选实施方案亦适用于特异性结合于CD3的此至少一个抗原结合位点。详言之，抗原结合位点内某些组件的次序，非TROP2或CDH17特异性的术语的定义及本发明的结合分子的组件的通用设计及结构的方面亦适用于此CD3特异性抗原结合位点。此外，对于此CD3特异性抗原结合位点，亦优选地，其完全由氨基酸构成，即其包含于多肽中和/或CDR为肽或多肽。应了解，此亦意为任何接头若存在，则优选为肽接头，优选如上文所定义的可挠性接头。优选地，任何此类接头包含SEQ ID NO:265、SEQ ID NO:266、SEQ ID NO:273、SEQ ID NO:274或SEQ ID NO:275中的任一者的氨基酸序列。更优选地，接头包含SEQ ID NO:265的氨基酸序列。
本文公开及SEQ ID NO:41至82中描绘的CDR亦根据Kabat命名法呈现，且展示于下表1中。同样，由于本领域已知额外命名法，因此基于这些命名法中最常用者的CDR序列亦展示于下表1中，但仅针对这些替代命名法的应用产生不同氨基酸序列的那些情况。
在本发明的结合分子的另一更优选实施方案中，该至少一个特异性结合于CD3的抗原结合位点包含第三免疫球蛋白重链可变域及第三免疫球蛋白轻链可变域，任选通过第三接头连接。
在本发明的结合分子之一更优选实施方案中，至少一个特异性结合于CD3的抗原结合位点为选自由抗原结合位点(i)至(xvi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:104的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:105、SEQ ID NO:106、SEQ ID NO:107、SEQ ID NO:109、SEQID NO:114、SEQ ID NO:115、SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:123及SEQ ID NO:129组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(ii)抗原结合位点，其包括包含SEQ ID NO:110的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:111的氨基酸序列的免疫球蛋白轻链可变域；
(iii)抗原结合位点，其包括包含SEQ ID NO:112的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:113的氨基酸序列的免疫球蛋白轻链可变域；
(iv)抗原结合位点，其包括包含SEQ ID NO:118的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:119及SEQ ID NO:122组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含SEQ ID NO:124的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:125、SEQ ID NO:126及SEQ ID NO:127组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含选自由SEQ ID NO:128及SEQ ID NO:130组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:127的氨基酸序列的免疫球蛋白轻链可变域；
(vi)抗原结合位点，其包括包含SEQ ID NO:131的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:132的氨基酸序列的免疫球蛋白轻链可变域；
(vii)抗原结合位点，其包括包含SEQ ID NO:133的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:134及SEQ ID NO:135组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(viii)抗原结合位点，其包括包含SEQ ID NO:136的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:137的氨基酸序列的免疫球蛋白轻链可变域；
(ix)抗原结合位点，其包括包含选自由SEQ ID NO:138及SEQ ID NO：156组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:139的氨基酸序列的免疫球蛋白轻链可变域；
(x)抗原结合位点，其包括包含选自由SEQ ID NO:140、SEQ ID NO:142、SEQ IDNO:143及SEQ ID NO:161组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:141的氨基酸序列的免疫球蛋白轻链可变域；
(xi)抗原结合位点，其包括包含选自由SEQ ID NO:144及SEQ ID NO:146组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:145的氨基酸序列的免疫球蛋白轻链可变域；
(xii)抗原结合位点，其包括包含选自由SEQ ID NO:147、SEQ ID NO:151、SEQIDNO:153及SEQ ID NO:162组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:148的氨基酸序列的免疫球蛋白轻链可变域；
(xiii)抗原结合位点，其包括包含选自由SEQ ID NO:149及SEQ ID NO:152组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:150的氨基酸序列的免疫球蛋白轻链可变域；
(xiv)抗原结合位点，其包括包含SEQ ID NO:154的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:155的氨基酸序列的免疫球蛋白轻链可变域；
(xv)抗原结合位点，其包括包含SEQ ID NO:157的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:158的氨基酸序列的免疫球蛋白轻链可变域；及
(xvi)抗原结合位点，其包括包含SEQ ID NO:159的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:160的氨基酸序列的免疫球蛋白轻链可变域。
亦优选地，该特异性结合于CD3的抗原结合位点为单链可变片段(scFV)。更优选地，该scFv经配置以使得重链可变域在其N端处且轻链可变域在其C端处。
连接包括scFv分子的所关注的多肽与例如IgG分子的重链的C端的方法为本领域熟知。应了解，该scFv与Ig分子的融合可为直接融合或可经由接头，优选长度为5至40个氨基酸的肽接头。更优选地，该肽接头包含SEQ ID NO:265、SEQ ID NO:266、SEQ ID NO:273、SEQ ID NO:274或SEQ ID NO:275中的任一者的氨基酸序列。更优选地，该接头包含SEQ IDNO:275的氨基酸序列。实际上，通常连接通过将编码所关注的IgG的核酸分子与编码期望多肽，例如scFv的核酸组合来达成，必要时通过编码连接序列的核酸分子隔开，由此形成包含所有三个组件的单个核酸分子。随后，此完整HC-scFv编码核酸分子置放于表达载体内且引入至适当宿主细胞中，以便形成完整IgG重链-scFv单一多肽。
在本发明的结合分子之一甚至更优选实施方案中，至少一个特异性结合于CD3的抗原结合位点包含选自由SEQ ID NO:222至264组成的组的氨基酸序列。甚至更优选地，CD3特异性抗原结合位点为选自SEQ ID No:222至245的scFv序列之一。甚至更优选地，CD3特异性抗原结合位点为选自SEQ ID No:222至224的scFv序列之一。
如上文所指示，本发明的结合分子的抗原结合位点的编号(a)、(b)及(c)并不意欲指示任何特定次序或形式。
然而，优选地，特异性结合于TROP2的第一抗原结合位点及特异性结合于CDH17的第二抗原结合位点皆包含于一个免疫球蛋白(Ig)分子内，即其配置成常规IgG抗体形式，形成Y形结构，如例如图3中所示，其中Ig分子之一半(例如包含连接于第一重链的第一轻链)含有TROP2的抗原结合位点且Ig分子的第二半(例如包含连接于第二重链的第二轻链)含有CDH17的抗原结合位点。优选地，该Ig分子为IgG或具有来源于IgG的形式。更优选地，该免疫球蛋白分子经修饰，其中至少一个特异性结合于CD3的抗原结合位点优选具有单链可变片段(scFv)与的融合。
因此，在本发明的结合分子之一尤其优选实施方案中，结合分子为经修饰的免疫球蛋白(Ig)分子，优选经修饰的IgG分子，其中该至少一个特异性结合于TROP2的抗原结合位点及该至少一个特异性结合于CDH17的抗原结合位点存在于该Ig分子的可变区，且其中该至少一个特异性结合于CD3的抗原结合位点为与该TROP2-CDH17特异性Ig分子融合的至少一个scFv。更优选地，该scFv与Ig分子的重链的C端融合，优选与两条重链中仅一者的C端融合，且更优选与Ig分子的包含至少一个特异性结合于CDH17的抗原结合位点的部分的重链，亦如图3中描绘。
在本发明的结合分子的另一更优选实施方案中，结合分子包含：
(a)选自(a-i)至(a-xii)的第一免疫球蛋白轻链及免疫球蛋白重链组合：
(a-i)包含SEQ ID NO:169的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:170的氨基酸序列的免疫球蛋白重链；
(a-ii)包含SEQ ID NO:171的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:172的氨基酸序列的免疫球蛋白重链；
(a-iii)包含SEQ ID NO:173的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:174的氨基酸序列的免疫球蛋白重链；
(a-iv)包含SEQ ID NO:175的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:176的氨基酸序列的免疫球蛋白重链；
(a-v)包含SEQ ID NO:177的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:178的氨基酸序列的免疫球蛋白重链；
(a-vi)包含SEQ ID NO:179的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:180的氨基酸序列的免疫球蛋白重链；
(a-vii)包含SEQ ID NO:181的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:182的氨基酸序列的免疫球蛋白重链；
(a-viii)包含SEQ ID NO:183的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:184的氨基酸序列的免疫球蛋白重链；
(a-ix)包含SEQ ID NO:185的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:186的氨基酸序列的免疫球蛋白重链；
(a-x)包含SEQ ID NO:187的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:188的氨基酸序列的免疫球蛋白重链；
(a-xi)包含SEQ ID NO:189的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:190的氨基酸序列的免疫球蛋白重链；或
(a-xii)包含SEQ ID NO:191的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:192的氨基酸序列的免疫球蛋白重链；
及
(b)选自(b-i)至(b-ii)的第二免疫球蛋白重链及免疫球蛋白轻链组合：
(b-i)包含SEQ ID NO:196的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:197的氨基酸序列的免疫球蛋白重链；或
(b-ii)包含SEQ ID NO:198的氨基酸序列的免疫球蛋白重链及包含SEQ ID NO:199的氨基酸序列的免疫球蛋白轻链；
及
(c)单链可变片段(scFv)，其包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组。
优选地，该第一免疫球蛋白重链经由第一接头，优选SEQ ID NO:266的接头与第一免疫球蛋白轻链融合，和/或该第二免疫球蛋白重链经由第二接头，优选SEQ ID NO:266的接头与第二免疫球蛋白轻链融合，和/或该scFv经由第三接头，优选SEQ ID NO:275的接头与第二免疫球蛋白重链的C末端融合。
在本发明的结合分子的又一甚至更优选实施方案中，结合分子包含：
(i)包含SEQ ID NO.:200的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(ii)包含SEQ ID NO.:200的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(iii)包含SEQ ID NO.:207的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(iv)包含SEQ ID NO.:207的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(v)包含SEQ ID NO.:208的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(vi)包含SEQ ID NO.:208的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(vii)包含SEQ ID NO.:209的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(viii)包含SEQ ID NO.:209的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(ix)包含SEQ ID NO.:210的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(x)包含SEQ ID NO.:210的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xi)包含SEQ ID NO.:211的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xii)包含SEQ ID NO.:211的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xiii)包含SEQ ID NO.:212的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xiv)包含SEQ ID NO.:212的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xv)包含SEQ ID NO.:213的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xvi)包含SEQ ID NO.:213的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xvii)包含SEQ ID NO.:214的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xviii)包含SEQ ID NO.:214的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xix)包含SEQ ID NO.:215的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xx)包含SEQ ID NO.:215的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xxi)包含SEQ ID NO.:216的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xxii)包含SEQ ID NO.:216的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；
(xxiii)包含SEQ ID NO.:217的氨基酸序列的第一多肽链、包含SEQ ID NO.:220的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链；或
(xxiv)包含SEQ ID NO.:217的氨基酸序列的第一多肽链、包含SEQ ID NO.:221的氨基酸序列的第二多肽链及包含选自由SEQ ID NO:222至264组成的组的氨基酸序列、更优选选自由SEQ ID NO:222至245组成的组且甚至更优选选自由SEQ ID No:222至224组成的组的第三多肽链。
在本发明的结合分子之一甚至更优选实施方案中，结合分子包含以下或由以下组成：选自由SEQ ID NO:200、207至217及436组成的组的第一氨基酸序列及选自由SEQ IDNO:267至272、424至427及437组成的组的第二氨基酸序列。
在本发明的结合分子的又一更优选实施方案中，该结合分子包含以下或由以下组成：
(a-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(b-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(c-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(c-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:269的氨基酸序列；
(d-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(d-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:270的氨基酸序列；
(e-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(e-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:271的氨基酸序列；
(f-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(f-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:272的氨基酸序列；
(g-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(g-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:424的氨基酸序列；
(h-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(h-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:425的氨基酸序列；
(i-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(i-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(j-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:427的氨基酸序列；或
(k)SEQ ID NO.:436的氨基酸序列及SEQ ID NO.:437的氨基酸序列。
在一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:267的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQID NO.:208的氨基酸序列及SEQ ID NO.:267的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:267的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:210的氨基酸序列及SEQ IDNO.:267的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:271的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:271的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:271的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:271的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:271的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:272的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:272的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:272的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:272的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:424的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQID NO.:211的氨基酸序列及SEQ ID NO.:425的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:426的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:211的氨基酸序列及SEQ IDNO.:427的氨基酸序列。在另一尤其优选实施方案中，本发明的结合分子包含SEQ ID NO.:436的氨基酸序列及SEQ ID NO.:437的氨基酸序列。
如随附实施例中所示，本发明的这些尤其优选的结合分子结合于所有三个目标抗原，由此，使T细胞与携带Trop2与CDH17的肿瘤细胞紧邻。意外地，发现并入高亲和力抗原结合位点在仅表达此两个目标中之一者的细胞上产生单价结合及活性，因此增加不希望副作用的风险。因此，本发明提供包含肿瘤细胞抗原的低亲和力结合剂的三特异性结合分子。如自以下实施例显而易见，本发明的这些低亲和力高亲和力三特异性结合分子提供对靶细胞的优良特异性。
本发明进一步关于一种三特异性结合分子，其包含以下或由以下组成：(i)SEQ IDNO.:207的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(ii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(iii)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(iv)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:267的氨基酸序列；(v)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(vi)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(vii)SEQ ID NO.:213的氨基酸序列及SEQID NO.:271的氨基酸序列；(viii)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(ix)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(x)本发明包含SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(xi)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(xii)SEQ ID NO.:216的氨基酸序列及SEQID NO.:272的氨基酸序列；(xiii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(xiv)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(xv)SEQ IDNO.:211的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(xvi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(xvii)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:427的氨基酸序列；或(xviii)SEQ ID NO.:436的氨基酸序列及SEQ ID NO.:437的氨基酸序列。
下表1中概述本发明的结合分子的优选氨基酸序列或其部分。
本文公开为Trop2#1、Trop2#8至Trop2#18、CDH17#1、CDH17#8以及CD3#1至CD3#43的优选抗原结合位点均由本发明人鉴别且作为适用于本发明的三特异性结合分子的抗原结合位点测试。详言之，所述抗原结合位点通过多肽链或接头的可挠性组件连接，所述可挠性组件不干扰所述抗原结合位点的结构及功能完整性。
TROP2的单特异性结合分子
本文进一步提供特异性结合于TROP2的抗体分子(例如具有具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，诸如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，对TROP2具有特异性的抗体分子为重组单克隆抗体、嵌合、人源化或人类抗体分子。
在一些实施方案中，对TROP2具有特异性的抗体分子包含(i)至(vi)中所示的以下CDR组合中的任一者：
(i)包含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及包含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)包含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及包含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)包含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及包含SEQ ID NO.:16(CDR1)、SEQ ID NO.:17(CDR2)及SEQ IDNO.:18(CDR3)的氨基酸序列的轻链CDR；
(iv)包含SEQ ID NO.:13(CDR1)、SEQ ID NO.:19(CDR2)及SEQ ID NO.:15(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:20(CDR1)、SEQ ID NO.:17(CDR2)及SEQ IDNO.:18(CDR3)的氨基酸序列的轻链CDR；
(v)包含SEQ ID NO.:21(CDR1)、SEQ ID NO.:22(CDR2)及SEQ ID NO.:23(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:24(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:26(CDR3)的氨基酸序列的轻链CDR；
或
(vi)包含SEQ ID NO.:27(CDR1)、SEQ ID NO.:28(CDR2)及SEQ ID NO.:29(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:30(CDR1)、SEQ ID NO.:25(CDR2)及SEQ IDNO.:31(CDR3)的氨基酸序列的轻链CDR。
在一些实施方案中，对TROP2具有特异性的抗体分子包含：
i)包含SEQ ID NO:83的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:84的氨基酸序列的免疫球蛋白轻链可变域；
(ii)包含SEQ ID NO:85的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:86的氨基酸序列的免疫球蛋白轻链可变域；
(iii)包含SEQ ID NO:87的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:88的氨基酸序列的免疫球蛋白轻链可变域；
(iv)包含SEQ ID NO:89的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:90的氨基酸序列的免疫球蛋白轻链可变域；
(v)包含SEQ ID NO:91的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:92的氨基酸序列的免疫球蛋白轻链可变域；
(vi)包含SEQ ID NO:93的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:94的氨基酸序列的免疫球蛋白轻链可变域；
(vii)包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:94的氨基酸序列的免疫球蛋白轻链可变域；
(viii)包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:96的氨基酸序列的免疫球蛋白轻链可变域；
(ix)包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:97的氨基酸序列的免疫球蛋白轻链可变域；
(x)包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(xi)包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:99的氨基酸序列的免疫球蛋白轻链可变域；
或
(xii)包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:96的氨基酸序列的免疫球蛋白轻链可变域。
在一些实施方案中，如上所定义的TROP2特异性抗体进一步包含人类重链恒定域(例如，IgG恒定域)及人类轻链恒定域(例如，κ或λ轻链恒定域)。在一些实施方案中，重链恒定域为人类IgG1野生型(例如，如SEQ ID NO:414中提供)、IgG1 KO(例如，如SEQ ID NO:415中提供)、IgG4 Pro野生型(例如，如SEQ ID NO:416中提供)或IgG1 FcRnmut(例如，如SEQID NO:417中提供)。在一些实施方案中，人类轻链恒定域为人类κ(例如，如SEQ ID NO:418)中提供。
在一些实施方案中，TROP2特异性抗体具有包含SEQ ID NO:83、85、87、89、91、93、95或98中的任一者的序列与SEQ ID No：414、415、416或417中的任一者的序列融合的重链及包含SEQ ID NO:84、86、88、90、92、94、96、97或99中的任一者的序列与SEQ ID NO:418的序列融合的轻链。
本文所提供的TROP2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、药物或另一分子而用于体外、体内或离体标记、定位、鉴别或靶向表达TROP2的细胞(例如在ELISA分析、FACS分析、免疫组织学或其类似方面中)。本文所述的TROP2特异性抗体单独时对表达TROP2的细胞的细胞活力无作用。在一些实施方案中，TROP2特异性抗体特异性结合于表达TROP2的细胞的表面且用于定位和/或鉴别此类细胞。在一些实施方案中，本文所提供的TROP2抗体用于鉴别表达TROP2的细胞(例如肿瘤细胞)。在一些实施方案中，本文所提供的TROP2抗体通过将药物或细胞毒性剂附接至该TROP2抗体用于递送此类药物或细胞毒性剂至靶细胞(例如表达TROP2的肿瘤细胞)，由此例如杀灭该靶细胞。
本文亦提供一种检测样品中的滋养层细胞表面抗原2(TROP2)的方法，该方法包含以下步骤：
(a)使该样品与如上文所定义的抗TROP2抗体分子接触；
(b)允许在该样品中形成抗体-抗原复合物；及
(c)检测抗TROP2抗体。
用于检测抗体的手段及方法为本领域所熟知且包括例如免疫组织化学、免疫墨点及ELISA。
本文进一步提供一种检测滋养层细胞表面抗原2(TROP2)的试剂盒，其中该试剂盒包含如上文所定义的抗TROP2抗体分子及使用说明书。
CDH17的单特异性结合分子
本文进一步提供特异性结合于CDH17的抗体分子(例如具有具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，诸如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，对CDH17具有特异性的抗体分子为重组单克隆抗体、嵌合、人源化或人类抗体分子。
在一些实施方案中，对CDH17具有特异性的抗体分子包含(i)至(ii)中所示的以下CDR组合中的任一者：
(i)包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:33(CDR2)及SEQ ID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:35(CDR1)、SEQ ID NO.:36(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR；
及
(ii)包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:38(CDR2)及SEQ ID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:39(CDR1)、SEQ ID NO.:40(CDR2)及SEQ IDNO.:37(CDR3)的氨基酸序列的轻链CDR。
在一些实施方案中，对CDH17具有特异性的抗体分子包含
(i)包含SEQ ID NO:100的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:101的氨基酸序列的免疫球蛋白轻链可变域；
或
(ii)包含SEQ ID NO:102的氨基酸序列的免疫球蛋白重链可变域及包含SEQ IDNO:103的氨基酸序列的免疫球蛋白轻链可变域。
在一些实施方案中，如上所定义的CDH17特异性抗体进一步包含人类重链恒定域(例如，IgG恒定域)及人类轻链恒定域(例如，κ或λ轻链恒定域)。在一些实施方案中，重链恒定域为人类IgG1野生型(例如，如SEQ ID NO:414中提供)、IgG1 KO(例如，如SEQ ID NO:415中提供)、IgG4 Pro野生型(例如，如SEQ ID NO:416中提供)或IgG1 FcRnmut(例如，如SEQID NO:417中提供)。在一些实施方案中，人类轻链恒定域为人类κ(例如，如SEQ ID NO:418中提供)。
在一些实施方案中，CDH17特异性抗体具有包含SEQ ID NO:100或102中的任一者的序列与SEQ ID NO:414、415、416或417中的任一者的序列融合的重链及包含SEQ ID NO:101或103中的任一者的序列与SEQ ID NO:418的序列融合的轻链。
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、药物或另一分子而用于体外、体内或离体标记、定位、鉴别或靶向表达CDH17的细胞(例如在ELISA分析、FACS分析、免疫组织学或其类似方面中)。本文所述的CDH17特异性抗体单独时对表达CDH17的细胞的细胞活力无作用。在一些实施方案中，CDH17特异性抗体特异性结合于表达CDH17的细胞的表面且用于定位和/或鉴别此类细胞。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抗体用于递送此类药物或细胞毒性剂至靶细胞(例如表达CDH17的肿瘤细胞)，由此例如杀灭该靶细胞。
本文亦提供一种检测样品中的钙黏素-17(CDH17)的方法，该方法包含以下步骤：
(a)使该样品与如上文所定义的抗CDH17抗体分子接触；
(b)允许在该样品中形成抗体-抗原复合物；及
(c)检测该抗CDH17抗体。
用于检测抗体的手段及方法为本领域所熟知且包括例如免疫组织化学、免疫墨点及ELISA。
本文进一步提供一种检测滋养层细胞表面抗原2(TROP2)的试剂盒，其中该试剂盒包含如上文所定义的抗TROP2抗体分子及使用说明书。
本发明的核酸分子、表达载体及宿主细胞
本发明进一步关于一种核酸分子，其编码本发明的结合分子或其一部分。本发明进一步涵盖一组编码本发明的结合分子的核酸分子。
根据本发明，该核酸分子“编码”本发明的结合分子或其一部分，此意为核酸分子具有可表达形式，即确保本发明的结合分子(或其各别部分)可自其表达的形式提供。
术语“其一部分”反映如下事实：如本领域技术人员了解，并非本发明的结合分子的所有组件均需要在单个核酸分子上编码。实情为，可依赖于两个或更多个核酸分子以单独地编码本发明的结合分子的某些部分。因此，本发明亦涵盖一组经分离的核酸分子，其中该组一起编码本发明的结合分子的所有部分，使得此组经分离的核酸分子的表达产生本发明的完整结合分子。换言之本文提供一种或多种核酸分子，其编码本发明的结合分子的个别多肽链，包括重链、轻链、scFv以及其组合，在个别核酸分子上分开编码或组合在一个核酸分子中。
优选地，本发明的结合分子由两种不同的经分离的核酸分子编码，其中第一核酸分子编码包含特异性结合于TROP2的抗原结合位点的全长链(包括单链Fab及Fc域)且第二核酸分子编码包含特异性结合于CDH17的抗原结合位点的全长链(包括单链Fab及Fc域)，两者连接于包含特异性结合于CD3的抗原结合位点的全长链(优选具有scFv形式)。在表达之后，表达的多肽将例如经由恒定域之间的二硫键等形成本发明的完整结合分子。
优选地，核酸分子为包含编码序列的DNA分子。更优选地，该DNA分子另外包含调控序列，及任选存在的天然或人工内含子(诸如来自具有嵌入的miRNA-557表达卡匣的智人的β-球蛋白内含子)。其可具有其初始密码子或可具有优化密码子使用，特别适用于在所需宿主细胞或宿主生物体中表达。本发明的此类核酸分子容易通过本领域技术人员依靠本身已知的方法，诸如通过自动化DNA合成、自天然来源分离和/或重组DNA技术，基于本文中所给出的关于本发明的结合分子的氨基酸序列的信息制备或获得。
本发明的核酸分子包括但不限于编码序列表中所示的多肽序列的DNA分子。此外，本发明涵盖与上文所定义的DNA分子互补的核酸分子，以及在如WO 2007/042309中所定义的高度严格结合及洗涤条件下与其杂交的核酸分子。优选分子(自mRNA视角)为与本文所述的DNA分子中之一者具有至少75％或80％(优选地至少85％，更优选地至少90％且最佳地至少95％)同源性或序列一致性的那些分子。举例而言，若目标为在真核细胞中表达本发明的结合分子，则DNA序列将必须经设计以匹配真核细胞中的密码子使用。若需要在大肠杆菌或其他原核系统中表达抗体，则这些序列将必须经设计以匹配大肠杆菌或各别原核系统中的密码子使用。可以若干种不同方式构筑本发明的DNA分子的变体，如例如WO 2007/042309中所描述。
优选地，分离核酸，术语“分离”在上文进一步定义。
本发明进一步关于一种表达载体，其包含本发明的核酸分子。
根据本发明，载体为表达载体，即可在体外和/或体内(例如在合适宿主细胞、宿主生物体和/或表达系统中)使各别多肽自编码核酸分子表达的载体。表达载体包括质体、逆转录病毒、黏质体、EBV来源的游离基因组及其类似物。通常选择与宿主细胞兼容的表达载体及表达控制序列。表达载体一般包含可操作地连接于一种或多种适合的调控组件(诸如启动子、强化子、终止子及其类似物)的至少一种本发明的核酸分子。适用于表达本发明的多肽或表达本发明的多肽所需的此类调控组件及其他组件，诸如整合因子、选择标记物、信号或前导序列、报导基因及其类似者的特定实施例公开于例如WO2006/040153的第131页至第133页上。
启动子序列的非限制性实施例(针对在哺乳动物细胞中表达所例示)为来源于CMV(诸如人类细胞巨大病毒的CMV启动子/强化子或CMV猿猴病毒40(SV40)启动子/强化子)、腺病毒(例如腺病毒主要晚期启动子(AdMLP))、多瘤病毒的启动子和/或强化子，及强哺乳动物启动子，诸如天然免疫球蛋白及肌动蛋白启动子。聚腺苷酸化信号的实施例为仓鼠生长激素或牛生长激素polyA、SV40晚期或早期polyA；或者，可使用免疫球蛋白基因的3′UTRs等。
重组表达载体亦可携带调控载体在宿主细胞中复制的序列(例如复制起点，诸如ColE1(pUC)复制起点)及可选择标记物基因(诸如赋予氨苄西林(ampicillin)抗性以在大肠杆菌中扩增质体的β-内酰胺酶基因)。重组表达载体亦可编码促进所得多肽分泌的信号肽。编码各别多肽链的核酸分子可克隆至载体中，以使得信号肽与成熟全长核酸分子链的氨基端同框连接。信号肽可为免疫球蛋白信号肽或来自非免疫球蛋白蛋白质的异源信号肽。或者，编码本发明的蛋白质的全长链的DNA序列可能已含有信号肽序列。
如上所指出，插入载体中的编码序列可例如通过标准方法合成，或自天然来源分离，或以半合成方式，即通过组合化学合成与重组技术产生。可使用已确立的方法将编码序列与转录调控组件和/或其他氨基酸编码序列接合。通常采用之一种方法为例如使用编码功能完整的人类CH(恒定重链)免疫球蛋白序列的载体，其中适当限制位点经工程改造以使得可容易插入及表达任何抗原结合位点，诸如单链Fab序列或任何重链/轻链可变域。对于抗体重链，其可为但不限于任何IgG同型(IgG1、IgG2、IgG3、IgG4)或其他免疫球蛋白，包括对偶基因变体。
在构成本发明的结合分子需要超过一种核酸分子的那些情况下，这些超过一种核酸分子可插入至不同表达载体中或插入至相同表达载体中。在后一情况下，其可在相同调控组件(例如启动子、强化子、终止子及其类似物)的控制下，或其可各自具有其自身之一组调控组件。根据本发明，尤其优选地，在超过一种核酸分子编码本发明的结合分子的个别组件的那些情况下(即，包含特异性结合于TROP2的抗原结合位点的多肽链、包含特异性结合于CHD17的抗原结合位点的多肽链及包含特异性结合于CD3的抗原结合位点的多肽链)，形成本发明的结合分子所需的所有个别核酸分子存在于单一表达载体且优选地，各核酸分子具有其自身之一组调控组件。
包含这些DNA分子的表达载体可根据本领域熟知的转染方法引入至宿主细胞，例如细菌细胞或(高等)真核细胞(例如哺乳动物细胞)中，所述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。
因此，本发明还涉及一种用本发明的表达载体转染的宿主细胞。
宿主细胞可为本领域已知的任何适合细胞，包括原核细胞，诸如细菌，以及真核细胞，诸如酵母细胞或哺乳动物细胞。哺乳动物细胞的非限制性实施例包括但不限于人类、小鼠、大鼠、猴及啮齿类动物细胞株。可用作宿主细胞进行表达的特定哺乳动物细胞株为本领域所熟知且尤其包括中国仓鼠卵巢(CHO)细胞、NS0、SP2/0细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人类癌瘤细胞(例如Hep G2及A549细胞)、3T3细胞或任何此类细胞株的衍生物/后代。用于上述宿主细胞的适当培养基及条件为本领域所已知。
用于产生本发明的结合分子的方法
本发明还涉及一种产生本发明的结合分子的方法，该方法包含以下步骤：
(a)在允许本发明的结合分子表达的条件下培养本发明的宿主细胞；
(b)任选回收该分子；及任选地
(c)进一步纯化和/或修饰和/或调配该结合分子。
本发明的蛋白质通过将宿主细胞培养一段足以允许宿主细胞表达该蛋白质的时间来制备。
适用于培养原核或真核宿主的条件为本领域技术人员所熟知。为提高表达产物的产率及溶解度，培养基可经缓冲或补充有已知增强或促进两者的适合添加剂。一般而言，本领域技术人员亦了解，这些条件可能必须适于宿主的需求及所表达的分子的要求。在诱导型启动子在宿主细胞中存在的载体中控制本发明的核酸分子的情况下，所关注分子的表达可通过添加适当诱导剂来诱导。适合的表达方案及策略为本领域技术人员所已知。
随后，回收本发明的结合分子，且必要时进一步纯化。优选地，以分泌分子形式自培养基回收其。然而，若例如在无分泌信号的情况下表达，则亦可自宿主细胞溶解物回收其。应了解，术语“回收该分子”是指分离由本发明的核酸分子编码的本发明的结合分子，即由于该宿主细胞经本发明的核酸分子或载体转型或转染而存在于本发明的宿主细胞中的结合分子。
纯化本发明的结合分子的任选选用的步骤进一步帮助获得分子的基本上均匀的制剂。用于纯化所关注分子的手段及方法为所熟知，且本领域技术人员可例如使用用于重组蛋白及宿主细胞蛋白质的标准蛋白质纯化方法且以适合于各别分子的方式对其进行调整。举例而言，适用于获得本发明的结合分子的目前先进技术纯化方法包括自培养基或溶解物移除细胞和/或颗粒细胞碎片作为第一步骤，接着例如通过在免疫亲和力或离子交换柱上分级分离、乙醇沉淀、反相HPLC、Sephadex色谱、二氧化硅或阳离子交换树脂上色谱来自污染性可溶蛋白质、多肽及核酸纯化。
作为获得本发明的结合分子的方法中的最终任选选用的步骤，纯化的蛋白质分子可经干燥，例如冻干，如下文针对治疗性应用所述，或按需要以其他方式调配。此外，本发明的所得结合分子可经受进一步修饰，例如移除非所需翻译后修饰及其类似修饰。
药物组合物及本发明的结合分子或药物组合物的医学用途
本发明进一步关于一种药物组合物，其包含一种或多种本发明的结合分子或由其组成。在一个实施方案中，该(等)结合分子为唯一药物活性剂。在一替代实施方案中，除该(等)结合分子以外，该组合物包含一种或多种其他药物活性剂，例如如下文进一步定义。
根据本发明，术语“药物组合物”是指用于向患者、优选地人类患者施用的组合物。本发明的药物组合物包含上文所述的单独或组合的化合物。其可任选包含能够改变本发明的化合物的特征的其他分子，由此例如稳定化、调节和/或活化其功能。组合物可呈固体、液体或气体形式，且可尤其呈粉末形式，例如冻干粉末、溶液、片剂或气溶胶。优选地，组合物为冻干粉末或溶液。
为用于疗法中，将本发明的结合分子或抗体调配成适于促进向动物或人类施用的药物组合物。因此，本发明的药物组合物优选亦包含药学上可接受的载剂。包含此类载剂的组合物可通过熟知的常规方法调配。通常，包含本发明的结合分子的药物组合物可通过将结合分子与此类药学上可接受的载剂以及(任选)赋形剂或稳定剂混合来调配。此外，“药学上可接受的载剂”意为任何类型的无毒固体、半固体或液体填充剂、稀释剂、囊封材料或调配助剂。其他赋形剂、调节剂或稳定剂在所采用的剂量及浓度下亦无毒。药学上可接受的载剂、赋形剂、调节剂及稳定剂包括但不限于缓冲系统，诸如磷酸盐、柠檬酸盐、乙酸盐及其他无机酸或有机酸及其盐；抗氧化剂，包括抗坏血酸及甲硫氨酸；防腐剂，诸如氯化十八烷基二甲基苯甲基铵；氯化六羟季铵；氯苄烷铵、苄索氯铵；苯酚、丁醇或苯甲醇；对羟苯甲酸烷基酯，诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯；儿茶酚；间苯二酚；环己醇；3-戊醇；及间甲酚；蛋白质，诸如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，诸如聚乙烯吡咯烷酮或聚乙二醇(PEG)；氨基酸，诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、双糖、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，诸如EDTA；糖醇，诸如甘露糖醇或山梨糖醇；成盐相对离子，诸如钠；金属错合物(例如Zn-蛋白质错合物)；和/或离子或非离子表面活性剂，诸如TWEENTM(聚山梨醇酯)、PLURONICSTM或脂肪酸酯、脂肪酸醚或糖酯。有机溶剂亦可含于调配物中，诸如乙醇或异丙醇。赋形剂亦可具有调节释放或调节吸收的功能。
通常，水溶液或悬浮液将为优选的。一般而言，用于治疗性蛋白质(诸如本发明的结合分子)的适合调配物为缓冲蛋白质溶液，诸如包括适合浓度(诸如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，诸如1.0至10.0mg/ml(静脉内施用)或100mg/ml(皮下施用))的蛋白质及水性缓冲液的溶液，该水性缓冲液诸如：
-磷酸盐缓冲盐水，pH 7.4，
-其他磷酸盐缓冲液，pH 6.2至pH 8.2，
-乙酸盐缓冲液，pH 3.2至pH 7.5，优选pH 4.8至pH 5.5
-组氨酸缓冲液，pH 5.5至pH 7.0，
-丁二酸盐缓冲液，pH 3.2至pH 6.6，或
-柠檬酸盐缓冲液，pH 2.1至pH 6.2，
及任选选用的用于提供溶液的等张性的盐(例如NaCl)和/或稳定剂(诸如蔗糖、海藻糖、赖氨酸)和/或其他多元醇(诸如甘露糖醇及甘油)，及任选选用的洗涤剂，例如以防止聚集(例如0.02％Tween-20或Tween-80)。
优选的用于静脉内施用的缓冲蛋白质溶液为包括约10mg/ml溶解于10mM柠檬酸盐缓冲液(pH 5.5)、207mM蔗糖、25mM赖氨酸HCl及0.02％聚山梨醇酯20中的本发明的结合分子的溶液。皮下施用的调配物可包括显著较高浓度，诸如高达100mg/ml或甚至大于100mg/ml的本发明的抗体。然而，本领域技术人员将清楚，如上所给出的成分及其量仅表示一种优选选择。其替代方案及变体将为本领域技术人员直接显而易见，或可易于自以上公开内容开始进行构想。
本发明的药物组合物可使用任何适合的施用模式向个体施用，包括例如通过输注或注射(静脉内、关节内、肌肉内、皮下、胸骨内、腹膜内、皮内)非经肠施用，以及经皮、鼻内、经颊或经口施用或通过吸入施用。为施用溶液或复原冻干粉末，非经肠施用模式为优选的。
一般而言，为治疗、预防和/或缓解本文所提及的疾病、病症及病状且视待治疗的特定疾病、病症或病状而定，待使用的本发明的特异性结合分子的效力、特定施用途径及所使用的特定药物调配物或组合物对待施用的实际剂量具有影响。此外，实际药学上有效量或治疗剂量亦将视本领域技术人员已知的因素而定，诸如患者的年龄及体重。在任何情况下，本发明的结合分子或本发明的药物组合物将基于患者独特病状以允许递送药学上有效量的剂量及方式施用。优选地，本发明的结合分子或本发明的药物组合物将以每公斤体重0.005与20.0mg之间的量及优选0.05与10.0毫克/公斤/剂之间且更优选0.5与5毫克/公斤/剂之间的剂量连续(例如通过输注)或更优选作为单次剂量施用。施用时间间隔可为例如一周两次、每周一次或每月一次剂量，但可显著变化，尤其视前面提及的参数而定。因此，在一些情况下，使用小于上文给出的最小剂量可为足够的，而在其他情况下必须超过上限。当施用较大量时，在一天内将其分成多个较小剂量为可取的。优选地，每周一次，以每公斤体重0.005与20.0mg之间的剂量范围，及优选0.05与10.0毫克/公斤/剂之间，且更优选0.5与5毫克/公斤/剂之间的剂量施用。
可使用任何适合的体外分析、基于细胞的分析、本身已知的体内分析和/或动物模型或其任何组合测试本发明的结合分子及包含其的组合物的功效，视所涉及的特定疾病而定。适合的分析及动物模型为本领域技术人员所清楚，且例如包括以下实施例中所用的分析及动物模型。
本发明的结合分子或本发明的药物组合物可独立地或与其他药理学活性成分组合使用，所述其他药理学活性成分诸如目前先进技术或标准照护化合物，诸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/检查点抑制剂及其类似物。
因此，本发明的另一方面提供本发明的结合分子或包含本发明的结合分子以及一种或多种其他活性成分及任选选用的药学上可接受的载剂的药物组合物。
根据本发明可作为组合搭配物施用的细胞生长抑制和/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(诸如血小板衍生生长因子(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)的生长因子)抑制剂、例如(抗)生长因子抗体、(抗)生长因子受体抗体的抑制剂及酪氨酸激酶抑制剂(诸如西妥昔单抗(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(例如抗叶酸盐，诸如甲胺喋呤(methotrexate)、雷替曲塞(raltitrexed)；嘧啶类似物，诸如5-氟尿嘧啶(5-fluorouracil，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，诸如巯基嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、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(例如蒽环霉素(anthracyclin))；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)、甲基二(氯乙基)胺(meclorethamine)、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulphan)、达喀尔巴嗪(dacarbazin)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、替莫唑胺(temozolomide)、亚硝基脲(诸如卡莫司汀(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，诸如长春花碱(vinblastine)、长春地辛(vindesin)、长春瑞滨(vinorelbin)及长春新碱(vincristine)；及紫杉烷(taxane)，诸如太平洋紫杉醇(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)(诸如依托泊苷(etoposide)及依托泊苷磷酸盐(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(诸如伏拉塞替(volasertib))、CDK抑制剂(包括CDK9抑制剂)、Aurora激酶抑制剂)、酪氨酸激酶抑制剂(例如PTK2/FAK抑制剂)、蛋白质蛋白质相互作用抑制剂、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)、地磷莫司(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、放射性药物、免疫治疗剂(诸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，诸如伊匹单抗(ipilimumab)、纳武利尤单抗(nivolumab)、帕博利珠单抗(pembrolizumab))及各种化学治疗剂(诸如阿米福汀(amifostin)、阿那格雷(anagrelid)、氯膦酸盐(clodronat)、非格司亭(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)、帕米膦酸盐(pamidronate)及卟吩姆(porfimer)))；蛋白酶体抑制剂(诸如硼替佐米(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；基质调节剂，诸如靶向CD137及FAP的分子(优选双特异性)；和/或细胞周期蛋白依赖性激酶9抑制剂。
根据本发明，优选为用本发明的结合分子或本发明的药物组合物与选自以下的药物组合进行的治疗：
(i)例如尤其在乳腺癌患者中，有或无化学疗法组合(包括新辅助背景下的多柔比星/环磷酰胺组合和/或卡培他滨/多西他赛组合；第一线及后续路线治疗的紫杉烷/铂方案)的抗VEGF抗体(贝伐珠单抗(bevacizumab)及其他抗血管生成物质)；
(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)例如用于治疗CRC患者的有或无化学疗法组合(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)或瑞戈非尼(regorafenib)组合的抗EGFR抗体(KRAS野生型肿瘤中的西妥昔单抗及帕尼单抗(panitumumab))；和/或
(iv)例如用于治疗CRC患者的免疫治疗剂，包括抗PD-1及抗PD-L1药剂及抗LAG3药剂，诸如埃本利单抗(ezabenlimab)、帕博利珠单抗及纳武利尤单抗以及如WO2017/198741所公开的其他抗体；和/或
(v)基质调节剂，诸如靶向CD137及FAP的分子(优选双特异性)。
在尤其优选实施方案中，本发明的结合分子或本发明的药物组合物用于与免疫检查点抑制剂组合，优选与PD-1拮抗剂，诸如抗PD-1抗体或抗PDL-1抗体组合治疗癌症。优选地，该抗PD-1抗体为选自由以下组成的组：帕博利珠单抗、纳武利尤单抗、皮立珠单抗(pidilizumab)、PD1-1、PD1-2、PD1-3、PD1-4及PD1-5，如WO2017/198741(以引用的方式并入本文中)中所述，更优选地，该抗PD-1抗体为埃本利单抗。优选地，该抗PDL-1抗体为选自由阿特珠单抗(atezolizumab)、阿维鲁单抗(avelumab)及德瓦鲁单抗(durvalumab)组成的组。
本发明进一步关于用于药物中的本发明的结合分子或本发明的药物组合物。本发明进一步关于用于制备药剂的本发明的结合分子或本发明的药物组合物。
此外，本发明还涉及本发明的结合分子或本发明的药物组合物，其用于治疗、改善或预防癌症的方法中。本发明进一步关于一种治疗、预防或改善癌症的方法，其包含向有需要的患者施用治疗有效量的本发明的结合分子或本发明的药物组合物。
待施用分子的“治疗有效量”为预防、改善或治疗癌症临床症状所必需的最小量，特别是对所治疗的特定癌症有效的最小量。
如本文所用，术语“癌症”意为包括所有类型的癌肿生长或致癌过程、转移性组织或恶性转型细胞、组织或器官(无论组织病理型或侵袭阶段)。因此，通过在体内的特定位置/源表征的下文提及的所有癌症、肿瘤、赘瘤等意为包括原发肿瘤及来源于其的转移性肿瘤。
生长可使用本文所述的多特异性结合分子抑制的癌症为任何表达TROP2/CDH17的肿瘤，包括(但不限于)T细胞淋巴瘤、骨髓白血病、乳腺癌；卵巢癌、口腔鳞状癌瘤及胃肠癌。胃肠癌包括但不限于食道癌(例如胃食管结合部癌)、胃部(胃)癌、肝细胞癌、胆道癌(例如胆管癌)、胆囊癌、胰腺癌或大肠直肠癌(CRC)。在一些实施方案中，以下癌症、肿瘤及其他增生性疾病可用本发明的多特异性结合分子治疗：头颈癌，优选HNSCC；肺癌；优选NSCLC；乳腺癌；甲状腺癌；子宫颈癌；卵巢癌；子宫内膜癌；肝癌(肝母细胞瘤或肝细胞癌)；胰腺癌；前列腺癌；胃肉瘤；胃肠基质瘤、食道癌；大肠癌；大肠直肠癌；肾癌；皮肤癌；脑瘤；神经胶母细胞瘤；非霍奇金氏淋巴瘤(Non-Hodgkin lymphoma)(T或B细胞淋巴瘤)；白血病(慢性或急性骨髓性白血病、非淋巴球性白血病)或多发性骨髓瘤。
在根据本发明使用的结合分子或药物组合物或者本发明的治疗、预防或改善癌症的方法或者本发明的用途之一优选实施方案中，癌症为大肠直肠癌(CRC)，包括转移性CRC(mCRC)、胃癌(GC)、胰腺癌(PAC)或食道癌。在本发明之一尤其优选实施方案中，癌症为mCRC。
大肠直肠癌(CRC)为ICD-10中列出的独特恶性疾病，且为全世界癌症发病率及死亡率的主要原因之一。大约25％CRC患者呈现明显癌转移且在40-50％新诊断的患者中产生转移性疾病。虽然近来化学疗法的改良已延长转移性CRC的存活持续时间，但大部分患者将死于其病。因此对治疗此疾病的其他治疗剂存在巨大需求。
已知大约30％-50％大肠直肠癌具有突变(异常)KRAS基因。在赘瘤中频繁发现的KRAS突变包括外显子2(密码子12及13)及外显子3(密码子61)处的突变且可由肿瘤生检分析。其包括活化突变，所述突变导致持续信号转导，刺激参与细胞生长、增殖、侵袭及癌转移的下游信号传导路径。因此，在一个实施方案中，本发明的结合分子用于治疗KRAS突变型大肠直肠癌(即，患有KRAS突变肿瘤的患者)。在一替代实施方案中，本发明的结合分子用于治疗KRAS野生型大肠直肠癌(即，患有KRAS野生型肿瘤的患者)。
胃部癌，也称为胃癌，为癌症相关死亡的第三大原因。虽然由于食物保存得到改善，使得20世纪早期以来发生率已降低，但胃部癌仍为具有不良预后的适应症，因为大部分患者呈现出已为晚期的疾病且疗法选择限于手术、化学疗法、放射及有限量的靶向疗法。
胰腺癌(PAC)为一种恶性疾病，其造成全世界每年>400,000例死亡。其为工业化国家中癌症相关死亡的最常见病因之一。尽管进行如手术及化学疗法的治疗性干预，占所有胰腺癌病例的约90％的胰腺癌通常具有极其不良预后，大约25％的人存活一年且仅5％的患者存活五年。
食道癌为全世界最常诊断出的癌症之一。类似于胰腺癌，其诊断困难且往往在已晚期阶段方诊断出，从而导致此适应症的预后极其不良。因此，其占癌症相关死亡的大约5％，因此使其成为第六最常见的癌症相关死亡病因。
两种主要类型的食道癌，即食道鳞状细胞细胞癌(ESCC，60-70％的病例)及食道腺癌(EAC，20-23％的病例)的发生率在不同地理区域之间极大地变化，其中ESCC在发展中国家中更常见，而EAC在工业化国家中为主型。当前治疗选择基本上限于手术及化学放射疗法。仅局部肿瘤在治愈性意向下治疗，而转移性疾病的疗法基本上为姑息性的。
如上文所陈述，本发明者已鉴别出本文所述的结合分子对靶向癌细胞具有许多效用且因此可用于表达TROP2及CDH17两者的癌症的疗法中。鉴别特定肿瘤是否表达TROP2及CDH17的方法为本领域所熟知。举例而言，免疫组织化学可用于判定肿瘤组织是否表达TROP2及CDH17(例如使用如本文所述的TROP2和/或CDH17抗体)且因此将适合于用本发明的结合分子治疗。
本发明的结合分子可用于第一线、第二线或任何其他路线治疗及维持治疗的情形中的治疗方案中。
在另一方面中，本发明的结合分子与适用于施用结合分子的装置，诸如注射器、注射笔、微型泵或其他装置组合使用。在另一方面中，本发明的结合分子包含于分装部分的试剂盒中，例如亦包括具有结合分子的使用说明的药品说明书。
实施例：
本发明现借助于以下非限制性实施例描述。
实施例1：鉴别Trop2及CDH17为在GI癌组织上共表达但不在正常组织上共表达的膜蛋白
用Affymetrix Chipset HGU133a及HGU133b量测自GeneLogic获得的肿瘤及关键正常组织中的Trop2及CDH17的基因表达，且证实在某些适应症，诸如胃、胰脏、食管及大肠直肠癌的肿瘤组织中的共表达，如图1中所示。在正常组织中未检测到共表达。
在人类肿瘤组织切片中，在单染色及双染色方案中，通过免疫组织化学，使用与Trop2(ENZ-ABS380，Enzo)及CDH17(760-4865，Roche Ventana)结合的抗体来进一步评估CDH17及Trop2蛋白的表达。此另外证实这些目标在胃、胰脏及大肠直肠来源的肿瘤细胞上的共表达(图2)。
实施例2：本发明的三特异性结合蛋白的示意图
为实现T细胞介导的共表达Trop2及CDH17的肿瘤细胞的溶解，设计结合Trop2、CDH17及CD3的多特异性结合蛋白。所使用之一种示例性分子设计具有IgG抗体支架及IgG样结构，如图3中所示。其特征在于本领域已知的用于异二聚的Fc域中的杵-臼技术，其中杵部分位于抗Trop2结合臂上且臼部分位于抗CDH17结合臂上。另外，结合蛋白在各臂中的轻链与相应重链之间具有可挠性肽序列。在此示例性设计中，CD3结合单链可变区附接至臼链的Fc部分。因此，结合蛋白包含三个抗原结合位点，一个结合于Trop2，另一个结合于CDH17，其中各臂包含单链Fab及Fc区，且第三抗原结合位点具有scFv结合于CD3。在优选分子设计中，结合分子为三特异性及三价的(即，对于三个目标中的各者分别为单价的)。
实施例3：抗原结合位点及三特异性结合分子的设计、构筑及验证
实施例3.1：使用自杂交瘤及培养的单B细胞回收的高通量V基因制备识别Trop2及CDH17的抗原结合位点.
为获得抗Trop2结合剂，在体外培养来源于经Trop2免疫接种的野生型及AlivaMab人源化小鼠(Ablexis,San Francisco,CA,USA：具有人类免疫球蛋白基因座的AlivaMab转基因小鼠平台)的杂交瘤或单B细胞。通过AlphaLISA(PerkinElmer,Waltham,MA,USA)关于针对重组人类Trop2的反应性来筛选上清液，且通过流动式细胞测量术证实与表达人类Trop2的原发癌细胞株的结合。
为获得抗CDH17结合剂，在Abpro(Abpro SOW#4)对野生型小鼠进行免疫接种。在体外培养来源于经免疫接种的小鼠的杂交瘤或单一B细胞。通过AlphaLISA(PerkinElmer,Waltham,MA,USA)，关于针对重组人类CDH17，且通过流动式细胞测量术，针对表达人类CDH17的AsPC-1胰脏肿瘤细胞株(CRL-1682)和/或NCI-H716大肠肿瘤细胞株(CCL-251)的细胞筛选上清液。淋巴结根据标准Abpro杂交瘤程序加工。通过ELISA，使用hCDH17-His(如下文实施例4.5中所描述来制备)进行初级筛选。通过流动式细胞测量术，针对上列2种细胞株筛选所有ELISA阳性孔。扩大所有ELISA及细胞株阳性孔且通过两种方法再测试。使用ForteBio Octet对扩增的阳性杂交瘤进行亲和力排序。
对于Trop2与CDH17，随后自鉴别的阳性克隆扩增免疫球蛋白(Ig)VH及VL基因。为自杂交瘤分离RNA，将约2×106个来自单一克隆的细胞粒化且用作源材料。对于单一B细胞，将自单独分离的B细胞扩增的100至500个细胞用作源材料。使用RNeasy Plus(Qiagen,Hilden,Germany)分离RNA。随后根据制造商说明书使用Smarter cDNA合成试剂盒(Clontech,Mountain View,CA)合成cDNA。
为促进cDNA合成，使用oligodT引发所有信使RNA的逆转录，之后用Smarter IIA寡核苷酸进行“5'封端”。使用靶向Smarter IIA端帽的5'引物及靶向CH1中的共有区的3'引物，使用2步PCR扩增进行VH及VL片段之后续扩增。简言之，各50μl PCR反应物由20μM正向及反向引物混合物、25μl PrimeStar Max DNA聚合酶预混合物(Clontech)、2μl未纯化的cDNA及21μl双蒸馏H2O组成。循环程序在94℃下开始，持续3分钟，接着35个周期(94℃持续30秒，50℃持续1分钟，68℃持续1分钟)，且在72℃下持续7分钟结束。用VL及VH第2轮引物进行第二轮PCR，所述引物含有“重叠”其各别pTT5母载体中的各别区域(VH及VL)的15bp互补延伸。用以下程序进行第二轮PCR：94℃持续3分钟；35个周期(94℃持续30秒，50℃持续1分钟，68℃持续1分钟)，及在72℃下持续7分钟结束。
使用HD克隆试剂盒(Clontech,U.S.A.)将VL基因定向克隆于pTT5huIgK载体中且将VH基因定向克隆于pTT5 huIgG1KO载体中。为促进HD克隆，PCR产物在In-Fusion HD克隆之前经纯化且用克隆增强剂处理。根据制造商的方案(Clontech,U.S.A.)进行克隆及转型。使Mini-prep DNA进行桑格定序(Sanger sequencing)以证实获得完整的V基因片段。
使用此方法，制备编码对Trop2及CDH17具有特异性的抗原结合位点的Ig VH与VL基因对。通过用相应的重链及轻链编码质体瞬时转染CHO-E37细胞制备重组抗体。
实施例3.2：重组抗体的证实筛选
通过流动式细胞测量术，分别针对与表达人类或食蟹猕猴Trop2及CDH17的细胞株的结合分析含有所表达重组抗体的上清液。简言之，将细胞与重组上清液一起培育，洗涤，且用抗人类-IgG-APC(Jackson ImmunoResearch 109-136-098)检测来自上清液的结合单克隆抗体(mAb)。通过以样品的中值荧光强度(MFI)除以同型对照的中值荧光强度来计算信号/背景比(S/B)(针对不相关蛋白质及不同恒定区主链的可变区)。
在Biacore 4000上对重组上清液进行表面等离子共振(SPR)。简言之，经由蛋白A/G将HTP上清液中的非优化IgG捕捉于传感器表面上，在10ul/min下持续60秒。监测100nM人类Trop2或100nM人类CDH17与捕捉的IgG的结合，在30ul/min下缔合180秒，随后在HBS-EP缓冲液中解离120秒。在各结合循环之间用甘氨酸pH 2.1进行蛋白A/G表面的再生。
在此分析中使用以下材料：蛋白质试剂：重组表达的人类Trop2及CDH17。系统操作缓冲液：HBS-EP缓冲液(10mM HEPES pH 7.4、150mM NaCl、3mM EDTA及0.005％v/v聚山梨醇酯P20)。捕捉试剂：蛋白A/G G(ThermoFisher Scientific,Waltham,MA,USA)，对所有人类IgG同型具有特异性。
选择所关注的克隆(Kd在nM范围内)用于多特异性形式化。随后产生多特异性结合蛋白且进一步在如下所述的机制及功能性筛选中评估(诸如细胞结合、细胞毒性及T细胞活化)。
实施例3.3：Trop2及CDH17结合剂的人源化及优化
如上文所述的Trop2及CDH17结合剂的序列经人源化和/或优化。抗体的序列优化/人源化为一种用于工程改造在非人类物种中产生(针对特异性抗原/抗原决定基)的用作治疗剂的抗体的方法，所述抗体与在人类中产生的抗体类似且由此在保留特异性的同时消除可能不良影响，诸如免疫原性。本文利用的序列优化/人源化方法为由Singh等人,2015(Singh S等人,mAbs 2015:7(4):778-91)描述。简言之，计算机仿真鉴别紧密匹配的人类生殖系，且使用噬菌体筛选方法评估优化/人源化变体。基于结合、人类评分百分比及Epivax(潜在免疫原性的计算机仿真预测工具)评分选择最终主要候选序列。
实施例3.4：CD3结合剂的scFv转变
为构筑编码CD3 scFv的基因区段，编码CD3结合可变域的VL与VH基因对来源于文献(Pessano等人,EMBO J.1985年2月；4(2):337-44；Salmerón A等人,J Immunol.1991年11月1日；147(9):3047-52)中描述的CD3结合剂的人源化，且通过编码肽序列GGSEGKSSGSGSESKSTGGS(SEQ ID NO:265)的可挠性接头的基因区段接合。
实施例3.5：结合Trop2、CDH17及CD3的三特异性蛋白质及对照的构筑
使用常用分子生物学技术，将Trop2、CDH17结合剂及CD3 scFv以及对应对照的可变区克隆至表达载体pTT5(National Research Council,Canada)中以形成具有一个Trop2特异性结合单元及CDH17特异性结合单元及CD3 scFv的三特异性结合蛋白，该Trop2特异性结合单元包含结合于Trop2的单链Fab及Fc区(此类结合单元在本文中也称为“Trop2臂”或“Trop2链”)，该CDH17特异性结合单元包含结合于CDH17的单链Fab及Fc区(此类结合单元在本文中也称为“CDH17臂”或“CDH17链”)，CD3 scFv附加至所述臂中之一者，优选CDH17臂的C端。使用20氨基酸之间隔子将scFv与Fc分开。Trop2及CDH17臂的Fc区包括“杵”或“臼”突变(Atwell等人,JMB,1997,270,26-35)且相应链称为杵或臼链。对于多片段DNA组装，根据制造商的方案，使用Gibson组装及NEBuilder HiFi DNA组装方法(New England Biolabs,Ipswich,MA,USA)。对DNA mini-prep定序。
各表达载体含有链编码基因(Trop2或CDH17臂/链)，即编码信号序列及轻链及重链的基因的真核启动子组件，原核选择标记基因(诸如氨苄西林)的表达卡匣及复制起点。使这些DNA质体在抗氨苄西林性大肠杆菌菌落中繁殖且纯化。
使用如上所述的Gibson组装及NEBuilder HiFi DNA组装方法，克隆包括Trop2/Trop2/CD3、CDH17/CDH17/CD3、Trop2/TNP/CD3、TNP/CDH17/CD3及TNP/TNP/CD3的各种组件中的对照分子，且克隆至pTT5载体中以进行短暂表达。
实施例4：结合Trop2、CDH17及CD3的三特异性三价结合蛋白的表达及纯化
通过用携带Trop2/CDH17/CD3-链编码基因的pTT5载体瞬时转染CHO-E细胞来产生结合Trop2、CDH17及CD3的三特异性分子以及对应对照。简言之，在摇瓶中在140rpm搅拌下在37℃及5％CO2下培养在无血清培养基中悬浮生长的经转染的CHO-E细胞且保持在指数生长的条件下。在转染当天，用杵链质体及臼链质体以1:3质量比以化学方式转染细胞。随后以1至2×106个细胞/毫升将其接种于1LFreeStyleTMCHO表达培养基(LifeTechnologies,NY,US)中。随后在轨道震荡下将细胞培育10天，一次馈送200ml市售进料溶液以允许表达蛋白质。根据制造商说明书，使用仪器(Pall ForteBio,CA,US)及protA生物传感器尖端测定细胞培养上清液中的抗体力价。
以两步法自培养上清液纯化重组Trop2/CDH17/CD3结合蛋白：首先通过蛋白A亲和色谱使用MabSelectTM柱(GE Healthcare)；其次，通过阳离子交换色谱使用Poros 50HS柱(Applied Biosystems,Carlsbad,CA,USA)。将经两步纯化的材料储存于50mM醋酸钠及100mM NaCl pH 5.0的最终缓冲液中，通过分析型尺寸排阻色谱、质谱分析及分析型超速离心评估样品的纯度及异质性程度。进行功能性测试的样品包含经两步纯化的材料，单体含量>98％。
实施例4.1：抗Trop2抗体的构架工程改造以降低等电点不平衡
随后对含有抗Trop2、抗CDH17及抗CD3的三特异性分子进一步修饰以将观测到的聚集的量减至最少(在单步ProA纯化之后单体约65％)。个别Fv臂的计算机仿真分析显示，抗Trop2抗体的pI(pI＝7.7)比抗CDH17(pI＝8.5)及抗CD3臂(pI＝8.8)低1个单位。此工程改造策略的假设为，抗Trop2臂的pI升高至与抗CDH17及抗CD3臂一致将减少聚集及增加单体百分比。突变为选自在至少一条天然存在的重链或κ轻链(无论家族如何)中的构架位置中具有赖氨酸或精氨酸的残基子集。重链(+亲本)中存在总共7个所选择的点突变且轻链(+亲本)中存在总共4个点突变。电荷变体的模型化显示单点突变的并入使抗Trop2 Fv的pI提高至8.3的平均值，且双突变体(重链上的一个，轻链上的一个)使pI提高至8.8。
以下突变经选择适合于提高抗Trop2 Fv的pI：VH：S19K、T23K、G43R、S61K、T72R、S83R、T85R，及VL：Q3R、S65K、S76R、Q79K。编号为基于Kabat编号方案且VH或VL域的第一个氨基酸分别计为编号1(即，突变S19K为VH域的第19个氨基酸中的突变等)。
实施例4.2：抗CD3 scFv的优化以提高稳定性
为提高抗CD3 scFv的稳定性，使用基于结构建模的方法。经由MOE(ChemicalComputing Group,ULC)中的Antibody Modeler进行的高通量抗体建模，建立CD3#1的Fv部分(SEQ ID NO:222)的分子模型。使用该结构模型计算Fv区中的VL及VH界面稳定性以及其溶液及分子表面的描述符。鉴别经计算机仿真确定影响生物物理学特性的位置，且产生变体的文库且针对三特异性形式中的提高的血清稳定性进行筛选。鉴别轻链中的八个突变(R23G、E40Q、L45A、G59W、V60T、L77I、E87D及F89Y)及重链中的9个突变(K19R、S30N、G49A、D68G、T80S、A81L、N87S、K89R及T90A)，所述突变个别(参见例如CD3#8，SEQ ID NO:229中)或组合地(参见例如CD3#2(SEQ ID NO:223)、3(SEQ ID NO:224)、5(SEQ ID NO:226)、7(SEQID NO:228)中)影响生物物理学特性。同样，编号为基于Kabat编号方案且VH或VL域的第一个氨基酸分别计为编号1(即，突变R23G为VL域的第23个氨基酸中的突变等)。
实施例4.3：Trop2/CDH17/CD3结合蛋白的单体含量百分比
通过分析型尺寸排阻色谱(aSEC)，确定示例性Trop2/CDH17/CD3结合蛋白的单体百分比，如表2中所示。在Waters(Milfrod,MA,USA)Acquity UPLC系统上使用蛋白质BEHSEC柱1.7μm，4.6×150mm(目录号186005225)进行aSEC。操作条件如下：移动相：50mM磷酸钠，200mM精氨酸及0.05％叠氮化钠；流动速率：0.5ml/min；运转时间：5分钟；样品负载量：10μg；峰值检测：A280nm；色谱图的自动化处理方法。
表2：含有Trop2、CDH17及CD3的三特异性分子的第一及第二纯化步骤之后的单体百分比。各别结合剂的序列可见于表1。
实施例4.4：热稳定性
通过热偏移分析(TSA)测定热稳定性且代表性Trop2/CDH17/CD3结合蛋白的第一熔融转变(Tm1)结果展示于表3中。使用QuantStudio 6Flex实时PCR系统(AppliedBiosystems,Waltham,MA)，利用SYPRO Orange(Invitrogen,Carlsbad,CA)作为外源性荧光团获得随温度而变的荧光强度概况。将样品在具有40mM氯化钠及0.02％叠氮化钠的10mM组氨酸pH6.0中稀释至0.4mg/ml。以2℃/min的速率用25℃至95℃的热斜变生成熔融曲线，经由过滤器组(Ex：580±10nm，Em：623±14nm)大约每0.4℃收集资料。使用蛋白质热偏移软件版本1.3(ThermoFisher Scientific,Waltham,MA)分析资料。
表3：通过代表性Trop2/CDH17/CD3结合蛋白的第一熔融转变(Tm1)量测的热稳定性实施例4.5：产生重组蛋白
人类Trop2-His及人类CDH17-His
使用HEK-293细胞(Thermo Fisher)、Lenti-X慢病毒系统(Clontech)及编码人类Trop2-His(人类Trop2寄存编号P09758)及人类CDH17-His(人类CDH17寄存编号Q12864)的质体生成产生人类Trop2-His及人类CDH17-His的细胞株。为了表达，在37℃、5％CO2及140rpm震荡下培养及扩增细胞。在表达第0天，粒化细胞且再悬浮于Expi 293培养基中。在表达第3天，通过在4700rpm下将细胞粒化40分钟来收获经调节的培养上清液。在纯化之前将蛋白酶抑制剂添加至生物质。通过西方墨点法证实表达。用0.5mM TCEP、0.02％CHAPS、10mM咪唑调整经调节的培养上清液。在HisTrap Ni excel柱及缓冲液A：50mM MES、50mMNaCl、0.5mM TCEP、0.02％CHAPS pH 6.5上进行纯化。在补充有0.5M咪唑的缓冲液A pH 8.5中，使用自20mM咪唑至500mM咪唑的洗脱梯度洗脱所关注蛋白质。将经汇集的洗脱份在以下缓冲液中渗析：50mM MES、50mM NaCl、1mM TCEP、0.02％CHAPS、0.2M精氨酸、3％甘油pH6.5。通过质谱分析及分析型超速离心检核纯化材料。
Cyno Trop2-His及Cyno CDH17-His
使用HEK-293细胞(Thermo Fisher)、Lenti-X慢病毒系统(Clontech)及编码CynoTrop2-His(Cyno Trop2寄存编号：寄存编号XP_001114599.1(RefSeq))及Cyno CDH17-His(Cyno CDH17寄存编号:XP_005563762.1(RefSeq))的质体生成产生Cyno Trop2-His及CynoCDH17-His的细胞株。为了表达，在37℃、5％CO2及140rpm震荡下培养及扩增细胞。在表达第0天，粒化细胞且再悬浮于Expi 293培养基中。在表达第3天，通过在4700rpm下将细胞粒化40分钟来收获经调节的培养上清液。在纯化之前将蛋白酶抑制剂添加至生物质。通过西方墨点法证实表达。用0.5mM TCEP、0.02％CHAPS、10mM咪唑调整经调节的培养上清液。在HisTrap Ni excel柱及缓冲液A：50mM MES、50mM NaCl、0.5mM TCEP、0.02％CHAPS pH 6.5上进行纯化。在补充有0.5M咪唑的缓冲液A pH 8.5中，使用自20mM咪唑至500mM咪唑的洗脱梯度洗脱所关注蛋白质。将经汇集的洗脱份在以下缓冲液中渗析：50mM MES、50mM NaCl、1mM TCEP、0.02％CHAPS、0.2M精氨酸、3％甘油pH6.5。通过质谱分析及分析型超速离心检核纯化材料。
实施例5：用于选择结合剂的细胞株的产生
为产生表达单独或与Trop2组合的全长人类CDH17的稳定HEK293细胞，将CDH17(蛋白质寄存编号Q12864)的编码序列克隆至pCMV6(Origene)中。为产生表达单独或与CDH17组合的全长人类Trop2的稳定HEK293细胞，自Origene(#RC202519)获得包含具有C端Myc-DDK卷标的Trop2的编码序列的pCMV6。使用细胞株核酸转染试剂盒V(Amaxa)根据制造商说明书转染HEK293细胞且分别使用遗传霉素(geneticin)及嘌呤霉素(puromycin)选择确立稳定克隆。
通过流动式细胞测量术，使用抗Trop2(R&D#MAB650)及抗CDH17(R&D#MAB1032)初级抗体，接着经PE标记的抗小鼠二级抗体(Dako#R0480)验证重组蛋白的表达。
实施例6：选择具有亲和力潜能的CDH17结合剂及证实三特异性形式的亲和力潜能
测试二价及单价形式的四种不同CDH17结合蛋白(即，CDH17#6、CDH17#4、CDH17#7及CDH17#1；均如实施例3中所述产生；各别结合剂的序列可见于表1)的结合。为此，通过流动式细胞测量术分析其与如实施例5中所述制备的重组表达人类CDH17的HEK293细胞株的结合。
将HEK293细胞在FACS缓冲液(PBS/0.5％BSA/0.05％叠氮化钠)中以增加浓度的经两步纯化的二价或单价CDH17结合蛋白染色。用FITC结合的抗人类二级抗体(Invitrogen05-4211)检测结合分子。各CDH17结合蛋白的亲和力潜能通过比较各别单价形式的结合曲线与二价形式的结合曲线来评估(图4)。选择展示自单价至二价形式的显著亲和力转变的结合蛋白用于后续实验。
为进一步测试这些CDH17结合剂活化T细胞的潜能，各种CDH17结合剂组装成三特异性Trop2/CDH17/CD3结合分子且在单独表达CDH17或表达CDH17与Trop2的组合的Hek293细胞存在下评估T细胞活化。在此分析中，以10:1的效应:靶细胞比率，将Trop2/CDH17阳性细胞株与作为效应细胞的人类T细胞及增加浓度的Trop2/CDH17/CD3结合分子共培养72小时。通过用携带链编码基因的pTT5载体瞬时转染CHO-E细胞产生Trop2/CDH17/CD3结合分子，如实施例4中所描述。
自Stemcell Technologies获得冷冻人类周边血液单核细胞(PBMC)。洗涤细胞且再悬浮于分析培养基中，该分析培养基含有无酚红的RPMI-1640(Gibco/Lonza#BE 12-918-F)、5％HiFBS(FBS、HyClone(Thermo Scientific，目录号：SH30071.03)，加热不活化，56℃，30分钟)、Glutamax(Gibco#35050-061)、27.5μMβ-巯基乙醇(Gibco#21985-023)。使用全T细胞分离试剂盒II(Miltenyi Biotec#130-091-156)通过阴性选择自洗涤的PBMC分离T细胞。简言之，将周边血液单核细胞再悬浮于40μl缓冲液PBS/0.5％BSA(Gibco ref#041-94553M)/2mM EDTA(Invitrogen ref#15575-038)/10个Mio细胞中且与10μl生物素-抗体混合物/10个Mio细胞一起在4℃下培育5分钟。接着，添加30μl缓冲液及20μl抗生物素MicroBeds/1千万个细胞且在4℃下培育10分钟。接着，在适合MACS分离器(MiltenyiBiotec)的磁场中将混合物置放于预冲洗的25LS柱(Miltenyi Biotec#130-042-401)中。收集包含T细胞的流过物且在分析培养基中洗涤。
随后，将靶细胞及T细胞以1:10的比率与指定浓度(参见图5)的Trop2/CDH17/CD3结合蛋白一起培育72小时。
为测定T细胞活化，将细胞离心且用针对CD4(Biolegend#31744)、CD8(BD#562428)及CD69(BD#557745)的抗体染色，且通过流动式细胞测量术量测荧光。结果描绘于图5中。
通过比较在仅表达人类CDH17(图5A)或表达CDH17与Trop2的组合(图5B)的HEK293细胞存在下诱导的CD8+T细胞活化的量来分析亲和力潜能。仅选择在仅表达CDH17的HEK293细胞存在下在100nM下引起小于20％T细胞活化的结合剂用于进一步评估。
实施例7：选择具有亲和力潜能的Trop2结合剂及证实三特异性形式的亲和力潜能
测试二价(IgG)或单价(具有虚拟结合臂的杵-臼形式)形式的七种不同Trop2结合剂(Trop2#1至Trop2#7；各别结合剂的序列可见于表1)的结合。在单价形式中，结合位点中之一者置换为与四硝基苯酚(TNP；包括SEQ ID No:167及168的VH及VL域)结合的结合位点，四硝基苯酚为真核情形中不存在的不相关抗原。为此，通过流动式细胞测量术分析其与如实施例5中所述制备的重组表达人类Trop2的HEK293细胞株的结合。如实施例4中所描述，产生Trop2结合蛋白。
将HEK293细胞在FACS缓冲液(PBS/0.5％BSA/0.05％叠氮化钠)中以增加浓度的经两步纯化的二价或单价Trop2结合蛋白染色。用FITC结合的抗人类二级抗体(Invitrogen05-4211)检测结合分子。各Trop2结合蛋白的亲和力潜能通过比较各别单价形式的结合曲线与二价形式的结合曲线来评估(图6)。选择展示自单价至二价形式的显著亲和力转变的结合蛋白用于以下实验。
为进一步测试这些Trop2结合剂活化T细胞的潜能，各种Trop2结合剂组装成三特异性Trop2/CDH17/CD3结合分子且在单独表达CDH17或单独表达Trop2或表达CDH17与Trop2的组合的Hek293细胞存在下评估T细胞活化。在此分析中，以10:1的效应:靶细胞比率，将Trop2/CDH17阳性HEK293细胞株与作为效应细胞的人类T细胞及增加浓度的Trop2/CDH17/CD3结合分子共培养72小时。将具有不同抗原亲和力的三种不同Trop2结合剂以三特异性形式与实施例6中鉴别的CDH17结合剂组合(图5A)以在仅表达CDH17的HEK293细胞存在下诱导最低T细胞活化。通过用携带链编码基因的pTT5载体瞬时转染CHO-E细胞产生Trop2/CDH17/CD3结合分子，如实施例4中所描述。如实施例6中所述分离人类T细胞。
随后，将靶细胞及T细胞以1:10的比率与指定浓度(参见图7)的Trop2/CDH17/CD3结合分子一起培育72小时。
如实施例6中所述确定T细胞活化状态。
通过比较在仅表达人类Trop2(图7B)、仅表达人类CDH17(图7C)或表达人类CDH17与人类Trop2的组合(图7A)的HEK293细胞存在下诱导的CD8+T细胞上CD69上调的量来分析亲和力潜能。同样，选择在单价结合情形下，即在表达CDH17(仅)或Trop2(仅)的细胞上在10nM下引起小于20％T细胞活化的结合剂用于后续实验。
通过基于流动式细胞测量术的史卡查方法(Scatchard method)评估对HEK293细胞上表达的Trop2的结合亲和力且揭露对Trop2#1的Kd为2.2nM，对Trop2#5的Kd为0.6且对Trop2#7的Kd为0.4。亲和力潜能与经由此方法确定的亲和力反相关，此表明仅二价形式的低亲和力结合剂允许区分单阳性细胞与双阳性细胞。
实施例8：在细胞结合分析中分析各种三特异性Trop2/CDH17/CD3结合剂组合的亲和力潜能
为证实基于亲和力的效力增加，将三种不同Trop2/CDH17/CD3三特异性结合分子(Trop2#1/CDH17#1/CD3#1、Trop2#5/CDH17#1/CD3#1、Trop2#7/CDH17#1/CD3#1，参见图8)的目标结合与双特异性Trop2/Trop2/CD3结合分子以及三特异性Trop2/TNP/CD3结合分子的结合相比较。为此，通过流动式细胞测量术测试这些分子与重组表达人类Trop2(图8A)或共表达人类Trop2及人类CDH17(图8B)的HEK293细胞株的结合。如实施例4中所述产生Trop2/CDH17/CD3、Trop2/TNP/CD3及Trop2/Trop2/CD3结合蛋白。
将重组表达人类Trop2或共表达人类Trop2及人类CDH17的HEK293细胞在FACS缓冲液(PBS/0.5％BSA/0.05％叠氮化钠)中以增加浓度的经两步纯化的Trop2/CDH17/CD3、Trop2/Trop2/CD3及Trop2/TNP/CD3结合分子染色。用FITC结合的抗人类二级抗体(Invitrogen 05-4211)检测结合分子。通过比较单价及二价结合曲线来评估各三特异性结合分子的亲和力潜能。不选择仅展示与Trop2的显著结合的结合蛋白用于亲和力优化的双特异性结合方法。结果展示于图8中。各别结合剂的序列可见于表1。
实施例9：表达CDH17、Trop2或共表达两者的细胞中介导T细胞诱导的溶解的效力。
为解决Trop2/CDH17/CD3结合蛋白对共表达Trop2及CDH17两种蛋白的人类细胞的选择性，测试通过重新引导未经刺激的T细胞至表达人类CDH17和/或人类Trop2的细胞来诱导溶解的能力。
如下所述，使用乳酸脱氢酶(LDH)释放作为细胞溶解的读取，确定T细胞介导的Trop2/CDH17阳性细胞株的溶解的效力。在此分析中，以10:1的效应:靶细胞比率，将表达Trop2或CDH17或两者的细胞株与作为效应细胞的人类T细胞及增加浓度的Trop2/CDH17/CD3结合分子共培养72小时。通过用携带链编码基因的pTT5载体瞬时转染CHO-E细胞产生Trop2/CDH17/CD3结合分子，如实施例4中所描述。
如实施例6中所述，自冷冻PBMC分离人类T细胞。
使用细胞毒性检测试剂盒PLUS(Roche)，根据制造商说明书测定细胞毒活性。简言之，此方法为基于LDH自死亡或细胞质膜受损细胞的释放。将细胞培养上清液与来自试剂盒的反应混合物一起培育30分钟且在分光亮度计中在500nm下量测作为细胞溶解的替代的因LDH活性而引起的甲臜形成。根据下式计算相对于最大溶解对照的细胞毒性百分比：
背景：靶细胞+效应细胞
最大溶解：靶细胞+5％Triton X-100
最小溶解：靶细胞
使用GraphPad Prism 5软件，针对相应Trop2/CDH17/CD3结合分子浓度绘制细胞毒性相对于最大溶解对照的百分比。用四参数逻辑斯谛方程(logistic equation)模型分析剂量反应曲线以评估S形剂量-反应曲线。
虽然三特异性Trop2/CDH17/CD3结合分子以良好功效介导Trop2+/CDH17+细胞的溶解，但仅表达Trop2或仅表达CDH17的细胞株的情况分别并非如此，因此证实所述三特异性分子的亲和力增强的生物活性(参见图9A)。亲和力方法的特异性通过以下事实进一步证实：单价结合Trop2(Trop2/TNP/CD3)或CDH17(TNP/CDH17/CD3)的对照分子不能诱导显著靶细胞溶解。相同形式的Trop2及CDH17的二价结合剂用作对照。
为在癌症背景下证实亲和力方法(参见图9B)，在共表达Trop2/CDH17的大肠直肠癌细胞株DLD-1以及经工程改造缺乏CDH17，因此仅表达Trop2的DLD-1克隆中评估重新引导的T细胞的细胞毒性。自ATCC获得DLD-1细胞且产生引入报导蛋白GFP的缺乏CDH17的DLD-1克隆。48小时之后，通过流动式细胞测量术(Sonysorter)分离GFP阳性转染物且通过限制稀释来分离克隆。通过使用CDH17特异性抗体用西方墨点法分析克隆蛋白质提取物的CDH17含量来证实CDH17的缺乏。
Trop2+CDH17-克隆的细胞溶解与对Trop2+CDH17+亲本细胞株的作用相比显著减少，由此证实基于亲和力的效力增加。Trop2/CDH17/CD3结合分子对Trop2+CDH17-克隆的活性对应于单价Trop2结合剂(Trop2/TNP/CD3)的活性，因此证实对Trop2+/CDH17-靶细胞的作用为Trop2介导的。
图9展示用代表Trop2结合剂(Trop2#1、#8、#9、#10、#11、#12、#13、#14、#15、#16、#17、#18)与CDH17结合剂(CDH17#1、#8)及CD3结合剂(CD3#1、#2、#3)的若干示例性组合的一系列分子获得的功能数据，其中显示基于亲和力的效力增加。各别结合剂的序列可见于表1。
实施例10：证实CDH17结合对亲和力诱导的效力增加的影响
为证实CDH17结合对亲和力诱导的效力增加的影响，将五种不同Trop2结合剂与CDH17结合臂或针对不相关目标四硝基苯酚(TNP)的结合剂分别组合成Trop2/CDH17/CD3或Trop2/TNP/CD3结合分子。在此分析中，以10:1的效应:靶细胞比率，将Trop2/CDH17阳性大肠直肠癌细胞株SK-CO1与作为效应细胞的未经刺激的人类T细胞及增加浓度的Trop2/CDH17/CD3或Trop2/TNP/CD3结合分子共培养72小时。通过用携带链编码基因的pTT5载体瞬时转染CHO-E细胞产生Trop2/CDH17/CD3结合分子，如实施例4中所描述。细胞毒性活性如实施例9中所述来测定。如实施例6中所描述，自健康供体PBMC分离T细胞。CDH17结合臂引起效力显著增加，Trop2/CDH17/CD3的EC50相对于Trop2/TNP/CD3增加40-60倍；如图10中所示(各别结合剂的序列可见于表1)。
实施例11：比较杵-臼形式
以两种不同杵-臼形式(即，臼臂上为Trop2且杵臂上为CDH17/CD3或反过来)产生三特异性分子，且如实施例9中所述来评估其对T细胞介导的细胞毒性的作用。尽管两种类型的形式均很好地起作用，但意外地发现CD3与CDH17结合部分均位于分子的臼部分上的构建物一致地具有较高效能，与所用结合剂无关(示例性结果参见图11；相应结合剂的序列可见于表1中)。
实施例12：证实体内肿瘤生长抑制
使用用人类T细胞重组的人类异种移植小鼠模型进行功效研究。详言之，将人类HPAF-II胰腺癌细胞(5×107)皮下注射(s.c.)至NOG小鼠的右背侧腹。平行地，如上所述，使用全T细胞分离试剂盒II(Miltenyi Biotec#130-091-156)通过阴性选择自PBMC分离人类T细胞。
随后，使用T细胞活化/扩增试剂盒人类(Miltenyi Biotec目录号130-091-441，批号5170720843)将T细胞扩增20天。简言之，抗生物素MACSiBeadTM粒子负载有CD2生物素、CD3生物素、CD28生物素且以每个粒子2个细胞的比率转移至经纯化的T细胞且在20个单位重组IL-2(R&D#202-IL-050/CF)存在下以0.5-1×106个细胞/毫升的密度培育20天。细胞每三天补充20个单位新鲜IL-2。在注射于动物中之前的三天，用装载有CD2生物素、CD3生物素、CD28生物素的抗生物素MACSiBeadTM粒子以每4个细胞1个珠粒的比率再刺激T细胞额外三天。最后，用MACSiMAG分离器(Miltenyi Biotec)移除珠粒且在PBS中洗涤T细胞。
第14天，基于肿瘤体积将动物随机分为处理组且腹膜内(i.p.)注射2×107个人类T细胞。第17天开始用三特异性分子进行处理。以每周一次给药方案，通过静脉内(i.v.)推注注射至侧尾静脉中，施用Trop2/CDH17/CD3结合蛋白、Trop2/TNP/CD3结合蛋白、TNP/CDH17/CD3结合蛋白或媒剂缓冲液(50mM NaOAc、100mM NaCl，pH 5.0)。通过外部测径规量测监测肿瘤生长且使用标准半椭球公式计算肿瘤体积。
在研究结束时，通过对人类CD3进行免疫组织化学(IHC)染色在脾中证实人类T细胞植入。仅将在研究结束时展示人类T细胞植入的那些动物包括于统计分析中。在研究期间早期出于道德原因对达到处死准则的动物施以安乐死。
如图12中所示，每周一次用三特异性Trop2/CDH17/CD3结合分子(由SEQ ID NO:436与437的组合或SEQ ID NO:214与271的组合表示)处理负载肿瘤小鼠诱导显著肿瘤消退，但用相同剂量及处理时间间隔的对照Trop2/TNP/CD3或TNP/CDH17/CD3结合分子处理无显著肿瘤消退。
序列表
<110> 勃林格殷格翰国际有限公司
<120> 新颖三特异性结合分子
<130> PJ12750A
<160> 437
<170> BiSSAP 1.3.6
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR1
<400> 1
Asp Tyr Thr Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR2
<400> 2
Gly Ile Tyr Pro Asn Tyr Gly Asp Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 3
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR3
<400> 3
Lys Thr Val Leu Leu Arg Leu Arg Tyr Phe Asp Val
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LCDR1
<400> 4
Arg Ala Ser Gly Asn Ile His Asn Tyr Leu Ala
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LCDR2
<400> 5
Asn Ala Ile Thr Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LCDR3
<400> 6
Gln His Phe Trp Ser Thr Pro Phe Thr
1 5
<210> 7
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR1
<400> 7
Arg Tyr Ser Val His
1 5
<210> 8
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR2
<400> 8
Met Ile Trp Gly Gly Gly Ser Thr Asp Tyr Asn Ser Asp Phe Lys Pro
1 5 10 15
<210> 9
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR3
<400> 9
Lys Gly Ser Tyr Tyr Thr Asn Tyr Gly Ala Met Asp Tyr
1 5 10
<210> 10
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LCDR1
<400> 10
Lys Ala Ser Gln Asp Ile Asn Lys Tyr Ile Ala
1 5 10
<210> 11
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LCDR2
<400> 11
Tyr Thr Ser Thr Leu Gln Pro
1 5
<210> 12
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LCDR3
<400> 12
Leu Gln Tyr Asp Asn Leu Trp Thr
1 5
<210> 13
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11, #12, #13, #14, #15, #16, #17, #18 HCDR1
<400> 13
Ser Gly Tyr Tyr Trp Asn
1 5
<210> 14
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HCDR2
<400> 14
Tyr Ile Ser Tyr Asp Gly Arg Asn Asn Tyr Asn Pro Ser Leu Lys Asn
1 5 10 15
<210> 15
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11, #12, #13, #14, #15, #16, #17, #18 HCDR3
<400> 15
Asp Thr Thr Ala Tyr Phe Asp Tyr
1 5
<210> 16
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 LCDR1
<400> 16
Arg Ala Ser Glu Ser Val Asp Ser Ser Val Asn Arg Phe Met His
1 5 10 15
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11, #12, #13, #14, #15, #16, #17, #18 LCDR2
<400> 17
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11, #12, #13, #14, #15, #16, #17, #18 LCDR3
<400> 18
Gln Gln Ser Asn Glu Asp Pro Tyr Thr
1 5
<210> 19
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12, #13, #14, #15, #16, #17, #18 HCDR2
<400> 19
Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 20
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12, #13, #14, #15, #16, #17, #18 LCDR1
<400> 20
Arg Ala Ser Glu Ser Val Ser Ser Ser Val Asn Arg Phe Leu His
1 5 10 15
<210> 21
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR1
<400> 21
Asp Tyr Tyr Met Asn
1 5
<210> 22
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR2
<400> 22
Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 23
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR3
<400> 23
Glu Asp Ser Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 24
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 LCDR1
<400> 24
Lys Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Phe Leu His
1 5 10 15
<210> 25
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9, #10 LCDR2
<400> 25
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 26
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 LCDR3
<400> 26
Ser Gln Ser Thr His Val Tyr Thr
1 5
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR1
<400> 27
Asn Tyr Tyr Ile His
1 5
<210> 28
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR2
<400> 28
Tyr Ile Tyr Pro Gly Asn Gly Ala Thr Ala Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 29
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR3
<400> 29
Glu Asp Tyr Tyr Tyr Ala Met Asp Tyr
1 5
<210> 30
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 LCDR1
<400> 30
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 31
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 LCDR3
<400> 31
Ser Gln Ser Thr His Val Trp Thr
1 5
<210> 32
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1, #8 HCDR1
<400> 32
Asp His Thr Ile His
1 5
<210> 33
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR2
<400> 33
Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 34
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1, #8 HCDR3
<400> 34
Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe Asp Tyr
1 5 10
<210> 35
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 LCDR1
<400> 35
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 36
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 LCDR2
<400> 36
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 37
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1, #8 LCDR3
<400> 37
Gln Gln Tyr Tyr Ser Tyr Pro Trp Thr
1 5
<210> 38
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR2
<400> 38
Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu Lys Phe Gln
1 5 10 15
Gly
<210> 39
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 LCDR1
<400> 39
Arg Ala Ser Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Gln Tyr Leu
1 5 10 15
Ala
<210> 40
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 LCDR2
<400> 40
Gly Ala Ser Thr Arg Glu Thr
1 5
<210> 41
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#1 至 #25 HCDR1
<400> 41
Thr Tyr Ala Met Asn
1 5
<210> 42
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#1 至 #5, CD3#8 至 #16, #21, #24, #25 HCDR2
<400> 42
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 43
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#1 至 #11, #13, #14, #16, #21, #24, #25 HCDR3
<400> 43
His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 44
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#1 至 #11, #13, #14, #15 LCDR1
<400> 44
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 45
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#1 至 #13, #17, #19, #20, #22, #23, #24 LCDR2
<400> 45
Gly Thr Asn Lys Arg Ala Pro
1 5
<210> 46
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#2, #11 LCDR3
<400> 46
Ala Leu Trp Tyr Ser Asn Lys Trp Val
1 5
<210> 47
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#1, all of CD3#3 至 #10, #13 至 #16 LCDR3
<400> 47
Ala Leu Trp Tyr Ser Asn Leu Trp Val
1 5
<210> 48
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CD3#6, #7, #17, #18, #19 HCDR2
<400> 48
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Gly
<210> 49
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#12, #15 HCDR3
<400> 49
His Gly Asn Phe Leu Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 50
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#12 LCDR1
<400> 50
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Tyr Tyr Ala Asn
1 5 10
<210> 51
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#12 LCDR3
<400> 51
Ala Leu Trp Tyr Ser Asn His Trp Val
1 5
<210> 52
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD3#14, #15, #16, #18, #21, #25 LCDR2
<400> 52
Gly Thr Asn Ile Arg Ala Pro
1 5
<210> 53
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 LCDR1
<400> 53
Ile Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 54
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#17, #18, #19, #22, #23 HCDR3
<400> 54
His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 55
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#17 LCDR1
<400> 55
Gly Arg Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 56
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#18, #23 LCDR1
<400> 56
Gly Ser Ser Thr Gly Ala Val Thr Thr Ser Trp Tyr Ala Asn
1 5 10
<210> 57
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#19, #22, #25 LCDR1
<400> 57
Gly Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 58
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CD3#20 HCDR2
<400> 58
Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Gly
<210> 59
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#20 HCDR3
<400> 59
His Gly Asn Phe Gly Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10
<210> 60
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#20 LCDR1
<400> 60
Val Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 61
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CD3#21, #24 LCDR1
<400> 61
Gly Ser Ser Thr Gly Ala Val Thr Thr Ser Tyr Tyr Ala Asn
1 5 10
<210> 62
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CD3#22 HCDR2
<400> 62
Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ile
1 5 10 15
Val Lys Gly
<210> 63
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CD3#23 HCDR2
<400> 63
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ile
1 5 10 15
Val Lys Gly
<210> 64
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#26, #27 HCDR2
<400> 64
Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asn
<210> 65
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#26, #27 HCDR3
<400> 65
Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 66
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#26 至 #30, #33, #35, #37, #39, #42, #43 LCDR1
<400> 66
Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 67
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#26 至 #43 LCDR2
<400> 67
Trp Ala Ser Thr Arg Lys Ser
1 5
<210> 68
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#26 至 #43 LCDR3
<400> 68
Ile Gln Ser Phe Ile Leu Arg Thr
1 5
<210> 69
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#28, #34 HCDR2
<400> 69
Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 70
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#28, #32, #39, #42, #43 HCDR3
<400> 70
Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 71
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#31, #32, #34, #36 LCDR1
<400> 71
Lys Ser Ser Gln Ser Leu Leu Asn Ala Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 72
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#29 HCDR2
<400> 72
Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Ala Glu Lys Phe Lys
1 5 10 15
Gly
<210> 73
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#30, #32 HCDR2
<400> 73
Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 74
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#31 HCDR2
<400> 74
Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe Lys
1 5 10 15
Gly
<210> 75
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#33 HCDR2
<400> 75
Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 76
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#35 HCDR2
<400> 76
Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Asn Gln Lys Phe Gln
1 5 10 15
Asn
<210> 77
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#36 HCDR2
<400> 77
Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe Gln
1 5 10 15
Asn
<210> 78
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#37 HCDR2
<400> 78
Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Ala Gln Lys Phe Lys
1 5 10 15
Gly
<210> 79
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#38, #40, #41 HCDR2
<400> 79
Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 80
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#38, #40, #41 LCDR1
<400> 80
Arg Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 81
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD3#39, #42, #43 HCDR2
<400> 81
Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe Gln
1 5 10 15
Gly
<210> 82
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> all of CD3#26 至 #43 HCDR1
<400> 82
Ser Tyr Trp Met His
1 5
<210> 83
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 VH
<400> 83
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Leu 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
Thr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Gly Ile Tyr Pro Asn Tyr Gly Asp Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Lys Thr Val Leu Leu Arg Leu Arg Tyr Phe Asp Val Trp Gly
100 105 110
Thr Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 84
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 VL
<400> 84
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Ile Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Ser Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 85
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 VH
<400> 85
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Leu Ser Leu Ser Arg Tyr
20 25 30
Ser Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Gly Gly Ser Thr Asp Tyr Asn Ser Asp Phe Lys
50 55 60
Pro Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Ser Tyr Tyr Thr Asn Tyr Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 86
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 VL
<400> 86
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr
20 25 30
Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile
35 40 45
His Tyr Thr Ser Thr Leu Gln Pro Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 87
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 VH
<400> 87
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Pro Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Ser Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 88
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 VL
<400> 88
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Phe Leu His 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
Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 89
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 VH
<400> 89
Gln Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Pro Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Gly Asn Gly Ala Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Asn Pro 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 Arg Glu Asp Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 90
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 VL
<400> 90
Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp
1 5 10 15
Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn
20 25 30
Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro
35 40 45
Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser Thr
85 90 95
His Val Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 91
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 VH
<400> 91
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Asp Gly Arg Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Glu Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 92
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 VL
<400> 92
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Ser
20 25 30
Val Asn Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 93
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 VH
<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> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 和 #13 VL
<400> 94
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 95
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Trop2#13, #14, #15 和 #17 VH
<400> 95
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 96
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#14 和 #18 VL
<400> 96
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Lys Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 97
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#15 和 #16 VL
<400> 97
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 98
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Trop2#16 和 #18 VH
<400> 98
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Arg Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 99
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#17 VL
<400> 99
Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 100
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 VH
<400> 100
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 Gly Ser 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 Tyr Gly Ser Ser Arg Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 101
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 VL
<400> 101
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys Leu Glu Ile
100 105 110
Lys
<210> 102
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 VH
<400> 102
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asp His
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile 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 Tyr Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 103
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 VL
<400> 103
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 104
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> All of CD3#1 至 #4, #8 至 #11, #13, #14, #16, #21 VH
<400> 104
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 105
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 VL
<400> 105
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 106
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#2 VL
<400> 106
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Lys Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 107
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#3, #4 VL
<400> 107
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 108
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#5 VH
<400> 108
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 109
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#5 VL
<400> 109
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 110
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#6 VH
<400> 110
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 111
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#6 VL
<400> 111
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 112
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#7 VH
<400> 112
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 113
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#7 VL
<400> 113
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 114
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#8 VL
<400> 114
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 115
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#9 VL
<400> 115
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 116
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#10 VL
<400> 116
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 117
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#11 VL
<400> 117
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Lys Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 118
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#12 VH
<400> 118
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Leu Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 119
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#12 VL
<400> 119
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Tyr Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 120
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#13 VL
<400> 120
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Val Gly Thr Lys Leu Thr Val Leu
100 105
<210> 121
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#14 VL
<400> 121
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Tyr Gly Thr Lys Leu Thr Val Leu
100 105
<210> 122
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#15 VL
<400> 122
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Trp Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 123
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 VL
<400> 123
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Ile Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 124
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#17, #18, #19 VH
<400> 124
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 125
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#17 VL
<400> 125
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Arg Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 126
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#18 VL
<400> 126
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Trp Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 127
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#19, #20, #22 VL
<400> 127
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 128
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#20 VH
<400> 128
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asp Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 129
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#21 VL
<400> 129
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Tyr Tyr Ala Asn Trp Val Lys Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 130
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#22 VH
<400> 130
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ile Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 131
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#23 VL
<400> 131
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ile Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 132
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#23 VL
<400> 132
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Trp Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 133
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CD3#24, #25 VH
<400> 133
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 134
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#24 VL
<400> 134
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Tyr Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 135
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 VL
<400> 135
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 136
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#26 VH
<400> 136
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Gly Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Thr Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 137
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#26 VL
<400> 137
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys 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 Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 138
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#27 VH
<400> 138
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 139
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#27, #39 VL
<400> 139
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 140
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#28 VH
<400> 140
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 141
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#28, #29, #30, #42 VL
<400> 141
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 142
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#29 VH
<400> 142
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Ala Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 143
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#30 VH
<400> 143
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 144
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#31 VH
<400> 144
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 145
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#31, #32
<400> 145
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 146
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#32 VH
<400> 146
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 147
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#33 VH
<400> 147
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 148
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#33, #35, #37, #43 VL
<400> 148
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 149
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#34 VH
<400> 149
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 150
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#34 VL
<400> 150
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 151
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#35 VH
<400> 151
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Gln Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 152
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#36 VH
<400> 152
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 153
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#37 VH
<400> 153
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 154
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#38 VH
<400> 154
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 155
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#38 VL
<400> 155
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 156
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#39 VH
<400> 156
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 157
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#40 VH
<400> 157
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 158
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#40 VL
<400> 158
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 159
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#41 VH
<400> 159
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 160
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> CD3#41 VL
<400> 160
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 161
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#42 VH
<400> 161
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 162
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD3#43 VH
<400> 162
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 163
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> Trop2#5 VL
<400> 163
Asp Val Val 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 Leu Val His Ser
20 25 30
His Gly Asn Ile Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Leu Ser
35 40 45
Pro Lys Leu Leu Ile Phe 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 Phe Cys Ser Gln Ser
85 90 95
Thr His Val Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 164
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> Trop2#5 VH
<400> 164
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Ile Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Asp Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 165
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> Trop2#7 VL
<400> 165
Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Arg Gly
50 55 60
Ser Arg Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 166
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> Trop2#7 VH
<400> 166
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Arg Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Ala Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Gly Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Ile Tyr Tyr Gly Ala Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 167
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> TNP VH
<400> 167
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Lys Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Ile Tyr Asp Gly Tyr His Trp Tyr Phe Asp Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 168
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> TNP VL
<400> 168
Asp Val Val 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 Leu Val His Ser
20 25 30
Ile Gly Asn Thr Tyr Leu His 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
Thr Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 169
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LC
<400> 169
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Ile Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Ser Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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> 170
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HC (杵)
<400> 170
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Leu 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
Thr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Gly Ile Tyr Pro Asn Tyr Gly Asp Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Lys Thr Val Leu Leu Arg Leu Arg Tyr Phe Asp Val Trp Gly
100 105 110
Thr Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 171
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LC
<400> 171
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr
20 25 30
Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile
35 40 45
His Tyr Thr Ser Thr Leu Gln Pro Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 172
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HC (杵)
<400> 172
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Leu Ser Leu Ser Arg Tyr
20 25 30
Ser Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Gly Gly Ser Thr Asp Tyr Asn Ser Asp Phe Lys
50 55 60
Pro Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Lys Gly Ser Tyr Tyr Thr Asn Tyr Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 173
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 LC
<400> 173
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Phe Leu His 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
Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 174
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HC (杵)
<400> 174
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Pro Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Ser Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 175
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 LC
<400> 175
Asp Val Val 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 Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His 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 Phe Cys Ser Gln Ser
85 90 95
Thr His Val Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 176
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HC (杵)
<400> 176
Gln Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Pro Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Gly Asn Gly Ala Thr Ala Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Asn Pro 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 Arg Glu Asp Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 177
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 LC
<400> 177
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Ser
20 25 30
Val Asn Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 178
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HC (杵)
<400> 178
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Asp Gly Arg Asn Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Glu Asn Gln Phe Phe
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 179
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 LC
<400> 179
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 180
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 HC (杵)
<400> 180
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 181
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#13 LC
<400> 181
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 182
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#13 HC (杵)
<400> 182
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 183
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#14 LC
<400> 183
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Lys Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 184
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#14 HC (杵)
<400> 184
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 185
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#15 LC
<400> 185
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 186
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#15 HC (杵)
<400> 186
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 187
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#16 LC
<400> 187
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 188
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#16 HC (杵)
<400> 188
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Arg Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 189
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#17 LC
<400> 189
Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 190
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#17 HC (杵)
<400> 190
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 191
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> Trop2#18 LC
<400> 191
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Lys Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 192
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Trop2#18 HC (杵)
<400> 192
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
20 25 30
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Arg Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 193
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> TNP LC
<400> 193
Asp Val Val 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 Leu Val His Ser
20 25 30
Ile Gly Asn Thr Tyr Leu His 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
Thr Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 194
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> TNP HC (臼)
<400> 194
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Lys Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Ile Tyr Asp Gly Tyr His Trp Tyr Phe Asp Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 195
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> TNP HC (杵)
<400> 195
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Lys Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Ile Tyr Asp Gly Tyr His Trp Tyr Phe Asp Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 196
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 LC
<400> 196
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys 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> 197
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HC (臼)
<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 Gly Ser 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 Tyr Gly Ser Ser Arg 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 Ser Cys Ala 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 Val 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 Arg Phe Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly
450
<210> 198
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 LC
<400> 198
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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> 199
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HC (臼)
<400> 199
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asp His
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile 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 Tyr Cys
85 90 95
Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro 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 Ser Cys Ala 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 Val 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 Arg Phe Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly
450
<210> 200
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 全长 (杵)
<400> 200
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Gly Asn Ile His Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Ile Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Ser Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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 Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser
210 215 220
Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser
225 230 235 240
Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Gln Gln Ser Gly Pro Glu Leu Leu Lys Pro Gly Ala Ser Val Lys Ile
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Thr Met His Trp
275 280 285
Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Gly Ile Tyr
290 295 300
Pro Asn Tyr Gly Asp Thr Asn Tyr Asn Glu Lys Phe Lys Asp Lys Ala
305 310 315 320
Thr Leu Thr Val Asp Glu Ser Ser Ser Thr Ala Tyr Met Glu Leu Arg
325 330 335
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ser Arg Lys Thr
340 345 350
Val Leu Leu Arg Leu Arg Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 201
<211> 705
<212> PRT
<213> 人工序列
<220>
<223> Trop2#2 全长 (杵)
<400> 201
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Asp Ser Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Arg Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Asn Gly Ser Gly Thr Lys Phe Ser Phe Lys Ile Ser Gly Leu Gln Ala
65 70 75 80
Glu Asp Phe Val Ser Tyr Phe Cys Gln Gln Leu Tyr Ser Thr Pro Tyr
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 Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser
210 215 220
Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser
225 230 235 240
Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Phe Met Asp Trp
275 280 285
Val Lys Leu Ser His Glu Lys Ser Leu Glu Trp Ile Gly Asp Ile Asn
290 295 300
Pro His Asn Gly Gly Ser Asp Tyr Asn Gln Lys Phe Lys Gly Lys Ala
305 310 315 320
Thr Leu Thr Val Asp Arg Ser Ser Ser Thr Ala Tyr Met Glu Leu Arg
325 330 335
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Lys Gly Pro
340 345 350
Tyr Tyr Tyr Gly Gly Gly Pro Tyr Trp Tyr Phe Asp Val Trp Gly Thr
355 360 365
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
370 375 380
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
385 390 395 400
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
405 410 415
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
420 425 430
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
435 440 445
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
450 455 460
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
465 470 475 480
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
485 490 495
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
500 505 510
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
515 520 525
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
530 535 540
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
545 550 555 560
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
565 570 575
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
580 585 590
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
595 600 605
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
610 615 620
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
625 630 635 640
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
645 650 655
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
660 665 670
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
675 680 685
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
690 695 700
Gly
705
<210> 202
<211> 696
<212> PRT
<213> 人工序列
<220>
<223> Trop2#3 全长 (杵)
<400> 202
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Asn Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Tyr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Gly Asp Tyr Tyr Cys Gln Gln Ser Asn Ser Trp Pro Phe
85 90 95
Thr Phe Gly Ser 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 Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser
210 215 220
Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser
225 230 235 240
Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Gln Val Gln Leu
245 250 255
Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Leu
260 265 270
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Ile Asn Trp
275 280 285
Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Asn Ile Tyr
290 295 300
Pro Gly Asn Ser Ile Thr Asn Tyr Asn Glu Asn Phe Lys Ser Lys Ala
305 310 315 320
Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
325 330 335
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Ser Ser Ser
340 345 350
Ser Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala
355 360 365
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
370 375 380
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
385 390 395 400
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
405 410 415
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
420 425 430
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
435 440 445
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
450 455 460
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
465 470 475 480
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
485 490 495
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
500 505 510
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
515 520 525
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
530 535 540
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
545 550 555 560
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
565 570 575
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
580 585 590
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
595 600 605
Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro
610 615 620
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
625 630 635 640
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
645 650 655
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
660 665 670
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
675 680 685
Lys Ser Leu Ser Leu Ser Pro Gly
690 695
<210> 203
<211> 696
<212> PRT
<213> 人工序列
<220>
<223> Trop2#4 全长 (杵)
<400> 203
Asp Ile Leu Leu Ile Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr His
20 25 30
Ile His Trp Phe Gln Gln Arg Lys Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Asp Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln His Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Ser 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 Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser
210 215 220
Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser
225 230 235 240
Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Gln Val Gln Leu
245 250 255
Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met
260 265 270
Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ile Tyr Trp Ile Asn Trp
275 280 285
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Asn Ile Phe
290 295 300
Pro Gly Arg Gly Ile Thr Asn Tyr Asn Glu Lys Phe Lys Thr Lys Ala
305 310 315 320
Ser Leu Thr Leu Asp Thr Ser Ser Ser Thr Val Tyr Met Gln Leu Ser
325 330 335
Ser Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys Ser Arg Gly Ser
340 345 350
Asn Ser Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala
355 360 365
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
370 375 380
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
385 390 395 400
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
405 410 415
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
420 425 430
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
435 440 445
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
450 455 460
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
465 470 475 480
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
485 490 495
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
500 505 510
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
515 520 525
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
530 535 540
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
545 550 555 560
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
565 570 575
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
580 585 590
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
595 600 605
Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro
610 615 620
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
625 630 635 640
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
645 650 655
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
660 665 670
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
675 680 685
Lys Ser Leu Ser Leu Ser Pro Gly
690 695
<210> 204
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> Trop2#5 全长 (杵)
<400> 204
Asp Val Val 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 Leu Val His Ser
20 25 30
His Gly Asn Ile Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Leu Ser
35 40 45
Pro Lys Leu Leu Ile Phe 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 Phe Cys Ser Gln Ser
85 90 95
Thr His Val Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
260 265 270
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Ile Phe Thr Asp Tyr
275 280 285
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
290 295 300
Gly Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Ala Tyr Asn Gln Lys Phe
305 310 315 320
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
325 330 335
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Glu Ser Asp Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
355 360 365
Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
370 375 380
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
385 390 395 400
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
405 410 415
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
420 425 430
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
435 440 445
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
450 455 460
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
465 470 475 480
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
485 490 495
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
500 505 510
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
515 520 525
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
530 535 540
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
545 550 555 560
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
565 570 575
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
580 585 590
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
595 600 605
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys
610 615 620
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
625 630 635 640
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
645 650 655
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
660 665 670
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
675 680 685
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 205
<211> 695
<212> PRT
<213> 人工序列
<220>
<223> Trop2#6 全长 (杵)
<400> 205
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Ser
20 25 30
Ile His Trp Phe Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Thr Asn Thr Trp Pro Phe
85 90 95
Thr Phe Gly Ser 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 Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser
210 215 220
Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser
225 230 235 240
Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Gln Val Gln Leu
245 250 255
Gln Gln Ser Gly Thr Glu Leu Val Arg Pro Gly Thr Ser Val Lys Met
260 265 270
Ser Cys Lys Ala Ala Gly Tyr Thr Phe Thr Asn Tyr Trp Ile Asn Trp
275 280 285
Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile Gly Asn Ile Tyr
290 295 300
Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala
305 310 315 320
Ser Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
325 330 335
Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys Ala Arg Gly Ile
340 345 350
Asn Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser
355 360 365
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
370 375 380
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
385 390 395 400
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
405 410 415
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
420 425 430
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
435 440 445
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
450 455 460
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
465 470 475 480
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
485 490 495
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
500 505 510
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
515 520 525
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
530 535 540
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
545 550 555 560
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
565 570 575
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
580 585 590
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
595 600 605
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
610 615 620
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
625 630 635 640
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
645 650 655
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
660 665 670
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
675 680 685
Ser Leu Ser Leu Ser Pro Gly
690 695
<210> 206
<211> 700
<212> PRT
<213> 人工序列
<220>
<223> Trop2#7 全长 (杵)
<400> 206
Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Arg Gly
50 55 60
Ser Arg Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly
210 215 220
Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser Gly
225 230 235 240
Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Glu Val Gln Leu Gln
245 250 255
Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser
260 265 270
Cys Arg Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Ala Met His Trp Val
275 280 285
Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro
290 295 300
Tyr Asn Gly Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Arg Ala Thr
305 310 315 320
Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser
325 330 335
Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Glu Gly Ile
340 345 350
Tyr Tyr Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr
355 360 365
Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
370 375 380
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
385 390 395 400
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
405 410 415
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
420 425 430
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
435 440 445
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
450 455 460
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
465 470 475 480
Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu
485 490 495
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
500 505 510
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
515 520 525
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
530 535 540
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
545 550 555 560
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
565 570 575
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
580 585 590
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
595 600 605
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
610 615 620
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
625 630 635 640
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
645 650 655
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
660 665 670
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
675 680 685
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 207
<211> 701
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 全长 (杵)
<400> 207
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Gly Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Lys Tyr
20 25 30
Ile Ala Trp Tyr Gln His Lys Pro Gly Lys Gly Pro Arg Leu Leu Ile
35 40 45
His Tyr Thr Ser Thr Leu Gln Pro Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Tyr Ser Phe Ser Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly
210 215 220
Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser Gly
225 230 235 240
Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser Gln Val Gln Leu Lys
245 250 255
Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Ile Thr
260 265 270
Cys Thr Val Ser Gly Leu Ser Leu Ser Arg Tyr Ser Val His Trp Val
275 280 285
Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Met Ile Trp Gly
290 295 300
Gly Gly Ser Thr Asp Tyr Asn Ser Asp Phe Lys Pro Arg Leu Ser Ile
305 310 315 320
Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu
325 330 335
Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala Arg Lys Gly Ser Tyr
340 345 350
Tyr Thr Asn Tyr Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val
355 360 365
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
370 375 380
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
385 390 395 400
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
405 410 415
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
420 425 430
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
435 440 445
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
450 455 460
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
465 470 475 480
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
485 490 495
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
500 505 510
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
515 520 525
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
530 535 540
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
545 550 555 560
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
565 570 575
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
580 585 590
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
595 600 605
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val
610 615 620
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
625 630 635 640
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
645 650 655
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
660 665 670
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
675 680 685
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 208
<211> 704
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 全长 (杵)
<400> 208
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Phe Leu His 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
Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Pro Val Lys Pro Gly Ala
260 265 270
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
275 280 285
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
290 295 300
Gly Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Gly Tyr Asn Gln Lys Phe
305 310 315 320
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
325 330 335
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Glu Asp Ser Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly
355 360 365
Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
370 375 380
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
385 390 395 400
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
405 410 415
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
420 425 430
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
435 440 445
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
450 455 460
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
465 470 475 480
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
485 490 495
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
500 505 510
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
515 520 525
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
530 535 540
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
545 550 555 560
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
565 570 575
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
580 585 590
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
595 600 605
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
610 615 620
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
625 630 635 640
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
645 650 655
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
660 665 670
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
675 680 685
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 209
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 全长 (杵)
<400> 209
Asp Val Val 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 Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His 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 Phe Cys Ser Gln Ser
85 90 95
Thr His Val Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
260 265 270
Pro Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
275 280 285
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
290 295 300
Gly Tyr Ile Tyr Pro Gly Asn Gly Ala Thr Ala Tyr Asn Gln Lys Phe
305 310 315 320
Lys Gly Lys Ala Thr Leu Thr Ala Asp Asn Pro Ser Ser Thr Ala Tyr
325 330 335
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
340 345 350
Ala Arg Glu Asp Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
355 360 365
Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
370 375 380
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
385 390 395 400
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
405 410 415
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
420 425 430
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
435 440 445
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
450 455 460
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
465 470 475 480
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
485 490 495
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
500 505 510
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
515 520 525
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
530 535 540
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
545 550 555 560
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
565 570 575
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
580 585 590
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
595 600 605
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys
610 615 620
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
625 630 635 640
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
645 650 655
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
660 665 670
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
675 680 685
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 210
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 全长 (杵)
<400> 210
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Ser
20 25 30
Val Asn Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
290 295 300
Met Gly Tyr Ile Ser Tyr Asp Gly Arg Asn Asn Tyr Asn Pro Ser Leu
305 310 315 320
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Glu Asn Gln Phe Phe
325 330 335
Leu Lys Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Thr Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
355 360 365
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 211
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 全长 (杵)
<400> 211
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 212
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#13 全长 (杵)
<400> 212
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 213
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#14 全长 (杵)
<400> 213
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Lys Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 214
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#15 全长 (杵)
<400> 214
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 215
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#16 全长 (杵)
<400> 215
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Arg Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 216
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#17 全长 (杵)
<400> 216
Asp Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Lys Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 217
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#18 全长 (杵)
<400> 217
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Ser Ser Ser
20 25 30
Val Asn Arg Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Lys Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
290 295 300
Ile Gly Tyr Ile Ser Tyr Ser Gly Arg Asn Leu Tyr Asn Pro Ser Leu
305 310 315 320
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
325 330 335
Leu Lys Leu Ser Arg Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 218
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> TNP 全长 (臼)
<400> 218
Asp Val Val 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 Leu Val His Ser
20 25 30
Ile Gly Asn Thr Tyr Leu His 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
Thr Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser
210 215 220
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly
225 230 235 240
Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly
245 250 255
Ser Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly
260 265 270
Glu Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn
275 280 285
Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp
290 295 300
Val Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Lys Tyr Ala Asp Asp
305 310 315 320
Phe Lys Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Ser Thr Ala
325 330 335
Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe
340 345 350
Cys Ala Arg Gly Ile Tyr Asp Gly Tyr His Trp Tyr Phe Asp Val Trp
355 360 365
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
370 375 380
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
385 390 395 400
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
405 410 415
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
420 425 430
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
435 440 445
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
450 455 460
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
465 470 475 480
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
485 490 495
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
500 505 510
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
515 520 525
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
530 535 540
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
545 550 555 560
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
565 570 575
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
580 585 590
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
595 600 605
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
610 615 620
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
625 630 635 640
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
645 650 655
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
660 665 670
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
675 680 685
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu
690 695 700
Ser Pro Gly
705
<210> 219
<211> 707
<212> PRT
<213> 人工序列
<220>
<223> TNP 全长 (杵)
<400> 219
Asp Val Val 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 Leu Val His Ser
20 25 30
Ile Gly Asn Thr Tyr Leu His 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
Thr Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser
210 215 220
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly
225 230 235 240
Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly
245 250 255
Ser Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly
260 265 270
Glu Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Asn
275 280 285
Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp
290 295 300
Val Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Lys Tyr Ala Asp Asp
305 310 315 320
Phe Lys Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Ser Thr Ala
325 330 335
Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe
340 345 350
Cys Ala Arg Gly Ile Tyr Asp Gly Tyr His Trp Tyr Phe Asp Val Trp
355 360 365
Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
370 375 380
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
385 390 395 400
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
405 410 415
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
420 425 430
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
435 440 445
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
450 455 460
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
465 470 475 480
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
485 490 495
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
500 505 510
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
515 520 525
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
530 535 540
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
545 550 555 560
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
565 570 575
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
580 585 590
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
595 600 605
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
610 615 620
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
625 630 635 640
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
645 650 655
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
660 665 670
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
675 680 685
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
690 695 700
Ser Pro Gly
705
<210> 220
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 全长 (臼)
<400> 220
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro
260 265 270
Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr
275 280 285
Asp His Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu
290 295 300
Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu
305 310 315 320
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr
325 330 335
Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
340 345 350
Phe Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly
705 710
<210> 221
<211> 710
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 全长 (臼)
<400> 221
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly
705 710
<210> 222
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 scFv
<400> 222
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 223
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#2 scFv
<400> 223
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Lys Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 224
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#3 scFv
<400> 224
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 225
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#4 scFv
<400> 225
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 226
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#5 scFv
<400> 226
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 227
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#6 scFv
<400> 227
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 228
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#7 scFv
<400> 228
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 229
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#8 scFv
<400> 229
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 230
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#9 scFv
<400> 230
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 231
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#10 scFv
<400> 231
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 232
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#11 scFv
<400> 232
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Lys Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 233
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#12 scFv
<400> 233
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Tyr Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Leu Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 234
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#13 scFv
<400> 234
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Val Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 235
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#14 scFv
<400> 235
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Tyr Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 236
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#15 scFv
<400> 236
Glu Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Trp Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Leu Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 237
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 scFv
<400> 237
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Ile Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 238
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#17 scFv
<400> 238
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Arg Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 239
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#18 scFv
<400> 239
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Trp Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 240
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#19 scFv
<400> 240
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 241
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#20 scFv
<400> 241
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Val Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Gly Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asp Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 242
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#21 scFv
<400> 242
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Tyr Tyr Ala Asn Trp Val Lys Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
245 250
<210> 243
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#22 scFv
<400> 243
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Gly Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ile Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 244
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#23 scFv
<400> 244
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Trp Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ile Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 245
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#24 scFv
<400> 245
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Tyr Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 246
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 scFv
<400> 246
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Lys Ser Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Ile Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Ser
100 105 110
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr
145 150 155 160
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
180 185 190
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
195 200 205
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp
225 230 235 240
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 247
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#26 scFv
<400> 247
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys 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 Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Gly
130 135 140
Lys Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Glu Lys Phe Lys Asn Arg Ala Thr Leu Thr Val Asp Lys Ser Ser
195 200 205
Ser Thr Ala Tyr Met Gln Leu Ser Thr Leu Thr Ser Glu Asp Ser Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 248
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#27 scFv
<400> 248
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Glu Lys Phe Lys Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 249
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#28 scFv
<400> 249
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 250
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#29 scFv
<400> 250
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr
180 185 190
Ala Glu Lys Phe Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 251
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#30 scFv
<400> 251
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr
180 185 190
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 252
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#31 scFv
<400> 252
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr
180 185 190
Ala Gln Lys Phe Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 253
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#32 scFv
<400> 253
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr
180 185 190
Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 254
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#33 scFv
<400> 254
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 255
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#34 scFv
<400> 255
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 256
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#35 scFv
<400> 256
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr
180 185 190
Asn Gln Lys Phe Gln Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 257
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#36 scFv
<400> 257
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ala
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Gln Lys Phe Gln Asn Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 258
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#37 scFv
<400> 258
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser Tyr
180 185 190
Ala Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 259
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#38 scFv
<400> 259
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 260
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#39 scFv
<400> 260
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 261
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#40 scFv
<400> 261
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 262
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#41 scFv
<400> 262
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys Tyr
180 185 190
Asn Gln Lys Phe Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 263
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#42 scFv
<400> 263
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Met Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Gln Lys Phe Gln Gly Arg Val Thr Met Thr Val Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
245 250
<210> 264
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CD3#43 scFv
<400> 264
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Phe Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ile Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
115 120 125
Thr Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
130 135 140
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn Tyr
180 185 190
Asn Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
195 200 205
Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Ala Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 265
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 接头，例如在VH 和 VL之间在CD3 scFv中
<400> 265
Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
1 5 10 15
Thr Gly Gly Ser
20
<210> 266
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> 接头，例如在LC和HC之间
<400> 266
Gly Gly Gly Gly Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser
1 5 10 15
Lys Ser Thr Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
20 25 30
Thr Gly Gly Gly Gly Ser
35
<210> 267
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1(臼) / CD3#1 全长
<400> 267
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro
260 265 270
Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr
275 280 285
Asp His Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu
290 295 300
Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu
305 310 315 320
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr
325 330 335
Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
340 345 350
Phe Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Glu Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 268
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1(臼) / CD3#2 全长
<400> 268
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro
260 265 270
Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr
275 280 285
Asp His Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu
290 295 300
Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu
305 310 315 320
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr
325 330 335
Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
340 345 350
Phe Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Glu Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 269
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1(臼) / CD3#3 全长
<400> 269
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro
260 265 270
Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr
275 280 285
Asp His Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu
290 295 300
Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu
305 310 315 320
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr
325 330 335
Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
340 345 350
Phe Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Glu Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 270
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (臼) / CD3#1 全长
<400> 270
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 271
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (臼) / CD3#2 全长
<400> 271
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Lys Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 272
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (臼) / CD3#3 全长
<400> 272
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 273
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 4aa 接头
<400> 273
Gly Gly Gly Ser
1
<210> 274
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 6aa linker
<400> 274
Gly Gly Ser Gly Gly Ser
1 5
<210> 275
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 20aa 接头；例如在Fc 和 CD3 scFv之间
<400> 275
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> 276
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR1 (CCG)
<400> 276
Gly Tyr Thr Phe Thr Asp Tyr Thr Met His
1 5 10
<210> 277
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR1 (CCG)
<400> 277
Gly Leu Ser Leu Ser Arg Tyr Ser Val His
1 5 10
<210> 278
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HCDR1 (CCG)
<400> 278
Gly Tyr Ser Ile Thr Ser Gly Tyr Tyr Trp Asn
1 5 10
<210> 279
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR1 (CCG)
<400> 279
Gly Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp Asn
1 5 10
<210> 280
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR1 (CCG)
<400> 280
Gly Tyr Thr Phe Thr Asp Tyr Tyr Met Asn
1 5 10
<210> 281
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR1 (CCG)
<400> 281
Gly Tyr Thr Phe Thr Asn Tyr Tyr Ile His
1 5 10
<210> 282
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR1 (CCG)
<400> 282
Gly Tyr Thr Phe Thr Asp His Thr Ile His
1 5 10
<210> 283
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR1 (CCG)
<400> 283
Gly Tyr Thr Phe Ser Asp His Thr Ile His
1 5 10
<210> 284
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #15, #20, #23, #24 HCDR1 (CCG)
<400> 284
Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn
1 5 10
<210> 285
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 至 #19, #21, #22 HCDR1 (CCG)
<400> 285
Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn
1 5 10
<210> 286
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDH17#25 至 #42 HCDR1 (CCG)
<400> 286
Gly Tyr Thr Phe Thr Ser Tyr Trp Met His
1 5 10
<210> 287
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 和 #9 HCDR1 (Chothia)
<400> 287
Gly Tyr Thr Phe Thr Asp Tyr
1 5
<210> 288
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR2 (Chothia)
<400> 288
Tyr Pro Asn Tyr Gly Asp
1 5
<210> 289
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR1 (Chothia)
<400> 289
Gly Leu Ser Leu Ser Arg Tyr
1 5
<210> 290
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR2 (Chothia)
<400> 290
Trp Gly Gly Gly Ser
1 5
<210> 291
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HCDR1 (Chothia)
<400> 291
Gly Tyr Ser Ile Thr Ser Gly Tyr
1 5
<210> 292
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HCDR2 (Chothia)
<400> 292
Ser Tyr Asp Gly Arg
1 5
<210> 293
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR1 (Chothia)
<400> 293
Gly Tyr Ser Ile Ser Ser Gly Tyr
1 5
<210> 294
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR2 (Chothia)
<400> 294
Ser Tyr Ser Gly Arg
1 5
<210> 295
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR2 (Chothia)
<400> 295
Tyr Pro Asn Asn Gly Ala
1 5
<210> 296
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR1 (Chothia)
<400> 296
Gly Tyr Thr Phe Thr Asn Tyr
1 5
<210> 297
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR2 (Chothia)
<400> 297
Tyr Pro Gly Asn Gly Ala
1 5
<210> 298
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR1 (Chothia)
<400> 298
Gly Tyr Thr Phe Thr Asp His
1 5
<210> 299
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR2 (Chothia)
<400> 299
Tyr Pro Arg Asp Gly Ser
1 5
<210> 300
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR1 (Chothia)
<400> 300
Gly Tyr Thr Phe Ser Asp His
1 5
<210> 301
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR2 (Chothia)
<400> 301
Tyr Pro Arg Leu Gly Ser
1 5
<210> 302
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #15, #20, #23, #24 HCDR1 (Chothia)
<400> 302
Gly Phe Thr Phe Asn Thr Tyr
1 5
<210> 303
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #18, #20, #22, #23, #24 HCDR1 (Chothia)
<400> 303
Arg Ser Lys Tyr Asn Asn Tyr Ala
1 5
<210> 304
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 至 #19, #21, #22 HCDR1 (Chothia)
<400> 304
Gly Phe Thr Phe Ser Thr Tyr
1 5
<210> 305
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#19, #21, HCDR1 (Chothia)
<400> 305
Arg Ser Ile Tyr Asn Asn Tyr Ala
1 5
<210> 306
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 至 #42 HCDR1 (Chothia)
<400> 306
Gly Tyr Thr Phe Thr Ser Tyr
1 5
<210> 307
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CD3#25, #26, #37 至 #42 HCDR1 (Chothia)
<400> 307
Asn Ala Asp Thr Gly Ser
1 5
<210> 308
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CD3#27 至 #36 HCDR1 (Chothia)
<400> 308
Asn Ala Ser Thr Gly Ser
1 5
<210> 309
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR1 (IMGT)
<400> 309
Gly Tyr Thr Phe Thr Asp Tyr Thr
1 5
<210> 310
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR2 (IMGT)
<400> 310
Ile Tyr Pro Asn Tyr Gly Asp Thr
1 5
<210> 311
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR3 (IMGT)
<400> 311
Ser Arg Lys Thr Val Leu Leu Arg Leu Arg Tyr Phe Asp Val
1 5 10
<210> 312
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LCDR1 (IMGT)
<400> 312
Gly Asn Ile His Asn Tyr
1 5
<210> 313
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LCDR1 (IMGT)
<400> 313
Gly Asn Ile His Asn Tyr
1 5
<210> 314
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR1 (IMGT)
<400> 314
Gly Leu Ser Leu Ser Arg Tyr Ser
1 5
<210> 315
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR2 (IMGT)
<400> 315
Ile Trp Gly Gly Gly Ser Thr
1 5
<210> 316
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR3 (IMGT)
<400> 316
Ala Arg Lys Gly Ser Tyr Tyr Thr Asn Tyr Gly Ala Met Asp Tyr
1 5 10 15
<210> 317
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LCDR1 (IMGT)
<400> 317
Gln Asp Ile Asn Lys Tyr
1 5
<210> 318
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LCDR1 (IMGT)
<400> 318
Gln Asp Ile Asn Lys Tyr
1 5
<210> 319
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HCDR1 (IMGT)
<400> 319
Gly Tyr Ser Ile Thr Ser Gly Tyr Tyr
1 5
<210> 320
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11HCDR2 (IMGT)
<400> 320
Ile Ser Tyr Asp Gly Arg Asn
1 5
<210> 321
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 至 #18 HCDR3 (IMGT)
<400> 321
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr
1 5 10
<210> 322
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 LCDR1 (IMGT)
<400> 322
Glu Ser Val Asp Ser Ser Val Asn Arg Phe
1 5 10
<210> 323
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 LCDR1 (IMGT)
<400> 323
Glu Ser Val Asp Ser Ser Val Asn Arg Phe
1 5 10
<210> 324
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR1 (IMGT)
<400> 324
Gly Tyr Ser Ile Ser Ser Gly Tyr Tyr
1 5
<210> 325
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR2 (IMGT)
<400> 325
Ile Ser Tyr Ser Gly Arg Asn
1 5
<210> 326
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 LCDR1 (IMGT)
<400> 326
Glu Ser Val Ser Ser Ser Val Asn Arg Phe
1 5 10
<210> 327
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR1 (IMGT)
<400> 327
Gly Tyr Thr Phe Thr Asp Tyr Tyr
1 5
<210> 328
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR2 (IMGT)
<400> 328
Ile Tyr Pro Asn Asn Gly Ala Thr
1 5
<210> 329
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR3 (IMGT)
<400> 329
Ala Arg Glu Asp Ser Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 330
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 LCDR1 (IMGT)
<400> 330
Gln Ser Leu Val His Ser Asn Gly Asn Thr Phe
1 5 10
<210> 331
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 LCDR1 (IMGT)
<400> 331
Gln Ser Leu Val His Ser Asn Gly Asn Thr Phe
1 5 10
<210> 332
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR1 (IMGT)
<400> 332
Gly Tyr Thr Phe Thr Asn Tyr Tyr
1 5
<210> 333
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR2 (IMGT)
<400> 333
Ile Tyr Pro Gly Asn Gly Ala Thr
1 5
<210> 334
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR3 (IMGT)
<400> 334
Ala Arg Glu Asp Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 335
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 LCDR1 (IMGT)
<400> 335
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 336
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR1 (IMGT)
<400> 336
Gly Tyr Thr Phe Thr Asp His Thr
1 5
<210> 337
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR2 (IMGT)
<400> 337
Ile Tyr Pro Arg Asp Gly Ser Thr
1 5
<210> 338
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 和 #8 HCDR3 (IMGT)
<400> 338
Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe Asp Tyr
1 5 10 15
<210> 339
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 LCDR1 (IMGT)
<400> 339
Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
1 5 10
<210> 340
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 LCDR1 (IMGT)
<400> 340
Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
1 5 10
<210> 341
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR1 (IMGT)
<400> 341
Gly Tyr Thr Phe Ser Asp His Thr
1 5
<210> 342
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR2 (IMGT)
<400> 342
Ile Tyr Pro Arg Leu Gly Ser Thr
1 5
<210> 343
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 LCDR1 (IMGT)
<400> 343
Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Gln Tyr
1 5 10
<210> 344
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 LCDR1 (IMGT)
<400> 344
Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Gln Tyr
1 5 10
<210> 345
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 # 15, #20, #23, #24 HCDR1 (IMGT)
<400> 345
Gly Phe Thr Phe Asn Thr Tyr Ala
1 5
<210> 346
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 # 18, #20, #22, #23, #24 HCDR2 (IMGT)
<400> 346
Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
1 5 10
<210> 347
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 # 10, #12, #13, #15, #20, #23, #24 HCDR3 (IMGT)
<400> 347
Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 348
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 # 10, #12 至 #16, #18, #19, #21, #24 LCDR1 (IMGT)
<400> 348
Thr Gly Ala Val Thr Thr Ser Asn Tyr
1 5
<210> 349
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 # 10, #12 至 #16, #18, #19, #21, #24 LCDR1 (IMGT)
<400> 349
Thr Gly Ala Val Thr Thr Ser Asn Tyr
1 5
<210> 350
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#11, #14 HCDR3 (IMGT)
<400> 350
Val Arg His Gly Asn Phe Leu Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 351
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#11, #20, #23 LCDR1 (IMGT)
<400> 351
Thr Gly Ala Val Thr Thr Ser Tyr Tyr
1 5
<210> 352
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 至 # 19, #21, #22 HCDR1 (IMGT)
<400> 352
Gly Phe Thr Phe Ser Thr Tyr Ala
1 5
<210> 353
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 至 # 18, #21, #22, HCDR2 (IMGT)
<400> 353
Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 354
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD3#17 和 # 22
<400> 354
Thr Gly Ala Val Thr Thr Ser Trp Tyr
1 5
<210> 355
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#19 和 #21 HCDR2 (IMGT)
<400> 355
Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr
1 5 10
<210> 356
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#19 HCDR3 (IMGT)
<400> 356
Val Arg His Gly Asn Phe Gly Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 357
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 至 #42 HCDR1 (IMGT)
<400> 357
Gly Tyr Thr Phe Thr Ser Tyr Trp
1 5
<210> 358
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#25, #26, #37 至 #42 HCDR2 (IMGT)
<400> 358
Ile Asn Ala Asp Thr Gly Ser Thr
1 5
<210> 359
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#25, #28 至 #30, #39 HCDR3 (IMGT)
<400> 359
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 360
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 至 #29, #32, #34, #36 至 #42 LCDR1 (IMGT)
<400> 360
Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr
1 5 10
<210> 361
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#26, #32 至 #37, #40 HCDR3 (IMGT)
<400> 361
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 362
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#27 至 #36 HCDR2 (IMGT)
<400> 362
Ile Asn Ala Ser Thr Gly Ser Thr
1 5
<210> 363
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#27, #31, #41 HCDR3 (IMGT)
<400> 363
Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 364
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#30, #31, #33, #35 LCDR1 (IMGT)
<400> 364
Gln Ser Leu Leu Asn Ala Arg Thr Arg Lys Asn Tyr
1 5 10
<210> 365
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#38, #42 HCDR3 (IMGT)
<400> 365
Ala Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 366
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR1 (North)
<400> 366
Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Thr Met His
1 5 10
<210> 367
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR2 (North)
<400> 367
Gly Ile Tyr Pro Asn Tyr Gly Asp Thr Asn
1 5 10
<210> 368
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 HCDR3 (North)
<400> 368
Ser Arg Lys Thr Val Leu Leu Arg Leu Arg Tyr Phe Asp Val
1 5 10
<210> 369
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#1 LCDR2 (North)
<400> 369
Tyr Asn Ala Ile Thr Leu Ala Asp
1 5
<210> 370
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR1 (North)
<400> 370
Thr Val Ser Gly Leu Ser Leu Ser Arg Tyr Ser Val His
1 5 10
<210> 371
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR2 (North)
<400> 371
Met Ile Trp Gly Gly Gly Ser Thr Asp
1 5
<210> 372
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 HCDR3 (North)
<400> 372
Ala Arg Lys Gly Ser Tyr Tyr Thr Asn Tyr Gly Ala Met Asp Tyr
1 5 10 15
<210> 373
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#8 LCDR2 (North)
<400> 373
His Tyr Thr Ser Thr Leu Gln Pro
1 5
<210> 374
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 HCDR1 (North)
<400> 374
Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly Tyr Tyr Trp Asn
1 5 10
<210> 375
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11HCDR2 (North)
<400> 375
Tyr Ile Ser Tyr Asp Gly Arg Asn Asn
1 5
<210> 376
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 至 #18 HCDR3 (North)
<400> 376
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr
1 5 10
<210> 377
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 至 #18 LCDR2 (North)
<400> 377
Tyr Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 378
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR1 (North)
<400> 378
Thr Val Ser Gly Tyr Ser Ile Ser Ser Gly Tyr Tyr Trp Asn
1 5 10
<210> 379
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Trop2#12 至 #18 HCDR2 (North)
<400> 379
Tyr Ile Ser Tyr Ser Gly Arg Asn Leu
1 5
<210> 380
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR1 (North)
<400> 380
Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Met Asn
1 5 10
<210> 381
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR2 (North)
<400> 381
Tyr Ile Tyr Pro Asn Asn Gly Ala Thr Gly
1 5 10
<210> 382
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 HCDR3 (North)
<400> 382
Ala Arg Glu Asp Ser Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 383
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> Trop2#9 和 #10 LCDR2 (North)
<400> 383
Tyr Lys Val Ser Asn Arg Phe Ser
1 5
<210> 384
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR1 (North)
<400> 384
Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Tyr Ile His
1 5 10
<210> 385
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10
<400> 385
Tyr Ile Tyr Pro Gly Asn Gly Ala Thr Ala
1 5 10
<210> 386
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Trop2#10 HCDR3 (North)
<400> 386
Ala Arg Glu Asp Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 387
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR1 (North)
<400> 387
Lys Val Ser Gly Tyr Thr Phe Thr Asp His Thr Ile His
1 5 10
<210> 388
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 HCDR2 (North)
<400> 388
Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys
1 5 10
<210> 389
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 和 #8 HCDR3 (North)
<400> 389
Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe Asp Tyr
1 5 10 15
<210> 390
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 LCDR2 (North)
<400> 390
Tyr Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 391
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR1 (North)
<400> 391
Lys Ala Ser Gly Tyr Thr Phe Ser Asp His Thr Ile His
1 5 10
<210> 392
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 HCDR2 (North)
<400> 392
Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys
1 5 10
<210> 393
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 LCDR2 (North)
<400> 393
Tyr Gly Ala Ser Thr Arg Glu Thr
1 5
<210> 394
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #15, #20, #23, #24 HCDR1 (North)
<400> 394
Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn
1 5 10
<210> 395
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #18, #20, #22, #23, #24 HCDR2 (North)
<400> 395
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
1 5 10
<210> 396
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #10, #12, #13, #15, #20, #23, #24 HCDR3 (North)
<400> 396
Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 397
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#1 至 #12, #16, #18, #19, #21, #22, #23 LCDR2 (North)
<400> 397
Gly Gly Thr Asn Lys Arg Ala Pro
1 5
<210> 398
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#11 和 #14 HCDR3 (North)
<400> 398
Val Arg His Gly Asn Phe Leu Asn Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 399
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#13 至 #15, #17, #20, #24 LCDR2 (North)
<400> 399
Gly Gly Thr Asn Ile Arg Ala Pro
1 5
<210> 400
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 至 #18, #21, #22 HCDR1 (North)
<400> 400
Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr Ala Met Asn
1 5 10
<210> 401
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#16 至 #18, #21, #22 HCDR3 (North)
<400> 401
Val Arg His Gly Asn Phe Ile Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 402
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#19 和 #21 HCDR2 (North)
<400> 402
Arg Ile Arg Ser Ile Tyr Asn Asn Tyr Ala Thr Tyr
1 5 10
<210> 403
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CD3#19 HCDR3 (North)
<400> 403
Val Arg His Gly Asn Phe Gly Asp Ser Tyr Val Ser Trp Phe Ala Tyr
1 5 10 15
<210> 404
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 至 #42 HCDR1 (North)
<400> 404
Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met His
1 5 10
<210> 405
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#25, #26, #38, # 41, #42 HCDR2 (North)
<400> 405
Asn Ile Asn Ala Asp Thr Gly Ser Thr Asn
1 5 10
<210> 406
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#25, #28 至 #30, #39 HCDR3(North)
<400> 406
Thr Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 407
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CD3#25 至 # 42 LCDR2 (North)
<400> 407
Tyr Trp Ala Ser Thr Arg Lys Ser
1 5
<210> 408
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#26, #32 至 #37, #40 HCDR3(North)
<400> 408
Ala Arg Asp Gly Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 409
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#27, #29 至 #31, #33, # 35 HCDR2 (North)
<400> 409
Asn Ile Asn Ala Ser Thr Gly Ser Thr Asn
1 5 10
<210> 410
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#27, #31, #41 HCDR3(North)
<400> 410
Thr Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 411
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#28, #32, #34, #36 HCDR2 (North)
<400> 411
Asn Ile Asn Ala Ser Thr Gly Ser Thr Ser
1 5 10
<210> 412
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CD3#37, #39, #40 HCDR2 (North)
<400> 412
Asn Ile Asn Ala Asp Thr Gly Ser Thr Lys
1 5 10
<210> 413
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD3#38 #42 HCDR3(North)
<400> 413
Ala Arg Asp Ala Tyr Ser Phe Tyr Tyr Phe Asp Tyr
1 5 10
<210> 414
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> IgG1 野生型 HC
<400> 414
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> 415
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> IgG1 KO HC
<400> 415
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> 416
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Pro 野生型 HC
<400> 416
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> 417
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> IgG1 FcRnmut
<400> 417
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> 418
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人类轻链恒定域(κ)
<400> 418
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> 419
<211> 323
<212> PRT
<213> 人工序列
<220>
<223> 人类Trop2
<400> 419
Met Ala Arg Gly Pro Gly Leu Ala Pro Pro Pro Leu Arg Leu Pro Leu
1 5 10 15
Leu Leu Leu Val Leu Ala Ala Val Thr Gly His Thr Ala Ala Gln Asp
20 25 30
Asn Cys Thr Cys Pro Thr Asn Lys Met Thr Val Cys Ser Pro Asp Gly
35 40 45
Pro Gly Gly Arg Cys Gln Cys Arg Ala Leu Gly Ser Gly Met Ala Val
50 55 60
Asp Cys Ser Thr Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala Arg Met
65 70 75 80
Ser Ala Pro Lys Asn Ala Arg Thr Leu Val Arg Pro Ser Glu His Ala
85 90 95
Leu Val Asp Asn Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro Glu Gly
100 105 110
Arg Phe Lys Ala Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val
115 120 125
Asn Ser Val Gly Val Arg Arg Thr Asp Lys Gly Asp Leu Ser Leu Arg
130 135 140
Cys Asp Glu Leu Val Arg Thr His His Ile Leu Ile Asp Leu Arg His
145 150 155 160
Arg Pro Thr Ala Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu
165 170 175
Arg Arg Leu Phe Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala
180 185 190
Ala Val His Tyr Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn
195 200 205
Thr Ser Gln Lys Ala Ala Gly Asp Val Asp Ile Gly Asp Ala Ala Tyr
210 215 220
Tyr Phe Glu Arg Asp Ile Lys Gly Glu Ser Leu Phe Gln Gly Arg Gly
225 230 235 240
Gly Leu Asp Leu Arg Val Arg Gly Glu Pro Leu Gln Val Glu Arg Thr
245 250 255
Leu Ile Tyr Tyr Leu Asp Glu Ile Pro Pro Lys Phe Ser Met Lys Arg
260 265 270
Leu Thr Ala Gly Leu Ile Ala Val Ile Val Val Val Val Val Ala Leu
275 280 285
Val Ala Gly Met Ala Val Leu Val Ile Thr Asn Arg Arg Lys Ser Gly
290 295 300
Lys Tyr Lys Lys Val Glu Ile Lys Glu Leu Gly Glu Leu Arg Lys Glu
305 310 315 320
Pro Ser Leu
<210> 420
<211> 832
<212> PRT
<213> 人工序列
<220>
<223> 人类CDH17
<400> 420
Met Ile Leu Gln Ala His Leu His Ser Leu Cys Leu Leu Met Leu Tyr
1 5 10 15
Leu Ala Thr Gly Tyr Gly Gln Glu Gly Lys Phe Ser Gly Pro Leu Lys
20 25 30
Pro Met Thr Phe Ser Ile Tyr Glu Gly Gln Glu Pro Ser Gln Ile Ile
35 40 45
Phe Gln Phe Lys Ala Asn Pro Pro Ala Val Thr Phe Glu Leu Thr Gly
50 55 60
Glu Thr Asp Asn Ile Phe Val Ile Glu Arg Glu Gly Leu Leu Tyr Tyr
65 70 75 80
Asn Arg Ala Leu Asp Arg Glu Thr Arg Ser Thr His Asn Leu Gln Val
85 90 95
Ala Ala Leu Asp Ala Asn Gly Ile Ile Val Glu Gly Pro Val Pro Ile
100 105 110
Thr Ile Lys Val Lys Asp Ile Asn Asp Asn Arg Pro Thr Phe Leu Gln
115 120 125
Ser Lys Tyr Glu Gly Ser Val Arg Gln Asn Ser Arg Pro Gly Lys Pro
130 135 140
Phe Leu Tyr Val Asn Ala Thr Asp Leu Asp Asp Pro Ala Thr Pro Asn
145 150 155 160
Gly Gln Leu Tyr Tyr Gln Ile Val Ile Gln Leu Pro Met Ile Asn Asn
165 170 175
Val Met Tyr Phe Gln Ile Asn Asn Lys Thr Gly Ala Ile Ser Leu Thr
180 185 190
Arg Glu Gly Ser Gln Glu Leu Asn Pro Ala Lys Asn Pro Ser Tyr Asn
195 200 205
Leu Val Ile Ser Val Lys Asp Met Gly Gly Gln Ser Glu Asn Ser Phe
210 215 220
Ser Asp Thr Thr Ser Val Asp Ile Ile Val Thr Glu Asn Ile Trp Lys
225 230 235 240
Ala Pro Lys Pro Val Glu Met Val Glu Asn Ser Thr Asp Pro His Pro
245 250 255
Ile Lys Ile Thr Gln Val Arg Trp Asn Asp Pro Gly Ala Gln Tyr Ser
260 265 270
Leu Val Asp Lys Glu Lys Leu Pro Arg Phe Pro Phe Ser Ile Asp Gln
275 280 285
Glu Gly Asp Ile Tyr Val Thr Gln Pro Leu Asp Arg Glu Glu Lys Asp
290 295 300
Ala Tyr Val Phe Tyr Ala Val Ala Lys Asp Glu Tyr Gly Lys Pro Leu
305 310 315 320
Ser Tyr Pro Leu Glu Ile His Val Lys Val Lys Asp Ile Asn Asp Asn
325 330 335
Pro Pro Thr Cys Pro Ser Pro Val Thr Val Phe Glu Val Gln Glu Asn
340 345 350
Glu Arg Leu Gly Asn Ser Ile Gly Thr Leu Thr Ala His Asp Arg Asp
355 360 365
Glu Glu Asn Thr Ala Asn Ser Phe Leu Asn Tyr Arg Ile Val Glu Gln
370 375 380
Thr Pro Lys Leu Pro Met Asp Gly Leu Phe Leu Ile Gln Thr Tyr Ala
385 390 395 400
Gly Met Leu Gln Leu Ala Lys Gln Ser Leu Lys Lys Gln Asp Thr Pro
405 410 415
Gln Tyr Asn Leu Thr Ile Glu Val Ser Asp Lys Asp Phe Lys Thr Leu
420 425 430
Cys Phe Val Gln Ile Asn Val Ile Asp Ile Asn Asp Gln Ile Pro Ile
435 440 445
Phe Glu Lys Ser Asp Tyr Gly Asn Leu Thr Leu Ala Glu Asp Thr Asn
450 455 460
Ile Gly Ser Thr Ile Leu Thr Ile Gln Ala Thr Asp Ala Asp Glu Pro
465 470 475 480
Phe Thr Gly Ser Ser Lys Ile Leu Tyr His Ile Ile Lys Gly Asp Ser
485 490 495
Glu Gly Arg Leu Gly Val Asp Thr Asp Pro His Thr Asn Thr Gly Tyr
500 505 510
Val Ile Ile Lys Lys Pro Leu Asp Phe Glu Thr Ala Ala Val Ser Asn
515 520 525
Ile Val Phe Lys Ala Glu Asn Pro Glu Pro Leu Val Phe Gly Val Lys
530 535 540
Tyr Asn Ala Ser Ser Phe Ala Lys Phe Thr Leu Ile Val Thr Asp Val
545 550 555 560
Asn Glu Ala Pro Gln Phe Ser Gln His Val Phe Gln Ala Lys Val Ser
565 570 575
Glu Asp Val Ala Ile Gly Thr Lys Val Gly Asn Val Thr Ala Lys Asp
580 585 590
Pro Glu Gly Leu Asp Ile Ser Tyr Ser Leu Arg Gly Asp Thr Arg Gly
595 600 605
Trp Leu Lys Ile Asp His Val Thr Gly Glu Ile Phe Ser Val Ala Pro
610 615 620
Leu Asp Arg Glu Ala Gly Ser Pro Tyr Arg Val Gln Val Val Ala Thr
625 630 635 640
Glu Val Gly Gly Ser Ser Leu Ser Ser Val Ser Glu Phe His Leu Ile
645 650 655
Leu Met Asp Val Asn Asp Asn Pro Pro Arg Leu Ala Lys Asp Tyr Thr
660 665 670
Gly Leu Phe Phe Cys His Pro Leu Ser Ala Pro Gly Ser Leu Ile Phe
675 680 685
Glu Ala Thr Asp Asp Asp Gln His Leu Phe Arg Gly Pro His Phe Thr
690 695 700
Phe Ser Leu Gly Ser Gly Ser Leu Gln Asn Asp Trp Glu Val Ser Lys
705 710 715 720
Ile Asn Gly Thr His Ala Arg Leu Ser Thr Arg His Thr Glu Phe Glu
725 730 735
Glu Arg Glu Tyr Val Val Leu Ile Arg Ile Asn Asp Gly Gly Arg Pro
740 745 750
Pro Leu Glu Gly Ile Val Ser Leu Pro Val Thr Phe Cys Ser Cys Val
755 760 765
Glu Gly Ser Cys Phe Arg Pro Ala Gly His Gln Thr Gly Ile Pro Thr
770 775 780
Val Gly Met Ala Val Gly Ile Leu Leu Thr Thr Leu Leu Val Ile Gly
785 790 795 800
Ile Ile Leu Ala Val Val Phe Ile Arg Ile Lys Lys Asp Lys Gly Lys
805 810 815
Asp Asn Val Glu Ser Ala Gln Ala Ser Glu Val Lys Pro Leu Arg Ser
820 825 830
<210> 421
<211> 171
<212> PRT
<213> 人工序列
<220>
<223> 人类CD3 δ链
<400> 421
Met Glu His Ser Thr Phe Leu Ser Gly Leu Val Leu Ala Thr Leu Leu
1 5 10 15
Ser Gln Val Ser Pro Phe Lys Ile Pro Ile Glu Glu Leu Glu Asp Arg
20 25 30
Val Phe Val Asn Cys Asn Thr Ser Ile Thr Trp Val Glu Gly Thr Val
35 40 45
Gly Thr Leu Leu Ser Asp Ile Thr Arg Leu Asp Leu Gly Lys Arg Ile
50 55 60
Leu Asp Pro Arg Gly Ile Tyr Arg Cys Asn Gly Thr Asp Ile Tyr Lys
65 70 75 80
Asp Lys Glu Ser Thr Val Gln Val His Tyr Arg Met Cys Gln Ser Cys
85 90 95
Val Glu Leu Asp Pro Ala Thr Val Ala Gly Ile Ile Val Thr Asp Val
100 105 110
Ile Ala Thr Leu Leu Leu Ala Leu Gly Val Phe Cys Phe Ala Gly His
115 120 125
Glu Thr Gly Arg Leu Ser Gly Ala Ala Asp Thr Gln Ala Leu Leu Arg
130 135 140
Asn Asp Gln Val Tyr Gln Pro Leu Arg Asp Arg Asp Asp Ala Gln Tyr
145 150 155 160
Ser His Leu Gly Gly Asn Trp Ala Arg Asn Lys
165 170
<210> 422
<211> 207
<212> PRT
<213> 人工序列
<220>
<223> 人类CD3 ε链
<400> 422
Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser
1 5 10 15
Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr
20 25 30
Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr
35 40 45
Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys
50 55 60
Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp
65 70 75 80
His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr
85 90 95
Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu
100 105 110
Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met
115 120 125
Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu
130 135 140
Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys
145 150 155 160
Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn
165 170 175
Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg
180 185 190
Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile
195 200 205
<210> 423
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> 人类CD3 γ链
<400> 423
Met Glu Gln Gly Lys Gly Leu Ala Val Leu Ile Leu Ala Ile Ile Leu
1 5 10 15
Leu Gln Gly Thr Leu Ala Gln Ser Ile Lys Gly Asn His Leu Val Lys
20 25 30
Val Tyr Asp Tyr Gln Glu Asp Gly Ser Val Leu Leu Thr Cys Asp Ala
35 40 45
Glu Ala Lys Asn Ile Thr Trp Phe Lys Asp Gly Lys Met Ile Gly Phe
50 55 60
Leu Thr Glu Asp Lys Lys Lys Trp Asn Leu Gly Ser Asn Ala Lys Asp
65 70 75 80
Pro Arg Gly Met Tyr Gln Cys Lys Gly Ser Gln Asn Lys Ser Lys Pro
85 90 95
Leu Gln Val Tyr Tyr Arg Met Cys Gln Asn Cys Ile Glu Leu Asn Ala
100 105 110
Ala Thr Ile Ser Gly Phe Leu Phe Ala Glu Ile Val Ser Ile Phe Val
115 120 125
Leu Ala Val Gly Val Tyr Phe Ile Ala Gly Gln Asp Gly Val Arg Gln
130 135 140
Ser Arg Ala Ser Asp Lys Gln Thr Leu Leu Pro Asn Asp Gln Leu Tyr
145 150 155 160
Gln Pro Leu Lys Asp Arg Glu Asp Asp Gln Tyr Ser His Leu Gln Gly
165 170 175
Asn Gln Leu Arg Arg Asn
180
<210> 424
<211> 164
<212> PRT
<213> 人工序列
<220>
<223> 人类CD3 ζ链
<400> 424
Met Lys Trp Lys Ala Leu Phe Thr Ala Ala Ile Leu Gln Ala Gln Leu
1 5 10 15
Pro Ile Thr Glu Ala Gln Ser Phe Gly Leu Leu Asp Pro Lys Leu Cys
20 25 30
Tyr Leu Leu Asp Gly Ile Leu Phe Ile Tyr Gly Val Ile Leu Thr Ala
35 40 45
Leu Phe Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
50 55 60
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
65 70 75 80
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
85 90 95
Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
100 105 110
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
115 120 125
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
130 135 140
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
145 150 155 160
Leu Pro Pro Arg
<210> 425
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (臼) / CD3#5 全长
<400> 425
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 426
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (臼) / CD3#6 全长
<400> 426
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Cys
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 427
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (臼) / CD3#7 全长
<400> 427
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 428
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (杵) / CD3#2 全长
<400> 428
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Lys Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 429
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (杵) / CD3#3 全长
<400> 429
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 430
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (杵) / CD3#4 全长
<400> 430
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Cys
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 431
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (杵) / CD3#5 全长
<400> 431
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 432
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (杵) / CD3#6 全长
<400> 432
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Cys
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 433
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#8 (杵) / CD3#7 全长
<400> 433
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Thr Gly Ile
50 55 60
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
260 265 270
Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser
275 280 285
Asp His Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
290 295 300
Trp Met Gly Tyr Ile Tyr Pro Arg Leu Gly Ser Thr Lys Tyr Ala Glu
305 310 315 320
Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr
325 330 335
Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Gln Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980
<210> 434
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> Fc 域杵
<400> 434
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 Trp 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> 435
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> Fc 域臼
<400> 435
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 Ser Cys Ala 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 Val 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 Arg Phe Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 436
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> Trop2#11 全长 (臼)
<400> 436
Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Ser
20 25 30
Val Asn Arg Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Glu
210 215 220
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu Gly Lys
225 230 235 240
Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly Gly Ser
245 250 255
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
260 265 270
Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly
275 280 285
Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
290 295 300
Met Gly Tyr Ile Ser Tyr Asp Gly Arg Asn Asn Tyr Asn Pro Ser Leu
305 310 315 320
Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Glu Asn Gln Phe Phe
325 330 335
Leu Lys Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Thr Tyr Tyr Cys
340 345 350
Ala Arg Asp Thr Thr Ala Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
355 360 365
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
370 375 380
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
385 390 395 400
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
405 410 415
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
420 425 430
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
435 440 445
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
450 455 460
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His
465 470 475 480
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
485 490 495
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
500 505 510
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
515 520 525
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
530 535 540
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
545 550 555 560
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
565 570 575
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
580 585 590
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
595 600 605
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala
610 615 620
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
625 630 635 640
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
645 650 655
Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg
660 665 670
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
675 680 685
His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
690 695 700
<210> 437
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> CDH17#1 (杵) / CD3#1 全长
<400> 437
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 Tyr 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 Leu 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 Ser Ser Val Lys Ala 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 Lys 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 Gly Gly Gly Gly
210 215 220
Ser Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Glu
225 230 235 240
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Gly
245 250 255
Gly Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro
260 265 270
Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr
275 280 285
Asp His Thr Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu
290 295 300
Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn Glu
305 310 315 320
Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr
325 330 335
Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr
340 345 350
Phe Cys Ala Arg Trp Gly Tyr Tyr Tyr Gly Ser Ser Arg Tyr Tyr Phe
355 360 365
Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr
370 375 380
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
385 390 395 400
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
405 410 415
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
420 425 430
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
435 440 445
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
450 455 460
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
465 470 475 480
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
485 490 495
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
500 505 510
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
515 520 525
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
530 535 540
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
545 550 555 560
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
565 570 575
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
580 585 590
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
595 600 605
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
610 615 620
Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
625 630 635 640
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
645 650 655
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
660 665 670
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
675 680 685
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
690 695 700
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
705 710 715 720
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala Val Val Thr Gln
725 730 735
Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys
740 745 750
Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val
755 760 765
Gln Glu Lys Pro Gly Gln Leu Pro Arg Gly Leu Ile Gly Gly Thr Asn
770 775 780
Lys Arg Ala Pro Trp Val Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly
785 790 795 800
Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala
805 810 815
Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly
820 825 830
Gly Thr Lys Leu Thr Val Leu Gly Gly Ser Glu Gly Lys Ser Ser Gly
835 840 845
Ser Gly Ser Glu Ser Lys Ser Thr Gly Gly Ser Glu Val Gln Leu Val
850 855 860
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
865 870 875 880
Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val
885 890 895
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
900 905 910
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
915 920 925
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
930 935 940
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
945 950 955 960
Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln
965 970 975
Gly Thr Leu Val Thr Val Ser Ala
980

Claims (21)

1.一种结合分子，其包含：
(a)至少一个以Kd≥1nM特异性结合于滋养层细胞表面抗原2(TROP2)的抗原结合位点，
(b)至少一个特异性结合于钙黏素-17(CDH17)的抗原结合位点，其中所述至少一个特异性结合于CDH17的抗原结合位点为选自由抗原结合位点(i)至(ii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:33(CDR2)及SEQ IDNO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:35(CDR1)、SEQ ID NO.:36(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR；
及
(ii)抗原结合位点，其包括包含SEQ ID NO.:32(CDR1)、SEQ ID NO.:38(CDR2)及SEQID NO.:34(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:39(CDR1)、SEQ ID NO.:40(CDR2)及SEQ ID NO.:37(CDR3)的氨基酸序列的轻链CDR，及
(c)至少一个特异性结合于分化簇3(CD3)的抗原结合位点。
2.如权利要求1的结合分子，其中所述至少一个特异性结合于TROP2的抗原结合位点为选自由抗原结合位点(i)至(vi)组成的组：
(i)抗原结合位点，其包括包含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及包含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，其包括包含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及包含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CDRS；
(iii)抗原结合位点，其包括包含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及包含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，其包括包含SEQ ID NO.:13(CDR1)、SEQ ID NO.:19(CDR2)及SEQID NO.:15(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:20(CDR1)、SEQ ID NO.:17(CDR2)及SEQ ID NO.:18(CDR3)的氨基酸序列的轻链CDR；
(v)抗原结合位点，其包括包含SEQ ID NO.:21(CDR1)、SEQ ID NO.:22(CDR2)及SEQ IDNO.:23(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:24(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:26(CDR3)的氨基酸序列的轻链CDR；
及
(vi)抗原结合位点，其包括包含SEQ ID NO.:27(CDR1)、SEQ ID NO.:28(CDR2)及SEQID NO.:29(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:30(CDR1)、SEQ ID NO.:25(CDR2)及SEQ ID NO.:31(CDR3)的氨基酸序列的轻链CDR。
3.如权利要求1或权利要求2的结合分子，其中所述至少一个特异性结合于TROP2的抗原结合位点为选自由抗原结合位点(i)至(xii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:83的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:84的氨基酸序列的免疫球蛋白轻链可变域；
(ii)抗原结合位点，其包括包含SEQ ID NO:85的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:86的氨基酸序列的免疫球蛋白轻链可变域；
(iii)抗原结合位点，其包括包含SEQ ID NO:87的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:88的氨基酸序列的免疫球蛋白轻链可变域；
(iv)抗原结合位点，其包括包含SEQ ID NO:89的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:90的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含SEQ ID NO:91的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:92的氨基酸序列的免疫球蛋白轻链可变域；
(vi)抗原结合位点，其包括包含SEQ ID NO:93的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:94的氨基酸序列的免疫球蛋白轻链可变域；
(vii)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:94的氨基酸序列的免疫球蛋白轻链可变域；
(viii)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:96的氨基酸序列的免疫球蛋白轻链可变域；
(ix)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(x)抗原结合位点，其包括包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:97的氨基酸序列的免疫球蛋白轻链可变域；
(xi)抗原结合位点，其包括包含SEQ ID NO:95的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:99的氨基酸序列的免疫球蛋白轻链可变域；
或
(xii)抗原结合位点，其包括包含SEQ ID NO:98的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:96的氨基酸序列的免疫球蛋白轻链可变域。
4.如权利要求1至3中任一项的结合分子，其中所述至少一个特异性结合于CDH17的抗原结合位点为选自由抗原结合位点(i)至(ii)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:100的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:101的氨基酸序列的免疫球蛋白轻链可变域；
及
(ii)抗原结合位点，其包括包含SEQ ID NO:102的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:103的氨基酸序列的免疫球蛋白轻链可变域。
5.如权利要求1至4中任一项的结合分子，其中所述至少一个特异性结合于CD3的抗原结合位点为选自由抗原结合位点(i)至(xxxi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ IDNO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(ii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:46(CDR3)的氨基酸序列的轻链CDR；
(iii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(iv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:49(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:50(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(v)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQ IDNO.:43(CDR3)的氨基酸序列的重链CDRS及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(vi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:49(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:44(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(vii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:53(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:47(CDR3)的氨基酸序列的轻链CDR；
(viii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:55(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(ix)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:56(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(x)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:48(CDR2)及SEQ IDNO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:58(CDR2)及SEQID NO.:59(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:60(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xiii)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:62(CDR2)及SEQID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xiv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:63(CDR2)及SEQID NO.:54(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:56(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xv)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:61(CDR1)、SEQ ID NO.:45(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xvi)抗原结合位点，其包括包含SEQ ID NO.:41(CDR1)、SEQ ID NO.:42(CDR2)及SEQID NO.:43(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:57(CDR1)、SEQ ID NO.:52(CDR2)及SEQ ID NO.:51(CDR3)的氨基酸序列的轻链CDR；
(xvii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:64(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xviii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:69(CDR2)及SEQ ID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xix)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:72(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xx)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:73(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:74(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:73(CDR2)及SEQID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxiii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:75(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxiv)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:69(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxv)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:76(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxvi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:77(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:71(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxvii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:78(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxviii)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:79(CDR2)及SEQ ID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:80(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxix)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:81(CDR2)及SEQID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
(xxx)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:79(CDR2)及SEQID NO.:65(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:80(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR；
及
(xxxi)抗原结合位点，其包括包含SEQ ID NO.:82(CDR1)、SEQ ID NO.:81(CDR2)及SEQID NO.:70(CDR3)的氨基酸序列的重链CDR及包含SEQ ID NO.:66(CDR1)、SEQ ID NO.:67(CDR2)及SEQ ID NO.:68(CDR3)的氨基酸序列的轻链CDR。
6.如权利要求1至5中任一项的结合分子，其中所述至少一个特异性结合于CD3的抗原结合位点为选自由抗原结合位点(i)至(xvi)组成的组：
(i)抗原结合位点，其包括包含SEQ ID NO:104的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:105、SEQ ID NO:106、SEQ ID NO:107、SEQ ID NO:109、SEQ IDNO:114、SEQ ID NO:115、SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO:120、SEQ ID NO:121、SEQ ID NO:123及SEQ ID NO:129组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(ii)抗原结合位点，其包括包含SEQ ID NO:110的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:111的氨基酸序列的免疫球蛋白轻链可变域；
(iii)抗原结合位点，其包括包含SEQ ID NO:112的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:113的氨基酸序列的免疫球蛋白轻链可变域；
(iv)抗原结合位点，其包括包含SEQ ID NO:118的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:119及SEQ ID NO:122组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含SEQ ID NO:124的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:125、SEQ ID NO:126及SEQ ID NO:127组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(v)抗原结合位点，其包括包含选自由SEQ ID NO:128及SEQ ID NO:130组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:127的氨基酸序列的免疫球蛋白轻链可变域；
(vi)抗原结合位点，其包括包含SEQ ID NO:131的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:132的氨基酸序列的免疫球蛋白轻链可变域；
(vii)抗原结合位点，其包括包含SEQ ID NO:133的氨基酸序列的免疫球蛋白重链可变域及包含选自由SEQ ID NO:134及SEQ ID NO:135组成的组的氨基酸序列的免疫球蛋白轻链可变域；
(viii)抗原结合位点，其包括包含SEQ ID NO:136的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:137的氨基酸序列的免疫球蛋白轻链可变域；
(ix)抗原结合位点，其包括包含选自由SEQ ID NO:138及SEQ ID NO：156组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:139的氨基酸序列的免疫球蛋白轻链可变域；
(x)抗原结合位点，其包括包含选自由SEQ ID NO:140、SEQ ID NO:142、SEQ ID NO:143及SEQ ID NO:161组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:141的氨基酸序列的免疫球蛋白轻链可变域；
(xi)抗原结合位点，其包括包含选自由SEQ ID NO:144及SEQ ID NO:146组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:145的氨基酸序列的免疫球蛋白轻链可变域；
(xii)抗原结合位点，其包括包含选自由SEQ ID NO:147、SEQ ID NO:151、SEQ ID NO:153及SEQ ID NO:162组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:148的氨基酸序列的免疫球蛋白轻链可变域；
(xiii)抗原结合位点，其包括包含选自由SEQ ID NO:149及SEQ ID NO:152组成的组的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:150的氨基酸序列的免疫球蛋白轻链可变域；
(xiv)抗原结合位点，其包括包含SEQ ID NO:154的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:155的氨基酸序列的免疫球蛋白轻链可变域；
(xv)抗原结合位点，其包括包含SEQ ID NO:157的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:158的氨基酸序列的免疫球蛋白轻链可变域；及
(xvi)抗原结合位点，其包括包含SEQ ID NO:159的氨基酸序列的免疫球蛋白重链可变域及包含SEQ ID NO:160的氨基酸序列的免疫球蛋白轻链可变域。
7.如权利要求1至6中任一项的结合分子，其中所述结合分子为经修饰的免疫球蛋白(Ig)分子，优选经修饰的IgG分子，其中所述至少一个特异性结合于TROP2的抗原结合位点及所述至少一个特异性结合于CDH17的抗原结合位点存在于所述Ig分子的可变区，且其中所述至少一个特异性结合于CD3的抗原结合位点为与所述TROP2-CDH17特异性Ig分子融合的scFv。
8.如权利要求7的结合分子，其中所述scFv与所述Ig分子的重链的C端融合，优选与包含所述至少一个特异性结合于CDH17的抗原结合位点的所述Ig分子的部分的重链融合。
9.如权利要求1至8中任一项的结合分子，其中所述结合分子包含：
(a)选自(a-i)至(a-xii)的第一免疫球蛋白轻链及免疫球蛋白重链组合，优选通过肽接头连接在一起：
(a-i)包含SEQ ID NO:169的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:170的氨基酸序列的免疫球蛋白重链；
(a-ii)包含SEQ ID NO:171的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:172的氨基酸序列的免疫球蛋白重链；
(a-iii)包含SEQ ID NO:173的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:174的氨基酸序列的免疫球蛋白重链；
(a-iv)包含SEQ ID NO:175的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:176的氨基酸序列的免疫球蛋白重链；
(a-v)包含SEQ ID NO:177的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:178的氨基酸序列的免疫球蛋白重链；
(a-vi)包含SEQ ID NO:179的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:180的氨基酸序列的免疫球蛋白重链；
(a-vii)包含SEQ ID NO:181的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:182的氨基酸序列的免疫球蛋白重链；
(a-viii)包含SEQ ID NO:183的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:184的氨基酸序列的免疫球蛋白重链；
(a-ix)包含SEQ ID NO:185的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:186的氨基酸序列的免疫球蛋白重链；
(a-x)包含SEQ ID NO:187的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:188的氨基酸序列的免疫球蛋白重链；
(a-xi)包含SEQ ID NO:189的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:190的氨基酸序列的免疫球蛋白重链；或
(a-xii)包含SEQ ID NO:191的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:192的氨基酸序列的免疫球蛋白重链；
及
(b)选自(b-i)至(b-ii)的第二免疫球蛋白重链及免疫球蛋白轻链组合，优选通过肽接头连接在一起：
(b-i)包含SEQ ID NO:196的氨基酸序列的免疫球蛋白轻链及包含SEQ ID NO:197的氨基酸序列的免疫球蛋白重链；或
(b-ii)包含SEQ ID NO:198的氨基酸序列的免疫球蛋白重链及包含SEQ ID NO:199的氨基酸序列的免疫球蛋白轻链；
及
(c)包含选自由SEQ ID NO:222至264组成的组的氨基酸序列的单链可变片段(scFv)，优选连接于所述第二免疫球蛋白重链及免疫球蛋白轻链组合的所述免疫球蛋白重链的C端。
10.如权利要求1至9中任一项的结合分子，其中所述结合分子包含以下或由以下组成：
(a-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(a-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:267的氨基酸序列；
(b-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:268的氨基酸序列；
(b-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-v)SEQ IDNO.:210的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-vii)SEQ ID NO.:212的氨基酸序列及SEQ IDNO.:268的氨基酸序列；(b-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-x)SEQID NO.:215的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:268的氨基酸序列；(b-xii)SEQ ID NO.:217的氨基酸序列及SEQ IDNO.:268的氨基酸序列；(c-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-iii)SEQ IDNO.:208的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-viii)SEQ IDNO.:213的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(c-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:269的氨基酸序列；(d-i)SEQ IDNO.:200的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-iii)SEQ ID NO.:208的氨基酸序列及SEQ IDNO.:270的氨基酸序列；(d-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-vi)SEQ IDNO.:211的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-viii)SEQ ID NO.:213的氨基酸序列及SEQ IDNO.:270的氨基酸序列；(d-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-xi)SEQ IDNO.:216的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(d-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:270的氨基酸序列；(e-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-iv)SEQ IDNO.:209的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-ix)SEQID NO.:214的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(e-xi)SEQ ID NO.:216的氨基酸序列及SEQ IDNO.:271的氨基酸序列；(e-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:271的氨基酸序列；(f-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-ii)SEQ IDNO.:207的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-iv)SEQ ID NO.:209的氨基酸序列及SEQ IDNO.:272的氨基酸序列；(f-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-vii)SEQ IDNO.:212的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-ix)SEQ ID NO.:214的氨基酸序列及SEQ IDNO.:272的氨基酸序列；(f-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(f-xii)SEQ IDNO.:217的氨基酸序列及SEQ ID NO.:272的氨基酸序列；(g-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-v)SEQ IDNO.:210的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-vii)SEQ ID NO.:212的氨基酸序列及SEQ IDNO.:424的氨基酸序列；(g-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-x)SEQID NO.:215的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:424的氨基酸序列；(g-xii)SEQ ID NO.:217的氨基酸序列及SEQ IDNO.:424的氨基酸序列；(h-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-iii)SEQ IDNO.:208的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-viii)SEQ IDNO.:213的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(h-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:425的氨基酸序列；(i-i)SEQ IDNO.:200的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-iii)SEQ ID NO.:208的氨基酸序列及SEQ IDNO.:426的氨基酸序列；(i-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-vi)SEQ IDNO.:211的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-viii)SEQ ID NO.:213的氨基酸序列及SEQ IDNO.:426的氨基酸序列；(i-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-xi)SEQ IDNO.:216的氨基酸序列及SEQ ID NO.:426的氨基酸序列；(i-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:426的氨基酸序列；
(j-i)SEQ ID NO.:200的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ii)SEQ ID NO.:207的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iii)SEQ ID NO.:208的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-iv)SEQ ID NO.:209的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-v)SEQ ID NO.:210的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vi)SEQ ID NO.:211的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-vii)SEQ ID NO.:212的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-viii)SEQ ID NO.:213的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-ix)SEQ ID NO.:214的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-x)SEQ ID NO.:215的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-xi)SEQ ID NO.:216的氨基酸序列及SEQ ID NO.:427的氨基酸序列；
(j-xii)SEQ ID NO.:217的氨基酸序列及SEQ ID NO.:427的氨基酸序列；或
(k)SEQ ID NO.:436的氨基酸序列及SEQ ID NO.:437的氨基酸序列。
11.一种核酸分子，其编码如权利要求1至10中任一项的结合分子或其一部分。
12.一种表达载体，其包含一种或多种如权利要求11的核酸分子。
13.一种宿主细胞，其经如权利要求12的表达载体转染。
14.一种产生如权利要求1至10中任一项的结合分子的方法，所述方法包含以下步骤：
(a)在允许如权利要求1至10中任一项的结合分子表达的条件下培养如权利要求13的宿主细胞；
(b)任选回收所述分子；及任选地
(c)进一步纯化和/或修饰和/或调配所述结合分子。
15.一种药物组合物，其包含一种或多种如权利要求1至10中任一项的结合分子及任选选用的药学上可接受的载剂或由其组成。
16.一种如权利要求1至10中任一项的结合分子或如权利要求15的药物组合物的用途，其用于药物。
17.如权利要求1-10中任一项的结合分子或如权利要求15的药物组合物，其用于治疗、改善或预防癌症的方法。
18.一种治疗、预防或改善癌症的方法，所述方法包含向有需要的患者施用治疗有效量的如权利要求1-10中任一项的结合分子或如权利要求15的药物组合物。
19.如权利要求1-10中任一项的结合分子用于制备治疗、预防或改善癌症的药物组合物的用途。
20.如权利要求17所用的结合分子或药物组合物，如权利要求18的方法，或如权利要求19的用途，其中所述癌症为大肠直肠癌(CRC)、胃癌(GC)或胰腺癌(PAC)。
21.如权利要求17所用的结合分子或药物组合物，如权利要求18的方法，或如权利要求19的用途，其中所述结合分子将与免疫检查点抑制剂，优选抗PD-1或抗PD-1-L1抗体组合使用。
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