与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体

摘要

本发明涉及与暴露于细胞外的赖氨酰‑tRNA合成酶N‑末端区域特异性结合的抗体，更详细地，涉及具有在本说明书中记载的特定互补决定区(CDR)序列，且与暴露于细胞外的赖氨酰‑tRNA合成酶(KRS，Lysyl‑tRNA synthetase)N‑末端区域特异性结合的抗体或其片段，以及包含所述抗体或其片段作为有效成分的组合物的癌症、癌症转移或免疫细胞迁移相关疾病的预防、治疗或诊断的用途。相比于现有的抗体，本发明的方法可有用地用于制备与赖氨酰‑tRNA合成酶N‑末端的亲和力高的抗体。

说明书

本申请要求于2018年9月17日申请的韩国专利申请第10-2018-0111046号的优先权，其申请文件全文以引用方式并入本文。

技术领域

本发明涉及与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体，更详细地，涉及具有在本说明书中记载的特定互补决定区(CDR)序列，且与暴露于细胞外的赖氨酰-tRNA合成酶(KRS，Lysyl-tRNA synthetase)N-末端区域特异性结合并具有高的亲和力及稳定性的抗体或其片段，以及包含所述抗体或其片段作为有效成分的组合物的癌症、癌症转移或免疫细胞迁移相关疾病的预防、治疗或诊断的用途。

背景技术

最近的研究已经确定，通常存在于胞质溶胶(cytosol)中的人赖氨酰-tRNA合成酶向质膜(细胞膜)迁移(translocation)并与存在于质膜上的67-kDa层粘连蛋白受体(67LR)相互作用，来促进肿瘤(或癌症)细胞的迁移以影响癌症的转移(metastasis)(Dae Gyu Kimet al.Chemical inhibition of prometastatic lysyl-tRNA synthetase–lamininreceptor interaction,Nat Chem Biol.2014 Jan；10(1):29–34,Dae Gye Kimet.al.Interaction of two translational components,lysyl-tRNA synthetase andp40/37LRP,in plasma membrane promotes laminin-dependent cell migration,FASEBJ.(2012)26,4142-4159)。人赖氨酰-tRNA合成酶(Genbank Accession No.NP_005539.1等)包含N-末端延伸(N-terminal extension，1-72)、反密码子结合域(anticodon-bindingdomain，73-209)及催化域(catalytic domain，220-597)。人赖氨酰-tRNA合成酶为蛋白质合成所必需的酶，通常存在于胞质溶胶中的多重tRNA合成酶复合物(multi-tRNAsynthetase complex，MSC)内。但是，在层粘连蛋白(laminin)信号发生后，p38 MAPK在T52残基上使赖氨酰-tRNA合成酶磷酸化，赖氨酰-tRNA合成酶向细胞膜迁移以保护67LR避免泛素介导的降解。并且，据报告，向细胞膜迁移的赖氨酰-tRNA合成酶使与癌症转移关联的67LR稳定化，并与其相互作用，从而促进癌症转移(cancer metastasis)。

在此情况下，在N末端延伸(N-terminal extension，N-ext)中缺失40个末端残基的Myc-KRS41-597(ΔN)不存在于(localize)质膜上的事实意味着，赖氨酰-tRNA合成酶N末端延伸区域是赖氨酰-tRNA合成酶向细胞膜迁移(translocation)过程的必要的区域。并且，关于癌症转移，具体地，赖氨酰-tRNA合成酶N末端延伸区域在与67LR的相互作用中参与其的结合。为了将该事实用于治疗或诊断目的，需根据构成赖氨酰-tRNA合成酶蛋白的多个域区域的特性，需要特异性靶向(targeting)蛋白质中的所目的的特定位点(特别是赖氨酰-tRNA合成酶N末端延伸)。由此，本发明人制备了不示出还与ARS结合的交叉反应的与赖氨酰-tRNA合成酶N-末端特异性结合的抗体(韩国专利申请号：10-2018-0035446)。

但是，将以往的赖氨酰-tRNA合成酶N-末端作为靶的抗体的亲和力低于完整的IgG形态的各种抗体的亲和力。因此，需制备对赖氨酰-tRNA合成酶N-末端具有更高亲和力的抗体。

发明内容

技术问题

因此，本发明人为了制备相比于以往的与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体，对于赖氨酰-tRNA合成酶N-末端区域的结合亲和力更好的抗体，对以往的抗体轻链可变区和重链可变区进行修饰来完成了本发明。

因此，本发明的目的在于，提供与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体或其片段，其包含：(a)，重链可变区(VH)；以及(b)，轻链可变区(VL)，所述重链可变区包括：(i)重链互补决定区1(CDR1)，包含氨基酸序列SYDMS；(ii)，重链互补决定区2(CDR2)，包含氨基酸序列X

本发明的再一目的在于，提供编码抗体或其片段的多核苷酸、包含其的重组表达载体、利用所述载体转化的细胞。

本发明的另一目的在于，提供制备与暴露于细胞外的赖氨酰-tRNA合成酶N末端特异性结合的抗体或其片段的方法，所述方法包括：步骤(a)利用所述重组表达载体转化宿主细胞；步骤(b)培养转化的宿主细胞以生成抗体或其片段；以及步骤(c)获取在宿主细胞中生成的抗体或其片段。

本发明的还有一目的在于，提供包含所述抗体或其片段作为有效成分的用于预防或抑制癌症转移的药学组合物。

并且，本发明的还有一目的在于，提供将所述抗体或其片段作为有效成分来构成的用于预防或抑制癌症转移的药学组合物。

并且，本发明的还有一目的在于，提供将所述抗体或其片段作为必须的有效成分来构成的用于预防或抑制癌症转移的药学组合物。

本发明的又一目的在于，提供包含所述抗体或其片段作为有效成分的用于预防或治疗免疫细胞迁移相关疾病的组合物。

并且，本发明的又一目的在于，提供将所述抗体或其片段作为有效成分来构成的用于预防或治疗免疫细胞迁移相关疾病的组合物。

并且，本发明的又一目的在于，提供将所述抗体或其片段作为必须的有效成分来构成的用于预防或治疗免疫细胞迁移相关疾病的组合物。

本发明的又一目的在于，提供包含所述抗体或其片段作为有效成分的用于诊断免疫细胞迁移相关疾病的组合物。

并且，本发明的又一目的在于，提供将所述抗体或其片段作为有效成分来构成的用于诊断免疫细胞迁移相关疾病的组合物。

并且，本发明的又一目的在于，提供将所述抗体或其片段作为必须的有效成分来构成的用于诊断免疫细胞迁移相关疾病的组合物。

本发明的又一目的在于，提供在制备用于预防或抑制癌症及癌症转移的制剂中的所述抗体或其片段的用途。

本发明的又一目的在于，提供向有需要的个体给药有效量的包含所述抗体或其片段的组合物的癌症及癌症转移预防或抑制方法。

本发明的又一目的在于，提供在制备用于诊断癌症或癌症转移的制剂中的所述抗体或其片段的用途。

本发明的又一目的在于，提供癌症或癌症转移诊断方法，其包括：步骤a)，从怀疑癌症转移的个体(受试者)获取生物学试样；步骤b)，向所述试样或个体给药包含所述抗体或其片段的组合物；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；以及步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为癌症及癌症转移已发生。

本发明的又一目的在于，提供在制备用于治疗免疫细胞迁移相关疾病的制剂中的所述抗体或其片段的用途。

本发明的又一目的在于，提供特征在于向有需要的个体给药有效量的包含所述抗体或其片段的组合物的免疫细胞迁移相关疾病的治疗方法。

本发明的又一目的在于，提供在制备用于诊断免疫细胞迁移相关疾病的制剂中的所述抗体或其片段的用途。

本发明的又一目的在于，提供免疫细胞迁移相关疾病诊断方法，其包括：步骤a)，从怀疑免疫细胞迁移相关疾病的个体获取生物学试样；步骤b)，向所述试样或个体给药包含所述抗体或其片段的组合物；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；以及步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为免疫细胞迁移相关疾病。

技术方案

为了实现如上所述的目的，本发明提供与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体或其片段，其包含：(a)，重链可变区；以及(b)，轻链可变区，所述重链可变区包括：(i)重链互补决定区1，包含氨基酸序列SYDMS；(ii)，重链互补决定区2，包含氨基酸序列X

为了实现本发明的再一目的，本发明提供编码抗体或其片段的多核苷酸、包含其的重组表达载体、利用所述载体转化的细胞。

为了实现本发明的另一目的，本发明提供制备与暴露于细胞外的赖氨酰-tRNA合成酶N-末端特异性结合的抗体或其片段的方法，其包括：步骤(a)，利用所述重组表达载体转化宿主细胞；步骤(b)，培养转化的宿主细胞以生成抗体或其片段；以及步骤(c)，获取在宿主细胞生成的抗体或其片段。

为了实现本发明的还有一目的，本发明提供包含所述抗体或其片段作为有效成分的用于预防或抑制癌症转移的药学组合物。

并且，本发明提供将所述抗体或其片段作为有效成分来构成的用于预防或抑制癌症转移的药学组合物。

并且，本发明提供将所述抗体或其片段作为必须的有效成分来构成的用于预防或抑制癌症转移的药学组合物。

为了实现本发明的又一目的，本发明提供包含所述抗体或其片段作为有效成分的用于预防或治疗免疫细胞迁移相关疾病的组合物。

并且，本发明提供将所述抗体或其片段作为有效成分来构成的用于预防或治疗免疫细胞迁移相关疾病的组合物。

并且，本发明提供将所述抗体或其片段作为必须的有效成分来构成的用于预防或治疗免疫细胞迁移相关疾病的组合物。

为了实现本发明的又一目的，本发明体用包含所述抗体或其片段作为有效成分的用于诊断免疫细胞迁移相关疾病的组合物。

并且，本发明提供将所述抗体或其片段作为有效成分来构成的用于诊断免疫细胞迁移相关疾病的组合物。

并且，本发明提供将所述抗体或其片段作为必须的有效成分来构成的用于诊断免疫细胞迁移相关疾病的组合物。

为了实现本发明的又一目的，本发明提供用于预防或抑制癌症及癌症转移的所述抗体或其片段的用途。

为了实现本发明的又一目的，本发明提供特征在于向有需要的个体给药有效量的包含所述抗体或其片段的组合物的癌症及癌症转移预防或抑制方法。

为了实现本发明的又一目的，本发明提供在制备用于诊断癌症或癌症转移的制剂中的所述抗体或其片段的用途。

为了实现本发明的又一目的，本发明提供癌症或癌症转移诊断方法，其包括：步骤a)，从怀疑癌症转移的个体(受试者)获取生物学试样；步骤b)，向所述试样或个体给药包含所述抗体或其片段的组合物；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；以及步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为癌症及癌症转移已发生。

为了实现本发明的又一目的，本发明提供在制备用于治疗免疫细胞迁移相关疾病的制剂中的所述抗体或其片段的用途。

为了实现本发明的又一目的，本发明提供特征在于向有需要的个体给药有效量的包含所述抗体或其片段的组合物的免疫细胞迁移相关疾病的治疗方法。

为了实现本发明的又一目的，本发明提供在制备用于诊断免疫细胞迁移相关疾病的制剂中的所述抗体或其片段的用途。

为了实现本发明的又一目的，本发明提供免疫细胞迁移相关疾病诊断方法，其包括：步骤a)，从怀疑免疫细胞迁移相关疾病的个体获取生物学试样；步骤b)，向所述试样或个体给药包含所述抗体或其片段的组合物的步骤；步骤c)，在所述步骤b)的试样或个体中检测赖氨酰-tRNA合成酶蛋白的表达水平的步骤；以及步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为免疫细胞迁移相关疾病。

以下，详细说明本发明。

如本发明所用，“暴露于细胞外的赖氨酰-tRNA合成酶N末端区域”是指当在细胞内生成的赖氨酰-tRNA合成酶迁移到细胞膜(或质膜)时，暴露于细胞外(extracellular)区域或在细胞膜表面的特定序列，通常，可指赖氨酰-tRNA合成酶N末端的1个至72个氨基酸区域的一部分或全长序列。另外，赖氨酰-tRNA合成酶N末端区域存在物种序列相似性，尤其，包括由SEQ ID NO:117表示的氨基酸序列。

如本发明所用，术语“赖氨酰-tRNA合成酶”是指以赖氨酰-tRNA合成酶周知的全长多肽或包括N末端区域(N-terminal extention)的任意赖氨酰-tRNA合成酶片段序列。如上所述，本发明的抗体或其片段特异性检测暴露于细胞外的赖氨酰-tRNA合成酶N末端区域，因此还可检测包括如上所述的赖氨酰-tRNA合成酶全长多肽或包括N末端区域的任意赖氨酰-tRNA合成酶片段序列。所述赖氨酰-tRNA合成酶的具体序列没有特别限制，只要以包含如由SEQ ID NO:117表示的多肽而在本领域周知的赖氨酰-tRNA合成酶即可。例如，本发明的赖氨酰-tRNA合成酶包括：来源于人(homo sapiens)且已知其NCBI(Genbank)登录号为NP_005539.1等的序列；来源于小鼠(Mus musculus)且已知其NCBI(Genbank)登录号为NP_444322.1等的序列，以及来源于大鼠(Rattus norvegicus)且已知其NCBI(Genbank)登录号为XP_006255692.1等的序列，除此之外，可参照下述序列信息，但并不限定于此：XP_005004655.1(豚鼠(guinea-pig)：Cavia porcellus)、XP_021503253.1(沙鼠(gerbil)，Meriones unguiculatus)、XP_002711778.1(兔(rabbit)，Oryctolagus cuniculus)、XP_536777.2(狗(dog)，Canis lupus familiaris)、XP_003126904.2(猪(swine)，Susscrofa)、XP_011755768.1(猴(monkey)，Macaca nemestrina)、XP_008984479.1(狨猴(marmoset)，Callithrix jacchus)、XP_019834275.1(牛(cow)，Bos indicus)、XP_511115.2(黑猩猩(chimpanzee)，Pan troglodytes)。最优选地，可以为NCBI(Genbank)登录号为NP_005539.1的序列。

如本发明所用，“抗体(antibody)”还称为免疫球蛋白(immunoglobulin，Ig)，为选择性地作用于抗原来参与生物体免疫的蛋白质的总称。在自然中发现的全抗体(wholeantibody)通常由两对轻链(light chain，LC)及重链(heavy chain，HC)组成，其中每条为由多个结构域组成的多肽，或具有两对HC/LC作为基本单位。构成哺乳动物的抗体的重链有5种类型，用希腊字母α、δ、ε、γ及μ表示，根据重链的种类，分别构成不同类型的抗体：IgA、IgD、IgE、IgG及IgM。构成哺乳动物的抗体的轻链有两种类型分别由λ及κ表示。

抗体的重链与轻链根据氨基酸序列的可变性在结构上分为可变区和恒定区。根据抗体的种类，重链的恒定区由三个或四个重链恒定区域组成，例如CH1、CH2及CH3(IgA、IgD及IgG抗体)及CH4(IgE及IgM抗体)，轻链具有一个恒定区CL。重链与轻链的可变区分别由重链可变区或轻链可变区的一个结构域形成。轻链与重链通过一个共价二硫键(disulfidebond)相互连接，其可变区和恒定区分别平行排列，并且与轻链结合的两个分子的重链通过两个共价二硫键相连接，来形成全抗体的形态。全抗体通过重链及轻链的可变区与抗原特异性结合。全抗体由两对重链和轻链(HC/LC)形成，因此，一个分子的全抗体具有二价单特异性，通过两个可变区与两个相同的抗原相结合。

包括抗体与抗原结合的位点的可变区细分为具有低序列变异性的构架区(framework region，FR)和高序列变异性的高变区(hypervariable region)的互补决定区(complementary determining region，CDR)。在重链可变区与轻链可变区中，三个互补决定区及四个构架区从N末端到C末端的方向以构架区1-互补决定区1-构架区2-互补决定区2-构架区3-互补决定区3-构架区4的顺序排列。在抗体的可变区域中，具有最高序列变异性的互补决定区为与抗原直接结合的位点，对于抗体的抗原特异性尤为重要。

本发明提供与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体或其片段，其包含：(a)，重链可变区；以及(b)，轻链可变区，所述重链可变区包括：(i)重链互补决定区1，包含氨基酸序列SYDMS；(ii)，重链互补决定区2，包含氨基酸序列X

具体地，其特征在于，所述(a)重链可变区包括：重链互补决定区1，包含由SEQ IDNO:1表示的氨基酸序列；重链互补决定区2，包含选自由SEQ ID NO:3、SEQ ID NO:17、SEQID NO:19、SEQ ID NO:21、SEQ ID NO:23及SEQ ID NO:118组成的群组中的一种以上的氨基酸序列；以及重链互补决定区3，包含选自由SEQ ID NO:5及SEQ ID NO:25组成的群组中的一种以上的氨基酸序列，(b)轻链可变区包括：轻链互补决定区1，包含由SEQ ID NO:7表示的氨基酸序列；轻链互补决定区2，包含选自由SEQ ID NO:9、SEQ ID NO:27及SEQ ID NO:29组成的群组中的一种以上的氨基酸序列；以及轻链互补决定区3，包含选自由SEQ ID NO:13及SEQ ID NO:15组成的群组中的一种以上的氨基酸序列。

由所述互补决定区序列构成的抗体具有与暴露于细胞外的赖氨酰-tRNA合成酶N末端区域特异性结合的优异能力。这在本发明的说明书的实施例中进行了详细描述。

在本发明的实施例中，为了制备与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合且亲和力高的抗体，对以往的N3抗体(韩国专利申请号：10-2018-0035446)的重链可变区和轻链可变区进行改良后，通过酵母表达筛选了改良的文库。通过第一次荧光激活细胞分选术(FACS)、第二次荧光激活细胞分选术、第三次荧光激活细胞分选术筛选了在赖氨酰-tRNA合成酶N-末端区域具有高亲和力及特异性的N3-1 scFv、N3-3 scFv、N3-4scFv，并筛选了将其VH及VL相互组合的新型N3-5 scFv。

之后，为了筛选与结合有GST的赖氨酰-tRNA合成酶N-末端特异性结合且亲和力高的改良文库，筛选了对N3-3 scFv的重链可变区进行改良的文库。通过第一次荧光激活细胞分选术、第二次荧光激活细胞分选术、第三次荧光激活细胞分选术、第四次荧光激活细胞分选术筛选了在赖氨酰-tRNA合成酶N-末端区域具有高亲和力及特异性的N3-6 scFv、N3-7scFv、N3-8 scFv、N3-9 scFv。

其中，为了改善具有最高的亲和力的N3-8 IgG抗体的生产率、稳定性等，在N3-8的重链可变区及轻链区域引入突变体来获取了7种(N3-8-1、N3-8-2、N3-8-3、N3-8-4、N3-8-5、N3-8-6、N3-8-7)抗体。

最终制备了N3-1 IgG、N3-3 IgG、N3-4 IgG、N3-5 IgG、N3-6 IgG、N3-7IgG、N3-8IgG、N3-9 IgG、N3-8-1IgG、N3-8-2IgG、N3-8-3IgG、N3-8-4IgG、N3-8-5IgG、N3-8-6IgG、N3-8-7IgG的抗体，经确认，所述抗体也对于赖氨酰-tRNA合成酶N-末端示出高亲和力。

本发明的“与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体或其片段”并不局限于此，但优选地，作为包括如下的重链可变区及轻链可变区的互补决定区结构的抗体，下述i、ii、iii、iv、v、vi、vii、viii、ix、x、xi、xii及xiii分别示出实施例的N3-1、N3-3、N3-4、N3-5、N3-6、N3-7、N3-8、N3-9、N3-8-1、N3-8-2、N3-8-3、N3-8-4、N3-8-5、N3-8-6及N3-8-7抗体的互补决定区组合：i)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQID NO:3表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:13表示的氨基酸序列；ii)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:3表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；iii)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:118表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:13表示的氨基酸序列；iv)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:118表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；v)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:17表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；vi)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:19表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；vii)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ IDNO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:21表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ IDNO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；viii)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:23表示的氨基酸序列，所述重链互补决定区3包含由SEQ IDNO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ IDNO:15表示的氨基酸序列；ix)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:21表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:27表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；x)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:21表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:5表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:29表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；xi)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:21表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:25表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:9表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；xii)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:21表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:25表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:27表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列；xiii)抗体，包含抗体重链可变区及抗体轻链可变区，所述抗体重链可变区包括重链互补决定区1、重链互补决定区2及重链互补决定区3，所述重链互补决定区1包含由SEQ ID NO:1表示的氨基酸序列，所述重链互补决定区2包含由SEQ ID NO:21表示的氨基酸序列，所述重链互补决定区3包含由SEQ ID NO:25表示的氨基酸序列，所述抗体轻链可变区包括轻链互补决定区1、轻链互补决定区2及轻链互补决定区3，所述轻链互补决定区1包含由SEQ ID NO:7表示的氨基酸序列，所述轻链互补决定区2包含由SEQ ID NO:29表示的氨基酸序列，所述轻链互补决定区3包含由SEQ ID NO:15表示的氨基酸序列。

最优选地，本发明的所述抗体或其片段的特征在于，包含如下的重链可变区及轻链可变区。

在所述抗体或其片段中，所述重链可变区包含选自由SEQ ID NO:31、SEQ ID NO:35、SEQ ID NO:37、SEQ ID NO:39、SEQ ID NO:41、SEQ ID NO:43、SEQ ID NO:45及SEQ IDNO:47组成的群组中的一种以上的氨基酸序列，所述轻链可变区包含选自由SEQ ID NO:49、SEQ ID NO:51、SEQ ID NO:53及SEQ ID NO:55组成的群组中的一种以上的氨基酸序列。

优选地，为如下的抗体，即，其包含：重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:31表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:49表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:31表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:35表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:49表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:35表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:37表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQID NO:39表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:41表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:43表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:45表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:45表示的氨基酸序列，所述轻链可变区包含由SEQID NO:53表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ IDNO:45表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:55表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:47表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:51表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:47表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:53表示的氨基酸序列；重链可变区及轻链可变区，所述重链可变区包含由SEQ ID NO:47表示的氨基酸序列，所述轻链可变区包含由SEQ ID NO:55表示的氨基酸序列。

具体地，包含所述重链可变区和轻链可变区的IgG形态的抗体可以为由重链及轻链组成的抗体，所述重链包含由SEQ ID NO:89、SEQ ID NO:93、SEQ ID NO:95、SEQ ID NO:97、SEQ ID NO:99、SEQ ID NO:101、SEQ ID NO:103及SEQ ID NO:105组成的群组中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:107、SEQ ID NO:109、SEQ ID NO:111、SEQID NO:113及SEQ ID NO:115组成的群组中的一种以上的氨基酸序列。

最优选地，抗体包含：重链及轻链，所述重链包含由SEQ ID NO:89表示的氨基酸序列，所述轻链包含由SEQ ID NO:107表示的氨基酸序列；重链及轻链，所述重链包含由SEQID NO:89表示的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:93表示的氨基酸序列，所述轻链包含由SEQ ID NO:107表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:93表示的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:95表示的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:97表示的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:99表示的氨基酸序列，所述轻链包含由SEQ IDNO:109表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:101表示的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含由SEQID NO:103表示的氨基酸序列，所述轻链包含由SEQ ID NO:111表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:103表示的氨基酸序列，所述轻链包含由SEQ ID NO:113表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:103表示的氨基酸序列，所述轻链包含由SEQ ID NO:115表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:105表示的氨基酸序列，所述轻链包含由SEQ ID NO:111表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:105表示的氨基酸序列，所述轻链包含由SEQ ID NO:113表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:105表示的氨基酸序列，所述轻链包含由SEQ ID NO:115表示的氨基酸序列；重链及轻链，所述重链包含由SEQ ID NO:99表示的氨基酸序列，所述轻链包含由SEQ ID NO:111表示的氨基酸序列。

本发明所述的“与暴露于细胞外的赖氨酰-tRNA合成酶N末端区域特异性结合的抗体”，其种类没有限制，只要是具有如上所述的互补决定区组合或具有重链可变区及轻链可变区的组合的抗体即可。作为一个具体实施例，所述抗体可选自由IgG、IgA、IgM、IgE及IgD组成的群组，优选地，可以为IgG抗体。

本发明的所述抗体，可以为单克隆(monoclonal)抗体或多克隆(polyc lonal)抗体，只要是与赖氨酰-tRNA合成酶N末端区域特异性结合的具有如上所述的互补决定区组合或具有重链可变区及轻链可变区组合的抗体，但优选为一组单克隆抗体，其中的每一个抗体具有基本上相同的重链和轻链氨基酸序列。

本发明的所述抗体可来源于包括哺乳动物、鸟类在内的任何动物，所述的哺乳动物包括人类，优选地，可以来源于人。然而，本发明的所述抗体可为包括来源于人的抗体的一部分和来源于其他种类的动物的抗体的一部分的嵌合(chimeric)抗体。即，本发明包括嵌合抗体、人源化抗体、人源抗体，优选地，可以为人源抗体。

另外，本发明中的所述抗体的片段指的是保留全抗体的抗原特异性结合力的抗体片段，优选地，所述片段与母源抗体的赖氨酰-tRNA合成酶N末端结合亲和力相似或保留至少20％、50％、70％、80％、90％、95％或100％或100％以上。具体地，所述片段可以为Fab、F(ab)

Fab(fragment，antigen-binding)为抗体的抗原结合片段，且由轻链和重链各自的一个可变区和恒定区构成。F(ab')

由于本发明的目的，所述抗体的片段不限于其结构或结构，只要是所述抗体的片段保留对于暴露于细胞外的赖氨酰-tRNA合成酶N末端区域的结合特异性即可，优选地，可以为scFv。本发明的scFv具有对赖氨酰-tRNA合成酶N末端区域特异性的互补决定区结构或重链可变区和轻链可变区结构，且其序列不特别限制，只要是重链可变区的C末端与轻链可变区的N末端通过连接子连接即可。所述连接子并没有特别限制，只要是在本领域周知的适用于scFv的连接子即可，可以为包含由SEQ ID NO:57表示的氨基酸序列的肽。由此，具体地，本发明的scFv可包含选自SEQ ID NO:61、SEQ ID NO:63、SEQ ID NO:65、SEQ ID NO:67、SEQ ID NO:69、SEQ ID NO:71、SEQ ID NO:73、SEQ ID NO:75、SEQ ID NO:77、SEQ ID NO:79、SEQ ID NO:81、SEQ ID NO:83、SEQ ID NO:85及SEQ ID NO:87组成的群组中的氨基酸序列。

本发明的抗体或其片段可包含实质上不改变其生物活性的保守氨基酸取代(称为抗体的保守变体)。

另外，如上所述的本发明的抗体或其片段可以为与酶、荧光物质、辐射物质及蛋白质等缀合的抗体或其片段，但并不限定于此。并且，使所述抗体与所述物质缀合的方法在本领域周知。

并且，本发明提供编码所述抗体或其片段的多核苷酸。

在本说明书中，所述多核苷酸还可描述为寡核苷酸或核酸，并且包含通过使用DNA分子[例如，cDNA或基因组DNA(genomic DNA)]、RNA分子(例如，mRNA)、核苷酸类似物生成的DNA或RNA的类似物(例如，肽核酸及非自然生成的核苷酸类似物)及它们的混合物质。所述多核苷酸可以为单链(single-stranded)或双链(double stranded)。

所述多核苷酸指的是编码由重链和轻链组成的抗体的碱基序列，所述重链和轻链具有对赖氨酰-tRNA合成酶N末端区域特异的互补决定区结构或重链可变区和轻链可变区的结构。本发明的所述多核苷酸的序列并不特别受限，只要是编码本发明的所述抗体或其片段的序列即可。在根据本发明的所述抗体中，编码前述互补决定区序列的所述多核苷酸并没有特殊限制，但优选地，可包含由SEQ ID NO:2、SEQ ID NO:4、SEQ ID NO:6、SEQ IDNO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14、SEQ ID NO:16、SEQ ID NO:18、SEQ IDNO:20、SEQ ID NO:22、SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28、SEQ ID NO:30、或SEQID NO:119表示的碱基序列。

另外，在本发明的抗体中，对编码如上所述的重链可变区和轻链可变区的多核苷酸的序列没有特殊限制，但优选地，可包含如由SEQ ID NO:32(重链可变区)、SEQ ID NO:34(轻链可变区)、SEQ ID NO:36(重链可变区)、SEQ ID NO:38(重链可变区)、SEQ ID NO:40(重链可变区)、SEQ ID NO:42(重链可变区)、SEQ ID NO:44(重链可变区)、SEQ ID NO:46(重链可变区)、SEQ ID NO:48(重链可变区)、SEQ ID NO:50(轻链可变区)、SEQ ID NO:52(轻链可变区)、SEQ ID NO:54(轻链可变区)或SEQ ID NO:56(轻链可变区)表示的碱基序列。

另外，优选地，编码所述抗体的片段的多核苷酸可包含选自由编码本发明的scFv的SEQ ID NO:62、SEQ ID NO:64、SEQ ID NO:66、SEQ ID NO:68、SEQ ID NO:70、SEQ ID NO:72、SEQ ID NO:74、SEQ ID NO:76、SEQ ID NO:78、SEQ ID NO:80、SEQ ID NO:82、SEQ IDNO:84、SEQ ID NO:86及SEQ ID NO:88组成的群组中的碱基序列。

可通过本领域周知的方法获取编码本发明的所述抗体或其片段的多核苷酸。例如，基于对所述抗体的重链及轻链的一部分或全部进行编码的DNA序列或相应氨基酸序列，通过本领域周知的寡核苷酸合成技术，如聚合酶链式反应(PCR)方法等合成多核苷酸。

另外，本发明提供了重组表达载体，其包含编码本发明的所述抗体或其片段的多核苷酸。

如本发明所用，“重组(recombinant)”与“基因操作(genetic anipulati on)”可互换使用，是指通过使用分子克隆(molecular loning)实验技术，例如基因转化、裂解或连接等来制备自然状态中不存在的形态的基因。

如本发明所用，术语“表达(expression)”指的是在细胞中生成蛋白质或核酸。

如本发明所用，术语“重组表达载体”为可以在适合的宿主细胞(host cell)中表达目的蛋白质或核酸(RNA)的载体，并且是指包含必需控制元件的基因构建体，所述必需控制元件可操作地连接以能够表达多核苷酸(基因)插入物。术语“可操作地连接(operablylinked)”是指以执行常规功能的方式编码核酸表达控制序列和所目的的蛋白质或RNA的核酸序列功能连接(functional linkage)，意味着通过表达控制序列以使基因表达的方式连接。“表达控制序列(expression control sequence)”是指控制在特定宿主细胞中可操作地连接的多核苷酸序列表达的DNA序列。这种控制序列包括用于转录的启动子、用于控制转录的任何操纵子序列、对适合的mRNA核蛋白体结合位点进行编码的序列、用于控制转录及翻译的终止子的序列、起始密码子、终止密码子、多腺苷酸化A信号及增强子等。

本发明的重组表达载体并不特别限于其类型，只要是在克隆领域通常使用的载体即可，所述重组表达载体的实例包括哺乳动物表达载体(mammalian expression vector)、质粒载体、黏粒载体、噬菌体载体及病毒载体等，但并不限定于此。所述质粒的实例包括来源于大肠杆菌的质粒[pBR322、pBR325、pUC118及pUC119、pET-22b(+)]、来源于枯草芽孢杆菌(Bacillus subtilis)的质粒(pUB110及pTP5)及来源于酵母的质粒(YEp13、YEp24及YCp50)等，所述病毒的实例可包括动物病毒，例如逆转录病毒、腺病毒或牛痘病毒；昆虫病毒，例如杆状病毒。

因此，本发明的重组表达载体是指可操作地连接的基因构建体，以便编码抗体或其片段的多核苷酸在适合的宿主细胞表达，所述抗体或其片段由具有可与赖氨酰-tRNA合成酶N末端区域特异性结合的如上所述的互补决定区或重链可变区和轻链可变区的结构的重链及轻链形成。

编码本发明的抗体的重链和轻链的多核苷酸可分别被包含在不同的重组表达载体，还可被包含在一个重组表达载体。

本发明提供利用如上所述重组表达载体转化的细胞。

本发明的细胞并不特别限于其类型，只要是用于表达编码抗体或其片段的多核苷酸即可，所述的抗体或其片段包含在本发明的重组表达载体中。本发明的利用重组表达载体转化的细胞(宿主细胞)可以为原核生物(例如，大肠杆菌)、真核生物(例如，酵母或其他菌类)、植物细胞(例如，烟草或番茄植物细胞)、动物细胞[例如，人类细胞、猴细胞、仓鼠(hamster)细胞、大鼠细胞(rat cell)、小鼠细胞(mouse cell)]、昆虫细胞或来源于它们的杂交瘤。优选地，所述细胞可以为来源于包括人类的哺乳类的细胞。

适合本目的的示例性原核生物包括革兰氏阴性或革兰氏阳性有机体，例如肠杆菌科(Enterobacteriaceae)如埃希氏菌属(Escherichia)例如大肠杆菌、肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯氏菌属(Klebsiella)、变形杆菌属(Proteus)、沙门氏菌属(Salmonella)如鼠伤寒沙门氏菌(Salmonella typhimurium)、沙雷氏菌属(Serratia)如粘质沙雷氏菌(Serratia marcescans)及志贺氏菌属(Shigella)及杆菌属(Bacilli)如枯草芽孢杆菌(B.subtilis)及地衣芽孢杆菌(B.licheniformis)、假单胞菌属(Pseudomonas)如铜绿假单胞菌(P.aeruginosa)及链霉菌属(Streptomyces)。本发明的细胞没有特别限制，只要是可表达本发明的载体即可，但可以优选为大肠杆菌。

酿酒酵母(Saccharomyces cerevisiae)最常用作本发明细胞中的真核生物。然而，可使用诸多其他种属、种及菌株，虽并不限定于此，可使用例如粟酒裂殖酵母(Schizosaccharomyces pombe)；克鲁维酵母属宿主例如乳酸克鲁维酵母(K.lactis)、脆壁克鲁维酵母(K.fragilis)(ATCC 12424)、保加利亚克鲁维酵母(K.bulgaricus)(ATCC16045)、威克克鲁维酵母(K.wickeramii)(ATCC 24178)、瓦尔提克鲁维酵母(K.waltii)(ATCC 56500)、果蝇克鲁维酵母(K.drosophilarum)(ATCC 36906)、耐热克鲁维酵母(K.thermotolerans)及马克斯克鲁维酵母(K.marxianus)；子囊菌酵母属(yarrowia)(EP402226)；巴斯德毕赤酵母(Pichia pastoris)(EP 183070)；念珠菌属(Candida)；里氏木霉(Trichoderma reesia)(EP 244234))；粗糙链孢菌(Neurospora crassa)；许旺酵母属(Schwanniomyces)如许旺酵母(occidentalis)；及丝状真菌，例如链孢菌属(Neurospora)、青霉属(Penicillium)、弯颈霉属(Tolypocladium)及曲霉属(Aspergillus)宿主如构巢曲霉(nidulans)及黑曲霉(A.niger)，但并不限定于此。

术语“转化(transformation)”是指由于外源多核苷酸的引入而导致的宿主细胞的基因型的修饰，也指与用于其转化的方法无关地，将外源多核苷酸导入至宿主细胞内。引入至宿主细胞的外源多核苷酸被整合到宿主细胞的基因组中来保留，或者不被整合到宿主细胞的基因组中来保留，本发明包括两者。

能够表达本发明的与赖氨酰-tRNA合成酶N末端区域特异性结合的抗体或其片段的重组表达载体可通过如下的本领域公知方法引入至用于生成抗体或其片段的细胞，即，如瞬时转染(transient transfection)、微注射、转导(transduction)、细胞融合、磷酸钙沉淀法、脂质体转染(liposomemediated transfection)、DEAE葡聚糖介导的转染(DEAEdextran-mediated transfection)、聚凝胺介导的转染(polybrene-mediatedtransfection)、电穿孔法(electroporation)、基因枪(gene gun)及将核酸引入至细胞中的方法，但并不限定于此。

本发明提供制备与暴露于细胞外的赖氨酰-tRNA合成酶N末端特异性结合的抗体或其片段的方法，所述方法包括：步骤(a)，利用所述重组表达载体转化宿主细胞；步骤(b)，培养转化的宿主细胞以生成抗体或其片段；以及步骤(c)获取在宿主细胞中生成的抗体或其片段。

在步骤(a)中，为了产生根据本发明的所述抗体或其片段，利用所述重组表达载体转化宿主细胞，在所述重组表达载体中，编码所述抗体或其片段的多核苷酸被可操作地连接。

如上所述，本领域普通技术人员可根据所选择的宿主细胞和重组表达载体选择适当的转化方法来进行此步骤。包括重链和轻链的碱基序列的重组表达载体可以在同一宿主细胞中共同转化以使重链和轻链在一个细胞中表达，或者可使包括重链和轻链的碱基序列的重组表达载体分别在不同的宿主细胞转化来单独表达重链和轻链。

在步骤(b)中，培养转化的所述宿主细胞以从导入至宿主细胞的重组表达载体生成本发明的抗体的重链、轻链或抗体片段的多肽。

可根据本领域通常使用的方法适当地选择用于培养所述宿主细胞的培养基组分、培养条件以及培养时间等。在宿主细胞中生成的抗体分子可累积于细胞的胞质溶胶内，或者通过适当的信号序列分泌于细胞外部或培养基中，或者使用周质等进行靶向(targeted)。并且，优选地，利用本领域公知的方法进行蛋白质复性(refolding)并使根据本发明的抗体具有功能性结构(conformation)，从而使其维持对于赖氨酰-tRNA合成酶N末端的结合特异性。对于IgG型抗体的产生，重链和轻链可以在不同的细胞表达，然后在单独的步骤中相互接触，以形成全抗体，或者使重链和轻链在相同的细胞中表达，在细胞内部形成全抗体。

在步骤(c)中，获得在宿主细胞生成的抗体或其片段。

本领域普通技术人员可考虑在宿主细胞中生成的抗体或其片段的多肽的特性、宿主细胞的特性、表达方式或多肽的靶向与否等来适当地选择及控制收集方法。例如，在利用培养基分泌的抗体或其片段中，可以通过获得培养宿主细胞的培养基并通过离心分离来去除杂质等方法收集抗体。根据需求，为了使存在于细胞中的特定细胞器或胞质溶胶的抗体外排到细胞外部并收集，可在不影响抗体或其片段功能结构的程度上裂解细胞。所获取的抗体可进一步通过层析、使用过滤器的过滤、透析等的方法进一步去除杂质，并浓缩。

本发明制备(生成)方法的多肽可以为本发明的抗体或其片段本身，还可以为与除本发明的抗体或其片段之外的其他氨基酸序列进一步结合的抗体或其片段。在此情况下，可利用本领域的普通技术人员所熟知的方法将所述氨基酸序列从本发明的抗体或其片段去除。

本发明的抗体或其片段与赖氨酰-tRNA合成酶N末端特异性结合，因此，可用于诊断分析，以检测并定量如特定细胞、组织或血清内的赖氨酰-tRNA合成酶蛋白。特别是，无需裂解细胞就可以特异性检测暴露于细胞外的赖氨酰-tRNA合成酶N末端区域。

本发明的所述检测方法可以包括制备试样的步骤，在将本发明的抗体或其片段与试样相接触之前，使用本发明的抗体或其片段对其进行检测以确定赖氨酰-tRNA合成酶(或暴露于细胞外的赖氨酰-tRNA合成酶N末端肽)的有无及其浓度[步骤(1)]。

本领域普通技术人员可适当地选择利用抗体检测蛋白质的公知方法，并可根据选择的方法准备适合的试样。另外，试样可以是为了诊断是否存在癌症(特别是乳腺癌或肺癌)，癌症是否转移及病理分期而通过活体组织检查等从个体获取的细胞或组织、血液、全血、血清、血浆、唾液、脑脊液等。利用所述抗体的检测蛋白质的方法实例包括，但不限于蛋白质印迹法、免疫印迹法、斑点印迹法、免疫组织化学染色(immunohistochemistry)、免疫细胞染色(immunocytochemistry)、酶联免疫吸附法(ELISA)、放射免疫检定法(radioimmunoassay)、竞争结合分析、免疫沉淀法等。例如，对于蛋白质印迹法，可通过向试样或细胞的溶解物添加适合于电泳的缓冲液，然后煮沸来制备制剂，对于免疫组织化学染色，可进行将细胞或组织的切片固定和封闭(blocking)等的预处理。

接着，进行使本发明的抗体或其片段与在如上所述的步骤中准备的试样相接触的步骤[步骤(2)]。

本发明的抗体为具有如上所述的互补决定区或重链可变区和轻链可变区的结构且与赖氨酰-tRNA合成酶N末端特异性结合的抗体或其片段，其具体种类和序列结构如上所述。

通常，可以用可检测部分(moiety)标记所述抗体或其片段，以进行其“检测”。例如，可利用本领域公知的技术使用放射性同位素或荧光标签来标记所述抗体或其片段。另外可利用各种酶-底物标签，所述酶标记的实例包括荧光素酶，如果蝇荧光素酶及细菌荧光酶(美国专利第4737456号)、萤光素(luciferin)、邻苯二甲酸二氢嗪二酮(2，3-dihydrophthalazine dionise)、苹果酸脱氢酶、尿素酶(urase)、过氧化物酶如辣根过氧化物酶(HRPO)、碱性磷酸酶、β-半乳糖苷酶、葡糖糖化酶、溶菌酶、糖氧化酶(例如，葡萄糖氧化酶、半乳糖氧化酶及葡萄糖-6-磷酸脱氢酶)、杂环氧化酶(例如，尿酸酶及黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。使抗体与酶缀合的技术是本领域公知的。可利用各种公知技术将标签与抗体直接或间接缀合。例如，抗体可与生物素(biotin)缀合，属于在所述内容中提及的三种大范围种类的任意标签可与亲和素缀合，反之亦然。生物素选择性地与亲和素(avidin)结合，因此，所述标签可通过如上所述的间接方式与抗体缀合。或者，为了实现标签与抗体的间接缀合，可将所述抗体与半抗原(hapten)[例如，地高辛(digoxin)]缀合，在所述内容中提及的不同类型的标签中的一个可与抗-半抗原抗体缀合(例如，抗-地高辛抗体)。因此，可实现抗体与标签之间的间接缀合。

如本发明所用，“接触(contacting)”的含义为其的普通含义，是指使两个以上的物质混合、结合或相接触。所述接触可在体外(in vitro)或其他容器(container)中进行，或者，可在原位(in situ)、体内、个体内、组织内、细胞内进行。

接着，在完成所述步骤(2)之后，进行从试样中检测根据本发明的抗体或其片段的步骤[步骤(3)]。

所述“检测”是对根据本发明的抗体或其片段与抗原的复合物进行的，所述的组合物在试样中形成，是指检测赖氨酰-tRNA合成酶N末端区域的肽(或包含肽的蛋白质，如赖氨酰-tRNA合成酶)的存在与否或测量所述肽的水平(包括定性测量或定量测量)。因此，在完成所述步骤(2)之后且后述的检测步骤[步骤(3)]之前，本发明的检测方法还可包括去除未与赖氨酰-tRNA合成酶N末端区域一同形成复合物的多余抗体或其片段的步骤。

在如上所述的步骤(2)中使用的抗体或其片段包含利用荧光、放射性同位素、酶等直接标记等的可检测的部分的情况下，可根据检测相应部分的本领域公知的方法进行检测。例如，放射性可通过如闪烁计数(scintillation counting)测量，荧光可利用荧光计进行定量。

并且，在所述步骤(2)中使用的抗体或其片段本身不包括如上所述的检测部分的情况下，如本领域周知的，可利用被荧光、放射性、酶等标记的二次抗体间接检测。所述二次抗体与根据本发明的抗体或其片段(一次抗体)结合。

本发明提供包含所述本发明的抗体或其片段作为有效成分的用于预防或质疑癌症转移的药学组合物及用于诊断癌症的组合物。

所述癌症并不特别限于其类型，只要是在本领域以恶性肿瘤而周知的癌症即可，其实例可以为选自由乳腺癌、大肠癌、肺癌、小细胞肺癌、胃癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门癌、结肠癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金氏病、食道癌、小肠癌、内分泌腺癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性白血病或急性白血病、淋巴瘤、膀胱癌、肾癌或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性中枢神经系统(CNS)淋巴瘤、脊髓肿瘤、脑干胶质瘤及垂体腺瘤组成的群组中。优选地，在本发明中，所述癌症可以为乳腺癌或肺癌。

根据本发明的药学组合物可单独包含本发明的抗体或其片段，或者还可包含一个以上的药学上可接受的载体。所述“药学上可接受的”是指如下的组合物，即，生理上可接受，当向人给药时，不抑制活性成分的作用，且通常不诱发严重的副作用的组合物。

在根据本发明的药学组合物中，当临床给药所述抗体或其片段时，能够以口服及肠外的各种剂型给药。所述抗体或其片段在制剂化时，可使用通常使用的如填充剂、增量剂、结合剂、润湿剂、崩解剂、表面活性剂等的稀释剂或赋形剂来制备。用于口服给药的固体制剂包括片剂、丸剂、粉末、颗粒、胶囊、锭剂等。这种固体制剂可通过在一种以上的芳基衍生物或其药学上可接受的盐混合至少一个赋形剂，如淀粉、碳酸钙、蔗糖(sucrose)或乳糖(lactose)或明胶等来制备。此外，除简单的赋形剂之外，还可使用润滑剂，如硬脂酸镁、滑石粉等。用于口服给药的液相制剂包括悬浮液、内服溶液、乳剂、糖浆等。除经常使用的简单稀释剂(如水和液体石蜡)外，液相制剂可包括几种赋形剂如润湿剂、甜味剂、芳香剂、防腐剂等。

用于肠外给药的制剂包括无菌水溶液、非水溶剂、悬浮溶剂、乳剂、冻干制剂和栓剂。本发明的治疗用组合物能够以冻干饼或者水溶液的形式制备，以将任任意生理上可接受的载体、赋形剂或稳定剂和具有优选纯度的抗体混合和储存。在使用剂量和浓度下，可接受的载体、赋形剂或稳定剂对使用者无毒，其实例包括缓冲溶液，例如磷酸、柠檬酸及其他有机酸；包括抗坏血酸在内的抗氧化剂；低分子(小于约10个的残基)的多肽；蛋白质，例如，血清白蛋白、明胶或免疫球蛋白；亲水聚合物，例如，聚乙烯吡咯烷酮；氨基酸，例如，甘氨酸、谷氨酸盐、天冬酰胺、精氨酸或赖氨酸；包括单糖类、双糖类及葡萄糖、甘露糖或糊精在内的其他碳水化合物；螯合剂，例如，乙二胺四乙酸(EDTA)；糖醇，例如，甘露醇或山梨糖醇；成盐反离子，例如，钠；和(或)非离子表面活性剂，例如，吐温、普朗尼克或聚乙二醇(PEG)。

本发明的抗体能够以药学有效量向对抗癌症的个体给药。如本发明所用，“药学有效量”是指相比于阴性对照组，显示更高反应的量，优选地是指足以治疗癌症的量或足以预防或抑制癌症转移的量。本发明的抗体或其片段的总有效剂量能够以单剂量(singledose)向患者给药，或者可通过多个剂量(multiple dose)长期给药的分次治疗方法(fractionated treatment protocol)给药。通常，本发明的抗体或其片段向人体给药量为0.01mg/kg/周～100mg/kg/周，优选为0.1mg/kg/周～20mg/kg/周，更优选为5mg/kg/周～10mg/kg/周。然而，所述本发明的抗体或其片段的剂量，根据如药学组合物的给药途径、治疗次数、患者的年龄、体重、健康状态、性别、疾病的严重程度、饮食及排泄率等各种因素来确定对于患者的有效剂量，因此，当考虑这一事实时，只要是本领域的普通技术人员，可确定将所述本发明的抗体或其片段用作癌症治疗剂或者用于预防或抑制癌症的制剂的特定用途确定适当的有效剂量。本发明的药学组合物只要呈现出本发明的效果，则其剂型、给药途径及给药方法没有特殊限制。

本发明的组合物的给药途径可以为公知的抗体给药方法，例如，通过静脉内、腹腔内、颅内、皮下、肌肉内、眼内、动脉内、脑脊液内或病灶内途径的注射或输注，或者通过下述记载的缓释(sustained release)系统注射或输注，但并不局限于此。例如，本发明的抗体可全身给药或局部给药。

为了预防或治疗癌症或癌症转移，本发明的药学组合物可单独使用，或者与手术、激素治疗、化学治疗及使用生物学反应调节剂的方法结合使用。

可通过检测生物学试样中的赖氨酰-tRNA合成酶蛋白(尤其，暴露于细胞外的赖氨酰-tRNA合成酶N末端区域)来执行本发明的癌症和癌症转移的诊断及预后。

如本发明所用，术语“诊断”是指确认病理状态的存在或特征。在本发明中，所述诊断用于确认癌症或癌症转移的发病与否、发病可能性(风险)及疾病的进行阶段。

术语“检测”如上所述，并且所述生物学试样包括血液及源于生物的其他液相试样、活检标本、固体组织试样(例如组织培养物)或来源于此的细胞。更具体地，生物样品的实例可包括但不限于组织、提取物、细胞裂解物、全血、血浆、血清、唾液、眼内液、脑脊液、汗液、尿液、乳液、腹水液、滑液、腹膜液等。所述试样可从动物获取，优选地，可从哺乳动物获取，最优选地，可从人获取。所述试样可在用于检测之前进行预处理。所述预处理的实例可包括过滤、蒸馏、萃取、浓缩、干扰成分失活、试剂添加等。此外，可从所述试样分离核酸及蛋白质来用于检测。

根据本发明的抗体或其片段可作为诊断试剂盒提供，所述试剂盒只要是在本领域作为提供具有抗体或特定结合域的肽作为成分的分析试剂盒而周知，则其种类没有特殊限制，并且，其实例包括用于蛋白质印迹法、酶联免疫吸附试验(ELISA)、放射免疫分析法、放射免疫扩散法、Ouchterlony免疫扩散法、火箭免疫电泳、免疫免疫染色、免疫细胞免疫染色、免疫沉淀分析法、补体固定分析法、荧光激活细胞分选术或蛋白质芯片用试剂盒等。

本发明的抗体或其片段可在所述试剂盒中使用，即，在用于执行诊断分析的诊断试剂盒中与使用说明书一同以预定量用于试剂的包装的组合中。在抗体被酶标记的情况下，所述试剂盒可包含酶所需的底物和辅因子(cofactor)(例如，提供发色团或荧光团的底物前体)。另外，可包含其他添加剂，如稳定剂、缓冲液(例如，阻断缓冲液或裂解缓冲液)等。各种试剂的相对量能够大幅度变化以提供试剂的溶液内浓度，这实质上优化了分析的灵敏度。试剂可作为干燥粉末提供，通常冻干，包含溶解时提供具有适当浓度的试剂溶液的赋形剂。

并且，本发明的所述抗体为包含野生型人IgG Fc区域的Fc变体的多肽，所述Fc变体包含由SEQ ID NO:126表示的野生型人IgG1 Fc区域的L117A、L118A、T182A、P212G或由SEQ ID NO:138表示的人IgG4 Fc区域的T179A的一种个以上的追加氨基酸取代，相比于包含野生型IgG Fc区域的多肽，所述多肽包含抗体依赖性细胞毒性/补体依赖性细胞毒性功能降低的多肽。

在本发明中，所述Fc区域是指包含恒定区的一部分以上的免疫球蛋白重链的C-末端区域，包含野生型序列Fc区域及变体Fc区域。在本发明中，“Fc变体”是指在Fc结构域中包含修饰的多肽。本发明的Fc变体根据构成其的氨基酸修饰定义。具体地，相比于亲本Fc多肽，L118A为在118位亮氨酸被丙氨酸取代的Fc变体，T182A为182位苏氨酸被丙氨酸取代的Fc变体，P212G为在212位脯氨酸被甘氨酸取代的Fc变体。氨基酸修饰可以为氨基酸添加、氨基酸缺失或氨基酸取代。氨基酸取代可包含天然存在的氨基酸及非天然存在的氨基酸。变体可包含非天然存在的氨基酸。

所述“氨基酸取代”是指规定的氨基酸序列中一种以上的现有氨基酸残基的被其他不同的“取代”氨基酸残基取代。取代残基或残基可以为“天然存在的氨基酸残基”(即，可被基因标记编码)，可选自由丙氨酸(Ala)、精氨酸(Arg)、天冬酰胺(Asn)、天冬氨酸(Asp)、半胱氨酸(Cys)、谷氨酰胺(Gln)、谷氨酸(Glu)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、亮氨酸(Leu)、赖氨酸(Lys)、甲硫氨酸(Met)、苯基丙氨酸(Phe)、脯氨酸(Pro)、丝氨酸(Ser)、苏氨酸(Thr)、色氨酸(Trp)、酪氨酸(Tyr)及缬氨酸(Val)组成的群组中。

所述“抗体依赖性细胞毒性/补体依赖性细胞毒性功能(ADCC/CDC)”是指抗体-依赖性细胞介导的细胞毒性(Antibody-dependent cellular cytotoxicity，ADCC)、补体-依赖性细胞毒性(complement-dependent cytotoxicity，CDC)功能。所述“补体依赖性细胞毒性”是指在补体存在的状态下，抗原-表达细胞通过本发明的抗体裂解。“抗体-依赖性细胞接到的细胞毒性”是指表达Fc受体(FcRs)的非特异性细胞毒性细胞(例：自然杀伤(NK)细胞、嗜中性粒细胞及巨噬细胞)识别在靶细胞结合的抗体，由此裂解所述靶细胞的细胞介导的反应。补体依赖性细胞毒性及抗体依赖性细胞毒性可通过使用本领域周知的能够使用的分析法来测量。(参考资料列：U.S.5500362及5821337以及Clynes et al.(1998)Proc.Natl.Acad.Sci.(USA)95:652-656)。抗体的恒定区固定补体，对于介导细胞依赖性细胞毒性的抗体的能力很重要。因此，抗体的亚型(isotype)可根据抗体对于介导细胞毒性是否优选来选择。

具体地，本发明的所述抗体包含：重链及轻链，所述重链包含选自由SEQ ID NO:140、SEQ ID NO:142、SEQ ID NO:144、SEQ ID NO:146、SEQ ID NO:148、SEQ ID NO:150、SEQID NO:152表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:91表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:140、SEQ ID NO:142、SEQID NO:144、SEQ ID NO:146、SEQ ID NO:148、SEQ ID NO:150、SEQ ID NO:152表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:107表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:140、SEQ ID NO:142、SEQ ID NO:144、SEQ ID NO:146、SEQ ID NO:148、SEQ ID NO:150、SEQ ID NO:152表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:154、SEQ ID NO:156、SEQ ID NO:158、SEQ ID NO:160、SEQ ID NO:162、SEQ ID NO:164、SEQ ID NO:166表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:107表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:154、SEQ ID NO:156、SEQ ID NO:158、SEQ ID NO:160、SEQ ID NO:162、SEQ ID NO:164、SEQID NO:166表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:168、SEQ ID NO:170、SEQID NO:172、SEQ ID NO:174、SEQ ID NO:176、SEQ ID NO:178、SEQ ID NO:180表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:182、SEQ ID NO:184、SEQ ID NO:186、SEQ ID NO:188、SEQ ID NO:190、SEQ ID NO:192、SEQ ID NO:194表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；所述重链包含选自由SEQ IDNO:224、SEQ ID NO:226、SEQ ID NO:228、SEQ ID NO:230、SEQ ID NO:232、SEQ ID NO:234、SEQ ID NO:236表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ IDNO:109表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:210、SEQ ID NO:212、SEQ ID NO:214、SEQ ID NO:216、SEQ ID NO:218、SEQ ID NO:220、SEQ ID NO:222表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:109表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:224、SEQ ID NO:226、SEQ ID NO:228、SEQ ID NO:230、SEQ ID NO:232、SEQ ID NO:234、SEQ ID NO:236表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:111表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:224、SEQ ID NO:226、SEQ ID NO:228、SEQ ID NO:230、SEQID NO:232、SEQ ID NO:234、SEQ ID NO:236表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:113表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:224、SEQ ID NO:226、SEQ ID NO:228、SEQ ID NO:230、SEQ ID NO:232、SEQ IDNO:234、SEQ ID NO:236表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:115表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:238、SEQID NO:240、SEQ ID NO:242、SEQ ID NO:244、SEQ ID NO:246、SEQ ID NO:248、SEQ ID NO:250表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:111表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:238、SEQ ID NO:240、SEQ IDNO:242、SEQ ID NO:244、SEQ ID NO:246、SEQ ID NO:248、SEQ ID NO:250表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:113表示的氨基酸序列；重链及轻链，所述重链包含选自由SEQ ID NO:238、SEQ ID NO:240、SEQ ID NO:242、SEQ ID NO:244、SEQ ID NO:246、SEQ ID NO:248、SEQ ID NO:250表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:115表示的氨基酸序列；或者重链及轻链，所述重链包含选自由SEQ ID NO:196、SEQ ID NO:198、SEQ ID NO:200、SEQ ID NO:202、SEQ ID NO:204、SEQ ID NO:206、SEQ ID NO:208表示的氨基酸序列中的一种以上的氨基酸序列，所述轻链包含由SEQ ID NO:111表示的氨基酸序列。

本发明提供包含所述抗体或其片段作为有效成分的用于预防或治疗免疫细胞迁移相关疾病的组合物及用于诊断免疫细胞迁移相关疾病的组合物。

在本发明中，例如，术语“免疫细胞迁移相关疾病”可选自由心血管疾病、纤维化疾病、炎性疾病和奥尔波特综合(Alport syndrome)组成的群组，但如果过度的免疫细胞迁移(和/或侵袭)以主要发病机制而在本领域周知，则不特别限制疾病的具体类型。

例如，所述心血管疾病可选自由高血压(包括高血压引起的炎症并发症)、肺动脉高压、动脉粥样硬化、心绞痛、心肌梗死、缺血性脑血管病、动脉硬化和肠系膜硬化组成的组，但具体疾病的类型并不特别受限。

所述纤维化疾病可选自由例如硬皮病(scleroderma)、类风湿关节炎(rheumatoidarthritis)、克罗恩氏病(Crohn's disease)、溃疡性结肠炎(ulcerative colitis)、骨髓纤维化(myelofibrosis)、肺纤维化(pulmonary fibrosis)、肝纤维化(hepathicfibrosis)、肝硬化(liver cirrhosis)、肾纤维化(kidney fibrosis)、肾小球硬化症、肌纤维化(myofibrosis)、心肌纤维化、间质性纤维化、胰腺纤维化、脾纤维化、纵隔纤维化、血管纤维化、皮肤纤维化、眼纤维化、黄斑变性、关节纤维化、甲状腺纤维化、心内膜心肌纤维化、腹膜纤维化、腹膜后纤维化、进行性大块纤维化、肾源性系统性纤维化、系统性红斑狼疮(systemic lupus erythematosu)、遗传性纤维化、感染性纤维化、刺激性纤维化、慢性自身免疫引起的纤维化、器官移植过程中抗原不相容引起的纤维化、外科手术的纤维并发症、高脂血症引起的纤维化、肥胖引起的纤维化、糖尿病性纤维化、高血压引起的纤维化及支架插入时纤维化引起的阻塞组成的群组，但具体疾病的类型并不特别受限。

在本发明中，所述炎性疾病可优选地选自由自身免疫性疾病、炎症性肠道疾病、皮炎(例如特应性皮炎、湿疹、银屑病等)、糖尿病性眼病(例如糖尿病视网膜病变等)、腹膜炎、骨髓炎、蜂窝性组织炎(cellulites)、脑膜炎、脑炎、胰腺炎、创伤性休克、支气管哮喘、鼻炎、鼻窦炎、中耳炎、肺炎、胃炎、肠炎、囊性纤维化、卒中(脑卒中等)、支气管炎、细支气管炎、肝炎(肝硬化、非酒精性脂肪肝炎(non-alcoholic steatohepatitis)等)、肾炎(糖尿病肾衰竭等)、蛋白尿、关节炎(银屑病关节炎、骨关节炎等)、肾炎(糖尿病性神经病变、多发性硬化)、痛风、脊椎炎、莱特氏综合征(Reiter'ssyndrome)、结节性多动脉炎、血管炎、肌萎缩性侧索硬化、韦格纳肉芽肿(Wegener's granulomatosis)、高细胞因子血症(hypercytokinemia)、风湿性多肌痛、关节细胞动脉炎、钙结晶性关节炎、假性痛风、非关节类风湿、滑囊炎、腱鞘炎、上髁炎(网球肘)、夏科氏关节(Charcot's joint)、关节积血(hemarthrosis)、过敏性紫癜(Henoch-Schonlein purpura)、肥大性骨关节炎、多中心网织细胞瘤、结节病(surcoilosis)、血色素沉着症、镰状细胞病、高脂蛋白血症、低球蛋白血症、甲状旁腺功能亢进、肢端肥大症、家族性地中海热、贝哈特氏病(Behatt's disease)、系统性红斑狼疮、回归热(recurrent fever)、银屑病、多发性硬化、脓毒症、脓毒性休克、急性呼吸窘迫综合征、多器官功能障碍、慢性阻塞性肺疾病(chronic obstructive pulmonarydisease)、急性肺损伤(acute lung injury)、支气管肺发育不良(broncho-pulmonarydysplasia)组成的群组，还可包括慢性炎性疾病，但疾病的类型并不特别受限。

在本发明中，自身免疫性疾病选自由类风湿性关节炎、系统性硬皮病、系统性红斑狼疮、银屑病、哮喘、溃疡性结肠炎、贝切特氏病(Behcet's disease)、克罗恩氏病、多发性硬化、皮肌炎、胶原病、血管炎、关节炎、肉芽肿病、器官特异性自身免疫性疾病、溃疡性大肠炎和移植物抗宿主病(GvHD，graft-versus-host disease)组成的群组。

所述慢性炎性疾病指参照所述炎性疾病类型的它们成为慢性(chronic)画的状态，其优选的实施例包括哮喘、特应性皮炎、湿疹、银屑病、骨关节炎、痛风、银屑病关节炎、肝硬化、非酒精性脂肪肝炎、慢性阻塞性肺疾病、鼻炎、糖尿病视网膜病变、糖尿病肾功能衰竭、糖尿病神经病变和多发性硬化，但不限于此。

并且，本发明的抗体能够以药学有效量向正在治疗免疫细胞迁移相关疾病的个体给药。在上文中，“药学有效量”是指相比于阴性对照组，示出其以上的反应的量，优选地，是指足以治疗免疫细胞迁移相关疾病的量。本发明的抗体或其片段的总有效量、所述组合物的剂型、给药方法及给药途径记载于上文中。

为了预防或治疗免疫细胞迁移相关疾病，本发明的药学组合物可单独使用或与手术、激素治疗、化学治疗及使用生物学反应调节剂的方法结合使用。

可通过从生物学试样中检测赖氨酰-tRNA合成酶蛋白(尤其，暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域)来执行本发明的免疫细胞迁移相关疾病的诊断及预后评价。

并且，本发明提供在制备用于预防或抑制癌症及癌症转移的制剂中的所述抗体或其片段的用途。

并且，本发明提供向有需要的个体给药有效量的包含所述抗体或其片段的组合物的癌症及癌症转移预防或抑制方法。

并且，本发明提供在制备用于诊断癌症或癌症转移的制剂中的所述抗体或其片段的用途。

本发明提供癌症或癌症转移诊断方法，其包括：步骤a)，从怀疑癌症转移的个体(受试者)获取生物学试样；步骤b)，向所述试样或个体给药包含所述抗体或其片段的组合物；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；以及步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为癌症及癌症转移已发生。

本发明提供在制备用于治疗免疫细胞迁移相关疾病的制剂中的所述抗体或其片段的用途。

本发明提供在制备用于诊断免疫细胞迁移相关疾病的制剂中的所述抗体或其片段的用途。

本发明提供向有需要的个体给药有效量的包含所述抗体或其片段的组合物的免疫细胞迁移相关疾病的治疗方法。

本发明提供免疫细胞迁移相关疾病诊断方法，其包括：步骤a)，从怀疑免疫细胞迁移相关疾病的个体获取生物学试样；步骤b)，向所述试样或个体给药包含所述抗体或其片段的组合物；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；以及步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为免疫细胞迁移相关疾病。

在一实施方式中，本发明提供包括下述步骤的癌症及癌症转移诊断及治疗方法：步骤a)，从怀疑癌症转移的个体(受试者)获取生物学试样；步骤b)，向所述试样或个体给药所述抗体或其片段；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在

在一实施方式中，本发明提供包括下述步骤的免疫细胞迁移相关疾病诊断及治疗方法：步骤a，从怀疑免疫细胞迁移相关疾病的个体获取生物学试样；步骤b)，向所述试样或个体给药所述抗体或其片段；步骤c)，在所述步骤b)的试样或个体检测赖氨酰-tRNA合成酶蛋白的表达水平；步骤d)，所述赖氨酰-tRNA合成酶蛋白的表达水平与正常对照组相比，在赖氨酰-tRNA合成酶蛋白的表达水平增加的情况下，诊断为免疫细胞迁移相关疾病；以及步骤e)，向所诊断的所述个体给药用于治疗免疫细胞迁移相关疾病的治疗药物或通过手术治疗所述疾病。

所述步骤e)为如下的步骤：通过向所述步骤d)中诊断疾病的个体给药治疗药物或手术等的手段治疗所述疾病。

本发明的所述“治疗”通常是指改善癌症及癌症转移或免疫细胞迁移相关疾病的症状，其可包括癌症及癌症转移或免疫细胞迁移相关疾病的治愈、实际预防或者状态的改善，包括所述疾病引起的一种症状或发部分症状的缓解、治愈或预防，但并不局限于此。

所述治疗药物只要是通常用助于治疗癌症、癌症转移或免疫细胞迁移相关疾病的药物种类，其种类并不特别受限，在一实施方式中，可以为选自由抗癌药、抗炎药(代表性一例为类固醇剂等)及肺动脉高血压治疗剂等组成的群组中的一种以上的药物，但并不局限于此。所述治疗药物以“治疗学有效量”向个体给药，对于所述治疗学有效量，普通技术人员可考虑药物的固有性质、给药途径及治疗次数、患者的年龄、体重、健康状态、性别、疾病的严重程度、饮食及排泄率等各种因素来确定对于患者的有效剂量。所述治疗药物的给药途径并不特别受限，可口服给药或肠胃外给药，不仅包括局部给药，还包括全身途径的给药。所述肠胃外给药可以为如鼻腔内药物涂敷、皮下注射等，如另一例，可使用肌内注射、静脉注射等的方法，但并不局限于此。

如本发明所用，术语“包含(comprising)”与“含有”或“特征在于”同义使用，在组合物或方法中，并不排除未提及的其他成分或步骤。术语“由……组成(consisting of)”是指排除其他未另外指定的要素、步骤或成分等。术语“基本上由……组成(essentiallyconsisting of)”是指在组合物或方法的范围内，包括所提及的要素或步骤，并包括对其的基本特性没有实质性影响的任何成分要素或步骤。

发明的效果

因此，本发明提供具有在本说明书中记载的特定互补决定区序列且与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的抗体。本发明的方法可有用地制备与以往的抗体相比对于赖氨酰-tRNA合成酶N-末端的亲和力高的抗体。

图1为示出为了提高赖氨酰-tRNA合成酶N末端靶抗体N3对于赖氨酰-tRNA合成酶N末端的亲和力，分别以N3抗体的重链可变区和轻链可变区为基础构建的两个文库的筛选及构建战略的示意图。

图2a为示出对于利用荧光激活细胞分选术(FACS，Fluorescence Activated CellSorting)筛选的各个步骤的文库表达酵母，利用流细胞分析仪(荧光激活细胞分选术)分析与结合有10nM、1nM或0.1nM的GST的赖氨酰-tRNA合成酶的肽(peptide)(残基1-72)的结合能力的结果。

图2b为示出对于最终筛选的文库中分别表达47个个别克隆的酵母，利用流细胞分析仪分析与结合有0.1nM的GST的赖氨酰-tRNA合成酶的肽(残基1-72)的结合能力的结果。

图3a及图3b均示出用于测量N3-1抗体、N3-3抗体、N3-4抗体和N3-5抗体对赖氨酰-tRNA合成酶的N-末端的亲和力的酶联免疫吸附试验(ELISA)结果，所述N3-1抗体、N3-3抗体、N3-4抗体和N3-5抗体是经选择的对赖氨酰-tRNA合成酶N-末端的肽(残基1-72)具有高亲和力和特异性的。

图4为示出确认N3抗体和N3-1抗体的细胞迁移抑制效果的结果。

图5示出通过表面等离子体共振(SPR，surface plasmon resonance)法比较N3抗体和N3-1抗体对赖氨酰-tRNA合成酶的亲和力的结果。

图6为示出对于利用磁性激活的细胞分类(MACS)及荧光激活细胞分选术筛选的各个步骤的文库表达酵母，利用流细胞分析仪分析与结合有10nM、1nM或0.1nM的GST的赖氨酰-tRNA合成酶的肽(残基1-72)的结合能力的结果。

图7为示出用于测量N3-1抗体、N3-6抗体、N3-7抗体、N3-8抗体和N3-9抗体对赖氨酰-tRNA合成酶的N-末端的亲和力的酶联免疫吸附试验结果。

图8为示出通过表面等离子体共振法比较N3-6抗体、N3-7抗体、N3-8抗体和N3-9抗体的赖氨酰-tRNA合成酶的亲和力进行比较的结果。

图9为示出确认N3抗体、N3-1抗体、N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体细胞迁移一直效果的结果。

图10为示出通过免疫组织化学(IHC，immunohistochemistry)方法确认N3抗体及N3-8抗体在乳腺癌细胞中的内吞作用(endocytosis)的结果。

图11为示出通过给药N3抗体的在肺动脉高压(PAH)模型中右心室收缩末压(rightventricular end-systolic pressure，RVESP)的变化(Mock IgG：阴性对照，Ab 1mpk：N3抗体1mpk，Ab 10mpk：N3抗体10mpk，西地那非(sildenafil)：阳性对照)。

图12为示出通过免疫组织化学染色确认通过在肺动脉高压(PAH)模型中给药N3抗体减少了免疫细胞迁移和侵袭的结果。

图13示出验证结果：在急性肺损伤小鼠模型的支气管肺泡灌洗液(BALF，Bronchoalveolar lavage fluid)中增加的免疫细胞总数依赖N3抗体(与赖氨酰-tRNA合成酶的N-末端结合的抗体)的处理浓度而减少。

图14示出验证结果：急性肺损伤小鼠模型的支气管肺泡灌洗液中特别增加的中性粒细胞依赖N3抗体(与赖氨酰-tRNA合成酶的N-末端结合抗体)的处理浓度而减少。

图15示出通过荧光激活细胞分选术验证的结果：急性肺损伤小鼠模型中肺组织中增加的巨噬细胞(IM，CD11b+/F4/80+)迁移和侵袭依赖N3抗体(与赖氨酰-tRNA合成酶的N-末端结合抗体)的处理浓度而减少。

图16为通过图表示出对图15的结果进行定量化的结果。

图17为示出在急性肺损伤小鼠模型的肺组织内进行的组织纤维通过用N3抗体(赖氨酰-tRNA合成酶N-末端结合抗体)的处理抑制的组织图像。进行Masson三色染色(Masson'strichrome staining)后在显微镜下观察各个实验组及对照组的组织。

图18为示出验证结果：通过N3-8抗体、N3-8-1抗体及去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的N3-8-1抗体处理来抑制细胞迁移(cell migration)。

图19为示出验证结果：通过N3-8抗体、N3-8-1抗体及去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的N3-8-1抗体处理来抑制癌细胞的细胞迁移。

具体实施方式

以下，详细说明本发明。

但是，下述实施例仅用于例示本发明，本发明的内容并不限定于下述实施例。

实施例1：用于增加亲和力的酵母细胞表面表达文库的构建

对于靶向以往的赖氨酰-tRNA合成酶的N末端的抗体N3抗体(韩国专利申请号：10-2018-0035446)的N末端的亲和力约为150nM，低于完整IgG形态的各种抗体的亲和力。由此，为了通过增加亲和力来制备具有更佳效果的抗体，对N3抗体的轻链可变区和重链可变区进行改良。

利用同源(Homology)模型预测了N3抗体的大致结构，由此，向预测为在抗原结合起到重要作用的互补决定区部位引入随机突变体。具体地，在基于重链可变区的文库中，使用了可包含互补决定区3残基的所有20个氨基酸序列的作为简并密码子(degeneratedcodon)的NNK。在基于轻链可变区的文库中，使用了可包含互补决定区3残基的所有20个氨基酸序列的作为简并密码子的NNK。

具体地，在编码所设计的文库的DNA中，利用聚合酶链式反应(PCR)方法扩增后，通过乙醇沉淀法浓缩。利用NheI和MluI限制酶对用于同源重组(Homologous recombination)的C-末端表达aga2蛋白的酵母表面表达载体(C-aga2)进行处理，利用琼脂糖胶提取法提纯并利用乙醇沉淀法浓缩。对于12μg的各个文库编码DNA，通过电穿孔法向酵母表面表达用酵母EBY10转化进行限制酶处理的4μg的载体，通过连续稀释(serial dilution)测量在选择培养基SD-CAA(20g/L的葡萄糖、6.7g/L的不含氨基酸的酵母氮碱(Yeast nitrogen basewithout amino acids)、5.4g/L的Na

在图1示出该过程。

实施例2：筛选对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)的亲和力得到改善的轻链可变区及重链可变区

利用结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)作为抗原，筛选了在所述实施例1中构建的2种基于N3抗体的亲和力改善文库。

具体地，为了第一次荧光激活细胞分选术筛选，利用SG-CAA(20g/L的半乳糖、6.7g/L的不含氨基酸的酵母氮碱、5.4g/L的Na

结果，如图2a及图2b所示，经确认，通过利用荧光激活细胞分选术的筛选过程，筛选了与N3抗体相比依赖重链可变区或轻链可变区地对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)具有高亲和力克隆，通过个别克隆结合能力分析，筛选了对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)具有高亲和力及特异性的3个独特克隆(N3-1抗体、N3-3抗体、N3-4抗体)。并且，可相互组合它们的轻链可变区及重链可变区，构建了另一个独特的克隆(N3-5抗体)。即，筛选了共4个独特的克隆(N3-1抗体、N3-3抗体、N3-4抗体、N3-5抗体)。

在表1示出对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)示出高结合能力的4个个别克隆的轻链可变区及重链可变区的互补决定区序列，在表2示出重链可变区序列及轻链可变区序列。

表1

表2

并且，为了确认对于赖氨酰-tRNA合成酶的N末端的亲和力是否增加，实施酶联免疫吸附法来测量了对于赖氨酰-tRNA合成酶的N末端的亲和力。

具体地，在25℃的温度下，将赖氨酰-tRNA合成酶的N末端部分(1-72残基)与96孔EIA/RIA板(COSTAR Corning)结合1小时后，利用磷酸盐缓冲液(PBS)(pH值为7.4，137mM的NaCl，12mM的磷酸盐(phosphate)，2.7mM的KCl)(SIGMA)洗涤3次，每次10分钟。之后，利用4％的牛血清白蛋白(BSA)磷酸盐缓冲液(PBS)(4％的牛血清白蛋白(Bovine SerumAlbumin)，pH值为7.4，137mM的NaCl，12mM的磷酸盐，2.7mM的KCl)(SIGMA)结合1小时后，利用磷酸盐缓冲液洗涤3次，每次10分钟。之后，结合IgG形态的作为赖氨酰-tRNA合成酶N末端靶抗体的N3抗体、N3-1抗体、N3-3抗体、N3-4抗体、N3-5抗体后，利用0.1％的PBST洗涤3次，每次10分钟。作为标记抗体，使用结合有辣根过氧化物酶(HRP)的抗-人抗体(Horseradishperoxidase-conjugated anti-human mAb)(SIGMA)。之后，利用3，3'，5，5'-四甲基联苯胺(TMB，3，3'，5，5'-Tetramethylbenzidine)(Sigma)进行反应，在450nm的吸光度下进行测量和定量。

结果可确认，如图3a及图3b所示，相比于野生型N3抗体，作为突变体的N3-1抗体、N3-3抗体、N3-4抗体、N3-5抗体的亲和力增加。经确认，所有克隆均未与用作阴性对照组的GST或NRP1-b1b2结合。作为突变体抗体的N3-1抗体、N3-3抗体、N3-4抗体、N3-5抗体之间的赖氨酰-tRNA合成酶结合力没有明显差异。

实施例3：N3抗体与N3-1抗体的亲和力比较

3-1.抗体的细胞迁移抑制效果

在所述实施例2的N3突变体抗体中，利用常规方法将N3-1抗体转化为IgG抗体。利用所转化的IgG抗体实施如下的实验。

利用通常使用的聚碳酸酯膜(8.0μm pore size，Costar)的24-孔转移孔腔室测量细胞迁移。在转移孔腔室中，利用10μg的层粘连蛋白(Laminin)涂敷下孔(lower well)。之后，在无血清(serum-free)RPMI培养基悬浮A549细胞，以每孔1×10

结果，如图4所示，可确认，N3-1抗体与N3抗体相比更显著地抑制A549细胞的移动。

3-2.抗体的赖氨酰-tRNA合成酶亲和力效果

使用赖氨酰-tRNA合成酶片段(1-207氨基酸)纯化蛋白作为抗原，通过表面等离子体共振分析了与N3抗体及N3-1抗体的结合能力。

使用配备有Series S传感器芯片CM5(GE Healthcare)的Biacore T200(GEHealthcare)，在25℃的温度下进行表面等离子体共振实验。使用胺偶联试剂盒(GEHealthcare)将抗体固定在芯片上后，将抗原在4.8nM～1250nM的磷酸盐缓冲液中稀释4倍，并使其流动60秒。然后，使磷酸盐缓冲液流动300秒。使用软件Biacore T200 Evaluationsoftwarev 2.0(GE Healthcare)分析所获得的数据。

如图5所示，结果显示，所测量的N3-1抗体的KD值为31nM，这表明与N3抗体相比，与赖氨酰-tRNA合成酶蛋白的结合能力得到提高。

实施例4：用于增加亲和力的酵母细胞表面表达文库的构建(N3-1抗体)

靶向在所述实施例2中导出的赖氨酰-tRNA合成酶的N末端的N3-1抗体、N3-3抗体、N3-4抗体、N3-5抗体对于赖氨酰-tRNA合成酶的亲和力相似，如N3-1抗体的结果所示，判断为具有约31nM的亲和力。这与完整IgG形态的各种抗体的亲和力相比，依然很低。为了增加其来获取更有效的抗体，所要集中改善抗体的重链可变区。

利用N3-3抗体固定轻链可变区序列，利用同源建模(homology modeling)预测N3-3抗体的近似建模结构，由此，向预测为在抗原结合中起到重要作用的互补决定区引入随机突变体。

具体地，使用了可包含重链可变区的互补决定区2和互补决定区3的残基的所有20个氨基酸序列的作为简并密码子的NNK，通过与实施例1相同的方法构建文库。

实施例5：筛选对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)的亲和力得到改善的轻链可变区及重链可变区

利用结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)作为抗原，筛选了在所述实施例4中构建的2种基于N3-3抗体的亲和力改善文库。经判断，N3-3抗体和N3-1抗体的亲和力几乎相同且序列几乎相似，因此，在抗体比较实验中利用N3-1抗体。

具体地，在4℃的温度下，将与结合有GTP的赖氨酰-tRNA合成酶的肽(残基1-72)结合的文库的酵母与链霉抗生物素蛋白(Streptavidin)Microbead

利用10nM的结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)进行第一次荧光激活细胞分选术筛选，利用1nM的结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)进行第二次荧光激活细胞分选术筛选，利用0.5nM的结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)进行第三次荧光激活细胞分选术筛选，利用0.1nM的结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)进行第四次荧光激活细胞分选术筛选。

结果，如图6所示，通过利用磁性激活的细胞分类及荧光激活细胞分选术的筛选过程，筛选了与N3-1抗体相比依赖重链可变区地对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)具有高亲和力的克隆，通过个别克隆结合能力分析，筛选了对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)具有高亲和力及特异性的4个独特的克隆(N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体)。

在表3示出对于结合有GST的赖氨酰-tRNA合成酶的肽(残基1-72)示出高结合能力的4个个别克隆的轻链可变区及重链可变区的互补决定区序列，在表4示出重链可变区序列及轻链可变区序列。

表3

表4

并且，为了确认对于赖氨酰-tRNA合成酶的N末端的亲和力是否增加，通过与实施例2相同的方法实施酶联免疫吸附法来测量了对于赖氨酰-tRNA合成酶的N末端的亲和力。

具体地在25℃的温度下，将赖氨酰-tRNA合成酶的N末端部分(1-72残基)与96孔EIA/RIA板(COSTAR Corning)结合1小时后，利用磷酸盐缓冲液洗涤3次，每次10分钟。之后，利用4％的牛血清白蛋白磷酸盐缓冲液结合1小时后，利用磷酸盐缓冲液洗涤3次，每次10分钟。之后，结合IgG形态的作为赖氨酰-tRNA合成酶N末端靶抗体的N3-1抗体、N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体后，利用0.1％的PBST洗涤3次，每次10分钟。使用结合有辣根过氧化物酶的抗-人抗体，利用3，3'，5，5'-四甲基联苯胺(TMB，3，3'，5，5'-Tetramethylbenzidine)进行反应，在450nm的吸光度下进行测量和定量。

结果可确认，如图7所示，相比于N3-1抗体，作为突变体的N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体的亲和力增加。经确认，所有克隆均未与用作阴性对照组的NRP1-b1b2结合。

实施例6：N3-1抗体和N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体的亲和力比较

6-1.抗体的赖氨酰-tRNA合成酶结合比较

使用赖氨酰-tRNA合成酶表位肽(epitope peptide)F4(EPKLSKNELKRRLKAEKKVAEKEAKQKE：SEQ ID NO:117)作为抗原表位(epitope)，通过表面等离子体共振分析与N3抗体、N3-6抗体、N3-7抗体、N3-8抗体和N3-9抗体的结合能力。以与所述实施例3-2相同的方式进行表面等离子体共振实验。将表位在磷酸盐缓冲液中稀释，并在15.7nM～4000nM的范围内稀释2倍，并使其流动90秒。然后，使磷酸盐缓冲液流动2400秒。使用软件Biacore T200 Evaluation software v2.0(GE Healthcare)分析所获得的数据。

结果，如图8所示，N3-8抗体的KD表现最为优良，N3-9抗体的KD和N3-6抗体的KD相似，并且N3-7抗体的KD值最大。N3-6抗体的解离比N3-7抗体和N3-9抗体的解离时间长，并且显示出具有更长时间结合的传感图(sensorgram)。

此外，使用其中赖氨酰-tRNA合成酶表位肽F4(SEQ ID NO:117)的单一氨基酸分别被丙氨酸(A)取代的肽，进行酶联免疫吸附法以确定对于抗体-表位结合重要的残基。结果显示，可在赖氨酰-tRNA合成酶表位肽F4中确定对结合各抗体重要的残基。

6-2.抗体的细胞细胞迁移抑制效果

通过与所述实施例3-1相同的方法实施实验。通过常规方法将在所述实施例中制备的N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体转化为IgG抗体。利用所转化的IgG抗体进行下述实验。

以每孔1×10

结果，如图9所示，相比于N3-1抗体，N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体显著抑制细胞的迁移。并且，在N3-6抗体、N3-7抗体、N3-8抗体、N3-9抗体中，细胞迁移抑制效果未示出显著差异。

实施例7：N3-8抗体的序列优化(sequence refinement)

7-1.N3-8抗体序列的突变体制备

在所述实施例中，确认了N3-8抗体的亲和力最为优秀。由此，为了确认N3-8抗体的生产率、稳定性等物性，实施如下的实验。

向预测为对于N3-8抗体序列的稳定性具有影响的序列诱导突变(mutation)。结果，可获得在N3-8抗体的重链序列(HC)引入变异的2种追加重链序列。并且，可获取引入突变的3种追加轻链序列。由此，在下述表5及表6示出N3-8的序列改变的7种抗体序列(N3-8衍生物(derivatives))。

表5

表6

7-2.N3-8抗体衍生物的生产和Tm的测量

对于表达在所述实施例7-1中获取的N3-8抗体研生物的载体，利用瞬时转染(transient transfection)表达及纯化蛋白质。

在摇瓶中，将悬浮于无血清FreeStyle 293表达培养基(Invitrogen)中的HEK293-F细胞(Invitrogen)转染为质粒及聚乙烯亚胺(Polyethylenimine，Polyscience)的混合物。在向摇瓶(Corning)转染200mL的过程中，将HEK293-F细胞以2×10

为了生成各个单克隆抗体，在10ml的FreeStyle 293表达培养基(Invitrogen)，以1∶或1∶2的重链∶轻链DNA的比例转染合适的重链和轻链质粒。在1∶1的情况下，以125μg的重链、125μg的轻链的共250μg(2.5μg/ml)进行稀释，将750μg的聚醚酰亚胺(PEI)(7.5μg/ml)与所稀释的10ml的培养基混合并在室温条件下反应10分钟。在1∶2的情况下，将轻链DNA的浓度设定为2倍。之后，将进行反应的混合培养基添加至之前以100ml接种的细胞，并在150rpm、8％CO

然后，将细胞培养液转移至50ml的试管中，并以3000rpm的条件离心分离5分钟。然后，从收集的细胞培养上清液中纯化蛋白质。将抗体适用于蛋白A琼脂糖凝胶柱(Protein ASepharose column)上，然后用磷酸盐缓冲液(pH值为7.4)洗涤。在pH值为3.0的条件下，用0.1M的甘氨酸缓冲液洗脱抗体后，立即用1M的Tris缓冲液中和样品。通过透析法通过与磷酸盐缓冲液(pH值为7.4)交换缓冲液来浓缩洗脱的抗体部分。使用在280nm的波长的吸光度和吸光系数对纯化的蛋白质进行定量。

此外，使用100μl的浓度为1mg/ml的所述纯化的抗体测量抗体的热稳定性(thermal stability)。利用蛋白质热转移染料试剂盒(Protein thermal shift Dye kit)(Thermofisher)，通过Quant Studio 3实时PCR设备(Thermofisher)反复执行4次。

结果，如下述表7所示，所测试的所有N3-8抗体衍生物的收率(yield)比N3-8抗体相比得到改善或示出与N3-8抗体相似水平的高收率。并且，如表7，获取Tm值。根据抗体，所观察到的热转化(thermal transition)为1-2，互不相同，但是，在所有N3-8抗体衍生物中，示出Tm值增加。

由此证实了N3-8抗体衍生物比N3-8抗体具有更高的收率和改善的热稳定性。

表7

在下述表8示出在所述实施例中使用的IgG全抗体的重链及轻链序列结构。

表8

7-3.N3-8-1抗体、N3-8-4抗体的亲和力比较

如所述实施例6中所记载，使用赖氨酰-tRNA合成酶表位肽F4(EPKLSKNELKRRLKAEKKVAEKEAKQKE:SEQ ID NO:117)作为抗原表位，通过表面等离子体共振分析与N3-8-1抗体、N3-8-4抗体的结合能力。以与所述实施例3-2相同的方式进行表面等离子体共振实验。将表位在磷酸盐缓冲液中稀释，并在15.7nM～4000nM的范围内稀释2倍，并使其流动90秒。然后，使磷酸盐缓冲液流动2400秒。使用软件Biacore T200 Evaluationsoftware v2.0(GE Healthcare)分析所获得的数据。

结果，如下述表9所示，N3-8-1抗体的KD最为优良。

表9

实施例8：抗体的机制确认

向抗体(Ab)缀合(conjugation)荧光探针(probe)，并在4T1乳腺癌细胞(breastcancer cell)处理后，确认了细胞膜的抗-赖氨酰-tRNA合成酶抗体(N3抗体、N3-8抗体)具有内吞作用(endocytosis)。

需用Alexa fluor 488(Thermofisher)荧光探针标记的抗-赖氨酰-tRNA合成酶抗体(N3抗体、N3-8抗体)和1μM的作为对照组的Mock IgG(Thermofisher)进行处理，4小时后，监测抗体的迁移。此时，为了确认是否具有内吞作用，作为溶酶体(lysosome)标记物使用溶酶体追踪剂(Lysot racker)(Thermofisher)，4'，6-二脒基-2-苯基吲哚(DAPI)表示细胞核染色。与Mock不同地，可在4小时后，确认N3抗体及N3-8抗体存在于细胞中。

结果，如图10所示，抗-赖氨酰-tRNA合成酶抗体迅速识别细胞膜赖氨酰-tRNA合成酶并被内吞，由此，可确认降低细胞膜赖氨酰-tRNA合成酶水平。

实施例9：去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的抗体的序列优化

9-1.去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的抗体序列的突变体制备

为了在所述抗体中去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能，实施如下的实验。在所述各个抗体序列中，向预测为重链(heavy chain)恒定区(constantregion)的具有抗体依赖性细胞毒性/补体依赖性细胞毒性功能的位点引入突变体。为了降低各个抗体的抗体依赖性细胞毒性/补体依赖性细胞毒性功能，使用IgG1来制备抗体，由此，可获取在所述抗体的重链序列引入变异的5种追加重链序列。并且，可获取引入IgG4的追加重链序列和在IgG4引入变异的追加重链序列。由此，在下述表10分别示出各个抗体中的去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体序列。

表10

9-2.去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体的纯化

在从所述实施例9-1中获取的去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体中，对于N3-8-1抗体的去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的表达突变体抗体的载体，利用瞬时转染表达及纯化蛋白质。

根据在所述实施例7-2中记载的方法，在摇瓶中，转染HEK293-F细胞(Invitrogen)。之后，将HEK293-F细胞以2×10

为了生成各个单克隆抗体，在10ml的FreeStyle 293表达培养基(Invitrogen)，以1∶或1∶2的重链∶轻链DNA的比例转染合适的重链和轻链质粒。在1∶1的情况下，以125μg的重链、125μg的轻链的共250μg(2.5μg/ml)进行稀释，将750μg的聚醚酰亚胺(PEI)(7.5μg/ml)与所稀释的10ml的培养基混合并在室温条件下反应10分钟。在1∶2的情况下，将轻链DNA的浓度设定为2倍。之后，将进行反应的混合培养基添加至之前以100ml接种的细胞，并在150rpm、8％CO

然后，将细胞培养液转移至50ml的试管中，并以3000rpm的条件离心分离5分钟。然后，从收集的细胞培养上清液中纯化蛋白质。将抗体适用于蛋白A琼脂糖凝胶柱(Protein ASepharose column)上，然后用磷酸盐缓冲液(pH值为7.4)洗涤。在pH值为3.0的条件下，用0.1M的甘氨酸缓冲液洗脱抗体后，立即用1M的Tris缓冲液中和样品。通过透析法通过与磷酸盐缓冲液(pH值为7.4)交换缓冲液来浓缩洗脱的抗体部分。使用在280nm的波长的吸光度和吸光系数对纯化的蛋白质进行定量。

并且，测量纯化的所述抗体的纯度(Purity)，利用蛋白质热转移染料试剂盒(Protein thermal shift Dye kit)(Thermofisher)，通过使用Quant Studio 3实时PCR设备(Thermofisher)反复执行4次。

结果，如下述表11所示，所测试的所有N3-8-1抗体突变体的收率与野生型(wildtype)相似或示出高于野生型的收率，其中，LALAPGTA突变体的收率最高。并且，所有N3-8-1抗体突变体示出与野生型抗体相似水平的高纯度。

由此，证实了去除N3-8-1的抗体依赖性细胞毒性/补体依赖性细胞毒性功能的抗体比N3-8-1抗体具有相似或更高的收率，且具有相似的纯度。

表11

实施例10：在体内(in vivo)模型中验证赖氨酰-tRNA合成酶-N末端特异性结合抗体对免疫细胞迁移相关疾病的功效_体内肺动脉高血压模型

若处理与赖氨酰-tRNA合成酶-N末端特异性结合的抗体，则由于细胞膜位置中的赖氨酰-tRNA合成酶水平减少(通过内吞作用等)免疫细胞的迁移/侵袭被抑制，从而具有细胞膜赖氨酰-tRNA合成酶水平减少效果。因此，本发明的赖氨酰-tRNA合成酶N-末端特异性抗体(通常为N3抗体)对于免疫细胞迁移相关疾病示出治疗效果，这是显而易见的，这通过后述的实施例进一步得到证明。

实验方法

1.构建肺动脉高压(PAH)模型制备及试验物质的给药

为了在7周龄的SD大鼠(Orientbio Inc.)中诱发肺动脉高压，皮下注射60mpk的野百合碱(MCT)。之后，将大鼠分为4个组(每组5只)，在3周内分别给药1mpk的Mock人IgG(赛默飞世尔科技，阴性对照组)、1mpk的N3 IgG抗体、10mpk的N3 IgG抗体、25mpk的西地那非(sildenafil)(阳性对照组)。所有抗体以1周2次的频率静脉(iv)注射，西地那非每天口服给药。

2.测量血流及血压

3周后，利用异氟烷(isoflurane)麻醉大鼠，利用动物用高精度气动测量系统(MPVS心血管压力和容量系统(MPVS Cardiovascular Pressure and Volume system)，型号名称：MPVS Ultra，制造商：Millar Instruments)测量血流和压力。利用专用导管(Mikro-Tip大鼠压力导管(Mikro-Tip rat pressure catheter)，制造商：MillarInstruments)测量右心室收缩末压(RVESP)及右心室舒张末压、左心室收缩末压及左心室舒张末压。利用血管周围(perivascular)超声流探头(TransonicFlowprobes，制造商：Millar Instruments)测量心输出量，并且其实验方法通过与下述文献中记载的相同方法进行：Pacher P,Nagayama T,Mukhopadhyay P,Batkai S,Kass DA.Measurement ofcardiac function using pressure-volume conductance catheter technique in miceand rats.Nat Protoc 2008；3(9):1422-34。

3.免疫组织化学染色(immunohistochemistry，IHC)

按照常规步骤，将收集的肺固定于多聚甲醛(PFA，paraformaldehyde)中，然后经过洗涤、脱水、洗涤后进行石蜡浸润包埋。将大鼠的肺组织石蜡块显微切片至3μm的厚度，并制备载玻片。之后，以如下的方式进行染色。样品首先用二甲苯(xylene)处理5分钟3次，以100％乙醇、95％乙醇、90％乙醇、70％乙醇、DW顺序依次处理2分钟，然后用磷酸盐缓冲液洗涤5分钟。经0.3％的H

实验结果

10-1.验证血压及心输出量变化

对于作为免疫细胞的浸润与病理现象的密切相关的疾病的肺动脉高压模型，用1mpk或10mpk的N3单克隆抗体处理3周(静脉注射，1周2次)，之后，测量右心室收缩末压(right ventricular end-systolic pressure；RVESP)、右心室舒张末压(rightventricular end-diastolic pressure；RVEDP)、左心室收缩末压(left ventricularend-systolic pressure；LVESP)左心室舒张末压(left ventricular end-diastolicpressure；LVEDP)及心输出量(cardiac output；CO)，在表12中示出结果。

表12

(MCT+mock IgG治疗组的一只动物在麻醉期间死亡，西地那非治疗组的一只动物在手术过程中死亡，因此，未测量其CO)。

在肺动脉高压中，由于肺动脉变窄，使右心室压力上升，最终导致右心室衰竭。另外，由于持续的高血压，其奖赏机制受损，则导致右心室肥大，随后右心室扩张。这导致室间隔迁移引起的左心室的压迫，导致左心室的收缩末期容量及心输出量的减少(WooSeokLee,et al.Clinical Characteristics and Prognostic Factors of Patients withSevere Pulmonary Hypertension,Korean Circulation J 2007；37:265-270)。最终，肺动脉高压主要与右心室相关，但是还与左心室的功能相关。

肺动脉高压患者显示右心室收缩末压增加，这在本实验的肺动脉高压模型中也观察到。对此，如图11所示，N3抗体(赖氨酰-tRNA合成酶N末端区域特异性结合的抗体)在两种浓度下均显著降低右心室收缩末压，并且比阳性对照组药物西地那非更有利地降低右心室收缩末压。

另外，未观察到由于给药N3抗体(赖氨酰-tRNA合成酶N末端区域特异性结合的抗体)而导致的左心室收缩末压(LVESP)降低，而是如图13所示，在给药本发明的抗体的组中，左心室收缩末压显著增加。因此，本发明的抗体与用作现有的肺动脉高压治疗剂的西地那非相反，其中西地那非引起肺动脉扩张和全身动脉扩张，从而具有降低全身性血压(systemic blood pressure)的风险。即，证实了相比于西地那非，本发明的N3抗体显示出对全身性动脉压(systemic artery pressure)的影响低的趋势，并且考虑到在临床现场中给药西地那非时具有诱发低血压的风险，这种效果将认为是治疗药剂的有利特性。不仅如此，严重的肺动脉高压可导致收缩期右心室衰竭(systolic RV failure)，并可伴有低心输出量(cardiac output)及全身性低血压(systemic hypotension)。然而，通过借助本发明的N3抗体使肺动脉高压好转的治疗有望增加心输出量(cardiac output)和全身性血压(systemic blood pressure)生成，由此，可预计血压正常化的效果。

综上所述，证明给药本发明的赖氨酰-tRNA合成酶N末端区域结合的抗体(特别是，N3抗体)可降低现有治疗药物的副作用风险，并显示肺动脉高压症状缓解和治疗的效果。

10-2.心脏超声波检查(Echocardiography)

分别在MCT单独给药组(即，试验物质非给药肺动脉高压模型)的3只动物、MCT+西地那非给药组的3只动物中观察到表明右心室压力超负荷的D形左心室(D-shaped leftventricle)，但在治疗抗体(N3抗体)给药组中未观察到所述征象。

不仅如此，如下述表13所示，各组的体重增加程度相似，没有显著差异。即，未观察到表明由于给药治疗抗体引起的异常征兆，包括异常体重减轻。

表13

10-3.单核细胞/巨噬细胞迁移及浸润程度的验证

通过使用每个实验组的肺组织，对作为单核细胞/巨噬细胞标记的CD68进行IHC染色。如图12所示，实验结果证实本发明的N3抗体(赖氨酰-tRNA合成酶N末端区域结合的抗体)治疗组明显降低单核细胞/巨噬细胞的肺组织浸润，且这种效果明显优于西地那非。

实施例11：在体内模型中验证赖氨酰-tRNA合成酶-N末端特异性结合抗体对免疫细胞迁移相关疾病的影响_急性肺损伤模型

实验方法

1)脂多糖(LPS)诱发的急性肺损伤模型的制备和测试物质的给药

急性肺损伤的小鼠模型是通过向7周龄的雄性C57BL/6小鼠(duothermal bio)进行气管内注射2.5mg/kg的脂多糖(Sigma)来制备。

为了研究赖氨酰-tRNA合成酶抑制剂对急性肺损伤的影响，首先，分别以1mg/kg或10mg/kg的剂量对C57BL/6小鼠静脉注射N3 IgG抗体，24小时后，气管内注射2.5mg/kg的脂多糖。脂多糖注射24小时后，安乐死每只小鼠以收集和分析肺组织和支气管肺泡灌洗液(BALF，Bronchoalveolar lavage fluid)。

2)支气管肺泡灌洗液(BALF)中的免疫细胞计数

收集通过用磷酸盐缓冲液洗涤肺而获得的支气管肺泡灌洗液，并通过在4℃、800xg的条件下离心分离10分钟来收集颗粒。悬浮细胞后，使用RBC裂解缓冲液(eBioscience目录号00-4333-57)洗去红细胞(red blood cell)。用磷酸盐缓冲液终止反应后，洗涤两次，并悬浮在400μl的磷酸盐缓冲液中以通过血球计数板(hemocytometer)测量细胞数并通过Hema3染色测量中性粒细胞数(neutrophil)。

3)荧光激活细胞分选术对肺组织免疫细胞的影响

收集肺组织，并使用温和的MACS Octo Dissociator(MACS Miltenyi Biotec，订单号：130-095-937)在37℃的温度下旋转(rotation)45分钟以压碎组织。使用细胞过滤器(Cell strainer)(40μm)过滤(filter)后，在室温下以1500rpm的条件离心分离5分钟。收集颗粒并使用RBC裂解缓冲液(eBioscience目录号：00-4333-57)洗去红细胞。收集细胞并将其悬浮在荧光激活细胞分选术缓冲液(含1％NaN

4)肺组织的Masson三色染色

将肺组织以原始方式包埋在石蜡中，然后切出。然后，用DW洗涤用二甲苯去除了石蜡的组织玻片，然后在56℃～60℃下用布安液(Bouin Fluid)处理1小时。用Weigert氏苏木精溶液(Weigert’s iron hematoxylin solution)染色10分钟后，洗涤组织玻片。再次用Biebrich绯红酸品红溶液(Biebrich scarlet-acid fuchsin solution)染色10分钟～15分钟后，洗涤玻片。将磷钼酸盐-磷钨酸溶液在玻片上处理10分钟～15分钟，然后将玻片转移到苯胺蓝溶液中并染色5分钟～10分钟。洗涤后，将玻片用1％的乙酸溶液处理2分钟～5分钟。洗涤和脱水后，将玻片用二甲苯处理并固定。

实验结果

11-1.对支气管肺泡灌洗液(BALF)中免疫细胞迁移的抑制效果的验证

如图13所示，证实了在通过脂多糖处理引起的急性肺损伤小鼠中，支气管肺泡灌洗液中的免疫细胞总数增加了，其通过N3抗体(赖氨酰-tRNA合成酶N-末端结合抗体)处理浓度依懒性地降低了。

特别地，如图14所示，证实了在通过脂多糖处理患有急性肺损伤的小鼠中，中性粒细胞增加了，并且N3抗体(赖氨酰-tRNA合成酶N-末端结合抗体)治疗降低了这些中性粒细胞的水平。结果证实了通过处理与赖氨酰-tRNA合成酶N端特异性结合的抗体，显著地抑制了支气管肺泡灌洗液中的免疫细胞，尤其中性粒细胞浸润到的肺。

11-2.肺组织中免疫细胞迁移的抑制效果的验证

图15和图16显示了由于急性肺损伤而迁移至肺组织的巨噬细胞的荧光激活细胞分选术分析结果。间质巨噬细胞(IM)是CD11b+/F4/80+细胞，它们不驻留在肺中且在特定情况下迁移到肺的巨噬细胞。脂多糖处理增加了间质巨噬细胞向肺的浸润，而N3抗体处理浓度依赖性地减少了间质巨噬细胞向肺的迁移。由此证实，通过与赖氨酰-tRNA合成酶N-末端特异性结合的抗体(通常为N3抗体)的治疗，抑制了巨噬细胞/单核细胞等免疫细胞向肺组织的迁移和侵袭。

如巨噬细胞/单核细胞等免疫细胞的过度迁移值肺组织和侵袭是组织纤维化疾病中的一个重要病理现象。通过对急性肺损伤模型的肺组织的Masson三色染色的观察(图17)，证实了肺组织中的相当大的纤维化进展。相反，证实了N3抗体(与赖氨酰-tRNA合成酶N-末端特异性结合的抗体)的治疗抑制了这种纤维化。

实施例12：去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体的免疫细胞迁移分析

为了确认所述去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体对于免疫细胞迁移的影响，根据在现有文献(Park,S.G.et al.Human lysyl-tRNAsynthetase is secreted to trigger pro-inflammatory respons e,Proc.Natl.Acad.Sci.U S A 102,6356-6361(2005))中记载的方法实施细胞迁移分析。

利用具有聚碳酸酯薄膜(5.0μm的孔隙尺寸，Costar)的转染孔腔室进行测量。在所述转染腔室中，以2.5μg/ml的浓度将LN421放入下段腔室。之后，以每孔5×10

结果，如图18所示，N3-8抗体、N3-8-1抗体、N3-8-1突变体LALA抗体、N3-8-1突变体LALATA抗体、N3-8-1突变体LALAPG抗体、N3-8-1突变体LALAPGTA抗体均与未经任何处理的对照组(Control，C)相似的水平抑制LN421引起的细胞迁移。

实施例13：去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体的癌细胞迁移分析

为了确认所述去除抗体依赖性细胞毒性/补体依赖性细胞毒性功能的突变体抗体对于免疫细胞迁移的影响，根据在实施例12记载的方法实施细胞迁移分析。

利用具有聚碳酸酯薄膜(8.0μm孔隙尺寸)的24-孔转染孔腔室进行测量。以1mg/ml的浓度将层粘连蛋白(laminin)放入下段腔室，使用作为磷酸化赖氨酰-tRNA合成酶的过表达T52D赖氨酰-tRNA合成酶的稳定MDA-MB-231细胞中执行细胞迁移分析。为了诱导T52D赖氨酰-tRNA合成酶表达，在无血清RPMI培养基悬浮将利用多西环素(doxycycline)(0.1μg/ml)处理一天的T52D赖氨酰-tRNA合成酶-MDA-MB-231稳定细胞后，以每孔4×10

结果，如图19所示，N3-8抗体、N3-8-1抗体、N3-8-1突变体LALA抗体、N3-8-1突变体LALATA抗体、N3-8-1突变体LALAPG抗体、N3-8-1突变体LALAPGTA抗体均抑制层粘连蛋白引起的癌细胞迁移。

产业上的可利用性

如上所述，本发明的抗体或其片段具有在本说明书中所记载的特定互补决定区序列，与暴露于细胞外的赖氨酰-tRNA合成酶N-末端区域特异性结合的能力及亲和力非常优秀，因此，可利用于如癌症或免疫细胞迁移相关疾病的伴随赖氨酰-tRNA合成酶的特异性形态的疾病的诊断，生产率及安全性优秀，且具有出色的癌症转移抑制效果，因此，可有用地用作癌症治疗剂、癌症转移预防或抑制剂，可有用地用于预防、改善及治疗与免疫细胞迁移相关的疾病。

SEQUENCE LISTING

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20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Asp Ser Leu

85 90 95

Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 34

<211> 330

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VL

<400> 34

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccgg 240

tccgaggatg aggctgatta ttactgtgct tcttgggatg atagcctgag tgcttatgtc 300

ttcggcggag gcaccaagct gacggtccta 330

<210> 35

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 1

<400> 35

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 36

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 1

<400> 36

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 37

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 2

<400> 37

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 38

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 2

<400> 38

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 39

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 3

<400> 39

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 40

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 3

<400> 40

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 41

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 4

<400> 41

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 42

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 4

<400> 42

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 43

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 5

<400> 43

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 44

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 5

<400> 44

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 45

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 6

<400> 45

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 46

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 6

<400> 46

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 47

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 7

<400> 47

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 48

<211> 348

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VH 突变体 7

<400> 48

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctca 348

<210> 49

<211> 110

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 1

<400> 49

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 50

<211> 330

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 1

<400> 50

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgtgct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta 330

<210> 51

<211> 110

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 2

<400> 51

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 52

<211> 330

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 2

<400> 52

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta 330

<210> 53

<211> 110

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 3

<400> 53

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 54

<211> 330

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 3

<400> 54

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta 330

<210> 55

<211> 110

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 4

<400> 55

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 56

<211> 330

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 VL 突变体 4

<400> 56

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat cggaataatc agcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta 330

<210> 57

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> 连接子 for scFv

<400> 57

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 58

<211> 45

<212> DNA

<213> Artificial Sequence

<220>

<223> 连接子 for scFv

<400> 58

ggtggaggcg gttcaggcgg aggtggatcc ggcggtggcg gatcg 45

<210> 59

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 scFv (VH+连接子+VL)

<400> 59

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp

210 215 220

Asp Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 60

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 scFv (VH+连接子+VL)

<400> 60

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cggtccgagg atgaggctga ttattactgt 660

gcttcttggg atgatagcct gagtgcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 61

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-1 scFv (VH+连接子+VL)

<400> 61

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 62

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-1 scFv (VH+连接子+VL)

<400> 62

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

gcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 63

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-3 scFv (VH+连接子+VL)

<400> 63

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 64

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-3 scFv (VH+连接子+VL)

<400> 64

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 65

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-4 scFv (VH+连接子+VL)

<400> 65

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 66

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-4 scFv (VH+连接子+VL)

<400> 66

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

gcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 67

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-5 scFv (VH+连接子+VL)

<400> 67

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 68

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-5 scFv (VH+连接子+VL)

<400> 68

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 69

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-6 scFv (VH+连接子+VL)

<400> 69

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 70

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-6 scFv (VH+连接子+VL)

<400> 70

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 71

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-7 scFv (VH+连接子+VL)

<400> 71

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 72

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-7 scFv (VH+连接子+VL)

<400> 72

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 73

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8-7 scFv (VH+连接子+VL)

<400> 73

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 74

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8-7 scFv (VH+连接子+VL)

<400> 74

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 75

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-9 scFv (VH+连接子+VL)

<400> 75

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 76

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-9 scFv (VH+连接子+VL)

<400> 76

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 77

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8 scFv, N3-8-1 scFv (VH+连接子+VL)

<400> 77

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 78

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8 scFv, N3-8-1 scFv (VH+连接子+VL)

<400> 78

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 79

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8-2 scFv (VH+连接子+VL)

<400> 79

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 80

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8-2 scFv (VH+连接子+VL)

<400> 80

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatagtaata atcagcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 81

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8-3 scFv (VH+连接子+VL)

<400> 81

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 82

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8-3 scFv (VH+连接子+VL)

<400> 82

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatcggaata atcagcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 83

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8-4 scFv (VH+连接子+VL)

<400> 83

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 84

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8-4 scFv (VH+连接子+VL)

<400> 84

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatgataata gtaatcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 85

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8-5 scFv (VH+连接子+VL)

<400> 85

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 86

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8-5 scFv (VH+连接子+VL)

<400> 86

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatagtaata atcagcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 87

<211> 241

<212> PRT

<213> Artificial Sequence

<220>

<223> N3-8-6 scFv (VH+连接子+VL)

<400> 87

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr

130 135 140

Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile

145 150 155 160

Gly Ser Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro

165 170 175

Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp

180 185 190

Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser

195 200 205

Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser

210 215 220

Asp Glu Leu Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val

225 230 235 240

Leu

<210> 88

<211> 723

<212> DNA

<213> Artificial Sequence

<220>

<223> N3-8-6 scFv (VH+连接子+VL)

<400> 88

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagg tggaggcggt 360

tcaggcggag gtggatccgg cggtggcgga tcgcagtctg tgctgactca gccaccctca 420

gcgtctggga cccccgggca gagggtcacc atctcttgta ctggctcttc atctaatatt 480

ggcagtaatt atgtcacctg gtaccagcag ctcccaggaa cggcccccaa actcctcatc 540

tatcggaata atcagcggcc aagcggggtc cctgaccgat tctctggctc caagtctggc 600

acctcagcct ccctggccat cagtgggctc cagtccgagg atgaggctga ttattactgt 660

tcttctttta gtgatgagtt gggggcttat gtcttcggcg gaggcaccaa gctgacggtc 720

cta 723

<210> 89

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 IgG 重链

<400> 89

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 90

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 IgG 重链

<400> 90

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 91

<211> 217

<212> PRT

<213> Artificial Sequence

<220>

<223> N3 IgG 轻链

<400> 91

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp Asp Ser Leu

85 90 95

Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr

100 105 110

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

115 120 125

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

130 135 140

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

145 150 155 160

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

165 170 175

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

180 185 190

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

195 200 205

Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 92

<211> 651

<212> DNA

<213> Artificial Sequence

<220>

<223> N3 IgG 轻链

<400> 92

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccgg 240

tccgaggatg aggctgatta ttactgtgct tcttgggatg atagcctgag tgcttatgtc 300

ttcggcggag gcaccaagct gacggtccta cgtacggtgg ctgcaccatc tgtcttcatc 360

ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420

aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480

aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540

accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600

catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651

<210> 93

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1

<400> 93

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 94

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1

<400> 94

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 95

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2

<400> 95

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 96

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2

<400> 96

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 97

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3

<400> 97

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 98

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3

<400> 98

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 99

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4

<400> 99

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 100

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4

<400> 100

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 101

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5

<400> 101

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 102

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5

<400> 102

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 103

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6

<400> 103

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 104

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6

<400> 104

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 105

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7

<400> 105

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 106

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7

<400> 106

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 107

<211> 217

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 轻链 1

<400> 107

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr

100 105 110

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

115 120 125

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

130 135 140

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

145 150 155 160

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

165 170 175

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

180 185 190

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

195 200 205

Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 108

<211> 651

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 轻链 1

<400> 108

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgtgct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta cgtacggtgg ctgcaccatc tgtcttcatc 360

ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420

aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480

aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540

accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600

catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651

<210> 109

<211> 217

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 轻链 2

<400> 109

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr

100 105 110

Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu

115 120 125

Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro

130 135 140

Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly

145 150 155 160

Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr

165 170 175

Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His

180 185 190

Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val

195 200 205

Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 110

<211> 651

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 轻链 2

<400> 110

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta cgtacggtgg ctgcaccatc tgtcttcatc 360

ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420

aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480

aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540

accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600

catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651

<210> 111

<211> 216

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 轻链 3

<400> 111

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Asp Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln

100 105 110

Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys

145 150 155 160

Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 112

<211> 648

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 轻链 3

<400> 112

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat gataatagta atcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta ggtcagccca aggctgcccc ctcggtcacg 360

ctcttcccac cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420

agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480

gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540

tacctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600

catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgctct 648

<210> 113

<211> 216

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 轻链 4

<400> 113

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln

100 105 110

Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys

145 150 155 160

Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 114

<211> 648

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 轻链 4

<400> 114

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta agtcagccca aggctgcccc ctcggtcacg 360

ctcttcccac cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420

agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480

gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540

tacctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600

catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgctct 648

<210> 115

<211> 216

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 轻链 5

<400> 115

Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln

1 5 10 15

Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn

20 25 30

Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Ser Asp Glu Leu

85 90 95

Gly Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln

100 105 110

Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys

145 150 155 160

Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 116

<211> 648

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 轻链 5

<400> 116

cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgtactg gctcttcatc taatattggc agtaattatg tcacctggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat cggaataatc agcggccaag cggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tccgaggatg aggctgatta ttactgttct tcttttagtg atgagttggg ggcttatgtc 300

ttcggcggag gcaccaagct gacggtccta ggtcagccca aggctgcccc ctcggtcacg 360

ctcttcccac cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420

agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480

gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540

tacctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600

catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgctct 648

<210> 117

<211> 28

<212> PRT

<213> Artificial Sequence

<220>

<223> KRS epitope F4

<400> 117

Glu Pro Lys Leu Ser Lys Asn Glu Leu Lys Arg Arg Leu Lys Ala Glu

1 5 10 15

Lys Lys Val Ala Glu Lys Glu Ala Lys Gln Lys Glu

20 25

<210> 118

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> CDR H2 突变体 5 氨基酸

<400> 118

Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 119

<211> 51

<212> DNA

<213> Artificial Sequence

<220>

<223> CDR H2 突变体 5 DNA

<400> 119

gtgatctctt ctgatggtgg taatacatat tacgctgatt ctgtaaaagg t 51

<210> 120

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> 轻链恒定区 ver.1_氨基酸

<400> 120

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> 121

<211> 321

<212> DNA

<213> Artificial Sequence

<220>

<223> 轻链恒定区 ver.1_DNA

<400> 121

cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60

ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120

tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180

agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240

aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300

agcttcaaca ggggagagtg t 321

<210> 122

<211> 106

<212> PRT

<213> Artificial Sequence

<220>

<223> 轻链恒定区 ver.2_氨基酸

<400> 122

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

1 5 10 15

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

20 25 30

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

35 40 45

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

50 55 60

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

65 70 75 80

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

85 90 95

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

100 105

<210> 123

<211> 318

<212> DNA

<213> Artificial Sequence

<220>

<223> 轻链恒定区 ver.2_DNA

<400> 123

ggtcagccca aggctgcccc ctcggtcacg ctcttcccac cctcctctga ggagcttcaa 60

gccaacaagg ccacactggt gtgtctcata agtgacttct acccgggagc cgtgacagtg 120

gcctggaagg cagatagcag ccccgtcaag gcgggagtgg agaccaccac accctccaaa 180

caaagcaaca acaagtacgc ggccagcagc tacctgagcc tgacgcctga gcagtggaag 240

tcccacagaa gctacagctg ccaggtcacg catgaaggga gcaccgtgga gaagacagtg 300

gcccctacag aatgctct 318

<210> 124

<211> 330

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 野生型_氨基酸

<400> 124

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

Lys 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> 125

<211> 990

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 野生型_DNA

<400> 125

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 720

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc cccgggtaaa 990

<210> 126

<211> 330

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体 TA_氨基酸

<400> 126

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

Lys 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 Ala 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> 127

<211> 990

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体 TA_DNA

<400> 127

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcgcctacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 720

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc cccgggtaaa 990

<210> 128

<211> 330

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体 LALA_氨基酸

<400> 128

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

Lys 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 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> 129

<211> 990

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体 LALA_DNA

<400> 129

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgccggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 720

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc cccgggtaaa 990

<210> 130

<211> 330

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体

LALATA_氨基酸

<400> 130

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

Lys 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 Ala 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> 131

<211> 990

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体 LALATA_DNA

<400> 131

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgccggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcgcctacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 720

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc cccgggtaaa 990

<210> 132

<211> 330

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体

LALAPG_氨基酸

<400> 132

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

Lys 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 Gly 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> 133

<211> 990

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体 LALAPG_DNA

<400> 133

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgccggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcggcgccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 720

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc cccgggtaaa 990

<210> 134

<211> 330

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体

LALAPGTA_氨基酸

<400> 134

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

Lys 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 Ala 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 Gly 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> 135

<211> 990

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG1 突变体

LALAPGTA_DNA

<400> 135

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgccggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcgcctacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcggcgccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtataccc tgcccccatc ccgggatgag 720

ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc cccgggtaaa 990

<210> 136

<211> 327

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG4 野生型_氨基酸

<400> 136

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 Ser 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> 137

<211> 981

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG4 野生型_DNA

<400> 137

gccagcacca agggcccttc cgtgtttccc ctggcccctt gctcccggtc cacatctgag 60

agcaccgccg ccctgggctg tctggtgaag gactacttcc cagagcccgt gaccgtgagc 120

tggaacagcg gcgccctgac aagcggcgtg cacacatttc ccgccgtgct gcagagctcc 180

ggcctgtact ccctgtctag cgtggtgaca gtgccttcct ctagcctggg caccaagaca 240

tatacctgta acgtggacca caagccaagc aataccaagg tggataagcg ggtggagtct 300

aagtacggcc ctccttgccc tagctgtcct gctccagagt ttctgggcgg cccttccgtg 360

ttcctgtttc cacccaaacc aaaggacaca ctgatgatct ctagaacacc agaggtgacc 420

tgcgtggtgg tggacgtgag ccaggaggat cccgaggtgc agttcaactg gtacgtggat 480

ggcgtggagg tgcacaatgc caagaccaag ccaagagagg agcagtttaa ctctacatac 540

agggtggtga gcgtgctgac cgtgctgcac caggattggc tcaacggcaa ggagtataag 600

tgcaaggtgt ccaataaggg cctgccctcc tctatcgaga agacaatctc taaggctaag 660

ggccagccaa gagagcctca ggtgtacacc ctgcctccaa gccaggagga gatgacaaag 720

aaccaggtgt ccctgacatg tctggtgaag ggcttctatc cctccgacat cgccgtggag 780

tgggagtcta atggccagcc tgagaacaat tacaagacca caccccctgt gctggactct 840

gatggcagct tctttctgta ttccaggctg accgtggata agtctcggtg gcaggagggc 900

aacgtgttca gctgctctgt gatgcacgaa gccctgcata atcactatac tcagaaaagt 960

ctgtcactgt cactgggaaa g 981

<210> 138

<211> 327

<212> PRT

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG4 突变体 TA_氨基酸

<400> 138

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 Ser 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 Ala 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> 139

<211> 981

<212> DNA

<213> Artificial Sequence

<220>

<223> 重链恒定区(CH1, CH2, CH3)_IgG4 突变体 TA_DNA

<400> 139

gccagcacca agggcccttc cgtgtttccc ctggcccctt gctcccggtc cacatctgag 60

agcaccgccg ccctgggctg tctggtgaag gactacttcc cagagcccgt gaccgtgagc 120

tggaacagcg gcgccctgac aagcggcgtg cacacatttc ccgccgtgct gcagagctcc 180

ggcctgtact ccctgtctag cgtggtgaca gtgccttcct ctagcctggg caccaagaca 240

tatacctgta acgtggacca caagccaagc aataccaagg tggataagcg ggtggagtct 300

aagtacggcc ctccttgccc tagctgtcct gctccagagt ttctgggcgg cccttccgtg 360

ttcctgtttc cacccaaacc aaaggacaca ctgatgatct ctagaacacc agaggtgacc 420

tgcgtggtgg tggacgtgag ccaggaggat cccgaggtgc agttcaactg gtacgtggat 480

ggcgtggagg tgcacaatgc caagaccaag ccaagagagg agcagtttaa ctctgcctac 540

agggtggtga gcgtgctgac cgtgctgcac caggattggc tcaacggcaa ggagtataag 600

tgcaaggtgt ccaataaggg cctgccctcc tctatcgaga agacaatctc taaggctaag 660

ggccagccaa gagagcctca ggtgtacacc ctgcctccaa gccaggagga gatgacaaag 720

aaccaggtgt ccctgacatg tctggtgaag ggcttctatc cctccgacat cgccgtggag 780

tgggagtcta atggccagcc tgagaacaat tacaagacca caccccctgt gctggactct 840

gatggcagct tctttctgta ttccaggctg accgtggata agtctcggtg gcaggagggc 900

aacgtgttca gctgctctgt gatgcacgaa gccctgcata atcactatac tcagaaaagt 960

ctgtcactgt cactgggaaa g 981

<210> 140

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 TA_氨基酸

<400> 140

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 141

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 TA_DNA

<400> 141

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 142

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALA_氨基酸

<400> 142

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 143

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALA_DNA

<400> 143

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 144

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALATA_氨基酸

<400> 144

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 145

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALATA_DNA

<400> 145

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 146

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALAPG_氨基酸

<400> 146

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 147

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALAPG_DNA

<400> 147

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 148

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALAPGTA_氨基酸

<400> 148

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 149

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG1 突变体 LALAPGTA_DNA

<400> 149

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 150

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG4 野生型_氨基酸

<400> 150

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 151

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG4 野生型_DNA

<400> 151

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 152

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG4 突变体 TA_氨基酸

<400> 152

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Tyr Asp Asn Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 153

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链_IgG4 突变体 TA_DNA

<400> 153

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcttatg ataatggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 154

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 TA_氨基酸

<400> 154

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 155

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 TA_DNA

<400> 155

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 156

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALA_氨基酸

<400> 156

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 157

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALA_DNA

<400> 157

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 158

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALATA_氨基酸

<400> 158

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 159

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALATA_DNA

<400> 159

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 160

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALAPG_氨基酸

<400> 160

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 161

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALAPG_DNA

<400> 161

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 162

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALAPGTA_氨基酸

<400> 162

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 163

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG1 突变体 LALAPGTA_DNA

<400> 163

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 164

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG4 野生型_氨基酸

<400> 164

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 165

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG4 野生型_DNA

<400> 165

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 166

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG4 突变体 TA_氨基酸

<400> 166

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Ser Ser Asp Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 167

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 1_IgG4 突变体 TA_DNA

<400> 167

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtg atctcttctg atggtggtaa tacatattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 168

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 TA_氨基酸

<400> 168

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 169

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 TA_DNA

<400> 169

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 170

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALA_氨基酸

<400> 170

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 171

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALA_DNA

<400> 171

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 172

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALATA_氨基酸

<400> 172

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 173

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALATA_DNA

<400> 173

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 174

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALAPG_氨基酸

<400> 174

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 175

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALAPG_DNA

<400> 175

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 176

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALAPGTA_氨基酸

<400> 176

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 177

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG1 突变体 LALAPGTA_DNA

<400> 177

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 178

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG4 野生型_氨基酸

<400> 178

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 179

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG4 野生型_DNA

<400> 179

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 180

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG4 突变体 TA_氨基酸

<400> 180

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Gln Met Gly Arg Val Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 181

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 2_IgG4 突变体 TA_DNA

<400> 181

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctcgccgc agatgggtcg ggtgtattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 182

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 TA_氨基酸

<400> 182

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 183

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 TA_DNA

<400> 183

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 184

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALA_氨基酸

<400> 184

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 185

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALA_DNA

<400> 185

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 186

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALATA_氨基酸

<400> 186

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 187

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALATA_DNA

<400> 187

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 188

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALAPG_氨基酸

<400> 188

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 189

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALAPG_DNA

<400> 189

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 190

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALAPGTA_氨基酸

<400> 190

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 191

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG1 突变体 LALAPGTA_DNA

<400> 191

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 192

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG4 野生型_氨基酸

<400> 192

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 193

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG4 野生型_DNA

<400> 193

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 194

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG4 突变体 TA_氨基酸

<400> 194

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Asp Pro Leu Gly Gly Asn Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 195

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 3_IgG4 突变体 TA_DNA

<400> 195

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcgatccgt tggggggtaa tatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 196

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 TA_氨基酸

<400> 196

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 197

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 TA_DNA

<400> 197

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 198

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALA_氨基酸

<400> 198

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 199

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALA_DNA

<400> 199

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 200

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALATA_氨基酸

<400> 200

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 201

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALATA_DNA

<400> 201

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 202

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALAPG_氨基酸

<400> 202

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 203

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALAPG_DNA

<400> 203

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 204

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALAPGTA_氨基酸

<400> 204

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 205

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG1 突变体 LALAPGTA_DNA

<400> 205

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 206

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG4 野生型_氨基酸

<400> 206

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 207

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG4 野生型_DNA

<400> 207

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 208

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG4 突变体 TA_氨基酸

<400> 208

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Ser

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 209

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 4_IgG4 突变体 TA_DNA

<400> 209

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactctgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 210

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 TA_氨基酸

<400> 210

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 211

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 TA_DNA

<400> 211

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 212

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALA_氨基酸

<400> 212

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 213

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALA_DNA

<400> 213

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 214

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALATA_氨基酸

<400> 214

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 215

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALATA_DNA

<400> 215

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 216

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALAPG_氨基酸

<400> 216

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 217

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALAPG_DNA

<400> 217

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 218

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALAPGTA_氨基酸

<400> 218

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 219

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG1 突变体 LALAPGTA_DNA

<400> 219

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 220

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG4 野生型_氨基酸

<400> 220

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 221

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG4 野生型_DNA

<400> 221

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 222

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG4 突变体 TA_氨基酸

<400> 222

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Ala Asp Gly Gly Pro Ser Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 223

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 5_IgG4 突变体 TA_DNA

<400> 223

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atcggggctg atgggggtcc gtcttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 224

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 TA_氨基酸

<400> 224

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 225

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 TA_DNA

<400> 225

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 226

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALA_氨基酸

<400> 226

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 227

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALA_DNA

<400> 227

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 228

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALATA_氨基酸

<400> 228

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 229

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALATA_DNA

<400> 229

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 230

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALAPG_氨基酸

<400> 230

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 231

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALAPG_DNA

<400> 231

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 232

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALAPGTA_氨基酸

<400> 232

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 233

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG1 突变体 LALAPGTA_DNA

<400> 233

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 234

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG4 野生型_氨基酸

<400> 234

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 235

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG4 野生型_DNA

<400> 235

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 236

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG4 突变体 TA_氨基酸

<400> 236

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Met Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 237

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 6_IgG4 突变体 TA_DNA

<400> 237

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagaatggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 238

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 TA_氨基酸

<400> 238

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 239

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 TA_DNA

<400> 239

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 240

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALA_氨基酸

<400> 240

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 241

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALA_DNA

<400> 241

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 242

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALATA_氨基酸

<400> 242

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 243

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALATA_DNA

<400> 243

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 244

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALAPG_氨基酸

<400> 244

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 245

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALAPG_DNA

<400> 245

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 246

<211> 446

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALAPGTA_氨基酸

<400> 246

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Ala Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 247

<211> 1338

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG1 突变体 LALAPGTA_DNA

<400> 247

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc ctccaccaag 360

ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 420

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 480

gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 540

ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 600

gtgaatcaca agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac 660

aaaactcaca catgcccacc gtgcccagca cctgaagccg ccgggggacc gtcagtcttc 720

ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 780

gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 840

gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cgcctaccgt 900

gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 960

aaggtctcca acaaagccct cggcgccccc atcgagaaaa ccatctccaa agccaaaggg 1020

cagccccgag aaccacaggt gtataccctg cccccatccc gggatgagct gaccaagaac 1080

caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1140

gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320

tccctgtccc cgggtaaa 1338

<210> 248

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG4 野生型_氨基酸

<400> 248

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 249

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG4 野生型_DNA

<400> 249

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctacatacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329

<210> 250

<211> 443

<212> PRT

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG4 突变体 TA_氨基酸

<400> 250

Glu Val Gln Leu Leu 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 Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Pro Tyr Ser Gly Arg Ile Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Leu Ala Leu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Ala Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 251

<211> 1329

<212> DNA

<213> Artificial Sequence

<220>

<223> IgG 重链 7_IgG4 突变体 TA_DNA

<400> 251

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttagc agttatgata tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagcg atctctccgt attcgggtag gatttattac 180

gctgattctg taaaaggtcg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtgt attactgtgc gagactggcg 300

cttgatttcg actactgggg ccagggtaca ctggtcaccg tgagctcagc cagcaccaag 360

ggcccttccg tgtttcccct ggccccttgc tcccggtcca catctgagag caccgccgcc 420

ctgggctgtc tggtgaagga ctacttccca gagcccgtga ccgtgagctg gaacagcggc 480

gccctgacaa gcggcgtgca cacatttccc gccgtgctgc agagctccgg cctgtactcc 540

ctgtctagcg tggtgacagt gccttcctct agcctgggca ccaagacata tacctgtaac 600

gtggaccaca agccaagcaa taccaaggtg gataagcggg tggagtctaa gtacggccct 660

ccttgcccta gctgtcctgc tccagagttt ctgggcggcc cttccgtgtt cctgtttcca 720

cccaaaccaa aggacacact gatgatctct agaacaccag aggtgacctg cgtggtggtg 780

gacgtgagcc aggaggatcc cgaggtgcag ttcaactggt acgtggatgg cgtggaggtg 840

cacaatgcca agaccaagcc aagagaggag cagtttaact ctgcctacag ggtggtgagc 900

gtgctgaccg tgctgcacca ggattggctc aacggcaagg agtataagtg caaggtgtcc 960

aataagggcc tgccctcctc tatcgagaag acaatctcta aggctaaggg ccagccaaga 1020

gagcctcagg tgtacaccct gcctccaagc caggaggaga tgacaaagaa ccaggtgtcc 1080

ctgacatgtc tggtgaaggg cttctatccc tccgacatcg ccgtggagtg ggagtctaat 1140

ggccagcctg agaacaatta caagaccaca ccccctgtgc tggactctga tggcagcttc 1200

tttctgtatt ccaggctgac cgtggataag tctcggtggc aggagggcaa cgtgttcagc 1260

tgctctgtga tgcacgaagc cctgcataat cactatactc agaaaagtct gtcactgtca 1320

ctgggaaag 1329